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Home News DOUBLE INTERNATIONAL DISTINCTION FOR V+O AT IPRA GOLDEN WORLD AWARDS 2018
DOUBLE INTERNATIONAL DISTINCTION FOR V+O AT IPRA GOLDEN WORLD AWARDS 2018
V+O COMMUNICATION has been awarded once again at this year’s IPRA Golden World Awards (GWA), the most important PR awards, organized annually by the International Public Relations Association (IPRA).
Having been honored with a total of four (4) IPRA Golden World Awards in three years, V+O has managed to earn worldwide recognition and to stand out among prestigious international agencies.
This year’s two winning projects were chosen for their strategic thinking, effective planning and creativity. V+O excelled in the categories of “Crisis Management” and “PR on a Shoestring” (an award given to highly effective projects on a small budget), showcasing its concrete experience, resourcefulness and expertise in these respective fields.
Specifically, V+O was awarded for the following:
GWA IPRA in the “Crisis Management” category, for the strategic planning and communication of the Sklavenitis Group after the acquisition of the Marinopoulos Group; one of the most significant corporate bailouts ever completed in the Greek Retail Industry. During this critical internal transformation period, V+O orchestrated the Sklavenitis Group's communication strategy, and managed to further strengthen the Group’s reputation and its image as a responsible employer, nurturing harmonious relations with employees, and protecting thousands of jobs.
“GWA IPRA in the “PR On A Shoestring” category (program of maximum effectiveness on the smallest available budget) for the design and implementation of an experiential PR activation presented at the Athens Bar Show 2017 on behalf of Jack Daniel’s. The respective project tapped into the visit of Chris Fletcher, Jack Daniel’s Assistant Master Distiller, creating unique experiences and remarkable storytelling, inspired by the brand. The activation generated an extensive Social Media buzz and enhanced Jack Daniel’s brand awareness and local footprint.
Mrs. Teti Kanellopolou, CEO of V+O, commented on this double distinction; “We are very happy that our projects and hard work have gathered international recognition, for a third year. This year in particular, our success in two very different categories proves that strategic PR has a great deal to offer; it can protect and build a company’s reputation but it can also generate multidimensional and engaging brand stories. We feel proud for our people. We have a highly qualified, creative and dynamic team. A team of talented, result-driven and ingenious professionals. We are also deeply satisfied that we successfully represent the Greek PR industry on an international level.
These awards constitute proof for our people’s value and potential, an acknowledgment for the trust of our customers, and most importantly a momentum, an inspiration and a driving force to attain the best, which is yet to come.”
The 4 IPRA GWA International Awards of Excellence that constitute V+O’s list of accolades, include the following: In the “Internal Communication” category for Astra Zeneca company in 2014, in the “Crisis Management” category for the Sklavenitis Group on 2017, and finally the double distinction in 2018 in “Crisis Management” and “PR on a Shoestring” for the communicational programs designed, and executed for the Sklavenitis group and Jack Daniel’s brand respectively.
The ever-growing importance of 360 communications was highlighted at a special panel during the 9th Panorama of Entrepreneurship & Career Development”
CURIOUS AHEAD: MUCH MORE THAN A NAME CHANGE
V+O actively participates in Delphi Economic Forum IV
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Board index Tomahawk Leader Message Board General Discussion
Larry, about your editorial...
Forum for General Topics not covered by other areas.
mitch622
Postby mitch622 » Fri Oct 08, 2004 7:50 am
Mr. Tobin,
I read your Ups-N-Downs editorial in last week’s (10/5/04) paper. I’m not sure why I did. As a long time reader of the Tomahawk Leader I know that the closer we get to a major election, the more you turn into a tool of the right-wing propaganda machine. But in this election I’ve been really trying to see both sides of the issues. I will grant you your opinion, after all, it was an editorial. However, one line offended me so much that I was driven to Start this topic.
The line was: “…any time other than the one in which he injured himself and got a Purple Heart for it”. Now, granted this is in an editorial, but this phrase is stated as a FACT, not an opinion. I’m sure, Mr. Tobin, as a professional journalist, you have a source for this information. I was not aware that the service gave out Purple Hearts for self inflicted wounds, and I can’t believe that the Swift Boat Vets didn’t pick up on this piece of information that you managed to uncover. Which of John Kerry’s three Purple Hearts was earned in this way?
My reason for writing this is not political. My father was awarded a Purple Heart for his injuries in World War II, and carries the scars to this day. When journalists make statements like you did, they diminish the value of these hard-earned medals. You, Mr. Tobin, wield a weapon as mighty as the guns you sought to defend in your editorial, and just like a gun, you need to look and think before you pull the trigger. There have been so many lies presented in this campaign on both sides, but I expected better from my hometown newspaper.
Steven Mitchell
Location: Tomahawk
Re: Larry, about your editorial...
Postby nugget » Fri Oct 08, 2004 8:37 am
Yes, the above post is right. Some people believe if it is printed it is true. Be careful.
Spay or nueter your pets!!!!!!!
anthrochick
General User
Postby anthrochick » Fri Oct 08, 2004 2:58 pm
Bravo, Steve Mitchell!
Tie to Tomahawk: Fourth generation native.
Location: Hatchet Creek, Wisconsin
Postby Brian » Sat Oct 09, 2004 12:02 am
The Swift Boat Liars for Bush have been discredited except among the hard-core zealots of the right wing. They march in partisan lockstep and are not interested in truth. No accusation or smear is beyond them.
Thirty years ago, official Navy reports documented John Kerry's service in Vietnam and awarded him the Silver Star, the Bronze Star and three Purple Hearts.
They allege that John Kerry's wounds were self-inflicted and not serious enough to justify a Purple Heart. That he must have lied in order to get it. Oh really?
The record shows:
The doctor who makes these claims did not see the incident, did not talk to crewmates who were there and does not even show up as the person who treated Kerry on the only Official Naval Record of the treatment.
Three people were there that night. Not one of them backs up the claims of the Swift Boat Liars for Bush. In fact, all three say they were firing on suspected Viet Cong who disobeyed an order to stop in a free-fire zone. One also called it the most frightening night of his entire service. Kerry earned that first Purple Heart in combat. Whether you like him or not the sacrifices of our combat veterans deserve our respect - not the lies, the mocking attacks, the innuendo, or the disgusting little 'Purple Heart' band-aids you Republicans came up with. You ought to be ashamed.
When you wish upon a falling star, your dreams can come true. Unless it's really a meteorite hurtling to the Earth which will destroy all life. Then you're pretty much hosed no matter what you wish for. Unless it's death by meteor.
Typical Poster
Location: Yellow Brick Road in Wisconsin
Postby Fushia » Sat Oct 09, 2004 12:06 am
Great Job Mr. Tobin! (Larry)
Always enjoy your paper and your column also!
Thanks for having a great newspaper in Tomahawk.
Subscriber for many years!
Postby Dave » Sat Oct 09, 2004 10:55 pm
Tobin's editorial was well written and adequately supported by the facts. In any case, Kerry threw the medals away so they must have meant nothing to him at all. I suspect that most people know why they meant nothing to him. Good job Larry.
Postby mitch622 » Sun Oct 10, 2004 6:20 am
MJC 135: Thank you for the link. I was not aware that this was among the Swift Boat
Vets charges.
I am hoping however that this is not the source Mr. Tobin used for his statement because it then would bring up an even more disturbing point. You and I on this web board can read and believe whatever we want, but a professional journalist has the responsibility to his readers (or listeners/viewers) to check his sources. If Mr. Tobin is verifying his facts with discredited web pages then his next editorial could well tell us that John Kerry was abducted by aliens and taken off to meet with Elvis.
Fushia: I agree totally with the last 3 lines of your post above. The Tomahawk leader is a first rate and award winning newspaper. I have enjoyed and agreed (or disagreed) with many of Mr. Tobin’s columns. He has every right to be proud of the newspaper he publishes. He also has the right to voice his opinion in his newspaper.
However I don’t think he did a “Great job” presenting as a fact that John Kerry was awarded a Purple Heart for self inflicted wounds. His editorial would have portrayed his beliefs without using this “fuzzy” piece of evidence. Using it calls into question the entire column.
This is really no different from what Dan Rather did a few weeks ago on CBS. The story was there even without the doctored evidence, but using it discredited the whole report. Professional journalists have to be held to a higher standard, whether on national television or our local newspaper.
Postby Dave » Sun Oct 10, 2004 9:32 am
MJC is correct regarding the medals issued in Vietnam. Not to denigrate the achievements and sacrifices of those who served, but there was a definite difference in philosophy regarding the award of decorations between Vietnam and previous conflicts. Virtualy all personnel who were actively involved in combat operations received what we in the military personnel business called "The Vietnam Package". It consisted of a Bronze Star, a Vietnam Service Medal, a Vietnam Campaign Medal, and the South Vietnamese Cross of Gallantry (foreign award). The award of Silver Stars in Vietnam versus WWII was even more out of proportion than the Medal Of Honor with over twice the number being awarded. In addition, the Navy had what we called an "administrative rule" regarding the Purple Heart. Three awards and you were reassigned out of the theater. Kerry claims he was not aware of this rule, and we will never know if he was or not, but knowledge of the rule by him would certainly help to explain his insistance that the Purple Heart be awarded for any and every scratch, chip, or dent he received; and it is difficult to believe that as an officer he had no knowledge of a rule that every enlisted man in the theater was aware of. Anyone doubting the difference in medal award philosophy need only drop by the bar at any VFW or American Legion Post and seek out a WWII combat veteran. You will be absolutely amazed what many of these old soldiers did and what they suffered without recognition anywhere near what their counterparts in Vietnam received. Again, this is not meant to denigrate the service of anyone, but things need to be properly interpreted in the context of the time and the rules in use. I agree that this could all be put to rest if the entire record was released complete with the working papers that are in Mr. Kerry's military personnel file. We will never see those, and based on the old maxim that there is always a good reason for everything, one can imagine why we will never see them.
Location: Tommyhatchet
Postby jimbo71 » Sun Oct 10, 2004 1:45 pm
Wether Kerry was in 'Nam 4 hours, 4 days or 4 months, at least he VOLUNTARILY went in harms way where the lead was flying. Where was GWB? And where was L. Tobin at that time? I think LT owes an apology to every GI that has been awarded a apurple Heart. But apparently LT has information that the US Navy didn't have that approved the medal.
jcg2
Postby jcg2 » Sun Oct 10, 2004 2:19 pm
The swift boat "liars" as they have been called make a very good case. A pro John Kerry person would discredit them at once, but anyone with an open mind who reads what they write would have to note they have a firm story that has yet to be refuted from the Kerry camp, as I am sure Mr. Tobin did.
What are you talking about? A very good case? The "Swift Boat Veterans" have been completely discredited from all parties. John McCain came forward and said that the claims were insane. Kerry's records were accessible to the public, even the Bush administration (after some time and public pressure) acknowledged that these adds were unacceptable and needed to be pulled. (by the way, did you know that one of Bush's lawyers was the major funder for the SBVFT, even though GW claimed he had no ties to the media campaign).
Ask yourself, why would John Kerry, a young man fighting in Vietnam, make false claims to recieve extra medals? What would be his motivation? To pad his resume for a political career over the next 40 years? He was a kid in a war, not a liar trying to milk the system for another medal. The people who question Kerry's service are political hypocrits, turning a blind eye to Bush's obvious air national guard b s, and grasping at straws with Kerry.
I don't care how many medals were handed out in WWII as compared to Vietnam. Kerry recieved several medals in Vietnam. It's been confirmed from many, many sources that he was involved in intense fighting. I salute him for serving in Vietnam, and he deserves the respect that every veteran shoud receive.
http://www.writenews.com/cgi-bin/mediacynic.pl?cynic=448200401
Postby anthrochick » Sun Oct 10, 2004 2:44 pm
The point that I took away from Steve's posts that I think he is trying to reiterate is the idea that although Larry's piece was an editorial, statements that are made need to be backed by credible resources. His comparison of the editorial to the CBS/Dan Rather fiasco of late is pointing to the practice by some journalists of using vague evidence and substandard sources. By not providing the source for his comment, I thought that Steve was saying that Larry was doing a disservice to his readers.
The adage, "The pen is mightier than the sword" applies here. I believe Steve is right in saying that journalists have a far greater power in influencing thought and opinions in their readers and I think that, as well as many of you may, that a journalist needs to carefully document his/her resources, regardles of who or what the article, editorial, essay, is about. We've seen a few instances in the last couple years, the New York Times comes to mind, where writers, in the interest of a great story, or dollars, numbers, etc. tweak their information or provide vague sources.
I thought Steve's post was in reference to fairness in journalism not a political agenda as he already stated for everyone and what some post-ers here have taken it to be. It is an especially hot political season and many of us are ready to jump at the chance to further our own political opinions. And I think that Steve's opinion has been unfairly misconstrued.
<small>[ October 10, 2004, 02:52 PM: Message edited by: anthrochick ]</small>
Postby jcg2 » Mon Oct 11, 2004 11:32 am
first, when the swift boat adds were airing, Bush came out and made the statement, "John Kerry should be proud of his service to America". He said that 527 adds were bad for the system,,, in response to the specific "swift boat veterans" topic. Also, I believe McCain probably knows a bit more about Kerry's records than you, I or most of the public. Why would he put himself out there, as a republican supporting our current administration in an election year? He did it because he knew the truth.
your story about Bush visiting Wausau reminded me of the Ohio factory shutdown. President Bush visited a Timken Company manufacturing plant in Ohio to press for passage of the tax cuts that he said would spur the economy. During the speech Bush said that "the future of this company is bright and therefore, the future of employment is bright for the families that work here" Less than a year after the tax cuts for the wealthy passed, that same factory shut down putting about 1,300 people out of work.
As for the farm bill you were speaking of, I think you're referring to the MILC (milk income loss contract) . Basically, money for dairy farmers during tough times. Did you know that President Bush opposed the creation of that program under the 2002 farm bill? Did you know that the USDA has publicly stated that MILC will be removed if Bush is re elected. Larry Salathe of USDA's Office of the Chief Economist, and William March and Milton Madison of FSA told the American Dairy Products Institute that the Administration would not act on dairy policy before the
election in order to maximize votes in swing dairy states such as Wisconsin, Minnesota and Michigan.
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Birmingham based Steel City Pops will mark their brick and mortar debut today, September 30th, when they open at 312 Church Street near the square in Decatur. ToNeTo Atlanta was first to report on the brand's metro Atlanta expansion this past May, and has followed along as the company introduced themselves to the Atlanta market with "pop carts" at both Atlantic Station and The Shops Buckhead Atlanta. The two carts will remain in operation with plans to open additional brick and mortar shops in Atlanta next year.
Eat Fit Go, a new healthy prepared meals franchise, plans to join Starbucks, MOD Pizza and Zoës Kitchen, among others, in the new The Plaza at City Springs center on Roswell Road in Sandy Springs. The company, which was founded in Omaha, Nebraska in 2015, signed a franchise agreement with "Eat Fit Group Atlanta" for development rights for up to thirteen locations in the metro Atlanta market. Eat Fit Go specializes in pre-made meals that are prepared to be re-heated off-premise, but the business does have an on-premise microwave for those wishing to dine in. The meals, which range from about $7-12, have a five day shelf life. A review last fall in The Daily Nebraskan, the student newspaper of the University of Nebraska, calls Eat Fit Go prices "not worth small, dull meals." The first Atlanta location opened earlier this month on Windward Parkway at Windward Plaza in Alpharetta. A second location is under construction adjacent to Schlotzsky's Deli in the Cumberland Festival shopping center on Cobb Parkway, across from Akers Mill. The Cumberland location is expected to open in October and will be followed by Sandy Springs and Johns Creek in the coming months. While it's not fair to call the concept a winner or loser so early into its Atlanta entrance, the prepared meal space has proved quite challenging. Chef Christophe Le Metayer opened a total of four locations of Christophe's to Go (Brookhaven, Sandy Springs, Johns Creek and Dunwoody) in 2012-2014, but had closed all of the shops by late 2015. Like Eat Fit Go, Christophe's offered assorted healthy prepared meals at a similar price. Elsewhere in the country, Austin based My Fit Foods, another similar concept, abruptly closed all of their 50+ locations earlier this year, while fellow Austin-based rival Snap Kitchen has expanded to a total of 54 restaurants in five markets.
Nation's Restaurant News reported Tuesday that Chipotle Mexican Grill has partnered with Top Chef All Stars winner Richard Blais to lead its Tasty Made burger concept. Blais will be tasked with infusing the fast-casual burger concept with “new, high-quality menu items.” The news comes just a year after the first, and so far only, Tasty Made location opened in Lancaster, Ohio. The partnership will be done in part to allow Chipotle CEO Steve Ells “to remain focused on continuing to grow and strengthen the Chipotle brand,” he said in a statement. “Richard is an extraordinary chef and an exceptionally capable restaurateur,” said Ells, who founded Chipotle in 1993. “I have long believed that there was an opportunity to make the fast food burger a great burger using better quality ingredients. Richard’s expertise is perfect to help us do that.” Chipotle said that Blais will revisit the restaurant “with a fresh eye” to perfect the existing menu and expand options. Tasty Made currently features a simple menu of burgers, fries, shakes and sodas. “There is no more iconic fast food than burgers, and I have always thought there is a way to do them on a really big scale without compromising the quality of the food or the overall restaurant experience,” Blais said. Blais, whose fame grew while he worked at various Atlanta area restaurants, also conceptualized the menu for FLIP Burger, the Atlanta based "better burger" concept now with three locations. Flip closed its Poncey-Highland location in late 2015 and its Nashville location earlier this month. Despite the fact that Blais is still listed as the restaurant's "creative director," one must think his role with Flip will be far more limited given his role with Tasty Made, not to mention that he now lives in San Diego where he has opened Juniper & Ivy and The Crack Shack, a chicken-centric eatery with two locations.
Poke Bar, the California based poke eatery that debuted in Atlanta last fall and has since opened a total of five locations in the area, has a sixth coming soon with as many as seven more in the works. The first Atlanta area Poke Bar opened on Roswell Road at Abernathy Road in Sandy Springs and has more recently been joined by new locations in Johns Creek, Edgewood, Duluth and Suwanee. The next Poke Bar will open on Peachtree Parkway in Peachtree Corners (Preachtree Corners on the Poke Bar website) in Peachtree Marketplace shopping center, where Aldi opened earlier this year. According to the Poke Bar website, other Atlanta area locations are planned for Dunwoody, Buckhead, Vinings, Alpharetta, Midtown and Kennesaw. The chain also plans to open in Athens.
Growing quick serve franchise Pita Mediterranean Street Food is planning to open its 10th overall location next week in Smyrna. The new Smyrna location is located in The Crossings, a Kroger-anchored center at 3240 South Cobb Drive. The restaurant will celebrate their opening by providing free food to customers between 6 and 9pm on Friday October 6. The Mediterranean eatery, which grew from a single family restaurant in Peachtree City in 2012, today also includes locations in Newnan, Dunwoody, Roswell, Kennesaw, Columbus, Sharpsburg, Marietta, Fayetteville and Peachtree Corners. In the coming months, the chain plans to add locations in Johns Creek, Downtown, Midtown, Covington, West Cobb and Greenville, South Carolina. The Johns Creek location, which will open in Johns Creek Town Center, is likely one of the next to open. This past March, Pita founder Nour Rabai told the Ledger-Enquirer “We’re looking to do about 38 locations in the metro Atlanta market, and then we’ll be reaching to Alabama, Tennessee, South Carolina and Florida in the near future.”
F&B Bistro in the Ritz-Carlton Residence building/3630 Peachtree Road office tower closed earlier this week due to what it referred to as an "unfortunate flood." The flood, reportedly caused by an HVAC company that failed to shut off he main water valve during maintenance, has the restaurant sidelined for at least 3 to 4 weeks, according to sources close to the restaurant. F&B posted an announcement of the temporary closure to its various social media platforms earlier this week and pledged to keep patrons updated as they work towards reopening.
The old mansion, aka "Castle" in midtown on 15th Street across from the Woodruff Arts Center, will reopen next month as Rose + Rye. The restaurant, from Thaddeus Keefe of south Buckhead's 1Kept, will feature food and drink options on three levels with multiple outdoor patios. Rose + Rye will be led by an all-woman culinary and management team including executive chef Lindsay Owens from Minneapolis (The Lynhall, Tilia, Unideli, Creamery Café) and sous chef Anu Adebara (Avalon Catering). The building, the Ferdinand McMillan mansion, was built in 1910 and is listed on the Georgia Register of Historic places. Local entrepreneurs attempted to turn the property into a hotel/club/lounge/bar called "The Castle" in 2015, but it didn't last long. Rose + Rye will begin with dinner service, adding lunch to their offerings in November and brunch after that.
ToNeTo Atlanta became aware of a new ramen shop coming to Brookhaven earlier this spring and the shop appears to now be gearing up to start construction. "Tanaka Ramen Noodle Bar Restaurant" is coming to TOWN Brookhaven in place of the short-lived Boneheads restaurant, close to Peachtree Road, in the same strip as at&t and Moe's Southwest Grille. Boneheads closed in 2014 and the roughly 2,500 square foot space has sat vacant in the years since. Despite the fact that proprietor Mei Chi Ku registered the business with the Georgia Secretary of State's office on March 3rd, and the restaurant has been on the TOWN Brookhaven siteplan since at least August, the restaurant will likely not open until next year. TOWN Brookhaven, on the whole, is one of the most parking challenged centers in metro Atlanta with tenants in the Tanka portion, especially restaurants, among the most negatively impacted by the parking issues. I hope Tanaka does well but they will definitely have an uphill battle.
The first Atlanta area location of Maple Street Biscuits opened yesterday on W. Lawrenceville Street in Duluth. The restaurant, located in Duluth’s Parsons Alley downtown entertainment district, is located in a converted Baptist church building. Like other breakfast-centric eateries, Maple Street is open from 7 a.m. until 2 p.m. Mondays through Thursdays, staying open an hour later, until 3 p.m. on Friday sand Saturdays. Maple Street is closed on Sundays. The Jacksonville-based chain has at least two other metro Atlanta locations in the works in Woodstock and Alpharetta.
Lenox Square and Atlanta Magazine will host the annual Best Burger Battle on Saturday, October 7 from 1-5 p.m. Atlanta's premier burger cook-off features more than two dozen of the best local burger spots, plus bourbon, blues and brews. Guests will have the opportunity to sample unlimited tastings and decide the best burger in Atlanta while listening to a live blues band and sipping on Bulleit Bourbon and craft beers from Brooklyn Brewery and Wild Heaven. The burgers of Old Fourth Ward's Venkman's, which is not participating this year, were named #1 in last year's competition. Burger participants this year include Zinburger, The Federal, Bantam + Biddy, The Cowfish Sushi Burger Bar, Grub Burger Bar, Oak Steakhouse, Ormsby's, Shake Shack, Piastra, Two Urban Licks, Canoe, Foundation Social Eatery, Bar Margot, KirbyG's Diner & Pub, Establishment Midtown, Flip Burger Boutique, Hard Rock Cafe, Dantanna's, Neiman Marcus Café, The Counter Burger, Botiwalla, There Brookhaven, Sage Woodfire Tavern, Vino Venue and Dakota Beef. The event is 21+ with tickets priced at $50 and all-inclusive. Tickets can be purchased here.
Thanks for the information! Love this site!
"Preachtree Corners" is amusingly appropriate considering the way the mayor's office works there...
Re: parking at Town Brookhaven - I have never had a problem. The basement parking at Publix always has available spaces - of course, it would require patrons to walk up stairs which may be difficult for lazy, obese folks that are looking to feed their faces.
Greenwave said...
50 bucks for a subpar burgers festival? They can suck it.....
I'm Obese said...
@Eric Smith - Not sure if there's a need for you to insult "obese" people. As someone who is 6' and 230lbs, I'm medically considered obese. And when I go to Publix, my goal is to buy food to feed my face. And if I need to park far away or on a different floor, I do that. And yesterday, I spent the day relaxing and being lazy. So I guess I am a lazy, obese person who is looking to feed my face. Choose your words like an adult.
@ I'm Obese This is about Starbucks, not your "medical" condition caused by your lifestyle choices. Thanks for trolling!
@Anon @10/2 1PM - So classy. Would love to see how disgusting you look in real life... Speaking of trolls...
Oh the PC crew is here. Eric, it's ok to call them obese. A hit dog will holler. We all know that Americans should do much more for personal fitness. It's like... if a fish could talk and it called us "air breathers," someone would take offense to that too.
Besides... this is one reason they are opening up Eat Fit Go right?
Oh my goodness! Grow some thick skin to match your thick thighs hilary!! Remember - sticks and stones will break my bones but words will never hurt me. This world can be mean ... move on!
So I am assuming Eric is not a chubby chaser! No soup for you!
@Anonymous 6:45 - funny!! Now back to the plantation!
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Today was a day of lots of motorway driving, and with it lots of tolls. We'd got the weather spot on for our day at Monaco as it now started out grey and murky. We topped up the Honda with some 98 RON thought we were out of luck with our food as the local supermarket was closed on a Sunday.
We decided not to hang around and got on the motorway to our first stop at a services near Genoa. Which meant as soon as we had crossed the border we were onto one of the best motorways in the world - the Autostrada dei Fiori - a series of viaducts with views across the Mediterranean separated by tunnels. What more could you want?
After our baguette stop at Spotorno and a chance for a soggy cheese sandwich we turned north and followed the windy motorway upwards towards Turin, where the rain decided to come down heavy, forcing us to get the roof up at the next toll booth.
The drive into Turin was straightforward enough and we were soon parked in the Lingotto car park ready to explore the old Fiat factory, another location from the Italian Job. We first found the north ramp where the cars went from level to level but were soon barred from going higher up. At the other end of the shopping centre was a lift to the former restaurant giving us a glimpse of the rooftop test track and it's banked corners. Still no further, I then spotted another glass lift this time to the rooftop art gallery, where we got right to the top and found an open door, then to be told we weren't allowed out. So near and yet so far... We did get a good view of what we came for though, so we left fairly happy.
We headed off towards Milan, our first mission to do as per the Minis and escape Turin. The place was a dump, with beggars on the street junctions and shantys on the road side. The day's comedy moment was watching a Citroen DS overtake us over some speed bumps, taking them all in it's stride and completely soaking them up. I now want one as a daily...
The next two hours of motorway was more of the same and another heavy downpour meant a quick hard shoulder stop to get the roof up again. After being split up again in the traffic and low visibility we all eventually made it to Monza where we had another stop for a look around.
Like Spa, it was all very open with us first walking into the Ascari grandstand before looking for the old original banking. Trying to run up that in the wet was not fun! It was a case of clinging to the fence and climbing up, it's steeper than you can imagine! It was even worse trying to get back down... We had a general exlpore around T1 and then set off in search for fuel for the Honda which was now on vapours. Firstly I found a station that wouldn't accept my car, so I stuck a note in and bent over as it cost me £1.95 a liter, secondly we found a Shell and had the same problem, this time to the tune of £2.07! In the meantime, Lee beached the Clio on a kerb and had to be pushed off.
We then set off on the final half hour of the journey to the hotel, until we spotted a DIY store, still just about open at 7pm on a Sunday, where we stopped for parts to fit my refurbed TCT. We quickly checked in and then fixed the spare back together, ready to replace in the morning in the (hopefully) drier weather.
We then had a ride into Como for our evening meal at the familiar restaurant on the shore of the lake that we had eaten at two years ago. The food was great and decently priced and the beer came in litres. The waitress was a bit of a clown though, pretending to spill everything on us.
Having found the cars again, with the rain now gone and the sky clearing it's just a hope that it stays good for tomorrow, though I'll be checking the Stelvio Pass webcam again in the morning I reckon!
Viaduct, tunnel, viaduct, tunnel, repeat x100. Autostrada di Fiori
Lingotto's famous Rampa Nord
Lingotto's even more famous rooftop, as far as we were going to get onto it
Insanely steep old Monza banking
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The Travelling Palate
a sommelier's guide to living well
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The Answer to California's Drought Problem Might Just Exist in Mendocino
Parducci Winery
August 27, 2014 by Rick Bakas in Wine Country Lifestyle, Winemakers, Wines
“What is that thing?” I ask Tim Thornhill half jokingly as we’re sitting in his 15-year old Ford F-250 in the middle of his vineyard in Mendocino. “It’s a tape player” he answers. “I don’t like to throw anything away. Someone gave me a CD of songs so I put them on this tape." I wonder aloud about the camera with super 400mm zoom lens sitting on the floor the cabin. He tells me he’s had it since 1983. It seems Tim doesn’t only talk about recycling, reducing and reusing at his winery, he actually lives it.
We’re driving around Parducci’s estate vineyards talking about water conservation. In California, you can’t go 24 hours without hearing about the drought or how bad it is on the nightly news. What Tim has accomplished here in since buying Parducci in 2004 will change the way wineries manage water usage in the future—and the whole state is paying attention. “I’ve been getting invited to speak at a number of conferences this year,” he says nonchalantly realizing his creation's possible impact on solving California's water crisis.
In his past, life Thornill reached a high level of success by planting a majority of landscapes around Disney World and other major theme parks in Florida as well as around the country. He knows how to see the big picture when it comes to brining harmony to an ecosystem.
California’s drought isn’t just a matter of not getting much rain for the past three winters. The problem is a compounding problem over three years that starts to impact the soil deep below the surface. We need compounding rainy seasons to get back to normal—one rainy season isn’t going to do it. If you have a credit card, you know what compounding interest is. It doesn’t matter if you make the minimum payment, the balance is still due.
Looking around the state at who the biggest offenders are of water use gets dicey as just about all corners of the state are planted to some sort of agriculture. Is it the residents wasting water on lawns and car washes? Is the pot growers in Northern California using all the water? Is it the almond tree farmers who have sights set on higher profits? Somewhere in the deck is the wine industry. If California were a country, it would be the 4th largest wine producing country in the world. With over 427,000 acres planted to vine in the state, there’s a significant chunk of farming that can learn from the water saving practices in place at Parducci.
Clean Water, Less Water
Take a look at the water reduction chart below. If there’s one thing to take away from this entire article, it’s this.
When Thornhill took over the winery in 2004, Parducci was using about 18 acre feet of water. That translates to roughly 300,000 gallons. Today, Parducci has dipped below 8 acre feet—a reduction of more than half in just a few vintages. A seemingly impossible goal to achieve, but for a wine industry newcomer with enough naiveté who asks enough questions it happened. Thornhill didn't know any better.
photo courtesy of Tim Thornhill
But to use less water, there must be a compromise somewhere else—maybe in water quality. Not so fast. Not only is Parducci using less. The water is actually cleaner and they're using less electricity to achieve it. Water is used inside the winery for cleaning tanks, cleaning barrels, cleaning gear and cleaning the winery. All that dirty water goes somewhere and in this case, the water came out of the winery with a purple hue. Excuse me, it was purple. And it the stench was so bad drivers on highway 101 could smell it as they drove by.
The Blueprint in Action
There's two ideas in action. First, to conserve water Thornhill came up with a brilliant solution—a broom and dust pan. "We walked around the winery and saw how much water was wasted cleaning the winery floors. I saw one guy using a broom handle to jam solid waste down the drain rather than use the broom to sweep the floor". Thornhill installed 22 water monitors around the winery to measure how much water was being used and where. "We uncovered a leak on one faucet that must've been have been leaking for twenty years."
What the water monitors achieved was a friendly rivalry between winery workers to see who could use the least amount of water in their respective area whether they were cleaning tanks, cleaning barrels or cleaning the floors. "Many people are afraid of change, but I actually embrace it as long as it can be measured," Thornhill points out. "one of our employees developed a new way to clean barrels using repurposed water. We can measure that reduction".
Thornhill credits this simple thinking to his dramatic reduction in water usage and points out how many wineries can follow suit starting with this harvest.
In the vineyard, Thornhill installed a double drip line. Although it might seem counterintuitive to add an additional drip line to reduce water consumption but the results are impressive. "The first drip line waters all the vines the same way any vineyard manager would. The second drip line only waters a handful of vines that need a bit extra from time to time," Thronhill points out. Depending on where a few keys vines sit on the contours of the hillside, they may require a bit of water because they drain faster than other vines. He adds, "most wineries would just turn on the first line and water all the vines that don't necessarily need it. Why waste that water?"
The second idea in action is cleaning the water coming out of the winery so it doesn't end up in the "purple pond". Water coming out of the winery begins its journey at the highest point on the property at Trickle Tower 1. Thornhill found a bunch of old barrel racks that he stacked together to make a tower. He then wraps wood staves in fabric and inserts them between the racks. Dirty winery water is pumped to the top and trickles down through the tower. "Where there's food, there's life," and in this case sugars from grapes in the water attract a healthy grayish fungus called Filamentous Fungi that feeds on organic materials in the water. The more organic material, the more fungus shows up to feed.
Trickle Tower 2 overlooking vineyards and marshland (Trickle Tower 3 not visible downhill)
Trickle towers allow the dirty water to de-gas, or release some of its dirty smell into the air as it trickles down. Because the first trickle tower sits on the highest part of the property, gravity takes it to Trickle Tower 2 where the process is repeated. Then on to Trickle Tower 3 where again the water airs out and grows Filamentous Fungi naturally. By the time the water reaches the pond, the water is clean enough to meet California standards for water quality (parts per million). So far, only one pump has been used to get the water to the top of the hill. From there gravity and fungus has done the rest of the work.
But the water in the pond doesn't have enough oxygen. Thornhill installed one single 5 horsepower pump at the pond that brings clean water up where it is diverted to either one of the aerators (modeled after rivers in the Colorado Rockies) or through the wetlands (modeled after swamps in Florida). Again, gravity takes the water through one of the two back to the pond where oxygen levels far exceed anything the state of California sets as a goal for wineries.
Aerators are essentially small water falls built out of repurposed materials. One aerator pictured above is made from an old cement truck mixer that was cut in half. When water flows through the aerator oxygen is introduced along the way.
The marshland is a labyrinth of twists and turns where water gently flows through before re-entering the pond. Thornhill removed treated posts from the vineyards to keep his organic practices in place, but instead of discarding the posts, he laid them horizontally underneath a layer of rubber in a maze-like pattern. The rubber keeps water from seeping into the ground, and is the only material Thornhill added reluctantly. Along the water's edge are hundreds of rocks that allow small organisms to feed on any remaining dirty organic materials in the water.
Measuring Change
Of the accolades and awards Thornhill has received, his biggest reward is looking out his window and seeing all the wildlife that calls Parducci home. Two large Osprey nests fashioned out of used palettes are home to a family of Osprey who raise babies each year. Migratory birds fly from Argentina to Alaska each year, and now stop at Parducci's pond along the way for a bite to eat.
California's Audubon society has awarded Thornhill an environmental award for the work on his property. Birds nobody has seen before now call the pond home either as permanent residents or as a stop along the way somewhere else.
California's wine industry can directly impact the severity of future drought problems starting now. A man with no prior wine industry experience motivated by leaving something to his children might just have the solution we've all been hoping for.
BY THE NUMBERS:
PARDUCCI IS OPERATING AT 20% OF THE POWER USAGE ORIGINALLY RECCOMENDED BY CONSULTANTS.
THE WATER QUALITY AT THE WINERY IS 2-3 TIMES BETTER THAN THE ORIGINAL BENCHMARK.
ALL THE INNOVATIONS WERE BUILT FOR 30% OF WHAT CONSULTANTS SUGGESTED.
THE WINERY LOWERED WATER CONSUMPTION BY 50% WHILE INCREASING PRODUCTION.
PARDUCCI USED TO HIRE PEOPLE TO HAUL DIRTY WATER OFFSITE.
August 27, 2014 /Rick Bakas
drought, winery, mendocino, parducci, pinot noir, chardonnay, cabernet, water consevation, California drought, audubon, osprey, organic, grapes, vineyard
Wine Country Lifestyle, Winemakers, Wines
copyright 2014 Bakas Media
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Preview: Surging U.S. Face Struggling Canada
Photo: Connie Hatfield
Last week was nearly perfect for the Eagles. They faced down a tough side in Argentina XV and came away with the win. They had never beaten the side before and now with a win they have a clear pathway to the repeating as Americas Rugby Championship title holders. Last week's win doesn't guarantee anything but it was a great start. All of that said, if there is a slip-up game it's this weekend against Canada. The Canadians have been struggling recently dropping both of their World Cup qualifying matches against Uruguay. They have also had their fair share of injuries which hasn't helped. Still, they have plenty of talent and coming off their disappointing losses and their repeated losses to the U.S. recently they will be hungry for a win.
The fact that the U.S. has only made one change to their starting line-up and that there European professionals on the roster is a strong indicator the U.S. will be heavy favorites in the match. Confidence is high amongst the Eagles. They had a some setbacks in the summer and the fall but they also have several comfortable victories. They won the ARC, beat Canada twice to qualify for the World Cup, and smoked Germany in the fall like they were supposed to. They have roughly kept the same group together for awhile and they seem to be on the right page. In fact, this might be one of the best stretches of play the Eagles have had in the last twenty years. All in all that should mean a win against Canada.
The match will be shown live from Sacramento on The Rugby Channel at 6:00 p.m. et/3:00 p.m. pt.
As mentioned the U.S. has only made one change with Dylan Audsley coming in for the injured Marcel Brache. Josh Whippy comes into the bench after being out last week. Everyone else remains the same after strong performances last week. Everyone did their role well and now with a week of chemistry they should be even better.
Forwards: Titi Lamositele, Joe Taufete'e, Dino Waldren, Nate Brakeley, Nick Civetta, Hanco Germishuys, Tony Lamborn, Cam Dolan
Backs: Nate Augspurger, Will Magie, Ryan Matyas, Bryce Campbell, Dylan Audsley, Blaine Scully (C), Mike Te'o
Bench: James Hilterbrand, Huluholo Moungaloa, Angus MacLellan, Ben Landry, Andrew Durutalo, Shaun Davies, Will Hooley, Josh Whippy
The Opponents
Canada have made a few changes to the team that lost to Uruguay in South America. They still have plenty of veteran talent but also look like they may struggle in other areas. Players to watch for include the timeless Phil Mack and DTH van der Merwe. Djustice Sears-Duru and the rest of their frontline are solid as well.
Forwards: Djustice Sears-Duru, Ray Barkwill, Jake Ilnicki, Josh Larsen, Kyle Baillie, Lucas Rumball, Matt Heaton, Luke Campbell
Backs: Phil Mack, Shane O'Leary, DTH vsn der Merwe, Nick Blevins, Guiseppe du Toit, Brock Staller, Pat Parfrey
Bench: Martial Lagain, Anthony Luca, Cole Keith, Conor Keys, Dustin Dobravsky, Gordon McRorie, Robbie Povey, Cole Davis
Keep on Keepin' On: As mentioned the Eagles are on a roll. They are doing most things well and the energy is there. If they play the same way they've done the last few weeks they should be alright.
Physicality: Canada hasn't had the answers for the U.S. physicality recently, especially late in matches. Just look back at the qualifying series to see what kind of impact players like Andrew Durutalo had off the bench. Durutalo is once again on the bench with big bodies like Josh Whippy. Canada should be in trouble once again.
Continued Defensive Effort: The U.S. defensive effort against Argentina was strong. They really limited what Argentina wanted to do. It should be even easier to accomplish that against Canada but only if they concentrate.
Score: The U.S. found ways to score last week when they needed thanks to a strong kicking day but multiple times they had the opportunity in the green zone only to come up empty. They need to score early and often against Canada.
This is a match the U.S. should win and should pick up the full points on offer. Uruguay was the only team to take five points away from their opener and if the U.S. doesn't want to put themselves in a difficult situation as the tournament progresses they need to take five points away from Canada. Given the difficulties that Canada has faced and the fact that the U.S. has now been in camp for two weeks we think that the U.S. will pick up a victory at the end of the day.
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Trying to get the fleet home
22nd February 2010 – 5.54 pm
It is going to be a quiet few days at the tower in w-space. The main body of our fleet is ditched in high-sec, probably being pestered by mission agents, scammers, and the lure of buying shiny new ships on the market, and that's where they are going to stay until a route back from New Eden can be found for them. I have my new Buzzard covert operations scanning boat ready, bought specifically for this purpose. I could use a colleague's Buzzard, but I like playing with new toys. I warp out of the tower's shields and start scanning, finding our home system's wormhole quickly enough and jumping through.
The neighbouring system is small, only around 10 AU across. The directional scanner shows two cargo containers in deep space somewhere, but no sign of inhabitants. I warp off, after bookmarking my way home, and start scanning. I am still trying to find a more reliable way to select possible wormhole signatures as early as possible, my 'most likely percentage' (ML%) theory needing to accommodate my unrigged ship. Taking note of wormhole positions within the solar system looks to be unlikely to help, partly because of the uncertainty in the initial scanning position compared to the actual location of the signature, but mostly because there seems to be no correlation between signature position and type.
The third signature I resolve turns out to be a wormhole, using an iterative ML% method. The first is before I realise my scan strength is a little weaker, the second signature with the promising Red Dwarf tag JMC is just gas. In retrospect, I should have known it would be a mining site. The wormhole leads to a lower-class w-space system, which probably increases its signature strength a little. I jump through to continue looking for an exit to get the fleet back. Starting to scan, I flip the display out of the system map to check the background colour of the system, and when I return to the map the irritating bug surfaces where the positioning arrows of the probes disappear. I don't know why this happens, but it wastes time. I normally only notice the bug when I initially launch probes, which I resolve by recalling the defective probe and launching another, becoming annoying when so many launch bugged that I have to reload. Having switched to the map when I hit the scan button makes me think that maybe the situation can be resolved without needing to recall the probes and launch new ones. I start a new scan and switch between the map and back, and the arrows reappear. I'm glad I don't have to mess around too much because of the bug, but it is still annoying when it happens.
A wormhole is found quite quickly, leading to a class 1 w-space system. I understand that wormholes leading in and out of class 1 systems don't allow the mass of a battleship through them, which scuppers recovering all of the fleet, but the Guardians could at least be brought back. I look for a different wormhole anyway, just in case a more suitable route can be found. It turns out there is another wormhole in this system but it leads to null-sec space, which we'll not use to ferry ships. I jump in to the class 1 system and have a look at what's there. The signature with the POD tag catches my eye as suitably threatening, but this just leads to more gas. A wormhole leading to low-sec space is soon found, and with a bit more looking a second wormhole to low-sec is also found, this second one reaching the end of its lifetime.
There are only five signatures left in this class 1 system, I may as well finish the scan. All I end up finding are mining sites and a third wormhole, leading to dangerous parts of unknown space. I could continue my search for a route to New Eden there, but it will likely not lead directly to a suitable exit and my time is running short. I check the stable low-sec exit and find it leads to Molden Heath, my old if brief stomping ground. I have twenty jumps to get my Crane, or nineteen to pick up the Guardian, with a bit of dangerous low-sec to pass through first. I don't much fancy the extended journey for now. I head back to the tower and drop off the bookmarks anyway, just in case the alt who is also still at the tower would like to use the information I've gathered. I'll try again tomorrow.
Tags: buzzard, eve online, mmorpg, penny ibramovic, scanning, w-space
2 Responses to “Trying to get the fleet home”
For the disappearing arrows, you can also try deactivating and reactivating the probe, without launching and relaunching.
By Kename Fin on Feb 23, 2010
I didn't even know it is possible to do that. Thank you.
By pjharvey on Feb 23, 2010
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Anita's Snack Foods
Anita's breaks ground on $2M Kingsport expansion
Anita’s is a privately owned, family-run snack food manufacturer based in San Bernardino, California. Since the company took over the former Pure Foods building in August 2018, employment has grown from 20 to 85 jobs and more are expected.
Estepp honored as Kingsport Chamber Lifetime Member
A past Kingsport Chamber president, Estepp currently serves as president of Citizens Bank. He is the 33rd recipient of the award.
Kingsport hotels, BMS campground prepare to house hurricane evacuees
Visit Kingsport Executive Director Jud Teague said Tuesday at the Kingsport Economic Development Board meeting that his organization has reached out to the eight hotels listed at www.visitkingsport.com to prepare for incoming guests from affected areas.
Kingsport Economic Development Board
Is Stone Drive KIA franchise on the way to Tri-Cities Crossing?
A group called Vision Automotive holds the KIA automotive franchise and has been negotiating a deal with developer Stewart Taylor to relocate their operation from their present location on Stone Drive to Taylor’s Tri-Cities Crossing at the intersection of Interstates 81 and 26.
How to do a salvage job
That’s apparently the mindset of the Kingsport Economic Development Board (KEDB) as it attempts to get something out of two failed business ventures the board had invested in.
KEDB OKs financial deal to revitalize Kingsport Town Center
The Kingsport Economic Development Board on Tuesday approved a Payment In Lieu Of Taxes (PILOT) agreement that would allow for a $2.3 million incentive over an 11-year period and require the retail mall’s owner, Augusta, Ga.-based Hull Property Group, to invest a minimum of $4.6 million in the facility over a five-year phase one period.
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Angry or Evil?
https://www.lrb.co.uk/v41/n06/michael-wood/angry-or-evil
Your spectator is sitting not only
In your theatre, but also
In the world.
‘I live in dark times,’ Brecht said, but he liked to believe the darkness would end. In the poem containing those words, written in the 1930s, he apologises to ‘those born after’, saying that
Hatred, even of meanness
Makes you ugly.
Anger, even at injustice
Makes your voice hoarse. Oh, we
Who wanted to prepare the land for friendliness
Could not ourselves be friendly
‘Could not be friendly’ is a discreet but painful understatement, a too amiable hint at horrors. Dark times mean not only that terrible things happen to the world and to us but also that we have had a hand in the terrible things. In a remarkable late poem Brecht imagines a loved landscape has changed, suddenly let him down. But it hasn’t changed. He has remembered where he is in moral time.
The white poplar, a famous local beauty
Today an old hag. The lake
A bowl of slops, don’t touch it!
The fuchsias among the snapdragon cheap and showy.
Last night in a dream I saw fingers pointing at me
As though at a leper. They were worn by work and
They were broken.
There are things you don’t know! I cried.
Knowing I was guilty
We don’t have to apologise for our times. We can gloat over their darkness, become the pointing fingers. This, I take it, is the implication of a much earlier epigram:
In the dark times
Will there be singing?
There will be singing.
Of the dark times.
Or there could be silence. Brecht covers this ground too.
They will not say: when the nut tree shook in the wind
But rather: it was when the housepainter trampled the workers.
They will not say: when the child skimmed the flat pebble over the rapids
But rather: when the ground was being prepared for great wars.
They will not say: when the woman walked into the room
But rather: when the great powers united against the workers.
But they will not say: the times were dark
But rather: why were their poets silent?
There is something clunky and too correct about the party line here – the house painter was far more ecumenical in his trampling – but the prophecy of the final question is eloquent and looks forward to the title of a Heinrich Böll novel: Where were you, Adam? Where were we when the unfriendliness got out of control?
‘Is there no grace, no credit,’ Brecht writes in a 1921 diary entry, ‘is there no one who does not believe in our sins, who thinks better of us than we ourselves do?’ The answer is probably no, but one implication of the cry is that we might try to be this person for others. Brecht’s plays and poems perform this role with a kind of stealthy splendour. Surely no other writer was ever so patient, funny and astute about human frailty. There is a sort of puzzle here, though, that we need to dispose of. Isn’t he just letting everyone else off the hook so he won’t have to hang there himself? There are moments when this seems to be what is happening. Brecht’s announcement that ‘in me you have someone you cannot count on’ sounds like a blank ethical cheque, an advance abolition of the need for forgiveness. But these moments are remarkably rare. Hannah Arendt says one of Brecht’s ‘great virtues’ was that he ‘never felt sorry for himself – hardly ever was even interested in himself’. The person he called ‘poor B.B.’ feels like a character in one of his plays, and we hear the confessional note only in poems like the one I quoted, about the altered white poplar, and the last but one piece in the Collected Poems:
And I always thought the very simplest words
Would be enough. If I say what is
Every heart will surely be lacerated.
That you will go under if you don’t fight back
Surely you must see that?
It is perhaps worth having Michael Hamburger’s version here, just to hear a slightly different lilt:
And I always thought: the very simplest words
Must be enough. When I say what things are like
Everyone’s heart must be torn to shreds.
That you’ll go down if you don’t stand up for yourself
Surely you see that.
Brecht is attentive to all kinds of weakness and forms of helplessness that he doesn’t have, and the ones he does have tend to make him an expert rather than a hypocrite, the man who will never cast the first stone. We remember too that the cry in the diary was not an address to an individual conscience but a dream of other, kinder minds.
‘The Infanticide Marie Farrar’ tells us that the sentenced woman shows ‘the frailties of all creation’ and the poem’s refrain, repeated nine times with very slight variations, runs: ‘But you, I beg of you, contain your wrath for all/God’s creatures need the help of all.’ The chorale that ends The Threepenny Opera – the music is Kurt Weill’s affectionate parody of Bach – makes the same recommendation: ‘Combat injustice but in moderation.’ In these and many other lines we hear the voice of the Protestant who grew up in a largely Catholic world, and who kept not the faith of his parents but his own form of fidelity to dissent. Brecht always knew how to catch the fakery in religious and social piety, but also knew what a genuine, secularised care for others might look like. ‘Don’t give up on your own kind’, he says; and praises doctors and nurses ‘who/Remember their obligation to those who/Have a human face.’
Brecht was born in Augsburg in 1898 and grew up there. He moved to Berlin in 1924, already something of a celebrity. The huge success of The Threepenny Opera in 1928 was not anticipated by anyone, but was unmistakable. Lotte Lenya, writing later about those days, said ‘Berlin was swept by a Dreigroschenoper fever. In the streets no other tunes were whistled.’ There were other fevers around, though, and in 1933, the day after the Reichstag fire, as Kuhn and Constantine tell us, Brecht and his Jewish wife, Helene Weigel, left Germany. Several years of exile followed, principally in Denmark and the United States, and it is possible that exile didn’t really end when both of them returned to Berlin. Brecht was a devout communist but not much of a party man, and famously mocked the East German government’s response to a 1953 revolt in these terms:
would it not
Be simpler if the government
Dissolved the people and
Elected another one?
And although he regularly defended the workers against all their enemies, his deep sympathy was with a certain kind of heroic disorder, as evoked in the wonderful poem ‘The breaking up of the ship, the Oskawa, by her crew’. The ostensible argument concerns the poor wages of the sailors, but what is shown is their recklessly reprehensible behaviour, the glorious slack they allow themselves. ‘Since the wages were bad’, we read,
We felt the need to drown
Our troubles in alcohol, so
Several cases of champagne found
Their way into the crew’s quarters.
The ship gets lost a few times but finally makes it from Hamburg to Rio. It sets off again with a new cargo (of meat) and the old crew. Negligence causes a fire, the dynamos won’t work, the meat goes bad, the engines are ruined by an inept use of salt water, various attempts at repair fail and the ship limps back to Hamburg – it has to be towed from Holland – and is scrapped. The last words of the poem are
Any child, we thought
Could see that our wages had
Really been too niggardly.
Kuhn and Constantine tell us that ‘less than half of [Brecht’s] output of poems was published by the time of his death in 1956,’ and every description of the opus sounds dizzying. The 1976 selection of translations edited by John Willett and Ralph Manheim contains ‘roughly five hundred poems’, while a German collected edition of 1967 has ‘approximately one thousand items’. The new book tells us that the latest complete works includes ‘more than two thousand poems’, of which ‘over twelve hundred’ are translated here.
I don’t know whether these numbers in themselves suggest variety or the possibility of a lot of repetition. Brecht’s style and diction are pretty consistent, witty, idiomatic, often close to ordinary speech, never far from the song or the ballad. The literary forms he uses are very diverse, though, and I’m not sure I can name them all. Among them are narrative poems, lyrical meditations, fables, aphorisms, maxims, instructions, polemics, parodies, satires, handbooks, elegies, songs from plays, sonnet sequences, prose reflections and an imitation of a book of devotions. I was delighted to see in this book a connection I didn’t know Brecht had made: one of the lines from the song celebrating the dark skills of Mack the Knife (‘Is not asked and does not know’, in Eric Bentley’s version) is attached to Göring.
In the house …
Lived a certain Mr Göring
Who knew nothing, or wasn’t asked.
There is a lot of formal travel between a cryptic, slightly self-mocking portrait like this one:
Wandering this way and that
Kept no note of my hither and thither
Don’t know where I left my hat
Nor the previous seven either
and the unprotected sweep of
Everything was beautiful on that sole evening, ma soeur
After it never again and never before –
True: all I was left with then were the great birds
That in the dark sky when evening comes are hungry.
Similarly, it’s good stretch from the quiet anger of this image of support for the Nazis:
Knowledge is cultivated too. Out from the libraries
Step the slaughtermen.
to this intimate evocation of the grief of mothers for their soldier sons:
And the years go by. He is not dead.
He will never die. It is only that he’ll never come back.
A coffee pot stays full and empty a chair.
And they save him a bed and they save him bread
And they pray for him and when they lack
Always they entreat him to come home here.
Haunting narratives include that of the dead soldier who is dug up and sent back to war on the grounds that when recruits are needed death is only a form of malingering, and that of the children’s march in Poland which ends in their disappearance, their only legacy a message tied around a dog’s neck:
Please help us, we are lost.
We can’t find the way anymore.
We are fifty-five, the dog will lead
You to where we are …
The writing was a child’s.
Peasants read it aloud.
That was a year and a half ago.
The dog hungered and died.
Brecht was a great believer in doubt; it was a form of faith for him. But he could be harsh on easy doubters:
Their only action is vacillation.
Their favourite phrase: it’s not yet certain.
So granted, when you praise doubt
Do not praise
The doubt that is despair!
What use is doubting to him
Who cannot make up his mind!
This example leads us to what is perhaps a good place to end these illustrations. Brecht loved the idea of reversible logic, because it leaves the reader or spectator with no option except thinking. In one poem he mentions a shelter for the homeless in New York:
The world is not changed by this …
But a few men have a bed for the night
The next stanza says
A few men have a bed for the night …
But the world is not changed by this
A later poem, this time quoted in full, repeats the move:
Everything changes. You can
Begin anew with your very last breath.
But what has been, has been. And the water
You once poured into the wine, you can
Never drain off again.
What has been, has been. The water
That you poured into the wine, you can
Never drain off again. But
Kuhn and Constantine rather sniffily say they are not ‘fond of translation theory and leave it to others to describe our practice, as they wish’. Of course any established academic pursuit is fair game for scepticism, but it seems a little defensive to suggest you don’t care how your work is described or couldn’t find any such description interesting. In fact these new versions hold up very well to close study, especially in matters of rhyming, usually the downfall of translators. Where there are questions they concern not correctness or fidelity but intriguing matters of interpretation. One of the tasks of the translator, to borrow a phrase from Walter Benjamin, apart from helping us to read texts we couldn’t otherwise approach, is to show what different languages allow their speakers to do with words – and also what those languages do not allow.
A good case arises with Brecht’s short poem ‘The mask of the angry one’, or is it ‘The mask of evil’?
On my wall hangs a Japanese carving
Mask of an angry demon, lacquered in gold.
Feelingly I observe
The swollen veins at his temples, hinting
What a great strain it is to be angry.
Here is what H.R. Hays (1947) has:
On my wall hangs a Japanese carving,
The mask of an evil demon, decorated with gold lacquer.
Sympathetically I observe
The swollen veins of the forehead, indicating
What a strain it is to be evil.
The German text is:
An meiner Wand hängt ein japanisches Holzwerk,
Maske eines bösen Dämons, bemalt mit Goldlack.
Mitfühlend sehe ich
Die geschwollenen Stirnadern, andeutend
Wie anstrengend es ist, böse zu sein.
We might say, if we are being theoretical, that ‘feelingly’ is a bit too literal for mitfühlend, which is just the Germanic form of ‘sympathetically’; but that ‘hinting’ gets us closer than ‘indicating’ does to the indirection of the idea. Still, the real point of division (and of this comparison) obviously lies in the word böse, which also appears in the poem’s title. It signifies ‘mean’ or ‘naughty’ or ‘cross’ or ‘evil’, depending on context and intention. When Kafka uses it in his aphorisms (‘Evil is what distracts’; ‘Evil knows about good, but good knows nothing of evil’) ‘evil’ clearly works best, and we can back up this sense with the memory that ‘Der Böse’ is also a name for Satan, the Evil One. The proximity of the word in the poem to ‘demon’ might lead us to prefer Hays’s version. But then with Brecht we may not want the theological dimension of Kafka’s claim, and if we’re in an atheistic mood, we can think he just means ‘very very bad’. In any case, the word certainly also means ‘angry’.
The situation becomes more delicate when Rilke, in the ‘Fourth Duino Elegy’, uses the word to say what he doesn’t understand about the mild manners of children who die young.
Murderers are easy
to understand. But this: that one can contain
death, the whole of death, even before
life has begun, can hold it to one’s heart
gently, and not refuse to go on living,
is inexpressible.
Mörder sind
leicht einzusehen. Aber dies: den Tod,
den ganzen Tod, noch vor dem Leben so
sanft zu enthalten und nicht bös zu sein,
ist unbeschreiblich.
For the phrase ‘nicht bös zu sein’ we need something that catches the sulkiness the children don’t have, and the literal ‘not to be angry’ used by C.F. MacIntyre, for example, won’t do the trick. I think Stephen Mitchell’s ‘not refuse to go on living’ is too metaphysical for these youngsters, but it does give a measure of what Rilke is getting ordinary language (and behind it the image of the behaviour of ordinary children) to do.
So with Brecht, angry or evil? We can guess at what Brecht meant, and if he was around, we could ask him. His response might settle things for some of us. But there is no way of making the word on the page not have, for a given reader, any or all of its meanings in current (or even ancient) usage. Kuhn and Constantine speak eloquently of the ways in which Brecht’s poems ‘are never just the servants of his politics … they exceed his engagement in the particular and necessary cause.’ And they are not entirely the servants of Brecht himself. As the above examples show, translators have to make choices on the behalf of writers, and even in the original language the reader may have a long sliding scale of options.
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Fantastic Fantasy by Cas Peace -Artesans of Albia
Series Synopsis:
On a foolhardy foray into a foreign realm, Taran Elijah is attacked by a terrible weapon known as the Staff. Killing its wielder, he escapes into Albia, inadvertantly carrying the Staff.
Concerned by the vicious raids that follow Taran's actions, Major Sullyan of the High King's forces crosses into Andaryon to seek diplomatic resolution to the crisis. She is captured and tortured by Lord Rykan, aspirant to the Andaryon throne.
Slowly dying, Sullyan escapes his clutches. She offers her skills to the Hierarch in defense of his throne, finally confronting Rykan on the field of battle.
Her handsome Captain and lover, Robin Tamsen, embarks on a desperate quest to recover the Staff. But Rykan's greedy General, Sonten, is two steps ahead of him. If Robin cannot lay his hands on the weapon before Sonten does, Sullyan's life and the lives of all Artesans are forfeit.
The race for the Staff has begun.
All Books available in print and digital form from www.amazon.com and www.amazon.co.uk
Find the author on her website: www.caspeace.com
Facebook: https://www.facebook.com/cas.peace?ref=tn_tnmn
Twitter: @CasPeace1
King’s Envoy by Cas Peace
Fabulous fantasy!
“The story and characters sparkled from the first page. Plenty of mystery, drawing the reader into the tale. Great world building with the five realms and look forward to seeing some of these other regions revealed in future books. Engaging characters with interesting interactions. Ended with suspense – just as well there’s more! Fantasy lovers will enjoy this series.” Fantasy author, Wendy Scott.
Reader Reviews for the Artesans series:
"Better than A Game of Thrones" - SCIFI, Amazon reviewer.
"Most impressive. Fantastic series ... don't miss it!" - K S, Amazon Vine Voice and Top 1000 Reviewer
"A must-read for fantasy fans" CR, Blogger and Amazon reviewer
"5 stars, but deserves so much more" AA, Amazon reviewer
"Splendidly written in a wonderful voice" RM, Author and Amazon reviewer
"One of the best fantasy books I've ever read" DC, Author and Amazon reviewer
Cas lives in the lovely county of Hampshire, southern UK, where she was born. On leaving school she trained for two years before qualifying as horse-riding instructor. During this time she also learned to carriage-drive. She spent thirteen years in the British Civil Service before moving to Rome, Italy, where she and her husband, Dave, lived for three years. They enjoy returning whenever they can. Cas supports many animal charities and owns two rescue dogs. She also loves to sing and is currently writing and recording nine folk-style songs to accompany each of her fantasy books. You can download all the songs from her website: www.caspeace.com
See the video of her performing live at the King’s Envoy book launch here:
http://www.caspeace.com/cas-peace/the-wheel-will-turn
See the Artesans of Albia series trailer here:
http://www.youtube.com/watch?v=76ORbCO_wGI
Twitter: @CasPeace
Final note from Wendy – Cas Peace has kindly re-edited Lodestone (Witch-Hunt) and I’ll be releasing soon on Amazon POD.
Cas Peace link
Wonderful post, Wendy, and lovely review! Many thanks for all your help!
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Long-term research shows domestic cattle resist oral exposure to Chronic Wasting Disease
06 2018 (June)
Livestock with CWD-infected elk in the Sybille Canyon pens.
Cattle fed extremely high oral doses of Chronic Wasting Disease-infected brain material or kept in heavily prion-contaminated facilities for 10 years showed no neurological signs of the disease.
The University of Wyoming’s Wyoming State Veterinary Laboratory (WSVL), Colorado Division of Parks and Wildlife and the Wyoming Game and Fish Department (WGFD) collaborated in the $1.5 million study. Results will be published in the July issue of the Journal of Wildlife Diseases. Details of the study are available at bit.ly/10yearCWD.
As part of the experiment, 41 calves were randomly distributed to WGFD pens in Sybille Canyon in Wyoming, Colorado Division of Wildlife pens in Fort Collins, the WSVL, and 18 to the National Animal Disease Center in Ames, Iowa.
“It was an elegant experiment in many ways,” says Hank Edwards, WGFD wildlife disease specialist. “You were taking cattle and housing them with heavily infected CWD elk and facilities. If CWD was going to jump the species barrier, it was likely you would see something in these cattle that had laid out in the pens for 10 years. That’s a big deal.”
The late Beth Williams, a veterinary sciences professor at UW, initiated the study. Authors of the article continued the research after she and husband, Tom Thorne, were killed in a motor vehicle crash in December 2004. Thorne had served as acting director of the WGFD and had also conducted CWD research.
Authors of the article are Donal O’Toole, a professor in the Department of Veterinary Sciences, which operates the WSVL; Michael Miller, a veterinary epidemiologist with the Colorado Division of Parks and Wildlife; Terry Kreeger, a wildlife veterinarian with the WGFD; and Jean Jewell, a molecular biologist with the WSVL. Williams is listed as lead author.
CWD is a contagious neurological disease affecting cervids: mule deer, white-tailed deer, elk, and moose. An abnormal form of cellular protein called a prion in the central nervous system infects an animal by converting normal cellular protein into the abnormal form. Brains show a spongy degeneration, with animals displaying abnormal behavior, loss of bodily functions, and emaciation. The disease is fatal. It is among a group of diseases called transmissible spongiform encephalopathies. (TSEs). TSE in cattle is also known as mad cow disease.
The long timespan of the research is important, since CWD is a slow disease, says Mary Wood, state WGFD veterinarian.
Even in deer or elk, animals can take years to succumb to the disease, she says. If the disease were to move into a different species, such as cattle, the timeline could be even longer for infection to occur.
“Many people are used to diseases moving quickly, but CWD doesn’t do that,” Wood says. “Nothing happens quickly – which is what makes this disease so insidious. It creeps up on you. It’s subtle. By the time you realize there is a problem, the disease is so widespread and established it’s difficult to try to address.”
Some cattle can get a form of TSE when CWD material is injected directly into their brains, particularly when it is of white-tail or mule deer origin, says O’Toole.
He says a more important question is one Williams and collaborators asked, since it involved a more natural challenge.
“What happens in cattle when you use a more real-life scenario involving oral exposure?” O’Toole asks. “Plus, we used high oral doses and heavily contaminated environments. Cattle coming out of endemic CWD areas and slaughtered for human consumption are likely to pose no risk to people based on the 10-year study and several earlier surveillance studies.”
That should be good news to livestock producers, says Wood.
“Managing disease in animals can be incredibly challenging,” she says. “It is even more challenging when the disease infects wildlife and is shared between wildlife and livestock.”
Wyoming cattle share the range with CWD-infected cervids, with CWD seen across almost the entire state of Wyoming, notes Edwards.
“This research indicated CWD doesn’t easily transmit to cattle. Cattle do not get the disease due to a big species barrier, which helps restrict the disease to cervids,” he says.
Some Wyoming deer populations have 20-30 percent infection rates.
“We have few tools in the toolbox to manage the disease,” Edwards says. “We are trying different management efforts to hold the prevalence level, if not reduce the spread. That’s the big thing coming up next for CWD. How do we control it in our wildlife populations?”
2018 Wyoming Agricultural Experiment Station Field Days Schedule
UW president special guest at sixth annual forage field day near Lingle
Ellbogen thank you and opportunities
Search Agademics
03 2018 (March)
04 2018 (April)
05 2018 (May)
Research & Extension Centers
SAREC
Copyright © All rights reserved Wyoming Agricultural Experiment Station.
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94-year-old U.S. runner becomes oldest woman to complete half-marathon
Source: Xinhua| 2017-06-05 04:22:45|Editor: yan
LOS ANGELES, June 4 (Xinhua) -- Harriette Thompson, 94, set record Sunday noon at the Rock 'N' Roll Marathon in San Diego, as the oldest woman to complete a half-marathon.
Thompson, wearing purple T-shirt and white hat, was surrounded by photographers and players when she reached the final line, finishing her incredible journey in an official time of 3 hour, 42 minutes and 56 seconds.
The previous record was held by Gladys Burrill, who ran a half marathon at 93 years old in 2012.
Thompson, a two-time cancer survivor, broke the world record in 2015 as the oldest woman to complete a full marathon.
"I never thought I would still be here!" Thompson told local NBC7 before the match, saying she ran to raise money for the Leukemia Lymphoma Society.
Through the years, she had raised 100,000 U.S. dollars for the organization, including 15,000 U.S. dollars in 2017, the report said.
She said her secret to a healthy life at her age was exercise on a regular basis and a balanced diet. Though she admitted it was hard for her to resist sugar.
"I might have to reward myself after the race with an ice cream cone," she said with a smile.
KEY WORDS: Marathon
Macaques attract tourists at scenic spot in SW China's Chongqing
Lotus flowers blooming in south China's Guangxi
Foreign students take part in TCM activity in E China's Nanjing
Chinese submersible Jiaolong dives in Yap Trench
Lost temple discovered after 1,000 years in Chengdu
Intangible cultural heritage expo opens in east China
China hopes Belgium can play positive role on EU's fulfillment of WTO obligations: Li
Weekly choices of Xinhua photos (May 29 - June 4)
Stockholm Marathon 2017 held in Sweden
/ 01. Chinese delegation successfully makes China's voice heard at Shangri-La Dialogue
/ 02. Wide consultation, joint contribution and shared benefits, key to Asia-Pacific security
/ 03. Big shareholder stock sales plummet after new rules
/ 04. With Li's visit, China forges closer ties with EU
/ 05. Chinese, Russian officials laud bilateral military ties
Musicians of Moscow military music school take part in street concert
Musical held in Estonia to mark Int'l Children's Day
Colorful salt lakes seen in Yuncheng city, China's Shanxi
In pics: scenery of Sayram Lake in China's Xinjiang
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Top things to do in Tampa Bay for Friday, July 12
‘Pippin’ and ‘’Sup Cones 2’ open in St. Petersburg, while Yes and Asia take the stage in Clearwater.
On Friday, Yes will perform at Clearwater’s Ruth Eckerd Hall alongside Asia. [Courtesy of Gottlieb Bros. via MSO PR]
Yes: The prog-rock pioneers bring their Royal Affair tour to town with Asia and its founding member Steve Howe. $63.25 and up. 7 p.m. Ruth Eckerd Hall, 1111 N McMullen-Booth Road, Clearwater. (727) 791-7400. rutheckerdhall.com.
’Sup Cones 2: Hip-hop culture meets ice cream in this group art show hosting its opening reception. The Clara Rose Ice Cream Truck and vegan wiener cart Nah Dogs are on-site. Runs through July 27. Free. 6 p.m. Mize Gallery, 689 Dr. Martin Luther King Jr. St. N, St. Petersburg. (727) 251-8529. chadmize.com.
Pippin: A new staging of the musical, which Bob Fosse originally directed on Broadway, follows a recent college graduate who goes on a quest to find meaning in his life. Runs through Aug. 11. $50. 8 p.m. Freefall Theatre, 6099 Central Ave., St. Petersburg. (727) 498-5205. freefalltheatre.com.
Spider-Man: Into the Spider-Verse: Take the family to a showing of this Oscar-winning animated film, rated PG. Free. 6:30 p.m. Carrollwood Cultural Center, 4537 Lowell Road, Tampa. (813) 269-1310. carrollwoodcenter.org.
Kountry Wayne: This social media star gained 2.5 million followers with his viral videos. $30, $50 VIP. 8 and 10:30 p.m. Tampa Improv, 1600 E Eighth Ave. (813) 864-4000. improvtampa.com.
Flick and Float: Bring a chair or jump in the pool during this family movie night. $5. 6:30 p.m. Southwest Recreation Complex and Pool, 13120 Vonn Road, Largo. (727) 518-3125.
Summer Movie Series: Ready for even more flicks? Then don’t miss the Scream screening with trivia. $5, $9 with unlimited soda and popcorn. 7 p.m. Nancy and David Bilheimer Capitol Theatre, 405 Cleveland St., Clearwater. (727) 791-7400.
Cinema on the Sand: The Meg gets projected on a screen aboard a floating boat. You can watch in the water, or enjoy the film from a blanket on the sand. Free. 8 p.m. Upham Beach, Gulf Boulevard and 68th Street, St. Pete Beach. (727) 363-9245.
Chuck Redd Album Release: The great vibraphonist and drummer joins local jazz trio La Lucha for a night of music as he debuts his new album Groove City. $20 and up. 8 p.m. The Palladium, 253 Fifth Ave. N, St. Petersburg. (727) 822-3590. mypalladium.org.
BB King Blues Band: The members tour in remembrance of B.B. King, performing on stages around the world. Sarasota Slim also plays. Free. 8 p.m. Jannus Live, 200 First Ave. N, St. Petersburg. (727) 565-0550. jannuslive.com.
Boombox Cartel: A Los Angeles-based producer act consisting of Americo Garcia and writing partner Jorge Medina. $15. 9 p.m. The Ritz Ybor, 1503 E Seventh Ave., Tampa. (813) 248-4050. theritzybor.com.
MetroCon: Now in its 17th year, a huge anime celebration featuring voice actors, exhibitors, video games and films, plus collectibles and cosplay artists. Runs through Sunday. $30 and up, $10 ages 6-12, 5 and younger free. Noon. Tampa Convention Center, 333 S Franklin St. (813) 274-8511.
Steve Trevino: The Mexican-American comic was a writer on Mind of Mencia and has specials on Showtime and Netflix. $18 and up. 8 and 10:15 p.m. Side Splitters Comedy Club, 12938 N Dale Mabry Highway, Tampa. (813) 960-1197. sidesplitterscomedy.com.
Martin Montana: Check out a performance from the comedian who voices the talking orange slice Wedgehead for Shock Top.
$20. 9:30 p.m. Coconuts Comedy Club, 5501 Gulf Blvd., St. Pete Beach. (727) 360-5653. coconutscomedyclubs.com.
Point Blank, Netflix: Frank Grillo, Anthony Mackie and Marcia Gay Harden star. The gritty new action film follows an emergency room nurse who, in an effort to rescue his abducted wife, unwillingly partners with a badly injured murder suspect. They run up against rival gangs and a deadly ring of corrupt cops.
Find date night ideas and things to do with kids at tampabay.com/thingstodo.
The Peach Truck creators on what you need to know about peaches this summer
Stephen and Jessica Rose released their first cookbook, ‘The Peach Truck Cookbook’, in June.
Before Fitz and the Tantrums hit Tampa, singer talks tireless touring and all-ages fans
Michael “Fitz” Fitzpatrick and his indie pop band play the Yuengling Center with Young the Giant on Thursday.
Radio station WMNF victim of ransomware cyberattack
Archived episodes of the station’s news and public affairs programming may be lost permanently.
What’s happening in Tampa Bay food: Florida Hard Seltzer Fest, tropical fruit tasting
A pair of Dunedin smorgasbords and a vegan popup in Tampa are also worth checking out, plus observe National Ice Cream Day.
WWE star Seth Rollins talks Tampa Bay memories and RAW battles
The former WWE Universal Champion headlines WWE RAW Live Monday in his old stomping ground.
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Ranch House
Cook House
Where the Old West and the New West Collide
The Ranch House
Our award winning restoration/reuse of the Ranch House is nationally recognized by its placement on the National Registry of Historic Places. It was also featured on Bob Vila's "Restore America."
The Ranch House Porch, popular for relaxing, reading and enjoying the view.
Relaxing on the TA Ranch House porch circa 1904
The first building on the TA Ranch, the Ranch House was built in 1882 and was used as "a place of gay entertainment, of hunt dinners and balls...." (Mari Sandoz, The Cattlemen, University of Nebraska Press, 1958.)
Ranch House Rooms
Each room in the Ranch House had its own pot bellied stove to provide heat. In historic photos, you can identify the TA Ranch House by its chimneys.
During the Johnson County war, the Ranch House became the head quarters of the Cattle Barons and the floor to ceiling ranch windows, a hallmark of luxury, became a liability as Billy Irvine was shot in the foot through the window in the Della Gammon room (also seen below).
The Common Room of the Ranch House, used by guests today for relaxing, surfing the internet and socializing.
The Charlie Ford room, named for the first Ranch Manager of the TA Ranch. Originally the "bunk" room for the territorial cowboys, we've dressed it up a little today.
The William Harris Room, named for the Union Pacific Railroad physician who founded the TA Ranch in 1882. Why the name "TA?" Click here to find out.
The Della Gammon Room, named for Della Gammon, matriarch of the Gammon legacy 1904-1979.
Elegant for its time, the Ranch House rooms have 10 foot ceilings and floor to ceiling windows.
There are three bedrooms in the ranch house. The largest, the Charlie Ford Room, served as the "bunk" for the territorial cowboys working the ranch.
The William Harris Room circa 1909
At the other end of the building, (separated by the Common Room) the Ranch Manager had an adjoining two bedroom suite, now called the William Harris and Della Gammon rooms. These rooms can be used independently or as an adjoining suite for families.
Home Location Lodging Cuisine Activities Conferences Weddings About Contact Us Blog
TA Guest Ranch 28623 Old Highway 87 Buffalo, Wyoming 82834 PH: 307.684.5833 FAX: 307.684.5123 Email: info@taranch.com
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Mueller to testify before Congress on July 17
by Jerry Dunleavy | Washington Examiner
Former special counsel Robert Mueller will testify in front of an open session of Congress on July 17.
Ending weeks of speculation, Chairman of the House Judiciary Committee Jerry Nadler and Chairman of the House Intelligence Committee Adam Schiff announced Tuesday evening that Mueller has agreed to testify before both committees in mid-July.
Nadler and Schiff announced in a joint statement that “pursuant to subpoenas issued by the House Judiciary and House Permanent Select Committee on Intelligence tonight, Special Counsel Robert S. Mueller III has agreed to testify before both Committees on July 17 in open session.”
“Americans have demanded to hear directly from the Special Counsel so they can understand what he and his team examined, uncovered, and determined about Russia’s attack on our democracy, the Trump campaign’s acceptance and use of that help, and President Trump and his associates’ obstruction of the investigation into that attack,” their statement continued. “We look forward to hearing his testimony, as do all Americans.”
Read the full article: https://www.washingtonexaminer.com/news/mueller-to-testify-before-congress-on-july-17?utm_source=WEX_Breaking%20News%20Alert_06/25/2019&utm_medium=email&utm_campaign=WEX_Breaking%20News&rid=175001
Categories Featured Content | Tags: Robert Mueller, Russiagate
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ZFF Travels
Festival Locations
Film submission
Zagreb Film Festival
Schedule by programmes and days
LUX Film Days
Established in 2007, LUX Prize is given annually by the European Parliament for cinematic achievements. The purpose of LUX Prize is to draw attention to the public debate on the European Union and its policies and to support the expansion of European (co-)productions. LUX Film Das takes place in autumn in more than 40 cities in European Union as a tangible manifestation of the European Parliament’s committed involvement in cinema and culture. Three films shortlisted for LUX Prize will be shown simultaneously in 24 languages in 28 EU countries.
Varšavska 3, 10000 Zagreb, Croatia
info@zagrebfilmfestival.com
Made with by 20interactive
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We're proud to present Dragon Troubles!
| 22 June
Spass is now ready to fly off to animation film festivals! We finalized our work on Dragon Troubles and it's officially out of the oven!
2016 Annecy International Animated Film Festival
The strong alpine wind and the constant rain didn't diminish the festival organizers’ warm welcome to our team. The Annecy streets were crowded but not only
A Week with Mr. Brown at the 2016 Balkan Film Food Festival
Awesome news! Our short animated film, A Week with Mr. Brown, was included in the 2016 Balkan Film Food Festival in Pogradec, Albania! As its name suggests,
We are happy to let you know that Zographic Films will have a representative at the 2016 Cartoon 360. It's a great pitching event that brings together digital
Dragon Troubles is Going to France!
Great news! We are so proud to have been selected for the outstanding co-pro event Cartoon Forum 2016 in Toulouse, France. Our latest creative effort, the
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Carlson, Melody
From BPL-YA-Series
Author A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Series # A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Booklists A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
1 Melody Carlson
2 Carter House Girls
3 Dating Games
4 Diary of a Teenage Girl: Caitlin
5 Diary of a Teenage Girl: Chloe
6 Diary of a Teenage Girl: Kim
7 Diary of a Teenage Girl: Maya
8 Life at Kingston High
9 Notes from a Spinning Planet
10 On the Runway
11 Secret Life Of Samantha McGregor
13 TrueColors
Melody Carlson
Official website- http://www.melodycarlson.com/
Carter House Girls
Mixed Bags
Stealing Bradford
Viva Vermont
Lost in Las Vegas 2/2009
New York Debut 5/2009
Spring Breakdown 2/2010
Last Dance 5/2010
First Date 10/2013
Blind Date 6/2014
Double Date 1/2015
Prom Date 7/2105
Diary of a Teenage Girl: Caitlin
Becoming Me
Diary of a Teenage Girl: Chloe
My Name Is Chloe
Diary of a Teenage Girl: Kim
Just Ask 7/2005
Meant to Be 10/2005
Falling Up 1/2006
That Was Then 5/2006
Diary of a Teenage Girl: Maya
Not So Simple Life 7/2008
It's a Green Thing 2/2009
What Matters Most 9/2009
Life at Kingston High
The Jerk Magnet 1/2012
The Best Friend 6/2012
The Prom Queen 1/2013
Notes from a Spinning Planet
Ireland 11/2006
Papua New Guinea 2/2007
Mexico 8/2007
Premiere 6/2010
Catwalk 6/2010
Rendezvous 8/2010
Spotlight 10/2010
Glamour 2/2011
Secret Life Of Samantha McGregor
Bad Connection 9/2006
Beyond Reach 1/2007
Playing With Fire 8/2007
Payback 2/2008
Forgotten: Seventeen and homeless 8/2010
Shattered: A daughter's secret 4/2011
Damaged: A violated trust 9/2011
Trapped: caught in a lie 3/2012
Deceived: Lured from the truth 9/2012
Enticed: A dangerous connection 4/2013
TrueColors
Dark Blue: Color Me Lonely
Deep Green: Color Me Jealous
Torch Red: Color Me Torn
Pitch Black: Color Me Lost
Burnt Orange: Color Me Wasted 1/2005
Fool's Gold: Color Me Consumed 7/2005
Blade Silver: Color Me Scarred 10/2005
Bitter Rose: Color Me Crushed 1/2006
Faded Denim: Color Me Trapped 6/2006
Bright Purple: Color Me Confused 8/2006
Moon White: Color Me Enchanted 1/2007
Harsh Pink: Color Me Burned 5/2007
Retrieved from "http://yaseries.bettendorflibrary.com/index.php?title=Carlson,_Melody&oldid=6355"
About BPL-YA-Series
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White Light begins new role at Central Hall Westminster
Emma Hudson July 1, 2015
Latest NewsSupplierVenues
White Light has begun its role as the production service partner at Central Hall Westminster, the largest conference venue in London.
Over the next year, White Light will be investing in new AV and lighting equipment, which will be permanently installed in a number of rooms.
The supplier’s role will involve delivering the technical production for any event held in this historic location, whether these are concerts, corporate or private parties.
Along with the installations, White Light is also adding three on-site staff members so that every technical aspect will be covered.
“White Light is a really exciting company to be working for. Just looking at what they have already achieved this year, from opening their dedicated audio department to acquiring Shock Solutions, the company is forever growing,” said Dan Cecchini, who takes on the position of production director.
“My role will focus mainly on client engagement. After seeing the spaces available at Central Hall Westminster, and hearing both their and White Light’s plans for the future of the venue, I want to get as many potential clients engaged as possible so that their future events can benefit from this extremely impressive arrangement.”
Joining Dan as part of the team based at Central Hall Westminster will be Nick Jemicz as technical production supervisor and Ieuan Watkins as production technician. Both will be on hand to ensure that any client using the spaces have support available and oversee all technical aspect. The facilities available at Central Hall Westminster include The Great Hall, The Lecture Hall and The Library.
The recent Meet the Future event held at Central Hall Westminster offered White Light the opportunity to showcase both their vast array of technical skills and extensive stock range. This included video mapping The Great Hall’s dome ceiling, lighting the main stage and operating three separate sound systems simultaneously.
“We want to offer a fresh, contemporary perspective on how events will be run at Central Hall Westminster,” said White Light director Richard Wilson. “We are in a unique position where we can offer clients not only the very latest in technology but a team of experts who will be on hand to ensure that this is used to its full potential. This type of service is simply not available in other venues.”
Central Hall Westminster has event space for up to 2,160 visitors.
Emma Hudson
Emma Hudson, Editor
White Light illuminates reopening of the V&A’s William and Judith Bollinger Gallery
Tom Hall May 20, 2019
White Light invests in the latest audio equipment
Stuart Wood November 28, 2018
Royal Horticultural Halls unveils new production company list
Stuart Wood October 16, 2018
Stand up to Cancer raises £15.7m
Nicola Macdonald November 10, 2016
White Light supplies Save the Children fundraiser
Nicola Macdonald September 29, 2016
Let’s talk about tech
Emma Hudson January 20, 2016
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Local time: 20:00 PALAIS DES SPORTS JEAN WEILLE
Olympiacos took care of SLUC Nancy 74-79
Olympiacos BC Pireaus finished second in regular season Group A by edging SLUC Nancy 74-79 at the Palais des Sports Jean Weille in France on Thursday. Olympiacos finished this group with a 6-4 second and was second due to its tie-break disadvantage with Fenerbahce Ulker. As such, the Reds avoided Montepaschi Siena, Panathinaikos BC Athens and Maccabi Electra in the upcoming Top 16 draw, which takes place next Wednesday. Nancy was sixth in Group A with a 3-7 record. Pero Antic led the winners with 20 points. Georgios Printezis added 18 while Kyle Hines pulled down 12 boards for Olympiacos. Jamal Shuler led Nancy with 18 points. Adrien Moerman added 11 while Victor Samnick had 10 for the hosts. Nancy had 12-of-16 two-pointers in the first quarter, as an outstanding Shuler helped the hosts to get a 27-21 after 10 minutes. Shuler got some help from Pape-Phillipe Amagou and Kenny Gregory to give Nancy a 43-34 margin late in the first half. Antic and Kostas Sloukas fueled an 1-17 run that gave Olympiacos a 44-51 marguin right after the break. Nancy answered with its own 16-2 run that Shuler capped with free throws to regain a 60-53 margin. Nancy led 64-56 but Antic and Printezis combined for 13 points in a 0-17 run that gave the Reds the lead for good, 64-73. Nancy managed to get within 74-77 but Kenny Grant missed from downtown and Printezis sealed the outcome from the foul line.
Printezis got Olympiacos going with a layup in transition that Shuler matched with a close jumper. A driving layup by John Linehan soon gave Nancy a 4-2 lead. Kostas Papanikolaou split free throws but and Martynas Gecevicius improved Moerman's driving layup with a rainbow triple for a 6-6 tie. Linehan made 1-of-2 foul shots and Gregory took over with a reverse layup but Printezis kept the Reds within 9-8. Moerman followed free throws with a jump hook and a jumper by Shuler boosted the hosts' lead to 15-10. Shuler banked in a running jumper that Kalin Lucas erased with a layup in transition. Gregory shined with a big basket in the low post but Michalis Pelekanos quickly brought Olympiacos as close as 19-15. Shuler kept pacing Nancy with a backdoor layup and another jumper for a 23-15 Nancy margin. Hines shined with a put-back layup and Antic added free throws but back-to-back baskets by Samnick kept Nancy way ahead, 27-19. A driving layup by Evangelos Mantzaris brought the guests within 27-21 after 10 minutes.
Gecevicius struck from downtown early in the second quarter but a jump hook by Moussa Badiane and free throws by Amagou restored a 31-24 Nancy lead. Badiane scored around the basket and an unstoppable Shuler added an acrobatic jumper in transition to make it a double-digit game, 35-24, forcing Olympiacos to call timeout. Amagou capped a 10-0 run with a driving basket, as Olympiacos found a go-to guy in Antic. He stepped up with a jump hook and free throws and soon added a two-handed dunk to bring the Reds within 37-30. Amagou made free throws but Hines and Badiane traded dunks for a 41-32 score. Antic kept pacing the Reds with foul shots but a fast break layup by Gregory sent the crowd to their feet at 43-34. Sloukas scored around the basket and a free throw by Hines made it a six-point game, 43-37. Andreas Glyniadakis took over with a three-point play and a jump hook by Printezis brought the Reds within 43-42. A three-pointer by Printezis and a layup by Sloukas completed the guests' comeback, 44-47, at halftime.
Sloukas shined with a fast break layup right after the break, as Nancy kept struggling to score. A jump hook by an unstoppable Antic capped an 1-17 run that bridged between both halves. Shuler tried to change things with a fallaway jumper and Linehan nailed a three-pointer to bring Nancy back to life, 49-51. Shuler kept pacing Nancy with free throws and a fast break dunk by Badiane that put the hosts back ahead, 53-51. Pelekanos rescued Olympiacos with a layup in transition but he didnt find much help around. Meanwhile, Linehan made free throws and collected an inbound steal that allowed Grant to down a triple, good for a 58-53 Nancy margin. Shuler capped an 16-2 run with free throws, as Printezis brought Olympiacos within 60-55. Samnick banked in a turnaround jumper and soon added a driving basket to give Nancy a 64-56 margin. Antic took over with a layup in transition and added his trademark catch-and-shoot three-pointer to bring Olympiacos back to life, 64-61, after 30 minutes.
Lucas swished a jumper early in the fourth quarter, as Olympiacos had improved its defense and locked down its defensive board. Nancy had been scoreless for more than 4 minutes already and a wide open three-pointer by Printezis put the guests back ahead, 64-66, with 7 minutes to go. Olympiacos was all over the place in defense, forcing Nancy to use long possessions and take off-balance shots. Meanwhile, a layup by Kostas Papanikolaou made the hosts call timeout at 64-68. The hosts could not find the way to the basket and Antic buried another triple from the left wing to break the game open, 64-71. Printezis shined with a fast break layup that capped a 0-17 run. Samnick tried to change things with a put-back layup off another Nancy timeout and free throws by Moerman gave the hosts some hope, 68-73, with 2:53 left. Hines scored down low but Moerman answered from downtown for a 71-75 score. Sloukas made free throws but Grant buried a triple and Nancy regained possession. Grant missed from beyond the arc and free throws by Printezis allowed Olympiacos to get a very important win.
Referees: HIERREZUELO, DANIEL; RYZHYK, BORYS; ZAMOJSKI, JAKUB
SLUC Nancy 27 17 20 10
Olympiacos Piraeus 21 26 14 18
4 POURCHOT, VINCENT DNP - - - - - - - - - - - - - - -
6 GRANT, KENNETH 10:12 6 0/3 2/3 1 1 1 1 1 2
7 BADIANE, MOUSSA 23:43 8 4/7 2 2 1 1 4 1 1 3 12
8 SHULER, JAMAL 40:00 18 7/14 0/2 4/4 1 8 9 3 3 1 2 3 18
9 SYLLA, ABDEL KADER 18:56 0/1 2 2 1 3 4 1
11 LINEHAN, JOHN 25:42 8 1/2 1/3 3/4 3 3 3 5 1 5 4 13
13 SAMNICK, VICTOR 15:48 10 5/7 2 1 3 1 1 3 1 9
14 PINDA, KINGSLEY DNP - - - - - - - - - - - - - - -
16 KURTIC, DZENAN DNP - - - - - - - - - - - - - - -
17 AMAGOU, PAPE-PHILIPPE 17:21 6 1/2 0/1 4/6 2 2 1 1 1 1 3 5 6
18 MOERMAN, ADRIEN 21:33 11 2/4 1/2 4/4 1 1 2 1 2 3 3 9
20 GREGORY, KENNY 26:45 7 3/6 0/1 1/4 1 1 1 1 1 2 2
Team 1 3 4 2 1 1
50% 33.3% 72.7%
Head coach: MONSCHAU, JEAN-LUC
Olympiacos Piraeus
4 HINES, KYLE 22:13 8 3/8 2/6 7 5 12 2 3 1 4 2 3 8
5 LUCAS, KALIN 16:38 4 2/6 0/3 1 1 1 3 -6
6 ANTIC, PERO 24:21 20 4/5 2/5 6/6 1 3 4 3 1 1 2 2 5 28
9 HOWARD, MATT DNP - - - - - - - - - - - - - - -
10 KESELJ, MARKO 2:38 1 -1
11 PELEKANOS, MICHALIS 14:06 5 2/2 0/3 1/2 2 2 4 2 2 1 4 2 6
13 GECEVICIUS, MARTYNAS 22:54 6 0/1 2/8 1 1 2 3
14 GLYNIADAKIS, ANDREAS 12:56 5 2/5 1/1 1 1 2 1 3 1 2 3
15 PRINTEZIS, GEORGIOS 24:10 18 4/7 2/4 4/4 2 3 5 2 2 1 2 19
16 PAPANIKOLAOU, KOSTAS 20:56 3 1/2 1/2 4 4 2 1 2 1 7
17 MANTZARIS, VANGELIS 20:48 2 1/2 0/1 2 3 5 4 2 1 2 1 9
18 SLOUKAS, KOSTAS 18:20 8 3/4 0/2 2/2 1 1 2 1 1 1 2 4 9
Head coach: IVKOVIC, DUSAN
MONSCHAU, JEAN-LUC
“My players gave their all, considering the many games they had to play before. They played an enormous third quarter. The absence of Akingbala made it more difficult. Even losing the rebound battle, we were still not far from winning at the end – at the 2-minute mark we were only 1 point behind. We were the little ones in this group; we've been eliminated but so has Caja Laboral. We were in a strong group with a lot of parity, even with four victories nobody knew if they’d made it through. With Nicolas Batum we were on track to qualify, without him it was a little bit Mission Impossible."
IVKOVIC, DUSAN
"It was important for us to win tonight against Nancy. Everybody wants to win every game in the Euroleague. It was difficult to adjust to the absence of Spanoulis and Papadopoulos, our two best players and creators. In general, the Euroleague is of a very high level."
BADIANE, MOUSSA
“This is a game we could have won; we had all the good cards in our hand, but unfortunately we gave them away. We lost the rebound fight, especially during the fourth quarter, and that led to the loss. Apart from the defeat against Caja Laboral, we were not far away from winning the other games.”
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Wells Stands Behind Wealth Business, At Least for the Short Term
by Mason Braswell
Jon Weiss, head of Wells Fargo Wealth and Investment Management
Wells Fargo & Co.’s wealth management businesses are not on the “short list” of units it is considering selling, despite advisor and client attrition, Chief Financial Officer John Shrewsberry said on Friday.
Wells earlier this week announced a plan to sell the retirement services business of its Wealth and Investment Management division, and on Friday reported that its broker ranks fell by another 140 advisors during the first quarter while all its wealth businesses had net “outflows” of client assets.
During a conference call to discuss the bank company’s first-quarter earnings Wolfe Research analyst Steven Chubak asked Shrewsberry if the bank would consider a “strategic sale” of the wealth division, given “the steady pace of advisor attrition and strong interest from peers to pursue M&A in this area.”
The business, which is dominated by its Wells Fargo Advisors brokerage units of almost 13,900 brokers, has “clearly been impacted by the account scandal,” Chubak said.
“It’s not on the short list of things that we’ve been talking about as we do the non-core trimming here and there, like the retirement business most recently,” Shrewsberry said. He noted that he was talking about prospects for “the relatively near term.”
Wells’ brokerage force has declined by a net 1,258 since it disclosed its fake account scandal in September 2016, and both customer assets and advisor headcount fell in this year’s first quarter.
Wealth and Investment is the smallest of Wells’ three business segments, which includes the company’s widespread retail banking network and its wholesale banking units. The wealth division’s first-quarter net income of $577 million was down 19% from the year-earlier period, and comprised 10% of the $6.2 billion of profit the three segments generated.
Referrals between the company’s advisory businesses for wealthy people and other parts of the bank remain the “path to the greatest value creation” for shareholders, Shrewsberry said, citing as one example the mortgages sold to wealthy customers of Wells Fargo Advisors.
Referrals from the bank to the wealth and investment division totaled $2.4 billion in the first quarter, up 10% from the fourth quarter of 2018 but down 8% from the year-earlier period, Wells said in its earnings report.
Shrewsberry expressed confidence in the executive running the Wealth and Investment Management division, which includes private banking services, the Abbot Downing family office and Wells Fargo Asset Management’s fund business, as well as the brokerage business.“The changes that Jon Weiss is making in running that business will continue to generate a high level of value creation,” Shrewsberry said.
Weiss began the first stage of a reorganization of his division last summer by merging Wells’s bank-branch brokerage operations for the mass affluent into its Wells Fargo Advisors’ private client group, which employs more than 9,000 brokers in standalone offices and is run by David Kowach.
Weiss had earlier exhorted employees employees in his division to exercise “discipline, fortitude, integrity and compassion” amid a broader restructuring he was planning.
While Shrewsberry said that Wells’ remaining wealth businesses are not on the auction block, he cautioned that the bank company has a fiduciary obligation to consider all offers.
“If anybody made a proposal that was value-maximizing for our shareholders, our job is to respond to that,” he said, adding that he doubts that any such proposal will be coming anytime soon.
on Apr 15 2019, whaddya think is gonna happen? says:
They won’t sell the wealth management arm, they will turn it into Merrill Lynch. Anyone that goes there for the big deals is making a huge mistake. The bait and switch is inevitable. The CEO mentions cross selling, it’s not even a veiled threat, it’s there for all to see
> Reply to whaddya think is gonna happen?
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Stay Nimble Out There: June Notes and Charts
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ADVANCED MISSION SYSTEMS
Intelligence | Surveillance | Tactical Cyber | Tactical Operations Support | Unmanned Systems
TACTICAL OPERATIONS SUPPORT
UAS FIELD OPERATORS COURSE
CBP / ICE Support
ADVANCED MISSION SYSTEMS (AMS) was established in 2006 and is a small business in Charlotte, North Carolina, We specialize in the delivery of advanced technologies, training, and professional services in the areas of Technical Surveillance, Tactical Cyber Operations, and Special Operations Technical Support. We are a trusted agent for Special Operations Forces, Department of Homeland Security, and Federal Law Enforcement Agencies. Our Team includes engineers with advanced degrees and operators with current experience in South America, Africa, Middle East, Afghanistan, Iraq, Eastern Europe, Central America, and Joint Task Forces within the continental U.S. We take pride in being on the cutting edge of technologies used for TTL, CTR, SSE, ISR and Tactical Cyber Operations, and have trained nearly 500 operators, special agents, and federal law enforcement officers in mission-critical skills.
With decades of experience and a willingness to listen to our customers, we dedicate Company resources to filling critical capabilities gaps with systems, equipment, and technologies developed through partnerships with industry leaders and independently modified/tested by our team of experienced operators and engineers.
Tactical Cyber
The AMS Team specializes in conducting advanced collections, SIGINT, physical and technical surveillance, special reconnaissance, and HUMINT in austere environments.
We applied our passion and experience in Tactical Cyber Operations to develop a set of Training Courses that are operationally relevant and directly applicable to addressing current capability gaps and TTPs used by our adversaries. We name our courses after individuals who made major contributions to this community and have dedicated their careers to the SOF and Intel missions. Our full-spectrum of training includes:
Multi-Source Collections and Analyses
Threat Vulnerability Assessments
Mobile Device Security and Exploitation
Operations over Unsecured Wired and Wireless Networks
Encrypted Commercial Communications
Persistent Cyber Surveillance
Cyber Situational Awareness
Counter-Cyber Surveillance
Social Engineering Methods and Social Media Exploitation
Cyber Training Operations
Open-Source Intelligence
Technical Surveillance
AMS has trained more than 250 Special Forces Operators in Physical and Technical Surveillance. We offer five physical and technical surveillance courses to ensure beginner, intermediate and advanced operators are up-to-date with the latest surveillance tools and techniques. AMS instructors have an average of 20 years experience in surveillance, having conducted operations in Eastern Europe, the Middle East, Africa, and South America. All surveillance courses focus on a unique curriculum of helping our customers learn and employ surveillance tactics, techniques, procedures, and, methods. The training is conducted for multiple areas of operation and against various threats, including terrorists, criminals, and fugitives. We provide custom training courses that include:
Tagging, Tracking and Locating
Sensitive Site Exploitation
Long-range, Digital and Aerial Photography
Covert and Tactical Audio/Video Collection
Special Reconnaissance
Copyright ©2016 | ADVANCED MISSION SYSTEMS | All Rights Reserved
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Anticipate This!™ | Patent and Trademark Law Blog
They Invented What? (No.99)
Posted in They Invented What? by Jake Ward on May 14, 2008
U.S. Pat. No. 5,996,127: Wearable device for feeding and observing birds and other flying animals.
I claim:
1. A device for feeding and observing flying animals comprising:
a hat, the hat including a front portion and a rear portion;
a first support mounted on the hat and extending forward of the front portion of the hat; and
a feeder configured to contain food for flying animals mounted on the first support, wherein the flying animals can be observed while they feed.
2. The device of claim 1, wherein the hat is a helmet.
3. The device of claim 1, wherein the hat further comprises a chin strap.
4. The device of claim 1, wherein the hat further comprises a rear strap, for securing the device by engaging a wearer’s clothing.
5. The device of claim 1, wherein the hat further comprises a counterweight capable of counterbalancing a weight of the support and feeder.
6. The device of claim 1, wherein the support comprises a pole.
7. The device of claim 6, wherein the pole is a telescoping pole.
8. The device of claim 6, wherein the pole is removably mounted on the hat.
9. The device of claim 6, wherein the pole further comprises a hook for mounting the feeder on the pole.
10. The device of claim 6, wherein the pole extends about 6 to 18 inches from the hat.
11. The device of claim 1, further including a second and a third support mounted on the hat and extending outward from the hat, a second feeder mounted on the second support, and a third feeder mounted on the third support.
12. The device of claim 11, wherein the first support extends forward from the hat, and the second and third supports are mounted on each side of the first support.
13. The device of claim 12, wherein the second and third supports are disposed at an angle ranging from about 30 to 60.degree. from the first support.
14. The device of claim 1, wherein the feeder is a nectar feeder.
15. The device of claim 1, wherein the feeder is a seed feeder.
16. The device of claim 1, further comprising a receptacle on the hat for attaching auxiliary devices.
17. The device of claim 16, wherein the auxiliary device is a perch apparatus.
18. The device of claim 16, wherein the auxiliary device is an ornament.
19. The device of claim 1, further comprising an optical device mounted on the hat.
20. The device of claim 19, wherein the optical device is selected from the group consisting of a magnifying glass, a camera, and a video camera.
21. The device of claim 1, further comprising a optical device mounted on the support.
23. A device for feeding and observing flying animals comprising:
a hat, including a front portion and a rear portion;
a first pole mounted on the hat and extending forward of the front portion of the hat;
a second pole and a third pole mounted on the hat on each side of the first pole and extending outward from the hat; and
first, second, and third feeders mounted on the first, second, and third poles, respectively, wherein the first pole is positioned so that the first feeder is visible to a wearer of the hat, whereby the flying animals can be observed while they feed.
a helmet with a chin strap;
a first pole mounted on the helmet and extending forward from the helmet, and a second and third poles mounted on the helmet on each side of the first pole and extending outward, wherein the poles have hooks; and
a nectar feeder mounted on each of the first, second, and third poles by the hooks, whereby the flying animals can be observed while they feed.
a hat;
a first telescoping pole mounted on the hat and extending outward from the hat; and
a feeder configured to contain food for flying animals mounted on the first telescoping pole, whereby the flying animals can be observed while they feed.
« In Re Bilski En Banc Oral Arguments.
They Invented What? (No. 100) »
Jake Ward said, on May 14, 2019 at 6:22 pm
Reblogged this on Anticipate This!™ | Patent and Trademark Law Blog.
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AAPA Research Poster Award
Linda Brandt Research Award
Linda Brandt Research Award for Physician Assistant Postgraduate Training
ANNOUNCEMENT AND CALL FOR PROPOSALS
Linda Brandt was one of the founding members the APPAP and served as its first president. Although not a PA herself, she was a driving force for PA post-graduate education. She was Director of the PA Surgical Residency at Norwalk Hospital /Yale University School of Medicine and a founding member of the Society for the Preservation of Physician Assistant History. She is remembered by her colleagues for her passion and tireless devotion to PA post-graduate education. She continuously fostered the professional development of hundreds of PA residents and contributed to the education of thousands of PA students from all over the country. Linda lost her battle with cancer in 2004. It is an honor for the APPAP to offer this award in her memory.
The purpose of this initiative is to support research regarding Physician Assistant Postgraduate Training Programs, PA Residents/Fellows and/or Graduates.
ELIGIBLE APPLICANTS
Physician Assistant Post-Graduate Residents
Physician Assistant students who have a research focus on PA Post-Graduate training, impact or outcomes
Other professionals who have a research interest in PA Post-Graduate education, impact or outcomes
APPLICANT EXPECTATIONS
Make a good-faith effort to complete the research project in the allotted time
Present the project at the APPAP annual fall meeting, held in conjunction with the fall PAEA Educational Forum. Applicants are encouraged to submit their research for presentation at the PAEA Educational Forum, AAPA conference or other appropriate venue
Applicants must submit a typed, double-spaced proposal that includes the following sections:
Applicant name, address (postal and e-mail), phone and fax numbers
Abstract (not more than 500 words)
Research Description (not more than 4 pages)
Background and Rationale
Identification and qualifications of key personnel
Expected timeline for completion of the project
CV of Applicant
CV of Mentor(s)*
Mentor Statement of support*
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Adobe announces Lightroom 5.7 with new Aperture and iPhoto importer tool, Black Friday subscription pricing
By AppleInsider Staff
Tuesday, November 18, 2014, 11:21 pm PT (02:21 am ET)
Adobe late Tuesday released an update to its Lightroom image processing and management software that includes a new tool for importing photos from Apple's iPhoto or Aperture, both of which will be discontinued in favor of a unified OS X Photos app in 2015.
The latest Lightroom version 5.7 appears to bundle in an importer tool Adobe first offered last month as a plug-in designed to ease the transition for customers currently using Apple's pro and consumer level editing apps. Apple will introduce OS X Photos as a hybrid prosumer app for OS X Yosemite next year.
Along with the importer tool, Lightroom 5.7 adds the ability to view comments and feedback from shared collections on Lightroom web.
Adobe also announced Adobe Camera Raw 8.7, bringing enhancements to batch processing speed when working with the "Save" button and converting images to DNG using DNG Converter. In addition, ACR now supports HiDPI displays for Windows, an option available under the "Experimental Features" menu.
A total of 24 new cameras have been added to ACR's list of supported RAW file formats, including the iPhone 6, iPhone 6 Plus, Canon EOS 7D Mark II, Nikon D750, and Sony ILCE-5100.
ACR 8.7 also fixes a few bugs discovered in the previous release, including an issue that caused the app to crash when rapidly applying the Spot Removal tool. Another bug squashed prevented the Filter Brush cursor from displaying in certain circumstances. Finally, Camera Matching color profiles have been fixed for the Nikon D810.
As always, Lightroom 5.7 is a free update for existing Lightroom 5 users, while Camera Raw 8.7 is free for Photoshop CC and Photoshop CS6 customers. New customers can download Lightroom as a 30-day free trial, or as part of Adobe's Creative Cloud subscriptions that start at $9.99 per month for the Creative Cloud Photography Plan, which comes with Photoshop, Lightroom mobile and more.
Adobe is also running a Black Friday promotion for Creative Cloud Complete, which includes Photoshop, Illustrator, access to Adobe's cloud, the ProSite portfolio website, Typekit desktop and web fonts and 20 GB of cloud storage for $39.99 per month or $15.99 per month for students and teachers. The promotional period ends Nov. 28.
Mac OS X,
Adobe,
Aperture,
Apple to repurpose Mesa, Ariz. sapphire plant after GT Advanced vacates
Apple pushes holiday gift ideas to shoppers ahead of Black Friday
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Topic: Chris Whitmore
Apple had ample supply of iPad Air, iPhone 5s over holiday weekend, Retina iPad mini was constrained
Apple's most popular products were met with strong demand over the Black Friday shopping weekend, and the company responded with plenty of iPhone 5s and iPad Air units available at its stores, though the new iPad mini with Retina display remains in short supply.
iPhone 5s demand healthy, margins for 5s and 5c higher than iPhone 5, analyst says
Apple's new flagship iPhone 5s and mid-range iPhone 5c contribute more value to Cupertino's profit margins than their predecessor, the iPhone 5, according to one Wall Street analyst.
China Mobile, NTT DoCoMo agreements predicted to drive 35M additional iPhone sales in 2014
If Apple were to reach agreements with carriers China Mobile and NTT DoCoMo to offer the iPhone before the end of the year, it would increase the company's addressable market by about 900 million total subscribers, providing a major boost to sales throughout 2014.
Buying back an additional $50B in stock estimated to boost Apple's 2014 EPS by $4.25
If Apple were to heed the advice of investor Carl Icahn and increase its share buyback program, it could have a quick and significant effect on the company's stock, a new analysis has found.
Wall Street disappointed by indications that Apple won't launch new products until fall
While Apple posted better-than-expected quarterly results and increased its quarterly dividend this week, market watchers are still concerned a lull in new product introductions is likely to continue until this fall.
Earnings preview: Apple expected to report record iPad sales, first shrinking profit in a decade
Expectations are low for Apple's recently concluded March quarter, in which some market watchers believe the company likely saw its first year-over-year profit decline in a decade, despite booming sales of its iPad lineup.
PC gross margins expected to decline as sales shrink, Dell goes private
The struggling PC market is forecast to go from bad to worse, as one analyst believes a number of market factors will push gross margins even lower in the already-cutthroat business.
Apple's current stock price doesn't reflect iOS 'stickiness,' analyst says
While Apple's recent stock woes have been driven by investor concerns over the company's slowing growth, one analyst believes the current stock price does not reflect the "stickiness" that will cause existing customers to stay with Apple.
Earnings call is Apple's opportunity to 'change the tone of the conversation'
Apple is in a position to work some of its "magic" during this week's quarterly earnings conference call, which could erase the negative sentiment that his surrounded the company's stock for months.
Despite having $121B in cash, Apple not expected to issue special dividend
With Apple's cash hoard swelling to more than $120 billion dollars, some investors have begun to hope that the company could issue an additional special dividend to shareholders. However, one analyst says while that decision would be welcome, it's very unlikely to happen.
Chris Whitmore
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All snapshots from host www.theguardian.com
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Breaking: Windows Blue will be a free update named Windows 8.1
162 posts •
twdog
Tribus: NM
Tymanthius wrote:
@twdog: What bad habits? And most ANY interface can "encourage" bad habits. Even CLI
As to those who like the start screen, my issue is it takes more mouse movement to get to items than the start menu/pinned items do.
Granted, if you search, that's pretty quick.
That's the point.
You shouldn't be mousing through a menu, you should search. Take Word, for example. It's dramatically faster to hit Win key then W then it is to mouse through a bunch of menus, or worse hit a desktop shortcut. Even pinned shortcuts aren't as fast as search. The start menu has been pointless even since search was introduced in Vista, but some people just won't let the damn thing go, even though search is far better.
I've done of ton of work with *nix systems, and my biggest complaint about the Windows interface was that it took longer to find a shortcut vs. just typing something on a command line. Win key search goes a long long way to alleviate that problem.
I'm not sure why some people are so emotionally wrapped tied to the start menu, and I've even seen it with "power users" who you'd expect to have been using search for years now. I don't know, maybe it's because they've never used anything besides Windows, whereas other people who use multiple OSs are comfortable with UI changes
Of course, the worst are those people who stick crap on the desktop, but there's no fixing that. Well, maybe if MS made the desktop read only. That's not a bad idea, actually.
macduff
Is it codenamed Windows Blue or Windows Oops We Fucked Up?
konroh
nathand496 wrote:
and the windows key doesn't always work reliably (RDP clients, KVMs, remote console hardware)
... indestructible Model M keyboards. (typing on one now.)
Maybe you know this, but I always like to help out a fellow Model M devotee: ctrl+esc functions as the Windows key.
Ctrl-esc opens the start menu, but does not replace the windows key. Ctrl-Esc-E does not equal WinKey-E
PseudonymAnon wrote:
nehinks wrote:
Looks like this might be the equivalent of the Vista update that actually made that system relatively stable. If it can just outlast the mediocre 8 launch press...
Windows 8 is the most stable OS i have used from Microsoft.
As soon as I installed Windows 8, my PC started locking up regularly.
I was sure that it must be Windows 8 related, but it turned out to be a bad disk.
TheStagesmith
Pen Drive wrote:
I think the whole idea of developing a single OS for Desktops and mobile devices is absurd at the moment. They use different processors and are miles apart in power and in things they are used for. The only winners are the developers.
That's the whole point. Applications are what draw people to a platform, and there are two ways to get developers to write for your platform: have a huge userbase and/or make it easy to develop for your platform. I believe there's a rather famous video of Steve Ballmer emphasizing the value of making your platform attractive to developers.
xsteven77x
Tribus: Pittsburgh, PA
________ wrote:
Blue's News. I used to love that site.
Good move by Microsoft. Improve the product, fix some problems, and make it free. Breaks down barriers to Windows 8 adoption and looks good against the competition.
If they were to break down all the barriers to make Windows 8 decent it would require all of Russia's nuclear arsenal.
The MAGE
Tribus: Florida
Great! What about systems where Microsoft Store is not available? For some reason, my Thinkpad T60 running Windows 8 from a Samsung SSD thinks it's running off a USB stick and it does not allow me to access the store. Not that I need anything from the store - I have deleted or disabled all the Metro applications.
Windows 8.1 "Blue"
Now, will Windows "Blue Screen" be 8.2 or 8.11?
Will it be followed by "Blue Screen of Death" or "Blue Screen for Workgroups"?
dynamo64
I may download an .iso of Windows 8 to use with the 8.1 update to see if I think its worth buying and replacing Windows 7 with. I will say it was noticeably faster than Windows 7.
All things considered, I wonder why the Start menu was replaced with a Start screen? It interrupts the workflow (for those who have a lot going on). Surely, the Start menu could have been optimized for touch devices.
@MAGE: Same here, if I migrate to Windows 8, I will have no use for Metro apps. My i7 desktop deserves a lot more dignity than to be treated like a smartphone or some cheap ARM-esque device.
gbjbaanb
MartinHatch wrote:
So why is this not "Windows 8 SP1"? Did Microsoft just make a decision to start using point updates instead of Service Pack nomenclature?
From what I've read and heard Microsoft wants to move away from major product releases and more into a general evolutionary rollout of improvements (they've said much the same across Windows, Windows Phone and a whole raft of other products like SharePoint and Office).
This is why they don't really want to use things like "SP1" otherwise you get into ridiculous naming conventions (like Server 2008 R2 SP1 ??)
Far easier to just go ..
Windows 9 (next major functional release .. probably paid upgrade
This is how most other software packages work, and allows them to easily ship regular updates (without everyone in Enterprise getting freaked out by the "service pack" name)
Nobody gets freaked out by the words "service pack", they get freaked out by changing functionality contained in an update - and that includes service packs as well as individual hotfixes. So effectively this is just a different way of saying the same thing - 'service pack 1 for windows 8'.
However, I wonder how it will affect the product lifecycle - will MS stop supporting the lower numbers and only support the latest and greatest, or will they keep the old ones security-patched too?
Heavy_D
So, how long before M$ pulls support for 7 to try and force us all on to 8? Just so I can plan to move everything over to Ubuntu (or whatever the distro of the month is by then). /s
Non-sarcastic comment:
Win8 is acceptable for a tablet, but totally unsuitable, barely even usable for a laptop or a desktop PC without 3rd party apps to make it look like 7. I'd still choose Android or even Blackberry over a Win8 tablet. Maybe Windows 9 will fix the problems and actually have it work. That's the track record, every 2nd release is the good one. 98SE was solid, ME was a stinker, XP was great, Vista sucked, 7's fantastic, 8 blows like a wind tunnel, so 9 should be pretty solid.
wjousts
twdog wrote:
I don't care too much what they do with it, just as long as the start menu doesn't come back. I'm glad it's dead; it enabled bad habits.
If by "bad habits" you mean working productively...
DamionW wrote:
maclancer wrote:
Hopefully they make available a free update for Windows Server 2012 which suffer similar issue with not start menu.
Windows 8 and Server 2012 have a start menu like feature.
Just go to the bottom left corner of the screen, the last few pixels. "Start" will pop up, you can either left click for the enlarged Tile Based start menu or right click for a lot of the more useful server options.
Try doing that over a laggy VNC connection.
I think you miss the point. It's easier to search ON THE SAME SCREEN YOU ARE WORKING ON, which is what the start menu lets you do, and the start screen doesn't.
Not to mention that you don't always remember exactly what you are looking for (because it some rarely used tool) and the start menu is much quicker to browse.
nathand496
konroh wrote:
Yes, you're right. I was only thinking about it in the context of the Start menu.
Tribus: Never Knows Best.
Plus the fact that a lot of people are visually oriented and know where and what to click but not necessarily the easiest way to search for something and get what they want. Try explaining to Mom that she needs to hit the windows key and then type in some application name and hope that she types it right when she used to just click on the big red icon on the desktop that she always knew.
Yeah you can replicate that stuff but Microsoft made things needlessly difficult, hard to find and even blew it on the basics of the features that seem nice. The start screen would be pretty great if I could actually search for and find stuff easily. Instead, I have to pop it up, start typing, remember the thing I want is not in the context of where I am searching, go over to the side, change to the settings area and search again there. Oh, there it is, I found it.
wjousts wrote:
And how often do you care about what's on your screen at the very same instance that you're launching a program? I can't think of any instance.
And as for launching a rarely used program, full screen is better because you can see more shortcuts at once.
Goofazoid
Belzebuth wrote:
But will it include a start menu? :-/
Hopefully by then all the nay-sayers will have realized that the Windows 8 start menu is just a full screen Windows 7 start menu.
It does need tweaked in terms of what it's indexing and in what order it presents the results, but those are easily fixed problems.
Aside from those minor issues, the start screen is unequivocally better, and I say this as someone who uses keyboard/mouse exclusively.
Unequivocally better for you, perhaps not so much for me, or someone else.
Bad habits such as?
KitsuneKnight
Paladin wrote:
Plus the fact that a lot of people are visually oriented and know where and what to click but not necessarily the easiest way to search for something and get what they want. Try explaining to Mom that she needs to hit the windows key and then type in some application name and hope that she types it right when she used to just click on the big red icon on the desktop that she always knew.(
Now Mom can press the windows key and see her bigger red icon. No annoying hierarchy of folders you have to open. No need to go minimizing windows.
My only "complaint" with the start screen is you only get 4 rows on a 1366 x 768 screen (I like 5 rows on my smaller 1440 x 900 screen)... but the real problem is that OEMs still sell 1366 x 768 screens. In 2013. It's pathetic how for nearly a decade we've seen a decline in desktop/laptop resolution (only now are we starting to see an increase in the mainstream).
Likewise the other complaint in this thread is really about using a crappy VNC connection... Which isn't the typical user's use case.
Goofazoid wrote:
Mousing through menus instead of searching, outside of edge cases
The start screen impedes hunting for shortcuts with the mouse, and that's a good thing. Forces you to take off the training wheels
My understanding was that the full-screen two-dimensional start screen was chosen in part because it was considered easier to remember where something is in two-dimensions (spatial memory) versus an endless one-dimensional list.
So to say that the new menu is all about search alone is a bit of a misnomer, I think...
pusher robot
Desktop icons are still in Windows 8.
nullifi
Registered: Aug 1, 2009
127.0.0.1 wrote:
For 4 years, I've spent about 13 hours a day with Vista Ultimate x64 16GB (3) 24" monitors. I've always said, "I think I'm the only person on the planet that likes Vista".
And I keep thinking I must be the only person in the universe who actually liked Windows ME
nullifi wrote:
My only complaint with Win8 is the Start Screen. It makes life so much more difficult. Here's an example:
My goal is to launch the Event Viewer under my domain admin credentials.
Hit Start
Type: event viewer
Shift+Right click on the entry
"Run as different user."
Mission accomplished.
Er, right. Hit Win+W (or click "settings") Aha! There it is.. oh wait.. there is no context menu.
Escape to the Start Screen.
Right click and select All Apps
Muddle through until you find event viewer. Nope, still no context menu or any way to do anything with it.
Discover Windows Journal, launch that to look at it later.
Get back on track, right, I needed event viewer.
Open Explorer, go to C:\Windows\System32
Shift+Right click on eventvwr.exe and run as different user.
Mission (finally) accomplished.
Also, creating shortcuts on the desktop (for other people) No more right click and "send to desktop" Now I need to navigate to C:\ProgramData\Microsoft\Windows\Start Menu\Programs. Yeah, that is so much easier.
* Yes, I know one alternative is to either create a shortcut on the desktop, or pin it to the task bar. However, if I pin something (say, powershell) to the taskbar, I can only ever shift+right click to launch it initially. Then the program is already open and I need a shortcut elsewhere to shift+right click on.
Nevarre
But it doesn't force developers do to anything sensible, nor does it address searching for software that's written for legacy UI conventions.
In 7, I'm typically launching from the start bar or icons-- and for rarely-accessed programs or files by using Start+type until the index finds what I'm looking for. What that *doesn't* do is show me an exhaustive list of what's available in edge cases where that's really critical. That's one area where the Start Menu shines-- when it's used successfully as a catalog of what's available to be consulted when necessary.
The Start menu folder may have the core executable, but it might also have additional links to programs for testing, diagnosis, etc-- stuff that I may not need, but have no other way of discovering without hunting through the filesystem and seeing if any of the executables in the application's folder do anything useful.
Productive computing is often done with apps that are complicated or specialized enough to be arcane. This particular method of hinting at additional content below the surface might not be the right one, but it's the one we have-- and the one we're going to have for years with the cost of specialized software. Without that Start Menu folder reference, you're left hoping that the developer named all of their programs consistently enough that you might search successfully...
I don't see that as a bad habit.
I see it as a function of people being visual.
Please tell me how it is faster to search for a program than it is to simply click a program pinned to the task bar, or a shortcut on the desktop?
Edit: BTW, what is this "training wheels" you are talking about? Or is that you just being snide because you feel that you are smarter/more accomplished than people who use things in a different manner than you do?
Last edited by Goofazoid on Tue May 14, 2013 1:25 pm
Captain Riker
I think using a .1 release instead of a Service Pack 1 makes much more sense and their competition does too. Apple releases Mac OSX "insert cat name here" every year and Ubuntu releases the next version of it's 'animal of the year' club. Both tie that naming to a .x release instead of a service pack and both include patches, new features, and tweaks. I think it's about time Microsoft did the same. As long as it's down to one release a year it's fine.
sarusa
BasP wrote:
When was Vista ever unstable?
Vista was ridiculously unstable at launch. Most of that was due to unstable drivers since they completely changed the driver model, but it doesn't really matter why when your stable as hell XP machine is blue screening mutliple times a day.
So as long as you didn't want to use any third party hardware like video cards, sound cards, or network cards, it could be stable. Then you had performance issues (fixed in 7), but at least it could stay up for a reasonable fraction of the time XP SP3 would stay up.
I never used it, but I've gathered that Vista performance was fine as long as you threw enough RAM at it.
My real objection to it was that all the features in it were for Microsoft's benefit, not mine. They had a long list of features they intended for Vista, but when the schedule slipped, almost everything that was actually good for end-users was cut, while everything that was good for Microsoft was retained. So of course it bombed. Win 7 actually gave users tangible benefits, so that version succeeded.
Then 8 is just back to Vista's tricks again -- most of the features in it, Metro in particular, are designed first and foremost to line Microsoft's wallet, not to make your life better. It's the first step toward closing the PC and destroying general purpose computing.
Microsoft inflicting a walled garden on users is particularly galling, because they didn't even make the hardware. It's your hardware, but if you install Windows 8, suddenly Microsoft is in control of whether or not you can run things in Metro mode. Any Metro program has to be approved by Microsoft, and obtained from Microsoft. And they're very clearly willing to use that ability to grant and deny permission for their own competitive advantage.
This is no longer general-purpose computing. This is permission-based computing.
Look around you, virtually speaking. Look at Ars, and the networks that were built to get to Ars, and the network you built at home. And think about all the programs you use every day, especially the huge amount of free software you almost certainly use, whether or not you know you're using it.
And just think to yourself, how much of this would exist if we had had to ask corporations for permission?
That's what Metro is. If you are a technologist, it is an existential threat to your way of life.
LarsFromMars
'Free' is exactly the right price for stuff that was broken/missing/incomplete in Win8. If MS had dared to ask $$ for Blue, chairs would have been thrown...
TheDarkerPhantom
You can also just use the shortcut that exists to open the control panel and search for "even" takes all of 3 steps to launch the control panel applet in question.
Smart people find ways to things quicker and easier, it took at least 6 steps in Windows 7 to launch the event viewer now its 3.
Last edited by TheDarkerPhantom on Tue May 14, 2013 2:03 pm
oldtaku wrote:
I remember Windows Vista RTM even thought it was unstable for some, after my Windows XP installation and my backup installation got corrupted I decided to upgrade, anything was better then BSODs every single time I launch my favorite program at the time.
It seems like you're making it harder than it needs to be, since so far as I know this works:
1. Hit Start
2. Type event
3. Select settings.
4. Hold down Ctrl+Shift, click Event Viewer icon.
Or, if even that is too much:
2. Type eventvwr ctrl+shift+enter
Also, hold down shift or ctrl+shift to launch multiple instances of open taskbar programs.
You can side-load any Modern UI application you create yourself, since you have to get a developer key to create a Modern UI application, you have this ability if you have the need.
Outside of that if you want to install a certain Windows Store application on your network there is also a way to do that.
pusher robot wrote:
At least there is one person who took the time to learn the keyboard shortcuts and actually learned the Windows 8 interface :$
Wolvenmoon
By any chance did you happen to write that post while butt naked? Possibly with a can of beer near your keyboard?
TheDarkerPhantom wrote:
It most certainly did not take 6 steps (as you just quoted):
2: event viewer
3: done.
Regardless, going through the Control Panel as you suggest does not allow me to launch it as a different user.
Mr_Cynical
Does it still turn desktop and laptop PCs into a Fisher Price My First Computer imitation of a tablet? No thanks Microsoft.
jaspercook
I think it's because there's a substantial (?) change to the look/feel of the OS, rather than a bunch of behind-the-scenes fixes.
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Snowden breaks silence to insist he didn’t help foreign agents
Famed leaker tells the NYT his decision to leak was built up gradually.
I wonder which encrypted communications provider will be voluntarily closing their business in about a week.
Arsenicum
What I really want to ask Snowden: Do you regret that because of you misguided hackers everywhere keep confusing NASA with NSA?
Association?
Tribus: Vermont
cgs wrote:
Affiliation.
Bluefinger
Arsenicum wrote:
Well, if it makes you feel better, in the UK, we had people protesting out of the EDF offices (Energy Company) after confusing them for the EDL (English Defense League).
Derps gonna derp.
catfitz40
The Kremlin propagandists are surely hoping everyone will stay focused literally on the laptops and not think about any other way that people can commit espionage, you know, by verbal descriptions about their job duties and office politics and all kinds of details in conversations that they may not even admit are interrogations or are related to the FSB.
Please do tell me, geeks, that when a geek claims he gave "all the files" away that he didn't actually keep a set for himself stashed away, someplace where he knew how to reach it, even if it weren't physically on his person. Remember, all of these hackers loved Julian Assange's invention called "rubberhose", the code that enabled you to have plausible deniability about your encryption.
The laptops might still have the encrypter for the comms on it, or may be merely decoys. It doesn't matter.
What matters is that they once existed, they had the EFF and Tor stickers on them, likely given to Snowden when Greenwald and Poitras came to visit him in his hotel room in Hong Kong -- he proudly displayed them on a laptop in a picture taken by Poitras published in the Guardian at the time.
knbgnu
catfitz40 wrote:
It's actually a good move for his own safety to make sure that he couldn't access the files. You are correct that he may have significant verbal knowledge remaining, but the Russian moles still in the NSA are going to be much better sources for that info.
mevans336
Edward is a coward. He took an oath and then betrayed that oath. To make matters worse, he admits he took positions specifically to violate the trust given to him. He was looking to violate his oath.
Wallslide
Tribus: Fujisawa, Kanagawa
"The decision to take action built up gradually, he said. Snowden's final chose to leak after seeing [...]"
I'm guessing the author meant "Snowden finally chose to leak [...]" or "Snowden's final choice to leak occured after seeing [...]".
Mister_E
Tribus: Thighland
With legislation pending to roll back or overhaul the programs Snowden has revealed, the head of the NSA and his lackey stepping down, James Clapper caught dead-to-rights lying to congress, Obama all but admitting in so many words that Snowden's leaks forced his hand and the realization that both FISA and congressional oversight failed, when is the government that is supposed to represent the people going to call this guy by his real title which is *whistleblower* and drop the trumped up espionage charge?
Some of us, myself included, would go so far as to call him "a hero".
mevans336 wrote:
Snowden is the hero! It would appear that there are many more NSA employees who feel the Constitution was written for everyone else!
robbak
Edward ... took an oath and then betrayed that oath.
No matter what 'oaths' you might take, you always have a greater obligation to justice. Anyone in Snowdon's position had the responsibility to release the information, and all the others are cowards for not doing it. Their cowardice is understandable and justifiable, but cowardice it is.
oath or not oath, as already mentioned, it's about the "shadow governments", the cryptic acronymed agencies within a government who believe they stand above the scrutiny of the public, who pays their salaries with their taxes. Those agencies scream "for the common good/against terrorism" and what-not.
Bottomline is - there is no safety in anything. There's ALWAYS a risk in just living! I see it from this angle, if a large percentage of this worlds population is angry enough to do something immoral/harmful, then they believe because they've been wronged. I think we've come to an age where "those in power" are scared to loose their "power" over their constituents. just 20 years ago, it was easy to manipulate peoples perspectives and opinions because there were only limited ways to propagate information. Today in the age of cellphone journalism and the internet's fast and vast capabilities to spread news destroyed this "information control".
I feel that there's a hardening of fronts happening, between people who "have power" and those who do not. Those with "no power"are having louder and louder cry outs and those "with power" manipulating and exploiting the law-making and law-executing branches/concepts of a government. I can see that things are escalation to very violent points as it is and has happened already in certain region on our world.
I'll stop soapboxing now but I find the nations provicialistic quarreling disgusting - remember, we all sit in the same boat called "Earth" - don't rock it, or we'll go all under. There's no Elysium L5 colony for those "with power", and there's no Federation Of Planets where one can emigrate to.
For me, Snowden is my personal hero right beside George Carlin - unfortunately only the 'educated' and 'technically inclined' (of those who have "no power") realize the scope of his exposures.
Last edited by atlana on Fri Oct 18, 2013 2:27 am
Edward is a coward. He took an oath and then betrayed that oath.
Was that, by any chance, the same oath that Alexander and Clapper took? They're causing a lot more harm to the Constitution and the trust of the American public than any low-level contractor.
But go ahead and focus your sanctimony on Snowden...
PietjePuk75
He added “the system does not work” since “you have to report wrongdoing to those most responsible for it.”
For a "high school drop-out", that's a pretty spot on analyses :-)
Thrownaway
Tribus: Petaluma/Sonoma County (SF Northbay)
dlux wrote:
In addition to that, my understanding is that their oath is to uphold/protect the Constitution, not their human superiors or the individuals currently in charge. On that level, Snowden didn't break his oath -- everyone else in the government aware of the truth that did nothing broke theirs, and the journalists that have helped cover it up or keep the public clueless is no better.
uckTheRIAA
The man is a hero... and I don't care on which watch list I get placed in for saying that.
magnusalpha
Tribus: Portland, OR
"National Security Association" sounds like some kind of fruity Tea Party militia.
It's National Security Agency, but it's not like I think the author doesn't know that. Joe just typed a different word than what he meant.
resthavener
Sounds like Snowden has only told us, the people, what the KGB and Chinese already know. In which case his crime mainly consists of telling the people who pay for all this and have the right to vote for or against it (though, of course, he may not have got it right).
The sad legacy of the Bush and chief side kick Blair era (I'm a Brit and my government is in this too up to their eyeballs) is kidnap, torture, drones killing kids and this mass surveillance. These databases will get misused - to further industrial espionage, to harrass whistleblowers and others speaking too plainly to power and probably by criminals who will hack them or "persuade" the minions to spill the beans. We may save a few lives by moving to the low moral ground and wallowing in this steaming heap - but will the result be the freedom or deomocracy that some of our ancestors purchased at a high price?
daemonios
People break oaths every single day.
It's sad you see this in such black and white terms. Know what? The world isn't a simple place. As he tells it - and we're free to believe it or not - he saw people breaking their own oaths to defend the US Constitution as a matter of course.
In certain cases, you will have to break your oaths to uphold higher values. As your "founding fathers" did when they rebelled against their government. As many Germans did when they secreted Jews out of Germany during WWII. As many whistleblowers do when they denounce injustices that would otherwise go uncorrected.
But it's ok if you find this too hard to understand. Just go about your life with your absolute views and pretend people are either 100% good or 100% evil.
ctbdp
of course Snowden is right ... any organisation of the size of the NSA behaves the same way - anyone being critic - no matter if founded or not - is going to be told to shut up - by the layers of middle management & supervisors.
jimrose
koolraap wrote:
Mumble will not be closing.
justsayno1
atlana wrote:
yes yes yes and yes
Tribus: Nyan Bruno, Califonya
National Security Association
Isn't it the National Security Agency?
CQLanik
robbak wrote:
Indeed, it reminds me of a six-year-old throwing a temper tantrum that he isn't being taken out for ice cream after Mom got in a car accident. "But you promised!!!" Circumstances change.
t1oracle
What basis do we have for trusting any of these statements? You gave nothing to the Russians? Then why is Russia protecting you? Because of their deep concern for the privacy of Americans? You had to lie to get those files and slip out of the country, every part of your plan required lying. How is anyone supposed to know when you are done lying?
The very system you exposed is the one that led us to Osama Bin Laden and continues to find his buddies. Now that it is exposed you expect us to believe that this will have no impact on national security?
I'm sorry Mr. Snowden but I am going to have to be skeptical here. Someone has to be.
Last edited by Guest on Fri Oct 18, 2013 7:53 am
BadassSailor
The US government is a coward. They have a constitution and betrayed that constitution. To make matters worse, they specifically passed laws predicated on the irrational fears they drummed up in the people they are supposed to protect in order to violate the trust the people placed in them. They are looking to violate the constitution.
See, your argument works both ways.
carldjennings
The "coward" is the one who knows it's wrong and doesn't do anything about it.
t1oracle wrote:
But you believe everything the Government/NSA says?
arcite
Tribus: Canuck in Cairo, Egypt
The US reach is long and does not forget. Putin will not be in power forever. Even if it takes decades, Snowden will eventually face justice.... of one kind or another.
ashappar
yeah, but this isnt the place for that. For the most part on public comment threads - hero worship of a kid being used to troll the west is in effect. Details and motivations are irrelevant and are all waved away with feel good phrases about freedom and duty to the public. sounds familiar? governments use the same language.
and whatever (unlikely) fallout occurs against the west for these revelations? All will be pinned on the 'greater good' and 'making a better future' - in that respect, snowden and his handlers are using the same playbook of the orgs they work against.
governments and media orgs are always in struggle. Both for power and relevance. most people get stuck in the hyperbole and dont realize there is actually little to see here besides a game between estates.
Judging from the tone, it looks like you believe Snowden would be facing Mafia-style 'justice.' That's not something we should encourage.
I don't see how you could infer I implied the US would resort to 'mafia justice'. Just a week ago special forces captured the terrorist mastermind in Libya responsible for Embassy bombings in East Africa in 1998. My point is simple, Snowden will be brought to justice, eventually.
The talk about reach and time sounds like something you'd hear in a mafia film. And you can't bring someone to justice if what they did is right unless your definition of justice is similar to that of the mafia.
MoonShark
Tribus: Ars' Lunar Server Room (status: meltdown)
I think the one paragraph from the NYT coverage is worth quoting in full.
James Risen wrote:
“So long as there’s broad support amongst a people, it can be argued there’s a level of legitimacy even to the most invasive and morally wrong program, as it was an informed and willing decision,” [Snowden] said. “However, programs that are implemented in secret, out of public oversight, lack that legitimacy, and that’s a problem. It also represents a dangerous normalization of ‘governing in the dark,’ where decisions with enormous public impact occur without any public input.”
Tribus: Divided Police States Of America
What are you talking about? This surveillance system did not help catch Osama. It was old fashioned detective work and infiltration that found Osama. Do you think he was sending emails and IM'ing people all day? Is this what NSA employees out of work due to the government shutdown do with their free time?
Yes I know the gov is open again, ready to continue their plan to destroy this country.
Edit: I'm giving him the benefit of the doubt because as far as I can tell what he has done has only served to help, and he has not lied. Unlike the government that has been consistently lying to us throughout this mess. I assume everything out of their mouths now is a lie.
Jousle
"I have lost control over the leaks"
He does not have very good arguments. In fact, some countries are already starting to use these leaks as an excuse to implement even more surveillance over the population. More surveillance, regulations and intranets created by governments in the near future, it is quite possible .
And this is not NSA's fault.
Jehos
Tribus: DFW, TX
I don't think you understand what cowardice is.
Whatever you think about his violating the oath he took, it took courage to do so.
jeromeyers2
Tribus: Arizona
daemonios wrote:
Hidden in your well worded response is the very thing you are pointing out. I could be wrong, but I assume that you are anti-NSA. A simplification, obviously, since there may be some NSA things you have no problem with, but in light of the recent revelations, I sense that you implicitly are very against the violations of our constitutional rights. Perhaps it is too black and white for you, too? Perhaps "total information awareness" is actually necessary and will continue to grow in necessity as the next 10 years pass.
My own view is probably more difficult than yours. I actually have no problem with total information awareness. I have a problem with the secret courts and the fact that no one knows. Who knew that "total information awareness" depended on one side being in the dark. That I don't agree with. As far as "search and seizure" and my private effects are concerned, I don't have a big problem if it's an algorithm that's looking electronic information in the case where I understand what it its looking for in spirit (intent to illegally destroy life and property). Of course, then comes up the thorny issue of how the system can/will be abused. I don't have any answers for that. And so my opinion is that until those answers are clear, it probably shouldn't exist.
Seeing things from the other side (because that's important too, if you want to get anywhere other than chest thumping and pacing behind your line looking outward menacingly), I get why "total information awareness" requires one side being in the dark. It's obvious when you assume a combatitive attitude paired with the idea of weaponizing one's infrastructure. You want to CATCH the bad guys, not just prevent them from using your systems against you. They don't want to simply SECURE our networks, they want to make them into TRAPS. And that's what Snowden's blown to shit.
Personally, I'd like to get to the point where information systems do exist that tie together the wealth of information out there (by performing the interesting AI problem of connecting pieces of information into knowledge about a system [namely, the human organism]). But I'd like it to be publicly auditable (by auditable, I don't mean anyone can access anything, but that anyone can mostly see what anyone accesses and certainly when their own info is accessed) and impervious to hacking. Ha. I don't have the answers, either. But what I know is that this sort of thing is coming. It is naive to assume otherwise. It is coming? Ha. It is here. Wake up. Corporations have it and are refining it. Governments have it and are refining it. Criminals either have it or are refining it. And search engines provide it to a certain degree for any everyday Joe and that is being refined too.
We could (and should) build in greater protection for privacy, but that will only go so far. It will put the key pieces of information behind this or that lock and key. The way the game works is that the other side will then zoom out a bit and try to find a different way to get the information that generates value for it. Basically, I think we're looking into a process with a magnifying glass. There may be no end to it. Just a constant give and take of privacy as systems compete to outdo each other.
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'Not about 24': Williams to face Halep in Wimbledon final
Aiken Standard
WIMBLEDON, England — Hours before her Wimbledon semifinal, Serena Williams spent some time deep in thought and arrived at a couple of conclusions.
For one thing, she shouldn't focus too much on trying to raise her Grand Slam title total to 24, a number achieved by just one other player in tennis history. And for
"It's really not about 24 or 23 or 25. It's really just about going out there and giving my best effort, no matter what. No matter what I do, I will always have a great career,"
Williams to face Halep in final
WIMBLEDON, England — Hours before her Wimbledon semifinal, Serena Williams spent some time deep in thought and arrived at a couple of conclusions. For one thing, she...
Columbia Missourian 2019-07-12
‘Not about 24’: Williams to face Halep in Wimbledon final
The Spokesman-Review 2019-07-12
'Not about 24': Williams to face Halep in Wimbledon final (copy)
Times Argus 2019-07-12
Williams to face Halep in Wimbledon final
The Brunswick Times Record 2019-07-12
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Pharrell Williams - Happy (Official Music Video)
J Balvin, Willy William - Mi Gente (Official Video)
LA RESISTENCIA - Entrevista a Iñaki Williams | #LaResistencia 13.05.2019
Robbie Williams - Feel (Official Video)
Venus WIlliams vs Cori Gauff Wimbledon 2019 First Round Highlights
\'Not about 24\': Williams to face Halep in final
WIMBLEDON, England (AP) — Hours before her Wimbledon semifinal, Serena Williams spent some time deep in thought and arrived at a couple of conclusions. For one thing, she shouldn't focus too much on trying to raise her Grand Slam title total to 24, a number achieved by just one other player in tennis history. And for another, she needs to stay calm on the court. With that in...
Serena Williams to face Halep in Wimbledon final
WIMBLEDON, England — Hours before her Wimbledon semifinal, Serena Williams spent some time deep in thought and arrived at a couple of conclusions. For one thing, she shouldn't focus too much on trying to raise her Grand Slam title total to 24, a number achieved by just one other player in tennis history. And for another, she needs to stay calm on the court. With that in mind,...
The Roseburg News-Review
Serena tops Strycova, will face Halep in Wimbledon final
Royal Oak Daily Tribune
Halep last hurdle as Serena eyes 24th Slam
The Associated PressWIMBLEDON (AP) — Hours before her Wimbledon semifinal, Serena Williams spent some time deep in thought and arrived at a couple of conclusions. For one thing, she shouldn’t focus too much on trying to raise her Grand Slam title total to 24, a number achieved by just one other player in tennis history. And for another, she needs to stay calm on the court. With...
The Japan News
Serena Williams to face Simona Halep in Wimbledon final
The Baytown Sun
Match Point: Serena Williams vs Carla Suarez Navarro Wimbledon 2019
This is the official Wimbledon YouTube page. The Championships 2019 will run from 1 July - 14 July. To join the Wimbledon story this year, visit wimbledon.com/mywimbledon SUBSCRIBE to The Wimbledon YouTube Channel: http://www.youtube.com/wimbledon LIKE Wimbledon on Facebook: https://www.facebook.com/Wimbledon FOLLOW Wimbledon on Twitter: https://twitter.com/Wimbledon FOLLOW Wimbledon on Instagram: https://instagram.com/Wimbledon FOLLOW Wimbledon on Snapchat: add Wimbledon VISIT: http://www.wimbledon.com/ ARCHIVE: To license footage, please go to: https://www.imgreplay.com/contact #Wimbledon...
Jason Williams immediately made a mark in the NBA with his flashy style of play. In honor of Throwback Thursday we count down the Top 10 Plays of his career! About the NBA: The NBA is the premier professional basketball league in the United States and Canada. The league is truly global, with games and programming in 215 countries and territories in 47 languages, as well as NBA rosters at the start of the 2013-14 season featuring a record 92 international players from 39 countries and territories. For the 2013-14 season, each of the leagues 30 teams will play 82 regular-season games, followed by a postseason for those that qualify. The NBA consists of the following teams: Atlanta Hawks; Boston Celtics; Brooklyn Nets; Charlotte Bobcats; Chicago Bulls; Cleveland Cavaliers; Dallas Mavericks; Denver Nuggets; Detroit Pistons; Golden State Warriors; Houston Rockets; Indiana Pacers; Los Angeles Clippers; Los Angeles Lakers; Memphis Grizzlies; Miami Heat; Milwaukee Bucks; Minnesota Timberwolves; New Orleans Pelicans; New York Knicks; Oklahoma City Thunder; Orlando Magic; Philadelphia 76ers; Phoenix Suns; Portland Trail Blazers; Sacramento Kings; San Antonio Spurs; Toronto Raptors; Utah Jazz; Washington Wizards. The NBA offers real time access to live regular season NBA games with a subscription to NBA LEAGUE PASS, available globally for TV, broadband, and mobile. Real-time Stats, Scores, Highlights and more are available to fans on web and mobile with NBA Game Time. For more information, as well as all the latest NBA news and highlights, log onto the leagues official websi...
Now available with english subtitles! Le titre \"Ego\" disponible ici: http://apple.co/2yd5BsD - Retrouvez Willy sur ses réseaux sociaux: Facebook: https://www.facebook.com/willywilliamofficiel Twitter: https://twitter.com/willy_william Instagram : http://www.instagram.com/WillyWilliamOfficiel/ - Audio Stream : - Spotify : http://bit.ly/Ego-SPOTIFY - Deezer : http://bit.ly/Ego-DEEZER - Google Play : http://bit.ly/Ego-GOOGLEPLAY - Apple Music : http://bit.ly/Ego-APPLEMUSIC - Napster : http://bit.ly/Ego-NAPSTER...
Get Pharrell\'s album G I R L on iTunes: http://smarturl.it/GIRLitunes Get Pharrell\'s album G I R L on Amazon: http://smarturl.it/GIRLamazonMP3 Follow Pharrell: http://pharrellwilliams.com http://facebook.com/pharrell http://twitter.com/pharrell http://instagram.com/pharrell #PharrellWilliams #Happy #Vevo #Pop #OfficialMusicVideo...
Escucha lo mejor de J Balvin: https://smarturl.it/jbalvinlomejor J BALVIN & WILLY WILLIAM “MI GENTE” https://UMLE.lnk.to/-Rc9DFp Connect with J Balvin: https://www.facebook.com/JBalvinOficial/ https://www.instagram.com/jbalvin/ https://twitter.com/JBALVIN Connect with Willy William: https://www.facebook.com/willywilliamofficiel/ https://www.instagram.com/willywilliamofficiel/ https://twitter.com/willy_william Music video by J. Balvin, Willy William performing Mi Gente. (C) 2017 Scorpio Music Under Exclusive License To Universal Music Latin Entertainment http://vevo.ly/cRfYgm...
La Resistencia 2x126 | Entrevista al delantero del Athletic Club de Bilbao. Suscríbete a /cerotube para tener lo mejor de #0, HAZ CLICK AQUÍ: http://www.youtube.com/channel/UCPgvCUSmHWm2177LkwLtZQw?sub_confirmation=1 Y DESCUBRE MÁS EN: http://www.movistarplus.es/cero...
Pre-order new album Swings Both Ways now: iTunes http://po.st/SBWYT | Amazon http://po.st/SBWAmYT http://www.robbiewilliams.com Follow Robbie: http://www.facebook.com/robbiewilliams http://www.twitter.com/robbiewilliams http://mind.robbiewilliams.com/ Best of Robbie Williams: https://goo.gl/prQ93D Subscribe here: https://goo.gl/LR2EUN #RobbieWilliams #Feel #Vevo...
Cori \"Coco\" Gauff vs Venus Williams at Wimbledon 2019 First Round This is the official Wimbledon YouTube page. The Championships 2019 will run from 1 July - 14 July. To join the Wimbledon story this year, visit wimbledon.com/mywimbledon SUBSCRIBE to The Wimbledon YouTube Channel: http://www.youtube.com/wimbledon LIKE Wimbledon on Facebook: https://www.facebook.com/Wimbledon FOLLOW Wimbledon on Twitter: https://twitter.com/Wimbledon FOLLOW Wimbledon on Instagram: https://instagram.com/Wimbledon FOLLOW Wimbledon on Snapchat: add Wimbledon VISIT: http://www.wimbledon.com/ ARCHIVE: To license footage, please go to: https://www.imgreplay.com/contact...
This is the official Wimbledon YouTube page. The Championships 2019 will run from 1 July - 14 July. To join the Wimbledon story this year, visit wimbledon.com/mywimbledon SUBSCRIBE to The Wimbledon YouTube Channel: http://www.youtube.com/wimbledon LIKE Wimbledon on Facebook: https://www.facebook.c
Jason Williams immediately made a mark in the NBA with his flashy style of play. In honor of Throwback Thursday we count down the Top 10 Plays of his career! About the NBA: The NBA is the premier professional basketball league in the United States and Canada. The league is truly global, with game
Now available with english subtitles! Le titre \"Ego\" disponible ici: http://apple.co/2yd5BsD - Retrouvez Willy sur ses réseaux sociaux: Facebook: https://www.facebook.com/willywilliamofficiel Twitter: https://twitter.com/willy_william Instagram : http://www.instagram.com/WillyWilliamOfficiel/ - Aud
Get Pharrell\'s album G I R L on iTunes: http://smarturl.it/GIRLitunes Get Pharrell\'s album G I R L on Amazon: http://smarturl.it/GIRLamazonMP3 Follow Pharrell: http://pharrellwilliams.com http://facebook.com/pharrell http://twitter.com/pharrell http://instagram.com/pharrell #PharrellWilliams #Ha
Escucha lo mejor de J Balvin: https://smarturl.it/jbalvinlomejor J BALVIN & WILLY WILLIAM “MI GENTE” https://UMLE.lnk.to/-Rc9DFp Connect with J Balvin: https://www.facebook.com/JBalvinOficial/ https://www.instagram.com/jbalvin/ https://twitter.com/JBALVIN Connect with Willy William: https://www.
La Resistencia 2x126 | Entrevista al delantero del Athletic Club de Bilbao. Suscríbete a /cerotube para tener lo mejor de #0, HAZ CLICK AQUÍ: http://www.youtube.com/channel/UCPgvCUSmHWm2177LkwLtZQw?sub_confirmation=1 Y DESCUBRE MÁS EN: http://www.movistarplus.es/cero
Pre-order new album Swings Both Ways now: iTunes http://po.st/SBWYT | Amazon http://po.st/SBWAmYT http://www.robbiewilliams.com Follow Robbie: http://www.facebook.com/robbiewilliams http://www.twitter.com/robbiewilliams http://mind.robbiewilliams.com/ Best of Robbie Williams: https://goo.gl/prQ
Cori \"Coco\" Gauff vs Venus Williams at Wimbledon 2019 First Round This is the official Wimbledon YouTube page. The Championships 2019 will run from 1 July - 14 July. To join the Wimbledon story this year, visit wimbledon.com/mywimbledon SUBSCRIBE to The Wimbledon YouTube Channel: http://www.youtub
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Pivotal Investment Corporation II Announces Pricing of $200 Million Initial Public Offering
The Galveston Daily News
NEW YORK--(BUSINESS WIRE)--Jul 11, 2019--
Pivotal Investment Corporation II (NYSE: PIC.U) (the “ Company ”) announced today that it priced its initial public offering of 20,000,000 units at $10.00 per unit. The units will commence trading July 12, 2019 on the NYSE under the symbol “PIC.U”. Each unit consists of one
Pivotal Investment Corporation II Announces Closing of $230 Million Initial Public Offering
NEW YORK--(BUSINESS WIRE)--Jul 16, 2019-- Pivotal Investment Corporation II (NYSE: PIC.U) (the “ Company ”) announced today that it closed its initial public offering of...
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Churchill Capital Corp II Announces Pricing of $600 Million Initial Public Offering
NEW YORK, June 26, 2019 /PRNewswire/ -- Churchill Capital Corp II (the "Company") announced today the pricing of its initial public offering of 60,000,000 units at $10.00...
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Diamond Eagle Acquisition Corp. Announces the Separate Trading of Its Class A Common Stock and ...
LOS ANGELES--(BUSINESS WIRE)--Jul 1, 2019-- Diamond Eagle Acquisition Corp. (Nasdaq: DEACU) (“Diamond Eagle” or the “Company”) announced that holders of the units sold in...
The Maryville Daily Times 2019-07-01
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Kevin Hart to host 2019 Oscars
Popular comedian and actor Kevin Hart to host 2019 Oscars. He made the announcement via his Instagram page, describing the gig as the “opportunity of a lifetime”.
The actor and comedian – who will take over from presenting duties from chat show host Jimmy Kimmel – confirmed his appointment on Instagram.
“I am so happy to say that the day has finally come for me to host the Oscars. I am blown away simply because this has been a goal on my list for a long time.
“To be able to join the legendary list of hosts that have graced that stage is unbelievable. I know my mom is smiling from ear to ear right now.”
He thanked his family, friends and fans for their support, and signed off his post by promising to “rise to the occasion” and make the ceremony “a special one”.
The 39-year-old began his career in stand-up before moving into TV and film, with recent years having seen him secure roles in a number of high-profile family movies.
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Deji Adeyanju remanded in prison 2nd time in a week
How abandoned torch exposed suspected robber in Katsina
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Power Metal Trio CROSSING ETERNITY New Video “Kingdom Come”; Debut Album “The Rising World” Out Now! via Rockshots Records
· Crossing Eternity (Rockshots Records) · Music News
Montreal, QC – October 18, 2018
Power Metal Trio CROSSING ETERNITY New Video “Kingdom Come”
Debut Album “The Rising World” Out Now! via Rockshots Records
Unleashing their debut album “The Rising World” this past June on Rockshots Records, Romanian/Swedish symphonic power metallers CROSSING ETERNITY have a new lyric video to share with fans for their track “Kingdom Come”, which can be viewed at the following link:
CROSSING ETERNITY‘s “The Rising World” blends elements of modern metal with psychedelic soundscapes alluding to the innocence of the 70s’ rock music. The album contains thirteen epic songs, widely varied in composition and arrangement. The lyrics are a natural extension of this musical experience and they are tales of a spiritual journey. At times they talk about the invisible side of the world, other times they speak of fairy tale magic characters. Human nature and the causal dynamic of human interactions are also among the approached topics.
In regards to recording of the album, singer Berti Barbera says:
“Recording this album was the most challenging vocal experience of my life. It brought back the times me and Manu were playing in a rock band, with all the jokes and high energy. The serious effort made me use a lot of techniques and ways of expression I thought I lost or never use again. This is a great achievement and definitely our best work together in a time I stopped believing in magic. There is something cosmos related in this, it must be. I can’t wait to be on stage with these guys.”
Manu Savu (Guitar/ Bass/ Keyboards) also reflects on the album:
“I wrote the music for this album as an introspective journey, like a confession, a deep soul search, a backward connection, a connection with the almost unseen world of metaphors and symbols, an essential part of our existence. It’s an act of honesty, a musical statement about what we can and cannot see, a story between the tangible and the magical world.”
Album order available on Rockshots Records here.
Music Video – “Ghost Of A Storm” – https://youtu.be/-4cDRo7IxLw
Music Video – “Crossing Eternity” – https://youtu.be/PpL_-a1_7vA
Lyric Video – “High Above The Crown” – https://youtu.be/SzAoXcChqWM
1 – Crossing Eternity (4:22)
2 – Ghost Of A Storm (4:30)
3 – Sand In The Sky (4:35)
4 – High Above The Crown (4:28)
5 – Kingdome Come (4:05)
6 – Embrace Your Voices (3:56)
7 – Journey To The End Of Dreams (4:33)
8 – Winter Poem (4:42)
9 – Haunted (5:17)
10 – Dreams Fall (4:56)
11 – Angles Cry, Rainbows Hide (4:30)
12 – Spirit Of The Forest (3:49)
13 – War Of Gods (4:50)
Album Length: 1:00:49
CROSSING ETERNITY is:
Berti Barbera – Lead Vocal/percussion instruments,
Manu Savu – Guitar/ Bass/ Keyboards
Uffe Tillman – Drums / Percussion
www.Rockshots.eu
http://crossing-eternity.com
https://www.facebook.com/CrossingEternity
https://twitter.com/CrossingEternit
EPK – https://wp.me/pciNW-c0t
The adventure of CROSSING ETERNITY started in the summer of 2017, when guitarist/composer Manu Savu entered the studio with a head full of great song ideas alongside fellow Romanian Berti Barbera, the band’s singer and Swedish Uffe Tillman taking on drum duties. Although the band is brand new, the three passionate, experienced musicians bring 25-30 years of experience across all genres with them. This mix of experience and wide variety of musical influences allows them to create a sound they describe as big, organic, personal, vibrant and honest.
Enjoying the privilege of sharing the stage with big names like Uriah Heep, Ten Years After, Scorpions, Larry Coryell, Blood, Sweat and Tears, the band’s main priority is to expand their boundaries and play worldwide, finding opportunities to make their music known and appreciated in as many countries as possible.
Power Metal Trio CROSSING ETERNITY New Video "Kingdom Come" Debut Album "The Rising World" Out Now! via Rockshots Records
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Glasgow’s ATLAS : EMPIRE Posts 3rd Live Session Video “Hostess” In Support of Canadian Tour April 2019 (ON/QC)
· Atlas : Empire · Music News
For fans of Thrice, Circa Survive, Glassjaw, At The Drive-In
New Album “The Stratosphere Beneath Our Feet” Out Now!
L-R – Robert Hasebe (Bassist), Jamie Sturt (Guitar and Vocals), Steven Gillies (Guitar and Vocals)
Glasgow’s ATLAS : EMPIRE is sharing their third live session video “Hostess” in support of their third Canadian tour this April (dates listed below). The track is off their debut album “The Stratosphere Beneath Our Feet” released this past December.
The video can be viewed at the following link: https://youtu.be/UyAuCYhex1M
Guitarist and vocalist Steven Gillies comments:
“‘Hostess’ is the third and final video from our Papercrane Recordings live session. The song has been a staple of our live set for a long time & was also a single from ‘The Stratosphere Beneath Our Feet’. The song is one of the more complex and proggier tracks on the record, incorporating a lot of time signature changes and different moods throughout its 6ish minutes.”
Weaving their way between the multitudes of different genres that influence them, the trio visits the worlds of heavy progressive rock and expansive ambient shoegaze. Crossing the Atlantic to North America, the proggers will be visiting Canada for their third time since their performances in Ontario in 2017, which included showcasing at Indie Week in Toronto.
Bassist Robert Hasebe adds:
“We are unbelievably excited to cross the Atlantic for our third tour of Canada. This is an important tour for us as we will be touring our brand new album ‘The Stratosphere Beneath Our Feet’. We worked really hard on this record and are elated to share live versions of these songs with our Canadian fans. Touring here is by far one of the most enjoyable things about Atlas : Empire. The unique challenges and rewards of touring this part of the world are what makes Canadian artists and performers truly great. They are not only so wonderful to work with but also so friendly and exceptional at their craft. Canada produces so many good bands and such talented musicians that we are so fortunate and so grateful to be able to tour here regularly. Also, poutine…”
ATLAS : EMPIRE‘s latest album “The Stratosphere Beneath Our Feet” is available for stream and download on Bandcamp, iTunes, and Spotify.
To date the band has released 3 EPs, “To The Astronaut…” (2012); “Somnus” (2013) and “For the Satellites” (2015) with “The Stratosphere Beneath Our Feet” as their 2018 debut full length.
“‘The Stratosphere Beneath Our Feet’ is a concept album that explores what would happen to humanity if we became entirely reliant on technology/automation in every aspect of our lives – and more importantly, what happens when that system fails? Across its 10 tracks, we delve into different aspects of that very-possible future, with each song takes place before, during or after a mass technological collapse, from the perspective of a different ‘character’.”
Music Video – “It’s All In The Reflexes” – https://youtu.be/ueSp6DFIJ4Q
Music Video – “Gethsemane” – https://youtu.be/qQTZKa49OLo
Music Video – “Hostess” – https://youtu.be/SYkm0vN79eE
Remaining Tour Dates:
April 17 – Windsor, ON – The Phog Lounge
April 18 – Toronto, ON – Bovine
April 19 – Montreal, QC – Brasserie Beaubien
April 20 – Ottawa, ON – Pressed
https://atlasempire.co.uk
https://facebook.com/atlasempire
https://twitter.com/atlasempireUK
https://www.instagram.com/atlas_empire
“A lesson in progressive rock” – Rocksound (UK)
“fiery, soaring, and thought-provoking heavy prog-/post-rock” – Rebel Noise
“Atlas : Empire has produced an album that is glued with beautiful instrumental and chill vibes for a weekend unwind. Overall the album is definitely worth a listen if you are a fan of early Incubus, early Thrice, or Minus the Bear.” – Boston Rock Radio
“The band show an impressive versatility throughout the record as they straddle various genres with ease. Post-hardcore sits neatly alongside the Maybeshewill inspired post-rock…” – abadgeoffriendship.com
“They hit you with a wall of sound, that has a slightly Math feel to it. The tracks have a lot of overlapping phrases, but with darker tones to the guitars, it almost feels like Deftones and Arcane Roots had a lovechild and raised it in ‘Bonnie’. Both vocalists lighten the mood and play upon a subtle gaelic charm in between tracks…There’s just the right level of melody combined with guitar-wrecking aggression for them to stand out in the Glasgow scene.” – threesongsandout.com
at the drive in circa survive Glasgow's ATLAS : EMPIRE Posts 3rd Live Session Video "Hostess" In Support of Canadian Tour April 2019 (ON/QC) Glassjaw Thrice
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Home News Asia News Pak Defence Diplomacy Falters on Iran Front
Pak Defence Diplomacy Falters on Iran Front
Iran's incumbent President Hassan Rouhani attending an election campaign in Tehran, Iran (Xinhua/Ahmad Halabisaz) (zcc)
Iran’s interests vis-à-vis Pakistan are different.It is concerned about Sunni terrorist groups like Jundallah and Jaish ul-Adl which have been regularly targeting Iran’s security forces, and Pakistani Shia pilgrims travelling to Iran….writes Dr Sakariya Kareem
Iran’s incumbent President Hassan Rouhani attending an election campaign in Tehran, Iran (Xinhua/Ahmad Halabisaz) (zcc)
Mutuality of interests have nudged Iran and Pakistan to give up the diplomatic stiff collar formally and informally these past few days. Directors General of the two foreign offices met in Islamabad and reviewed the Afghan scene and took stock of regional stability; Iran’s envoy in Pakistan, Medhi Honardoost visited the General Headquarters in Rawalpindi and held long discussions with the Army Chief Gen Bajwa on “regional security, the Pak-Iran border management, visits and exchanges in the defence realm”.
For Bajwa, these talks as also a visit to Tehran are a part of his new found love -‘defence diplomacy’. The outcomes are still shrouded in diplomatic haze. Well, there is no commonality of interest between the two countries. Pakistan is forced to turn to its western neighbour to have a feel of the role Tehran plays in Afghanistan. It also wants to know first-hand the role of India in the war ravaged country since India and Iran are working closely in matters of interest in Afghanistan, particularly transit trade through Chabahar port.
Iran’s interests vis-à-vis Pakistan are different. It is concerned about Sunni terrorist groups like Jundallah andJaish ul-Adl which have been regularly targeting Iran’s security forces, and Pakistani Shia pilgrims travelling to Iran.
Some five months back, Pak –based terrorists had kidnapped one Iranian border guard, Saeed Barati and killed eleven others in an attack near the town of Mirjaveh in the south eastern Iranian province of Sistan-and-Baluchestan.
Defense Minister Brigadier General Hossein Dehqan has gone on record warning that the Islamic Republic reserves the right to give a crushing response to the terrorist crime.
“While we reserve the right to give a firm response to such acts of terror, we call on Pakistani officials to arrest and punish the perpetrators of this crime at the earliest,” he stated.
Major General Mohammad Baqeri, the head of the Iranian armed forces, also declared that they will hit militant ‘safe havens’ inside Pakistan, if Islamabad does not arrest the terrorists and shut down their bases.
“We cannot accept the continuation of this situation,” he has been quoted as saying by state news agency IRNA.
With this warning, Iran has joined the ranks of India and Afghanistan in holding Pakistan guilty of cross-border terrorism. In a manner of speaking, with the US too, since President Donald Trump has also asked Islamabad to close down the safe havens along the Durand Line to establish peace in Afghanistan.
Islamabad and Tehran have also differences over politics in the Middle East; a sore point is the fact that retired Pakistani army chief is heading the Islamic Military Alliance organised by Saudi Arabia for action in Yemen in particular.
Both sides are not allowing these differences to dominate their bilateral agenda, which is more trade and investment oriented.
Gen Qamar Javed Bajwa
Their focus is on “maintaining a trajectory of positive progress” and this follows the pull aside meeting Pakistan Premier Shahid Khaqan Abbasi and Iranian President Hassan Rouhani had during the UN General Assembly session this September.
The positives range from Iran’s electricity supply to Gwadar and other border areas of Pakistan to business in perishable and non-perishable consumer items. Smuggled Iranian petrol has been powering vehicles across Balochistan.
Iran is ready to step up supply of electricity since it has abundant surplus. The offer has been grabbed by Pakistan, which is short of power to light homes and to run factories.
The trade-off Iran expected was a new lease to the much talked gas pipeline project.
As recently as 25 October, the Iranian government has called for revival of the Iran-Pakistan gas pipeline project, a front page by-lined dispatch in the Express Tribune said.
The project has been stalled following persistent pressure from Saudi Arabia and unilateral sanctions imposed by the United States.“The Iranian government has written a letter, seeking to hold talks on issues that have caused delay in executing the project,” a senior government official told The Express Tribune.
This was not the first time for such a communication. A month earlier, in September also Iran conveyed its annoyance at Pakistan backing out of IP Gas pipeline under US and Saudi pressure. Even Chia is annoyed at Pakistan decision because it has spent time and money to be part of the IP venture
What appears to have upset Tehran is the fact that Islamabad has not bothered to convey that it is shelving the pipeline. “Iran was not officially told by Pakistan that the said project is not alive which has also irritated the authorities in Iran”, Khalid Mustafa reported in The News International, a leading Karachi daily, on 28 September.
Muharaam procession, one of the most prominent relgiious events in the Shia calendar, in Karachi
“Iran has come up with its annoyance and reservations about the project in a letter written to the federal minister for petroleum and natural resources who is right now the Prime Minister of Pakistan,” a top energy ministry official familiar with the IP project told the daily. The two countries had entered into gas deal by signing Gas Sales Purchase Agreement (GSPA) under IP project in 2009 when Pakistan Peoples’ Party was in Islamabad’s driver seat. A Chinese company, CPP was engaged to lay the 700 kilometer long LNG pipeline from Gwadar to Nawabshah as a part of IP project. China’s EXIM bank offered 85 per cent of the funding. An agreement was even signed in September last year.
But no progress was made. And a Chinese delegation that visited Pakistan recently tried to revive the shelved project by offering more price concessions. They too drew a blank.
Iran has invested a huge amount in laying pipeline with diameter of 56 inches from Paras gas field up to the border with Pakistan. There is zero progress on the Pakistan end of the pipeline. Iran offered help in laying the pipeline inside Pakistan over a 780km long stretch. There was neither a yes nor a no from Islamabad till date.
Yet, Iran has been more than accommodative of Pakistani concerns particularly over gas price. The Turkmenistan gas to be received through TAPI pipe line is cheaper than the Iranian gas price.So it conveyed willingness to re-negotiate gas price. This is in line with a proviso in the IP deal which states that in the event the buyer (Pakistan) gets gas at a lower price from any other country, the seller (Iran) will make a matching offer.
Pakistan is worried over the penalties it has to pay for the delay in laying the pipeline. Tehran has not yet invoked the penalty clause of the Gas Sales Price Agreement (GSPA); the penalties are due from January 1, 2015since the pipeline should have been laid by December 2014.The project cost was pegged at a hefty$2 billion.
Yet, Pakistan did not bother to send officials to Tehran to renegotiate the Iran gas price after TAPI deal was finalised. “Unfortunately, no delegation from Islamabad went to Tehran for reviewing the gas price downward on account of unknown reasons and this has irked authorities in Iran,” an unidentified source was quoted as saying in The News.
Interestingly, when it came to power in 2013, the Nawaz government saw IP pipeline as a short cut to energy nirvana and adopted innovative strategies to complete it despite US-led sanctions on Iran. It decided to construct $1.6 billion strategic and vital Gwadar-Nawabshah LNG Terminal and Pipeline Project (GNGP). Under this project, 700 kilometers LNG pipeline was to be constructed from Nawabshah to Gwadar.
Iran was told LNG pipeline would be funded by China and that once the sanctions were lifted, the pipeline would be extended backward to Iran from Gwadar. That would be the stage for the pipeline to be rechristened as Iran-Pakistan gas pipeline. Impressed by the argument, Iran did not invoke the penalty clause to the great relief of Pakistan.
Iran-Pakistan (IP) pipeline was originally conceived as a three nation venture including India. I-P-I line did not take off due to India’s security concerns as the line was to be laid through trouble torn Baluchistan. Now Pakistan has backed out without offering any valid ground formally. Well, Iran has reasons to be upset with Pakistan.
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Audiobooks > Romance > Paranormal > Into the Fire: A Night Prince Novel
Download Into the Fire: A Night Prince Novel Audiobook
Author: Jeaniene Frost Narrator: Tavia Gilbert Publisher: HarperCollins Format: Unabridged Audiobook Delivery: Instant Download Audio Length: 9.25 hours Series: The Night Prince Series Release Date: February 2017 ISBN: 9780062129468
In the explosive finale to New York Times bestselling author Jeaniene Frost’s Night Prince series, Vlad is in danger of losing his bride to an enemy whose powers might prove greater than the Prince of Vampires’ . . .In the wrong hands, love can be a deadly weapon
For nearly six hundred years, Vlad Tepesh cared for nothing, so he had nothing to lose. His brutal reputation ensured that all but the most foolhardy stayed away. Now, falling in love with Leila has put him at the mercy of his passions. And one adversary has found a devastating way to use Vlad’s new bride against him.
A powerful spell links Leila to the necromancer Mircea. If he suffers or dies, so does she. Magic is forbidden to vampires, so Vlad and Leila enlist an unlikely guide as they search for a way to break the spell. But an ancient enemy lies in wait, capable of turning Vlad and Leila’s closest friends against them . . . and finally tearing the lovers apart forever.
“Narrator Tavia Gilbert’s voice seduces the listener into a dangerous fantasy world of vampires whose relationships include love, hate, and all-out vengeance…Gilbert’s vocal variations balance the masculine strength of Vlad and the feminine yet strong aspects of his new wife…Gilbert’s raspy timbre amplifies the book’s spookiness, enriching the listening experience. This is fantasy at its best. Listening to the series in order is recommended so as not to miss any of its creepy, dark elements.”
AudioFile
“The courtship of Vlad and Leila has never been easy or tame, which means it sure has been exciting to follow. In this closing chapter they face their most difficult challenge yet and one that will test the limits of their love. This book also has the bonus of showcasing that scoundrel vampire Ian, which is entertaining to say the least. Fans of this author and this series will not be disappointed, so hang on and enjoy this emotionally powerful ride!”
RT Book Reviews (4½ stars, Top Pick!)
“[An] enjoyable read that wraps up loose ends and sets up new stories in Frost’s paranormal world.”
Jeaniene Frost, New York Times and USA Today bestselling author, lives with her husband and their very spoiled dog in Florida. Although not a vampire herself, she confesses to having pale skin, wearing a lot of black, and sleeping in late whenever possible. And while she can’t see ghosts, she loves to walk through old cemeteries. She also loves poetry and animals but fears children and hates to cook.
Tavia Gilbert is an acclaimed narrator of more than four hundred full-cast and multivoice audiobooks for virtually every publisher in the industry. Named the 2018 Voice of Choice by Booklist magazine, she is also an Audie Award nominee and the recipient of numerous Earphones Awards, a Voice Arts Award, and a Listen-Up Award. With frequent inclusion on best of year and annual top ten lists, she is a trusted and increasingly sought-after actress for work across every genre, from children’s and YA, to literary fiction, nonfiction, and genre fiction. Audible has named her a Genre-Defining Narrator: Master of Memoir, and Library Journal said of her, “as close as you can get to a full-cast narration with a solo voice.” She is a producer, singer, photographer, and a writer, as well as the cofounder of a feminist publishing company, Animal Mineral, with fiction and nonfiction focusing on relationships, love, and identity.
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Audiobooks > Juvenile Fiction > Animals > Splat the Cat: On with the Show
Download Splat the Cat: On with the Show Audiobook
Author: Rob Scotton Narrator: Dan Bittner Publisher: HarperCollins Format: Unabridged Audiobook Delivery: Instant Download Audio Length: 0 hours and 05 min. Release Date: April 2013 ISBN: 9780062282552
FlexPass Price: $9.95$7.95$7.95 for new members!
Splat the Cat can't wait to be in his school play about castles and kings and queens—maybe he'll even get to play a knight! Will Splat find a way to steal the show? Join him and his classmates for another hilarious Splat the Cat adventure!
axmr
Rob Scotton is the bestselling author and illustrator of Russell the Sheep; Russell and the Lost Treasure; Russell’s Christmas Magic; Splat the Cat; Love, Splat; Merry Christmas, Splat; Scaredy-Cat, Splat!; Splish, Splash, Splat!; and Secret Agent Splat!, among other books. His work can also be found on greeting cards, ceramics, textiles, prints, stationery, and glassware. An honors graduate of Leicester Polytechnic, Rob now lives in Rutland, England, with his wife, Liz, who is also an artist.
Dan Bittner is an actor and voice talent and winner of several AudioFile Earphones Awards for audio narration. He has starred on stage and on the screen, in movies such as Men in Black, Adventureland, and the Producers: The Movie Musical. He has also appeared onstage as Macbeth and Sherlock Holmes in the Edinburgh Fringe Festival.
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Author: Émile Zola; Leonard W. Tancock (Introduction by, Translator)
Publisher : Penguin Publishing Group
Imprint : Penguin Publishing Group
Publication date : November 1954
Dimensions : .82 Inches X 5.5 Inches X 8.25 Inches
Author : Émile Zola; Leonard W. Tancock (Introduction by, Translator)
Series : Classics Ser.
Dewey classification : FIC
A paperback copy in very good condition.
Zola's masterpiece of working life, Germinal (1885), exposes the inhuman conditions of miners in northern France in the 1860s. By Zola's death in 1902 it had come to symbolise the call for freedom from oppression so forcefully that the crowd which gathered at his State funeral chanted'Germinal! Germinal!'.The central figure, Etienne Lantier, is an outsider who enters the community and eventually leads his fellow-miners in a strike protesting against pay-cuts - a strike which becomes a losing battle against starvation, repression, and sabotage. Yet despite all the violence and disillusion which rockthe mining community to its foundations, Lantier retains his belief in the ultimate germination of a new society, leading to a better world.Germinal is a dramatic novel of working life and everyday relationships, but it is also a complex novel of ideas, given fresh vigour and power in this new translation.
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Category Archives: Elections
Trump Still Stands
Posted on April 11, 2019 by libertas
From VDH:
Right after the 2016 election, Green Party candidate Jill Stein—cheered on by Hillary Clinton dead-enders—sued in three states to recount votes and thereby overturn Donald Trump’s victory in the Electoral College. Before the quixotic effort imploded, Stein was praised as an iconic progressive social justice warrior who might stop the hated Trump from even entering the White House.
When that did not work, B-list Hollywood celebrities mobilized, with television and radio commercials, to shame electors in Trump-won states into not voting for the president-elect during the official Electoral College balloting in December 2016. Their idea was that select morally superior electors should reject their constitutional directives and throw the election into the House of Representatives where even more morally superior NeverTrump Republicans might join with even much more morally superior Democrats to find the perfect morally superior NeverTrump alternative.
When that did not work, more than 60 Democratic House members voted to bring up Trump’s impeachment for vote. Trump had only been in office a few weeks. Then San Francisco billionaire Tom Steyer toured the country and lavished millions on advertisements demanding Trump’s removal by impeachment—and was sorely disappointed when he discovered that billion-dollar-fueled virtue-signaling proved utterly bankrupt virtue-signaling.
When that did not work, celebrities and politicians hit social media and the airwaves to so demonize Trump that culturally it would become taboo even to voice prior support for the elected president. Their chief tool was a strange new sort of presidential assassination chic, as Madonna, David Crosby, Robert de Niro, Johnny Depp, Snoop Dogg, Peter Fonda, Kathy Griffin, and a host of others linguistically vied with one another in finding the most appropriately violent end of Trump—blowing him up, burning him up, beating him up, shooting him up, caging him up, or decapitating him. Apparently, the aim—aside from careerist chest-thumping among the entertainment elite—was to lower the bar of Trump disparagement and insidiously delegitimize his presidency.
When that did not work, during the president’s first year in office, the Democrats and the media at various times sought to invoke the 25th Amendment, claiming Trump was so mentally or physically impaired that he was not able to carry out the duties of president. At one point, congressional Democrats called Yale University psychiatrist Dr. Bandy X. Lee to testify that Trump was unfit to continue. In fact, to prove her credentials, Lee edited The Dangerous Case of Donald Trump that offered arguments from 27 psychiatrists and other mental health experts. In May 2017, acting FBI Director Andrew McCabe and Deputy Attorney General Rod Rosenstein met secretly in efforts to poll Trump cabinet members to discover whether they could find a majority to remove Trump from office—again on grounds that he was mentally unbalanced. According to McCabe, Rosenstein offered to wear a wire, in some sort of bizarre comic coup attempt to catch Trump off-guard in a confidential conversation.
When that did not work, 200 congressional Democrats in late 2018 sued in federal court to remove President Trump, claiming he had violated the esoteric Emoluments Clause of the Constitution that forbids federal officials from taking gifts, jobs, and titles from foreign governments. They alleged Trump’s presidency has enhanced his overseas real estate holdings and interests. Yet, according to some sources, the various Trump companies have lost some $1 billion in value after he took office—to the delight of the same critics who swore he has profited enormously as president.
When that did not work, the ongoing “Resistance” both covertly and overtly sought ways to retard or destroy the Trump presidency—often by leaking presidential memos, conversations, and phone calls. An anonymous op-ed published in the New York Times on September 15, 2018 boasted of a plan of resistance to his governance and initiatives from those in the administrative state from inside the Trump Administration, most of them allegedly establishment Republicans.
When that did not work, progressive heartthrob lawyer and now indicted Michael Avenatti reintroduced pornographic film star Stormy Daniels to the public. He claimed that Daniels had somehow been tricked into signing a supposedly improper and now invalid non-disclosure agreement not to talk about an alleged sexual encounter of a decade earlier with private citizen Trump in an exchange for a payment of $135,000.
Allegedly, Trump’s acquiescence to Daniels’ veritable blackmail demands had now impaired her own opportunities of further profiting to a far greater degree from the past alleged tryst with a now President Trump. Until his recent indictment for a number of felonies, Avenatti himself had translated his work with Daniels into media celebrity-hood, appearing over 100 times on cable news shows to damn Trump, predict his impeachment, and prep his promised 2020 presidential run against Trump.
When that did not work, federal law enforcement officials stormed the offices of Trump lawyer Michael Cohen, in search of incriminating materials. Cohen quickly was leveraged by federal attorneys, flipped, and offered anti-Trump testimonies and documents in exchange for leniency. He produced stealth tapes of private conversations with his own client Trump—and shortly afterward was disbarred by the New York State Supreme Court for pleading guilty to a series of felonies.
When that did not work, Russian collusion hysteria continued to sweep the country. The moribund phony Steele dossier (that had failed to derail the Trump campaign and transition) was reignited by the media and progressive politicos after the firing of FBI director James Comey, leading to the recusal of Attorney General Jeff Sessions, and the emergence of Deputy Attorney General Rosenstein.
Rosenstein then appointed Robert Mueller as special counsel—in a series of events prompted by none other than fired James Comey, who admitted that he illegally leaked confidential, if not some classified, presidential memos to create the conditions necessary for such a special appointment. Mueller’s subsequent media darling attorneys—praised as the “dream team,” “all-stars,” “army,” “untouchables,” and “hunter-killer team”—of mostly Democratic partisans, some Clinton donors, and a few who had defended either the Clinton Foundation or Clinton aides then spent 22 months, and between $30-40 million trying to build a case. In the end, they leveraged mostly minor Trump satellites on process crimes, misleading testimonies, or past business deals in hopes of finding collusionary guilt. Leaking was a Mueller team trademark as each week the collusionary media announced another “bombshell” or “noose tightening” around the neck of Donald Trump—or mysteriously showed up at the home of the next Mueller victim, to wait for the arrival of SWAT teams to swoop into make an arrest.
When that did not work, congressional committees and the left-wing mob next went after William Barr, Trump’s “hand-picked” attorney general (are not all AGs “hand-picked” by the president?). Barr’s crime was that he had followed the law to the letter. And so Barr spent a few days after the arrival of the exonerating Mueller collusion report to ensure first, before releasing it to the public, that it did not endanger national security or besmirch the reputations of innocent named individuals. If in a blink, “collusion” had died, soon in its death throes it birthed “obstruction”—as if Trump’s objections to vast resources wasted on chasing an imaginary non-crime of collusion was obstruction
When that did not work, congressional committees mobilized to sue and force Trump to release at least six years of his private income tax records, elements of which already in bits and pieces had been leaked.
Are such efforts in the future to be institutionalized?
Will the Left nod and keep still, if Republicans attempt to remove an elected Democratic President before his tenure is up? Are appeals to impeachment, the 25th Amendment, the Emoluments Clause, the Logan Act, and a Special Counsel the now normal cargo of political opposition to any future elected president?
Is it now permissible in 2020 for Trump’s FBI director to insert an informant into the campaign of the Democratic presidential nominee? If Joe Biden is the 2020 nominee, will the Trump Justice Department seek FISA warrants to monitor the communications of Biden’s campaign team—in worries that Biden son’s business practices in the Ukraine had earlier compromised Biden who had intervened on his behalf by threatening to cut off aid to Ukraine? Will they investigate Biden’s propensity to hug and kiss under-aged girls? Will Trump’s CIA director contact foreign nationals to aid in spying on Biden’s aides? Will National Security Advisor John Bolton request that the names of surveilled Biden campaign officials become unmasked as a way of having them leaked to the media? Will Trump hire a British ex-spy to gather together rumors and gossip about Biden’s previous overseas trips and foreign contacts, especially in the Ukraine, and then see them seeded among the Trump CIA, FBI, Justice Department, and State Department? Is that the sort of country we have now?
America over the last half century had been nursed on the dogma that the Left was the guarantor of civil liberties. That was the old message of the battles supposedly waged on our behalf by the ACLU, the free-speech areas on campuses, and the Earl Warren Court.
Not now. The left believes that almost any means necessary, extra-legal and anti-constitutional or not, are justified to achieve their noble ends. Progressive luminaries at CNN and the New York Times have lectured us that reporters need not be disinterested any more in the age of Trump—or that it might be a crime to shout “lock her up” at a Trump rally. Will those standards apply to coverage of future Democratic presidents?
No reporter seems to care that Hillary Clinton hired a foreign national to work with other foreign nationals to sabotage, first, her opponent’s campaign, then his transition and his presidency, along with the wink and nod help from key Obama officials at the Department of Justice, State Department, National Security Council, FBI and CIA.
The final irony? If the CIA, FBI, and DOJ have gone the banana republic way of Lois Lerner’s IRS and shredded the Constitution, they still failed to remove Donald Trump.
Trump still stands. In Nietzschean fashion what did not kill him apparently only made him stronger.
Posted in Donald Trump, Mueller Investigation, Russia Collusion | Leave a comment
The Folly of the Mueller Investigation
Posted on April 5, 2019 by libertas
A great synopsis of the Mueller investigation by former federal prosecutor Andrew McCarthy.
Posted in Donald Trump, Mueller Investigation, Robert Mueller, Rod Rosenstein, Russia Collusion | Leave a comment
Posted in Ballot Propositions, Elections | Tagged Tom McClintock | Leave a comment
They Know So Many Things That Aren’t True
Posted on August 4, 2018 by libertas
Posted in Leftism, Progressivism, UC Berkeley, Voter ID | Tagged Ami Horowitz | Leave a comment
A Russian Ham Sandwich
Posted on July 16, 2018 by libertas
From Derek Hunter:
If there’s one thing Special Counsel Robert Mueller is exceedingly good at it is indicting Russians over whom he has zero jurisdiction. Mueller had previously indicted 13 Russian individuals and companies, and Friday he added 12 more to the list.
It’s a neat little trick – bring charges against people you’ll never get in court, therefore you’ll never have to prove them. This allows Mueller and his team to say they’re “doing something,” that the American people are getting something for the millions his investigation has cost us, while not having to actually prove anything.
Maybe there is something to these charges. I don’t know, and to be honest, I don’t care. I do know the old saying that a prosecutor could indict a ham sandwich, proving those charges are something else entirely.
What the Russians are alleged to have done amounts to nothing – Facebook posts, fake social media accounts, etc. It’s nothing 12-year-olds couldn’t do, and likely do regularly.
The one thing they are alleged to have done that is serious is hacking the servers of the Democratic National Committee. That’s a serious charge. It’s also completely unprovable, which makes it a brilliant political move by Mueller.
It’s a serious charge. But if any of the people charged with doing it were to show up in court, which is highly unlikely, their lawyers would demand to see the DNC’s servers so they could have their experts examine them. Mueller says Russians hacked them, but the servers have magically disappeared. So how can anyone be certain who hacked them, or if they were even really hacked at all?
Since none of those charged are going to show up in court, there will be no challenge to the allegation, no demand to see the evidence, and no legal embarrassment for Mueller when the charges are dropped because the key piece of evidence not only can’t be provided to the defense, it wasn’t even examined by the prosecutor. He appears to have simply taken the word of the Democratic Party about what happened.
Democrats, naturally, have a vested interest in advancing a story of Russian hacking costing Hillary Clinton the election because the alternative is she was a horrible candidate, the American people wanted nothing to do with her or her ideas, and they ran an awful campaign.
The fact that their “hacked” server disappeared should be a red flag. It’d be like someone claiming they cleaned up a murder scene they stumbled across before calling the police because they’re a neat freak, not because they’re trying to cover up their guilt.
This “problem” with the server having vanished won’t be an issue because there’s no one to make it an issue. But there are plenty of people willing to exploit the charges because this is Washington, and Washington doesn’t need proof or have standards when there is a narrative or an agenda to advance.
And let’s not forget that John Podesta’s email password was “password,” and he gave it to a hacker by falling for a fishing email. Not exactly James Bond-level spying.
Elected Democrats immediately started whining about how President Trump should cancel his planned meeting with Vladimir Putin Monday.
Democrat Senator Elizabeth Warren, the proud chieftain of the “so white she’s almost translucent” tribe, told the President to “cancel your ridiculous Putin summit and get your butt on a plane back to the United States.” Kamala Harris of California, whose record in the Senate makes Barack Obama’s look like it was riddled with accomplishments, said, “It’s unconscionable for the President to meet one-on-one with Putin, especially given these latest indictments. We need to prevent the next attack, not reward the attackers.”
And that’s just a sampling of the liberal brain trust considered leading contenders for their party’s 2020 nomination.
I don’t know what’s going to happen with the Mueller investigation, but I do know what is being portrayed as a major development really isn’t. I also know that the idea that politics stops at the water’s edge is now dead. Liberals so hate Donald Trump they’re willing to do anything in an attempt to damage him.
Prepare for more hyperventilating about Russians from leftists than there was during the Cold War, when they actually were trying to destroy us. But keep this in mind – Democrats are now clamoring for “something” to be done to protect our elections in the future. OK, fine.
But first remember no votes were changed, and nothing related to voting or vote counting was “hacked,” even though Democrats and media like to fudge that fact. Second, if you want to protect the integrity of the election bring back paper ballots and require photo ID.
Computer voting started after Democrats claimed paper ballots were flawed after they lost in 2000. After Hillary lost they went in the opposite direction. Their real problem is the American people not wanting them in the White House, because their complaints disappear when they win.
Liberals love to talk about the importance of the integrity of the vote, but they aren’t willing to do literally the least they could do to protect it by requiring people to prove they are who they say they are when they show up at the polls.
Instead of something that will matter, we will get posturing about the need to regulate the Internet to “protect” people from fake stories planted by Russians. Not mentioned will be the fact that, if the allegations are true, all they did was exposed to the voting public things Democrats were saying to each other when they thought no one else was listening. That’s bad, that’s illegal, but that’s not fake.
Exactly how you control what is shared on the Internet will remain a mystery. The people who demand illegal aliens are imbued with Constitutional protections the second they sneak across the border will have difficulty arguing to control what actual Americans protected by that same document can read and share online.
In the end, this will likely amount to nothing. There are show trials and show indictments. What happened Friday appears to be the latter, especially since there will never be a trial. But there sure will be a lot of campaign commercials…
Funny how that works.
Posted in Democrats, Elizabeth Warren, Robert Mueller, Russia Collusion | Tagged Derek Hunter | Leave a comment
Election Therapy Guide for Leftists
Posted on December 2, 2016 by libertas
From Kevin Dowd:
Donald Trump pulled off one of the greatest political feats in modern history by defeating Hillary Clinton and the vaunted Clinton machine.
The election was a complete repudiation of Barack Obama: his fantasy world of political correctness, the politicization of the Justice Department and the I.R.S., an out-of-control E.P.A., his neutering of the military, his nonsupport of the police and his fixation on things like transgender bathrooms. Since he became president, his party has lost 63 House seats, 10 Senate seats and 14 governorships.
The country had signaled strongly in the last two midterms that they were not happy. The Dems’ answer was to give them more of the same from a person they did not like or trust.
Preaching — and pandering — with a message of inclusion, the Democrats have instead become a party where incivility and bad manners are taken for granted, rudeness is routine, religion is mocked and there is absolutely no respect for a differing opinion. This did not go down well in the Midwest, where Trump flipped three blue states and 44 electoral votes.
The rudeness reached its peak when Vice President-elect Mike Pence was booed by attendees of “Hamilton” and then pompously lectured by the cast. This may play well with the New York theater crowd but is considered boorish and unacceptable by those of us taught to respect the office of the president and vice president, if not the occupants.
Here is a short primer for the young protesters. If your preferred candidate loses, there is no need for mass hysteria, canceled midterms, safe spaces, crying rooms or group primal screams. You might understand this better if you had not received participation trophies, undeserved grades to protect your feelings or even if you had a proper understanding of civics. The Democrats are now crying that Hillary had more popular votes. That can be her participation trophy.
If any of my sons had told me they were too distraught over a national election to take an exam, I would have brought them home the next day, fearful of the instruction they were receiving. Not one of the top 50 colleges mandate one semester of Western Civilization. Maybe they should rethink that.
Mr. Trump received over 62 million votes, not all of them cast by homophobes, Islamaphobes, racists, sexists, misogynists or any other “ists.” I would caution Trump deniers that all of the crying and whining is not good preparation for the coming storm. The liberal media, both print and electronic, has lost all credibility. I am reasonably sure that none of the mainstream print media had stories prepared for a Trump victory. I watched the networks and cable stations in their midnight meltdown — embodied by Rachel Maddow explaining to viewers that they were not having a “terrible, terrible dream” and that they had not died and “gone to hell.”
The media’s criticism of Trump’s high-level picks as “not diverse enough” or “too white and male” — a day before he named two women and offered a cabinet position to an African-American — magnified this fact.
Here is a final word to my Democratic friends. The election is over. There will not be a do-over. So let me bid farewell to Al Sharpton, Ben Rhodes and the Clintons. Note to Cher, Barbra, Amy Schumer and Lena Dunham: Your plane is waiting. And to Jon Stewart, who talked about moving to another planet: Your spaceship is waiting. To Bruce Springsteen, Jay Z, Beyoncé and Katy Perry, thanks for the free concerts. And finally, to all the foreign countries that contributed to the Clinton Foundation, there will not be a payoff or a rebate.
As Eddie Murphy so eloquently stated in the movie “48 Hrs.”: “There’s a new sheriff in town.” And he is going to be here for 1,461 days. Merry Christmas.
Posted in 2016 Presidential Election, Barack Obama, Democrats, Donald Trump, Elections, Hillary Clinton | Leave a comment
Stay home, you pathetic whining maggots!
Posted on November 20, 2016 by libertas
Apropos to today, here is Calgary Sun columnist Ian Robinson from November 2004:
Anyway, the day after the U.S. election, 115,628 Americans checked out the [Canadian immigration] site and those numbers haven’t fallen off very much.
Before the election, some U.S. celebrities and numerous other Democrats vowed that they’d move to Canada if Bush were re-elected.
I hope I’m not alone in gently suggesting to those considering coming to Canada: Stay home, you pathetic whining maggots.
Particularly celebrities. Canada has suffered enough without having to put up with any of the Baldwin brothers or — heaven forfend! — Barbra Streisand.
And frankly, I don’t know if we can afford to feed Michael Moore.
Posted in 2016 Presidential Election, Democrats, Elections | Tagged Ian Robinson | Leave a comment
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Revolts and Warrior Maidens
November 20, 2015 Bernard Lee MusicLeave a comment
Everyone, perhaps, knows Vltava, the second and most often heard separately of the six nationalistic symphonic poems that make up Smetana’s Má vlast – My homeland, but what about the one that follows it, Šárka?
Sounds a bit scary, you say. She was!
A female warrior in Bohemian legend, she first appears in 12th century Czech literature in connection with The Maidens’ War which was ignited by the actions of Přemysl, the husband of Libuše after her death.
Libuše, the successor of one, Krok, who had ruled over most of Bohemia, was the fabled foundress of Prague – she was also the subject of a superb grand Festive Opera by Smetana!
However, one of her chambermaids, Vlasta, took exception to Přemysl’s decrees and led a revolt of women against him, which is where Smetana’s scenario takes up the story.
Šárka, a close confidant of Vlasta, had herself tied to a tree to trap a band of armed men led by Ctirad. She claims that rebel maidens tied her to the tree when they find her and placed a jug of mead and a horn out of reach to taunt her.
Ctirad instantly falls in love with her and she pours the mead as a thank-you to the men who drink it unaware that it is drugged. When they are out to the world, Šárka blows the horn and the maidens come out of hiding to join her in killing the men.
Smetana, the founding father of Czech nationalism in music, not Dvořák as some say, wrote the symphonic poems between 1874 (Šárka in 1875) and 1879 against a growing background of nationalist awareness and desire to rid Bohemia of its pervasive German dominance.
They succeeded, only to be invaded by the same country in 1938 and Prague occupied by Nazis from March 1939 – cue the astonishing patriotic resonance of Má vlast!
On the 5th of June that year, the legendary Václav Talich conducted the Czech Philharmonic Orchestra in a live broadcast performance from the Prague National Theatre of Smetana’s cycle.
The audience greeted each tone poem with a rapturous, shouting ovation and then burst into singing the Czech National anthem at the end!
Another great Czech conductor, Rafael Kubelik left Prague and the country for good in 1948 when the Soviet Union moved in.
An ailing, semi-retired Kubelik returned 42 years later following the ‘Velvet Revolution’ to open the 1990 Prague Festival on the 12th of May with the Czech Philharmonic.
Do you need telling what it was he conducted!?
Smetana’s Šárka from Má vlast is performed by the Prague Symphony Orchestra at the City Hall this coming Thursday.
‘The Swedish Mozart’
Review: Prague Symphony Orchestra
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Bremont History: Luxury Mechanical Watches With An Adventurous Streak
Bremont History: Luxury Mechanical Watches With An Adventurous StreakPaul Anthony2018-06-12T23:37:21-04:00
Image: Bremont
Bremont is a British newcomer to the luxury watch scene, founded by aviator brothers Nick and Giles English in 2002.
Due to their aviation background, they focus on meticulously crafted, exceptionally durable chronometers fit for military aviation. Therefore, many of the company’s watch series are only available to select groups of pilots, for example, from specific squadrons.
Bremont watches seek to suit the discriminating tastes and lifestyles of daring individuals: pilots, sailors, and explorers.
This article covers the young manufacture’s brief yet meteoric rise to popularity. Click the links below to jump ahead, or keep reading:
Bremont’s Origins And Foundation
What Are The Bremont MBI And MBII?
What Makes Bremont Watches Sturdy?
Bremont Sets Up Shop In Henley-On-Thames
Nick and Giles English, lifelong flight enthusiasts, began their foray into watches after a tragic and fateful flight in 1995. Their father, Royal Air Force veteran Euan English, had a terrible crash while flying with Nick at an air show. Euan enjoyed fixing and tinkering with all things intricate and mechanical, especially timepieces.
Hence, to honor their father’s memory, the brothers quit their jobs to begin learning the art and business of watchmaking. However, they were unsure of what to name their company; they suspected using their own name, English, might sound corny. This was resolved by a flight over France undertaken by the brothers, which was interrupted by an unexpected storm. As a result, they had to make an emergency landing on a nearby farm.
The farmer sheltered Nick, Giles, and their plane; by great coincidence, this farmer was a watch enthusiast and veteran pilot. Hence, the brothers named their company in tribute to this kind man, Antoine Bremont.
Rugged Refinement With British Military Tech
Bremont watch frozen in lab test
From the start, the English brothers sought to make sure their watches would prove worthy of the family’s RAF heritage.
Therefore, they saw the need to make their watches able to withstand the rigors of military airflight. So, they worked with companies like Martin-Baker, the Middlesex-based manufacturer of aircraft ejection seats.
Martin-Baker’s test labs subject Bremont’s watch prototypes to extremes of vibration, altitude, and climate, preparing for the worst. So, the watches endure military jet seat ejections, freezing, free-falling, and even simulated aircraft crashes, as shown in this video:
While this may be the most spectacular collaboration, other British aircraft component manufacturers have a hand in developing these watches. For example, a factory in Cambridge which produces turbine engines for Rolls-Royce finishes many of the watch cases.
While working with Martin-Baker, Bremont developed a watch collection with a specific type of user in mind: Martin-Baker seat ejectees. Only pilots who have ejected from Martin-Baker seats are able to buy the MBI, the first in this series.
Hence, few MBI watches exist, due to their bespoke nature. Each watch is personalized: pilots ordering an MBI get their callsign or date of ejection engraved on the watch’s caseback.
Bremont later released a companion model, the MBII, which is available to all buyers. The MBII is very similar to the MBI, and has since become perhaps their most iconic watch.
Although not available with the MBI’s signature red barrel, the MBII comes in orange, green, and anthracite.
Bremont MBII watch, midsection and pushers visible
Custom-Built For High-Flyers
As a company run by aviators, Bremont often consults with pilots of specific aircraft and with individual squadrons. They create watches based on their popular collections with added details relevant to the history of the aircrew.
London Air Ambulance watch
Most of these crews are military but not all. For example, Bremont made a watch for London’s Air Ambulance. This watch is based on the Bremont Solo with a custom rotor and dial.
On the dial, the numbers “2” and “7” are in red, referring to Helimed 27, London Air Ambulance’s main callsign. This particular model is only available to the aircrews and employees of London Air Ambulance.
In some cases, the crews receive bespoke versions of a watch that Bremont then releases to the public. This is typically done when there is a lot of public interest in such a model.
The watches for the crews of the U2, the B-2 Spirit, and the C17 Globemaster, for example, are openly available.
The ALT1-WT: A Perfect Watch For Any Destination
Commissioned in 2010, the ALT1-WT World Timer was developed specifically for the needs of C-17 Globemaster transport jet crews.
Primarily used by the United States Airforce, C-17 Globemaster planes deliver cargo to destinations across the world, across many different timezones.
Consequently, C-17 aircrews sought a watch to easily keep track of any timezone in which they might land.
The result of this collaboration was the ALT1-WT, which makes adjusting to local time zones easy. Like the other models of the ALT1, the watch features a 24-hour hand which displays UTC time by default.
In addition, the ALT1-WT has an easily adjustable “Roto-Click” inner bezel with all of the world’s timezones inscribed on it. Due to this, all it takes is a turn of the bezel to adjust the 24-hour hand to local time.
ALT1-WT caseback with window.
Bremont creates such durable watches by using very tough materials and keeping extreme airflight conditions in mind. They machine the cases in three separate pieces, making a larger range of shapes possible.
This process, known as “Trip-Tick,” also allows them to make the bezel, midsection, and caseback out of different materials. An electron bombardment process hardens the steel case components, resulting in an exceptionally durable, scratch-resistant finish.
Bremont uses titanium or for most of their watch midsections as well as hardened steel coated with diamond-like carbon for black watches.
Convex sapphire crystals, ubiquitous in the company’s watches, resist scratches while their anti-reflective coating maximizes visibility. On many models, the movement is visible through a sapphire window in the caseback, as seen on the ALT1-WT. This allows Bremont owners to easily admire the skilful engineering of each watch’s inner components.
The black rubberized mount is visible on this MBII
Glucydur, an antimagnetic alloy, gives the watch high resistance to thermal deformation and expansion. Because of this, the watch movements easily endure extremes of temperature and pressure and stay on time.
A special shock-absorbing rubberized mount protects the inner parts from heavy impacts, “floating” components inside the case to soften vibrations.
Finally, a Faraday cage surrounds the inner case, nullifying the effects of magnetic interference on sensitive watch mechanisms. All of this adds up to a watch that commands respect, whether on the ground or soaring in the sky.
Diving Deep With The Supermarine
With the Supermarine line, Bremont extends their expertise to the diving world. Of course, aircraft are still part of this watch’s story. Bremont named this line “Supermarine” because they wanted to pay homage to the makers of the legendary Supermarine Spitfire.
The first of these watches was the Supermarine 500, which brings the usual sturdy-yet-sleek Bremont design to the deep sea. Depth of water resistance determines each model’s name, hence, the S500 is submersible to 500 meters.
Bremont’s engineers designed this watch with an extra metal bumper to protect its crown from accidental bumps and impacts.
Several years later, a new Supermarine watch was released: the Supermarine S2000. The S2000 can withstand a depth of 2000 meters, because of its bigger, sturdier case.
The anti-shock inner housing built to withstand aircraft crashes serves here to cushion the movement against immense deep-sea pressures. Also, since no mechanical watch is totally helium-proof at these depths, both the S2000 and S500 have a helium-release valve.
Bremont S2000 dive watch
To put the 2000-meter capability in perspective, the scuba deep-diving record was 332.35 meters when the S2000 was released. Probably, very few will need that level of depth resistance, but Bremont builds above and beyond for explorers and trailblazers. The S2000 looks quite similar to the S500, but features a larger face.
The Bremont S300 Honors Naval History
Dr. Timmy Gambin, wearing S500 watch
After the S2000, Bremont released the third in the series, the S300. This model features a smaller, slimmer case than its predecessors, with a diameter of 40mm and thickness of 13mm.
Also, the crown protector present on the S500 and S2000 is absent on this model for a less bulky look.
In 2017, Bremont worked with marine archaeologist, Dr. Timmy Gambin, to create a commemorative HMS Olympus S300. This coincided with Dr. Gambin’s project to install a memorial plaque next to the submarine, sunk in 1942.
Dr. Gambin’s teams use Bremont watches on their dives, which consist of analyzing wrecks ranging in era from WWII to the ancient Phoenicians. Not all of these are naval vessels. In fact, many of these are crashed aircraft shot down in WWII.
On their expeditions, these archaeological teams use both the S500 and the S300. They rely on these tough, accurate watches to help them keep coordinated underwater.
Bremont’s commemorative HMS Olympus Supermarine S300.
At the start, Bremont assembled all of its watches in Biel-Bienne, Switzerland, using both British and Swiss-manufactured parts. In 2013, however, they began moving their assembly operations to their new workshop in Henley-on-Thames, Oxfordshire. Some parts are also manufactured there, as shown in the video below:
Because of this, Bremont’s watches now proudly sport “London” on their dials to emphasize their connection to English watchmaking heritage. Though they operate in Oxfordshire, Bremont uses “London” for its instantly-recognizable connection with British industry and innovation.
“London” dial visible on a newer Bremont ALT1-ZT.
Luxury Metals Meet Ingenious Bremont Construction
Since moving their workshop to Oxfordshire, Bremont has released some watch models in luxury metals. Notable among these is the Kingsman Rose Gold, a design based off of the ALT1-WT World Timer.
The Kingsman RG sports an 18-carat rose gold case, and a barrel coated in diamond-like carbon. This affords some of the typical Bremont toughness to the watch without distracting from the rose gold bezel and lugs.
This watch and other models were featured prominently in the film, which spotlights British brands with impeccable style. Bremont cofounder, Nick English, makes a cameo in the movie as a “Kingsman” agent.
The Kingsman BKM-RG is no longer available as it was only made in a limited edition of 100. Though their watches are mainly titanium and steel, Bremont has since released 7 other lines of rose gold watches (At time of writing – March 7th 2018).
Bremont Kingsman limited editions; Bremont cofounder Nick English on the film’s set.
Where Do I Learn More About Bremont?
As Bremont is a new company, their history is still very much in the making. Newly-released models can be seen on their website. Also, their blog frequently updates on the adventures of their users.
Bremont also hosts ALT1TUDE, a community forum for discussion about their watches.
Find more of our watch histories, watch reviews, and in-depth information on buying and wearing watches on our main watch homepage.
Bremont MBII-WH/OR
Reviewed by Paul Anthony, on February 28, 2018 .
"Bremont is a classic in the making. Their approach to designing, testing, and constructing watches is uncompromising. This newcomer from the UK is truly a brand to look out for."
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IBC Offerings Expand Digital and Streaming Infrastructure for Broadcasters
Whether you’re a traditional broadcaster, a cable giant, or just a video podcaster, something new is waiting for you at this year’s IBC in Amsterdam.
Mon., Sept. 10, by Tim Siglin
By Tim Siglin
If there’s a hint of Fall in the Amsterdam air, the trams are packed, and the RAI Congress Center is packed, it must mean that it’s September and time for IBC. The yearly confab, which occurs about six months after the annual NAB show, allows product manufacturers and service providers in the broadcast space to show off their wares, many of which were demoed in prototype or pre-release form at NAB.
Several infrastructure products of interest caught my eye during the pre-event briefings. These aren’t the sexy products that everyone’s talking about (and which will be covered in a second article), but these are the ones that can make a difference regardless of what type of broadcaster you are.
Hamlet Reel-Check
The first product of interest comes from a company named Hamlet, which has been in the broadcast test and measurement business for several years. Hamlet sells analog and digital scopes, but in a nod to the growing file-based delivery trend that broadcasters are using to deliver everything from ads to B-roll news packages out to air, the company is now offering a quality control file checker. Following in the footsteps of a company familiar to most StreamingMedia readers—Inlet Technologies—Hamlet’s Reel-Check is a video and audio offline test and measurement system. This software-based system, which runs only on Windows-based machines, provides, according to the company, "comprehensive quality automated monitoring tools, including video and audio error checking video and audio waveform monitoring, video and audio vectorscope and surround sound checking." The logging feature, along with a video monitor and measurement displays, allows those familiar with traditional tape-based error checking to monitor the progress, although the company also touts that the application can run unattended and flag anomalies in the log.
MultiDyne SDI Cards and Accessories
Another infrastructure area that’s seeing traction is the gain of SDI transport within the studio broadcast space. And it’s not just the big boys that are using SDI, a single-cable Serial Digital Interface that uses a BNC video connector but carries up to 270Mbps of data or enough to carry a fully uncompressed digital component video and 8 tracks of 24-bit 48kHz audio. The downside to SDI (and HD-SDI, its HD equivalent) is that everything runs on a single cable, so splitting out the audio from the video or recombining them back together takes additional hardware. Fortunately the price on these hardware pieces, called de-embedders and embedders, respectively, is dropping. If you only need to carry four channels of audio (or 2 stereo AES/SPDIF channels) a company called MultiDyne has released an embedder/de-embedder on a card (the DTV250) that slides into the company’s card cage (the UTIL-200). Additionally, the card option for the product is innovative, since multiple cards can be cascaded to support up to 16 audio channels per SDI stream.
Gefen USB-to-DVI- Graphics Adapter
For those who are doing rich media recording using products like SonicFoundry’s MediaSite or Accordent’s PresenterPro, but only have a laptop with a VGA output and don’t want to carry a separate splitter box, Gefen has a possible solution for you in its new USB to DVI Graphics Adapter product. The product allows a DVI or VGA display to be connected up to a USB 2.0 port for simultaneous video delivery through the laptop’s built-in graphics port as well as the USB port. Since output is delivered in DVI-I format, which sends both analog VGA and digital DVI signals, this allows for VGA or DVI output capability (and with the right splitter cable available from other companies, both VGA and DVI output). Screen resolutions of up to 1600x1200 can be used, but the product currently only supports Windows platforms (32-bit versions of Windows XP, Windows Vista 32 bit and Windows 2000, according to the company). Never a company to shirk from maxing out their product, Gefen also demonstrated the ability to use up to six USB to DVI Graphics Adapters connected to a desktop computer, with mirrored video being delivered to all six displays.
Orad and InLive Interactive
And, finally, if you’re pining to make virtual sets part of your reality—or are just a local video podcaster who wants to expand into live events with audience participation but can’t afford to rent a studio—Orad and InLive have a solution for you: Orad makes virtual sets, while InLive makes mass audience participation software. The combined partnership allows mass audience polling to be integrated into virtual sets, which means that the graphics portions for interactive voting, betting, shopping, quizzes and auctions will be integrated directly into the virtual set, shaving integration coding time from the process of broadcasting to a large audience. Fair warning, though, for smaller broadcasters: the pricing is a bit steep as it’s geared toward InLive’s typical customer base such as Sat1, RAI 1 and RTL. Still, it’s a large step beyond even what iChat Theater will offer in the upcoming OS X Leopard release.
All these products and solutions can be seen on the show floor at IBC through September 11.
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CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
JP2012528176 PDE10 inhibitor by which the radiation sign was carried out
JP2004524350 Rho kinase inhibitor
JP2007516194 Medicine compound
BUCKMAN, Brad, Owen (2042 Leimert Boulevard, Oakland, CA, 94602, US)
YUAN, Shendong (2328 Elan Lane, San Ramon, CA, 94582, US)
ADLER, Marc (110 El Toyonal, Orinda, CA, 94563, US)
EMAYAN, Kumaraswamy (555 Pierce Street, #1424Albany, CA, 94706, US)
MA, Jingyuang (3206 Louis Rd, Palo Alto, CA, 94303, US)
BLADE THERAPEUTICS, INC. (442 Littlefield, Suite EastSouth San Francisco, CA, 94080, US)
C07D403/14; A61K31/4155; A61K31/4178; A61K31/422; A61K31/427; A61K31/433; A61K31/44; A61P7/04; A61P35/00; C07D231/14; C07D233/66; C07D261/10; C07D263/16; C07D275/03; C07D277/30; C07D285/06; C07D403/04; C07D405/04; C07D405/14; C07D407/04; C07D409/04; C07D409/14; C07D413/04; C07D413/14; C07D417/04; C07D417/14
CA2328440A1 1999-10-28
KLING, A. ET AL.: "Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, 2017, pages 7123 - 7138, XP055497543
MALLON, Joseph, J. (Knobbe, Martens Olson & Bear, LLP,2040 Main Street,14th Stree, Irvine CA, 92614, US)
or a pharmaceutically acceptable salt thereof, wherein:
Ai is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl provided the 6-10-membered heterocyclyl is not substituted with oxo; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C3_io carbocyclyl;
A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3_io carbocyclyl, -CR2-, -S-, -S(=0)-, -S02-, -0-, -C(=S)-, - C(=0)-, -NR-, -CH=CH-, -C≡C-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, - NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
A4 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, optionally substituted Ci-4 alkyl, -(CR2)n-S-(CR2)n-, -
(CR2)„-S(=0)-(CR2)„-, -(CR2)„-S02-(CR2)„-, -(CR2)„_0-(CR2)„-, -(CR2)„-C(=S)-(CR2)„-, - (CR2)n-C(=0)-(CR2)n-, -(CR2)n-NR-(CR2)n-, -(CR2)n-CH=CH-(CR2)n-, -(CR2)n-OC(0)NH- (CR2)„-, -(CR2)„-NHC(0)NH-(CR2)„-, -(CR2)„-NHC(0)0-(CR2)„-, -(CR2)„-NHC(0)-(CR2)„-, -(CR2)n-NHC(S)NH-(CR2)n-, -(CR2)n-NHC(S)0-(CR2)n-, -(CR2)n-NHC(S)-(CR2)n-, and single bond;
when A2 and A4 are single bond, A3 is directly attached to A8;
A3 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C3_io carbocyclyl, or if A2 is selected from optionally substituted 3- 10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C3_io carbocyclyl, then A3 is selected from the group consisting of hydrogen, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, -C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
A5 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3_io carbocyclyl, optionally substituted C1-8 alkyl, -S-, - S(=0)-, -SO2-, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, - NHC(0)0-, -NHC(O)-, -NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
A6 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, optionally substituted Ci_8 alkyl, optionally substituted C2_8 alkenyl, optionally substituted -O-Ci-6 alkyl, optionally substituted -O C2-6 alkenyl, -OS02CF3, and any natural or non-natural amino acid side chain;
A7 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, optionally substituted Ci-8 alkyl, -S-, S(=0)-, -S02-, - 0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, -NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
when A5 and A7 are single bond, A6 is directly attached to the carbon to which R is attached;
A8 is a ring member of Ai and is selected from the group consisting of C and N;
R8 is selected from the group consisting of -COR1, -CN, -CH=CHS02R, and
-CH2N02;
R1 is selected from the group consisting of H, -OH, C1-4 haloalkyl, -COOH, -CH2N02i -C(=0)NOR, -NH2, -CONR2R3, -CH(CH3)=CH2, -CH(CF3)NR2R3,
R is halo;
each R, R 2 , and R 3 are independently selected from -H, optionally substituted C1-4 alkyl, optionally substituted Q-g alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted C6-io aryl(Ci- C6)alkyl, and optionally substituted 5-10 membered heteroaryl;
R6 is independently selected from -H and optionally substituted Q-4 alkyl; and each n is independently selected to be an integer from 0 to 3.
2. The compound of claim 1, provided that the compound is not selected from the group consisting of:
3. The compound of claims 1 or 2, wherein:
A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3_io carbocyclyl, -CR2-, -S-, -S(=0)-, -S02-, -0-, -C(=S)-, - C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, -NHC(S)NH- , -NHC(S)0-, -NHC(S)-, and single bond;
A3 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C3_io carbocyclyl;
A6 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, optionally substituted Ci_8 alkyl, optionally substituted -0-Ci_6 alkyl, optionally substituted -O C2_6 alkenyl, and any natural or non- natural amino acid side chain; and
each R, R 2 , and R 3 are independently selected from -H, optionally substituted Ci-4 alkyl, optionally substituted C3_7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-io aryl, and optionally substituted 5-10 membered heteroaryl.
4. The compound of any one of claims 1-3 having the structure of formula I-a:
I-a
A, B, and D are each independently selected from the group consisting of C(R4) and
N; and
each R4 is independently selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Q- C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy.
5. The compound of claim 4, wherein A, B, and D are independently selected from the group consisting of CH and N.
6. The compound of claim 5, wherein A is N, B is CH, and D is CH.
7. The compound of claim 5, wherein A is CH, B is N, and D is CH.
8. The compound of claim 5, wherein A is N, B is N, and D is N.
9. The compound of any one of claims 1-3 having the structure of formula I-b:
I-b
tiarmaceutically acceptable salt thereof, wherein: A, B, and D are each independently selected from the group consisting of C(R4) and
10. The compound of claim 9, wherein A, B, and D are independently selected from the group consisting of CH and N.
11. The com ound of any one of claims 1-3 having the structure of formula I-c:
Y is selected from the group consisting of NR5, O, S, and S02;
X and Z are each independently selected from the group consisting of C(R4) and N; each R4 is independently selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Q- C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy; and
R5 is selected from the group consisting of -H, Ci_4 alkyl, Ci_4 haloalkyl, and C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy).
12. The compound of claim 11, wherein X and Z are independently selected from the group consisting of CH and N.
13. The compound of any one of claims 1-3 having the structure of formula I-d:
I d
14. The compound of claim 13, wherein X and Z are independently selected from the group consisting of CH and N
15. The com ound of any one of claims 1-3 having the structure of formula I-e:
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from the group consisting of NR5, O, S, and S02;
R5 is selected from the group consisting of -H, Ci_4 alkyl, Ci_4 haloalkyl, and
C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy).
17. The compound of any one of claims 1-3 having the structure of formula I-f:
I-f
X and Z are each independently selected from the group consisting of C(R4) and N; each R4 is independently selected from the group consisting of -H, Ci-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy; and
18. The compound of claim 17, wherein Z is N, Y is NR5, and X is CH.
19. The compound of claim 18, wherein R5 is selected from the group consisting -H, Ci_4 alkyl, Q-C4 haloalkyl, and cyclopropyl.
20. The compound of claim 17, wherein Z is N, Y is O, and X is C(R4).
21. The compound of claim 17, wherein Z is N, Y is S, and X is C(R4).
22. The compound of claim 17, wherein Z is C(R4), Y is S, and X is C(R4).
23. The compound of claim 17, wherein Z is C(R4), Y is O, and X is C(R4).
24. The compound of claim 17, wherein Z is N, Y is S, and X is N.
25. The compound of claim 17, wherein Z is N, Y is O, and X is N.
26. The compound of any one of claims 1-3 having the structure of formula I-g:
X and Z are each independently selected from the group consisting of C(R4) and N; each R4 is independently selected from the group consisting of -H, Ci_4 alkyl, Ci_4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci- C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy; and
R5 is selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, and C3-7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Q-C6 haloalkyl, and Ci-C6 haloalkoxy).
27. The compound of claim 26, wherein X and Z are independently selected from the group consisting of CH and N. The compound of claim 26, wherein Y is NR5, Z is N, and X is CH..
The compound of an one of claims 1-3 having the structure of formula I-h:
X and Z are each independently selected from the group consisting of C(R4) and N;
each R4 is independently selected from the group consisting of -H, Ci_4 alkyl, Ci_4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy; and
R5 is selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, and C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Q-C6 haloalkyl, and Ci-C6 haloalkoxy).
31. The compound of claim 29, wherein X is CH, Z is N, and Y is NR5.
32. The compound of claim 29, wherein X is N, Z is C(R4), and Y is O.
33. The compound of claim 32, wherein R4 is selected from -H and Ci_4 alkyl.
34. The compound of claim 29, wherein X is N, Z is C(R4), and Y is S.
35. The compound of claim 29, wherein X is N, Z is N, and Y is S.
36. The compound of any one of claims 1-3 having the structure of formula I-j
or a pharmaceutically acceptable salt thereof.
37. The compound of an one of claims 1-3 having the structure of formula I-k
X is selected from the group consisting of C(OR5), C(R4), and N;
R4 is selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Q-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy; and
38. The compound of claim 37, wherein X is independently selected from the group consisting of CH and N.
39. The compound of any one of claims 1-3 having the structure of formula I-m:
or a pharmaceutically acceptable salt thereof, wherein X and Z are independently selected from the group consisting of C(R4) and N;
E is selected from the group consisting of an optionally substituted C5-6 carbocyclyl and an optionally substituted 5- to 6-membered heterocyclyl; and
40. The compound of any one of claims 1-3 having the structure of formula I-n:
or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of C(R4) and N; E is selected from the group consisting of an optionally substituted C5-6 carbocyclyl, an optionally substituted 5- to 6-membered heterocyclyl, an optionally substituted 5- to 6- membered heteroaryl, and an optionally substituted phenyl; and
each R4 is independently selected from the group consisting of -H, Q-4 alkyl, C i_4 haloalkyl, C3-7 carbocyclyl, halo, hydroxy, and Ci-C6 alkoxy.
41. A compound having the structure of formula III:
Ai is selected from the group consisting of optionally substituted 5- 10 membered heterocyclyl provided the 6-10-membered heterocyclyl is not substituted with oxo; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C3_io carbocyclyl;
A2 is selected from the group consisting of optionally substituted 3- 10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted C3_io carbocyclyl, -CR2-, -S-, -S(=0)-, -SO2-, -0-, -C(=S)-, - C(=0)-, -NR-, -CH=CH-, -C≡C-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, - NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
A4 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted 3- 10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, optionally substituted Q-4 alkyl, -(CR2)n-S-(CR2)n-, - (CR2)„-S(=0)-(CR2)„-, -(CR2)„-S02-(CR2)„-, -(CR2)„_0-(CR2)„-, -(CR2)„-C(=S)-(CR2)„-, - (CR2)n-C(=0)-(CR2)n-, -(CR2)n-NR-(CR2)n-, -(CR2)n-CH=CH-(CR2)n-, -(CR2)n-OC(0)NH- (CR2)„-, -(CR2)„-NHC(0)NH-(CR2)„-, -(CR2)„-NHC(0)0-(CR2)„-, -(CR2)„-NHC(0)-(CR2)„-, -(CR2)n-NHC(S)NH-(CR2)n-, -(CR2)n-NHC(S)0-(CR2)n-, -(CR2)n-NHC(S)-(CR2)n-, and single bond; when A2 and A4 are single bond, A3 is directly attached to A8;
A3 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C3_io carbocyclyl, or if A2 is selected from optionally substituted 3- 10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C3_io carbocyclyl, then A3 is selected from the group consisting of hydrogen, optionally substituted Ce-w aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3_io carbocyclyl, -C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
G is an optionally substituted C3 to C7 carbocyclyl or an optionally substituted 4- to 7- membered heterocyclyl;
R8 is selected from the group consisting of -COR1, -CN, -CH=CHS02R, -CH2N02;
R1 is selected from the group consisting of H, -OH, C1-4 haloalkyl, -COOH, -CH2N02, -C(=0)NOR, -NH2, -CONR2R3, -CH(CH3)=CH2, -CH(CF3)NR2R3,
R is halo; and
each R, R 2 , and R 3 are independently selected from -H, optionally substituted Ci-4 alkyl, optionally substituted Ci-8 alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C3_7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted C6-1o aryl(Ci- C6)alkyl, and optionally substituted 5-10 membered heteroaryl;
R6 is independently selected from -H and optionally substituted C1-4 alkyl; and each n is independently selected to be an integer from 0 to 3.
The compound of claim 41, having the structure of formula (III-
Ili a
43. The compound of any one of claims 1-42, wherein at least one of the optionally substituted moieties of A2, A4, and 18
A3 is substituted with F
44. The compound of any one of claims 1-43, wherein at least one of the optionally substituted moieties of A2, A4, and A3 is substituted with Ci-C6 alkyl containing one or more nC.
45. The compound of any one of claims claim 1-44, wherein A3 is selected from
the group consisting of
A9 is selected from the group consisting of H, C6-io aryl, 5-10 membered heteroaryl, 3- 10 membered heterocyclyl, and C3_io carbocyclyl, C1-4 alkyl;
X2, Xi, and Z are each independently selected from the group consisting of C(R4) and
Yi is selected from the group consisting of NR5, O, and S;
J, L, Mi and M2 are each independently selected from the group consisting of C(R4) and N;
R4 is selected from the group consisting of -H, Ci_4 alkyl, Ci_4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy;
46. The compound of any one of the claims 1-44, wherein A3 is optionally substituted C6-1o aryl.
47. The compound of claim 46, wherein A3 is phenyl. The com ound of claim 46, wherein A3 is selected from the group consisting
49. The compound of any one of the claims 1-44, wherein A3 is optionally substituted 5-10 membered heteroaryl.
50. The compound of claim 49, wherein A3 is selected from the group consisting
51. The compound of any one of claims 1-50 wherein A2 is single bond.
52. The compound of any one of the claims 1-50, wherein A2 is -CH2-.
53. The compound of any one of the claims 1-50, wherein A2 is -CH=CH
54. The compound of any one of the claims 1-50, wherein A2 is -0-.
55. The compound of any one of the claims 1-50, wherein A2 is -S-.
56. The compound of any one of claims 1-50, wherein A2 is phenyl.
57. The compound of any one of claims 1-50, wherein A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5- or 7-10 membered heteroaryl, optionally substituted C3-1o carbocyclyl, -S-, -S(=0)-, -S02-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -C≡C-, -OC(0)NH-, - NHC(0)NH-, -NHC(0)0-, -NHC(S)NH-, -NHC(S)0-, and -NHC(S)-.
58. The compound of any one of claims 1-50, wherein A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3_io carbocyclyl, and -C≡C-.
59. The compound of any one of claims 1-50, wherein A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C3_io carbocyclyl.
60. The compound of any one of claims 1-59, wherein A4 is single bond.
61. The compound of any one of claims 1-44, wherein A2 is a single bond, A4 is a single bond, and A3 is an optionally substituted C6-io aryl or an optionally substituted 5-10 membered heteroaryl.
62. The compound of claim 61, wherein A3 has the structure:
, wherein
J, L, Mi, M2, and M3 are each independently selected from the group consisting of C(R4) and N; and
each R4 is independently selected from the group consisting of -H, Ci-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy.
63. The compound of claim 62, wherein each of J, L, Mi, M2, and M3 are C(R4).
64. The compound of claim 63, wherein each R4 is independently selected from -H and halo.
65. The compound of claim 62, wherein Mi is halo and each of J, L, M2, and M3 are CH.
66. The compound of claim 62, wherein L is halo and each of J, Mi, M2, and M3 are CH.
67. The compound of claim 61, wherein A3 has a structure selected from the group consistin of:
J, L, Mi, M2, M3, M4, and M5 are each independently selected from the group consisting of C(R4) and N; and
each R4 is independently selected from the group consisting of -H, Q-4 alkyl, Ci_4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy.
compound of claim 61, wherein A3 has the structure:
X is selected from the group consisting of C(R4) and N;
Y is selected from O and S; and
R4 is selected from the group consisting of -H, Ci-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy.
69. The compound of any one of claims 1-3 having the structure of formula I-o:
Xi is selected from the group consisting of C(R4) and N;
J, L, Mi, M2, and Μ3 are each independently selected from the group consisting of C(R4) and N;
R4 is selected from the group consisting of -H, C1-4 alkyl, C1-4 haloalkyl, C3_7 carbocyclyl (optionally substituted with halo, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 haloalkyl, and Ci-C6 haloalkoxy), halo, hydroxy, and Ci-C6 alkoxy;
70. The compound of claim 69, wherein J, L, Mi, M2, and M3 are independently selected from the group consisting of CH and N.
71. The compound of any one of claims 1-40 and 43-70, wherein at least one of the optionally substituted moieties of 18
A5, A7, and A6 is substituted with F.
72. The compound of any one of claims 1-40 and 43-70, wherein at least one of the optionally substituted moieties of A5, A7, and A6 is substituted with Ci-C6 alkyl containing one or more nC.
73. The compound of any one of the claims 1-40 and 43-70, wherein A6 is phenyl.
74. The compound of anyone of claims 1-40 and 43-70, wherein A6 is selected from the group consisting of optionally substituted C6-io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3-1o carbocyclyl, optionally substituted C1-8 alkyl, optionally substituted -0-Ci_6 alkyl, and optionally substituted -O C2-6 alkenyl.
75. The compound of any one of the claims 1-40 and 43-70, wherein A7 is -CH2-.
76. The compound of any one of the claims 1-40 and 43-70, wherein A7 is O.
77. The compound of any one of the claims 1-40 and 43-70, wherein A7 is -
CH=CH-.
78. The compound of any one of the claims 1-40 and 43-70, wherein A7 is S.
79. The compound of any one of the claims 1-40 and 43-70, wherein A7 is single bond.
80. The compound of any one of the claims 1-40 and 43-70, wherein A7 is optionally substituted C6-1o aryl.
81. The compound of claim 80, wherein A7 is phenyl.
82. The compound of any one of claims 1-81, wherein A5 is -CH2-.
83. The compound of any one of claims 1-40 and 43-70, wherein A5 is -CH2- or - CH2CH2-; A7 is a single bond; and A6 is selected from the group consisting of C1-C4 alkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl.
84. The compound of claim 83, wherein A6 is optionally substituted phenyl.
85. The compound of claim 83, wherein A6 is unsubstituted phenyl.
86. The compound of claim 83, wherein A6 is phenyl optionally substituted with one or more Q-4 alkyl, C3_7 carbocyclyl, halo, hydroxy, and Q-C6 alkoxy.
ound of claim 83, wherein A6 has the structure:
88. The compound of any one of claims 1-40 and 43-70, wherein A5 is a single bond, A7 is a single bond; and A6 is C1-C5 alkyl.
89. The compound of claim 88, wherein A6 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2-dimethylpropyl.
90. 1 2 3 The compound of any one of the claims 1-89, wherein R is CONR R .
91. 2 3
The compound of claim 90, wherein R is -H and R is optionally substituted Ci-4 alkyl.
The compound of claim 90, wherein R is -H and R is selected from the group consisting of -H, C1-C4 alkyl optionally substituted with C-amido, and C3-C6 cycloalkyl.
93. The compound of claim 92, wherein R is selected from ethyl or cyclopropyl.
94. The compound of claim 92, wherein R is methyl substituted with C-amido.
95. The compound of claim 92, wherein R is -H.
96. The compound of claim 90, wherein R is optionally substituted Ci_4 alkyl.
97. The compound of claim 90, wherein R is benzyl.
98. The compound of any one of claims 1-40 and 43-97, wherein R6 is -H and optionally substituted C1-4 alkyl.
99. The compound of claim 98, wherein R6 is optionally substituted Ci_4 alkyl.
100. The compound of claim 99, wherein R6 is methyl.
101. The compound of any one of claims 1-3, wherein Ai is selected from the group consisting of optionally substituted 6-10 membered heterocyclyl; 5-membered heterocyclyl optionally substituted with one or more Ci_4 alkyl, C3_7 carbocyclyl, halo, hydroxy, or Ci-C6 alkoxy; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C3_io carbocyclyl.
102. The compound of any one of claims 1-3, wherein Ai is selected from the group consisting of 5-membered heterocyclyl optionally substituted with one or more Ci_4 alkyl, C3_7 carbocyclyl, halo, hydroxy, or Ci-C6 alkoxy and optionally substituted 5- membered heteroaryl.
103. The compound of any one of claims 1-3, wherein Ai is optionally substituted 5-membered heteroaryl.
104. The compound of any one of claims 1-3, having the structure of formula I-p:
105. The compound of claim 1, having the structure selected from the group consisting of: compounds 1 to 90, compounds 92-94, compound 195, compounds 197 to 235, compounds 238 to 273, compounds 276 to 281, compounds 283 to 299, compounds 303 to 309, compounds 313 to 363, compound 365, compounds 367-410, compounds 413-424, compounds 428-445, compounds 447-448, compounds 454-532, compound 540, compounds 546-588, compounds 591-605, compounds 607-611, compounds 613-630, and pharmaceutically acceptable salts thereof.
106. A compound having the structure selected from the group consisting of: compounds 91, 196, 274, 282, 310 to 312, 364, 366, 411, 541, and pharmaceutically acceptable salts thereof.
107. A compound having the structure of the formula II:
or a pharmaceutically acceptable salt thereof, wherein: P2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 P2 pocket moiety selected from the group consisting of Glyl90, Phe233, Gly253, His254, and Ala255;
Li is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 P3 pocket moiety selected from the group consisting of Glyl89, Glyl90, Serl91, Thr236, and Gly253;
R10 is oxo and is positioned by P2 such that, upon binding of the compound to calpain 9, R10 forms a polar interaction with, and is within 4 A or less of, calpain 9 Glyl90 amide;
R11 is nitrogen and is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R11 forms a polar interaction with, and is within 4 A or less of, calpain 9 Gly253 carbonyl;
L2 is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
Pi is a moiety positioned by L2 and having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 PI pocket moiety selected from the group consisting of Gly95, Lysl88, Glyl89, and Ser242;
R9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 9 moiety selected from the group consisting of Gln91, Cys97, and His254; and
R6 is selected from -H and optionally substituted C1-4 alkyl.
108. The compound of claim 107, wherein:
R9 is -(C=R12)(C=R13)NR2R3; R is oxo and is positioned such that, upon binding of the compound to calpain 9, R forms a polar interaction with, and is within 4 A or less of, calpain 9 His254 imidazole;
R 13 is oxo and is positioned such that, upon binding of the compound to calpain 9, R 13 forms a polar interaction with, and is within 4 A or less of, at least one calpain 9 moiety selected from the group consisting of Gln91 side chain carboxamide and Cys97 backbone amide; and
R 2" and R 3J are independently selected from -H, optionally substituted C1-4 alkyl, optionally substituted C3_7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted C6-ioaryl(Ci-C6)alkyl, and optionally substituted 5-10 membered heteroaryl.
109. The compound of claim 108, wherein R 12 is positioned such that, upon binding of the compound to calpain 9, R 12 is within 2.6 to 3.2 0
A or less of, calpain 9 His254 imidazole.
111. The compound of any one of claims 108 to 110, wherein R 13 is positioned such that, upon binding of the compound to calpain 9, R 13 is within 2.6 to 3.5 0
A to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
113. The compound of claim 107, wherein R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R9 forms a polar interaction with, and is within 3.6 A or less of, at least one calpain 9 moiety selected from the group consisting of Gln91, Cys97, and His254.
114. The compound of claim 113 wherein R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R9 is within 2.6 to 3.6 A to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
115. The compound of claim 114, wherein R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R9 is within 2.9 to 3.2 A to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
116. The compound of claim 107, wherein a carbon atom in R9 at its point of attachment forms a covalent bond with Cys97
117. The compound of claim 79, wherein the covalent bond length is between 1.7 and 1.9 A.
118. The compound of any one of claims 107 to 117, wherein P2 is an optionally substituted 5-membered heteroaryl.
119. The compound of any one of claims 107 to 118, wherein R11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R11 forms a polar interaction with, and is within 3.6 A or less of, calpain 9 Gly253 carbonyl.
120. The compound of any one of claims 107 to 119, wherein:
P2 has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P2 pocket moiety selected from the group consisting of Gly208, Ser251, Gly271, His272, and Ala273;
P3 is positioned by Li and has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P3 pocket moiety selected from the group consisting of Gly207, Gly208, Ser209, Ile254, and Gly271;
R10 is positioned by P2 such that, upon binding of the compound to calpain 1, R10 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly208 amide;
R11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 1, R11 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly271 carbonyl; Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 PI pocket moiety selected from the group consisting of Glyl l3, Ser206, Gly207, and Met260; and
R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09, Cysl l5, and His272.
P2 has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P2 pocket moiety selected from the group consisting of Glyl98, Ser241, Gly261, His262, and Ala263;
P3 is positioned by Li and has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P3 pocket moiety selected from the group consisting of Glyl97, Glyl98, Alal99, Ile244, and Gly261;
R10 is positioned by P2 such that, upon binding of the compound to calpain 2, R10 forms a polar interaction with, and is within 4 A or less of, calpain 2 Glyl98 amide;
R11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 2, R11 forms a polar interaction with, and is within 4 A or less of, calpain 2 Gly261 carbonyl;
Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 PI pocket moiety selected from the group consisting of Glyl03, Serl96, Glyl97, and Ser250; and
R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262.
122. The compound of any one of claims 68 to 121, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.6 to 3.6 A of Glyl90 carbonyl oxygen.
123. The compound of claim 122, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.9 to 3.3 A of Glyl90 carbonyl oxygen.
124. The compound of any one of claims 68 to 123, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.8 to 4.8 A of a carbon atom in Phe233.
125. The compound of claim 124, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.9 to 3.3 A of a carbon atom in Phe233.
126. The compound of any one of claims 68 to 125, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.6 to 3.7 A of Gly253 carbonyl oxygen.
127. The compound of claim 126, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.9 to 3.3 A of Gly253 carbonyl oxygen.
128. The compound of any one of claims 68 to 127, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 2.9 to 4.8 A of Ala255 nitrogen.
129. The compound of claim 128, wherein P2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P2 is within 3.2 to 4.0 A of Ala255 nitrogen.
130. The compound of any one of claims 68 to 129, wherein P3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P3 is within 3.1 to 4.3 A of Glyl89 C-alpha.
131. The compound of claim 130, wherein P3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P3 is within 3.2 to 4.0 A of Glyl89 C-alpha.
134. The compound of any one of claims 68 to 133, wherein P3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P3 is within 3.2 to 4.8 A of Serl91 nitrogen.
135. The compound of claim 134, wherein P3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P3 is within 3.2 to 4.0 A of Serl91 nitrogen.
136. The compound of any one of claims 1 to 135, wherein R10 is positioned by P2 such that, upon binding of the compound to calpain 9, R10 is within 2.6 to 3.5 A of, calpain 9 Glyl90 amide.
137. The compound of claim 136, wherein R10 is positioned by P2 such that, upon binding of the compound to calpain 9, R10 is within 2.9 to 3.3 A of, calpain 9 Glyl90 amide.
138. The compound of any one of claims 68 to 137, wherein R11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R11 is within 2.6 to 3.6 A or less of, calpain 9 Gly253 carbonyl.
139. The compound of claim 138, wherein R11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R11 is within 2.9 to 3.3 A or less of, calpain 9 Gly253 carbonyl.
140. The compound of any one of claims 68 to 139, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.4 A Gly95 carbonyl oxygen.
141. The compound of claim 140, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.0 A Gly95 carbonyl oxygen.
142. The compound of any one of claims 68 to 141, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.7 A of Lysl88 carbonyl carbon.
143. The compound of claim 142, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 2.6 to 4.0 A of Lysl88 carbonyl carbon.
144. The compound of any one of claims 68 to 143, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.0 to 4.1 A of Glyl89 C-alpha.
145. The compound of claim 144, wherein Pi is positioned by L2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.0 A of Glyl89 C-alpha.
P2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P2 pocket moiety selected from the group consisting of Gly208, Ser251, Gly271, His272, and Ala273;
P3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P3 pocket moiety selected from the group consisting of Gly207, Gly208, Ser209, Ile254, and Gly271;
R10 is oxo and is positioned by P2 such that, upon binding of the compound to calpain 1, R10 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly208 amide;
Pi is a moiety positioned by L2 and having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 PI pocket moiety selected from the group consisting of Glyl l3, Ser206, Gly207, and Met260;
R9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09, Cysl l5, and His272; and
R9 is -(C=R12)(C=R13)NR2R3;
R 12 is oxo and is positioned such that, upon binding of the compound to calpain 1, R 12 forms a polar interaction with, and is within 4 A or less of, calpain 1 His272 imidazole;
R 13 is oxo and is positioned such that, upon binding of the compound to calpain 1, R 13 forms a polar interaction with, and is within 4 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09 side chain carboxamide and Cysl l5 backbone amide; and
R 2" and R 3J are independently selected from -H, optionally substituted Q-4 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted C6-ioaryl(Ci-C6)alkyl, and optionally substituted 5-10 membered heteroaryl.
148. The compound of claim 146, wherein R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R9 forms a polar interaction with, and is within 3.5 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09, Cysl l5, and His272.
149. The compound of claim 146, wherein a carbon atom in R9 at its point of attachment forms a covalent bond with Cysl 15.
150. The compound of claim 149, wherein the covalent bond length is between 1.7 and 1.9 A.
151. The compound of claim 146 or 150, wherein P2 is an optionally substituted 5- membered heteroaryl.
P2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P2 pocket moiety selected from the group consisting of Glyl98, Ser241, Gly261, His262, and Ala263; Li is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
P3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P3 pocket moiety selected from the group consisting of Glyl97, Glyl98, Alal99, Ile244, and Gly261;
Pi is a moiety positioned by L2 and having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 PI pocket moiety selected from the group consisting of Glyl03, Serl96, Glyl97, and Ser250;
R9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262; and
R 13 is oxo and is positioned such that, upon binding of the compound to calpain 2, R 13 forms a polar interaction with, and is within 4 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99 side chain carboxamide and Cysl05 backbone amide; and
FT 2 and R 3J are independently selected from -H, optionally substituted C1-4 alkyl, optionally substituted C3_7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-1o aryl, optionally substituted C6-ioaryl(Ci-C6)alkyl, and optionally substituted 5-10 membered heteroaryl.
155. The compound of claim 153, wherein R9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R9 forms a polar interaction with, and is within 3.5 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262.
156. The compound of claim 153, wherein a carbon atom in R9 at its point of attachment forms a covalent bond with Cysl95.
160. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-159 and a pharmaceutically acceptable excipient.
161. A method of treating fibrotic disease or a secondary disease state or condition thereof, comprising administering to a subject in need thereof, a compound according to any one of claims 1-159.
162. The method of claim 161, wherein the disease is selected from the group consisting of liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis.
163. The method of claim 161, wherein the treatment decreases the expression level and/or activity of a calpain.
164. The method of claim 163, wherein the calpain is CAPN1, CAPN2, or CAPN9.
165. The method of claim 161, wherein the treatment inhibits myofibroblast differentiation or treats a disease associated with myofibroblast differentiation.
166. The method of claim 161, wherein the treatment inhibits Fibroblast-to- Myofibroblast Transition (FMT).
167. The method of claim 161, wherein the treatment inhibits Epithelial to Mesenchymal Transition or Endothelial to Mesenchymal Transition.
168. The method of claim 167, wherein the myofibroblast differentiation is a TGF -mediated myofibroblast differentiation.
169. The method of claim 161, wherein the fibrotic disease is a cancer.
170. The method of claim 169, wherein the cancer is a cancer of epithelial origin.
171. The method of claim 170, wherein the cancer of epithelial origin is selected from the group consisting of breast cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, brain, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, prostate cancer, and renal cell carcinoma.
172. The method of claim 161, wherein the fibrotic disease is stiff skin syndrome
(SKS).
173. The method of claim 161, wherein the compound is of Formula I.
174. The method of claim 161, wherein the subject is a mammal.
175. The method of claim 161, wherein the subject is a human.
176. The method of claim 161, wherein the route of administration is selected from the group consisting of: enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal.
177. The method of claim 161, wherein the administration is intravenous.
178. A method of inhibiting myofibroblast differentiation comprising contacting a cell with a compound of anyone of claims 1-159.
179. The method of claim 178, wherein the cell is in a fibrotic tissue.
180. The method of claim 178, wherein the cell is in a cancerous tissue.
181. The method of claim 178, wherein the cell is in a tissue with high TGF signaling.
182. A method for inhibiting calpain, the method comprising contacting a compound of any one of claims 1-159 with a CAPNl, CAPN2, and/or CAPN9 enzyme residing inside a subject.
183. A method of competitive binding with calpastatin (CAST), the method comprising contacting a compound of anyone of claims 1-159 with CAPNl, CAPN2, and/or CAPN9 enzymes residing inside a subject.
BLADT.004WO PATENT CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
[0001] The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to non-macrocyclic a-keto amide compounds as small molecule calpain modulators, compositions, their preparation, and their use as therapeutic agents.
Description of the Related Art
[0002] Fibrotic disease accounts for an estimated 45% of deaths in the developed world but the development of therapies for such diseases is still in its infancy. The current treatments for fibrotic diseases, such as for idiopathic lung fibrosis, renal fibrosis, systemic sclerosis, and liver cirrhosis, are few in number and only alleviate some of the symptoms of fibrosis while failing to treat the underlying cause.
[0003] Despite the current limited understanding of the diverse etiologies responsible for these conditions, similarities in the phenotype of the affected organs, across fibrotic diseases, strongly support the existence of common pathogenic pathways. At present, it is recognized that a primary driver of fibrotic disease is a high transforming growth factor-beta (TGF ) signaling pathway which can promote the transformation of normally functioning cells into fibrosis- promoting cells. Termed "myofibroblasts," these transformed cells can secrete large amounts of extracellular matrix proteins and matrix degrading enzymes, resulting in the formation of scar tissue and eventual organ failure. This cellular process is transformative and termed "myofibroblast differentiation" (which includes Epithelial-to-Mesenchymal Transition (EpMT) and its variations like Endothelial-to-Mesenchymal Transition (EnMT) and Fibroblast-to- Myofibroblast Transition (FMT)). This process is a major target for the treatment of fibrotic diseases. Myofibroblast differentiation has also been shown to occur within cancer cells that have been chronically exposed to high TGF , causing stationary epithelial cells to become motile, invasive, and metastasize. Thus, within the context of cancer, the signaling has been documented to associate with the acquisition of drug resistance, immune system evasion, and development of stem cell properties. [0004] Despite the tremendous potential of myofibroblast differentiation-inhibiting drugs, and the numerous attempts to develop a working treatment, the data gathered thus far has yet to translate into practical therapy. This is partly due to the lack of an ideal target protein. Initial strategies to target the myofibroblast differentiation process focused on proximal inhibition of the TGF signaling pathway by various methods, including targeting ligand activators (e.g. alpha-v integrins), ligand-receptor interactions (e.g., using neutralizing antibodies) or TGF receptor kinase activity (e.g., small molecule chemical compound drugs to block signal transduction). Unfortunately, TGF is a pleiotropic cytokine with many physiological functions such that global suppression of TGFP signaling was also associated with severe side effects. Additionally, current data suggests that such proximal inhibition may be vulnerable to pathologic workaround strategies (i.e., due to redundancy or compensation), that would limit the utility of such drugs. Further complicating matters is that, in cancer, TGFP signaling early on functions as an anti-tumorigenic growth inhibitor but later becomes tumor promoting and is another reason why selective inhibition of pathogenic elements of signaling is so strongly desired. In light of these inherent limitations, current treatment strategies have refocused on identification and inhibition of critical distal events in TGFP signaling, which in theory would preferentially target the pathologic, but not physiological functions of TGFP signaling.
or a pharmaceutically acceptable salt thereof, wherein: Ai is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl provided the 5-10 membered heterocyclyl is not substituted with oxo, optionally substituted 5-, 8-, or 9- membered heteroaryl, and optionally substituted C 3-1 o carbocyclyl;
A 2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-1 o aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C 3 _i 0 carbocyclyl, -CR 2 -, -S-, -S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, - NR-, -CH=CH-, -C≡C-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, -NHC(S)NH-, - NHC(S)0-, -NHC(S)-, and single bond;
A 4 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted Ci- 4 alkyl, -(CR 2 ) n -S-(CR 2 ) n -, - (CR 2 ) n -S(=0)-(CR 2 ) n -, -(CR 2 ) n -S0 2 -(CR 2 ) n -, -(CR 2 ) n _0-(CR 2 ) n -, -(CR 2 ) n -C(=S)-(CR 2 ) n -, -(CR 2 )„- C(=0)-(CR 2 ) n -, -(CR 2 )„-NR-(CR 2 )„-, -(CR 2 )„-CH=CH-(CR 2 )„-, -(CR 2 )„-OC(0)NH-(CR 2 )„-, - (CR 2 ) n -NHC(0)NH-(CR 2 ) n -, -(CR 2 ) n -NHC(0)0-(CR 2 ) n -, -(CR 2 ) n -NHC(0)-(CR 2 ) n -, -(CR 2 )„- NHC(S)NH-(CR 2 )„-, -(CR 2 )„-NHC(S)0-(CR 2 )„-, -(CR 2 )„-NHC(S)-(CR 2 )„-, and single bond; when A 2 and A 4 are single bond, A 3 is directly attached to A 8 ;
A 3 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3 _io carbocyclyl, or if A 2 is selected from optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C 3 _io carbocyclyl, then A 3 is selected from the group consisting of hydrogen, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl,-C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
A5 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 3 _io carbocyclyl, optionally substituted Ci_ 8 alkyl, -S-, -S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, - NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond; A 6 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3-1 o carbocyclyl, optionally substituted C 1-8 alkyl, optionally substituted C 2 -8 alkenyl, optionally substituted -0-C 1-6 alkyl, optionally substituted -O C 2 -6 alkenyl, - OSO 2 CF 3 , and any natural or non-natural amino acid side chain;
A 7 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted Q-g alkyl, -S-, S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, - NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
when A5 and A 7 are single bond, A 6 is directly attached to the carbon to which R is attached;
A 8 is a ring member of Ai and selected from the group consisting of C, CH, and N;
R 8 is selected from the group consisting of -COR 1 , -CN, -CH=CHS0 2 R, and -CH 2 N0 2 ; R 1 is selected from the group consisting of H, -OH, C 1-4 haloalkyl, -COOH, -CH 2 N0 2 , - C(=0)NOR, -NH 2 , -CONR 2 R 3 , -CH(CH 3 )=CH 2 , -CH(CF 3 )NR 2 R 3 ,
each R, R 2 , and R 3 are independently selected from -H, optionally substituted
C1-4 alkyl, optionally substituted Ci-g alkoxyalkyl, optionally substituted 2- to 5- membered polyethylene glycol, optionally substituted C 3 _ 7 carbocyclyl, optionally substituted 5- 10 membered heterocyclyl, optionally substituted C 6 -io aryl, and optionally substituted 5-10 membered heteroaryl; and
R 6 is independently selected from -H and optionally substituted C1-4 alkyl.
[0006] Other embodiments disclosed herein include a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein and a pharmaceutically acceptable excipient.
[0007] Other embodiments disclosed herein include a method of treating diseases and conditions mediated at least in part by the physiologic effects of CAPNl, CAPN2, or CAP9, or combinations thereof, comprising administering to a subject in need thereof a compound disclosed herein.
[0008] In some embodiments, compounds disclosed herein are specific inhibitors of one of: CAPNl, CAPN2 or CAPN9.
[0009] In some embodiments, compounds disclosed herein are selective inhibitors of one of: CAPNl, CAPN2 or CAPN9.
[0010] In some embodiments, compounds disclosed herein are selective inhibitors of: CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9.
[0011] In some embodiments, compounds disclosed herein are effective inhibitors of CAPNl, CAPN2 and/or CAPN9.
[0012] In some embodiments, the non-macrocyclic oc-keto amide compounds disclosed herein are broadly effective in treating a host of conditions arising from fibrosis or inflammation, and specifically including those associated with myofibroblast differentiation. Accordingly, compounds disclosed herein are active therapeutics for a diverse set of diseases or disorders that include or that produces a symptom which include, but are not limited to: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post- vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders. In other embodiments, the compounds disclosed herein can be used can be used in metabolic and reaction kinetic studies, detection and imaging techniques and radioactive treatments.
[0013] In some embodiments, the compounds disclosed herein are used to treat diseases or conditions or that produces a symptom in a subject which include, but not limited to: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic - reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases.
[0014] In certain embodiments methods are provided for alleviating or ameliorating a condition or disorder, affected at least in part by the enzymatic activity of calpain 1 (CAPN1), calpain 2 (CAPN2), and/or calpain 9 (CAPN9), or mediated at least in part by the enzymatic activity of CAPN1, CAPN2, and/or CAPN9 wherein the condition includes or produces a symptom which includes: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and/or rheumatoid arthritis.
[0015] In some embodiments, the methods, compounds, and/or compositions of the present invention are used for prophylactic therapy.
[0016] In some embodiments, the CAPN1, CAPN2, and/or CAPN9 inhibiting compounds demonstrate efficacy in animal models of human disease. Specifically, in-vivo treatment of mice, rabbits, and other mammalian subjects with compounds disclosed herein establish the utility of these compounds as therapeutic agents to modulate CAPN1, CAPN2, and/or CAPN9 activities in humans and thereby ameliorate corresponding medical conditions. [0017] Some embodiments provide compounds, pharmaceutical compositions, and methods of use to inhibit myofibroblast differentiation. Some embodiments provide compounds, pharmaceutical compositions, and methods of use for inhibiting CAPNl, CAPN2, and/or CAPN9 or combinations of these enzyme activities such as CAPNl and CAPN2, or CAPNl and CAPN9, or CAPN2 and CAPN9. Some embodiments provide methods for treatment of diseases and disorders by inhibiting CAPNl, CAPN2, and/or CAPN9 or combinations of these enzymatic activities.
[0018] In some embodiments, compounds that are non-macrocyclic oc-keto amides are provided that act as calpain modulators. Various embodiments of these compounds include compounds having the structures of Formula I as described above or pharmaceutically acceptable salts thereof. The structure of Formula I encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:
[0019] In some embodiments of compounds of Formula (I), the compound is not selected from the group consisting of:
[0020] In some embodiments of compounds of Formula (I):
Ai is selected from the group consisting of optionally substituted 6-10 membered heterocyclyl provided the 6-10-membered heterocyclyl is not substituted with oxo; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C 3-1 o carbocyclyl;
A 2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-1 o aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-10 carbocyclyl, -CR 2 -, -S-, -S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, -NHC(S)NH-, -NHC(S)0-, - NHC(S)-, and single bond;
A 4 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted Ci- 4 alkyl, -S-, S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, - NHC(S)NH-, -NHC(S)0-, -NHC(S)-, and single bond;
A 3 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3 _io carbocyclyl;
A 6 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted Ci-g alkyl, optionally substituted - 0-Ci_6 alkyl, optionally substituted -O C 2 _ 6 alkenyl, and any natural or non-natural amino acid side chain; and
each R, R 2 , and R 3 are independently selected from -H, optionally substituted Q- 4 alkyl, optionally substituted C 3 _ 7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6 -io aryl, and optionally substituted 5-10 membered heteroaryl.
[0021] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-a):
A, B, and D are each independently selected from the group consisting of C(R 4 ) and N; and each R 4 is independently selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0022] In some embodiments of compounds of Formula (I-a) or their pharmaceutically acceptable salts; A, B, and D are independently selected from the group consisting of CH and N. In some embodiments, A is N, B is CH, and D is CH. In some embodiments, A is CH, B is N, and D is CH.
[0023] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-b):
harmaceutically acceptable salt thereof, wherein: A, B, and D are each independently selected from the group consisting of C(R 4 ) and N; and each R 4 is independently selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0024] In some embodiments of compounds of Formula (I-b) or their pharmaceutically acceptable salts; A, B, and D are independently selected from the group consisting of CH and N.
[0025] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-c :
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, C 3 _7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy; and R 5 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, and C 3 _ 7 carbocyclyl.
[0026] In some embodiments of compounds of Formula (I-c) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N.
[0027] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-d):
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy; and R 5 is selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3 _7 carbocyclyl.
[0028] In some embodiments of compounds of Formula (I-d) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N.
[0029] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-e :
armaceutically acceptable salt thereof, wherein: Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy; and R 5 is selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3 _7 carbocyclyl.
[0030] In some embodiments of compounds of Formula (I-e) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N.
[0031] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-f):
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, Q- 4 alkyl, Ci_ 4 haloalkyl, C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Q-C 6 alkoxy; and R 5 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, and C 3 _ 7 carbocyclyl.
[0032] In some embodiments of compounds of Formula (I-f), Z is N, Y is NR 5 , and X is CH. [0033] In some embodiments of compounds of Formula (I-f), R 5 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci-C 4 haloalkyl, and cyclopropyl.
[0034] In some embodiments of compounds of Formula (I-f), Z is N, Y is O, and X is C(R 4 ). In some embodiments of compounds of Formula (I-f), Z is N, Y is S, and X is C(R 4 ). In some embodiments of compounds of Formula (I-f), Z is C(R 4 ), Y is S, and X is C(R 4 ).
[0035] In some embodiments of compounds of Formula (I-f), Z is C(R 4 ), Y is O, and X is C(R 4 ).
[0036] In some embodiments of compounds of Formula (I-f), Z is N, Y is S, and X is N. In some embodiments of compounds of Formula (I-f), Z is N, Y is O, and X is N.
[0037] Some embodiments of compounds of Formula (I) include compounds having the structure of formula (I-g):
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy; and R 5 is selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl and C 3 _7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Q-C 6 haloalkyl, and Ci-C 6 haloalkoxy). [0038] In some embodiments of compounds of Formula (I-g) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N. In some embodiments of compounds of Formula (I-g), Y is NR 5 , Z is N, and X is CH.
[0039] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-h):
I-h
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; X and Z are each independently selected from the group consisting of C(R 4 ) and N; each R 4 is independently selected from the group consisting of -H, Ci- 4 alkyl, C 1-4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy; and R 5 is selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3 _7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Q- C 6 haloalkyl, and Ci-C 6 haloalkoxy).
[0040] In some embodiments of compounds of Formula (I-h) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N. In some embodiments of compounds of Formula (I-h), X is CH, Z is N, and Y is NR 5 .
[0041] In some embodiments of compounds of Formula (I-h), X is CH, Z is N, and Y is NR 5 . In some embodiments of compounds of Formula (I-h), X is N, Z is C(R 4 ), and Y is O. [0042] In some embodiments of compounds of Formula (I-h), wherein R 4 is selected from -H and Ci_ 4 alkyl.
[0043] In some embodiments of compounds of Formula (I-h), X is N, Z is C(R 4 ), and Y is S. In some embodiments of compounds of Formula (I-h), X is N, Z is N, and Y is S.
[0044] Some embodiments of compounds of Formula (I) include compounds having the structure of formula (I-j):
[0045] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-k :
or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of C(OR 5 ), -C(R 4 ), and N; R 4 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, C 3 _7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci- C 6 alkoxy; and R 5 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, and C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci- C 6 haloalkoxy).
[0046] In some embodiments of compounds of Formula (I-k) or their pharmaceutically acceptable salts; X and Z are independently selected from the group consisting of CH and N.
[0047] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-m):
X and Z are independently selected from the group consisting of C(R 4 ) and N; E is selected from the group consisting of an optionally substituted C5-6 carbocyclyl and an optionally substituted 5- to 6-membered heterocyclyl; and each R 4 is independently selected from the group consisting of -H, Ci- 4 alkyl, C 1-4 haloalkyl, C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci- C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0048] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-n):
I n
A is selected from the group consisting of C(R 4 ) and N; E is selected from the group consisting of an optionally substituted Cs_6 carbocyclyl, an optionally substituted 5- to 6- membered heterocyclyl, an optionally substituted 5- to 6- membered heteroaryl, and an optionally substituted phenyl; and each R 4 is independently selected from the group consisting of -H, Q- 4 alkyl, C 1-4 haloalkyl, C 3 -7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0049] Some embodiments include compounds of Formula (III)
Ai is selected from the group consisting of optionally substituted 5-10 membered heterocyclyl provided the 6-10-membered heterocyclyl is not substituted with oxo; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C 3 -10 carbocyclyl; A 2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-10 carbocyclyl, -CR 2 -, -S-, -S(=0)-, -S0 2 -, -0-, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -C≡C-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, -NHC(O)-, -NHC(S)NH-, - NHC(S)0-, -NHC(S)-, and single bond;
A 4 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted C1-4 alkyl, -(CR 2 ) n -S-(CR 2 ) n -, - (CR 2 )„-S(=0)-(CR 2 )„-, -(CR 2 )„-S0 2 -(CR 2 )„-, -(CR 2 )„_0-(CR 2 )„-, -(CR 2 )„-C(=S)-(CR 2 )„-, -(CR 2 )„- C(=0)-(CR 2 ) n -, -(CR 2 ) n -NR-(CR 2 ) n -, -(CR 2 ) n -CH=CH-(CR 2 ) n -, -(CR 2 ) n -OC(0)NH-(CR 2 ) n -, - (CR 2 )„-NHC(0)NH-(CR 2 )„-, -(CR 2 )„-NHC(0)0-(CR 2 )„-, -(CR 2 )„-NHC(0)-(CR 2 )„-, -(CR 2 )„- NHC(S)NH-(CR 2 )„-, -(CR 2 )„-NHC(S)0-(CR 2 ) n -, -(CR 2 )„-NHC(S)-(CR 2 )„-, and single bond; when A 2 and A 4 are single bond, A 3 is directly attached to A 8 ;
A 3 is selected from the group consisting of optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C 3 _io carbocyclyl, or if A 2 is selected from optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C 3 _io carbocyclyl, then A 3 is selected from the group consisting of hydrogen, optionally substituted C 6 -io aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, -C≡CH, and optionally substituted 2- to 5-membered polyethylene glycol;
G is an optionally substituted C 3 to C 7 carbocyclyl or an optionally substituted 4- to 7- membered heterocyclyl;
A 8 is a ring member of Ai and is selected from the group consisting of C and N;
R 8 is selected from the group consisting of -COR 1 , -CN, -CH=CHS0 2 R, -CH 2 N0 2 ;
R 1 is selected from the group consisting of H, -OH, Ci_ 4 haloalkyl, -COOH, -CH 2 N0 2i - C(=0)NOR, -NH 2 , -CONR 2 R 3 , -CH(CH 3 )=CH 2 , -CH(CF 3 )NR 2 R 3 ,
each R, R 2 , and R 3 are independently selected from -H, optionally substituted C1-4 alkyl, optionally substituted Q-g alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C 3 _ 7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted C 6 -io aryl(Ci-C6)alkyl, and optionally substituted 5-10 membered heteroaryl; R 6 is independently selected from -H and optionally substituted Q- 4 alkyl; and each n is independently selected to be an integer from 0 to
[0050] Some embodiments of compounds of Formulas (III) include compounds having the structure of Formula -a):
Ill-a
or a pharmaceutically acceptable salt thereof. [0051] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), at least one of the optionally substituted moieties of A 2 , A 4 , and A 3 is substituted with F.
[0052] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), at least one of the optionally substituted moieties of A 2 , A 4 , and A 3 is substituted with Ci-C 6 alkyl containing one or more H C.
[0053] In some embodiments of compounds of Formulas (I), (III), (Ill-a), (I-a), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p) or their pharmaceutically
acce table salts; A 3 is selected from the group consisting of
; and Ag is selected from the group consisting of H, C 6 -io aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, and C 3-1 o carbocyclyl, Ci- 4 alkyl; X 2 , Xi, and Z are each independently selected from the group consisting of C(R 4 ) and N; Yi is selected from the group consisting of NR 5 , O, and S; J, L, Mi and M 2 are each independently selected from the group consisting of C(R 4 ) and N; R 4 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, C 3 _ 7 carbocyclyl, halo, hydroxy, and Ci-C 6 alkoxy; R 5 is selected from the group consisting of -H, Ci_ 4 alkyl, Ci_ 4 haloalkyl, and C 3 _ 7 carbocyclyl.
[0054] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is -CH 2 -.
[0055] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is -CH=CH-.
[0056] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is -0-.
[0057] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is S.
[0058] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is single bond.
[0059] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is phenyl.
[0060] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 3 is optionally substituted C 6 -io aryl-
[0061] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is selected from the group consisting of optionally substituted 3- 10 membered heterocyclyl, optionally substituted C6-io aryl, optionally substituted 5- or 7-10 membered heteroaryl, optionally substituted C 3 _io carbocyclyl, -S-, -S(=0)-, -SO 2 -, -C(=S)-, -C(=0)-, -NR-, -CH=CH-, -C≡C-, -OC(0)NH-, -NHC(0)NH-, -NHC(0)0-, - NHC(S)NH-, -NHC(S)0-, and -NHC(S)-.
[0062] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is selected from the group consisting of optionally substituted 3- 10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5- 10 membered heteroaryl, optionally substituted C 3 _io carbocyclyl, and -C≡C-,
[0063] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 2 is selected from the group consisting of optionally substituted 3- 10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted 5- 10 membered heteroaryl, and optionally substituted C 3 _io carbocyclyl.
[0065] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 3 is selected from the group consisting
of henyl, , and
[0066] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), A 3 is optionally substituted 5- 10 membered heteroaryl.
[0068] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A 2 is a single bond, A 4 is a single bond, and A 3 is an optionally substituted C 6 -io aryl or an optionally substituted 5-10 membered heteroaryl.
[0069] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A 3 has the structure:
, wherein J, L, Mi, M 2 , and M 3 are each independently selected from the group consisting of C(R 4 ) and N; and each R 4 is independently selected from the group consisting of - H, Ci-4 alkyl, C 1-4 haloalkyl, C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0070] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein each of J, L, Mi, M 2 , and M 3 are C(R 4 )
[0071] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein each R 4 is independently selected from -H and halo. [0072] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein Mi is halo and each of J, L, M 2 , and M 3 are CH.
[0073] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein L is halo and each of J, Mi, M 2 , and M 3 are CH.
[0074] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A 3 has a structure selected from the group consisting of:
, wherein J, L, Mi, M 2 , M , M 4 , and M5 are each independently selected from the group consisting of C(R 4 ) and N; and each R 4 is independently selected from the group consisting of -H, C 1 -4 alkyl, Ci_ 4 haloalkyl, C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci- C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy.
[0075] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), -e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-m), (I-n), or (I-p), wherein A 3 has the structure:
, wherein X is selected from the group consisting of C(R 4 ) and N; Y is selected from O and S; and R 4 is selected from the group consisting of -H, Q- 4 alkyl, Ci_ 4 haloalkyl, C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci- C 6 haloalkoxy), halo, hydroxy, and Ci-C 6 alkoxy. [0076] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula I-o):
Y is selected from the group consisting of NR 5 , O, S, and S0 2 ; Xi is selected from the group consisting of C(R 4 ) and N; J, L, Mi, M 2 , and M 3 are each independently selected from the group consisting of C(R 4 ) and N; R 4 is selected from the group consisting of -H, Ci- 4 alkyl, C 1-4 haloalkyl, C 3 _ 7 carbocyclyl, halo, hydroxy, and Q-C 6 alkoxy; R 5 is selected from the group consisting of -H, C 1-4 alkyl, C 1-4 haloalkyl, and C 3 _ 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Q-C 6 alkoxy, Q-C 6 haloalkyl, and Q-C 6 haloalkoxy).
[0077] In some embodiments of compounds of Formula (I-o) or their pharmaceutically acceptable salts; J, L, Mi, M 2 , and M 3 are independently selected from the group consisting of CH and N.
[0078] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6 is substituted with 18 F.
[0079] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein at least one of the optionally substituted moieties of A 5 , A 7 , and A 6 is substituted with Ci-C 6 alkyl containing one or more n C.
[0080] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 6 is phenyl. [0081] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 6 is selected from the group consisting of optionally substituted C 6-1 o aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 3 _io carbocyclyl, optionally substituted C 1-8 alkyl, optionally substituted -0-Ci_6 alkyl, and optionally substituted -O C 2 _ 6 alkenyl.
[0082] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is -CH 2 -.
[0083] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is -CH=CH-.
[0084] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is -0-.
[0085] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is S.
[0086] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is single bond.
[0087] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is optionally substituted C 6 -io aryl-
[0088] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 7 is phenyl.
[0090] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A 5 is -CH 2 - or -CH 2 CH 2 -; A 7 is a single bond; and A 6 is selected from the group consisting of C 1 -C4 alkyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl.
[0091] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 6 is optionally substituted phenyl.
[0092] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A 6 is unsubstituted phenyl. [0093] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A 6 is phenyl optionally substituted with one or more Q- 4 alkyl, C 3 -7 carbocyclyl, halo, hydroxy, and Ci-C 6 alkoxy.
[0094] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- -h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 6 has the structure:
[0095] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), wherein A5 is a single bond, A 7 is a single bond; and A 6 is C 1 -C5 alkyl.
[0096] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), A 6 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, 2,2-dimethylpropyl, and 1,2-dimethylpropyl.
[0097] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 1 is CONR 2 R 3 .
[0098] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 2 is -H and R 3 is optionally substituted Ci_ 4 alkyl.
[0099] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) wherein R 2 is -H and R 3 is selected from the group consisting of -H, Ci-C 4 alkyl optionally substituted with C-amido, and C 3 -C6 cycloalkyl.
[0100] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R is selected from ethyl or cyclopropyl.
[0101] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 3 is methyl substituted with C-amido.
[0102] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 3 is H. [0103] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 3 is optionally substituted Ci_ 4 alkyl.
[0104] In some embodiments of Formulas (I), (III), (Ill-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-j), (I-k), (I-o), or (I-p) R 3 is benzyl.
[0105] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R 6 is -H and optionally substituted Ci_ 4 alkyl.
[0106] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R 6 is optionally substituted Ci_ 4 alkyl.
[0107] In some embodiments of Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-h), (I-j), (I-k), (I-m), (I-n), (I-o), or (I-p), R 6 is methyl.
[0108] In some embodiments of Formula (I), Ai is selected from the group consisting of optionally substituted 6-10 membered heterocyclyl; 5-membered heterocyclyl optionally substituted with one or more C 1-4 alkyl, C3-7 carbocyclyl, halo, hydroxy, or Ci-C 6 alkoxy; optionally substituted 5-, 8-, or 9- membered heteroaryl; and optionally substituted C 3 _io carbocyclyl.
[0109] In some embodiments of Formula (I), Ai is selected from the group consisting of 5-membered heterocyclyl optionally substituted with one or more C 1-4 alkyl, C 3 _ 7 carbocyclyl, halo, hydroxy, or Ci-C 6 alkoxy and optionally substituted 5-membered heteroaryl.
[0110] In some embodiments of Formula (I), Ai is optionally substituted 5-membered heteroaryl.
[0111] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (I-p):
[0112] Some embodiments provide a compound of Formula (II):
[0113] P 2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 P2 pocket moiety selected from the group consisting of Glyl90, Phe233, Gly253, His254, and Ala255;
[0114] Li is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
[0115] P 3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 P3 pocket moiety selected from the group consisting of Glyl89, Glyl90, Serl91, Thr236, and Gly253;
[0116] R 10 is oxo and is positioned by P 2 such that, upon binding of the compound to calpain 9, R 10 forms a polar interaction with, and is within 4 A or less of, calpain 9 Glyl90 amide;
[0117] R 11 is nitrogen and is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R 11 forms a polar interaction with, and is within 4 A or less of, calpain 9 Gly253 carbonyl;
[0118] L 2 is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur; [0119] Pi is a moiety positioned by L 2 and having a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 9 PI pocket moiety selected from the group consisting of Gly95, Lysl88, Glyl89, and Ser242;
[0120] R 9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R 9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 9 moiety selected from the group consisting of Gln91, Cys97, and His254; and
[0121] R 6 is selected from -H and optionally substituted C 1 -4 alkyl.
[0122] Some embodiments of compounds of Formula (II) include compounds wherein; R 9 is -(C=R 12 )(C=R 13 )NR 2 R 3 ;
[0123] R 12 is oxo and is positioned such that, upon binding of the compound to calpain 9, R 12 forms a polar interaction with, and is within 4 A 0 or less of, calpain 9 His254 imidazole;
[0124] R 13 is oxo and is positioned such that, upon binding of the compound to calpain 9, R 13 forms a polar interaction with, and is within 4 A 0 or less of, at least one calpain 9 moiety selected from the group consisting of Gln91 side chain carboxamide and Cys97 backbone amide; and
[0125] R 2 and R 3 are independently selected from -H, optionally substituted C 1 -4 alkyl, optionally substituted C 3 _7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted C 6 -ioaryl(Ci-C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl.
[0126] Some embodiments of compounds of Formula (II) include compound wherein
R 12 is positioned such that, upon binding of the compound to calpain 9, R 12 is within 2.6 to 3.2 A 0 or less of, calpain 9 His254 imidazole.
R 13 is positioned such that, upon binding of the compound to calpain 9, R 13 is within 2.6 to 3.5 A 0 to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
R 13 is positioned such that, upon binding of the compound to calpain 9, R 13 is within 2.6 to 3.2 A ° to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
[0130] Some embodiments of compounds of Formula (II) include compound wherein R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R 9 forms a polar interaction with, and is within 3.6 A or less of, at least one calpain 9 moiety selected from the group consisting of Gln91, Cys97, and His254.
[0131] Some embodiments of compounds of Formula (II) include compound wherein R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 9, at least one atom of R 9 is within 2.6 to 3.6 A to the calpain 9 moieties including both Gln91 side chain carboxamide and Cys97 backbone amide.
[0133] Some embodiments of compounds of Formula (II) include compound wherein a carbon atom in R 9 at its point of attachment forms a covalent bond with Cys97
[0134] Some embodiments of compounds of Formula (II) include compound wherein the covalent bond length is between 1.7 and 1.9 A.
[0135] Some embodiments of compounds of Formula (II) include compound wherein P 2 is an optionally substituted 5-membered heteroaryl.
[0136] Some embodiments of compounds of Formula (II) include compound wherein R 11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R 11 forms a polar interaction with, and is within 3.6 A or less of, calpain 9 Gly253 carbonyl.
[0137] Some embodiments of compounds of Formula (II) include compound wherein, P 2 has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P 2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P2 pocket moiety selected from the group consisting of Gly208, Ser251, Gly271, His272, and Ala273;
[0138] P 3 is positioned by Li and has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P 3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P3 pocket moiety selected from the group consisting of Gly207, Gly208, Ser209, Ile254, and Gly271;
[0139] R 10 is positioned by P 2 such that, upon binding of the compound to calpain 1, R 10 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly208 amide;
[0140] R 11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 1, R 11 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly271 carbonyl;
[0141] Pi is positioned by L 2 and has a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 PI pocket moiety selected from the group consisting of Glyl l3, Ser206, Gly207, and Met260; and
[0142] R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R 9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 1 moiety selected from the group consisting of Gin 109, Cysl l5, and His272.
[0143] Some embodiments of compounds of Formula (II) include compound wherein:
[0144] P 2 has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P 2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P2 pocket moiety selected from the group consisting of Glyl98, Ser241, Gly261, His262, and Ala263;
[0145] P 3 is positioned by Li and has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P 3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P3 pocket moiety selected from the group consisting of Glyl97, Glyl98, Alal99, Ile244, and Gly261; [0146] R is positioned by P 2 such that, upon binding of the compound to calpain 2, R 10 forms a polar interaction with, and is within 4 A or less of, calpain 2 Glyl98 amide;
[0148] Pi is positioned by L 2 and has a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 PI pocket moiety selected from the group consisting of Glyl03, Serl96, Glyl97, and Ser250; and
[0149] R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R 9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262.
[0150] Some embodiments of compounds of Formula (II) include compound wherein P 2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 is within 2.6 to 3.6 A of Glyl90 carbonyl oxygen.
[0152] Some embodiments of compounds of Formula (II) include compound wherein P 2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 is within 2.8 to 4.8 A of a carbon atom in Phe233.
[0154] Some embodiments of compounds of Formula (II) include compound wherein P 2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 is within 2.6 to 3.7 A of Gly253 carbonyl oxygen. [0155] Some embodiments of compounds of Formula (II) include compound wherein P 2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 is within 2.9 to 3.3 A of Gly253 carbonyl oxygen.
[0156] Some embodiments of compounds of Formula (II) include compound wherein P 2 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 2 is within 2.9 to 4.8 A of Ala255 nitrogen.
[0158] Some embodiments of compounds of Formula (II) include compound wherein P 3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 3 is within 3.1 to 4.3 A of Glyl89 C-alpha.
[0162] Some embodiments of compounds of Formula (II) include compound wherein P 3 has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of P 3 is within 3.2 to 4.8 A of Serl91 nitrogen.
[0164] Some embodiments of compounds of Formula (II) include compound wherein R 10 is positioned by P 2 such that, upon binding of the compound to calpain 9, R 10 is within 2.6 to 3.5 A of, calpain 9 Glyl90 amide. [0165] Some embodiments of compounds of Formula (II) include compound wherein R 10 is positioned by P 2 such that, upon binding of the compound to calpain 9, R 10 is within 2.9 to 3.3 A of, calpain 9 Glyl90 amide.
[0166] Some embodiments of compounds of Formula (II) include compound wherein R 11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 9, R 11 is within 2.6 to 3.6 A or less of, calpain 9 Gly253 carbonyl.
[0168] Some embodiments of compounds of Formula (II) include compound wherein Pi is positioned by L 2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.4 A Gly95 carbonyl oxygen.
[0170] Some embodiments of compounds of Formula (II) include compound wherein Pi is positioned by L 2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.2 to 4.7 A of Lysl88 carbonyl carbon.
[0172] Some embodiments of compounds of Formula (II) include compound wherein Pi is positioned by L 2 and has a size and configuration such that, upon binding of the compound to calpain 9, at least one atom of Pi is within 3.0 to 4.1 A of Glyl89 C-alpha.
[0175] P 2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P 2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P2 pocket moiety selected from the group consisting of Gly208, Ser251, Gly271, His272, and Ala273;
[0177] P 3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of P 3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 P3 pocket moiety selected from the group consisting of Gly207, Gly208, Ser209, Ile254, and Gly271;
[0178] R 10 is oxo and is positioned by P 2 such that, upon binding of the compound to calpain 1, R 10 forms a polar interaction with, and is within 4 A or less of, calpain 1 Gly208 amide;
[0180] L 2 is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
[0181] Pi is a moiety positioned by L 2 and having a size and configuration such that, upon binding of the compound to calpain 1, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 1 PI pocket moiety selected from the group consisting of Glyl l3, Ser206, Gly207, and Met260;
[0182] R 9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R 9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09, Cysl 15, and His272; and R 6 is selected from -H and optionally substituted Q- 4 alkyl.
[0183] Some embodiments of compounds of Formula (II) include compound wherein R 9 is -(C=R 12 )(C=R 13 )NR 2 R 3 ;
[0184] R 12 is oxo and is positioned such that, upon binding of the compound to calpain 1, R 12 forms a polar interaction with, and is within 4 A ° or less of, calpain 1 His272 imidazole;
[0185] R 13 is oxo and is positioned such that, upon binding of the compound to calpain 1, R 13 forms a polar interaction with, and is within 4 A ° or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09 side chain carboxamide and Cysl 15 backbone amide; and
[0186] R 2 and R 3 are independently selected from -H, optionally substituted Q- 4 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted C 6 -ioaryl(Ci-C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl.
[0187] Some embodiments of compounds of Formula (II) include compound wherein R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 1, at least one atom of R 9 forms a polar interaction with, and is within 3.5 A or less of, at least one calpain 1 moiety selected from the group consisting of Glnl09, Cysl 15, and His272.
[0188] Some embodiments of compounds of Formula (II) include compound wherein a carbon atom in R 9 at its point of attachment forms a covalent bond with Cysl 15.
[0190] Some embodiments of compounds of Formula (II) include compound wherein P 2 is an optionally substituted 5-membered heteroaryl. [0191] Some embodiments of compounds of Formula (II) include compound wherein R 11 is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 1, R 11 forms a polar interaction with, and is within 3.5 A or less of, calpain 1 Gly271 carbonyl.
or a pharmaceutically acceptable salt thereof, wherein
[0193] P 2 is an optionally substituted cyclic moiety having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P 2 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P2 pocket moiety selected from the group consisting of Glyl98, Ser241, Gly261, His262, and Ala263;
[0195] P 3 is an optionally substituted cyclic moiety positioned by Li and having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of P 3 forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 P3 pocket moiety selected from the group consisting of Glyl97, Glyl98, Alal99, Ile244, and Gly261;
[0197] R 11 is nitrogen and is positioned by the carbons to which it is bonded such that, upon binding of the compound to calpain 2, R 11 forms a polar interaction with, and is within 4 A or less of, calpain 2 Gly261 carbonyl; [0198] L 2 is a bond or a moiety consisting of from 1 to 25 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur;
[0199] Pi is a moiety positioned by L 2 and having a size and configuration such that, upon binding of the compound to calpain 2, at least one atom of Pi forms a non-polar interaction with, and is within 5 A or less of, at least one calpain 2 PI pocket moiety selected from the group consisting of Glyl03, Serl96, Glyl97, and Ser250;
[0200] R 9 is a moiety positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R 9 forms a polar interaction with, and is within 4 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262; and R 6 is selected from -H and optionally substituted Q- 4 alkyl.
[0203] R 13 is oxo and is positioned such that, upon binding of the compound to calpain 2, R 13 forms a polar interaction with, and is within 4 A ° or less of, at least one calpain 2 moiety selected from the group consisting of Gln99 side chain carboxamide and Cysl05 backbone amide; and
[0204] R 2 and R 3 are independently selected from -H, optionally substituted Q- 4 alkyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C 6 -io aryl, optionally substituted C 6-1 oaryl(C 1 -C 6 )alkyl, and optionally substituted 5-10 membered heteroaryl.
[0205] Some embodiments of compounds of Formula (II) include compound wherein R 9 is positioned by the carbon to which it is attached such that, upon binding of the compound to calpain 2, at least one atom of R 9 forms a polar interaction with, and is within 3.5 A or less of, at least one calpain 2 moiety selected from the group consisting of Gln99, Cysl05, and His262.
[0206] Some embodiments of compounds of Formula (II) include compound wherein a carbon atom in R 9 at its point of attachment forms a covalent bond with Cysl95. [0207] Some embodiments of compounds of Formula (II) include compound wherein the covalent bond length is between 1.7 and 1.9 A.
[0210] Some embodiments include a compound selected from the group consisting of compounds 1 to 90, compounds 92-94, compound 195, compounds 197 to 235, compounds 238 to 273, compounds 276 to 281, compounds 283 to 299, compounds 303 to 309, compounds 313 to 363, compound 365, compounds 367-410, compounds 413-424, compounds 428-445, compounds 447-448, compounds 454-532, compound 540, compounds 546-588, compounds 591-605, compounds 607-611, compounds 613-630, and pharmaceutically acceptable salts thereof, as such compounds are described herein.
[0211] Some embodiments include a compound selected from the group consisting of compounds 91, 196, 274, 282, 310 to 312, 364, 366, 411, 536, 541, and pharmaceutically acceptable salts thereof, as such compounds are described herein.
[0212] Some embodiments include a compound selected from the group consisting of:
[0213] or a pharmaceutically acceptable salt thereof. Various embodiments include the S-enantiomer, the R-enantiomer, or the racemate of the above compounds.
[0214] Additional compounds suitable for use as described herein and that can be made by using the methods described herein are presented in Table 1.
- 106-
- Ill -
[0215] Where the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers, including racemates. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein including any polymorphic forms. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included in the scope of the compounds disclosed herein.
[0216] The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically; the artisan recognizes that such structures may only represent a very small portion of a sample of such compound(s). Such compounds are considered within the scope of the structures depicted, though such resonance forms or tautomers are not represented herein.
Isotopically-Labeled Compounds
[0217] Isotopes may be present in the compounds described. Each chemical element as represented in a compound structure may include any isotope of said element. The isotopes may be isotopes of carbon, chlorine, fluorine, hydrogen, iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including U C, 13 C, 14 C, 36 C1, 18 F, 2 H, 3 H, 123 I, 125 I, 13 N, 15 N, 15 0, 17 0, 18 0,
31 P, 32 P, 35 S, and 99 m Tc. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. Isotopically-labeled compounds of the present embodiments are useful in drug and substrate tissue distribution and target occupancy assays. For example, isotopically labeled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography), as discussed further herein.
[0218] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0219] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water- solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.
[0220] The term "pro-drug ester" refers to derivatives of the compounds disclosed herein formed by the addition of any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of pro-drug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art, including a (5-R-2-oxo-l,3-dioxolen-4-yl)methyl group. Other examples of pro-drug ester groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems", Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); and "Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examples of esters useful as prodrugs for compounds containing carboxyl groups). Each of the above-mentioned references is herein incorporated by reference in their entirety.
[0221] "Metabolites" of the compounds disclosed herein include active species that are produced upon introduction of the compounds into the biological milieu.
[0222] "Solvate" refers to the compound formed by the interaction of a solvent and a compound described herein, a metabolite, or salt thereof. Suitable solvates are pharmaceutically acceptable solvates including hydrates.
[0223] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical. In many cases, the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein in its entirety).
[0224] As used herein, "C a to Cb" or "C a -b" in which "a" and "b" are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "Ci to C 4 alkyl" or "C 1-4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH- , CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
[0225] The term "halogen" or "halo," as used herein, means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
[0226] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as "C 1-4 alkyl" or similar designations. By way of example only, "Ci_ 4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec -butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
[0227] As used herein, "haloalkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain, substituting one or more hydrogens with halogens. Examples of haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 F, - CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 C1, -CH 2 CF 2 CF 3 and other groups that in light of the ordinary skill in the art and the teachings provided herein, would be considered equivalent to any one of the foregoing examples.
[0228] As used herein, "alkoxy" refers to the formula -OR wherein R is an alkyl as is defined above, such as "C 1-9 alkoxy", including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like. [0229] As used herein, "polyethylene glycol" refers to the formula wherein n is an integer greater than one and R is a hydrogen or alkyl. The number of repeat units "n" may be indicated by referring to a number of members. Thus, for example, "2- to 5- membered polyethylene glycol" refers to n being an integer selected from two to five. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
[0230] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. In various embodiments, the heteroalkyl may have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compounds may be designated as "C 1-4 heteroalkyl" or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "Ci-4 heteroalkyl" indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
[0231] The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
[0232] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term "aryl" where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as "C 6 -io aryl," "C 6 or Cio aryl," or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
[0233] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an aryl as is defined above, such as "C 6 -io aryloxy" or "C 6 -io arylthio" and the like, includingbut not limited to phenyloxy.
[0234] An "aralkyl" or "arylalkyl" is an aryl group connected, as a substituent, via an alkylene group, such "C 7-14 aralkyl" and the like, including but not limited to benzyl, 2- phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
[0235] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heteroaryl" where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. In various embodiments, a heteroaryl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, a heteroaryl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
[0236] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
[0237] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl" where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as "C 3 _6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3- dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
[0238] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as a substituent, via an alkylene group, such as "C4_io (carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
[0239] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0240] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.
[0241] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3-6 membered heterocyclyl" or similar designations.
[0242] In various embodiments, a heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, a heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-l,2-oxazinyl, trioxanyl, hexahydro-l,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-l,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.
[0243] A "(heterocyclyl)alkyl" is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
[0244] As used herein, "acyl" refers to -C(=0)R, wherein R is hydrogen, Ci_ 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 carbocyclyl, aryl, 5- 10 membered heteroaryl, and 5- 10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl. [0245] An "O-carboxy" group refers to a "-OC(=0)R" group in which R is selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0246] A "C-carboxy" group refers to a "-C(=0)OR" group in which R is selected from hydrogen, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=0)OH).
[0247] A "cyano" group refers to a "-CN" group.
[0248] A "cyanato" group refers to an "-OCN" group.
[0249] An "isocyanato" group refers to a "-NCO" group.
[0250] A "thiocyanato" group refers to a "-SCN" group.
[0251] An "isothiocyanato" group refers to an " -NCS" group.
[0252] A "sulfinyl" group refers to an "-S(=0)R" group in which R is selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0253] A "sulfonyl" group refers to an "-S0 2 R" group in which R is selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0254] An "S-sulfonamido" group refers to a "-S0 2 NRAR B " group in which RA and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0255] An "N-sulfonamido" group refers to a "-N(RA)S0 2 R B " group in which RA and R are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0256] An "0-carbamyl" group refers to a "-OC(=0)NRAR B " group in which RA and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. [0257] An "N-carbamyl" group refers to an "-N(R A )OC(=0)R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0258] An "O-thiocarbamyl" group refers to a "-OC(=S)NR A R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0259] An "N-thiocarbamyl" group refers to an "-N(R A )OC(=S)R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0260] A "C-amido" group refers to a "-C(=0)NR A R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0261] An "N-amido" group refers to a "-N(R A )C(=0)R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0262] An "amino" group refers to a "-NR A R B " group in which R A and R B are each independently selected from hydrogen, Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 7 carbocyclyl, C 6- io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0263] An "aminoalkyl" group refers to an amino group connected via an alkylene group.
[0264] An "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as a "C 2 _ 8 alkoxyalkyl" and the like.
[0265] As used herein, a "natural amino acid side chain" refers to the side-chain substituent of a naturally occuring amino acid. Naturally occurring amino acids have a substituent attached to the a-carbon. Naturally occurring amino acids include Arginine, Lysine, Aspartic acid, Glutamic acid, Glutamine, Asparagine, Histidine, Serine, Threonine, Tyrosine, Cysteine, Methionine, Tryptophan, Alanine, Isoleucine, Leucine, Phenylalanine, Valine, Proline, and Glycine.
[0266] As used herein, a "non-natural amino acid side chain" refers to the side-chain substituent of a non-naturally occurring amino acid. Non-natural amino acids include β-amino acids (β 3 and β 2 ), Homo-amino acids, Proline and Pyruvic acid derivatives, 3-substituted Alanine derivatives, Glycine derivatives, Ring-substituted Phenylalanine and Tyrosine Derivatives, Linear core amino acids and N-methyl amino acids. Exemplary non-natural amino acids are available from Sigma-Aldridge, listed under "unnatural amino acids & derivatives." See also, Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in its entirety.
[0267] As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be "substituted," it is meant that the group is substituted with one or more subsitutents independently selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, Ci-C 6 heteroalkyl, C3-C 7 carbocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), C 3 -C 7 -carbocyclyl-Ci- C 6 -alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), 5-10 membered heterocyclyl-Ci-C 6 -alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), aryl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), aryl(Ci-C 6 )alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), 5-10 membered heteroaryl(Ci-C 6 )alkyl (optionally substituted with halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, and Ci-C 6 haloalkoxy), halo, cyano, hydroxy, Ci-C 6 alkoxy, Ci-C 6 alkoxy(Ci- C 6 )alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci-C 6 )alkyl (e.g., -CF 3 ), halo(Ci- C 6 )alkoxy (e.g., -OCF 3 ), Ci-C 6 alkylthio, arylthio, amino, amino(Ci-C 6 )alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N- sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as "optionally substituted" that group can be substituted with the above substituents.
[0268] In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C 1 -C4 alkyl, amino, hydroxy, and halogen.
[0269] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as "alkylene" or "alkenylene."
[0270] When two R groups are said to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with the atom to which they are attached," it is meant that the collective unit of the atom and the two R groups are the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, when the following substructure is present:
1 2 1 and R and R are defined as selected from the group consisting of hydrogen and alkyl, or R and
R together with the nitrogen to which they are attached form a heterocyclyl, it is meant that R and R can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
where ring A is a heterocyclyl ring containing the depicted nitrogen.
[0271] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," it is meant that the collective unit of the atoms, intervening bonds, and the two R groups are the recited ring. For example, when the following substructure is present:
and R 1 and R2 are defined as selected from the group consisting of hydrogen and alkyl, or R 1 and R together with the atoms to which they are attached form an aryl or carbocyclyl, it is meant that
R 1 and 2" can be selected from hydrogen or alkyl, or alternatively, the substructure has structure:
where A is an aryl ring or a carbocyclyl containing the depicted double bond.
[0272] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of the molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. Thus, for example, a substituent depicted as -AE- or ¾ E includes the substituent being oriented such that the A is attached at the leftmost attachment point of the molecule as well as the case in which A is attached at the rightmost attachment point of the molecule.
[0273] As used herein, the substructure:
that the n any ring atom position within the ring or ring
s ystem Ai. The substructure: means that the A 8 atom is in the ring atom position immediately adjacent (i.e., alpha) to the point of attachment indicated by *.
[0274] As used herein, "isosteres" of a chemical group are other chemical groups that exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated include -SO 3 H, -SO 2 HNR, -P0 2 (R) 2 , - P0 3 (R) 2 , -CONHNHS 0 2 R, -COHNS0 2 R, and -CONRCN, where R is selected from hydrogen, Ci-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C 3 _ 7 carbocyclyl, C 6 -io aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH 2 , O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of carbocyclic and heterocyclic isosteres contemplated. The atoms of said ring structure may be optionally substituted at one or more positions with R as defined above.
[0275] It is also contemplated that when chemical substituents are added to a carboxylic isostere, the compound retains the properties of a carboxylic isostere. It is contemplated that when a carboxylic isostere is optionally substituted with one or more moieties selected from R as defined above, then the substitution and substitution position is selected such that it does not eliminate the carboxylic acid isosteric properties of the compound. Similarly, it is also contemplated that the placement of one or more R substituents upon a carbocyclic or heterocyclic carboxylic acid isostere is not a substitution at one or more atom(s) that maintain(s) or is/are integral to the carboxylic acid isosteric properties of the compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the compound.
[0276] Other carboxylic acid isosteres not specifically exemplified in this specification are also contemplated.
[0277] The term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent", "substance", and "compound" are used interchangeably herein.
[0278] The term "analog" is used herein to refer to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent.
Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such as higher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry. [0279] The term "mammal" is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.
[0280] The term "microbial infection" refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to a host mammal. Thus, a mammal is "suffering" from a microbial infection when excessive numbers of a microbial population are present in or on a mammal's body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal. Specifically, this description applies to a bacterial infection. Note that the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.
[0281] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.
[0282] "Subject" as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. [0283] An "effective amount" or a "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. "Curing" means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).
[0284] "Treat," "treatment," or "treating," as used herein refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a
[0285] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., known to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are both hereby incorporated herein by reference in their entirety. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
[0286] In the following schemes, protecting groups for oxygen atoms are selected for their compatibility with the requisite synthetic steps as well as compatibility of the introduction and deprotection steps with the overall synthetic schemes (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).
[0287] If the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
[0288] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California , USA), Emka- Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989)..
Synthesis of Compounds of Formula I
[0289] In one embodiment, the method involves reacting an appropriately substituted intermediate with an acidic hydrogen (IV) with an ester (V) under base catalyzed conditions to yield the ester derivative (VI). The resulting product was then subjected to hydrolysis under basic conditions to yield the carboxylic acid derivative (VII) which was then subjected to amide- coupling conditions with an amino acid derivative (VIII) wherein the carboxylic acid group is functionalized with the R 1 group (Scheme 1). Alternatively, the carboxylic acid product (VII) is then subjected to amide coupling conditions with the amino alcohol derivative (VHI-a) to yield the corresponding adduct (IX). The resulting adduct (IX) is subjected to oxidation conditions with DMP oxidation (with hypervalent iodine) or by an oxidizing agent such as PCC (pyridinium chlorochromate) to yield the oc-ketoamide product (X). Alternately, the adduct (IX) was subjected to oxidation conditions using EDC and dichloroacetic acid or using IBX as the oxidizing agent to yield the oc-ketoamide product (X). The skilled artisan will once again appreciate that there are many other oxidizing conditions and agents which are within the scope of this disclosure to oxidize the hydroxyl group. This synthesis route is generally shown in Scheme 2.
Scheme 1;
Scheme 2:
[0290] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds encompassed herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
Uses of Isotopically-Labeled Compounds
[0291] Some embodiments provide a method of using isotopically labeled compounds and prodrugs of the present disclosure in: (i) metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2H or 3H); (ii) detection or imaging techniques [such as positron emission tomography (PET) or single -photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays; or (III) in radioactive treatment of patients.
[0292] Isotopically labeled compounds and prodrugs of the embodiments thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. An 18 F or 11 C labeled compound may be particularly preferred for PET, and an I labeled compound may be particularly preferred for SPECT studies. Further substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
Synthesis of Isotopically Labeled Compounds
[0293] 18 F labeled compounds are synthesized as shown in the schemes below. In one embodiment, the method involves reacting the intermediate 450 with a 18 F-labeling agent using conditions as described in Rotstein, et al., Spirocyclic hypervalent iodine(III) -mediated radiofluorination of non-activated and hindered aromatics, Nature Communications, 2014, Vol. 5, 4365-4371 and Rotstein, et ah, Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides, Chemical Science, 2016, Vol. 7,
4407-4417, both of which are incorporated herein by reference in their entirety, to yield the 18 F- labeled intermediate methyl 2-((ethoxycarbonyl)amino)-3-(4-(fluoro- 18 F)phenyl)propanoate (631) which is then transformed into the final oc-ketoamide product represented by the general structure XI (Scheme 3).
[0294] Alternately, 18 F-labeled compound XV is synthesized as shown in Scheme 4.
In one embodiment, iodanylidene intermediate XII is used to introduce the 18 F label yielding using conditons as described in Rotstein, et ah, Spirocyclic hypervalent iodine(III) -mediated radiofluorination of non-activated and hindered aromatics, Nature Communications, 2014, Vol. 5,
4365-4371 and Rotstein, et al., Mechanistic Studies and Radiofluorination of Structurally
Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides, Chemical Science, 2016, Vol. 7,
4407-4417 to yield the labeled oc-ketoamide product XV. In another embodiment, iodanylidene intermediate (XIV) is (Scheme 4) subjected to oxidation conditions with DMP oxidation (with hypervalent iodine) or by an oxidizing agent such as PCC (pyridinium chlorochromate) to yield the oc-ketoamide product (XV). In yet another embodiment, iodanylidene intermediate (XIII)
(Scheme 4) is subjected to 18 F-labeling reaction conditions as described earlier followed by hydrolysis of the ester under basic conditions to yield the carboxylic acid derivative which is then subjected to amide-coupling conditions with an amino acid derivative wherein the carboxylic acid group is functionalized with the R 1 group to yield the labeled oc-ketoamide product XV. Scheme 4:
Administration and Pharmaceutical Compositions
[0295] The compounds are administered at a therapeutically effective dosage. While human dosage levels have yet to be optimized for the compounds described herein, generally, a daily dose may be from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
[0296] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
[0297] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
[0298] In addition to the selected compound useful as described above, come embodiments include compositions containing a pharmaceutically-acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety. [0299] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
[0300] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
[0301] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
[0302] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
[0303] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
[0304] The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.
[0305] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
[0306] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
[0307] Compositions described herein may optionally include other drug actives.
[0308] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
[0309] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
[0310] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
[0311] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
[0312] Tonicity adjusters may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.
[0313] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
[0314] In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
[0315] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
[0316] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co- solvent, emulsifier, penetration enhancer, preservative system, and emollient. [0317] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
[0318] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
[0319] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
[0320] The compounds and compositions described herein, if desired, may be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compounds and compositions described herein are formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0321] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01 99.99 wt % of a compound of the present technology based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 80 wt %. Representative pharmaceutical formulations are described below.
Formulation Examples
[0322] The following are representative pharmaceutical formulations containing a compound of Formula I.
Formulation Example 1— Tablet formulation
[0323] The following ingredients are mixed intimately and pressed into single scored tablets.
Quantity per
Ingredient tablet, mg
Compounds disclosed herein 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
Formulation Example 2 - Capsule formulation
[0324] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient capsule, mg
lactose, spray-dried 148 magnesium stearate
Formulation Example 3 - Suspension formulation
[0325] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount
Compounds disclosed herein 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.0 g
sorbitol (70% solution) 13.00 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL
colorings 0.5 mg
distilled water q.s. to 100 mL
Formulation Example 4— Injectable formulation
[0326] The following ingredients are mixed to form an injectable formulation.
Compounds disclosed herein 0.2 mg-20 mg
sodium acetate buffer solution, 0.4 M 2.0 mL
HC1 (IN) or NaOH (IN) q.s. to suitable pH
water (distilled, sterile) q.s. to 20 mL
Formulation Example 5— Suppository Formulation
[0327] A suppository of total weight 2.5 g is prepared by mixing the compound of the present technology with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid;
Riches-Nelson, Inc., New York), and has the following composition:
Compounds disclosed herein 500 mg
Witepsol® H-15 balance
Methods of Treatment
[0328] The compounds disclosed herein or their tautomers and/or pharmaceutically acceptable salts thereof can effectively act as CAPNl, CAPN2, and/or CAPN9 inhibitors and treat conditions affected at least in part by CAPN1, CAPN2, and/or CAPN9. Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient. Some embodiments provide a method for treating a fibrotic disease with an effective amount of one or more compounds as disclosed herein.
[0329] In some embodiments, the subject is a human.
[0330] Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
[0331] Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By "coadministration," it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.
[0332] Some embodiments include combinations of a compound, composition or pharmaceutical composition described herein with any other pharmaceutical compound approved for treating fibrotic or myofibroblast differentiation associated diseases or disorders..
[0333] Some embodiments provide a method for inhibiting CAPN1, CAPN2, and/or CAPN9 and/or a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9 with an effective amount of one or more compounds as disclosed herein.
[0334] The compounds disclosed herein are useful in inhibiting CAPN1, CAPN2, and/or CAPN9 enzymes and/or treating disorders relating to fibrosis or myofibroblast differentiation.
[0335] Some embodiments provide a method for inhibiting CAPN1, CAPN2, and/or CAPN9 which method comprises contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds as disclosed herein. [0336] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds or a pharmaceutical composition disclosed herein comprising a pharmaceutically acceptable excipient.
[0337] Some embodiments provide a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds or a pharmaceutical composition disclosed herein comprising a pharmaceutically acceptable excipient.
[0338] Some embodiments provide a method for inhibiting CAPNl, CAPN2, and/or CAPN9 is provided wherein the method comprises contacting cells with an effective amount of one or more compounds disclosed herein. In some embodiments a method for inhibiting CAPNl, CAPN2, and/or CAPN9 is performed in- vitro or in- vivo.
[0339] Calpains are also expressed in cells other than neurons, microglia and invading macrophages. In particular, they are important in skeletal muscle and herein inhibition of calpains also refers to inhibition in these cells as well.
Selective inhibition
[0340] Some embodiments provide a method for competitive binding with calpastatin (CAST), the method comprising contacting a compound disclosed herein with CAPNl, CAPN2, and/or CAPN9 enzymes residing inside a subject. In such a method, the compound specifically inhibits one or more of the enzymes selected from the group consisting of: CAPNl, CAPN2, and CAPN9 by at least 2-fold, by at least 3-fold, by at least 4-fold, by at least 5-fold, by at least 10- fold, by at least 15-fold, by at least 20-fold, by at least 50-fold, by at least 100-fold, by at least 150-fold, by at least 200-fold, by at least 400-fold, or by at least 500-fold.
[0341] Some embodiments provide a method for selectively inhibiting CAPNl in the presence of CAPN2 and CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds disclosed herein.
[0342] Some embodiments provide a method for selectively inhibiting CAPN2 in the presence of CAPNl and CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds disclosed herein. [0343] Some embodiments provide a method for selectively inhibiting CAPN9 in the presence of CAPN2 and CAPNl, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds disclosed herein.
[0344] Some embodiments provide a method for selectively inhibiting CAPNl and CAPN2 in the presence of CAPN9, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds disclosed herein.
[0346] Some embodiments provide a method for selectively inhibiting CAPN2 and CAPN9 in the presence of CAPNl, which includes contacting cells (including neurons/microglia /invading macrophages) with an effective amount of one or more compounds disclosed herein.
[0347] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPNl, CAPN2, and/or CAPN9, said compounds or a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.
[0348] Some embodiments provide a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits CAPNl, CAPN2, and/or CAPN9, said compounds being selected from compounds disclosed herein or a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.
[0349] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPNl, CAPN2, and/or CAPN9, said compounds being selected from compounds disclosed herein or a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient..
[0350] Some embodiments provide a method for treating a disease affected at least in part by CAPNl, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits CAPNl, CAPN2, and/or CAPN9, said compounds being selected from compounds disclosed herein or a pharmaceutical composition comprising one or more compounds disclosed herein and a pharmaceutically acceptable excipient.
[0351] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1: 1:5.
[0352] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1: 1: 10.
[0353] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1: 1:20.
[0355] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 100.
[0356] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPNl, CAPN2, and CAPN9 in a ratio of at least 1: 1:200.
[0357] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:250.
[0359] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:5.
[0360] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1: 10.
[0361] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:20.
[0363] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1 : 1 : 100.
[0364] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:200. [0365] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:250.
[0366] Some embodiments provide a method for treating a fibrotic disease, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:500.
[0367] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.
[0368] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1: 10.
[0369] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.
[0371] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1: 100.
[0372] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:200.
[0374] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which specifically inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1: 1:500.
[0375] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:5.
[0376] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1: 10.
[0377] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:20.
[0379] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1: 100. [0380] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:200.
[0381] Some embodiments provide a method for treating a disease affected at least in part by CAPN1, CAPN2, and/or CAPN9, which method comprises administering to a subject an effective amount of one or more compounds which selectively inhibits two or more enzymes selected from the group consisting of CAPN1, CAPN2, and CAPN9 in a ratio of at least 1:1:250.
[0383] Some embodiments provide a method for prophylactic therapy or treatment of a subject having a fibrotic disorder wherein said method comprising administering an effective amount of one or more compounds disclosed herein to the subject in need thereof.
[0384] Some embodiments provide a method for prophylactic therapy or treatment of a subject having a disorder affected by CAPN1, CAPN2, and/or CAPN9 wherein said method comprising administering an effective amount of one or more compounds disclosed herein to the subject in need thereof.
[0385] Some embodiments provide a method for inhibiting myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)) is provided wherein the method comprises contacting cells with an effective amount of one or more compounds disclosed herein. In one aspect, the method for inhibiting myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)) is performed in- vitro or in-vivo.
[0386] Some embodiments provide a method for treating a disease or condition selected from the group consisting of or that produces a symptom selected from the group consisting of: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic - reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases, wherein which method comprises administering to a subject an effective amount of one or more compounds disclosed herein to a subject in need thereof.
[0387] Some embodiments provide a method for treating liver fibrosis.
[0388] Some embodiments provide a method for treating cardiac fibrosis.
[0389] Some embodiments provide a method for treating fibrosis in rheumatoid arthritis diseases.
[0390] Some embodiments provide a method for treating a condition affected by CAPNl, CAPN2, and/or CAPN9, which is in both a therapeutic and prophylactic setting for subjects. Both methods comprise administering of one or more compounds disclosed herein to a subject in need thereof.
[0391] Some embodiments provide a method for treating stiff skin syndrome.
[0392] Preferred embodiments include combinations of a compound, composition or pharmaceutical composition described herein with other CAPNl, CAPN2, and/or CAPN9 inhibitor agents, such as anti-CAPNl, CAPN2, AND/OR CAPN9 antibodies or antibody fragments, CAPNl, CAPN2, and/or CAPN9 antisense, iRNA, or other small molecule CAPNl, CAPN2, and/or CAPN9 inhibitors.
[0393] Some embodiments include combinations of a compound, composition or pharmaceutical composition described herein to inhibit myofibroblast differentiation (e.g., Epithelial/Endothelial-to-Mesenchymal Transition (EpMT/EnMT)). Some embodiments include combinations of one or more of these compounds which are inhibitors of one or more (or all three) CAPNl, CAPN2, and/or CAPN9, alone or in combination with other TGF signaling inhibitors, could be used to treat or protect against or reduce a symptom of a fibrotic, sclerotic or post inflammatory disease or condition including: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, postvasectomy pain syndrome, and rheumatoid arthritis.
[0394] Some embodiments include a combination of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, such as antiinflammatories including glucocorticoids, analgesics (e.g. ibuprofen), aspirin, and agents that modulate a Th2-immune response, immunosuppressants including methotrexate, mycophenolate, cyclophosphamide, cyclosporine, thalidomide, pomalidomide, leflunomide, hydroxychloroquine, azathioprine, soluble bovine cartilage, vasodilators including endothelin receptor antagonists, prostacyclin analogues, nifedipine, and sildenafil, IL-6 receptor antagonists, selective and nonselective tyrosine kinase inhibitors, Wnt-pathway modulators, PPAR activators, caspase-3 inhibitors, LPA receptor antagonists, B cell depleting agents, CCR2 antagonists, pirfenidone, cannabinoid receptor agonists, ROCK inhibitors, miRNA-targeting agents, toll-like receptor antagonists, CTGF-targeting agents, NADPH oxidase inhibitors, tryptase inhibitors, TGFD inhibitors, relaxin receptor agonists, and autologous adipose derived regenerative cells.
[0395] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a host of conditions arising from fibrosis or inflammation, and specifically including those associated with myofibroblast differentiation. Example conditions include liver fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type Π diabetes), lung fibrosis (idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders), cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and/or chronic rejection in transplanted organs, ischemic reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.
[0396] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples. The following examples will further describe the present invention, and are used for the purposes of illustration only, and should not be considered as limiting.
General procedures
[0397] It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.
[0398] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in their entirety) and the like. All the intermediate compounds of the present invention were used without further purification unless otherwise specified.
[0399] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.
[0400] The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application.
[0401] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.
[0402] The following abbreviations have the indicated meanings:
DCM dichloromethane
DIEA N,N-Diisopropylethylamine
DJ EA N,N-Diisopropylethylamine
DMF N,N-dimethylformamide
DMP Dess Martin Periodinane
DNs dinitrosulfonyl
ESBL extended- spectrum β-lactamase
EtOAc ethyl acetate EA = ethyl acetate
FCC = Flash Column Chromatography
HATU = 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluoropho sphate
MeCN = acetonitrile
NMR = nuclear magnetic resonance
PE = Petroleum Ether
Prep = preparatory
Py = pyridine
Sat. = saturated aqueous
TBDMSC1 = tert-butyldimethylsilyl chloride
TBS = ie/ -butyldimethylsilyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
[0403] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
COMPOUNDS 1-2, 5-6, 8, 91-92
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-PHENYL-lH-IMIDAZOLE-5-
[0404] A mixture of compound 1A (102 mg, 1.0 eq), compound IB (160 mg, 1.2 eq) and HBTU (250 mg, 1.25 eq) in DMF (8 mL) was stirred at room temperature for 5mins, and then DIEA (0.3mL, 3.0eq) was added. After stirred at room temperature for 30mins, the reaction mixture was diluted with 50 mL ethyl acetate and 20 mL Hexane, washed with water, saturated NaHC0 3 and brine and concentrated in vacuo to afford intermediate compound 1C (190 mg, yield 92%).
[0405] A solution of compound 1C (190 mg, 1.0 eq) in dry THF (15 mL) was cooled to -50 °C under N 2 , and then was added a solution of IN LAH in THF (0.55 mL, 1.1 eq) dropwise at -50 °C. The reaction mixture was stirred at -30 °C to - 10 °C for 2hrs, quenched with saturated NaHC0 3 at -20 °C, and then extracted with 3 x 30 mL ethyl acetate. The combined organic phase was dried over Na 2 S0 4 to give the crude mixture, which was purified on silica gel column. Compound 1 (105 mg, 65%): MS (ESI) m/z (M+H) + : 320.3; 1H NMR (400 MHz, CDC1 3 ): δ 9.64 (s, 1H), 7.65 (s, 1H), 7.56 (s, 1H), 7.46 (m, 3H), 7.26-7.33 (m, 5H), 7.09 (m, 2H), 6.29 (d, 1H), 4.81(m, 1H), 3.19 (d, 2H) ppm
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-PHENYL-lH-PYRAZOLE-5-
CARBOXAMIDE (2)
((5)-5-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-PHENYL-lH-PYRA ZOLE-3-
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-4-PHENYLTHIAZOLE-5-CARBOXA MIDE
(5)-3-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-PHENYL-lH-PYRAZ OLE-5-
[0406] Compounds 2, 5, 6 and 8 were prepared as in Example 1 using the corresponding carboxylic acid, respectively. Compound 2: MS (ESI) m/z (M+H) + : 320.2; 1H NMR (400 MHz, DMSO): δ 9.6 (s, 1H), 9.15 (d, 1H), 7.73 (s, 1H), 7.4 - 7.2 (m, 10H), 6.8 (s, 1H), 4.53 (m, 1H), 3.25 (dd, 1H), 2.8 (dd, 1H) ppm.
[0407] Compound 5: MS (ESI) m/z (M+H) + : 334.3; 1H NMR (400 MHz, CDC1 3 ): δ 9.67 (s, 1H), 7.54 - 7.4 (m, 6H), 7.3 - 7.2 (m, 5H), 6.73 (s, 1H), 4.82 (m, 1H), 3.21 (d, 2H), 2.33 (s, 3H) ppm. [0408] Compound 6: MS (ESI) m/z (M+H) + : 337.5; 1H NMR (400 MHz, CDC1 3 ): δ 9.56 (s, IH), 8.88 (s, IH), 7.5 - 7.34 (m, 5H), 7.27 - 7.2 (m, 3H), 6.94 (m, 2H), 6.35 (d, IH), 4.73 (m, IH), 3.1 (dd, IH), 3.08 (dd, IH) ppm.
[0409] Compound 8: MS (ESI) m/z (M+H) + : 334.3; 1H NMR (400 MHz, DMSO): δ 9.59 (s, 0.6H), 9.01 (d, 0.6 H), 8.35 (d, 0.4 H), 7.38 -7.06 (m, 10H), 6.58 (s, 0.6H), 6.48 (s, 0.4 H), 4.82 (m, 0.2 H), 4.54 (m, 0.6 H), 3.98 (m, 0.4 H), 3.25 (dd, 0.6 H), 2.98 (dd, 0.4 H), 2.78 (dd, 0.6 H), 2.7 (dd, 0.4 H), 2.48 (s,
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)THIAZOLE-5-CARBOXAMIDE (91)
[0410] Compound 91 was prepared as in Example 1 from the corresponding starting materials, compounds 91A and IB. Compound 91: 1H NMR (400 MHz, CDC1 3 ): δ 9.69 (s, IH), 8.85 (s, IH), 8.21 (s, IH), 7.06 (d, IH), 7.32 -7.18 (m, 8H), 4.88 (m, IH), 3.26 (m, 2H) ppm. MS (ESI) m/z (M+H) + 261.3.
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-2-PHENYL-lH-BENZO[rf]IMIDA ZOLE-7-
C ARB OXAMIDE (92)
[0411] Compound 92 was prepared as in Example 1 using the corresponding carboxylic acid. 1H NMR (400 MHz, CDC1 3 ): δ 12.07 (s, IH), 11.92 (d, IH), 9.84 (s, IH), 8.1 - 8.0 (m, 3H), 7.5 - 7.46 (m, 10H), 7.32 -7.18 (m, 8H), 5.04 (m, IH), 3.34 (d, 2H) ppm. MS (ESI) m/z (M+H) + 370.4.
COMPOUNDS 3-4
(5)-l-(BENZO[£ ) ]THIAZOL-2-YL)-N-((5)-l-OXO-3-PHENYLPROPAN-2-
YL)PYRROLIDINE-2-CARBOXAMI (3)
3A 3B
[0412] A mixture of compound 3A (500 mg, 1.0 eq), compound 3B (738 mg, 1.0 eq), Cul (124 mg, 0.15 eq) and K 2 C0 3 (1.8 g, 3.0 eq) in DMA (15 mL) was heated at 100 °C for 18 hrs, and then the inorganic was removed by filtration. The mixture was diluted with water (50 mL), adjusted pH ~ 6, and then extracted with 3 x 50 mL acetate to afford intermediate compound 3C. Compound 3 was prepared as in Example 1 using the corresponding carboxylic acid, intermediate compound 3C. Compound 3: MS (ESI) m/z (M+H) + : 380.2; 1H NMR (400 MHz, CDC1 3 ): δ 9.66 (s, IH), 8.32 (d, IH), 7.63 (d, IH), 7.52 (d, IH), 7.30 (t, IH), 7.10 (t, IH), 6.92-7.01 (m, 5H), 4.69 (m, 2H), 3.45 (m, IH), 3.36 (m, IH), 3.17 (dd, IH), 2.90 (dd, IH), 2.55 (m, IH), 2.03 (m, 3H) ppm.
(5)-l-(BENZO[£ ) ]OXAZOL-2-YL)-N-((5)-l-OXO-3-PHENYLPROPAN-2-
YL)PYRROLIDINE-2-CARBOXAMIDE (4)
[0413] Compound 4 was prepared as in Example 2 using the corresponding starting materials. MS (ESI) m/z (M+H) + : 364.3; 1H NMR (400 MHz, CDC1 3 ): δ 9.65 (s, IH), 7.69 (br d, IH), 7.37 (d, IH), 7.33 (t, IH), 7.18 (t, IH), 6.98-7.10 (m, 6H), 4.71 (m, 2H), 4.59 (m, IH), 3.61 (m, 2H), 3.19 (dd, IH), 2.97 (dd, IH), 2.41 (m, IH), 1.91-2.12 (m, 3H) ppm. EXAMPLE 3
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-3-PHENYLISOTHIAZOLE-4-
[0414] To a suspension of compound 9A (1.2 g) in toluene (15 ml) was added chlorocarbonylsulfenyl chloride (1.3 ml). The mixture was heated at 100° C for 2 hrs to obtain a clear solution (gas evolution was observed). When TLC showed complete conversion, the reaction mixture was concentrated and the solid residue was triturated with hexane, filtered and dried to yield compound 9B.
[0415] To a solution of compound 9B (1.4 g) in α,α,α-trifluorotoluene (10 mL) was added diethyl acetylenedicarboxylate (2.0 ml). After heated in the microwave at 170° C for 1 hr, the reaction mixture was concentrated, and the oily residue was purified by flash column chromatography. The product-containing fractions were combined, concentrated, and the residue was triturated with hexane, filtered and dried to yield compound 9C.
[0416] A solution of compound 9C (2.1 g) and NaOH (1.4 g) in water (20 mL) was refluxed for 2.5 hrs. The reaction mixture was cooled, diluted with water (150 mL) and acidified with concentrated HC1 (aqueous). A precipitate was formed. The water layer was extracted with EtOAc (2 x 200 mL; the precipitate slowly dissolved). The combined organic layers were washed with brine, dried (Na 2 S0 4 ) and concentrated to yield compound 9D.
[0417] A suspension of compound 9D (1.8 g) in 1,2-dichlorobenzene (20 mL) was refluxed for 20 mins (gas formation is observed). The reaction mixture was cooled diluted with hexane (50 mL) and filtered to precipitate the product. To a suspension of the crude product in water (40 mL) was added IN NaOH (10 ml). The water layer was extracted with ethyl acetate (2x100 mL) and acidified with concentrated HC1 to pH ~ 3. The product was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na 2 S0 4 ) and concentrated to yield intermediate compound 9E.
[0418] Compound 9 was prepared as in Example 1 using the corresponding carboxylic acid, intermediate compound 9E. MS (ESI) m/z (M+H) + : 359.1; 1H NMR (400 MHz, CDC1 3 ): δ 9.59 (s, 1H), 9.16 (s, 1H), 7.56 - 7.5 (m, 2H), 7.48 - 7.4 (m, 3H), 7.27 - 7.22 (m, 3H), 6.94 (m, 2H), 6.15 (d, 1H), 4.79 (m, 1H), 3.1 (d, 2H) ppm.
COMPOUNDS 7, 10-11, 14, 18, 20
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-lH- IMIDAZOLE-5-
[0419] A mixture of compound 7A (50 mg, 1.0 eq), compound 7B (74 mg, 1.2 eq) and HBTU (126 mg, 1.25 eq) in DMF (3mL) was stirred at room temperature for 5 mins, and then DIEA (0.15 mL, 3.0 eq) was added. After stirred at room temperature for 30 mins, the reaction mixture was diluted with ethyl acetate (30 mL) and hexane (10 mL), washed with IN HCl, water, saturated NaHC0 3 and brine and concentrated in vacuo to afford intermediate compound 7C (65 mg, yield 67%) as white solid.
[0420] To a solution of compound 7C (65 mg, 1.0 eq) in dry DCM (10ml) and
DMSO (2 mL) was added DMP (305 mg, 4.0 eq). After stirred at room temperature for 1 hr, the mixture was diluted with DCM (30 mL), quenched by adding 10% aqueous Na 2 S 2 0 3 /saturated aqueous NaHC0 3 (v/v = 1/1, ~ 10 mL). The organic layer was separated by extracting the aqueous layer with DCM (30 mL x 5). The combined organic layer was washed with H 2 0 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated to afford white solid, which was then triturated in CH 2 C1 2 /Hexane to provide pure product compound 7 (29 mg, yield 45%). MS (ESI) m/z (M+H) + : 363.4; 1H NMR (400 MHz, CDC1 3 ): δ 7.66 (s, 1H), 7.57 (s, 1H), 7.45 (m, 3H), 7.26-7.35 (m, 5H), 7.05 (m, 2H), 6.72 (s, 1H), 6.24 (d, 1H), 5.58 (m, 2H), 4.81(m, 1H), 3.38 (dd, 1H), 3.14 (dd, 1H) ppm. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-lH-PYR AZOLE-5-
CARBOXAMIDE (10)
[0421] Prepared as in Example 4 using the corresponding carboxylic acid. MS
(ESI) m/z (M+H) + : 363.3; 1H NMR (400 MHz, DMSO): δ 9.15 (d, IH), 8.11 (s, IH), 7.71 (s, IH), 7.4 - 7.2 (m, 10H), 7.07 (d, IH), 6.72 (s, IH), 5.26 (m, IH), 2.81 (dd, IH), 2.64 (dd, IH) ppm.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-PHENYLISOTHIA ZOLE-4-
[0422] Prepared as in Example 4 using the corresponding carboxylic acid, intermediate compound 9E. MS (ESI) m/z (M+H) + 380.2; 1H NMR (400 MHz, DMSO): δ 9.15 (d, IH), 9.05 (s, IH), 8.14 (s, IH), 7.89 (s, IH), 7.5 -7.4 (m, 2H), 7.3 -7.2 (m, 8H), 5.34 (m, IH), 3.2 (d, 2H) ppm.
(5)-l-(BENZO[£ ) ]OXAZOL-2-YL)-N-((5)-l-OXO-3-PHENYLPROPAN-2- YL)PYRROLIDINE-2-CARBOXAMIDE (14)
[0423] Intermediate compound 14E was prepared as in Example 3. Compound 14 was then prepared as in Example 4 using the corresponding intermediate carboxylic acid, compound 14E. Compound 14: MS (ESI) m/z (M+H) + : 431.5; 1H NMR (400 MHz, DMSO): δ 9.14 (s, IH), 9.05 (d, IH), 8.16 (d, IH), 7.9 (s, IH), 7.62 -7.56 (m, 2H), 7.3 -7.2 (m, 8H), 5.36 (m, IH), 3.17 (dd, IH), 2.78 (dd, IH) ppm.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYLTHIAZOL E-5-
(ESI) m/z (M+H) + : 380.1; 1H NMR (400 MHz, DMSO): δ 10.1 l(d, IH), 9.33 (s, IH), 8.49 (d, IH), 8.13 (s, IH), 8.07 (d, IH), 8.03 (d, IH), 7.85 (s, IH), 7.74 (m, 2H), 7.65 (m, IH), 7.12 - 7 (m, 5H), 5.51 (m, IH), 3.18 (dd, IH) 2.89 (dd, IH) ppm. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-(BENZO[£ ) ][l,3]DIOXOL-5- YL)-3-METHYLISOXAZOLE-4-CARBOXAMIDE (20)
(ESI) m/z (M+H) + : 422.1; 1H NMR (400 MHz, DMSO-d6): δ 8.88 (d, 1H), 8.19 (s, 1H), 7.91 (s, 1H), 7.17-7.30 (m, 7H), 6.94 (d, 1H), 6.11 (s, 2H), 5.45 (m, 1H), 3.22 (dd, 1H), 2.72 (dd, 1H), 2.03 (s, 3H) ppm.
COMPOUNDS 12-13, 15-17, 19, 27, 44, 47, 54, 60, 94, 117-118, 128, 148, 207, 235, 303-305,
309-312, 23, 39, 456, 461, 492
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-( PYRIDIN-2-YL)- -PYRAZOLE-5-CARBOXAMIDE (12)
[0426] To a solution of compound 12A (5.0 g, l .Oeq) and compound 12B (2.64 g, l .Oeq) in dry DMF (20 mL) was added 4A° molecular sieve (5.0 g, powder). The resulting mixture was stirred room temperature under N 2 for 20 hrs, filtrated to remove the molecular sieves, diluted with hexane (80 mL) and ethyl acetate (80 mL), and then washed with 3 x 50 mL water, 50 mL saturated NaHC0 3 and brine. The crude mixture was purified on silica gel column to provide compound 12C (3.2 g, yield 48%) as clear oil.
[0427] A mixture of compound 12C (350 mg, l .Oeq) and compound 12D (190 mg, 1.0 eq) in acetic acid (8 mL) was heated at 100 °C for lhr. The residue, upon in-vauo removal of solvent, was suspended in ethyl acetate (80 mL), washed with saturated NaHC0 3 and brine. The crude mixture was purified on silica gel column to provide compound 12E (100 mg, yield 25%). Compound 12E (100 mg) was treated with LiOH in MeOH/water to afford compound 12F (87 mg, yield 100%).
[0428] A mixture of compound 12F (85 mg, 1.0 eq), compound 12G (116 mg, 1.2 eq) and HBTU (190 mg, 1.2 eq) in DMF (5 mL) was stirred at room temperature for 5 mins, and then DIEA (0.3 mL, 4.0 eq) was added. After stirred at room temperature for 30 mins, the mixture was diluted with 50 mL ethyl acetate and 20 mL hexane, washed with IN HC1, water, saturated NaHC0 3 and brine and concentrated in vacuo to afford intermediate compound 12H (150 mg, yield 94%) as white solid.
[0429] To a solution of compound 12H (150 mg, 1.0 eq) in dry DCM (20ml) and
DMSO (2.5 mL) was added DMP (673 mg, 4.0 eq). After stirred at room temperature for 1 hr, the mixture was diluted with DCM (80 mL), quenched by adding 10% Na 2 S 2 0 3 /saturated NaHC0 3 (v/v = 1/1, ~ 20 mL). The organic layer was separated. The aqueous layer was extracted with DCM (30 mL x 2). The combined organic layer was washed with H 2 0 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated to afford white solid. The solid was triturated in CH 2 C1 2 /Hexane to provide pure compound 12 (95 mg, yield 64%). MS (ESI) m/z (M+H) + : 378.3; 1H NMR (400 MHz, DMSO-d6): δ 9.15 (d, IH), 8.21 (d, IH), 7.91 (t, IH), 7.82 (s, IH), 7.54 (d, IH), 7.17-7.32 (m, 6H), 6.49 (s, IH), 5.29 (m, IH), 3.15 (dd, IH), 2.84 (dd, IH), 2.23 (s, 3H) ppm.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(BENZO[D]T HIAZOL-2-YL)- 3-METHYL-1H-PYRAZOLE-5-CARBOXAMIDE (13) (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(QUI NOLIN-2-
YL)-lH-PYRAZOLE-5-CARBOXAMIDE (15)
(5)-l-([l,l , -BIPHENYL]-3-YL)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2- YL)-3- METHYL-1H-PYRAZOLE-5-CARBOXAMIDE (16) (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- (METHYLSULFONYL)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE (17) (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- (TRIFLUOROMETHOXY)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE (19)
[0430] Compounds 13, 15-17 and 19 were prepared, respectively, as in Example 5 by utilizing the corresponding hydrazine derivative.
[0431] Compound 13: MS (ESI) m/z (M+H) + : 434.3; 1H NMR (400 MHz, DMSO- d6): δ 10.09 (d, IH), 8.10 (d, IH), 7.99 (d, IH), 7.83 (s, IH), 7.62 (d, IH), 7.40 (m, 2H), 7.04- 7.24 (m, 5H), 6.68 (s, IH), 5.51 (m, IH), 3.16 (dd, IH), 2.95 (dd, IH), 2.24 (s, 3H) ppm.
[0432] Compound: 15: MS (ESI) m/z (M+H) + : 428.4; 4H NMR (400 MHz,
DMSO): δ 9.28 (d, 0.5 H), 8.77 (d, 0.5 H), 8.45 (d, IH), 8 (d, IH), 7.9 - 7.5 (6 H), 7.2 - 7.1 (6 H), 5.4 (m, 0.5 H4.44 (m, 0.5 H), 3.2 - 2.7 (m, 2H) ppm.
[0433] Compound 16: MS (ESI) m/z (M+H) + : 453.3; 1H NMR (400 MHz,
DMSO-d6): δ 9.10 (d, IH), 8.09 (s, IH), 7.87 (s, IH), 7.35-7.62 (m, 8H), 7.19-7.29 (m, 5H), 7.09 (d, IH), 6.61 (s, IH), 5.30 (m, IH), 3.17 (dd, IH), 2.81 (dd, IH), 2.25 (s, 3H) ppm.
[0434] Compound 17: MS (ESI) m/z (M+H) + : 455.3; 1H NMR (400 MHz, DMSO- d6): δ 9.27 (d, IH), 8.14 (s, IH), 7.88 (m, 2H), 7.82 (d, IH), 7.35-7.62 (m, 8H), 7.19-7.45 (m, 7H), 6.62 (s, IH), 5.25 (m, IH), 3.19 (m, 4H), 2.82 (dd, IH), 2.25 (s, 3H) ppm.
[0435] Compound 19: MS (ESI) m/z (M+H) + : 461.3; 1H NMR (400 MHz, DMSO- d6): δ 9.15 (d, IH), 8.11 (s, IH), 7.87 (s, IH), 7.82 (d, IH), 7.21-7.35 (m, 9H), 6.61 (s, IH), 5.23 (m, IH), 3.20 (dd, IH), 2.82 (dd, IH), 2.24 (s, 3H) ppm.
(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-3-PHENYLISOX AZOLE-
4-CARBOXAMIDE (27)
[0436] Compound 27 (30.0 mg, 43.0% yield, white solid) was prepared as in Example 12 from the corresponding carboxylic acid, compound 27A. Compound 27: 1H NMR (400MHz, DMSO-de) δ 8.94 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.49 - 7.41 (m, 3H), 7.41 - 7.34 (m, 2H), 7.33 - 7.21 (m, 5H), 5.42 - 5.35 (m, 1H), 3.29 - 3.21 (m, 1H), 2.80 - 2.70 (m, 1H), 2.35 - 2.27 (m, 3H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-l,2,3-
THIADIAZOLE-5-CARBOXAMIDE (44)
[0437] Compound 44 (42.4 mg, yield: 47.7%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 44A. Compound 44: 1H NMR (400 MHz, DMSO-i¾) δ 9.60 (br d, J = 7.5 Hz, 1 H), 8.19 (s, 1 H), 7.93 (s, 1 H), 7.79 - 7.67 (m, 2 H), 7.52 - 7.39 (m, 3 H), 7.34 - 7.21 (m, 5 H), 5.52 - 5.39 (m, 1 H), 3.23 (dd, J = 14.0, 3.5 Hz, 1 H), 2.78 (dd, 7 = 13.6, 10.5 Hz, 1 H). MS (ESI) m/z (M+H) + 381.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-5- PHENYLTHIAZOLE-4-CARBOXAMIDE (54)
[0438] Compound 54 (75 mg, yield: 75.4%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 54A. 1H NMR (400 MHz, DMSO- e) δ 8.46 (br d, J = 7.7 Hz, 1 H) 8.05 (br s, 1 H) 7.81 (br s, 1 H) 7.43 - 7.29 (m, 1 H) 7.41 - 7.29 (m, 1 H) 7.29 - 7.29 (m, 1 H) 7.41 - 7.29 (m, 1 H) 7.30 - 7.28 (m, 1 H) 7.28 - 7.08 (m, 5 H) 5.37 (td, = 8.1, 4.5 Hz, 1 H) 3.22 - 3.09 (m, 1 H) 3.17 (br dd, J = 14.0, 4.1 Hz, 1 H) 3.06 - 2.92 (m, 1 H) 2.72 - 2.60 (m, 3 H). MS (ESI) m/z (M+H) + 394.0. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-PHENYLISOXAZO LE-4-
[0439] Compound 60 (40 mg, yield 36.20%, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 60A. Compound 60: 1H NMR (400MHz, DMSO- e) δ 9.02 (d, 7=7.5 Hz, 1H), 8.83 (s, 1H), 8.16 (s, 1H),7.92 - 7.78 (m, 3H), 7.59 - 7.42 (m, 3H), 7.35 - 7.17 (m, 4H), 5.43 - 5.34 (m, 1H),3.27 - 3.17 (m, 1H), 2.90 - 2.79 (m, 1H). MS (ESI) m/z (M +H) + 364.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-CHLORO-l-METH YL-3- PHENYL-1H-PYRAZOLE-4-CARBOXAMIDE (94)
[0440] Compound 94 was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 94A. Compound 94: 1H NMR (400 MHz, DMSO): δ 8.8 (d, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.5 - 7.46 (m, 2H), 7.32 -7.18 (m, 8H), 5.41 (m, 1H), 3.82 (s, 3H), 3.17 (dd, 1H), 2.76 (dd, 1H) ppm. MS (ESI) m/z (M+H) + 410.9.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-ISOPROPYL-l-P HENYL-lH-
PYRAZOLE-5-CARBOXAMIDE (117)
[0441] Compound 117 (10 mg, yield 18.29%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 117A. Compound 117: 1H NMR (400MHz, DMSO-i¾) δ 8.36 (d, 7=7.8 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.63 - 7.47 (m, 5H), 7.32 - 7.14 (m, 5H), 6.66 (s, 1H), 5.50 - 5.39 (m, 1H), 3.23 - 3.13 (m, 1H), 3.09 - 2.89 (m, 2H), 1.12 (d, 7=6.8 Hz, 6H). MS (ESI) m/z (M + H) + 405.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-2- PHENYLFURAN-3-CARBOXAMIDE (118)
[0442] Compound 118 (58 mg, yield: 55.4%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 118A. Compound 118: 1H NMR (400MHz, DMSO-d 6 ) δ 8.54 (d, 7 = 7.5 Hz, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.68 (d, 7 = 7.0 Hz, 2H), 7.35 - 7.26 (m, 7H), 7.23 - 7.17 (m, 1H), 6.39 (d, 7 = 0.9 Hz, 1H), 5.30 (br d, 7 = 0.7 Hz, 1H), 3.19 - 3.12 (m, 1H), 2.88 - 2.79 (m, 1H), 2.33 - 2.29 (m, 3H). MS (ESI) m/z (M+H) + 377.1. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(TERT-BUTYL)- l-PHENYL- lH-PYRAZOLE-5-CARBOXAMIDE (128)
[0443] Compound 128 (101.7 mg, 68.04% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 128A. Compound 128: 1H NMR (400 MHz, CDC1 3 ) δ 7.55 - 7.44 (m, 3H), 7.42 - 7.35 (m, 2H), 7.34 - 7.28 (m, 1H), 7.25 - 7.14 (m, 5H), 6.74 (br s, 1H), 6.70 (s, 1H), 5.73 - 5.64 (m, 1H), 5.53 (br s, 1H), 3.44 - 3.35 (m, 1H), 3.18 - 3.09 (m, 1H), 1.16 (s, 9H). MS (ESI) m/z (M+l) + 419.3.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-PHENYLOXAZOLE -4-
CARBOXAMIDE (148)
[0444] Compound 148 (10 mg, yield: 30.8%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 148A. Compound 148: 1H NMR (400MHz, DMSO-i¾) δ 8.57 (s, 1H), 8.44 (d, =7.7 Hz, 1H), 8.14 - 8.03 (m, 3H), 7.85 (s, 1H), 7.49 - 7.42 (m, 3H), 7.30 - 7.15 (m, 5H), 5.49 - 5.40 (m, 1H), 3.26 - 3.17 (m, 1H), 3.12 - 3.02 (m, 1H). MS (ESI) m/z (M +H) + 364.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-CYCLOPROPYL-4 - PHENYLTHIAZOLE-5-CARBOXAMIDE (207)
[0445] Compound 207 (54.0 mg, 44.09% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 135A. Compound 207: 1H NMR (400 MHz, CDCI 3 ) δ 7.52-7.45 (m, 2H), 7.43 - 7.38 (m, 3H), 7.21 - 7.17 (m, 3H), 6.79-6.77 (m, 2H), 6.70 (s, 1H), 6.19 - 6.17 (d, 7 = 6.0Hz, 1H), 5.53 (s, 1H), 5.50 - 5.45 (m, 1H), 3.25 - 3.21 (m, 1H), 2.90- 2.85 (m, 1H), 2.33-2.27 (m, 1H), 1.19 - 1.16 (m, 2H), 1.13 - 1.10 (m, 2H). MS (ESI) m/z (M+l) + 420.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2,6-DIMETHYL PYRIMIDIN- 4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (235)
[0446] Compound 235 (61.6 mg, 51.11% yield, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 235A. Compound 235: 1H NMR (400 MHz, CDCI 3 ) δ 9.83 (d, = 7.2 Hz, 1H), 7.57 (s, 1H), 7.21 - 7.16 (m, 3H), 7.11 - 7.06 (m, 2H), 6.87 (s, 1H), 6.75 (br s, 1H), 5.84 - 5.76 (m, 1H), 5.56 (br s, 1H), 3.49 - 3.31 (m, 2H), 2.55 (s, 3H), 2.34 - 2.32 (m, 6H). MS (ESI) m/z (M+l) + 407.1. ((5)-N-(l-AMINO-l,2-DIOXOPENTAN-3-YL)-3-METHYL-5-PHENYLISOXA ZOLE-4-
[0447] Compound 47 (90.00 mg, yield 60.4%, white solid) was prepared as in Example 5 from the corresponding starting materials, 23A and 47A. Compound 47: 1H NMR (400MHz, DMSO- e) δ 8.98 (d, 7 = 6.6 Hz, 1H), 8.12 (br s, 1H), 7.88 - 7.79 (m, 3H),7.57 - 7.50 (m, 3H), 5.12 - 5.02 (m, 1H), 2.32 (s, 3H), 1.95 - 1.77 (m,lH), 1.65 - 1.48 (m, 1H), 0.93 (t, 7=7.4
Hz, 3H). MS (ESI) m/z (M +H) + 316.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYLOXAZ OLE-5-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-PHENYLISOXAZO LE-4-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-3- (TRIFLUOROMETHYL)-lH-PYRAZOLE-5-CARBOXAMIDE (305) (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l,3-DIPHENYL-lH - PYRAZOLE-4-CARBOXAMIDE (309)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(TERT-BUTY L)-3-METHYL- lH-PYRAZOLE-5-CARBOXAMIDE (310)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-CHLORO-l-ETHY L-lH-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-CHLORO-l-ETHY L-3- METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (312)
[0448] Compounds 303-305 and 309-312 were prepared as in Example 5 from the corresponding carboxylic acid with compound 12G, respectively.
[0449] Compound 303: 1H NMR (400MHz, DMSO-d 6 ) δ 1H NMR (400 MHz, DMSO): δ 8.51 (s, 1H), 7.9 - 7.85 (m, 2H), 7.81 (d, 1H), 7.4 - 7.0 (m, 10H), 4.53 (m, 1H), 2.98 (dd, 1H), 2.57 (dd, 1H) ppm. MS (ESI) m/z (M+H) + 364.3.
[0450] Compound 304: 1H NMR (400MHz, DMSO-d 6 ) δ 9.2 - 8.9 (m, 1H), 8.11 (m, 1H), 7.7 - 7.1 (m, 12H), 5.3 (m, 0.5 H), 4.4 (m, 0.5H), 2.85 - 2.55 (m, 2H) ppm. MS (ESI) m/z (M+H) + 364.3. [0451] Compound 305: 1H NMR (400MHz, DMSO-d 6 ) δ 9.3 (d, IH), 8.07 (s, IH), 7.83 (s, IH), 7.4 - 7.1 (m, 10H), 5.24 (m, IH), 3.14 (dd, IH), 2.74 (dd, IH) ppm. MS (ESI) m/z (M+H) + 431.3.
[0452] Compound 309: 1H NMR (400MHz, DMSO-d 6 ) δ 8.7 (m, IH), 8.49 (d, IH), 8.1 - 7.1 (m, 17H), 5.31 (m, 0.5 H), 4.6 - 4.4 (m, 0.5H), 3.1 - 2.7 (m, 2H) ppm. MS (ESI) m/z (M+H) + 439.3.
[0453] Compound 310: 1H NMR (400MHz, DMSO-d 6 ) δ 7.75 (d, IH), 7.4 - 7.1 (m, 5H), 6.38 (s, IH), 6.1 (d, 2H), 4.48 (m, IH), 3.02 (dd, IH), 2.52 (dd, IH) 2.08 (s, 3H), 1.31 (s, 9H) ppm. MS (ESI) m/z (M+H) + 379.3.
[0454] Compound 311: 1H NMR (400MHz, DMSO-d 6 ) δ 8.89 (d, IH), 8.13 (d, IH), 7.86 (s, IH), 7.33 (s, IH), 7.3 - 7.1 (m, 5H), 6.8 (s, IH), 5.38 (m, IH), 3.99 (q, 2H), 3.21 (dd, IH), 2.78 (dd, IH) 1.11 (t, 3H) ppm. MS (ESI) m/z (M+H) + 349.2.
[0455] Compound 312: 1H NMR (400MHz, DMSO-d 6 ) δ 8.74 (d, IH), 8.1 (s, IH), 7.83 (s, IH), 7.4 - 7.2 (m, 5H), 6.58 (s, IH), 5.29 (m, IH), 4.25 (q, 2H), 3.18 (dd, IH), 2.87 (dd, IH), 2.13 (s, 3H), 1.15 (t, 3H) ppm. MS (ESI) m/z (M+H) + 329.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-5- PHEN YLI -4- C ARB OX AMIDE (23)
[0456] To a solution of compound 23A (500 mg, 2.46 mmol) in THF (10 mL) was added 23B (311 mg, 2.71 mmol) and EDCI (566 mg, 2.95 mmol) with DCM (10 mL). The mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated and diluted with EA (20 mL). Then the mixture was washed with HCl (1M, 20 mL), saturated aqueous NaHC0 3 (20 mL), dried over Na 2 S0 4 and concentrated. Compound 23C (800 mg, crude, yellow oil): 1H NMR (400MHz, DMSO-i¾) δ 7.93 - 7.88 (m, 2H), 7.69 - 7.63 (m, IH), 7.62 - 7.56 (m, 2H), 2.87 (s, 4H), 2.54 - 2.51 (m, 3H). [0457] Compound 23 (30.0 mg, yield 35.0%, white solid) was prepared as in Example 5 from the corresponding intermediate compounds 23C and 12G. Compound 23: 1H NMR (400MHz, DMSO-d 6 ) δ 9.08 (br d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.64 (br d, = 7.2 Hz, 2H), 7.55 - 7.41 (m, 3H), 7.35 - 7.21 (m, 5H), 5.54 - 5.45 (m, 1H), 3.29 - 3.23 (m, 1H), 2.81 - 2.71 (m, 1H), 2.09 (s, 3H). MS (ESI) m/z (M+H) + 378.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(4-PHENYL-lH- PYRAZOL-l-
YL)THIAZOLE-5-CARBOXAMIDE (39)
[0458] Compound 39 (5.20 mg, 26.12% yield, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 21F and 12G. Compound 39: 1H NMR (CDC1 3, 400 MHz): δ 11.75 (d, J = 4.8 Hz, 1H), 8.73 - 8.71 (m, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 7.69 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.45 - 7.41 (m, 2H), 7.35 - 7.31 (m, 1H), 7.29 - 7.27 (m, 1H), 7.25 - 7.21 (m, 4H), 6.78 (br s, 1H), 5.82 - 5.74 (m, 1H), 5.48 (br s, 1H), 3.46 - 3.41 (m, 1H), 3.27 - 3.20 (m, 1H). MS (ESI) m/z (M+H) + 446.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METH YL-l- (PYRIDIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (456)
[0459] Compound 456 (240 mg, 86.0% yield, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 12F and 3-amino-N- cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride. Compound 456: 1H NMR (CDCl 3i 400 MHz): δ 9.15 (d, = 7.2 Hz, 1H), 8.80 (d, = 5.2 Hz, 1H), 8.21 - 8.17 (m, 1H), 7.92 - 7.86 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 - 7.16 (m, 6H), 6.50 (s, 1H), 5.36 - 5.27 (m, 1H), 3.17 - 3.09 (m, 1H), 2.88 - 2.79 (m, 1H), 2.79 - 2.70 (m, 1H), 2.24 (s, 3H), 0.69 - 0.53 (m, 4H). MS (ESI) m/z (M+H) + 418.2.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-
PHENYLISOXAZOLE-4-CARBOXAMIDE (461)
[0460] Compound 461 (270 mg, 68.77% yield, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 60A and 3-amino-N- cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride. Compound 461: 1H NMR (CDCl 3i 400 MHz): δ 9.04 (d, J = 7.5 Hz, 1H), 8.87 (d, J = 4.8 Hz, 1H), 8.82 (s, 1H), 7.85 (d, J = 7.3 Hz, 2H), 7.59 - 7.44 (m, 3H), 7.36 - 7.19 (m, 5H), 5.37 (br.s., 1H), 3.27 - 3.17 (m, 1H), 2.90 - 2.73 (m, 2H), 0.72 - 0.51 (m, 4H). MS (ESI) m/z (M+H) + 404.1. (5)-N-(4-AMINO-l-(4-HYDROXYPHENYL)-3,4-DIOXOBUTAN-2-YL)-3-ME THYL-5- PHENYLISOXAZOLE-4-CARBOXAMIDE (492)
[0461] Compound 492 (35 mg, 60.9% yield, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 23A and (3S)-3-amino-4-(4- (ieri-butoxy)phenyl)-2-hydroxybutanamide followed by removal of the ie/ -butyl group to obtain the final compound 492. Compound 492: 1H NMR (DMSO-d 6, 400 MHz): δ 9.29 (s, 1H), 9.01 (d, J = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.66 - 7.41 (m, 5H), 7.07 (d, J = 8.4 Hz, 2H), 6.68 (d, = 8.6 Hz, 2H), 5.46 - 5.29 (m, 1H), 3.13 (br d, J = 10.8 Hz, 1H), 2.63 (br d, J = 2.9 Hz, 1H), 2.13 (s, 3H). MS (ESI) m/z (M+H) + 394.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYRIDIN -2-YL)-lH-
[0462] Compound 495 (4.0 g, 44.68% yield, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 12F and 3-amino-2- hydroxy-4-phenylbutanamide hydrochloride to obtain the final compound 495. Compound 495: 1H NMR (DMSO-d 6, 400 MHz): δ 7.74 (br d, J = 9.0 Hz, 1H), 7.31 (d, = 8.5 Hz, 2H), 7.20 - 7.08 (m, 5H), 7.04 (d, J = 9.0 Hz, 1H), 6.97 (d, = 8.5 Hz, 2H), 5.40 (d, = 6.3 Hz, 1H), 4.96 (s, 2H), 4.79 (d, = 2.3 Hz, 2H), 4.48 - 4.15 (m, 2H), 3.97 - 3.86 (m, 1H), 3.68 (t, = 8.2 Hz, 1H), 3.63 - 3.49 (m, 2H), 2.98 (dd, / = 3.4, 13.9 Hz, 1H), 2.70 - 2.59 (m, 1H), 1.78 (qd, = 6.8, 13.6 Hz, 1H), 0.72 (d, = 6.8 Hz, 3H), 0.69 - 0.62 (m, 1H), 0.67 (d, = 6.8 Hz, 2H). MS (ESI) m/z (M+Na) + 493.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-PHENYLISOXAZOLE-4 -
[0463] Compound 531 (4.0 g, 44.68% yield, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 60A and 3-amino-2- hydroxy-4-phenylbutanamide hydrochloride to obtain the final compound 531. Compound 531: 1H NMR (CD 3 CN 400 MHz): δ 8.52 (s, 1H), 7.84 - 7.75 (m, 2H), 7.57 - 7.51 (m, 1H), 7.51 - 7.43 (m, 2H), 7.32 - 7.23 (m, 3H), 7.23 - 7.17 (m, 2H), 7.17 - 7.07 (m, 1H), 7.06 - 6.93 (m, 1H), 6.23 (s, 1H), 5.55 - 5.47 (m, 1H), 3.29 (dd, / = 4.9, 14.1 Hz, 1H), 2.92 (dd, = 8.9, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 364.1. EXAMPLE 6
Compounds 21-22, 322, 29, 31, 75, 90, 279
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-4-(4-PHENYL-lH-PYRAZOL-l- -5-CARBOXAMIDE (21)
[0464] A mixture consisting of compound 21A (500 mg, 2.12 mmol), compound 21B (306 mg, 2.12 mmol) and Cs 2 C0 3 (2.07 g, 6.36 mmol) was stirred at 110.6 °C for 16 hrs. The reaction mixture was cooled to room- temperature, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether: Ethyl acetate = 3:2 and then Acetic acid: Ethyl acetate = 1: 100) to afford compound 21C (80 mg, 12.61% yield) as a light yellow solid, and compound 21D (125 mg, 21.73% yield) as a yellow solid.
[0465] Compound 21C: 1H NMR (CDC1 3, 400 MHz): δ 8.85 (s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 7.57 (d, 7 = 7.6 Hz, 2H), 7.40 (t, 7 = 7.6 Hz, 2H), 7.30 - 7.26 (m, 1H), 4.41 - 4.32 (m, 2H), 1.34 (t, 7 = 7.2 Hz, 3H).
[0466] Compound 21D: 1H NMR (CDC1 3, 400 MHz): (514.70 (br. s., 1H), 9.33 (s, 1H), 8.87 (d, 7 = 0.8 Hz, 1H), 8.41 (d, 7 = 0.8 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.43 - 7.38 (m, 2H), 7.30 - 7.24 (m, 1H). MS (ESI) m/z (M+H) + 271.8.
[0467] To a solution of compound 21C (80 mg, 267.25 umol) in MeOH (5 mL) and
H 2 0 (2.5 mL) was added LiOH (19.20 mg, 801.75 umol) in one portion at 25 °C under N 2 . The mixture was stirred at 25 °C for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and adjusted with IN HCl to pH ~ 3, extracted with ethyl acetate 90 mL (30 mL x 3). The combined organic layers were washed with brine 30 mL, dried over anhyrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 21D (71.1 mg, 98.07% yield) as white solid. 1H NMR (CDC1 3, 400 MHz): δ 8.84 (s, 1H), 8.78 (d, 7 = 0.8 Hz, 1H), 8.13 (d, 7 = 0.8 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.45 (t, 7 = 7.6 Hz, 2H), 7.39 - 7.34 (m, 1H). MS (ESI) m/z (M+H) + 271.8.
[0468] To a solution of compound 21D (80 mg, 294.89 umol) and 1- hydroxypyrrolidine-2,5-dione (21E) (35.6 mg, 309.63 umol) in DME (3.50 mL) was added EDCI (84.8 mg, 442.34 umol) in one portion at 25 °C under N 2 . The resultant mixture was stirred at 25 °C for 6 hrs. The mixture was concentrated under reduced pressure, diluted with EtOAc (100 mL), washed with IN HCl (10 mL) and saturated aqueous NaHC0 3 (10 mL x 3), and then washed with brine (20 mL). The organic phase was dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to afford intermediate compound 21F (100 mg, crude) as yellow oil. MS (ESI) m/z (M+H) + 368.9.
[0469] A mixture consisting of compound 21F (100 mg, 271.47 umol) and compound 21G (41.1 mg, 271.47 umol) in DME (3 mL) was stirred at 25 °C for 2 hrs. The mixture was concentrated in vacuum, diluted with ethyl acetate (100 mL), washed with IN HCl (10 mL) and saturated aqueous NaHC0 3 (10 mL x 3), and then washed with brine (20 mL). The organic phase was dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether: Ethyl acetate = 3:2) to afford compound 21H (65 mg, 59.20% yield). 1H NMR (CDC1 3, 400 MHz): δ 10.54 (d, 7 = 7.6 Hz, 1H), 9.21 (d, 7=0.4 Hz, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.78 (d, 7=7.6 Hz, 2H), 7.45 - 7.38 (m, 2H), 7.31 - 7.26 (m, 1H), 7.24 - 7.18 (m, 4H), 7.15 - 7.10 (m, 1H), 4.96 - 4.89 (m, 1H), 4.13 - 4.02 (m, 1H), 3.52 - 3.43 (m, 2H), 2.97 - 2.91 (m, 1H), 2.82 - 2.74 (m, 1H). MS (ESI) m/z (M+H) + 405.0.
[0470] DMP (63 mg, 148.34 umol) was added to a solution of compound 21H (30 mg, 74.17 umol) in dichloromethane (6 mL). The mixture was stirred at 25 °C for 12 hrs. Additional DMP (63 mg, 148.34 umol) was added and the mixture was stirred for additional 6 hrs at 25 °C. Additional DMP (157 mg, 0.37 mmol) was added. After stirred for additional 39 hrs, the mixture was diluted with dichloromethane (35 mL), quenched by the addition of 10 % Na 2 S 2 0 3 /saturated aqueous NaHC0 3 (v/v = 1/1, -35 mL). The organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layer was washed with H 2 0 (10 mL), brine (10 mL), dried over anhydrous MgS0 4 , filtered and concentrated. The residue was triturated with z ' -Pr 2 0 (3 mL). The insoluble substance was collected and dried in vacuum. Compound 21 (20 mg, 67% yield, pale yellow solid): 1H NMR (CDC1 3, 400 MHz): δ 11.71 (br. d, J = 6.0 Hz, 1H), 9.67 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.48 - 7.46 (m, 2H), 7.36 - 7.34 (m, 3H), 7.24 - 7.22 (m, 2H), 7.20 - 7.16 (m, 3H), 4.86 - 4.81(m, 1H), 3.21 - 3.18 (m, 2H). MS (ESI) m/z (M+H) + 403.1.
(5)-4-(lH-INDAZOL-l-YL)-N-(l-OXO-3-PHENYLPROPAN-2-YL)THIAZOL E-5-
[0471] Compound 22 (4.70 mg, 16.87% yield, yellow solid) was prepared as in
Example 6 from the corresponding starting materials through intermediate compound 22E and then compound 22G. Compound 22: 1H NMR (CD 3 CN 400 MHz): δ 10.41 (br. s, 1H), 9.67 (s, 1H), 9.04 (s, 1H), 8.21 - 8.19 (m, 1H), 8.15 (s, 1H), 7.91 - 7.89 (m, 1H), 7.61 - 7.58 (m, 1H), 7.40 - 7.37 (m, 1H) 7.12 - 7.10 (m, 5H) 4.77 - 4.72 (m, 1H), 3.29 - 3.24 (m, 1H), 3.11 - 3.05 (m, 1H). MS (ESI) m/z (M+H) + 377.0.
(5)-2-METHYL-/V-(l-OXO-3-PHENYLPROPAN-2-YL)-4-PHENYLOXAZOLE- 5-
[0472] Compound 322 (102.9 mg, 36.1% yield, off-white solid) was prepared as in Example 6 from the corresponding intermediate compounds 107B and 21G ((S)-2-amino-3- phenylpropan- l-ol). Compound 322: 1H NMR (400 MHz, CDC1 3 ) δ 9.70 (s, 1H), 8.17 - 8.09 (m, 2H), 7.47 - 7.36 (m, 3H), 7.35 - 7.26 (m, 3H), 7.19 (d, = 6.84 Hz, 2H), 6.82 (d, = 6.00 Hz, 1H), 4.96 - 4.86 (m, 1H), 3.40 - 3.28 (m, 1H), 3.26 - 3.19 (m, 1H), 2.55 (s, 3H). MS (ESI) m/z (M+l) + 335.1. (5)-l-(BENZO[£)]THIAZOL-2-YL)-N-(l-OXO-3-PHENYLPROPAN-2-YL) -lH- -5-CARBOXA
[0473] A mixture of compound 29A (20 g, 133 mmol), ethyl 2-oxoacetate (136 g, 665 mmol), TsOH.H 2 0 (2.5 g, 13.3 mmol) in toluene (200 mL) was stirred at 120 °C for 1 hour. TLC (Petroleum ether: Ethyl acetate = 3: 1, R f = 0.5) indicated reactant 29A was almost consumed and one new spot formed. LCMS showed one peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 5: 1) to give compound 29B (30.0 g, crude) as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 9.40 (s, 1H), 7.98 - 7.78 (m, 1H), 7.77 - 7.57 (m, 1H), 7.55 - 7.31 (m, 1H), 7.30 - 7.07 (m, 1H), 5.38 - 5.26 (m, 1H), 4.33 - 4.21 (m, 3H). MS (ESI) m/z (M+H) + 234.9.
[0474] A mixture of methyl 29B (10 g, 45.4 mmol), Tosmic (17.7 g, 90.8 mmol), K 2 C0 3 (9.4 g, 68.1 mmol) in MeOH (200 mL) was stirred at 70 °C for 0.5 hour. TLC (Petroleum ether: Ethyl acetate = 3: 1, R f = 0.4) indicated 29B was consumed completely and some new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 3: 1) to give compound 29C (1.2 g, yield: 10.2%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 8.22 (d, = 0.9 Hz, 1H), 8.06 (d, = 7.9 Hz, 1H), 7.93 - 7.88 (m, 3H), 7.58 (dt, = 1.3, 7.7 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.49 - 7.43 (m, 1H), 4.58 (s, 1H), 3.87 (s, 3H), 2.51 (s, 1H). MS (ESI) m/z (M+H) + 259.9.
[0475] To a solution of 29C (1.1 g, 4.24 mmol in THF (30 mL), H 2 0 (5 mL) was added NaOH (339 mg, 8.48 mmol). The reaction mixture was stirred at 25 °C for 3hrs. LCMS showed 29C was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give a residue. The residue was dissolved in water (10 mL), adjusted by aqueous HC1 (2M) to pH ~ 5, filtered and the filtered cake was concentrated to give the product 29D (600 mg, yield: 57.7%) as a gray solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.48 (d, 7 = 1.1 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.06 (dd, 7 = 0.8, 8.0 Hz, 1H), 7.81 (d, 7 = 0.9 Hz, 1H), 7.64 - 7.53 (m, 2H). MS (ESI) m/z (M+H) + 245.9.
[0476] Compound 29 (55.00 mg, yield: 76.12%, offwhite solid) was prepared as in Example 21 from the corresponding intermediate compounds 29D and 21G. Compound 29: 1H NMR (400MHz ,CDC1 3 ) δ 9.75 (s, 1 H), 9.01 (d, 7 = 6.2 Hz, 1 H), 8.14 (s, 1 H), 7.90 - 7.75 (m, 3 H), 7.57 - 7.42 (m, 2 H), 7.19 - 7.00 (m, 5 H), 5.04 - 4.94 (m, 1 H), 3.37 - 3.21 (m, 2 H). MS (ESI) m/z (M+H) + 377.2.
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(PYRIDIN-2-YL)-lH-IMIDAZ OLE-5-
[0477] Compound 31 (25 mg, yield: 57.86%, light yellow solid) was prepared as in Example 6 from the corresponding intermediate compounds 24E and 21G. Compound 31: 1H NMR (400MHz ,CDC1 3 ) δ 9.70 (s, 1 H), 8.45 - 8.39 (m, 1 H), 7.94 (d, 7 = 1.1 Hz, 1 H), 7.89 - 7.82 (m, 1 H), 7.67 - 7.59 (m, 2 H), 7.39 - 7.32 (m, 2 H), 7.30 - 7.27 (m, 1 H), 7.26 - 7.21 (m, 2 H), 7.17 - 7.11 (m, 2 H), 4.87 (q, 7 = 6.6 Hz, 1 H), 3.25 (dd, 7 = 2.5, 6.5 Hz, 2 H). MS (ESI) m/z (M+H) + 321.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(5-PHENYLPYRI MIDIN-2- YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (75)
[0478] Compound 75 (43.1 mg, yield: 66.6%, white solid) was prepared as in Example 6 from the corresponding intermediate compounds 74E and 21G. Compound 75:. 1H NMR (CDC1 3, 400 MHz) δ 9.79 (s, 1H), 9.61 (br d, 7 = 6.0 Hz, 1H), 8.75 (s, 2H), 8.65 (s, 1H), 7.84 (s, 1H), 7.58 - 7.53 (m, 5H), 7.25 - 7.14 (m, 5H), 5.06 - 5.01 (m, 1H), 3.43 - 3.38 (m, 1H), 3.33 - 3.28 (m, 1H). MS (ESI) m/z (M+H) + 398.1.
(5)-l-(lH-BENZO[rf]IMIDAZOL-2-YL)-N-(l-OXO-3-PHENYLPROPAN-2- YL)-lH-
IMIDAZOLE-5-CARBOXAMIDE (90)
[0479] Compound 90 (20 mg, yield: 44.4%, white solid) was prepared as in Example 6 from the corresponding intermediate compounds 70D and 21G ((S)-2-amino-3-phenylpropan- l-ol). Compound 90: 1H NMR (400MHz,CDCl 3 ) δ 12.77 (br s, 1H), 12.87 - 12.63 (m, 1H), 9.75 (s, 1H), 8.85 (s, 1H), 7.71 (br s, 1H), 7.57 (s, 1H), 7.50 (br s, 1H), 7.36 - 7.27 (m, 4H), 7.19 (br d, J = 6.8 Hz, 2H), 6.99 (br d, J = 5.3 Hz, 1H), 4.93 (q, J = 6.7 Hz, 1H), 3.32 (d, J = 6.4 Hz, 2H). MS (ESI) m/z (M+H) + 360.1.
(5)-3-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(PYRIMIDIN-4-YL )-lH-
[0480] Compound 279 (102.0 mg, 304.15 umol, 55.26% yield, white solid) was prepared as in Example 6 from the corresponding intermediate compounds 245D and 21G ((S)-2- amino-3-phenylpropan- l-ol). Compound 279: 1H NMR (400 MHz, CDC1 3 ): δ 9.88(d, J = 5.6 Hz, 1H), 9.76 (s, 1H), 8.74 (d, J = 5.6 Hz, 1H), 8.61 (s, 1H), 7.91 - 7.87 (m, 1H), 7.27 - 7.23 (m, 3H), 7.19 - 7.17 (m, 2H), 8.89 (s, 1H), 5.02 - 4.97 (m, 1H), 3.40 - 3.35 (m, 1H), 3.30 - 3.25 (m, 1H), 2.34 (s, 1H). MS (ESI) m/z (M+l) + 336.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(PYRIDIN-2-YL )-lH-
IMIDAZOLE-5-CARBO
24D 24E
[0481] To a solution of compound 24B (16.2 g, 79.7 mmol) in MeOH (25 mL) was added compound 24A (5 g, 53.1 mmol). The mixture was stirred at 80 °C for 6 hrs. TLC (Petroleum ether: Ethyl acetate = 2: 1, R f = 0.24) indicated compound 24A was remained and one major new spot with lower polarity was detected. Then the reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 30: 1 to 15: 1) to give compound 24C (6 g, yield: 53.7%) as a yellow oil.
[0482] To a mixture of compound 24C (6 g, 28.5 mmol) in EtOH (15 mL) was added TosMIC (8.3 g, 42.8 mmol), K 2 C0 3 (11.8 g, 85.6 mmol). The mixture was stirred at 80 °C for 12 hrs. TLC (Petroleum ether: Ethyl acetate = 1 : 1, R f = 0.70) indicated compound 24C remained and one major new spot with higher polarity was detected. Then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 30: 1 to 3: 1) to give compound 24D (1.60 g, yield: 25.8%) as a white solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.61 - 8.54 (m, 1H), 7.98 (s, 1H), 7.92 - 7.83 (m, 2H), 7.45 - 7.38 (m, 2H), 4.25 (q, J = 1.1 Hz, 2H), 1.28 (t, = 7.2 Hz, 4H).
[0483] To a solution of compound 24D (1.6 g, 7.37 mmol) in THF (15 mL) and H 2 0 (5 mL) was added LiOH.H 2 0 (618 mg, 14.7 mmol). The reaction mixture was stirred at 25 °C for 12 hrs. LCMS showed compound 24D was consumed completely and one main peak with desired MS was detected. Then the mixture was adjusted to pH ~ 5 by adding HC1 (1M), and then white solid was precipitate out. The white solid was filtered and dried over to give compound 24E (1 g, yield: 71.7%) as a white solid. MS (ESI) m/z (M+H) + 189.1.
[0484] Compound 24 (20 mg, yield: 33.5%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 24E, and compound 12G. Compound 24: 1H NMR (400 MHz, DMSO-i¾) δ 8.95 (d, = 7.6 Hz, 1H), 8.50 - 8.38 (m, 1H), 8.12 (s, 1H), 8.03 (br.s., 1H), 7.89 - 7.85 (m, 1H), 7.80 (br.s., 1H), 7.53 (s, 1H), 7.43 - 7.40 (m, 1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.19 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.25 - 5.20 (m, 1H), 3.17 (dd, J = 4.0, 14.4 Hz, 1H), 2.83 (dd, J = 10.0, 13.6 Hz, 1H). MS (ESI) m/z (M+H) + 364.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-4- -5-CARBOXAMIDE (25)
[0485] To a solution of compound 25A (20 g, 104 mmol) in CC1 4 (200 ml) was added S0 2 C1 2 (14 g, 104 mmol) at 45-50 °C during a period of 0.3 h. Then the mixture was stirred at 45 - 50 °C for 1 h. The reaction mixture was diluted with ice- water (200 mL). The organic layer was separated, washed with H 2 0 (200 mL x 2), brine (200 mL) dried over anhydrous MgS0 4 , filtered and concentrated under reduced pressure to afford compound 25B
(25. g, crude) as pale yellow oil, which was used for next step directly. 1H NMR
(CDCI 3 400MHz,): δ 8.03 - 7.98 (m, 2H), 7.67 - 7.62 (m, 1H), 7.54 - 7.50 (m, 2H), 5.62 (s, 1H),
4.32 - 4.26 (q, = 7.2 Hz, 2H), 1.25 (t, = 7.2 Hz, 3H). [0486] A mixture of compound 25B (6.8 g, 30 mmol) and thioacetamide (2.25 g, 30.0 mmol) in EtOH (75 mL) was heated to 80 °C and stirred for 6 hrs. The solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: Petroleum Ether/Ethyl Acetate = 50/1) to afford compound 25C (3.0 g, yield 40.4%) as yellow oil. 1H NMR (CDC1 3 , 400 ΜΗζ) δ 7.77 - 1.11 (m, 2H), 7.47 - 7.40 (m, 3H), 4.28 (q, = 7.2 Hz, 2H), 2.77 (s, 3H), 1.29 (t, = 7.2 Hz, 3H).
[0487] A solution of NaOH (2N, 12 mL, 24 mmol) was added to a solution of compound 25C (1.24 g, 5.01 mmol) in MeOH/H 2 0 mixture (39 mL/13 mL). The mixture was stirred at 25 °C for 3 hrs. The mixture was diluted with H 2 0 (5 mL). The volatile solvent was removed by evaporation. The residue was treated with HC1 (IN) until pH ~ 3. The precipitate was collected by filtration, dried under reduced pressure to afford compound 25D (650 mg, yield 59.2%) as white solid, which was used directly in next step. 1H NMR (DMSO-i¾, 400 ΜΗζ):δ 7.72 - 7.65 (m, 2H), 7.43 - 7.36 (m, 3H), 2.68 (s, 3H).
[0488] Compound 25 (25 mg, yield 42%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 25D. Compound 25: 1H NMR (DMSO-i¾ , 400 MHz): δ 8.81 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.55 - 7.53 (m, 2H), 7.31 - 7.19 (m, 8H), 5.35 - 5.31 (m, 1H), 3.15 (dd, J = 3.6, 13.8 Hz, 1H), 2.77 (dd, J = 9.9, 13.8 Hz, 1H), 2.67 (s, 3H). MS (ESI) m/z (M+H) + 394.1.
[0489] To a mixture of compound 26A (7.2 g, 37.46 mmol, 6.5 mL) and ammonium acetate (5.8 g, 74.92 mmol) were mixed in EtOH (70 mL) and refluxed at 80 °C for 16 hrs. After removal of the solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100 mL x 2). This combined organic phase was washed with sat. NaHC0 3 (50 mL x 2) and brine (50 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20: 1 to 10: 1) to give compound 26B (3.5 g, yield: 48.9%) as yellow oil. 1H NMR (CDC1 3, 400 MHz): δ 7.57 - 7.53 (m, 2H), 7.48 - 7.37 (m, 3H), 5.07 - 4.89 (m, 1H), 4.22 - 4.11 (m, 2H), 1.33 - 1.25 (m, 3H).
[0490] To a mixture of compound 26B (2 g, 10.46 mmol) in DCE (4 mL) was added PhI(OAc) 2 (4.4 g, 13.60 mmol) in one portion at 25 °C under N 2 . The mixture was stirred at 25 °C for 16 hrs. The reaction mixture was quenched with saturated aqueous NaHC0 3 (50 mL) and extracted with DCM (50 mL x 3). The organic layers were combined and dried over anhydrous Na 2 S0 4 . The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20: 1 to 5: 1) to give compound 26C (400 mg, yield: 15.3%) as yellow oil. 1H NMR (CDC1 3, 400 MHz): δ 7.58 (dd, = 1.1, 7.7 Hz, 1H), 7.44 - 7.39 (m, 4H), 4.28 - 4.21 (m, 2H), 1.94 (s, 3H), 1.66 - 1.60 (m, 1H), 1.62 (br s, 1H), 1.30 - 1.26 (m, 3H).
[0491] To a mixture of compound 26C (400 mg, 1.60 mmol) in DCE (5 mL) and AcOH (10 mL) was stirred at 90 °C for 16 hrs. The solvent was removed. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10: 1 to 5: 1) to give compound 26D (220 mg, yield: 53.0%) as yellow oil. 1H NMR (CDC1 3, 400 MHz): δ 8.11 - 7.89 (m, 2H), 7.56 - 7.32 (m, 3H), 4.40 (t, = 7.3 Hz, 2H), 2.59 (s, 3H), 1.39 (q, = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 231.8.
[0492] To a mixture of iodobenzene (2.5 g, 12.25 mmol, 1.4 mL) and compound 26E (3.59 g, 13.48 mmol) in CHC1 3 (25 mL), was added m-CPBA (2.33 g, 13.48 mmol). The mixture was stirred for 2 hrs at 25 °C under an N 2 atmosphere. After the reaction, MTBE (20 mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid was washed with MTBE (30 mL) Compound 26F was obtained as a white solid
[0493] Ethyl 3-oxo-3-phenyl-propanoate 26A (500 mg, 2.60 mmol) and compound 26F (1.58 g, 3.38 mmol,) in CH 3 CN (30 mL) were heated to reflux for 1 h at 80 °C, and acetamide (461 mg, 7.80 mmol) was added to the mixture. The reaction mixture was heated at 120 °C for 0.1 h under microwave irradiation. After being cooled to room temperature, the suspension was diluted with saturated NaHC0 3 solution (30 mL), extracted with EtOAc (10 mL x 2), dried over Na 2 S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1) and by preparatory-TLC (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 26G (50 mg, yield: 8.32%) was obtained as a white solid. 1H NMR (CDC1 3, 400 MHz): δ 8.06 - 7.93 (m, 2H), 7.48 - 7.39 (m, 3H), 4.38 (q, = 7.1 Hz, 2H), 2.58 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 231.8.
[0494] To a mixture of compound 26G (60 mg, 259.46 umol) in THF (2 mL) and H 2 0 (2 mL) was added NaOH (1 M, 778 uL) in one portion at 0 °C. The mixture was stirred at 25 °C for 16 hrs. The mixture was extracted with MTBE (2 x 30 mL) and washed with water (3 x 30 mL). The water layers were acidified to pH ~ 4 with IN HC1, then, the solution extracted with EtOAc (3 x 30 mL). The organic layers were dried over Na 2 S0 4 and concentrated to give compound 5 (50 mg, yield: 86.6%) as yellow oil, which was used directly for next step without further purification. 1H NMR (CDC1 3, 400 MHz): δ 8.05 - 8.01 (m, 2H), 7.48 - 7.43 (m, 3H), 2.62 (s, 3H). MS (ESI) m/z (M+H) + 203.8.
[0495] Compound 26 (15 mg, yield: 23.0%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 26H. Compound 26: 1H NMR (CDC1 3, 400 MHz): δ 8.08 (br d, J = 6.6 Hz, 2H), 7.41 (br d, = 6.8 Hz, 2H), 7.32 - 7.24 (m, 4H), 7.13 (br d, = 6.6 Hz, 2H), 6.77 (br s, 2H), 5.76 - 5.68 (m, 1H), 5.55 (br s, 1H), 3.45 (br dd, = 5.3, 14.3 Hz, 1H), 3.24 (br dd, = 7.3, 14.1 Hz, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-PHENYL-l,2,3- THIADIAZOLE-4-CARBOXAMIDE (28)
[0496] A mixture consisting of compound 28A (200 mg, 843.63umol), phenyl boronic acid (23 mg, 110.98 umol) and Na 2 C0 3 (22.4 mg, 2.11 mmol) was stirred at 110 °C for 1.5 hrs under microwave. The reaction mixture was cooled to room-temperature, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Pre-HPLC (base condition) to afford compound 28B (23 mg, yield 11.64%) as a light yellow oil. 1H NMR (CDC1 3, 400 MHz): 57.44 - 7.58 (m, 5 H), 4.44 (q, = 7.20 Hz, 2 H), 1.32 (t, = 7.17 Hz, 3 H).
[0497] To a mixture of compound 28B (50 mg, 213.43 umol) in MeOH (3 mL) and H 2 0 (1.50 mL) was added LiOH » H 2 0 (26.9 mg, 640.29 umol) in one portion and the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (8 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 28C (38 mg, crude) as brown solid. 1H NMR (CDCI 3, 400 MHz): δ 7.63 - 7.57 (m, 2H), 7.54 - 7.45 (m, 3H). MS (ESI) m/z (M+l) + 206.7.
[0498] Compound 28 (18.9 mg, 38.00% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 28C. Compound 28: 1H NMR (CDCI3, 400 MHz): δ 8.07 (d, = 7.2 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.49 - 7.41 (m, 3H), 7.33 - 7.27 (m, 3H), 7.23 - 7.19 (m, 2H), 6.77 (br s, 1H), 5.84 - 5.76 (m, 1H), 5.52 (br s, 1H), 3.51 - 3.45 (m, 1H), 3.25 - 3.18 (m, 1H). MS (ESI) m/z (M+l) + 381.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-PHENYL-lH-PYR AZOLE-4- ARBOXAMIDE (30)
[0499] To a solution of i-BuONO (3.8 mL, 30.94 mmol) in CH 3 CN (60 mL) was added CuBr 2 (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for 1 h under N 2 . Then compound 30A (4 g, 25.78 mmol) was added protionwise. The mixture was then heated to 70 °C and stirred for 12 hrs. The reaction was washed with H 2 0 (100 mL), extracted with EtOAc (100 mL x 2). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 30B (6 g, crude) as black brown oil. MS (ESI) m/z (M+ H) + 218.9, 220.9.
[0500] To a solution of NaH (1.64 g, 41.09 mmol, 60% purity) in THF (80 mL) at 0 °C was added a solution of compound 30B (6 g, 27.39 mmol) in THF (20 mL). After addition, the mixture was warmed up to 25 °C and stirred for 2 hrs. Then the solution was cooled to 0 °C and a solution of SEM-C1 (5.34 mL, 30.13 mmol) in THF (100 mL) was added at 0 °C. The mixture was then warmed up to 25 °C and stirred for 12 hrs. The reaction was quenched with H 2 0 (100 mL) dropwise. The mixture was extracted with EtOAc (100 mL x 2). The organics were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 10: 1) to afford compound 30C (3 g, yield: 31.14%) as yellow oil. [0501] To a solution of compound 30C (2.60 g, 7.44 mmol) and PhB(OH) 2 (1.09 g, 8.93 mmol) in dioxane (36 mL) and H 2 0 (12 mL) was added Pd(dtbpf)Cl 2 (485 mg, 0.74 mmol) and K 3 PO 4 (4.74 g, 22.32 mmol). The mixture was stirred at 70 °C under N 2 for 2 hrs. The reaction was diluted with H 2 0 (20 mL), extracted with EtOAc (20 mL x 2). The organics were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 10: 1) to afford compound 30D (2.40 g, yield: 93.1%) as colorless oil. MS (ESI) m/z (M+H) + 347.1. 1H NMR (400MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 7.78 - 7.72 (m, 2H), 7.56 - 7.34 (m, 3H), 5.52 (s, 2H), 4.25 - 4.16 (m, 2H), 3.70 - 3.62 (m, 2H), 1.26 (t, =7.1 Hz, 3H), 0.94 - 0.85 (m, 2H), 0.03 - 0.02 (m, 9H).
[0502] A solution of compound 30D (200 mg, 577.20 umol) in MeOH (4 mL), and then NaOH (230 mg, 5.77 mmol) in H 2 0 (4 mL) was added dropwise. The mixture was stirred at 25 °C for 19 hrs. The reaction mixture was diluted by addition H 2 0 (10 mL), and then extracted with MTBE (10 mL x 2). The water layers were neutralized by IN HC1 to pH ~ 3, and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 30E (140 mg, yield: 76.17%) as a yellow oil. 1H-NMR (400MHz, DMSO-d 6 ) δ 12.41 (br s, 1H), 8.54 (s, 1H), 7.81 - 7.74 (m, 2H), 7.53 - 7.36 (m, 3H), 5.50 (s, 2H), 3.66 (t, J = 8.0 Hz, 2H), 0.90 (t, = 7.9 Hz, 2H), 0.01 - 0.04 (m, 9H).
[0503] Compound 30G (140 mg, yield: 93.72%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 30E. Compound 30G: 1H-NMR (400MHz, OMSO-d 6 ) δ 8.54 (d, = 7.3 Hz, 1H), 8.25 (s, 1H), 8.15 - 8.00 (m, 1H), 7.87 (s, 1H), 7.66 - 7.52 (m, 2H), 7.43 - 7.23 (m, 9H), 5.46 (br d, = 6.8 Hz, 1H), 5.38 - 5.30 (m, 1H), 3.76 - 3.57 (m, 2H), 3.27 - 3.12 (m, 1H), 2.96 - 2.76 (m, 1H), 0.94 - 0.89 (m, 2H), 0.03 - 0.00 (m, 9H).
[0504] To a solution of compound 30G (18.00 mg, 36.54 umol) in ethyl acetate (1.00 mL) was added 4M HCl/EtOAc (5.00 mL). Then the reaction was stirred at 30 °C for 4hrs. The reaction mixture was added petroleum ether (50 mL), the mixture was stirred for 3 mins, filtered and the desired solid was dried in vacuo to give compound 30 (6.00 mg, yield: 45.31%) as white solid. 1H NMR (400MHz, DMSO-d6) δ 8.34 (d, =7.5 Hz, 1H), 8.02 (s, 1H), 7.99 - 7.95 (m, 1H), 7.77 (s, 1H), 7.59 - 7.53 (m, 2H), 7.35 - 7.28 (m, 4H), 7.28 - 7.23 (m, 5H), 7.23 - 7.16 (m, 2H), 5.30 - 5.21(m, 1H), 3.19 - 3.10 (m, 1H), 2.83 (dd, 7=9.8, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 363.1.
COMPOUNDS 32, 458, 476-479, 521
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-PHEN YL-lH-
PYRAZ LE-4-CARBOXAMIDE (32)
[0505] To a solution of t-BuONO (3.19 g, 30.94 mmol, 3.67 mL) in C¾CN (60 mL) was added CuBr 2 (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for 1 hour under N 2 . Then compound 32A (4.00 g, 25.78 mmol) was added portionwise. After heated to 70 °C and stirred for 12 hrs, the mixture was concentrated and diluted with ethyl acetate (100 mL). The mixture was then washed with HCl (1M, 100 mL), saturated NaHC0 3 (100 mL), brine (100 mL), dried over Na 2 S0 4 and concentrated to obtain intermediate compound 32B (5.6 g, crude) as yellow oil. MS (ESI) m/z (M+H) + 220.9.
[0506] To a solution of compound 32B (5.6 g, 25.57 mmol) in DMF (200 mL) was added Mel (14.52 g, 102.28 mmol, 6.37 mL) and Cs 2 C0 3 (33.32 g, 102.28 mmol). The mixture was stirred at 25 °C for 12 hrs. The mixture was diluted with H 2 0 (1000 mL) and extracted with ethyl acetate (500 mL), then the organic layer was washed with brine (500 mL x 3), dried over Na 2 S0 4 and concentrated. The residue (4 g) was purified by preparatory-HPLC (basic condition). The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l to 5: 1). Compound 32C (lg, yield: 16.8%) was obtained as a white solid. Compound 32D (2 g, yield: 33.6%) was obtained as a white solid.
[0507] Compound 32C : 1H NMR (400MHz, DMSO-d 6 ) δ 7.93 (s, 1H), 4.24 - 4.18 (m, 2H), 3.85 (s, 3H), 1.28 - 1.23 (m, 3H). [0508] Compound 32D : 1H NMR (400MHz, DMSO-d 6 ) δ 8.33 (s, 1H), 4.22 - 4.16 (m, 2H), 3.83 (s, 3H), 1.26 - 1.22 (m, 3H).
[0509] A mixture of ethyl compound 32D (500.0 mg, 2.15 mmol), phenylboronic acid (314.6 mg, 2.58 mmol), Pd(dtbpf)Cl 2 (140.1 mg, 215.00 umol), K 3 P0 4 (1.37 g, 6.45 mmol) in dioxane (30 mL) and H 2 0 (10 mL) was degassed and purged with N 2 for 3 times. After stirred at 70 °C for 1 hour under N 2 atmosphere, the mixture was concentrated and diluted with ethyl acetate (30 mL). The mixture was then washed with HC1 (1M, 50 mL), saturated aqueous NaHC0 3 (50 mL), brine (50 mL), dried over Na 2 S0 4 and concentrated to obtain intermediate compound 32E (480 mg, crude) as a brown oil. MS (ESI) m/z (M+H) + 230.9.
[0510] To a solution of compound 32E (380.0 mg, 1.65 mmol) in MeOH (5 mL) and THF (5 mL) was added NaOH (2 M, 16.5 mL). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated and diluted with H 2 0 (10 mL), the mixture was extracted with ethyl acetate (10 mL), the water phase was added HC1 (1M) until pH ~ 3, then the mixture was extracted with ethyl acetate (20 mL), the organic layer was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated. Compound 32F (320 mg, yield: 95.9%) was obtained as a brown solid. 1H NMR (400MHz, DMSO-i¾) δ 12.03 - 11.85 (m, 1H), 8.27 (s, 1H), 7.74 - 7.68 (m, 2H), 7.40 - 7.30 (m, 3H), 3.87 (s, 3H).
[0511] Compound 32 (40.0 mg, yield: 64.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 32F. Compound 32: 1H NMR (400MHz, DMSO-i¾) δ 8.33 (d, = 7.2 Hz, 1H), 8.05 (s, 2H), 7.81 (br s, 1H), 7.63 - 7.53 (m, 2H), 7.39 - 7.20 (m, 8H), 5.33 - 5.26 (m, 1H), 3.93 - 3.86 (m, 3H), 3.21 - 3.13 (m, 1H), 2.88 - 2.79 (m, 1H). MS (ESI) m/z (M+H) + 377.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METH YL-3- PHENYL- 1H-PYRAZOLE-4-CARBOXAMIDE (458)
[0512] Compound 458 (270 mg, yield: 67.4%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, compound 32F and 3-amino- N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride. Compound 458: 1H NMR (400MHz, DMSO-i¾) δ 8.80 (d, J = 4.4 Hz, 1H), 8.38 (d, = 7.3 Hz, 1H), 8.05 (s, 1H), 7.56 (s, 2H), 7.36 - 7.17 (m, 8H), 5.28 (s, 1H), 3.89 (s, 3H), 3.16 (d, J = 11.2 Hz, 1H), 2.89 - 2.73 (m, 2H), 0.71 - 0.52 (m, 4H). MS (ESI) m/z (M+H) + 417.1. (5 N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-PHENYL-lH-
[0513] Compound 476 (36.8 mg, yield: 34.22%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, compound 32F and (2S,3S)- 3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride. Compound 476: 1H NMR (400MHz, CDC1 3 ) δ 7.91 (s, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.37 (m, 3H), 7.25 - 7.19 (m, 3H), 6.94 - 6.84 (m, 2H), 6.06 (d, J = 6.4 Hz, 1H), 5.03 - 4.71 (m, 3H), 3.93 (s, 3H), 3.09 - 3.01 (m, 1H), 2.85 - 2.76 (m, 1H). MS (ESI) m/z (M+H) + 366.1.
(5)-N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYRAZI N-2-YL)- lH-PYRAZOLE-5-CARBOXAMIDE (477)
[0514] Compound 477 (110 mg, yield: 90.33%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, compound 85B and (2S,3S)- 3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride. Compound 477: 1H NMR (400MHz, CDCI 3 ) δ 9.20 (s, 1H), 9.08 - 9.00 (m, 1H), 8.50 - 8.48 (m, 1H), 8.11 (s, 1H), 7.27 - 7.24 (m, 3H), 7.17 - 7.12 (m, 2H), 6.79 (s, 1H), 5.33 - 5.24 (m, 1H), 5.11 - 4.79 (m, 2H), 3.45 - 3.33 (m, 1H), 3.15 - 3.11 (m, 1H), 2.38 (s, 3H). MS (ESI) m/z (M+H) + 368.1.
(5)-N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYRIDI N-2-YL)- lH-PYRAZOLE-5-CARBOXAMIDE (478)
[0515] Compound 478 (82 mg, yield: 54.97%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, compound 12F and (2S,3S)- 3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride. Compound 478: 1H NMR (400MHz, CDCI 3 ) δ 10.70 (d, = 6.40 Hz, 1H), 8.14 (d, = 4.40 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.26 - 7.14 (m, 6H), 6.88 (s, 1H), 5.24 - 5.20 (m, 1H), 5.05 - 4.74 (m, 2H), 3.29 - 3.18 (m, 2H), 2.35 (s, 3H). MS (ESI) m/z (M+l) + 367.2.
(5)-N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-PHENYL- lH-
[0516] Compound 479 (100 mg, yield: 82.06%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, 3-methyl- l-phenyl-lH- pyrazole-5-carboxylic acid and (2S,3S)-3-amino-l-fluoro-4-phenylbutan-2-ol hydrochloride. Compound 479: 1H NMR (400MHz, CDC1 3 ) δ 7.46 - 7.28 (m, 8H), 7.08 - 7.03 (m, 2H), 6.51 (s, 1H), 6.28 (br d, 7 = 7.0 Hz, 1H), 5.20 - 5.13 (m, 1H), 5.03 - 4.73 (m, 2H), 3.22 - 3.15 (m, 1H), 3.02 - 2.95 (m, 1H), 2.35 (s, 3H). MS (ESI) m/z (M+H) + 366.1.
(5)-N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUORO-4-((PR OP-2-YN-l- YLOXY)METHYL)PHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (521)
[0517] Compound 521 (250 mg, yield: 78.40%, white solid) was prepared using coupling conditions as in compound 476 from the corresponding intermediate ethyl 3-iodo- l- methyl-lH-pyrazole-4-carboxylate and (2-fluoro-4-(hydroxymethyl)phenyl)boronic acid followed by alkylation with 3-bromoprop- l-yne and then the intermediate obtained was subjected to hydrolysis and coupling with (2S,3S)-3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride as in compound 12 to yield compound 521. Compound 521: 1H NMR (400MHz, CDC1 3 ) δ 7.89 (s, 1H), 7.40 (t, 7=7.6 Hz, 1H), 7.24 - 7.13 (m, 5H), 6.94-6.92 (m, 2H), 5.97 (d, 7=6.4 Hz, 1H), 5.09 - 5.01 (m, 1H), 4.96 - 4.83 (m, 1H), 4.83 - 4.70 (m, 1H), 4.66 (s, 2H), 4.19 (d, 7=2.4 Hz, 2H), 3.95 (s, 3H), 3.03 (d, 7=6.4 Hz, 1H), 2.95 - 2.88 (m, 1H), 2.49 (t, 7=2.3 Hz, 1H). MS (ESI) m/z (M+H) + 452.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-ETHYL-l-PHENY L-lH-
[0518] A mixture of compound 33A (46.73 mL, 342.14 mmol) and butan-2-one (30.46 mL, 342.14 mmol) was added dropwise to the solution of NaOEt (prepared by Na (9.5 g) in EtOH (200 mL)) at 0 °C. Then the reaction was stirred at 20-25 °C for 16 hrs. The reaction was adjusted to pH ~ 6-7 with HC1 (2M) and then removed the solvent to give a residue, which was diluted with ethyl acetate (500 mL), washed with brine (150 mL), dried over Na 2 S0 4 and concentrated to give the crude product which was purified by flash column chromatography (Petroleum Ether : Ethyl Acetate = 1:0 to 10: 1) to give compound 33B (23.0 g, yield: 39.0 %) as a yellow oil. 1 H NMR (CDC1 3 , 400 MHz) δ 14.34 (br s, 1H), 6.31 (s, 1H), 4.28 (q, 7 = 7.2 Hz, 2H), 2.47 (q, 7 = 7.3 Hz, 2H), 1.34 - 1.27 (m, 3H), 1.11 (t, 7 = 7.5 Hz, 3H).
[0519] The mixture of compound 33B (10 g, 58.08 mmol), O-methylhydroxylamine (4.85 g, 58.08 mmol, HC1) and 4A° molecular sieve (10 g) in DMF (100 mL) was stirred at 20- 25 °C for 20 hrs. Filtered to remove the 4 A 0 molecular sieve and the filtrate was diluted with H 2 0 (800 mL), extracted with ethyl acetate (300 mL x 3). The organic phase was combined and washed with brine (300 mL x 3) and concentrated to give the crude product, which was purified by flash column chromatography (Petroleum Ether : Ethyl Acetate = 1:0 to 5: 1) to give compound 33C (3.5 g, yield: 29.95%) as a yellow oil. 1H NMR (CDC1 3 , 400 MHz) (5 4.41 - 4.29 (m, 2H), 4.06 (s, 3H), 3.71 (s, 2H), 2.60 - 2.46 (m, 2H), 1.42 - 1.32 (m, 3H), 1.08 (t, 7 = 7.3 Hz, 3H).
[0520] The mixture of compound 33C (3.5 g, 17.39 mmol) and phenylhydrazine (1.88 g, 17.39 mmol) in AcOH (20 mL) was stirred at 100 °C for 2 hrs. The solvent was removed and the residue was adjusted to pH ~ 7-8 with saturated NaHC0 3 aqueous and extracted with ethyl acetate (60 mL x 2). The organic phase were combined and washed with brine (50 mL), concentrated to give a residue, which was purified by flash column chromatography (Petroleum Ether : Ethyl Acetate = 1:0 to 5: 1) to give compound 33D (0.3 g, 1.23 mmol, 7.05% yield) as a yellow solid and compound 33E (3.0 g, 12.21 mmol, yield 70.19%) as a yellow oil.
[0521] Compound 33D : 1H NMR (CDC1 3 , 400 MHz) δ 7.50 - 7.37 (m, 5H), 6.87 (s, 1H), 4.24 (q, 7 = 7.0 Hz, 2H), 2.76 (q, 7 = 7.5 Hz, 2H), 1.32 (t, 7 = 7.5 Hz, 3H), 1.25 (t, 7 = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 245.0. Compound 33E : 1H NMR (CDC1 3 , 400 MHz) (5 7.46 - 7.31 (m, 1H), 6.70 (s, 1H), 4.35 (q, 7 = 7.1 Hz, 1H), 2.58 (q, 7 = 7.4 Hz, 1H), 1.33 (t, 7 = 7.2 Hz, 1H), 1.16 (t, 7 = 7.5 Hz, 1H). MS (ESI) m/z (M+H) + 245.0.
[0522] The mixture of compound 33D (3.0 g, 12.28 mmol) and LiOH.H 2 0 (3.09 g, 73.68 mmol) in MeOH (10 mL) and H 2 0 (3 mL) was stirred at 25 °C for 16 hrs. The reaction was adjusted with HC1 (2M) to pH ~ 3-4 and removed the solvent. The residue was extracted with ethyl acetate (100 mL x 3) and combined, washed with brine (100 mL), dried over Na 2 S0 4 . Filter and the filtrate were concentrated to give compound 33F (2.7 g, crude) as a yellow solid. 1H NMR (CDCI3, 400 MHz) δ 8.58 (br s, 1H), 7.46 - 7.34 (m, 5H), 6.89 (s, 1H), 2.73 (q, = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). MS (ESI) m/z (M+H) + 216.9.
[0523] The mixture of compound 33F (2.7 g, 12.49 mmol) and 1- hydroxypyrrolidine-2,5-dione (1.44 g, 12.49 mmol) in THF (20 mL) was stirred at 0 °C for 15 min, then solution of DCC (2.6 g, 12.61 mmol, 2.55 mL) in THF (10 mL) was added dropwise at 0 °C and stirred at 25-30 °C for 16 hrs. After filtered and the filtrate was concentrated to give compound 33G (4.0 g, crude) as a yellow solid. The product was used directly in next step.
[0524] The mixture of compound 33G (0.2 g, 638.35 umol), compound 12G (147.3 mg, 638.35 umol, HC1) and DIEA (0.25 mL, 1.28 mmol) in DMF (10 mL) was stirred at 20-25 °C for 16 hrs. The reaction was diluted with H 2 0 (60 mL) and ethyl acetate (30 mL) and stirred at 20-25 °C for 0.5 h. White solid precipitated out and was filtered, the filter cake was washed with H 2 0 (10 mL x 2) and dried over under reduced pressure to give compound 33H (100.0 mg, yield: 39.24%) as a white solid. 1H NMR (DMSO-d 6 , 400 MHz) δ 8.53 - 8.11 (m, 1H), 7.40 - 7.20 (m, 10H), 7.16 - 7.01 (m, 2H), 6.59 (s, 1H), 5.96 - 5.69 (m, 1H), 4.49 - 4.36 (m, 1H), 4.03 - 3.90 (m, 1H), 2.96 - 2.70 (m, 2H), 2.62 (q, = 7.7 Hz, 2H), 1.22 (t, = 7.5 Hz, 3H). MS (ESI) m/z (M+H) + 393.0.
[0525] The mixture of compound 33H (100 mg, 254.81 umol) and DMP (540.4 mg, 1.27 mmol, 394.44 uL) in DMSO (5.0 mL) was stirred at 25-30 °C for 16 hrs. The reaction was diluted with DCM (20 mL) and quenched with a mixture of saturated NaHC0 3 aqueous and Na 2 S 2 0 3 aqueous (10%) (80 mL, 1: 1) and stirred at 20-25 °C for 0.5 hours. White solid precipitated out and was filtered, the filter cake was washed with H 2 0 (3 mL x 2) and dried under reduced pressure to give compopund 33 (20.0 mg, yield: 20%) as a white solid. 1H NMR (DMSO- e, 400 MHz) δ 9.10 (d, = 7.9 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.36 - 7.20 (m, 8H), 7.18 - 7.10 (m, 2H), 6.58 (s, 1H), 5.30 - 5.21 (m, 1H), 3.18 (dd, / = 3.5, 13.9 Hz, 1H), 2.80 (dd, = 10.6, 13.7 Hz, 1H), 2.60 (q, =7.7 Hz, 2H), 1.20 (t, = 7.6 Hz, 3H). MS (ESI) m/z (M+H) + 391.1. EXAMPLE 14
(5)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(l-PHENYL-lH-PYRAZOL-3-Y L)-lH- -5-CARBOXAMIDE (34)
[0526] To a solution of 34A (15 g, 180.53 mmol) in THF (200 mL) was added ethyl 2-oxoacetate (47.9 g, 234.69 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate compound 34B (55.3 g, crude) as brown solid. MS (ESI) m/z (M+H) + 167.8.
[0527] To a solution of 34B (40 g, 239 mmol) in EtOH (400 mL) was added K 2 C0 3 (50 g, 362 mol) and l-(isocyanomethylsulfonyl)-4-methyl-benzene (40 g, 204.88 mmol). The mixture was stirred at 90 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1 : 0 to 5: 2) to afford compound 34C (12 g, yield: 24.3%) as brown solid. 1H NMR (400 MHz, CDC1 3 ) δ 11.80 - 11.35 (m, 1H), 7.87 (d, = 1.10 Hz, 1H), 7.84 (d, = 1.10 Hz, 1 H), 7.58 (d, = 2.43 Hz, 1H), 6.45 (d, = 2.43 Hz, 1H), 4.25 (q, = 7.06 Hz, 2H), 1.29 (t, J = 7.17 Hz, 3H). MS (ESI) m/z (M+H) + 207.0.
[0528] A mixture of 34C (5 g, 24.3mmol), phenylboronic acid (4.4 g, 36.4mmol), Cu(OAc) 2 (4.4 g, 24.3mmol), triethylamine (7.4 g, 72.8mmol) in DCM (200 mL) was degassed and purged with 0 2 for 3 times, and then the mixture was stirred at 25 °C for 10 hrs under 0 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate= 1 : 0 to 2: 1). Compound 34D (2.3 g, yield: 33.6%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 8.04 - 7.94 (m, 2H), 7.87 (s, 1H), 7.71 (br d, J = 7.7 Hz, 2H), 7.49 (br t, = 7.1 Hz, 2H), 7.36 (br d, = 7.1 Hz, 1H), 7.27 (d, = 2.0 Hz, 2H), 6.70 - 6.61 (m, 1H), 4.29 (dd, J = 2.1, 7.2 Hz, 2H), 1.38 - 1.22 (m, 3H). MS (ESI) m/z (M+H) + 282.9. [0529] To a solution of 34D (2.5 g, 8.86 mmol) in THF (30 mL) and H 2 0 (6 mL) was added NaOH (708 mg, 17.7 mmol). The mixture was stirred at 80 °C for 1.5 hrs. The reaction mixture was concentrated under reduced pressure to remove THF, and then washed with EtOAc (20 mL). The aqueous layer was acidized with 1M HCl (to pH ~ 5) and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H 2 0 (40 mL), brine (40 mL), dried over Na 2 S0 4 , filtered and concentrated to afford intermediate compound 34E (1.90 g, yield: 84.31%) as yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.62 (d, = 2.6 Hz, 1H), 8.19 (s, 1H), 7.86 (d, = 7.9 Hz, 2H), 7.76 (s, 1H), 7.53 (t, = 7.9 Hz, 2H), 7.39 - 7.31 (m, 1H), 6.77 (d, J = 2.6 Hz, 1H). MS (ESI) m/z (M+H) + 254.9.
[0530] Compound 34 (50 mg, yield: 62.8%, white solid) was prepared as in Example 6 from the corresponding intermediate compounds 34E and 21G. Compound 34: 1H NMR (400MHz, CDC1 3 ) δ 9.66 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 7.58 (d, = 8.2 Hz, 2H), 7.45 (t, = 7.8 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.26 - 7.19 (m, 4H), 7.08 (d, = 6.4 Hz, 2H), 6.55 (d, = 2.4 Hz, 1H), 4.84 (q, = 6.4 Hz, 1H), 3.21 (d, = 6.4 Hz, 2H). MS (ESI) m/z (M + H 2 0 + H) + 404.1.
COMPOUNDS 35, 205
(5)-N-(l-AMINO-5-METHYL-l,2-DIOXOHEXAN-3-YL)-3-METHYL-5- PHE YLIS OXAZOLE-4- C ARB OX AMIDE (35)
[0531] To a solution of compound 35A (20 g, 86.47 mmol), N-methoxymethanamine (12.65 g, 129.71 mmol, HCl), HOBt (11.68 g, 86.47 mmol) in DCM (400 mL) was added DIEA (33.53 g, 259.41 mmol, 45.31 mL) at 0 °C. After that, the reaction mixture was stirred at 0 °C for 0.1 h, and then EDCI (19.89 g, 103.76 mmol) was added, after addition, the reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated to give a residue and the residue was dissloved in EtOAc (400 mL), washed with IN HCl (400 mL x 2), sat.NaHC0 3 (400 mL x 2) and brine (400 mL). The organic phase was dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum Ether-Petroleum Ether: EtOAc = 10: 1). Compound 35B (40.32 g, yield: 84.98%) was obtained as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 5.04 (br d, = 9.0 Hz, 1H), 4.71 (br s, 1H), 3.77 (s, 3H), 3.18 (s, 3H), 1.80 - 1.63 (m, 2H), 1.42 (s, 10H), 0.93 (dd, = 6.5, 14.2 Hz, 6H).
[0532] To a mixture of LAH (1.53 g, 40.41 mmol) in THF (200 mL) was added dropwise a solution of compound 35B (10.08 g, 36.74 mmol) in THF (100 mL) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hrs. EtOAc (150 mL) was added dropwise into the reaction mixture at 0 °C and acidified to pH ~ 1-2 with IN HCl, then added saturated aqueous NaHC0 3 (150 mL x 3) and brine (150 mL). The organic layer was dried over Na 2 S0 4 and concentrated. The compound 35C (27.89 g, yield: 88.15%) was obtained as a yellow oil, which was used for next step directly without purification. 1H NMR (400MHz, CDC1 3 ): δ 9.71 - 9.32 (m, 1H), 4.99 (br s, 1H), 4.20 (br d, J = 2.9 Hz, 1H), 1.79 - 1.69 (m, 1H), 1.67 - 1.57 (m, 1H), 1.43 - 1.40 (m, 10H), 0.93 (dd, 7 = 1.4, 6.5 Hz, 6H).
[0533] To a solution of compound 35C (4 g, 18.58 mmol), compound 35D (3.16 g, 37.16 mmol, 3.40 mL) and Et 3 N (2.26 g, 22.30 mmol, 3.09 mL) in dry DCM (40 mL) was stirred at 25 °C for 16 hrs. The reaction mixture was diluted with 50 mL DCM, washed with 0.5 N HCl (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over Na 2 S04, concentrated. Then the residue was purified by column chromatography (Si0 2 , Petroleum Ether: EtOAc = 10: 1). Compound 35E (3.9 g, yield: 86.63%) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ): δ 4.80 (br s, 1H), 4.58 - 4.36 (m, 1H), 4.02 - 3.91 (m, 0.5H), 3.77 (br s, 0.5H), 1.75 - 1.60 (m, 2H), 1.51 - 1.33 (m, 10H), 1.03 - 0.89 (m, 6H)
[0534] To a solution of compound 35E (15 g, 61.90 mmol) and K 2 C0 3 (17.11 g, 123.80 mmol) in DMSO (300 mL) was added H 2 0 2 (70.17 g, 2.15 mol, 60 mL) under N 2 at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 1 h. Then the reaction mixture was diluted with water (150 mL) and quenched with saturated aqueous Na 2 S 2 0 3 (300 mL) slowly at ice water. The mixture was extracted with EtOAc (300 mL x 3) and the combined extracts were washed with saturated aqueous Na 2 S 2 0 3 (300 niL x 3). The organic layer was dried over Na 2 S0 4 and concentrated. The residue was diluted with EtOAc (20 niL) and MTBE (200 niL), the solid was collected and dried in vacuo. Compound 35F (15.15 g, yield: 47.01%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.31 - 6.96 (m, 2H), 6.33 (br d, J = 9.0 Hz, 0.6H), 5.95 (d, = 9.5 Hz, 0.4H), 5.44 (br d, = 5.1 Hz, 1H), 3.93 - 3.65 (m, 2H), 1.57 - 1.47 (m, 1H), 1.41 - 1.23 (m, 10H), 0.95 - 0.70 (m, 7H).
[0535] To a solution of compound 35F (5.42 g, 20.82 mmol) in dioxane (10 mL) was added HCl/dioxane (4M, 55 mL) at 25 °C. After addition, the reaction mixture was stirred at 25 °C for 2 hrs. The reaction was concentrated, and 40 mL of MTBE was added into the reaction mixture and the mixture was stirred for 5 min. Then the mixture was filtered to afford desired compound. Compound 35G (3.8 g, yield: 92.80%) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.12 (br s, 1.5H), 7.87 (br s, 0.5H), 7.57 - 7.35 (m, 2H), 4.22 (d, = 2.5 Hz, 0.7H), 4.02 (d, = 3.8 Hz, 0.3H), 3.57 (s, 1H), 3.45 (br d, = 3.5 Hz, 1H), 1.81 - 1.58 (m, 1H), 1.54 - 1.33 (m, 1.3H), 1.21 (ddd, = 4.3, 9.5, 14.1 Hz, 0.7H), 0.93 - 0.67 (m, 6H).
[0536] Compound 35 (48 mg, yield: 44.55%, white solid) was prepared as in Example 5 from the corresponding intermediate compounds 23A and 35G. Compound 35: 1H NMR (400MHz, DMSO-d 6 ) δ 8.99 (br d, = 7.1 Hz, 1H), 8.13 (s, 1H), 7.89 - 7.77 (m, 3H), 7.54 - 7.48 (m, 3H), 5.20 (ddd, = 3.3, 7.0, 10.6 Hz, 1H), 2.29 (s, 3H), 1.74 - 1.62 (m, 1H), 1.56 - 1.36 (m, 2H), 0.92 (d, = 6.4 Hz, 3H), 0.89 - 0.84 (m, 3H).
(5)-N-(l-AMINO-l,2-DIOXO-5-PHENYLPENTAN-3-YL)-3-METHYL-5- -4-CARBOXAMIDE 205)
[0537] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-4-phenylbutanoic acid (5 g, 17.90 mmol) and N-methoxymethanamine (2.76 g, 28.26 mmol, HCl), HOBt (2.55 g, 18.84 mmol) in DCM (100.00 mL) was added dropwise DIEA (9.88 mL, 56.53 mmol) and EDCI (4.33 g, 22.61 mmol) in portion at 0°C under N 2 . The mixture was stirred at 0 °C for 30 min, then the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with H 2 0 (200 mL). The two layers were separated and the aqueous phase was extracted with Ethyl Acetate (2 x 150 mL). The combined organic layers were washed with 0.5 N HCl (2 x 150 mL) and NaHC0 3 (2 x 150 mL), dried over Na 2 S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=10: l to 3: 1) to afford compound 205A (4.15 g, 68.32% yield) as a white solid. 1H NMR (400MHz, DMSO- e) δ 7.35 - 7.23 (m, 2H), 7.22 - 7.04 (m, 4H), 4.45 - 4.21 (m, 1H), 3.59 (s, 3H), 3.06 (s, 3H), 2.81 - 2.68 (m, 1H), 2.61 - 2.54 (m , 1H), 1.86 - 1.65 (m, 2H), 1.45 - 1.29 (s, 9H).
[0538] To a solution of LiAlH 4 (88.3 mg, 2.32 mmol) in THF (15 mL) was added drop wise a solution of compound 205A (500 mg, 1.55 mmol) in THF (15 mL) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with IN HCl (20 mL), saturated NaHC0 (2 x 20 mL), brine (15 mL). The organic layer was dried over Na 2 S0 4 and concentrated to afford compound 205B (400 mg, 1.52 mmol) a s a yellow oil. 1H NMR (400MHz, DMSO-i¾) δ 9.4 (s, 1H), 7.33 - 7.05 (m, 5H), 3.82 - 3.72 (m, 1H), 2.71 - 2.51 (m, 2H), 1.97 - 1.9 (m, 1H), 1.81 - 1.66 (m, 1H), 1.51 - 1.25 (m, 10H).
[0539] A solution of compound 205B (1.86 g, 7.06 mmol), 2-hydroxy-2- methylpropanenitrile (1.29 mL, 14.12 mmol) and Et 3 N (1.17 mL, 8.47 mmol) in dry DCM (60 mL) was stirred at 30 °C for 16 hours. The reaction mixture was diluted with DCM (50 mL), washed with 0.5N HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over Na2S04, concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=5/l to 3: 1) to afford compound 205C (900mg, 43.90% yield) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.44 - 7.21 (m, 5H), 6.75 - 6.58 (m, 1H), 4.70 - 4.29 (m, 1H), 3.80 - 3.51 (m, 1H), 2.86 - 2.68 (m, 1H), 2.62 - 2.59 (m, 1H), 2.04 - 1.64 (m, 2H), 1.53 - 1.43 (m, 9H).
[0540] To a solution of compound 205C (900 mg, 3.1 mmol) and K 2 C0 3 (856.9 mg, 6.2 mmol) in DMSO (18 mL) was added H 2 0 2 (3.06 mL, 106.14 mmol) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for lh. The reaction mixture was diulted with water (200 mL) and quenched with saturated aqueous Na 2 S 2 0 3 (500 mL) slowly at ice water.The mixture was extracted with EtOAc (3 x 500 mL) and the combined extracts were washed with saturated aqueous Na 2 S 2 0 3 (2 x 300 mL).The organic layer was dried over Na 2 S0 4 and concentrated. The mixture was treated with MTBE and then it was filtered to afford Compound 205D (500 mg, 52.30% yield) as white solid. 1H NMR (CDC1 3, 400 MHz): δ 7.34 - 7.11 (m, 1H), 6.81 - 6.67 (m, 1H), 5.54 - 5.35 (m, 1H), 5.19 - 5.05 (m, 2H), 4.28 - 4.12 (m, 1H), 3.85 - 3.72 (s, 1H), 2.81 - 2.54 (m, 2H), 2.24 - 1.99 (m, 2H), 2.98 - 2.78 (m, 1H), 1.65 - 1.41 (m, 9H).
[0541] To a solution of compound 205D (250 mg, 810.71 umol) in dioxane (2 mL) was added HCl/dioxane (4M, 1.06 mL) at 25 °C. After addition, the reation was stirred at 32°C for 2 hours and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10: 1 to 1: 2) to afford compound 205E (180 mg, 90.64% yield) as white solid. 1H NMR (400MHz, DMSO-i¾): δ 8.15 - 8.02 (m, 1H), 8.01 - 7.75 (m, 1H), 7.65 - 7.48 (m, 2H), 7.37 - 7.26 (m, 2H), 7.25 - 7.05 (m, 5H), 6.52 - 6.24 (s, 1H), 4.16 - 4.05 (m, 1H), 3.45 - 3.39 (m, 1H), 1.95 - 1.61 (m, 2H), 1.41 - 1.28 (m, 2H).
[0542] Compound 205 (23.5 mg, 31.69% yield, yellow solid) was prepared as in Example 5 from the corresponding intermediate compounds 23A and 205E. Compound 205: 1H NMR (400MHz, CDC1 3 ) δ 7.84 - 7.72 (m, 2H), 7.60 - 7.50 (m, 3H), 7.26 - 7.12 (m, 4H), 7.07 - 7.00 (m, 2H), 6.66 (br s, 1H), 6.19 (br s, 1H), 5.51 - 5.34 (m, 2H), 2.66 - 2.54 (m, 2H), 2.47 (s, 3H), 2.38 - 2.25 (m, 1H), 1.99 - 1.85 (m, 1H). MS (ESI) m/z (M+H) + 392.1.
COMPOUNDS 36, 49, 409, 455
(S)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYR IMIDIN-2- -lH-PYRAZOLE-5-CARBOXAMIDE (36)
[0543] To a solution of compound 36B (1.31 g, 9.08 mmol) in AcOH (50 mL) was added compound 36A (1 g, 9.08 mmol). The mixture was stirred at 120 °C for 1 h. The mixture was in DCM (50 mL). The organic layer was washed with water (10 mL), NaHC0 3 to pH ~ 8-9 and dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10: 1 to 5: 1) to afford compounds 36C and 36D. Compound 36C (500 mg, 2.29 mmol, 25.24% yield, white solid): 1H NMR (400MHz, DMSO- d 6 ) δ 9.03 - 8.79 (m, 2H), 7.67 - 7.45 (m, 1H), 6.87 (s, 1H), 3.73 (s, 3H), 2.29 (s, 3H). Compound 36D (1 g, 50.47% yield, white solid): 1H NMR (400MHz, DMSO-d 6 ) δ 9.03 - 8.89 (m, =4.9 Hz, 2H), 7.67 - 7.55 (m, 1H), 6.81 (s, 1H), 3.84 (s, 3H), 2.60 (s, 3H).
[0544] Intermediate compound 36F (39.6 mg, 90% yield, white solid) was prepared as in Example 85 from compound 36C. MS (ESI) m/z (M+l) + 205. Compound 36 (15.5 mg, 43.77% yield, brown solid) was prepared as in Example 5 from the corresponding intermediate compound 36F. Compound 36: 1H NMR (400MHz, DMSO-d 6 ) δ 8.99 - 8.95 (m, 2H), 8.50 - 8.39 (m, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.65 - 7.57 (m, 1H), 7.31 - 7.17 (m, 5H), 6.68 (s, 1H), 5.51 - 5.45 (m, 1H), 3.26 - 3.18 (m, 1H), 3.13 - 3.03 (m, 1H), 2.58 (s, 3H).
(5 N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYRIMID IN-2-
[0545] Following the procedure as used for compound 36, compound 49 (21 mg, 38.4% yield, white solid) was prepared from the corresponding intermediate compound 36D. 1H NMR (400MHz, DMSO-d 6 ) δ 9.08 - 8.98 (m, 1H), 8.76 - 8.70 (m, 2H), 8.05 (s, 1H), 7.82 (s, 1H), 7.49 - 7.44 (m, 1H), 7.35 - 7.26 (m, 4H), 7.26 - 7.19 (m, 1H), 6.58 (s, 1H), 5.31 - 5.25 (m, 1H), 3.19 - 3.09 (m, 1H), 2.90 - 2.78 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+Na) + 379.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYRI MIDIN-4-YL)- lH-PYRAZOLE-5-CARBOXAMIDE (409)
[0546] Following the procedure as used for compound 36, compound 409 (4225.7 mg, 80.2% yield, white solid) was prepared from the corresponding starting materials, namely 4- hydrazinylpyrimidine and intermediate compound 274D. 1H NMR (400MHz, DMSO-^) δ 9.22 (d, = 7.2 Hz, 1H), 8.84 (d, = 5.6 Hz, 1H), 8.75 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.78 - 7.74 (m, 1H), 7.31 - 7.21 (m, 5H), 6.52 (s, 1H), 5.41 - 5.33 (m, 1H), 3.22 - 3.12 (m, 1H), 2.90 - 2.78 (m, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+l) + 379.0.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METH YL-l- (PYRIMIDIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (455)
[0547] Following the procedure as used for compound 36, compound 455 (180 mg, 71.6% yield, white solid) was prepared from the corresponding starting materials, namely 36F and 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide. 1H NMR (400MHz, DMSO-i/ 6 ) δ 9.05 - 9.00 (m, 1H), 9.03 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.44 (t, J = 4.9 Hz, 1H), 7.29 - 7.18 (m, 5H), 6.56 (s, 1H), 5.31 - 5.24 (m, 1H), 3.12 (dd, J = 3.7, 13.9 Hz, 1H), 2.84 - 2.71 (m, 2H), 2.24 (s, 2H), 2.27 - 2.19 (m, 1H), 0.67 - 0.54 (m, 4H). MS (ESI) m/z (M+H) + 419.2. EXAMPLE 17
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(2H-INDAZOL-2 - -5-CARBOXAMIDE (37)
[0548] A mixture of compound 37A (250 mg, 2.12 mmol), Cs 2 C0 3 (2.07 g, 6.36 mmol) in toluene (40 mL) was stirred at 110 °C for 13 hrs. The mixture was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1 to 5: 1) to afford compound 37B (43.75 mg, 7.55% yield) as white solid. MS (ESI) m/z (M+l) + 274. 1H NMR (400MHz, CDC13) δ 8.93 (s, 1H), 8.68 (s, 1H), 7.85 - 7.65 (m, 2H), 7.39 - 7.30 (m, 1H), 7.17 - 7.05 (m, 1H), 4.44 - 4.24 (m, 2H), 1.28 (m, 3H).
[0549] A mixture of compound 37B (35 mg, 128.06 umol), LiOH (9.2 mg, 384.18 umol) in water (1 mL) and MeOH (5 mL) was stirred at 27 °C for 2 hrs. MeOH was evaporated. To the residue was added water (10 mL). The mixture was extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH ~ 3 with IN HC1 and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried and concentrated to afford compound 37D (25.3 mg, 80.55% yield) as brown solid.
[0550] Compound 37 (4 mg, 8.47 umol, yield 5.95%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 37D. Compound 37: 1H NMR (400MHz, CDC1 3 ) δ 12.72 - 12.49 (m, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 7.80 - 7.64 (m, 1H), 7.46 - 7.29 (m, 2H), 7.20 - 6.98 (m, 6H), 6.83 - 6.72 (m, 1H), 5.97 - 5.84 (m, 1H), 5.52 - 5.40 (m, 1H), 3.56 - 3.33 (m, 2H). EXAMPLE 18
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(NAP HTHALEN- -YL)-lH-PYRAZOLE-5-CARBOXAMIDE (38)
[0551] A mixture consisting of compound naphthalen- l-yl hydrazine hydrochloride (4.05 g, 20.81 mmol) and compound 38A (3.0 g, 20.81 mmol) in AcOH (30 mL) was stirred at 120 °C for 1 hour. The reaction mixture was cooled to 25 °C, concentrated under reduced pressure and diluted with CH 2 CI 2 (100 mL). The organic phase was washed with sat. NaHC0 3 (20 mL x 2), dried over anhydrous Na 2 S0 4 , filtered, and the filtration was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Petroleum ether: Ethyl acetate = 4: 1) to afford compound 38B (154.3 mg, 2.79% yield) as a brown solid. 1H NMR (CDC1 3 , 400 MHz): δ 7.96 (d, = 8.0 Hz, 1H), 7.91 (d, = 8.4 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.51 - 7.47 (m, 2H), 7.46 - 7.41 (m, 1H), 7.22 (d, = 8.4 Hz, 1H), 6.90 (s, 1H), 3.62 (s, 3H), 2.43 (s, 3H). MS (ESI) m/z (M+l) + 267.1.
[0552] To a mixture of compound 38B (160 mg, 570.78 umol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH.H 2 0 (71.9 mg, 1.71 mmol) in one portion and the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 38C (140 mg, yield 97.23%) as a white solid. 1H NMR (CDC1 3 , 400 MHz): δ 7.96 - 7.83 (m, 2H), 7.52 - 7.44 (m, 2H), 7.44 - 7.36 (m, 2H), 7.15 (d, = 8.4 Hz, 1H), 6.87 (s, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+l) + 252.9.
[0553] Compound 38 (10.6 mg, yield 13.31%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 38C. Compound 38: 1H NMR (400 MHz, CDC1 3 ) δ 8.00 - 7.89 (m, 2H), 7.57 - 7.43 (m, 4H), 7.28 (d, = 8.4 Hz, 1H), 7.22 - 7.10 (m, 3H), 6.82 - 6.72 (m, 2H), 6.69 (s, 1H), 6.54 (br s, 1H), 6.16 (d, = 6.8 Hz, 1H), 5.48 - 5.33 (m, 2H), 3.19 - 3.09 (m, IH), 2.94 - 2.84 (m, IH), 2.40 (s, 3H). MS (ESI) m/z (M+l) + 427.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(lH-INDAZOL-l - -5-CARBOXAMIDE (40)
[0554] A mixture consisting of compound 40A (500 mg, 2.12 mmol), indazole (250.5 mg, 2.12 mmol), Cs 2 C0 3 (2.07 g, 6.36 mmol) in toluene (40 mL) was stirred at 110.6 °C for 16 hrs. The reaction mixture was cooled to 25 °C, filtered, concentrated under reduced pressure. The obtained residue was purified by preparatory-HPLC (HC1 condition) to afford compound 40B (56 mg, 9.67% yield) as a light yellow solid. 1H NMR (CDC1 3, 400 MHz): δ 8.94 (s, IH), 8.26 (s, IH), 7.80 (d, = 8.0 Hz, IH), 7.62 (d, = 8.4 Hz, IH), 7.48 - 7.43 (m, IH), 7.28 - 7.24 (m, IH), 4.24 (q, = 7.2 Hz, 2H), 1.17 - 1.12 (m, IH), 1.14 (t, = 7.2 Hz, 2H).
[0555] To a mixture of compound 40B (50 mg, 182.94 umol) in MeOH (2 mL) was added LiOH (13.1 mg, 548.83 umol) in one portion and the mixture was stirred at 25 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (8 mL), adjusted to pH ~ 3 with 1 N HC1, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 40C (42 mg, 93.61% yield) as a white solid. 1H NMR (CDC1 3 , 400 MHz): δ 8.95 (s, IH), 8.73 (d, = 8.4 Hz, IH), 8.38 (s, IH), 7.89 (d, = 8.0 Hz, IH), 7.67 (t, = 7.6 Hz, IH), 7.43 (t, 7 = 7.6 Hz, IH).
[0556] To a solution consisting of compound 40C (42 mg, 171.25 umol) and 1- hydroxypyrrolidine-2,5-dione (20.7 mg, 179.81 umol) in DME (5 mL) was added EDCI (49.24 mg, 256.87 umol) in one portion at 25 °C under N 2 . The mixture was stirred at 25 °C for 9 hrs. The reaction mixture was concentrated under reduced pressure to remove DME. The residue was diluted with EtOAc (60 mL), washed with IN HCl (10 mL) and saturated aqueous NaHC0 3 (10 mL x 3). The organic layers was washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 40D (60 mg, crude) as a light yellow oil. MS (ESI) m/z (M+l) + 342.8.
[0557] Compound 40 (15.10 mg, 50.57% yield, white solid) was prepared as in Example 6 from the corresponding starting materials, compounds 40D and 12G. Compound 40: 1H NMR (CDC1 3 , 400 MHz): δ 11.07 (d, = 6.0 Hz, 1H), 8.85 (s, 1H), 8.33 - 8.28 (m, 1H), 7.86 (d, = 0.8 Hz, 1H), 7.77 (d, = 8.0 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.35 - 7.31 (m, 1H), 7.16 - 7.08 (m, 5H), 6.77 (br s, 1H), 5.81 - 5.75 (m, 1H), 5.55 (br s, 1H), 3.43 - 3.37 (m, 1H), 3.26 - 3.19 (m, 1H). MS (ESI) m/z (M+l) + 420.1.
COMPOUNDS 41-43, 64-65, 67, 71, 76, 87, 100, 116, 132, 134-135, 137, 203-204 (5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (PYRIDIN- -YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (41)
[0558] To a mixture of compound 24E (100 mg, 528 umol) and compound 41B (148 mg, 634 umol) in DMF (1.5 mL) was added HBTU (240 mg, 634 umol) in one portion at 25 °C and stirred for 5 mins, and then DIEA (273 mg, 2.1 mmol) was added. The mixture was stirred at 25 °C for 30 mins. LCMS showed compound 24E remained and desired MS was detected. Then the residue was purified by preparatory-HPLC (TFA condition) to give compound 41A (130 mg, yield: 60.6%) as a white solid. 1H NMR (400 MHz, Methanol-^) δ 9.12 (br s, 1H), 8.49 (br d, J = 3.8 Hz, 1H), 7.95 - 7.74 (m, 2H), 7.50 (br s, 1H), 7.37 - 7.16 (m, 5H), 7.13 - 7.01 (m, 1H), 4.69 - 4.52 (m, 1H), 4.22 - 4.03 (m, 1H), 3.29 (br s, 1H), 3.11 - 2.74 (m, 2H), 2.69 - 2.51 (m, 1H), 0.77 - 0.59 (m, 2H), 0.56 - 0.38 (m, 2H). MS (ESI) m/z (M+H) + 405.2.
[0559] To a solution of compound 41A (130 mg, 320 umol) in DCM (10 mL) was added DMP (543 mg, 1.3 mmol, 397 uL) in one portion at 0 °C. The mixture was stirred at 25 °C for 10 mins. LCMS showed compound 41A was consumed completely and one main peak with desired MS was detected. Then the mixture was diluted with DCM (80 mL), quenched by adding 10% Na 2 S203/saturated aqueous NaHC0 3 (v/v = 1/1, 20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (30 mL x 2). The combined organic layer was washed with H 2 0 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated to afford white solid. Then the residue was purified by re-crystallization from isopropyl ether (20 mL) to give compound 41 (20.6 mg, yield: 30.9%) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.96 (d, = 7.8 Hz, 1H), 8.79 (br d, = 5.0 Hz, 1H), 8.45 (br d, = 4.6 Hz, 1H), 8.14 (s, 1H), 7.88 (t, 7 = 7.8 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 7.0, 5.2 Hz, 1H), 7.34 - 7.28 (m, 4H), 7.24 (br d, J = 4.2 Hz, 1H), 7.18 (d, = 8.2 Hz, 1H), 5.32 - 5.22 (m, 1H), 3.31 (s, 1H), 3.19 (dd, J = 13.8, 3.6 Hz, 1H), 2.89 - 2.71 (m, 2H), 0.70 - 0.64 (m, 2H), 0.60 - 0.55 (m, 2H). MS (ESI) m/z (M+H) + 403.2.
(5)-/V-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l -(l-
PHENYL-lH-PYRAZOL-3-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (42)
[0560] Compound 42 (19.3 mg, yield: 55.2%, yellow solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 34E. 1H NMR (400 MHz, DMSO- e) δ 8.91 (d, = 7.7 Hz, 1 H), 8.82 (d, J = 5.1 Hz, 1 H), 8.57 (d, = 2.6 Hz, 1 H), 8.14 (s, 1 H), 7.83 (d, = 7.9 Hz, 2 H), 7.63 (s, 1 H), 7.53 (t, = 8.0 Hz, 2 H), 7.36 (t, = 7.4 Hz, 1 H), 7.32 (d, = 4.4 Hz, 4 H), 7.27 - 7.20 (m, 1 H), 6.48 (d, = 2.6 Hz, 1 H), 5.34 - 5.26 (m, 1 H), 3.21 (dd, = 13.8, 3.6 Hz, 1 H), 2.86 (dd, = 13.8, 10.3 Hz, 1 H), 2.81 - 2.72 (m, 1 H), 0.71 - 0.63 (m, 2 H), 0.62 - 0.53 (m, 2 H). MS (ESI) m/z (M+H) + 469.1.
(5)-l-(BENZO[£ ) ]THIAZOL-2-YL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l- PHENYLBUTAN-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (43)
[0561] Compound 43 (24.4 mg, yield: 43%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 29D. Compound 43: 1H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (d, = 7.7 Hz, 1 H), 8.77 (br d, J = 4.9 Hz, 1 H), 8.39 (s, 1 H), 8.08 (d, = 7.9 Hz, 1 H), 7.96 (d, = 8.2 Hz, 1 H), 7.67 (s, 1 H), 7.59 - 7.43 (m, 2 H), 7.27 (d, = 4.0 Hz, 4 H), 7.22 - 7.12 (m, 1 H), 5.34 - 5.16 (m, 1 H), 3.18 (dd, = 13.9, 3.3 Hz, 1 H), 2.83 (dd, = 13.7, 10.1 Hz, 1 H), 2.72 (br d, J = 4.2 Hz, 1 H), 0.69 - 0.58 (m, 2 H), 0.54 (br d, = 2.9 Hz, 2 H). MS (ESI) m/z (M+H) + 460.1
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(PYRIMIDI -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (65)
[0562] A mixture of compound 65A (80 mg, 366.62 umol) in MeOH (5 mL) and H 2 0 (1 mL) was added LiOH.H 2 0 (27.1 mg, 645.87 umol). The mixture was stirred at 31°C for lh. The mixture was evaporated to remove MeOH, then it was washed with water (3 x 50 mL) and extracted with MTBE (2 x 50 mL). The water layers were acidized to pH ~ 4 with IN HC1, then, the solution extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over Na 2 S0 4 and concentrated to give compound 65B (50 mg, 66.79% yield) was obtained as white solid.
[0563] Compound 65 (11.8 mg, 87.93% yield, white solid) was prepared as in Example 20 from the corresponding intermediate compounds 65B and 41B. Compound 65: 1H
NMR (400MHz, DMSO- 6 ) S 8.94 (s, 2H), 8.87 - 8.79(m, 1 H), 8.51 - 8.44 (m,lH), 7.62 - 7.55 (m, lH), 7.34 - 7.09 (m, 5H), 6.65 (s, 1H), 5.53 - 5.39 (m, 1H), 3.26 - 3.12 (m, 4H), 3.10 - 3.00 (m, 1H),2.81 - 2.71 (m, lH), 2.56 (s, 3H), 0.71 - 0.54 (m, 4H). MS (ESI) m/z (M+H) + 419.2.
(S)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4- (2H- INDAZOL-2-YL)THIAZOLE-5-CARBOXAMIDE (64)
[0564] Compound 64 (48.2 mg 87.93% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 64A. Compound 64: 1H NMR (400MHz, DMSO-d 6 ) δ 11.99 - 11.83 (m, 1H), 9.33 (s, 1H), 9.16 (s, 1H), 8.95 - 8.84 (m, 1H), 7.93 - 7.80 (m, 1H), 7.56 - 7.50 (m, 1H), 7.44 - 7.33 (m, 1H), 7.27 - 7.15 (m, 1H), 7.12 - 6.99 (m, 5H), 5.71 - 5.60 (m, 1H), 3.34 - 3.24 (m, 3H), 3.19 - 3.10 (m, 1H), 2.84 - 2.74 (m, 1H), 0.73 - 0.54 (m, 4H). MS (ESI) m/z (M+H) + 460.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(3-METHYLPYRIDIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (67)
[0565] Compound 67 (30.8 mg, 38.6% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 67A. Compound 67: 1H NMR (CDC1 3, 400 MHz) δ 8.24 (d, = 4.4 Hz, 1H), 7.67 (d, = 7.6 Hz, 1H), 7.2 (d, = 7.2 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.25 - 7.20 (m, 3H), 6.99 (d, J = 4.4 Hz, 2H), 6.86 (s, 1H), 6.56 (s, 1H), 5.66 - 5.58 (m, 1H), 3.38 - 3.29 (m, 1H), 3.21 - 3.13 (m, 1H), 2.82 - 2.74 (m, 1H), 2.34 (s, 3H), 2.16 (s, 3H), 0.91 - 0.84 (m, 2H), 0.64 - 0.57 (m, 2H). MS (ESI) m/z (M+H) + 432.1. (5 l-(lH-BENZO[rf]IMIDAZOL-2-YL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DI OXO-l- PHENYLBUTAN-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (71)
[0566] Compound 71 (75 mg, yield: 78.1%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 70D. Compound 71: 1H NMR (400MHz, DMSO-d 6 ) δ 12.93 (br s, 1H), 9.25 (br s, 1H), 8.74 (d, = 4.9 Hz, 1H), 8.29 (s, 1H), 7.83 (s, 1H), 7.52 (br s, 2H), 7.30 - 7.18 (m, 6H), 7.18 - 7.13 (m, 1H), 5.42 - 5.25 (m, 1H), 3.17 (dd, J = 3.5, 13.7 Hz, 1H), 2.83 (dd, J = 10.0, 13.8 Hz, 1H), 2.74 - 2.64 (m, 1H), 0.70 - 0.42
(m, 4H). MS (ESI) m/z (M+H) + 443.0.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL) -l-(5- PHENYLPYRIMIDIN-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (76)
[0567] Compound 76 (24.7 mg, yield: 44.7%, white solid) was prepared as in Example 20 from the corresponding intermediate compound 74E. Compound 76: 1H NMR (CDC1 3, 400 MHz) δ 9.46 (br d, J = 6.4 Hz, 1H), 8.66 (s, 2H), 8.62 (s, 1H), 7.80 (s, 1H), 7.57 - 7.49 (m, 5H), 7.22 - 7.16 (m, 2H), 7.16 - 7.07 (m, 3H), 6.93 (br s, 1H), 5.86 - 5.82 (m, 1H), 3.53 - 3.46 (m, 1H), 3.41 - 3.32 (m, 1H), 2.86 -2.82 (m, 1H), 0.92 - 0.86 (m, 2H), 0.64 -0.62 (m, 2H). MS (ESI) m/z (M+H) + 481.0.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4- (4- PHENYL-lH-PYRAZOL-l-YL)THIAZOLE-5-CARBOXAMIDE (87)
[0568] Compound 87 (60.0 mg, 75.3% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 21D. 1H NMR (400MHz, CDCI 3 ) δ 11.72 (br. d, J = 6.0 Hz, 1H), 8.73 (s, 1H), 8.68 - 8.64 (m, 1H), 7.76 - 7.72 (m, 1H), 7.58 - 7.52 (m, 2H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.29 - 7.21 (m, 5H), 6.97 - 6.91 (m, 1H), 5.86 - 5.74 (m, 1H), 3.53 - 3.41 (m, 1H), 3.29 - 3.17 (m, 1H), 2.88 - 2.75 (m, 1H), 0.93 - 0.82 (m, 2H), 0.68 - 0.58 (m, 2H). MS (ESI) m/z (M+l) + 486.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- 5-PHENYLISOXAZOLE-4-CARBOXAMIDE (100)
[0569] Compound 100 (85 mg, yield: 83.27%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 23A. Compound 100: 1H NMR (400MHz, OMSO-d 6 ) δ 9.09 (d, = 7.5 Hz, 1H), 8.94 (br d, = 5.1 Hz, 1H), 7.62 (d, = 7.1 Hz, 2H), 7.53 - 7.46 (m, 1H), 7.44 - 7.39 (m, 2H), 7.32 - 7.20 (m, 5H), 5.48 (ddd, = 3.3, 7.6, 10.7 Hz, 1H), 3.25 (br dd, = 3.2, 14.0 Hz, 1H), 2.85 - 2.67 (m, 2H), 2.07 (s, 3H), 0.73 - 0.56 (m, 4H). MS (ESI) m/z (M+H) + 418.1. (5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- 5-PHENYLISOTHIAZOLE-4-CARBOXAMIDE (116)
[0570] Compound 116 (88.00 mg, 87.41% yield, off-white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 96D. Compound 116: 1H NMR (400MHz, CDC1 3 ) δ 7.44 (s, 5H), 7.20 - 7.09 (m, 3H), 6.86 (br s, 1H), 6.77 - 6.68 (m, 2H), 5.93 (br d, 7=6.6 Hz, 1H), 5.68 - 5.57 (m, 1H), 3.24 - 3.14 (m, 1H), 2.99 - 2.89 (m, 1H), 2.83 - 2.73 (m, 1H), 2.46 (s, 3H), 0.93 - 0.81 (m, 2H), 0.69 - 0.53 (m, 2H). MS (ESI) m/z (M+H) + 434.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(PYRIDIN-3-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (132)
[0571] Compound 132 (72.8 mg, 60.40% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 136C. Compound 132: 1H NMR (400 MHz, CDCI 3 ): δ 8.61 (d, 7 = 2.4 Hz, 1H), 8.57 - 8.54 (m, 1H), 7.72 - 7.66 (m, 1H), 7.34 - 7.26 (m, 4H), 7.10 - 7.05 (m, 2H), 7.03 - 6.94 (m, 1H), 6.64 - 6.56 (m, 1H), 6.44 (s, 1H), 5.62 - 5.54 (m, 1H), 3.44 - 3.36 (m, 1H), 3.18 - 3.10 (m, 1H), 2.85 - 2.76 (m, 1H), 2.33 (s, 3H), 0.92 - 0.85 (m, 2H), 0.66 - 0.59 (m, 2H). MS (ESI) m/z (M+l) + 418.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (ISOQUINOLIN-4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (134)
[0572] Compound 134 (57.4 mg, 62.9% yield, yellow solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 133D. Compound 134: 1H NMR (400 MHz, CDCI 3 ) δ 9.31 (br s, 1H), 8.47 (br s, 1H), 8.06 (d, 7 = 7.6 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.43 (d, 7 = 8.0 Hz, 1H), 7.25 - 7.20 (m, 3H), 6.92 (br s, 2H), 6.84 (br s, 1H), 6.60 (s, 1H), 6.46 (d, 7 = 7.2 Hz, 1H), 5.50 - 5.41 (m, 1H), 3.30 - 3.22 (m, 1H), 3.14 - 3.04 (m, 1H), 2.79 - 2.70 (m, 1H), 2.40 (s, 3H), 0.87 - 0.82 (m, 2H), 0.63 - 0.53 (m, 2H). MS (ESI) m/z (M+H) + 468.1.
(5)-2-CYCLOPROPYL-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYL BUTAN- 2-YL)-4-PHENYLTHIAZOLE-5-CARBOXAMIDE (135)
[0573] Compound 135 (52.8 mg, 53.03% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 135A. Compound 135: 1H NMR (CDC1 3, 400 MHz) δ 1H NMR (400 MHz, CDC13) δ 7.53 - 7.45 (m, 2H), 7.45 - 7.35 (m, 3H), 7.22 - 7.11 (m, 3H), 6.85 (br s, 1H), 6.80 - 6.70 (m, 2H), 6.17 (d, J = 6.4 Hz, 1H), 5.54 - 5.45 (m, 1H), 3.27 - 3.22 (m, 1H), 2.89 - 2.84 (m, 1H),2.80 - 2.75 (m, 1H), 2.33 - 2.26 (m, 1H), 1.20 - 1.14 (m, 2H), 1.13 - 1.08 (m, 2H), 0.91 - 0.79 (m, 2H), 0.64 - 0.54 (m, 2H). MS (ESI) m/z (M+H) + 460.1.
(5)-3-(tert-BUTYL)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENY LBUTAN-2- YL)-l-PHENYL-lH-PYRAZOLE-5-CARBOXAMIDE (137)
[0574] Compound 137 (96.70 mg, 64.74% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 128A. Compound 137: 1H NMR (400 MHz, CDC1 3 ) δ 7.54 - 7.45 (m, 3H), 7.41 - 7.36 (m, 2H), 7.31 - 7.27(m, 1H), 7.25 - 7.13 (m, 5H), 6.87 (br s, 1H), 6.69 (s, 1H), 5.77 - 5.68 (m, 1H), 3.44 - 3.36 (m, 1H), 3.17 - 3.09 (m, 1H), 2.82 - 2.74 (m, 1H), 1.16 (s, 9H), 0.89 - 0.81 (m, 2H), 0.64 - 0.54 (m, 2H). MS (ESI) m/z (M+H) + 459.2.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(4-PHENYLTHIAZOL-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (203)
[0575] Compound 203 (30 mg, yield 60.18%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 82D. Compound 203: 1H NMR (CDC1 3, 400ΜΗζ) δ 7.69 - 7.64 (m, 2H), 7.41 - 7.33 (m, 3H), 7.22 (s, 1H), 7.12 - 7.06 (m, 3H), 7.01 - 6.94 (m, 3H), 6.84 (br s, 1H), 5.65 - 5.58 (m, 1H), 3.41 - 3.34 (m, 1H), 2.97 - 2.89 (m, 1H), 2.79 - 2.71 (m, 1H), 2.32 (s, 3H), 0.86 - 0.80 (m, 2H), 0.61 - 0.53 (m, 2H). MS (ESI) m/z (M+H) + 500.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5- PHENYL- lH-l,2,3-TRIAZOLE-4-CARBOXAMIDE (204)
[0576] Compound 204 (4 mg, 8.9% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 204A. Compound 204: 1H NMR (CDCI 3, 400 MHz) T = 80 : δ 8.55 (br s, 1H), 8.41 (d, = 7.2 Hz, 1H), 7.82 - 7.78 (m, 2H), 7.50 - 7.35 (m, 4H), 7.32 - 7.20 (m, 5H), 5.51 - 5.45 (m, 1H), 3.30 - 3.22 (m, 1H), 3.05 (br s, 1H), 2.81 - 2.74 (m, 1H), 0.71 - 0.66 (m, 2H), 0.64 - 0.59 (m, 2H). MS (ESI) m/z (M+H) + 404.1. EXAMPLE 21
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-PHEN YL-lH- -4-CARBOXAMIDE (45)
[0577] A mixture of ethyl compound 32C (500.0 mg, 2.15 mmol), phenylboronic acid (262.1 mg, 2.15 mmol), Pd(dtbpf)Cl 2 (140.1 mg, 215.00 umol), K 3 P0 4 (1.37 g, 6.45 mmol) in dioxane (30 mL) and H 2 0 (10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70 °C for 1 hour under N 2 atmosphere. The mixture was concentrated and diluted with ethyl acetate (30 mL), washed with HC1 (1M, 50 mL), sarurated aqueous NaHC0 3 (50 mL), brine (50 mL), dried over Na 2 S0 4 and concentrated to afford intermediate compound 45A (490 mg, crude) as a brown oil. MS (ESI) m/z (M+H) + 230.9.
[0578] To a solution of compound 45A (490.0 mg, 2.13 mmol) in MeOH (5 mL) and THF (5 mL) was added NaOH (2M, 21.28 mL). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated and diluted with H 2 0 (10 mL), the mixture was extracted with ethyl acetate (10 mL), the water phase was added HC1 (1M) until pH ~ 3, then the mixture was extracted with ethyl acetate (20 mL), the organic layer was washed with brine (10 mL), dried over Na 2 S0 4 and concentrated. Compound 45B (400 mg, yield: 93.0%) was obtained as a brown solid. 1H NMR (400MHz, DMSO-d 6 ) δ 12.09 (br s, 1H), 7.87 (s, 1H), 7.50 - 7.40 (m, 5H), 3.63 (s, 3H).
[0579] Compound 45 (50.0 mg, yield: 71.4%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 45B. Compound 45: 1H NMR (400MHz, CDC1 3 ) δ 7.97 (s, 1H), 7.55 - 7.43 (m, 3H), 7.32 - 7.27 (m, 2H), 7.23 - 7.15 (m, 3H), 6.85 - 6.65 (m, 3H), 5.80 - 5.71 (m, 1H), 5.55 - 5.40 (m, 2H), 3.71 - 3.60 (m, 3H), 3.29 - 3.19 (m, 1H), 2.94 - 2.84 (m, 1H), 2.94 - 2.84 (m, 1H). MS (ESI) m/z (M+H) + 377.1. EXAMPLE 22
(5 N-(4-AMINO-l-(4-METHOXYPHENYL)-3,4-DIOXOBUTAN-2-YL)-3-METHYL -5- -4- C ARB OX AMIDE (46)
[0580] To a solution of compound 46A (13 g, 44.02 mmol, 1 eq) in DMF (150 mL) was added K 2 CO 3 (12.17 g, 88.04 mmol, 2 eq) at 0 °C. After addition, the mixture was stirred at this temperature for 0.2 h, and then CH 3 I (8.97 g, 63.20 mmol, 3.93 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 18.8 hours. The reaction mixture was diluted with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 46B (13.4 g, yield: 98.4%) as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 7.04 (d, = 8.6 Hz, 2H), 6.84 (d, = 7.7 Hz, 2H), 4.96 (br d, J = 7.3 Hz, 1H), 4.55 (br d, = 7.1 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.09 - 2.94 (m, 2H), 1.43 (s, 9H).
[0581] To a solution of LAH (490 mg, 12.92 mmol, 2 eq.) in THF (10 mL) was degassed and purged with N 2 for 3 times at 0 °C and the mixture of compound 46B (2 g, 6.46 mmol, 1 eq) in THF (30 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2 hrs under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (0.5 mL), then add NaOH (15% in H 2 0, 0.5 mL), H 2 0 (1.5 mL), and then diluted with EtOAc (20 mL), dried over Na 2 S0 4 , and stirred for 30 min, then filtered to give the organic layers. The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 46C (1.48 g, yield: 81.4%) was obtained as a colorles oil. 1H NMR (400MHz, CDCI 3 ) δ 7.12 (d, = 8.4 Hz, 2H), 6.89 - 6.78 (m, 2H), 4.69 (br s, 1H), 3.88 - 3.80 (m, 1H), 3.79 (s, 3H), 3.69 - 3.48 (m, 2H), 2.77 (d, J = 7.1 Hz, 2H), 1.41 (s, 9H).
[0582] A solution of DMP (1.51 g, 3.56 mmol) in DCM (10 mL) was degassed and purged with N 2 for 3 times, and then compound 46C (500 mg, 1.78 mmol) in DCM (10 mL) was added dropwise, and then the mixture was stirred at 25 °C for 20 hrs under N 2 atmosphere. The reaction mixture was quenched by addition of saturated aqueous Na 2 S 2 0 3 (15 mL) and saturated aqueous NaHC0 3 (15 mL), and then diluted with DCM (10 mL) and extracted with H 2 0 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 46D (430 mg, yield: 86.48%) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 9.62 (s, 1H), 7.13 - 7.02 (m, 2H), 6.84 (br d, =8.6 Hz, 2H), 5.05 (br d, =5.5 Hz, 1H), 4.46 - 4.32 (m, 1H), 3.78 (s, 3H), 3.06 (br d, = 6.4 Hz, 2H), 1.43 (s, 9H).
[0583] To a solution of compound 46D (1.53 g, 5.48 mmol) in DCM (20 mL) was added compound 2-hydroxy-2-methylpropanenitrile (3.30 g, 38.78 mmol, 3.55 mL) and Et 3 N (832 mg, 8.22 mmol, 1.14 mL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition IN HCl (20 mL), and then diluted with H 2 0 (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1 to 4: 1) to give the compound 46E (980 mg, yield: 58.37%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.16 - 6.97 (m, 2H), 6.90 - 6.71 (m, 2H), 4.96 - 4.72 (m, 1H), 4.52 - 4.37 (m, 1H), 3.74 - 3.72 (m, 3H), 3.07 - 2.66 (m, 2H), 1.37 (s, 9H).
[0584] To a solution of compound 46E (980 mg, 3.20 mmol) and K 2 C0 3 (885 mg, 6.40 mmol) in DMSO (15 mL) was added H 2 0 2 (9.3 mL, purity: 30%). The mixture was stirred at 0 °C for 2 hrs. The reaction mixture was diluted with H 2 0 (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 46F (560 mg, yield: 53.95%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.16 - 6.97 (m, 2H), 6.90 - 6.71 (m, 2H), 4.96 - 4.72 (m, 1H), 4.52 - 4.37 (m, 1H), 3.74 - 3.72 (m, 3H), 3.07 - 2.66 (m, 2H), 1.37 (s, 9H). [0585] To a solution of compound 46F (500 mg, 1.54 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with MTBE (20 mL), and filtered to give the compound 46G (300 mg, yield: 73.97%, HC1) was obtained as a white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 8.06 - 7.81 (m, 3H), 7.51 (br s, 2H), 7.26 - 7.07 (m, 2H), 6.95 - 6.79 (m, 2H), 6.65 - 6.35 (m, 1H), 4.21 - 3.78 (m, 1H), 3.71 (d, / = 1.5 Hz, 3H), 3.53 (br s, 1H), 2.87 - 2.62 (m, 2H).
[0586] Compound 46 (65 mg, yield: 65.3%, white solid) was prepared as in Example 15 from the corresponding intermediate compounds, 23A and 46G. Compouond 46: 1H NMR (400MHz, DMSO-d 6 ) δ 9.05 - 8.64 (m, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.67 - 7.55 (m, 2H), 7.53 - 7.32 (m, 3H), 7.24 - 7.10 (m, 2H), 6.89 - 6.76 (m, 2H), 5.48 - 5.36 (m, 1H), 3.74 - 3.65 (m, 3H), 3.23 - 2.95 (m, 1H), 2.76 - 2.58 (m, 1H), 2.17 - 2.00 (m, 3H). MS (ESI) m/z (M +H) + 408.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-lH-IMI DAZOLE-5-
48C 48D
[0587] To a solution of compound 48A (40 g) in CHC1 3 (200 mL) cooled to 0 °C was added dropwise sulfuryl dichloride (34 g). The mixture was warmed to 30 °C for 0.5 h and heated at 70 °C for 5 hrs. After cooling to room temperature, the reaction mixture was diluted with chloroform (40 mL), washed with aqueous NaHC0 3 (40 mL x 2), water (20 mL) and then brine (30 mL) successively. The organic phase was dried over Na 2 S0 4 and evaporated to afford compound 48B (47 g, crude) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 8.06 - 7.87 (m, 2H), 7.67 - 7.56 (m, 1H), 7.52 - 7.42 (m, 1H), 7.48 - 7.39 (m, 1H), 7.48 - 7.39 (m, 1H), 7.67 - 7.38 (m, 1H), 7.26 (s, 1H), 5.61 (s, 1H), 5.29 - 5.26 (m, 1H), 4.39 - 4.21 (m, 2H), 1.70 (s, 1H), 1.40 - 1.14 (m, 3H).
[0588] A solution of compound 48B (20 g) in NH 2 CHO (40 g, 882.40 mmol, 35 mL) and Water (3.2 g, 176.48 mmol) was heated at 180 °C for 3.5 hrs. The mixture was allowed to cool to room temperature, then water (50 ml) was added and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na 2 S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0 ~ 100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford compound 48C (1.3 g) as yellow solid. 1H NMR (400MHz, DMSO- e) δ 8.09 (d, 7=7.3 Hz, 7H), 4.28 - 4.08 (m, 2H), 1.24 (br t, 7=6.8 Hz, 1H), 1.29 - 1.10 (m, 1H).
[0589] To a solution of ethyl compound 48C (800 mg, 3.70 mmol) in EtOH (20 mL) was added a solution of KOH (2.1 g, 37.00 mmol) in H 2 0 (20 mL) at 0 °C. After addition, the reaction mixture was stirred at 70 °C for 16 hrs 20 mL of water was added into the reaction mixture and the mixture was extracted with MTBE (20 mL). The aqueous layer was acidified with IN HC1 to pH ~ 4 and filtered to afford desired compound. The filtrate was extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (50 mL) and dried over Na 2 S0 4 , the mixture was concentrated in vacuum to afford desired compound 48D (500 mg, yield 71.81%) as white solid. 1H NMR (400MHz, DMSO-i¾) δ 13.42 - 12.33 (m, 1H), 7.97 - 7.67 (m, 3H), 7.48 - 7.21 (m, 3H).
[0590] Compound 48 (10 mg, yield 25.1%, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 48D. Compound 48: 1H NMR (400MHz, DMSO-i¾) δ 8.30 - 8.17(m, 1H), 8.00-7.53 (m, 5H), 7.46 - 7.13 (m, 8H), 5.50 - 5.30 (m, 1H), 4.31 - 4.05 (m, 1H), 3.32 - 3.21(m, 1H), 2.71-2.61 (m, 1H). MS (ESI) m/z (M +H) + 363.2.
(S)-^V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(BENZO[rf]TH IAZOL-2-YL)-
1H-IMIDAZOLE-5-CARBOXAMIDE (50)
[0591] A mixture of compound 50A (20 g, 133 mmol), compound 50B (136 g, 665 mmol), TsOH.H 2 0 (2.5 g, 13.3 mmol) in toluene (200 mL) was stirred at 120 °C for 1 hour.
TLC (Petroleum ether: Ethyl acetate = 3: 1, R f ~ 0.5) indicated 50A was almost consumed and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 5: 1) to give compound 50C (30 g, crude) as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 9.40 (s, 1H), 7.98 - 7.78 (m, 1H), 7.77 - 7.57 (m, 1H), 7.55 - 7.31 (m, 1H), 7.30 - 7.07 (m, 1H), 5.38 - 5.26 (m, 1H), 4.33 - 4.21 (m, 3H). MS (ESI) m/z (M+H) + 234.9.
[0592] A mixture of methyl 50C (10 g, 45.4 mmol), TosMIC (17.7 g, 90.8 mmol), K 2 CO 3 (9.4 g, 68.1 mmol) in MeOH (200 mL) was stirred at 70 °C for 0.5 hour. TLC (Petroleum ether: Ethyl acetate = 3: 1, R f = 0.4) indicated 50C was consumed completely and some new spots formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 20: 1 to 3: 1) to give compound 50D (1.2 g, yield: 10.2%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 8.22 (d, = 0.9 Hz, 1H), 8.06 (d, = 7.9 Hz, 1H), 7.93 - 7.88 (m, 3H), 7.58 (dt, = 1.3, 7.7 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.49 - 7.43 (m, 1H), 4.58 (s, 1H), 3.87 (s, 3H), 2.51 (s, 1H). MS (ESI) m/z (M+H) + 259.9.
[0593] To a solution of 50D (1.1 g, 4.24 mmol in THF (30 mL), H 2 0 (5 mL) was added NaOH (339 mg, 8.48 mmol). The reaction mixture was stirred at 25 °C for 3 hrs. LCMS showed 50D was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated to give a residue. The residue was dissolved in water (10 mL), adjusted pH ~ 5 by aqueous HC1, filtered and the filtered cake was concentrated to give the product 50E (0.6 g, yield: 57.7%) as a gray solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.48 (d, = 1.1 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.06 (dd, J = 0.8, 8.0 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 7.64 - 7.53 (m, 2H). MS (ESI) m/z (M+H) + 245.9.
[0594] Compound 50 (12.9 mg, yield: 18.8%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 50E. Compound 50: 1H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (br d, / = 7.7 Hz, 1 H) 8.39 (s, 1 H) 8.12 - 8.03 (m, 2 H) 7.96 (d, = 8.2 Hz, 1 H) 7.81 (s, 1 H) 7.66 (s, 1 H) 7.57 - 7.45 (m, 2 H) 7.26 (d, = 4.2 Hz, 4 H)
7.20 - 7.16 (m, 1 H) 5.33 - 5.20 (m, 1 H) 3.18 (br dd, J = 13.9, 3.5 Hz, 1 H) 2.90 - 2.76 (m, 1 H). MS (ESI) m/z (M+H) + 420.0. EXAMPLE 25
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (lH- -3-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (51)
[0595] To a solution of 51A (8.7 g, 65.3 mmol) in MeOH (90 mL) was added ethyl 2-oxoacetate (20 g, 98.01 mmol). After stirred at 25 °C for 2 hours, the mixture was filtered and concentrated to give crude product 51B (15 g, crude) as brown solid, which was used for the next step without purification.
[0596] To a solution of 51B (15 g, 69.1 mmol) in EtOH (400 mL) was added K 2 C0 3 (14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). After stirred at 90 °C for 0.5 hour, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1 :0 to 1 : 1) to give compound 51C (2.9 g, yield: 16.4%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 11.04 (br s, 1H), 7.98 (d, = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H), 7.25 - 7.19 (m, 1H), 4.24 - 4.14 (m, 2H), 1.14 (t, 7 = 7.1 Hz, 3H).
[0597] To a solution of 51C (2.9 g, 11.3 mmol) in THF (40 mL) and H 2 0 (8 mL) was added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The mixture was concentrated under reduced pressure to remove the organic solvent, and extracted with EtOAc (20 mL). The aqueous layer was acidized with 1M HC1 to pH ~ 5 and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H 2 0 (40 mL), brine (40 mL), dried over Na 2 S0 4 , filtered and concentrated to give 51D (1.5 g, yield: 58.1%) as yellow solid. 1H NMR (400MHz, DMSO- 6 ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.3
Hz, 1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) + 228.9. [0598] To a solution of 51D (500 mg, 2.19 mmol,) and l-hydroxypyrrolidine-2,5- dione (252 mg, 2.19 mmol) in THF (10 mL), DCM (5 mL) and DMF (10 mL) was added EDCI (420 mg, 2.19 mmol) at 0 °C. After addition, the mixture was stirred at 25°C for 12 h. The solvent was removed under vacuum. The residue was diluted with EtOAc (50 mL), washed with IN HC1 (20 mL), saturated NaHC0 3 (20 mL) and brine (20 mL). The organics were combined, dried over Na 2 S0 4 , filtered, and concentrated to give crude 51E (476 mg, yield: 66.8%) as yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 13.52 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.63 (d, 7 = 8.6 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.24 - 7.17 (m, 1H), 2.77 (s, 5H).
[0599] Compound 51 (28.5 mg, yield: 29.1%, yellow solid) was prepared as in Example 20 from the corresponding intermediate compounds 51E and 41B. Compound 51: 1H NMR (400 MHz, CDC1 3 ) δ 10.66 (br s, 1 H), 7.86 (s, 1 H), 7.73 (s, 1 H), 7.49 - 7.34 (m, 3 H), 7.34 - 7.28 (m, 1 H), 7.23 - 7.10 (m, 4 H), 7.09 - 6.90 (m, 3 H), 5.65 - 5.53 (m, 1 H), 3.33 (dd, 7 = 14.1, 5.1 Hz, 1 H), 3.15 (dd, 7 = 14.1, 7.3 Hz, 1 H), 2.75 (td, 7 = 7.2, 3.6 Hz, 1 H), 0.76 - 0.86 (m, 2 H), 0.55 (br d, 7 = 2.6 Hz, 2 H). MS (ESI) m/z (M+H) + 443.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(5-PHENYLTHIA ZOL-2-YL)-
[0600] A mixture of compound 52A (4.2 g, 23.8 mmol) and ethyl 2-oxoacetate (14.6 g, 71.4 mmol) in MeOH (40 mL) was stirred at 70 °C for 6 hours. TLC (Petroleum ether: Ethyl acetate = 2: 1, R f ~ 0.7) indicated compound 52A was consumed completely, and one major new spot with lower polarity was detected. The reaction mixture was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 20: 1 to 10: 1) to give compound 52B (7 g, crude) as a yellow oil.
[0601] To a mixture of compound 52B (7 g, 23.9 mmol) and K 2 C0 3 (6.6 g, 47.8 mmol) in EtOH (15 mL) was added TosMIC (6.9 g, 35.9 mmol). The mixture was stirred at 90 °C for 2 hours. TLC (Petroleum ether: Ethyl acetate = 2: 1, R f ~ 0.55) indicated compound 52B was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was concentrated to give residue. The crude product was purified by silica gel chromatography eluted with Petroleum ether: Ethyl acetate = 15: 1 to 5: 1 to give compound 52C (6 g, crude) as a yellow solid. MS (ESI) m/z (M+H) + 299.9.
[0602] To a solution of compound 52C (3.5 g, 11.69 mmol) in THF (20 mL) and H 2 0 (6 mL) was added LiOH.H 2 0 (981 mg, 23.3 mmol) in one portion. The mixture was stirred at 25 °C for 12 hours. TLC (Petroleum ether: Ethyl acetate = 1 : 1, R f ~ 0.25) indicated compound 52C was consumed completely and one new spot formed. The mixture was adjusted to pH ~ 5 by adding HCl (2M), and then white solid was precipitate out, filtered and dried under reduced pressure to give compound 52D (1.5 g, yield: 47.3%) as a white solid. 1H NMR (400 MHz,
DMSO-d 6 ) δ 8.37 (s, 1H), 8.19 (s, 1H), 7.76 - 7.70 (m, 3H), 7.53 - 7.46 (m, 2H), 7.45 - 7.38 (m, 1H).
[0603] Compound 52 (50.9 mg, yield: 43%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 52D. Compound 52: 1H NMR
(400MHz, DMSO-d 6 ) δ 9.05 (d, J = 7.5 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 2H), 7.85 (s, 1H), 7.71 - 7.66 (m, 3H), 7.48 (t, = 7.5 Hz, 2H), 7.44 - 7.39 (m, 1H), 7.30 (d, = 4.4 Hz, 4H), 7.23 - 7.19 (m, 1H), 5.35 - 5.25 (m, 1H), 3.21 (dd, = 3.7, 13.8 Hz, 1H), 2.85 (dd, = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 446.0.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (5- PHENYLTHIAZOL-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (53)
[0604] To a mixture of compound 53A (600 mg, 2.21 mmol) and compound 1- hydroxypyrrolidine-2,5-dione (254 mg, 2.21 mmol) in THF (10 mL) at 0 °C was added a solution of EDCI (423 mg, 2.21 mmol) in DCM (5 mL) dropwise. The mixture was stirred at 25 °C for 12 hours. TLC (Petroleum ether: Ethyl acetate = 1: 1, R f ~ 0.4) indicated compound 53A was consumed completely, and one major new spot with lower polarity was detected. The reaction mixture was concentrated to remove solvent. The residue was diluted with EtOAc (50 mL), washed with H 2 0 (20 mL), saturated NaHC0 3 (20 mL), brine (20 mL). The organics were collected, dried with Na 2 S0 4 , filtered, and concentrated to give desired intermediate compound 53B (700 mg, yield: 85.9%) as a yellow solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.29 (s, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.57 (d, 7 = 6.5 Hz, 2H), 7.48 - 7.36 (m, 3H), 7.27 (s, 1H), 2.88 (s, 4H).
[0605] Compound 53 (41 mg, yield: 34.3%, white solid) was prepared as in Example 20 from the corresponding intermediate compound 53B. Compound 53: 1H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (d, 7 = 7.7 Hz, 1H), 8.82 (d, 7 = 5.0 Hz, 1H), 8.32 (d, 7 = 0.8 Hz, 1H), 8.11 (s, 1H), 7.72 - 7.64 (m, 3H), 7.52 - 7.46 (m, 2H), 7.44 - 7.39 (m, 1H), 7.30 (d, J = 4.4 Hz, 4H), 7.24 - 7.18 (m, 1H), 5.31 - 5.22 (m, 1H), 3.21 (dd, 7 = 13.7, 3.6 Hz, 1H), 2.90 - 2.70 (m, 2H), 0.66 - 0.54 (m, 4H). MS (ESI) m/z (M+H) + 486.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-METHYL-l-PHEN YL-lH- l,2,3-TRIAZOLE-5-CARBOXAMIDE (55)
[0606] A solution of compound 55A (2.5 g, 26.8 mmol) in MeCN (50 mL) was added t-BuONO (4.15 g, 40.3 mmol) at 0 °C followed with TMSN 3 (4.64 g, 40.3 mmol). The reaction mixture was stirred at 20°C for lhr. The solvent was evaporated to give intermediate compound 55B (4 g, crude) as yellow oil.
[0607] A mixture of compound 55B (4 g, crude) and compound ethyl but-2-ynoate (1 g, 8.92 mmol) in toluene (20 mL) was stirred at 110 °C for 5hrs. The solvent was evaporated. The crude product was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 20: 1 ~ 5: 1) to give compound 55C (150 mg, yield: 7.27%) as yellow oil. 1H NMR (400 MHz, CDC1 3 ) δ 7.54 - 7.49 (m, 2H), 7.44 - 7.40 (m, 2H), 7.37 (d, 7 = 5.1 Hz, 1H), 4.25 (q, 7 = 7.1 Hz, 2H), 1.21 (t, 7 = 7.1 Hz, 3H). [0608] A solution of compound 55C (150 mg, 649 umol) in THF (2 mL) and H 2 0 (2 mL) was added NaOH (51.9 mg). The reaction mixture was stirred at 20 °C for 30min. TLC showed a new peak with higher polarity was generated. The solvent was evaporated and 1M HCl was added until pH ~ 6. The mixture was filtered and the cake was dried to give compound 55D (120 mg, yield: 91.0%) as a yellow solid.
[0609] Compound 55 (46 mg, 121 umol, yield: 42.0%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 55D. Compound 55: 1H NMR (400 MHz, OMSO-d 6 ) δ 9.36 (br d, J = 7.9 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.51 - 7.43 (m, 3H), 7.36 - 7.28 (m, 7H), 5.38 (br t, = 7.7 Hz, 1H), 3.26 (br s, 1H), 2.82 - 2.73 (m, 1H), 2.21 (s, 3H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-METHYL-l-PHEN YL-lH- -TRIAZOLE-5-CARBOXAMIDE (56)
[0610] A mixture of compound 56A (1.0 g, 4.08 mmol), compound Ν,Ο- dimethylhydroxylamine (478 mg, 4.90 mmol, HCl) , HOBt (552 mg, 4.08 mmol) and NMM (1.24 g, 12.24 mmol, 1.35 mL) in CHC1 3 (20 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (1.17 g, 6.12 mmol) was added in portions. The mixture was stirred at 25 °C for 20 hrs under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (20 mL), and then diluted with DCM (10 mL). The combined organic layers were washed with IN HCl (15 mL x 2), saturated aqueous NaHC0 3 (15 mL x 2) and brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 56B (1.15 g, yield: 97.7%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 6.97 (br d, = 8.8 Hz, 1H), 4.47 (br t, J = 8.4 Hz, 1H), 3.73 - 3.64 (m, 3H), 3.06 (s, 3H), 1.51 - 1.27 (m, 11H), 0.87 (s, 9H).
[0611] To a solution of LAH (303 mg, 7.98 mmol) in THF (10 mL) was degassed and purged with N 2 for 3 times at 0 °C , and the mixture of compound 56B (1.15 g, 3.99 mmol) in THF (20 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2 hrs under N 2 atmosphere. The reaction mixture was quenched by add EtOAc (10 mL), then add IN HCl (50 mL), and then diluted with EtOAc (20 mL), dried over Na 2 S0 4 , and stirred for 30 min, then filtered to give the organic layers. The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 56C (900 mg, yield: 98.4%) was obtained as a white solid. 1H NMR (400MHz,CDCl 3 ) δ 9.55 (s, 1H), 4.83 (br s, 1H), 4.24 (br s, 1H), 1.86 - 1.55 (m, 2H), 1.44 (s, 9H), 1.03 - 0.91 (m, 9H).
[0612] To a solution of compound 56C (900 mg, 3.92 mmol) in DCM (20 mL) was added compound 2-hydroxy-2-methylpropanenitrile (2.33 g, 27.32 mmol, 2.50 mL) and Et 3 N (595 mg, 5.88 mmol, 815 uL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched by addition IN HCl (20 mL), and then diluted with H 2 0 (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 56D (930 mg, yield: 92.55%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 5.06 - 4.66 (m, 1H), 4.55 - 4.35 (m, 1H), 4.05 - 3.73 (m, 1H), 1.80 - 1.65 (m, 2H), 1.45 (br d, = 6.8 Hz, 9H), 1.10 - 0.80 (m, 9H).
[0613] To a solution of compound 56D (930 mg, 3.63 mmol) and K 2 C0 3 (1.00 g, 7.26 mmol) in DMSO (15 mL) was added H 2 0 2 (4.12 g, 36.30 mmol, 3.49 mL, purity: 30%). The mixture was stirred at 0 °C for 2 hrs. The reaction mixture was diluted with H 2 0 (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was stirred in DCM (0.1 mL) and PE (5 mL) for 30 min and filtered to give the compound 56E (480 mg, yield: 48.20%) was obtained as a white solid. 1H NMR (400MHz,CDCl 3 ) δ 6.83 (br s, 1H), 5.65 (br s, 1H), 5.27 - 5.06 (m, 1H), 4.99 - 4.82 (m, 1H), 4.23 - 4.00 (m, 1H), 3.88 (br t, =8.6 Hz, 1H), 1.77 (br s, 1H), 1.60 - 1.51 (m, 1H), 1.42 (d, = 9.3 Hz, 9H), 0.94 (d, = 10.1 Hz, 9H). [0614] To a solution of compound 56E (480 mg, 1.75 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with PE (20 mL), filtered and concentrated under reduced pressure to give the compound 56F (360 mg, yield: 97.63%, HCl) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.00 (br s, 1H), 7.92 - 7.70 (m, 1H), 7.58 - 7.41 (m, 2H), 4.21 - 3.93 (m, 1H), 3.33 (br d, 7=3.5 Hz, 2H), 1.76 - 1.24 (m, 2H), 0.86 (s, 9H).
[0615] Compound 56 (94.20 mg, yield: 85.26%, white solid) was prepared as in Example 35 from the corresponding intermediate compounds, 23A and 56F. Compound 56: 1H NMR (400MHz, DMSO-d 6 ) δ 8.98 - 8.61 (m, 1H), 8.20 - 7.95 (m, 1H), 7.85 - 7.71 (m, 2H), 7.57 - 7.37 (m, 3H), 5.25 (br t, 7 = 6.8 Hz, 1H), 2.35 - 2.20 (m, 3H), 1.63 - 1.28 (m, 2H), 0.98 - 0.76 (m, 9H). MS (ESI) m/z (M+H) + 358.2.
(5)-N-(4-AMINO-l-(lH-INDOL-3-YL)-3,4-DIOXOBUTAN-2-YL)-3-METH YL-5- -4- C ARB OX AMIDE (57)
57E 57F
[0616] A mixture of compound 57A (5.00 g, 16.43 mmol), compound Ν,Ο- dimethylhydroxylamine (1.76 g, 18.07 mmol, HCl), HOBt (2.22 g, 16.43 mmol) and NMM (4.99 g, 49.29 mmol, 5.42 mL) in CHC1 3 (150 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (4.72 g, 24.65 mmol) was added in portions, and then the mixture was stirred at 25 °C for 23 hrs under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (100 mL), and then diluted with IN HCl (200 mL) and extracted with NaHC0 3 (50 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 6/1 to 1/1) to give the compound 57B (5.94 g) was obtained as a yellow solid. 1H NMR (400MHz, OMSO-d 6 ) δ 10.79 (br s, 1H), 7.50 (d, 7 = 7.7 Hz, 1H), 7.32 (d, 7 = 8.2 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.07 - 6.96 (m, 3H), 4.59 (br s, 1H), 3.70 (br s, 3H), 3.10 (s, 3H), 3.03 - 2.94 (m, 1H), 2.89 - 2.77 (m, 1H), 1.29 (s, 9H).
[0617] To a solution of LAH (330 mg, 8.64 mmol) in THF (10 mL), and then compound 57B (2.00 g, 5.76 mmol) in THF (20 mL) was added dropwise. The mixture was stirred at 0 °C for 2 hrs. The reaction mixture was quenched by addition EtOAc (10 mL) at 0°C, and then diluted with IN HCl (40 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with IN HCl (40 mL) and NaHC0 3 (30 mL x 2) and brine (100 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 57C (1.55 g, yield: 93.33%) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 11.02 - 10.75 (m, 1H), 9.52 (s, 1H), 7.50 (br d, 7 = 7.7 Hz, 1H), 7.32 (d, 7 = 7.9 Hz, 1H), 7.25 (br d, 7 = 7.3 Hz, 1H), 7.14 (d, 7 = 1.8 Hz, 1H), 7.05 (t, 7 = 7.2 Hz, 1H), 7.00 - 6.92 (m, 1H), 4.14 - 4.05 (m, 1H), 3.19 - 3.10 (m, 1H), 2.95 - 2.85 (m, 1H), 2.52 - 2.45 (m, 4H), 1.39 - 1.23 (m, 9H).
[0618] To a solution of compound 57C (1.50 g, 5.20 mmol) in DCM (30.00 mL) was added compound Ν,Ο-dimethylhydroxylamine (885 mg, 10.40 mmol, 960 uL) and Et 3 N (790 mg, 7.80 mmol, 1.08 mL). After stirred at 25 °C for 20 hrs, the reaction mixture was quenched by addition 0.5N HCl 30 mL, and then extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. Compound 57D (1.74 g, yellow solid): 1H NMR (400MHz, CDC1 3 ) δ 9.64 (s, 1H), 8.14 (br s, 1H), 7.60 (d, 7 = 7.7 Hz, 1H), 7.37 (d, 7 = 8.2 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.17 - 7.11 (m, 1H), 7.03 (d, 7 = 2.2 Hz, 1H), 5.14 (br s, 1H), 4.51 (br d, 7 = 6.6 Hz, 1H), 3.41 - 3.16 (m, 2H), 1.44 (s, 9H).
[0619] To a solution of compound 57D (1.74 g, 5.52 mmol) and K 2 C0 3 (1.53 g, 11.04 mmol) in DMSO (25.00 mL) was added H 2 0 2 (6.43 g, 189.00 mmol, 5.45 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H 2 0 (50 mL), and then quenched by addition Na 2 S 2 0 3 (50 mL) and extracted with EtOAc (50 mL x 3) and Na 2 S 2 03 (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1/2 to 0: 1) to give the compound 57E (689.60 mg, yield: 37.47%) was obtained as a yellow solid. 1H NMR (400MHz,CDCl 3 ) δ 8.06 (br s, 1H), 7.70 (d, / = 8.3 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25 - 7.06 (m, 4H), 5.42 (br s, 1H), 5.19 - 5.04 (m, 1H), 4.21 - 4.08 (m, 3H), 3.30 - 3.12 (m, 2H), 1.41 (s, 9H).
[0620] To a solution of compound 57E (680.00 mg, 2.04 mmol) in EtOAc (5.00 mL) was added HCl/EtOAc (5.00 mL). The mixture was stirred at 25 °C for 2.5 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent to give the compound 57F (400.00 mg, yield: 72.69%, HC1) was obtained as a brown solid. 1H NMR (400MHz, DMSO-d 6 ) δ 11.01 (br s, 1H), 7.92 (br s, 2H), 7.70 - 7.46 (m, 3H), 7.39 - 7.26 (m, 2H), 7.12 - 6.95 (m, 2H), 4.01 - 3.89 (m, 1H), 3.81 - 3.64 (m, 1H), 3.14 (s, 2H), 3.08 - 2.80 (m, 2H).
[0621] Compound 57 (11.20 mg, yield: 29.41%, white solid) was prepared as in Example 15 from the corresponding intermediate compounds, 23A and 57F. Compound 57: 1H NMR (400MHz, DMSO-d 6 ) δ 10.89 (br s, 1H), 9.03 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.48 (br d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.4 Hz, 3H), 7.17 (d, J = 1.8 Hz, 1H), 7.13 - 6.96 (m, 2H), 5.56 (br s, 1H), 2.97 - 2.87 (m, 1H), 2.70 - 2.54 (m, 1H), 2.11 (s, 3H). MS (ESI) m/z (M+H) + 417.1.
[0622] To a solution of N-methoxymethanamine (1.89 g 19.42 mmol), compound 58A (5.0 g, 17.65 mmol), HOBt (2.38 g, 17.65 mmol) and NMM (52.95 mmol, 5.8 mL) in CHC1 3 (100 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (5.1 g, 26.48 mmol) was added in portions. The mixture was stirred at 25 °C for 16 hrs under N 2 atmosphere. The reaction mixture was washed with H 2 0 (100 mL). The organic layers were washed with lmol/L HCl (100 mL x 2), saturated NaHC0 3 (100 mL x 2) and saturated brine (100ml), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®;80 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 30% Ethyl acetate/Petroleum ether gradient @ 40mL/min) to afford compound 58B (4.00 g, yield 69.4%) as white solid. 1 H NMR (400MHz,CDCl 3 ) δ 7.11 (dd, 7=5.6, 8.3 Hz, 2H), 6.94 (t, 7=8.7 Hz, 2H), 5.18 (br d, 7=7.9 Hz, 1H), 4.98 - 4.80 (m, 1H), 4.13 - 4.07 (m, 2H), 3.72 -
3.64 (m, 4H), 3.14 (s, 3H), 3.08 - 2.94 (m, 1H), 2.91 - 2.70 (m, 1H), 2.02 (s, 2H), 1.78 (br s, 1H), 1.37 (s, 10H), 1.28 - 1.20 (m, 3H).
[0623] To LiAlH 4 (128 mg 3.37 mmol) in 100 mL of dry flask was added dropwise THF (15 mL) at 0 °C. After addition, the mixture was stirred at this temperature, and then a solution of compound 58B (1.0 g 3.06 mmol) in THF (15 mL) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 hrs. The reaction mixture was quenched by slowly added EtOAc (20 mL) at 0 °C, and then added IN HCl (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with NaHC0 3 (30 mL x 2) and brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 58C (810 mg, yield 99.0%) as white solid. 1H NMR (400MHz,CDCl 3 ) δ
9.65 (br s, 1H), 9.63 (br s, 1H), 7.21 - 7.08 (m, 2H), 7.00 (br d, 7=8.6 Hz, 2H), 5.05 (br s, 1H), 4.42 (br s, 1H), 3.09 - 3.02 (m, 1H), 3.11 (br d, 7=6.2 Hz, 1H), 1.51 - 1.38 (m, 9H).
[0624] To a solution of compound 58C (3.2 g, 11.86 mmol) and 2-hydroxy-2- methyl-propanenitrile (2.2 mL, 23.72 mmol) in DCM (30 mL) was added TEA (2 mL, 14.23 mmol). After addition, the reaction mixture was stirred at 28 °C for 14 hrs. The reaction mixture was diluted with 30 mL of DCM and the mixture was quenched by addition 0.5N HCl 30 mL. The organic layer were washed with H 2 0 (30 mL) and brine (50mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 58D (3.4 g, yield 89.2%) as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.15 - 7.07 (m, 2H), 7.01 - 6.90 (m, 2H), 4.94 - 4.70 (m, 1H), 4.52 - 4.36 (m, 1H), 4.16 - 3.67 (m, 1H), 3.11 - 2.78 (m, 2H), 1.57 - 1.47 (m, 2H).
[0625] To a solution of compound 58D (3.42 g 11.62 mmol) and K 2 C0 3 (3.21 g, 23.24 mmol) in DMSO (30 mL) was added H 2 0 2 (395.08 mmol, 12 mL,) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 1.5 hrs. The reaction mixture was diluted with water (100 mL) and quenched with saturated aqueous Na 2 S 2 0 3 slowly into ice water. The mixture was extracted with EtOAc (200 mL x 3) and the combined extracts were washed with saturated aqueous Na 2 S 2 0 3 (100 mL x 3). The organic layer was dried over Na 2 S0 4 , concentrated and to yield a residue. The residue was diluted with EtOAc (10 mL) and filtered to give the compound 58E (2.25 g, yield 61.99%) as a white solid. 1H NMR (400MHz, DMSO- 6 ) δ 7.25 (br s, 6H), 6.62 - 6.03 (m, 1H), 5.75 - 5.55 (m, 1H), 4.02 - 3.67 (m, 2H), 2.80 - 2.52 (m, 2H), 2.52 - 2.51 (m, 1H), 1.26 (d, 7=3.7 Hz, 9H). MS (ESI) m/z (M +Na + ) 334.9.
[0626] To a solution of compound 58E (1 g 3.20 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4 mmol, 20 mL). The mixture was stirred at 28 °C for 2 hrs. The reaction mixture diluted with MTBE and filtered to give the compound 58F (750 mg, yield 94.25%) as white solid. 1H NMR (400MHz, DMSO- 6 ) δ 8.25 - 7.94 (m, 3H), 7.58 - 7.43 (m, 2H), 7.41 - 7.33 (m, 1H), 7.30 - 7.23 (m, 1H), 7.41 - 7.23 (m, 1H), 7.20 - 7.05 (m, 2H), 6.90 - 6.37 (m, 1H), 6.80 - 6.25 (m, 1H), 4.24 (br s, 1H), 3.88 - 3.81 (m, 1H), 3.85 (br s, 1H), 3.68 - 3.50 (m, 1H), 2.96 - 2.76 (m, 2H). MS (ESI) m/z (M +H) + 213.1.
[0627] Compound 58 (130 mg, yield 78.40%, light yellow solid) was prepared as in Example 15 from the corresponding intermediate compounds, 23A and 58F. Compound 58: 1 H NMR (400MHz, DMSO- 6 ) δ 9.05 (d, 7=7.7 Hz, 1H), 8.20 (br s, 1H), 7.93 (brs, 1H), 7.66 - 7.59 (m, 2H), 7.55 - 7.49 (m, 1H), 7.48 - 7.41 (m, 2H), 7.35 - 7.26(m, 2H), 7.17 - 7.06 (m, 2H), 5.51 - 5.40 (m, 1H), 3.28 - 3.19 (m, 1H), 2.81 - 2.69 (m, 1H), 2.11 (s, 3H). MS (ESI) m/z (M +H) + 396.1.
(5)-N-(4-AMINO-l-(lH-INDOL-3-YL)-3,4-DIOXOBUTAN-2-YL)-3-METH YL-5- PHEN YLIS OXAZOLE-4- C ARB OX AMIDE (59)
[0628] To a solution of compound 59A (10 g, 55.08 mmol) in EtOH (30 mL) was added NH 2 NH 2 .H 2 0 (32 mL, 550.80 mmol). After addition, the reaction mixture was stirred at 80 °C for 14 hrs. The reaction mixture was concentrated and the residue was dissolved into 150 mL of EtOAc, the mixture was washed with water (50 mL) and brine (50 mL), then dried over Na 2 S0 4 and concentrated in vacuum to afford compound 59B (9.7 g, yield 99.4%) as white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.02 (s, 1H), 7.71 - 7.53 (m, 1H), 7.03 - 6.79 (m, 2H), 4.23 (s, 2H).
[0629] To a solution of compound 59B (1 g, 5.65 mmol) in AcOH (10 mL) was added ethyl 2-methoxyimino-4-oxo-pentanoate (1.1 g, 5.65 mmol). After addition, the reaction mixture was stirred at 120 °C for 14 hrs. The mixture was concentrated in vacuum and the residue was dissolved into 80 mL of EtOAc, the mixture was washed with 30 mL of saturated aqueous NaHC0 3 and brine (30 mL). The mixture was dried over Na 2 S0 4 and concentrated in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20/1 to 10: 1) to afford desired compound 59C (1.2 g, yield: 71%) as white solid. 1H NMR (400MHz, DMSO- 6 ) δ 8.34 - 8.25 (m, 1H), 8.05 (d, = 8.2 Hz, 1H), 7.93 (d, = 7.5 Hz, 1H), 6.86 (s, 1H), 4.18 (q, = 7.1 Hz, 2H), 2.29 (s, 3H), 1.11 (t, = 7.1 Hz, 3H). MS (ESI) m/z (M +H) + 299.9.
[0630] To a solution of compound 59C (700 mg, 2.34 mmol) in THF (10 mL) was added a solution of LiOH.H 2 0 (393 mg, 9.36 mmol) in H 2 0 (10 mL) at 0 °C. After addition, the reaction mixture was stirred at 28 °C for 16 hrs, 20 mL of MTBE was added into the reaction mixture, then the mixture was separated and the aqueous layer was acidified by IN HC1 to pH ~ 4, the mixture was filtered to afford white solid which was dried to afford compound 59D (330 mg, yield 51.95%) as white solid. 1H NMR (400MHz, DMSO- 6 ) δ 13.48 (br s, 1H), 8.31 - 8.22 (m, 1H), 8.02- 7.89 (m, 2H), 6.81 (s, 1H), 2.27 (s, 3H). MS (ESI) m/z (M +H) + 271.8.
[0631] Compound 59 (50 mg, yield: 37.9%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 59D. Compound 59: 1H NMR (400MHz, DMSO-i¾) δ 9.07 (d, J = 7.3 Hz, 1H), 8.27 - 8.16 (m, 1H),8.04 (s, 1H), 7.89 - 7.77 (m, 3H), 7.30 - 7.19 (m, 5H), 6.59 (s, 1H), 5.40 - 5.28 (m,lH), 3.15 (dd, J = 4.0, 13.8 Hz, 1H), 2.82 (dd, J = 9.5, 13.8 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z (M +H) + 446.1. EXAMPLE 33
[0632] A mixture of compound 61B (500 mg, 2.12 mmol), compound 61A (859 mg, 2.33 mmol), Pd(PPh 3 )4 (122 mg, 106 umol) was stirred at 105 °C for 14 hours. The mixture was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 3/1 to 1/1) to afford compound 61C (376 mg, 74.95% yield) as yellow oil. MS (ESI) m/z (M+H) + 234.9.
[0633] To a solution of compound 61C (320 mg, 1.37 mmol) in MeOH (20 mL) was added LiOH.H 2 0 (144 mg, 3.43 mmol). The mixture was stirred at 32 °C for 0.5 h. MeOH was evaporated. To the residue was added water (20 mL). The mixture was extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH~ 3 with IN HC1 and extracted with Ethyl Acetate (3 x 20 mL). The combined organic layers were dried over Na 2 S0 4 and concentrated to afford compound 61D (220 mg, 77.9% yield) as white solid.
[0634] Compound 61 (21.8 mg, 21.78% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 61D. Compound 61: 1H NMR (400MHz, DMSO- 6 ) δ 13.06 - 12.79 (m, 1H), 9.27 (s, 1H), 8.95 - 8.84 (m, 1H), 8.42 - 8.32 (m, 1H), 8.32 - 8.24 (m, 1H), 8.13 - 8.00 (m, 1H), 7.55 - 7.45 (m, 1H), 7.21 - 7.10 (m, 3H), 7.22 - 7.03 (m, 2H), 5.70 - 5.59 (m, 1H), 3.32 - 3.25 (m, 1H), 3.20 - 3.12 (m, 1H), 2.85 - 2.74 (m, 1H), 0.72 - 0.63 (m, 2H), 0.63 - 0.54 (m, 2H). MS (ESI) m/z (M+H) + 421.1.
(5)-N-(l-amino-l,2-dioxoheptan-3-yl)-3-methyl-5-phenylisoxaz ole-4-carboxamide (62)
[0635] To a mixture of compound 62A (2 g, 8.65 mmol) and compound N,0- dimethylhydroxylamine hydrochloride (970.3 mg, 9.95 mmol), HOBt (1.34g, 9.95 mmol) in CHC1 3 (40 mL) was added dropwise 4-methylmorpholine (2.62 g, 25.95 mmol) and EDCI (2.32 g, 12.11 mmol) in portion at 0 °C under N 2 atmosphere. The mixture was stirred at 0 °C for 30 min, and then the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with H 2 0 (5 mL). The two layers were separated and the aqueous phase was extracted with EA (5 mL x 2). The combined organic layers were washed with 0.5 N HCl (5 mL x 2) and NaHC0 3 (5 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 62B (1.7 g, yield 71.7%) as colorless oil. 1H NMR (CDC1 3, 400 MHz): δ 5.19 - 5.06 (m, 1H), 4.66 (br s, 1H), 3.77 (s, 3H), 3.20 (s, 3H), 1.76 - 1.66 (m, 1H), 1.55 - 1.39 (m, 10H), 1.37 - 1.28 (m, 4H), 0.93 - 0.83 (m, 3H). MS (ESI) m/z (M - Boc + H) + 175.0.
[0636] To a solution of LiAlH 4 (258.7 mg, 6.82 mmol) in THF (36 mL) was added drop wise a solution of compound 62B (1.7 g, 6.2 mmol) in THF (18 mL) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with IN HCl (20 mL), saturated NaHC0 3 (20 mL x 2), brine (15 mL). The organic layer was dried over anhydrous Na 2 S0 4 and concentrated to give compound 62C (1.5 g, crude) as yellow oil. 1H NMR (CDC1 3, 400 MHz) δ 9.58 (s, 1H), 5.03 (br s, 1H), 4.28 - 4.16 (m, 1H), 1.58 - 1.19 (m, 15H), 1.01 - 0.80 (m, 3H).
[0637] A solution of compound 62C (1.5 g, 6.97 mmol), compound 2-hydroxy-2- methylpropanenitrile (1.3 mL, 13.94 mmol) and Et 3 N (1.16 mL, 8.36 mmol) in dry DCM (30 mL) was stirred at 30 °C for 16 hours. The reaction mixture was diluted with DCM (50 mL), washed with 0.5 N HCl (20 mL), water (20 mL)and brine(20 mL). The organic phase was dried over Na 2 S0 4 , concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum Ether/Ethyl Acetate = 5/1 to 3: 1) to afford compound 62D (1.12 g, 66.32% yield) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 5.44 - 4.34 (m, 3H), 3.94 - 3.83 (m, 1H), 3.74 - 3.61 (m, 1H), 3.98 - 3.55 (m, 1H), 1.66 - 1.28 (m, 14H), 0.99 - 0.90 (m, 3H).
[0638] The mixture of compound 62D (1.12 g, 4.62 mmol) and K 2 C0 3 (1.28 g, 9.24 mmol) in DMSO (18 mL) was added H 2 0 2 (4.6 mL, 158.19 mmol) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for lh. After the reaction, MTBE (20 mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid was washed with MTBE (30 mL) to afford compound 62E (1.1 g, 91.46% yield) as white solid. 1H NMR (400MHz, DMSO-i¾) δ 7.32 - 7.08 (m, 2H), 6.42 - 5.86 (m, 1H), 5.54 - 5.30 (m, 1H), 3.88 - 3.59 (m, 2H), 1.42 - 1.21 (m, 15H), 0.92 - 0.78 (m, 3H).
[0639] The solution of compound 62E (600 mg, 20.82 mmol) in dioxane (10 mL) was added HCl/dioxane (3 mL, 4M) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was filtered to afford compound 62F (320 mg, 70.7%, yield, HC1) was obtained as white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 7 ' .90 (br s, 2H), 7.54 - 7.35 (m, 2H), 6.26 - 6.17 (m, 1H), 4.09 (br s, 1H), 1.66 - 1.37 (m, 2H), 1.37 - 1.12 (m, 5H), 0.93 - 0.72 (m, 3H)
[0640] Compound 62 (9.1 mg, yield: 38.6%, white solid) was prepared as in Example 15 from the corresponding intermediate compounds, 23A and 62F. Compound 62: 1H NMR (CDCI3, 400 MHz): δ 7.84-7.67 (m, 2H), 7.57 - 7.43 (m, 3H), 6.73 (s, 1H), 6.17-6.03 (m, 1H), 5.52 - 5.29 (m, 2H), 2.46 ( s, 3H), 1.99 - 1.84 (m, 1H), 1.41- 1.04 (m, 5H), 0.90-0.78 (m, 3H). MS (ESI) m z (M+H)+ 344.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYR AZIN-2- YL)-lH-PYRAZOLE-5-CARBOXAMIDE (63)
[0641] To a solution of compound methyl 2,4-dioxopentanoate (100 mg, 693.82 umol) in AcOH (20 mL) was added compound 63A (76.4 mg, 693.82 umol). The mixture was stirred at 120 °C for 1 hour. The mixture was in DCM (5 mL). The organic layer was washed with water (10 mL), NaHC0 3 to pH ~ 8-9 and dried over Na 2 S0 4 and concentrated to afford compound 63B (500 mg, 25.24% yield) as white solid.
[0642] To a solution of compound 63B (61 mg, 279.55 umol, ) in MeOH (6 mL) and H 2 0 (1 mL) was added LiOH.H 2 0 (46.9 mg, 1.12 mmol). The mixture was stirred at 31 °C for lh. MeOH was evaporated. To the residue was added water (10 mL) and the mixture was extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH ~ 3 with IN HCl and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na 2 S0 4 and concentrated to afford the product. (50 mg, 87.59% yield) as white solid.
[0643] Compound 63 (25.1 mg, 63.1% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 63C. Compound 63: 1H NMR (400MHz, CDC1 3 ) δ 9.16 (s, 2 H), 9.08- 8.97 (m, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.20 (s, 3 H), 7.08 (s, 2H), 5.78 (m, 1H), 5.54 (s, 1H), 3.45 (m, 1H), 3.38 - 3.24 (m, 1H), 2.36 (s, 3H). MS (ESI) m/z (M+H) + 379.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METH YL-l- (PYRAZIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (454)
[0644] Compound 454 (210 mg, 91.7% yield, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, compound 63C and 3-amino- N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride. Compound 454: 1H NMR (400MHz, DMSO-i¾) δ 9.07 (d, = 7.2 Hz, 1H), 8.84 - 8.77 (m, 2H), 8.57 (d, = 2.8 Hz, 1H), 8.31 - 8.27 (m, 1H), 7.30 - 7.17 (m, 5H), 6.64 (s, 1H), 5.33 - 5.25 (m, 1H), 3.17 - 3.09 (m, 1H), 2.83 - 2.70 (m, 2H), 2.27 (s, 3H), 0.69 - 0.53 (m, 4H). MS (ESI) m/z (M+H) + 419.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3- -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (66)
[0645] A mixture of compound 2-hydrazinyl-3-methylpyridine hydrochloride (2 g, 12.53 mmol) and compound 66A (1.81 g, 12.53 mmol) in AcOH (30 mL) was degassed and purged with N 2 for 3 times, and then stirred at 120 °C for 1.5 hrs under N 2 atmosphere. The resultant mixture was concentrated under reduced pressure to remove AcOH and diluted with DCM (10 mL), neutralized with saturated aqueous NaHC0 3 . The mixture was extracted with DCM (20 mL x 3) and the combined organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (Petroleum ether : Ethyl acetate = 1 :0 to 0: 1) to afford compound 66B (800.0 mg, 27.6% yield) as a white solid and compound 66B-1 (110.0 mg, 4.04% yield) as a white solid and crude 66B-1 (~ 800.0 mg).
[0646] Compound 66B: Methyl 3-methyl-l-(3-methylpyridin-2-yl)- lH-pyrazole-5- carboxylate: 1H NMR (CDC1 3 , 400 MHz) δ 8.42 - 8.37 (m, 1H), 7.70 (d, 7 = 7.6 Hz, 1H), 7.33 (d, 7 = 7.6 Hz, 1H), 6.79 (s, 1H), 3.74 (s, 3H), 2.38 (s, 3H), 2.14 (s, 3H).
[0647] Compound 66B-1: Methyl 5-methyl-l-(3-methylpyridin-2-yl)- lH-pyrazole-3- carboxylate: 1H NMR (CDC1 3 , 400 MHz) δ 8.42 (d, 7 =3.6 Hz, 1H), 7.72 (d, 7=6.8 Hz, 1H), 7.34 (d, 7 = 7.6 Hz, 1H), 6.74 (s, 1H), 3.92 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H).
[0648] To a mixture of compound 66B (200.0 mg, 864.86 umol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH » H 2 0 (145.2 mg, 3.46 mmol) in one portion. After stirred at 25 °C for 1 hour, the reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 66C (150 mg, 79.84% yield, white solid). Compound 66C: 1H NMR (DMSO- 6, 400 MHz) δ 13.11 (br s, 1H), 8.31 (d, = 3.7 Hz, 1H), 7.84 (d, = 7.3 Hz, 1H), 7.47 -7.40 (m, 1H), 6.78 (s, 1H), 2.25 (s, 3H), 2.03 (s, 3H). MS (ESI) m/z (M+l) + 218.1.
[0649] Compound 66 (24.5 mg, 54.7% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 66C. Compound 66: 1H NMR (CDC1 3, 400 MHz) δ 8.23 (d, = 3.6 Hz, 1H), 7.67 (d, = 7.2 Hz, 1H), 7.34 (d, = 7.2 Hz, 1H), 7.27 (br s, 1H), 7.25 - 7.21 (m, 3H), 7.04 - 6.99 (m, 2H), 6.70 (br s, 1H), 6.57 (s, 1H), 5.65 - 5.6 (m, 1H), 5.57 ( br s, 1H), 3.37 - 3.29 (m, 1H), 3.2 - 3.14 (m, 1H), 2.34 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z (M+H) + 392.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(l-PHENYL-lH- PYRAZOL-3-
YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (68)
[0650] To a solution of 68A (15 g, 181 mmol) in THF (200 mL) was added ethyl 2- oxoacetate (47.9 g, 235 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate compound 68B (55.3 g, crude) as brown solid. MS (ESI) m/z (M+H) + 167.8.
[0651] To a solution of 68B (40 g, 239 mmol) in EtOH (400 mL) was added K 2 C0 3 (50 g, 362 mmol) and TosMIC (40 g, 204.88 mmol). The mixture was stirred at 90 °C for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1 : 0 to 5: 2) to afford compound 68C (12 g, yield: 24.3%) as brown solid. 1H NMR (400 MHz, CDC1 3 ) δ 11.80 - 11.35 (m, 1H), 7.87 (d, = 1.10 Hz, 1H), 7.84 (d, = 1.10 Hz, 1 H), 7.58 (d, = 2.43 Hz, 1H), 6.45 (d, = 2.43 Hz, 1H), 4.25 (q, = 7.06 Hz, 2H), 1.29 (t, J = 1.11 Hz, 3H). MS (ESI) m/z (M+H) + 207.0.
[0652] A mixture of 68C (5 g, 24.3 mmol), phenylboronic acid (4.4 g, 36.4 mmol), Cu(OAc) 2 (4.4 g, 24.3 mmol), TEA (7.4 g, 72.8 mmol) in DCM (200 mL) was degassed and purged with 0 2 for 3 times, and then the mixture was stirred at 25 °C for 10 hours under 0 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1: 0 to 2: 1). Compound 68D (2.3 g, yield: 33.6%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 8.04 - 7.94 (m, 2H), 7.87 (s, 1H), 7.71 (br d, 7 = 7.7 Hz, 2H), 7.49 (br t, 7 = 7.1 Hz, 2H), 7.36 (br d, 7 = 7.1 Hz, 1H), 7.27 (d, 7 = 2.0 Hz, 2H), 6.70 - 6.61 (m, 1H), 4.29 (dd, 7 = 2.1, 7.2 Hz, 2H), 1.38 - 1.22 (m, 3H). MS (ESI) m/z (M+H) + 282.9.
[0653] To a solution of 68D (2.5 g, 8.86 mmol) in THF (30 mL) and H 2 0 (6 mL) was added NaOH (708 mg, 17.7mmol). The mixture was stirred at 80°C for 1.5 hour. The reaction mixture was concentrated under reduced pressure to remove THF, and then washed with EtOAc (20 mL). The aqueous layer was acidized with 1M HC1 to pH ~ 5 and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H 2 0 (40 mL), brine (40 mL), dried over Na 2 S0 4 , filtered and concentrated to afford crude intermediate compound 68E (1.90 g, yield: 84.3%) as yellow solid. 1H NMR (400MHz, OMSO-d 6 ) δ 8.62 (d, 7 = 2.6 Hz, 1H), 8.19 (s, 1H), 7.86 (d, 7 = 7.9 Hz, 2H), 7.76 (s, 1H), 7.53 (t, 7 = 7.9 Hz, 2H), 7.39 - 7.31 (m, 1H), 6.77 (d, 7 = 2.6 Hz, 1H). MS (ESI) m/z (M+H) + 254.9.
[0654] Compound 68 (33.5 mg, yield: 42.1%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 68E. Compound 68: 1H NMR (400 MHz, DMSO-d 6 ) δ 8.86 (d, 7 = 7.7 Hz, 1 H), 8.51 (d, 7 = 2.6 Hz, 1 H), 8.10 (d, 7 = 0.9 Hz, 1 H), 8.06 (s, 1 H), 7.79 (dd, 7 = 8.7, 1.0 Hz, 3 H), 7.60 (d, 7 = 0.9 Hz, 1 H), 7.46 - 7.53 (m, 2 H), 7.30 - 7.36 (m, 1 H), 7.24 - 7.29 (m, 4 H), 7.16 - 7.23 (m, 1 H), 6.44 (d, 7 = 2.6 Hz, 1 H), 5.23 - 5.32 (m, 1 H), 3.17 (dd, 7 = 13.8, 3.9 Hz, 1 H), 2.83 (dd, 7 = 13.9, 10.4 Hz, 1 H). MS (ESI) m/z (M+H) + 429.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(lH-INDAZOL-3 -YL)-lH-
IMIDAZOLE-5-CARBOXAMIDE 69)
[0655] To a solution of 69A (8.7 g, 65.3 mmol) in MeOH (90 mL) was added ethyl 2- oxoacetate (20 g, 98.01 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was filtered and concentrated to give intermediate compound 69B (15 g, crude) as brown solid.
[0656] To a solution of 69B (15 g, 69.1 mmol) in EtOH (400 mL) was added K 2 C0 3 (14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). The mixture was stirred at 90 °C for 0.5 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1 :0 to 1 : 1) to give compound 69C (2.9 g, yield: 16.4%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 11.04 (br s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H), 7.25 - 7.19 (m, 1H), 4.24 - 4.14 (m, 2H), 1.14 (t, 7 = 7.1 Hz, 3H).
[0657] To a solution of 69C (2.9 g, 11.3 mmol) in THF (40 mL) and H 2 0 (8 mL) was added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The mixture was concentrated under reduced pressure to remove the organic solvent, and extracted with EtOAc (20 mL). The aqueous layer was acidized with 1M HC1 to pH ~ 5 and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H 2 0 (40 mL), brine (40 mL), dried over Na 2 S0 4 , filtered and concentrated to give 69D (1.5 g, yield: 58.1%) as yellow solid. 1HNMR (400MHz, DMSO- 6 ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) + 228.9.
[0658] Compound 69 (16.7 mg, yield: 20.9%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 69D. Compound 69: 1H NMR (400MHz, DMSO- 6 ) δ 13.16 (br s, 1H), 8.84 (br d, J = 7.7 Hz, 1H), 8.08 - 7.95 (m, 2H), 7.80 - 7.70 (m, 2H), 7.52 (d, = 8.4 Hz, 1H), 7.36 (br t, = 7.5 Hz, 1H), 7.30 - 7.23 (m, 4H), 7.22 - 7.13 (m, 3H), 7.08 - 7.01 (m, 1H), 5.21 - 5.12 (m, 1H), 3.17 - 3.09 (m, 1H), 2.84 2.75 (m, 1H). MS (ESI) m/z (M+H) + 403.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(lH-BENZO[rf] IMIDAZOL-2- -lH-IMIDAZOLE-5-CARBOXAMIDE (70)
[0659] A mixture of 70A (10 g, 75.1 mmol), ethyl 2-oxoacetate (30.6 g, 150 mmol) in MeOH (300 mL) was stirred at 70 °C for 12 hour under N 2 atmosphere. LCMS showed 70A was consumed completely and one peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give crude product 70B (15 g, crude) as yellow oil. MS (ESI) m/z (M+H) + 235.9.
[0660] A mixture of 70B (15 g, 63.7 mmol), K 2 C0 3 (13.2 g, 95.6 mmol), TosMIC (24.9 g, 127 mmol) in MeOH (300 mL) was stirred at 70 °C for 1 hour. LCMS showed 70B was consumed completely and one small peak with desired MS was detected. TLC (Petroleum ether : Ethyl acetate = 1 : 1, R f ~ 0.3) indicated 70B was consumed completely and one new spot formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 10/1 to 1 : 1) to give 70C (350 mg, yield: 2.3%) as a yellow oil. 1H NMR (400 MHz, CDC1 3 ) δ 12.52 (br s, 1 H) 8.96 (s, 1 H) 7.98 (s, 1 H) 7.69 (br d, J = 4.4 Hz, 1 H) 7.48 (br s, 1 H) 7.28 (br dd, = 5.8, 2.8 Hz, 2 H) 3.99 (s, 3 H). MS (ESI) m/z (M+H) + 243.1.
[0661] A mixture of 70C (350 mg, 1.44 mmol), LiOH.H 2 0 (120 mg, 2.88 mmol) in THF (5 mL), H 2 0 (2 mL) was stirred at 25 °C for 4 hours. LCMS showed 70C was consumed completely and one peak with desired MS was detected. The reaction mixture was added aqueous HC1 (1M) to adjust the pH ~ 5, filtered and the filtered cake was concentrated under reduced pressure. The filtered cake was washed with water. Compound 70D (230 mg, yield: 70.1%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) S 8.57 (d, 7 = 1.3 Hz, 1 H) 7.38 - 7.63 (m, 3 H) 7.03 - 7.22 (m, 1 H) 7.03 - 7.17 (m, 1 H). MS (ESI) m/z (M+H) + 229.0.
[0662] Compound 70 (40 mg, yield: 46.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 70D. Compound 70: 1HNMR (400MHz, DMSO-d 6 ) δ 12.94 (br s, 1H), 9.31 (br s, 1H), 8.38 - 8.23 (m, 1H), 8.04 (br s, 1H), 7.87 - 7.74 (m, 2H), 7.60 - 7.43 (m, 2H), 7.29 - 7.10 (m, 6H), 5.33 (br t, 7 = 6.6 Hz, 1H), 3.17 (br dd, 7 = 3.1, 13.9 Hz, 1H), 3.22 - 3.09 (m, 1H), 2.84 (br dd, 7 = 10.3, 13.8 Hz, 1H), 2.91 - 2.74
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-l,2,5- THIADIAZ LE-3-CARBOXAMIDE (72)
72A 72B
[0663] A mixture of compound 72A (800 mg, 3.59 mmol) and phenylboronic acid (1.31 g, 10.8 mmol) in toluene (10 mL) and H 2 0 (500 uL) was added KF (417 mg, 7.18 mmol) and Pd(PPh 3 ) 4 (414 mg, 359 umol) under N 2 . Then the reaction mixture was stirred at 100 °C under N 2 for 16hrs. The solvent was evaporated. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 20: 1 to 5: 1) to give compound 72B (400 mg, crude) as an oil. 1H NMR (400 MHz, CDC1 3 ) δ 7.70 - 7.68 (m, 2H), 7.48 - 7.46 (m, 3H), 3.94 (s, 3H).
[0664] A solution of compound 72B (500 mg, 2.27 mmol) in THF (5 mL), H 2 0 (5 mL) and MeOH (5 mL) was added NaOH (182 mg, 4.54 mmol). The reaction mixture was stirred at 20 °C for lhr. 1M HC1 was added to the reaction mixture until pH ~ 4. The solvent was evaporated to give a crude product 72C (500 mg, crude) as a white solid. The crude product was used in the next step without purification.
[0665] Compound 72 (50.5 mg, yield: 43.9%, white solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 72C. Compound 72:
1H NMR (400 MHz, DMSO- 6 ) δ 9.42 (d, 7 = 7.7 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.60 - 7.55 (m, 2H), 7.48 - 7.43 (m, 1H), 7.42 - 7.36 (m, 2H), 7.31 - 7.22 (m, 5H), 5.51 (ddd, = 3.6, 7.7, 10.0 Hz, 1H), 3.23 (dd, = 3.6, 14.0 Hz, 1H), 2.87 (dd, = 10.1, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 381.0.
N-((35,4R)-l-AMINO-4-METHYL-l,2-DIOXOHEXAN-3-YL)-3-METHYL-5- PHEN YLIS OXAZOLE-4- C ARB OX AMIDE (73)
73D 73E 73F
[0666] A mixture of N-methoxymethanamine (2.32 g, 23.78 mmol), compound 73A (5.00 g, 21.62 mmol), HOBt (2.92 g, 21.62 mmol) and NMM (6.56 g, 64.86 mmol) in CHCI 3 (100 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (6.22 g, 32.43 mmol) was added in portions. The mixture was stirred at 25 °C for 16 hrs under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (100 mL). The organic layers were washed with HCl (IN, 100 mL x 2), and saturated NaHC0 3 (100 mL x 2), and saturated brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0-10% Ethyl acetate/Petroleum ether gradient) to give compound 73B (5.0 g, yield: 84.3%) as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 5.10 (d, =9.5 Hz, 1H), 4.67 - 4.53 (m, 1H), 3.76 (s, 3H), 3.20 (s, 3H), 1.70 (qt, = 6.8, 9.9 Hz, 1H), 1.54 - 1.51 (m, 1H), 1.41 (s, 9H), 1.15 - 1.07 (m, 1H), 0.91 - 0.85 (m, 6H). MS (ESI) m/z (M + Na + ) 296.9.
[0667] To a solution of LiAlH 4 (350 mg, 9.22 mmol) in THF (30 mL) was added a solution of compound 73B (2.30 g, 8.38 mmol) in THF (30 mL) at 0 °C. After addition, the reaction mixture was stirred for lhr at 5 °C. The reaction mixture was quenched by addition of ethyl acetate (10 mL) and HCl (IN, 10 mL), and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with HCl (IN, 30 mL x 2), sat. NaHC0 3 (30 mL x 3), and brines (30mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 73C (1.50 g, yield: 83.2%) as a colourless oil. 1H NMR (400MHz, OMSO-d 6 ) δ 9.45 (d, 7 = 1.3 Hz, 1H), 7.22 (br d, 7 = 7.5 Hz, 1H), 3.79 (br t, 7= 6.4 Hz, 1H), 1.89 - 1.75 (m, 1H), 1.42 - 1.32 (m, 10H), 1.25 - 1.10 (m, 1H), 0.86 (d, 7=6.8 Hz, 3H), 0.81 (t, 7=7.4 Hz, 3H). MS (ESI) m/z (M+H) + 216.0.
[0668] To a solution of compound 73C (1.5 g, 6.97 mmol) in DCM (10 mL) was added 2-hydroxy-2-methylpropanenitrile (1.28 mL, 13.93 mmol) and TEA (1.16 mL, 8.36 mmol), and then stirred at 25 °C for 14 hours. The reaction mixture was diluted with DCM (25 mL), washed with HCl (IN, 20 mL x 2), H 2 0 (30 mL), and brine (30mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 73D (1.5 g, yield: 88.8%) as a colorless liquid. 1H NMR (400MHz, CDC1 3 ) δ 5.24 - 5.08 (m, 1H), 4.92 - 4.56 (m, 1H), 3.90 - 3.25 (m, 1H), 2.04 - 1.80 (m, 1H), 1.66 - 1.52 (m, 1H), 1.50 - 1.40 (m, 9H), 1.33 - 1.09 (m, 2H), 1.02 - 0.75 (m, 6H).
[0669] To a solution of compound 73D (1.50 g, 6.19 mmol) and K 2 C0 3 (1.71 g, 12.38 mmol) in DMSO (15 mL) was added H 2 0 2 (7.21 g, 211.95 mmol) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for lh. The reaction mixture was diulted with water (20 mL) and quenched with saturated aqueous Na 2 S 2 0 3 slowly at ice water. The mixture was extracted with EtOAc (50 mL x 3) and the combined extracts were washed with saturated aqueous Na 2 S 2 0 3 (30 mL x 3). The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0 ~ 20% Ethyl acetate/Petroleum ethergradient) to give compound 73E (870 mg, yield: 54.0%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) <5 7.31 - 6.97 (m, 2H), 6.29 - 5.87 (m, 1H), 5.44 - 5.12 (m, 1H), 3.99 - 3.80 (m, 1H), 3.71 - 3.50 (m, 1H), 1.67 - 1.41 (m, 2H), 1.39 - 1.30 (m, 9H), 1.11 - 0.92 (m, 1H), 0.89 - 0.75 (m, 6H). MS (ESI) m/z (M + Na) + 282.9.
[0670] To a solution of compound 73E (870 mg, 3.34 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4M, 16.70 mL) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was washed with MTBE (30 mL), filtered to give compound 73F (620 mg, yield: 94.4%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.14 - 7.71 (m, 3H), 7.64 - 7.37 (m, 2H), 6.57 - 6.28 (m, 1H), 4.32 - 3.99 (m, 1H), 3.21 (br s, 1H), 1.82 - 1.43 (m, 2H), 1.30 - 1.03 (m, 1H), 0.99 - 0.71 (m, 6H). MS (ESI) m/z (M +H) + 161.1.
[0671] Compound 73 (100 mg, yield: 63.6%, white solid) was prepared as in Example 15 from the corresponding intermediate compounds, 23A and 73F. Compound 73: 1H NMR (400MHz, DMSO-i¾) δ 8.92 (d, = 7.0 Hz, 1H), 8.15 (s, 1H), 7.96 - 7.65 (m, 3H), 7.62 - 7.44 (m, 3H), 5.19 (t, J = 6.5 Hz, 1H), 3.33 (br s, 1H), 2.30 (s, 3H), 2.10 - 1.94 (m, 1H), 1.36 - 1.13 (m, 2H), 0.92 (d, J = 6.8 Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H). MS (ESI) m/z (M +H) + 344.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(5-PHENYLPYRI MIDIN-2- -lH-IMIDAZOLE-5-CARBOXAMIDE (74)
[0672] The mixture of compound 74A (10.0 g, 57.47 mmol), phenylboronic acid (10.5 g, 86.21 mmol), K 3 P0 4 (24.4 g, 114.94 mmol), Pd(OAc) 2 (1.3 g, 5.75 mmol) in ethylene glycol (200 mL) was stirred at 80 °C for 12 hrs. The reaction mixture was added to H 2 0 (200 mL), the insoluble substance was removed by filtration; the filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with saturated aqueous NaHC0 3 (150 mL x 3), saturated aqueous NaCl (150 mL x 3), dried over Na 2 S0 4 and concentrated in vacuum. The resulting solid was treated with ethyl acetate (10 mL). The precipitate was filtered and dried in vacuum to afford compound 74B (4.97 g, yield: 50.5%) as light yellow solid. 1H NMR (DMSO- e , 400 MHz) δ 8.55 (s, 2H), 7.62 - 7.58 (m, 2H), 7.43 - 7.40 (m, 2H), 7.33 - 7.27 (m, 1H), 6.76 (br.s., 2H).
[0673] The mixture of compound 74B (3.0 g, 17.35 mmol) and compound ethyl 2- oxoacetate (2.3 g, 22.55 mmol) in MeOH (50 mL) was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated and the solid was filtered. The resulting solid was treated with MeOH (10 mL), filtered and dried in vacuum to afford compound 74C (3.23 g, yield: 64.8%) as light yellow solid. 1H NMR (DMSO-d 6, 400 MHz) δ 8.71 (s, 2H), 8.24 (d, = 8.8 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.47 - 7.41 (m, 2H), 7.37 - 7.31 (m, 1H), 5.64 (d, = 8.8 Hz, 1H), 4.19 - 4.10 (m, 2H), 3.33 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).
[0674] The mixture of compound 74C (500 mg, 1.74 mmol), Tosmic (680 mg, 3.48 mmol), K 2 C0 3 (720 mg, 5.22 mmol) in absolute EtOH (50 mL) was stirred at 65 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure; the resulting residue was added in water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate = 15: 1 to 8: 1) to afford compound 4 (293 mg, yield: 52.2%) as white solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 9.30 (s, 2H), 8.46 (s, 1H), 7.89 (t, = 7.2 Hz, 2H), 7.76 (s, 1H), 7.59 - 7.49 (m, 3H), 4.23 - 4.13 (m, 2H), 1.17 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 295.1.
[0675] To the mixture of compound 74D (1.15 g, 3.91 mmol) in THF (10 mL) and MeOH (10 mL) was added KOH (2M, 1.96 mL, 3.92 mmol) dropwise at 25 °C. The mixture was stirred at 25 °C for 23 hrs, and then concentrated under reduced pressure to afford intermediate compound 74E (2 g, crude).
[0676] Compound 74 (14.9 mg, yield 28.2%, white solid) was prepared as in Example 5 from the corresponding intermediate compounds 74E and 12G. 1H NMR (DMSO-i¾ , 400 MHz) δ 9.60 (br d, J = 6.4 Hz, 1H), 8.64 (br s, 3H), 7.82 (s, 1H), 7.59 - 7.50 (m, 6H), 7.22 - 7.11 (m, 5H), 5.83 (m, 1H), 5.61 (br s, 1H), 3.52 - 3.44 (m, 1H), 3.40 - 3.31 (m, 1H). MS (ESI) m/z (M+H) + 441.0.
COMPOUNDS 77, 88
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (4- (OXAZOL-2-YL)PYRIDIN-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (77)
[0677] A mixture of 77A (20 g, 115.60 mmol) and ethyl 2-oxoacetate (30.7g, 150.28 mmol) in MeOH (300 mL) was heated to 80 °C for 3 hrs. LCMS showed desired MS. TLC (Petroleum ethenEthyl acetate = 3: 1, R f -0.8) showed new point, the mixture was concentrated and residue purified by silica gel column (Petroleum ether : Ethyl acetate = 20: 1). Compound 77B (28.9g, yield 86.5%, yellow solid): 1H NMR (400 MHz, CDC1 3 ) δ 7.96 (d, = 5.2 Hz, 1 H), 6.86 (dd, = 5.2, 1.75 Hz, 1 H), 6.77 (d, = 1.3 Hz, 1 H), 5.75 (br s, 1 H), 5.61 (d, = 8.3 Hz, 1 H), 4.29 (q, = 7.0 Hz, 2 H), 3.41 (s, 3 H), 1.37 - 1.31 (m, 3 H).
[0678] A mixture of 77B (15 g, 51.9 mmol) and K 2 C0 3 (21.5 g, 156 mmol) in EtOH (300 mL) was stirred at 80 °C for 0.5 hr, then TosMIC (15.2 g, 77.82 mmol) was added, the resulting mixture was stirred at 80 °C for another 2 hrs. LCMS showed desired MS, most of ethanol was removed and a precipitate was formed, the solid was filtered and washed with water (100 mL x 2), the solid was dried and concentrated to give 77C (6.4 g, yield: 41.7%), as yellow solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.38 (d, = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.85 (s, 1 H), 7.61 (s, 1 H), 7.56 (dd, = 5.26 1.3 Hz, 1 H), 4.27 (q, = 7.02Hz, 2 H), 1.29 (t, = 7.02Hz, 3 H).
[0679] Compound 77C (3 g, 10.13 mmol), Pin 2 B 2 (2.57 g, 10.13 mmol), KOAc (2.98 g, 30.4 mmol) and Pd(dppf)Cl 2 (741 mg, 1.01 mmol) in dioxane (100 mL) was de-gassed and then heated at 70 °C for 4 hours under N 2 . LCMS showed desired MS, TLC (Ethyl acetate: Methanol = 10: 1, Rf ~ 0), the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel chromatography (DCM: Methanol = 5: 1) to give 77D (1.70 g, crude) as black solid.
[0680] Compound 77D (300 mg, 1.15 mmol), 2-iodooxazole (157 mg, 805.00 umol), Pd(dppf)Cl 2 (84.1 mg, 115.00 umol) and Na 2 C0 3 (244 mg, 2.30 mmol) in toluene (2 mL), EtOH (2 mL), H 2 0 (1 mL) was de-gassed and then heated to 120 °C for lh under microwave condition. LCMS showed desired MS, the mixture was added water (5 mL) and extracted with ethyl acetate (10 mL x 2), the organic phases were dried and concentrated, the residue was purified by preparatory- TLC (Petroleum ether : Ethyl acetate = 1: 1) to give 77E (80 mg, yield: 24.5%) as yellow solid.
[0681] A mixture of 77E (80 mg, 281.42 umol) and LiOH.H 2 0 (17.7 mg, 422.13 umol) in THF (5 mL), H 2 0 (1 mL) was stirred at 25 °C for 12 hrs. LCMS showed desired MS, THF was removed under vacuum, the water layer was extracted with ethyl acetate (10 mL x 2), the water layer was adjusted to pH ~ 6 with IN HC1 and lyophilized, the residue was purified by preparatory-HPLC (TFA) to give 77F (35 mg, yield: 48.5%), as white solid. 1 H NMR (400MHz, methanol-^) δ 8.70 (d, J = 5.3 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.81 (s, 1H), 7.46 (s, 1H).
[0682] Compound 77 (38.4 mg, yield: 64.3%, white solid) was prepared as in Example 41 from the corresponding intermediate carboxylic acid, compound 77F. Compound 77: 1H NMR (400MHz, OMSO-d 6 ) δ 8.93 (d, J = 7.5 Hz, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.60 (d, = 5.7 Hz, 1H), 8.39 (d, = 0.7 Hz, 1H), 8.22 (d, = 0.7 Hz, 1H), 7.94 (dd, 7 = 1.4, 5.2 Hz, 1H), 7.82 (s, 1H), 7.65 (d, = 0.7 Hz, 1H), 7.54 (d, = 0.7 Hz, 1H), 7.28 (d, = 4.4 Hz, 4H), 7.20 (qd, J = 4.2, 8.5 Hz, 1H), 5.30 - 5.22 (m, 1H), 3.16 (dd, J = 3.9, 13.8 Hz, 1H), 2.85 (dd, = 10.1, 13.9 Hz, 1H), 2.77 - 2.68 (m, 1H), 0.67 - 0.59 (m, 2H), 0.58 - 0.50 (m, 2H). MS (ESI) m/z (M+H) + 471.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4-(OXAZOL-2- YL)PYRIDIN- 2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (88)
[0683] Compound 88 (18.5 mg, yield: 46.5%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 77F. 1H NMR (400MHz, DMSO-d 6 ) δ 8.93 (d, J = 7.5 Hz, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.01 (br s, 1H), 7.91 (d, / = 5.1 Hz, 1H), 7.79 (s, 2H), 7.62 (s, 1H), 7.52 (s, 1H), 7.25 (d, = 4.2 Hz, 4H), 7.18 (br dd, = 4.5, 8.7 Hz, 1H), 5.25 - 5.17 (m, 1H), 3.14 (dd, = 3.6, 14.0 Hz, 1H), 2.83 (dd, 7 = 10.5, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 431.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l- INOLIN-5-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (78)
[0684] A mixture consisting of compound 78A (1.0 g, 6.94 mmol) in cone. HC1 (4.00 mL) at 0 °C was added NaN0 2 (526.8 mg, 7.63 mmol) dropwise and the resultant mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was warmed to 25 °C over 0.5 hour, and then cooled to 0 °C. The SnCl 2 « 2H 2 0 (3.13 g, 13.88 mmol, in 1.2 mL cone. HC1) was added dropwise to the reaction mixture, and stirred at 0 °C for 0.5 hour. The resulting mixture was allowed to warm to room temperature with vigorous stirring over 4 hours and then concentrated under reduced pressure to remove solvent. The residue was filtered, and the cake was washed with ethanol (30 mL x 3), and then dried under reduced pressure to afford compound 78B (700.0 mg, 51.55% yield) as a yellow solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 9.95 (br s, 1H), 9.25 - 9.13 (m, 2H), 8.04 - 7.95 (m, 2H), 7.88 (d, = 8.8 Hz, 1H), 7.26 (d, = 7.6 Hz, 1H), 7.28 - 7.23 (m, 1H).
[0685] To a mixture of compound 78B (500 mg, 3.14 mmol) and compound ethyl 2- (methoxyimino)-4-oxopentanoate (588 mg, 3.14 mmol) in AcOH (1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 110 °C for 2 hrs under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with CH 2 C1 2 (100 mL), adjusted to pH - 7 - 8 with saturated aqueous NaHC0 3 , and then extracted with CH 2 C1 2 (40 mL x 2). The organic phase was dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1:0 to 1 :0) to give compound 78C (200 mg, 22.6% yield) as a yellow solid. 1H NMR (CDC1 3 , 400 MHz) δ 8.93 (d, = 4.0 Hz, 1H), 8.23 (d, = 8.4 Hz, 1H), 7.78 (t, = 8.0 Hz, 1H), 7.64 (d, = 8.4 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+l) + 282.0.
[0686] Intermediate compound 78D (135 mg, 74.98% yield, white solid) was prepared as in Example 85 from compound 78C. Compound 78D: 1H NMR (DMSO-d 6, 400 MHz) δ 8.97 (d, = 4.0 Hz, 1H), 8.17 (d, = 8.4 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.67 - 7.52 (m, 3H), 6.97 (s, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+l) + 253.9.
[0687] Compound 78 (8.8 mg, 16.77% yield, yellow solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 78D. Compound 78: 1H NMR (CDC1 3 , 400 MHz): δ 8.95 (d, = 4.0 Hz, 1H), 8.22 (d, = 8.4 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.49 (d, = 6.4 Hz, 1H), 7.38 (d, = 8.4 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.87 (d, = 7.6 Hz, 2H), 6.79 (br s, 1H), 6.64 (s, 1H), 6.33 (d, = 7.2 Hz, 1H), 5.49 - 5.42 (m, 1H), 3.27 - 3.19 (m, 1H), 3.08 - 2.98 (m, 1H), 2.78 - 2.69 (m, 1H), 0.90 - 0.83 (m, 2H), 0.61 - 0.50 (m, 2H). MS (ESI) m/z (M+H) + 468.1.
COMPOUNDS 79, 146, 160, 264
(5 N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-5-PHENYL-l H-
IMIDAZ LE-4-CARBOXAMIDE (79)
[0688] The solution of compound 79A (500 mg, 3.96 mmol) in HCl/MeOH (4 M, 50 was stirred at 80 °C for 12 hrs. The solvent was removed in vacuo. The residue was adjusted to pH ~ 8 with saturated aqueous NaHC0 3 . The solution was extracted with EtOAc (100 mL x 3). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated. Compound 79B (360 mg, yield: 64.87%, light yellow solid): 1H NMR (CDC1 3, 400 MHz) δ Ί .90 - 7.88 (m, 1H), 7.34 - 7.31 (m, 1H), 7.15 - 7.09 (m, 2H), 5.72 - 5.63 (m, 1H), 4.87 - 4.76 (m, 2H), 2.90 - 2.86 (m, 2H), 1.92 - 1.87 (m, 2H), 1.50 - 1.47 (m, 2H), 1.26 - 1.14 (m, 8H).
[0689] To a solution of compound 79B (360 mg, 2.57 mmol) in DMF (5 mL) at 0 °C was added NBS (550 mg, 3.08 mmol). The mixture was then warmed up to 25 °C and stirred for 12 hrs. The reaction was washed with H 2 0 (10 mL), extracted with DCM (20 mL). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 79C (550 mg, crude) as yellow solid. MS (ESI) m/z (M+2) + 220.7.
[0690] To a solution of NaH (151 mg, 3.76 mmol, 60% purity) in THF (8 mL) at 0 °C was added a solution of compound 79C (550 mg, 2.51 mmol) in THF (2 mL) dropwise. After addition, the mixture was warmed up to 25 °C and stirred for lh. Then SEM-C1 (0.5 mL, 2.76 mmol) was added. The mixture was stirred at 25 °C for 12 hrs. The reaction was quenched with H 2 0 (10 mL), extracted with EtOAc (20 mL x 2). The organics were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 5: 1) to afford compound 79D (180 mg, yield: 20.51%) as colorless oil. MS (ESI) m/z (M+2) + 350.9.
[0691] To a solution of compound 79D (180 mg, 0.52 mmol) and phenylboronic acid (76 mg, 0.62 mmol) in dioxane (12 mL) and H 2 0 (4 mL) was added Pd(dtbpf)Cl 2 (34 mg, 0.052 mmol) and K 3 P0 4 (330 mg, 1.55 mmol). The mixture was stirred at 80 °C under N 2 for 2 hrs. The reaction was washed with H 2 0 (10 mL), extracted with EtOAc (15 mL x 2). The organics were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 5: 1) to afford compound 79E (150 mg, yield: 84.0%) as yellow oil. MS (ESI) m/z (M+H) + 347.0.
[0692] To a solution of compound 79E (180 mg, 0.52 mmol) in THF (5 mL), MeOH (5 mL) and H 2 0 (5 mL) was added LiOH.H 2 0 (110 mg, 2.60 mmol). The mixture was stirred at 25 °C for 12 hrs. The reaction was acidified with IN HC1 to pH ~ 3. The mixture was extracted with EtOAc (10 mL x 2). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated to afford compound 79F (130 mg, crude) as yellow oil. MS (ESI) m/z (M+H) + 333.0. Intermediate compound 79H (65 mg, crude, yellow oil) was prepared as in Example 5 from the corresponding carboxylic acid, compound 79F. Compound 79H: MS (ESI) m/z (M+H) + 507.2.
[0693] To a solution of compound 79H (65 mg, 0.13 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 10 mL) dropwise. After addition, the mixture was stirred at 25 °C for 12 hrs. The solvent was removed in vacuo. The residue was purified by prep-HPLC (HQ) to afford compound 79 (10.00 mg, yield: 18.7%) as white solid. 1H NMR (400MHz, D 2 0) δ 7.45 - 7.28 (m, 3H), 7.23 - 6.97 (m, 7H), 4.46 - 4.38 (m, 1H), 3.02 - 2.93 (m, 1H), 2.48 - 2.41 (m, 3H), 2.39 - 2.29 (m, 1H). MS (ESI) m/z (M+H) + 377.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3- ((BENZYLAMINO)METHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-
CARBOXAMIDE 146)
[0694] To a mixture of compound 140C (250 mg, 0.72 mmol) and benzyl bromide (310 mg, 1.8 mmol) in DMF (10 mL) was added NaH (87 mg, 2.2 mmol, 60% purity) in batches at 0 °C under N 2 . The mixture was stirred at 25 °C for 3h. The mixture was quenched with NH 4 C1 (10 mL), diluted with H 2 0 (30 mL), extracted with ethyl acetate (20 mL x 3). The organic phase was combined and washed with brine (30 mL x 2), dried over Na 2 S0 4 , filtered and concentrated to give a residue. The residue was purified by Flash Column Chromatography (Si02, Petroleum ether/Ethyl acetate=l/0 to 5/1) to afford compound 146A (182 mg, yield: 57.7%) as colorless clear liquid.
[0695] To a mixture of compound 146A (180 mg, 0.41 mmol) in MeOH (10 mL) and
H 2 0 (2 mL) was added LiOH.H 2 0 (52 mg, 1.24 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 3h. The reaction mixture was concentrated under reduced pressure to move
MeOH. Then the residue was diluted with water (15 mL) and extracted with MTBE (20 mL), the aqueous phase was acidified with aqueous HC1 (1M) till pH ~ 5-6 and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (40 mL) and dried over Na 2 S0 4 , filtered and concentrated to afford compound 146B (158 mg, yield: 90. 8%) as colorless liquid, which was used directly for next step without purification. 1H NMR (DMSO-<i6,
400 MHz): δ 7.44 - 7.39 (m, 1H), 7.37 - 7.30 (m, 3H), 7.26 (q, J = 6.9 Hz, 5H), 6.81 (s, 1H), 4.48 - 4.26 (m, 4H), 2.25 (s, 3H), 1.39 (s, 9H).
[0696] Compound 146 was prepared as in Example 45 from the intermediate compound 146B. Compound 146 (40.0 mg, yield 74.6%, white solid): 1H NMR (D 2 0 , 400 MHz): δ 7.51 - 7.42 (m, 6H), 7.41 - 7.36 (m, 1H), 7.36 - 7.27 (m, 5H), 7.25 (s, 1H), 6.78 (d, = 8.6 Hz, 1H), 6.60 (s, 1H), 4.52 - 4.43 (m, 1H), 4.30 - 4.18 (m, 4H), 3.24 - 3.15 (m, 1H), 2.82 - 2.71 (m, 1H), 2.29 (s, 3H). MS (ESI) m/z (M-HC1+H) + 496.2.
[0697] To a solution of compound 153E (350 mg, 1.01 mmol) and benzyl bromide (432 mg, 2.53 mmol, 0.3 mL) in DMF (10 mL) was added NaH (121 mg, 3.03 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for lh. The mixture was quenched with NH 4 C1 (5 mL), diluted with H 2 0 (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, and washed with NaCl (30 mL x 2), dried over Na 2 S0 4 , concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20/1 to 5/1) to give compound 160A (400 mg, yield: 41.47%) as a yellow oil. 1H NMR (400MHz, CDCI 3 ) δ 8.02 (dd, = 1.1 Hz, 1H), 7.37 - 7.25 (m, 9H), 6.88 - 6.75 (m, 1H), 4.49 - 4.28 (m, 4H), 2.98 - 2.88 (m, 4H), 2.46 - 2.30 (m, 3H), 1.57 - 1.41 (m, 8H). MS (ESI) m/z (M- 56) + 380.0.
[0698] To a mixture of compound 160A (400 mg, 918.46 umol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (116 mg, 2.76 mmol) in portion at 25 °C and stirred for 2.5h. The mixture was diluted with H 2 0 (10 mL) and concentrated to remove THF, then the water was extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with IN HC1, then, the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 160B (350 mg, yield: 86.82%) as white solid. 1 H NMR (400MHz, CDC1 3 ) δ 7.40 - 7.20 (m, 9H), 6.85 (s, 1H), 4.43 (s, 2H), 4.33 (dd, = 13.9 Hz, 2H), 2.34 (s, 3H), 1.47 (s, 8H). MS (ESI) m/z (M-56) + 366.1.
[0699] Compound 160 was prepared as in Example 79 from the corresponding carboxylic acid, compound 160B, and then through intermediate compound 160D. Compound
160 (30 mg, yield: 53.02%, light yellow solid): 1H NMR (400MHz, DMSO-d 6 ) S 9.62 - 9.57 (m, 1H), 9.15 (d, J = 7.9 Hz, 1H), 8.12 (s, 1H), 7.88 (s, 1H), 7.58 - 7.49 (m, 4H), 7.44 (dd, J = 6.8 Hz, 3H), 7.36 - 7.27 (m, 5H), 7.22 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H), 5.35 - 5.28 (m, 1H), 4.18 (s, 4H), 3.25 - 3.18 (m, 1H), 2.83 (dd, J = 10.6, 13.9 Hz, 1H), 2.26 (s, 3H). MS (ESI) m/z (M+H) + 496.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(lH-BENZO[rf] IMIDAZOL-2- YL)-5-M -lH-PYRAZOLE-3-CARBOXAMIDE (264)
[0700] 2-chloro- lH-benzo[d]imidazole (5 g, 32.8 mmol) was added to a solution of NaH (1.31 g, 32.8 mmol, 60%) in DMF (50 mL) below 10 °C. After addition, the reaction mixture was stirred at 20 °C for 2h. Then SEM-C1 (5.46 g, 32.8 mmol,) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16hrs. Water (150 mL) and EtOAc (150 mL) were added. The organic layer was separated and washed by brine (100 mL), concentrated to give a residue. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 20: 1~ 4: 1) to give compound 264A (3.50 g, yield: 37.8%) as an oil. 1H NMR (400MHz, CDC1 3 ) δ 7.78 - 7.71 (m, 1H), 7.54 - 7.48 (m, 1H), 7.41 - 7.32 (m, 2H), 5.62 (s, 2H), 3.66 - 3.59 (m, 2H), 0.99 - 0.93 (m, 2H), 0.07 (d, J = 2.0 Hz, 2H), 0.00 (s, 9H).
[0701] Compound 264 was prepared as in Example 79 from the corresponding intermediate compound 264B, and then through intermediate compound 264D. Compound 264 (31.8 mg, yield: 28.0%, off-white solid): 1H NMR (400MHz, CDCI 3 ) δ 13.04 (br s, 1H), 8.39 (d, = 7.6 Hz, 1H), 8.13 (br s, 1H), 7.88 (br s, 1H), 7.67 (br d, = 7.2 Hz, 1H), 7.53 (br d, = 7.5 Hz, 1H), 7.34 - 7.19 (m, 7H), 6.79 (s, 1H), 5.51 (dt, = 4.0, 8.2 Hz, 1H), 3.27 (br d, = 4.0 Hz, 1H), 3.02 (dd, = 9.3, 13.9 Hz, 1H), 2.73 (s, 3H). MS (ESI) m/z (M+H) + 417.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-l-(4- PHENYLTHIAZOL-2-YL)-lH-PYRAZOLE-3-CARBOXAMIDE (80) (5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5- METHYL- l-(4-PHENYL -2-YL)-lH-PYRAZOLE-3-CARBOXAMIDE (125)
[0702] Intermediate compound 80B (182.00 mg, 99.95% yield, white solid): 1H NMR (DMSO-i¾ , 400 MHz) δ 8.02 (s, 1H), 7.96 (br d, =7.5 Hz, 2H), 7.47 (br t, =7.5 Hz, 2H), 7.41 - 7.32 (m, 1H), 6.80 (s, 1H), 2.78 (s, 3H).
[0703] Compound 80 (44 mg, 64.6% yield, white solid) was prepared as in Example 5 from the corresponding intermediate compounds 80B and 12G. Compound 80: 1 H NMR (DMSO-d 6, 400 MHz) δ 8.53 (br d, =7.3 Hz, 1H), 8.12 (br s, 1H), 8.04 - 7.94 (m, 3H), 7.86 (br s, 1H), 7.52 - 7.44 (m, 2H), 7.39 (br d, =6.4 Hz, 1H), 7.32 - 7.17 (m, 5H), 6.76 (s, 1H), 5.43 (br s, 1H), 3.24 (br d, =12.1 Hz, 1H), 3.12 - 3.03 (m, 1H), 2.78 (s, 3H). MS (ESI) m/z (M+H) + 460.1.
[0704] Compound 125 (118 mg, yield 77.6%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic compounds 80B and 41B. Compound 125: 1H NMR (DMSO-i¾ , 400 MHz) δ 8.84 (br s, 1H), 8.60 - 8.53 (m, 1H), 8.06 - 7.94 (m, 3H), 7.52 - 7.44 (m, 2H), 7.42 - 7.35 (m, 1H), 7.29 (br s, 4H), 7.21 (br s, 1H), 6.76 (s, 1H), 5.44 (br s, 1H), 3.27 - 3.19 (m, 1H), 3.11 - 3.02 (m, 1H), 2.78 (br s, 4H), 0.72 - 0.57 (m, 4H). MS (ESI) m/z (M+H) + 500.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(2'- METHYL- '-BIPHENYL]-3-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (81)
[0705] To a mixture of compound 81A (25 g, 111.86 mmol) and compound ethyl 2- (methoxyimino)-4-oxopentanoate (22 g, 117.45 mmol) in AcOH (150 mL) was stirred at 110 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove a large amount of AcOH. The residue was acidified with saturated aqueous NaHC0 3 till pH ~ 7-8. The precipitate was collected by filtration and the cake was triturated with petroleum ether (20 mL), filtered and dried in vacuum to afford compound 81B (26.41 g, yield: 74.0%) as gray solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 7.71 - 7.68 (m, 1H), 7.65 (td, J = 1.5, 7.7 Hz, 1H), 7.50 - 7.38 (m, 2H), 6.95 - 6.84 (m, 1H), 4.18 (q, = 7.0 Hz, 2H), 2.27 (s, 3H), 1.17 (t, = 7.0 Hz, 3H). MS (ESI) m/z (M+H) + 310.8.
[0706] To a mixture of compound 81B (5 g, 16.17 mmol) in MeOH (20.00 mL) was added NaOH (2M, 40 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was added ¾0 (10 mL) and ethyl acetate (20 mL), and then the mixture was acidified with 1M HC1 till the aqueous phase pH ~ 5-6. The separated aqueous layer was extracted with ethyl acetate (30 x 3 mL), the combined organic layers were washed with brine (60 mL), dried over Na 2 S0 4 , filtered under reduced pressure to give crude product. The crude product was treated with isopropyl ether (15 mL), the precipitate was filtered and dried in vacuum to afford compound 81C (4.21 g, yield: 80.67%) as white solid. 1H NMR (DMSO-d 6 , 400 MHz) δ 7.65 - 7.58 (m, 2H), 7.45 - 7.36 (m, 2H), 6.83 (s, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 282.8.
[0707] To a solution of compound 81C (1 g, 3.56 mmol) in DMF (50 mL) was added HOBt (144 mg, 1.07 mmol), compound 12G (903 mg, 3.92 mmol, HCl) and DIEA (1.38 g, 10.68 mmol). After stirring for 5 min, EDCI (682 mg, 3.56 mmol,) was added at 0 °C. Then the reaction mixture was stirred at 25 °C for 9 hrs. The reaction mixture was concentrated under reduced pressure to move DMF, and to the residue was added ethyl acetate (100 mL) and respectively washed with H 2 0 (80 mL), saturated aqueous NaHC0 3 (80 mL x 2), brine (80 mL x 3). The organic phase was dried over Na 2 S0 4 and concentrated. The crude product was treated with z ' -propyl ether. The solid was collected and dried in vacuum to afford compound 81D (1.3 g, yield: 79.85%) as white solid. 1H NMR (DMSO-d 6 , 400 MHz) δ 8.55 - 8.18 (m, 1H), 7.54 - 7.45 (m, 2H), 7.34 (br d, 7=18.5 Hz, 1H), 7.30 - 7.14 (m, 7H), 7.00 - 6.89 (m, 1H), 6.58 (d, 7=1.5 Hz, 1H), 5.98 - 5.73 (m, 1H), 4.44 - 4.33 (m, 1H), 4.00 - 3.89 (m, 1H), 2.93 - 2.87 (m, 0.5 H), 2.84 - 2.73 (m, 1H), 2.71 (br s, 0.6 H), 2.22 (s, 3H).
[0708] To a mixture of compound 81D (150 mg, 328.00 umol) and compound o- tolylboronic acid (89.2 mg, 656.00 umol) in THF (50 mL) and H 2 0 (10 mL) was added Na 2 C0 3 (70 mg, 656.00 umol,) and Pd(PPh 3 ) 4 (38 mg, 32.80 umol) in one portion at 25 °C under N 2 . The mixture was stirred at 80 °C for 12 hrs. Then to the reaction mixture was added H 2 0 (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saturated aqueous NaHC0 3 (150 mL x 3), brine (150 mL x 3), dried over Na 2 S0 4 and concentrated to afford compound 81E (110 mg, yield: 71.58%) was obtained as white solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 8.50 - 8.11 (m, 1H), 7.38 - 7.32 (m, 2H), 7.31 - 7.22 (m, 6H), 7.18 (br s, 5H), 7.10 (br d, 7 = 6.4 Hz, 1H), 7.00 (br.dd, 7 = 8.0, 16.4 Hz, 1H), 6.57 (s, 1H), 5.96 - 5.69 (m, 1H), 4.51 - 4.30 (m, 1H), 4.03 - 3.85 (m, 1H), 2.92 - 2.63 (m, 2H), 2.27 - 2.12 (m, 6H). MS (ESI) m/z (M+H) + 469.2.
[0709] The mixture of compound 81E (70 mg, 149.4 umol) in DCM (10 mL) and DMSO (0.5 mL) was added DMP (190 mg, 448.2 umol) in one portion at 0 °C. The mixture was stirred at 0 °C for 5 min, then heated to 25 °C and stirred for 1.5 hours. The reaction was quenched by 20 mL of 10 % aqueous Na 2 S203 solution and 20 mL of saturated aqueous NaHC0 3 solution and then extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (40 mL x 3), dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was treated with z ' -propyl ether/CH3CN (v/v = 10/1, 10 mL). The solid was collected and dried in vacuum to afford compound 81 (48.3 mg, yield: 66.3%) as white solid. 1H NMR
(DMSO-i¾, 400 MHz) δ 9.11 (br d, = 8.0 Hz, 1H), 8.18 - 7.79 (m, 2H), 7.49 - 7.37 (m, 1H), 7.29 - 7.26 (m, 8H), 7.21 - 7.12 (m, 4H), 6.60 (s, 1H), 5.32 (br.s., 1H), 3.21 - 3.18 (m, 1H), 2.86 - 2.76 (m, 1H), 2.25 (br.s., 3H), 2.18 (br.s., 3H). MS (ESI) m/z (M+H) + 467.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- -2-YL)-lH-PYRAZOLE-5-CARBOXA
[0710] To a solution of compound 82A (2.0 g, 10.46 mmol) in CH 3 COOH (30.0 mL) was added compound ethyl 2,4-dioxopentanoate (1.65 g, 10.46 mmol, 1.48 mL) dropwise, then the mixture was heated to 120 °C and stirred for 2 hrs and removed the solvent under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and treated with NaHC0 3 until pH ~ 8, and then the organic layer was collected and evaporated under reduced pressure. The residue was purified by flash column chromatography (Petroleum Ether/Ethyl Acetate: 0 to 10/1).
[0711] Compound 82B (660.0 mg, 2.11 mmol, 20.14% yield) was obtained as white solid. Compound 82B (low polarity): 1H NMR (CDC1 3 , 400 MHz,) δ 7.88 - 7.83 (m, 2H), 7.43 - 7.38 (m, 3H), 7.36 - 7.31 (m, 1H), 6.71 (s, 1H), 4.33 (q, 7 = 7.2 Hz, 2H), 2.37 (s, 3H), 1.24 (t, = 7.2 Hz, 3H).
[0712] To a solution of compound 82B (650.0 mg, 2.07 mmol) in MeOH (10.00 mL) was added NaOH (2M, 6.00 mL) drop wise and the mixture was stirred at 25 °C for 2 hrs. The reaction was diluted with H 2 0 (10 mL) and extracted with MBTE(10 mL x 2). The water phase was treated with HC1 (1M) until pH ~ 4, then the precipitate was filtered and dried under reduced pressure. Compound 82D (540.0 mg, 91.3% yield) was obtained as white solid. 1H NMR (DMSO-de , 400 MHz) δ 8.04 (s, 1H), 7.88 (d, =7.1 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.38 - 7.33 (m, 1H), 6.83 (s, 1H), 2.27 (s, 3H)
[0713] Compound 82 (20.0 mg, 42.74% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 82D. Compound 82: 1H NMR (DMSO-i¾ , 400MHz) S 9.49 (d, = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.88 (br s, 1H), 7.78 (br d, J = 7.2 Hz, 2H), 7.42 - 7.37 (m, 2H), 7.35 - 7.29 (m, 1H), 7.22 - 7.12 (m, 5H), 6.55 (s, 1H), 5.55 - 5.47 (m, 1H), 3.16 (m, 1H), 2.80 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) + 403.1.
COMPOUNDS 83, 126, 130
(5 l-([l,l , -BIPHENYL]-4-YL)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2- YL)-3- METHYL-1H-PYRAZ LE-5-CARBOXAMIDE (83)
[0714] To a solution of compound 83A (20.0 g, 89.49 mmol, HC1) in CH 3 COOH (150.0 mL) was added compound ethyl 2-(methoxyimino)-4-oxopentanoate (14.0 g, 89.49 mmol), then the mixture was heated to 120 °C and stirred for 2 hrs and removed the solvent under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), treated with NaHC0 3 until pH ~ 7 and filtered. The solid was treated with petroleum ether. Compound 83B (22.0g, 71.16 mmol, 79.52% yield) was obtained as yellow solid. 1H NMR (CDC1 3 , 400MHz) δ 7.56 (d, 7 = 8.4 Hz, 2H), 7.31 - 7.24 (m, 2H), 6.81 (s, 1H), 4.23 (q, 7 = 7.2 Hz, 2H), 2.34 (s, 3H), 1.26 (t, 7 = 7.2 Hz, 3H).
[0715] To a solution of compound 83B (5.0 g, 16.17 mmol) in MeOH (40.0 mL) was added NaOH (2M, 45.0 mL) dropwise and the mixture was stirred at 25 °C for 3 hrs and removed the solvent under reduced pressure, then the mixture was diluted with H 2 0 (30 mL) and extracted with MTBE (60 mL x 2). Water phase was treated with HC1 (1M) until pH ~ 4, and then the precipitate was filtered and dried under reduced pressure. The water phase was extracted with ethyl acetate (50 mL x 2), the organic layer (extracted with ethyl acetate) was evaporated under reduced pressure. The solid collected was compound 83C (3.75 g, 82.5% yield) obtained as white solid. 1H NMR (DMSO-i¾ , 400MHz) δ 7.62 (d, 7 = 8.8 Hz, 2H), 7.36 (d, 7 = 8.8 Hz, 2H), 6.81 (s, 1H), 2.23 (s, 3H).
[0716] Compound 83 (25.0 mg, 61.24% yield, white solid) was prepared as in Example 47 from the corresponding intermediate compounds 83C, 12G and phenylboronic acid. Compound 83: 1H NMR (CDC1 3, 400 MHz) δ 9.49 (d, 7 = 7.3 Hz, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.88 (br s, 1H), 7.78 (br d, 7 = 7.3 Hz, 2H), 7.48 - 7.27 (m, 4H), 7.26 - 6.96 (m, 7H), 6.55 (s, 1H), 5.55 - 5.47 (m, 1H), 3.16 (br dd, 7 = 4.2, 14.1 Hz, 1H), 2.80 (br dd, 7 = 9.7, 13.9 Hz, 1H), 2.27 (s, 3H), 2.06 (s, 1H). MS (ESI) m/z (M+H) + 453.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4 , -FLUORO-[l,l'- BIPHENYL]-4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (126)
[0717] Compound 126 (32 mg, yield 25.5%, light yellow solid) was prepared as in Example 63 from the corresponding starting materials, compound 83D and (4- fluorophenyl)boronic acid. Compound 126: 1H NMR (CD 3 CN, 400ΜΗζ ) δ 1.13 - 7.67 (m, 2H), 7.63 - 7.59 (m, 2H), 7.37 - 7.22 (m, 10H), 7.02 (br s, 1H), 6.54 (s, 1H), 6.27 (br s, 1H), 5.42 (ddd, 7 = 4.5, 7.8, 9.5 Hz, 1H), 3.32 (dd, 7=4.5, 13.8 Hz, 1H), 2.93 (dd, 7 = 9.6, 14.0 Hz, 1H), 2.31 (s, 3H). MS (ESI) m/z (M+H) + 471.1.
[0718] Compound 130 (30 mg, yield 34.7%, light yellow solid) was prepared as in Example 105 from the corresponding starting materials, compound 83D and p-tolylboronic acid. Compound 130: 1H NMR (DMSO-i¾ 400MHz) § 9.14 (br d, 7 = 7.7 Hz, 1H), 8.11 (br s, 1H), 7.87 (br s, 1H), 7.60 - 7.55 (m, 3H), 7.33 - 7.22 (m, 10H), 6.56 - 6.50 (m, 1H), 5.24 (br s, 1H), 3.20 (br d, J = 13.5 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 467.1.
[0719] A mixture of compound 84A (5 g, 39.19 mmol) and ΝΗ 2 ΝΗ 2 .Η 2 0 (20 g, 391.94 mmol) was heated under reflux (119 °C) for 36 hours. The reaction mixture was concentrated under reduced pressure to remove the unreacted hydrazine hydrate. The residue was diluted with H 2 0 (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brines (30 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by re-crystallization from Petroleum Ether (15 mL) at -10 °C to give compound 84B (2.40 g, yield: 49.35%) as a black brown solid. 1H NMR (400MHz, OMSO-d 6 ) δ 7.39 - 7.29 (m, 1H), 7.25 (s, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 7.3 Hz, 1H), 4.06 (s, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H) + 127.8.
[0720] To a solution of compound 84B (970 mg, 7.88 mmol) in AcOH (20 mL) was added compound ethyl 2-(methoxyimino)-4-oxopentanoate (1.36 g, 7.88 mmol). The mixture was stirred at 120 °C for 20 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 0 (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated aqueous NaHC0 3 (15 mL x 3), dried over Na 2 S0 4i filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography, and then by preparatory-HPLC (HCl condition) to give compound 84C (160 mg, yield: 8.22%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.88 (t, = 7.8 Hz, 1H), 7.50 (d, = 8.0 Ηζ,ΙΗ), 7.28 (d, = 7.5 Hz, 1H), 6.76 (s, 1H), 4.20 (d, = 7.3 Hz, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 1.14 (t, = 7.0 Hz, 3H). MS (ESI) m/z (M+H) + 246.0. [0721] To a solution of compound 84C (100 mg, 432.43 umol) in THF (5 mL) was added a solution of LiOH.H 2 0 (91 mg, 2.16 mmol) in H 2 0 (5 mL) at 0 °C. After addition, the reaction mixture was stirred for 14 hrs at 25 °C. The reaction mixture was diluted with H 2 0 (10 mL) and extracted with MTBE (30 mL). The aqueous phase was neutralized by IN HC1 to the pH ~ 4 and then was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 84D (50 mg, yield: 53.2%) as a red solid. 1H NMR (400MHz, CDC1 3 ) δ 8.06 (d, = 8.4 Hz, 1H), 7.89 (t, = 8.0 Hz, 1H), 7.20 - 7.14 (m, 2H), 2.64 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z (M +H) + 217.9.
[0722] Compound 84 (70 mg, yield: 54.12%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 84D. Compound 84: 1H NMR (400MHz, DMSO-d 6 ) δ 9.09 (d, = 7.3 Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.76 (t, = 7.7 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.29 - 7.17 (m, 5H), 7.15 (d, = 7.5 Hz, 1H), 6.44 (s, 1H), 5.37 - 5.25 (m, 1H), 3.13 (dd, J = 4.0, 13.9 Hz, 1H), 2.82 (dd, J = 9.7, 13.9 Hz, 1H), 2.24 (s, 6H). MS (ESI) m/z (M +H) + 392.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(PYRAZIN- -YL)-lH-PYRAZOLE-5-CARBOXAMIDE (85)
[0723] To a mixture of compound 63B (200 mg, 916.55 umol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH » H 2 0 (153.8 mg, 3.67 mmol) in one portion and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure to afford intermediate compound 85B (160 mg, 85.49% yield) as a white solid. 1H NMR (400 MHz, CDCI 3 ) δ 9.60 (br s, 1H), 8.67 (br s, 1H), 8.32 (br s, 1H), 7.25 (br s, 1H), 2.41 (br s, 3H). MS (ESI) m/z (M+l) + 205.0.
[0724] Compound 85 (30.7 mg, 59.7% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 85B. Compound 85: 1H NMR (400 MHz, CDCI3) δ 8.95 (d, = 4.0 Hz, 1H), 8.22 (d, = 8.4 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.49 (d, = 6.4 Hz, 1H), 7.38 (d, = 8.4 Hz, 1H), 7.24 - 7.16 (m, 3H), 6.87 (d, =7.6 Hz, 2H), 6.79 (br s, 1H), 6.64 (s, 1H), 6.33 (d, = 7.2 Hz, 1H), 5.49 - 5.42 (m, 1H), 3.27 - 3.19 (m, 1H), 3.08 - 2.98 (m, 1H), 2.78 - 2.69 (m, 1H), 0.90 - 0.83 (m, 2H), 0.61 - 0.50 (m, 2H). MS (ESI) m/z (M+H) + 419.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4- (lH- -l-YL)THIAZOLE-5-CARBOXAMIDE (86)
[0725] A mixture consisting of compound 86A (250 mg, 1.06 mmol), lH-indazole (125.2 mg, 1.06 mmol) and Cs 2 C0 3 (1.04 g, 3.18 mmol) in toluene (15 mL) was stirred at 110 °C for 32 hours. The reaction mixture was cooled to room-temperature, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparatory-HPLC (HCl condition) to afford compound 86B (20 mg, 6.90% yield) as a white solid. 1H NMR (CDC1 3, 400 MHz) δ 8.87 (s, 1H), 8.19 (d, = 0.8 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.54 (d, = 8.4 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.22 - 7.17 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).
[0726] To a mixture of 86B (40 mg, 146.35 umol) in MeOH (5 mL) and H 2 0 (1 mL) was added LiOH » H 2 0 (24.6 mg, 585.40 umol) in one portion and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH and the residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HCl, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 86C (30 mg, 83.58% yield) as a white solid. MS (ESI) m/z (M+l) + 245.8.
[0727] Compound 86 (5.4 mg, 10.0% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 86C. Compound 86: 1H NMR (400 MHz, CDC1 3 ) δ 10.97 (d, 7 = 5.2 Hz, 1H), 8.78 (s, 1H), 8.23 (d, 7 =6.4 Hz, 1H), 7.82 (s, 1H), 7.71 (d, 7 =3.2 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.32 - 7.23 (m, 1H), 7.11 - 6.96 (m, 5H), 6.85 (br s, 1H), 5.79 - 5.66 (m, 1H), 3.40 - 3.29 (m, 1H), 3.21 - 3.09 (m, 1H), 2.78 - 2.69 (m, 1H), 0.80 (d, 7 = 6.2 Hz, 2H), 0.55 (br s, 2H). MS (ESI) m/z (M+H) + 460.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (5- (OXAZ -2-YL)PYRIDIN-2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (89)
[0728] To a solution of compound 89A (40 g, 231 mmol) in MeOH (500 mL) was added ethyl 2-oxoacetate (188 g, 924 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for lhr. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 50 : 1 to 30 : 1). Compound 89B (70 g, crude) was obtained as yellow oil. MS (ESI) m/z (M+H) + 258.8.
[0729] To a solution of compound 89B (35 g, 136 mmol) in EtOH (300 mL) was added TosMIC (66.4 g, 340 mmol) and K 2 C0 3 (28.2 g, 204 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for lhr. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleumether: Ethylacetate = 20 : 1 to 3 : 1). Compound 89C (17 g) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 8.62 (d, = 2.4 Hz, 1H), 8.00 - 7.96 (m, 2H), 7.86 (d, = 0.9 Hz, 1H), 7.36 - 7.32 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 297.0.
[0730] To a solution of compound 89C (5g, 16.8 mmol) in dioxane (100 mL) was added bis(pinacolato)diboron (8.58 g, 33.7mmol), KOAc (16.5 g, 168 mmol) at 25 °C. The mixture was degassed and purged with N 2 for 3 times, followed by addition of Pd(dppf)Cl 2 (617 mg, 844 umol). The reaction mixture was degassed and purged with N 2 for 3 times and stirred at 75 °C for 4hrs. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether : Ethyl acetate = 20 : 1 to Dichlorome thane: Methanol = 5 : 1). Compound 89D (2.7 g, yield: 61.2%) was obtained as a white solid. 1H NMR (400MHz, methanol-^) δ 8.63 (br s, 1H), 8.06 (s, 2H), 7.76 (s, 1H), 7.36 (br d, J = 7.1 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 261.9.
[0731] To a solution of compound 89D (500mg, 1.92 mmol) in dioxane (4 mL) was added 2-iodooxazole (561.48 mg, 2.88 mmol) K 2 C0 3 (796.09 mg, 5.76 mmol) H 2 0 (1 mL) at 25 °C. The reaction mixture was degassed and purged with N 2 . Then Pd(dppf)Cl 2 (140 mg, 192 umol) was added. The mixture was degassed and purged with N 2 and stirred at 150 °C for lhr under microwave conditions. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 10: 1 ~ 1.5: 1). Compound 89E (300 mg, crude) was obtained as a grey solid. MS (ESI) m/z (M+H) + 285.0.
[0732] To a solution of compound 89E (200 mg, 703 umol) in THF (2 mL) H 2 0 (500 uL) was added LiOH.H 2 0 (59 mg, 1.41 mmol) and stirred at 25 °C for 12 hrs. The reaction mixture was acidified by HC1 (IN) to pH ~ 5, and the precipitation was filtered to give a crude product. Compound 89F (60 mg, crude) was obtained as a grey solid. MS (ESI) m/z (M+H) + 257.0.
[0733] Compound 89 (35 mg, yield: 65.4%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 89F. Compound 89: 1H NMR (400MHz, OMSO-d 6 ) δ 9.04 - 8.93 (m, 2H), 8.77 (br d, = 5.1 Hz, 1H), 8.38 - 8.28 (m, 2H), 8.20 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.29 - 7.22 (m, 4H), 5.32 - 5.14 (m, 1H), 3.28 (br s, 1H), 3.20 - 3.10 (m, 1H), 2.81 (br dd, = 10.1, 13.7 Hz, 1H), 2.77 - 2.69 (m, 1H), 0.73 - 0.42 (m, 4H). MS (ESI) m/z (M+H) + 471.1.
(5)-N-(l-(4-(ALLYLOXY)PHENYL)-3-OXOPROPAN-2-YL)-3-METHYL-l-( PYRIDIN-2- -lH-PYRAZOLE-5-CARBOXAMIDE (93)
[0734] Compound 93A (1 g, 1.0 eq), Ν,Ο-dimethylhydroxylamine (607 mg, 2 eq) and HBTU (1.36 g, 1.15 eq) were combined in 10 mL DMF, the mixture was stirred at room temperature for 5 mins, and then TEA (1.3 mL, 3.0 eq) was added. The resulting mixture was stirred at room temperature for lh. The mixture was diluted with 100 mL ethyl acetate and 20 mL Hexane, washed with 0.25N HC1, water, saturated aqueous NaHC0 3 , and brine and concentrated in vacuo to afford intermediate compound 93B (1 g, yield 88%) as white solid.
[0735] To a solution of compound 93B (1 g, 1.0 eq) in 6 mLdry DCM was added 3 mL of 4M HC1 in Dioxane. Resulting mixture was stirred at room temperature for 2 hrs. DCM and Dioxane were removed under vacuo, residue was diluted with EtOAc, washed with saturated aqueous NaHC0 3 and brine and concentrated in vacuo to afford intermediate compound 93C (650mg, yield 90%) as white solid.
[0736] Compound 93C (125 mg, 1.0 eq), compound 12F (115 mg, 1.2 eq) and HBTU (226 mg, 1.25 eq) were combined in 5 mL DMF, the mixture was stirred at room temperature for 5 mins, and then DIEA (0.23 mL, 3.0 eq) was added. The resulting mixture was stirred at room temperature for 30 mins. The mixture was diluted with 50 mL ethyl acetate and 20 mL Hexane, washed with water, saturated aqueous NaHC0 3 and brine and concentrated in vacuo to afford intermediate compound 93D (180 mg, yield 85%). [0737] Compound 6 (90 mg, 1.0 eq) was dissolved in 8 mL dry THF, cooled to -50 °C under N 2 . A solution of IN LAH in THF (0.22 mL, 1.1 eq) was added dropwise at -50 °C. The resulting mixture was stirred at -30 to - 10 °C for 2 hrs. The reaction was quenched with saturated aqueous NaHC0 3 at -20 °C, and then extracted with 3 x 15 mL acetate. The combined organic phase was dried over Na 2 S0 4 . The crude mixture was purified on silica gel column to provide compound 93 (40 mg, 51%).
[0738] To a solution of benzaldehyde (10.00 g, 94.23 mmol) and malononitrile (6.54 g, 98.94 mmol) in EtOH (75.00 mL) was added catalytic piperidine (80.24 mg, 942.30 umol). Then the reaction was stirred at 90°C for 2h. Yellow solid was precipitated out when the reaction mixture was cooled to room temperature, the mixture was filtered, the desired yellow solid was washed with EtOH (20 mL) and dried in vacuo to give intermediate compound 96A (23.00 g, 79.2% yield) as yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 7.91 (d, 7 = 7.7 Hz, 2H), 7.79 (s, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.50 (m, 2H).
[0739] To a mixture of compound 96A (17.50 g, 113.51 mmol) and chlorosulfanyl thiohypochlorite (70.00 g, 518.36 mmol, 41.42 mL) was added pyridine (900.00 mg, 11.38 mmol). Then the reaction was stirred at 140°C for 16h. The reaction mixture was cooled to room temperature and quenched with ice/H 2 0 (200 mL) and EtOAc (500 mL), yellow solid was was precipitate out, filtered and the filtrate was extracted with EtOAc(100 mL x 2), the combined organic was washed with brine (100 mL), dried over Na 2 S0 4 , filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent of 0 ~ 10% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give compound 96B (21.00 g, 70.4% yield) as light yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ 7.77 (br d, 7=7.1 Hz, 2H), 7.65 - 7.53 (m, 3H). [0740] To a mixture of compound 96B (2.00 g, 9.06 mmol) in dioxane (150.00 mL) was added AlMe 3 (2M, 20.00 mL) and Pd(PPh 3 ) 4 (1.05 g, 906.00 umol) under N 2 , Then the reaction was stirred at 110 °C for 3h. The reaction mixture was cooled to room temperature and quenched with ice/H 2 O(100 mL) and EtOAc(150 mL), yellow solid was precipitate out, filtered and the filtrate was extracted with EtOAc(60 mL x 2), the combined organic was washed with brine (70 mL), dried over Na 2 S0 4 , filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®;40 g SepaFlash® Silica Flash Column, eluent of 0 ~ 10% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to give compound 96C (700.00 mg, 16.59% yield, 43% purity) as light yellow solid. 1 H NMR (400MHz, CHLOROFORM-d) δ 7.79 - 7.75 (m, 2H), 7.56 - 7.51 (m, 3H), 2.67 (s, 3H). MS (ESI) m/z (M+H) + 200.9.
[0741] To compound 96C (490.00 mg, 2.45 mmol) was added H 2 S0 4 (9.20 g, 93.81 mmol, 5.00 mL), and the reaction was stirred at 135 °C for 1.5h. Then the reaction was cooled to 0 °C and a solution of NaN0 2 (339.79 mg, 4.92 mmol) in H 2 0 (2.00 mL) was added to the above mixture and the reaction mixture was stirred at 70 °C for lh. The reaction mixture was cooled to room temperature and poured into ice/H 2 O(40 mL) and EtOAc(40 mL), extracted with EtOAc(50 mL x 2), the combined organic was extracted with 0.1N NaOH (40 mL x 2), the desired basic water phase was then added IN HC1 to pH<4, then extracted with EtOAc(40 mL x 3) and washed with brine (40 mL), dried over Na 2 S0 4 , filtered and the filtrate was concentrated in vacuo to give compound 96D (410.00 mg, 76.25% yield) as light yellow solid. 1 H NMR (400MHz, DMSO-i¾) δ 7.49 (s, 5H), 2.57 (s, 3H). MS (ESI) m/z (M+H) + 219.9.
[0742] Compound 96 (35 mg, yield: 65.86%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 96D. Compound 96: 1 H NMR (400MHz, CD 3 CN) δ 7.48 - 7.33 (m, 5H), 7.29 - 7.17 (m, 3H), 7.15 - 7.06 (m, 3H), 7.01 (br s, 1H), 6.26 (br s, 1H), 5.56 (ddd, J=4.4, 7.5, 9.5 Hz, 1H), 3.23 (dd, J=4.3, 14.2 Hz, 1H), 2.77 (dd, J=9.5, 14.3 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 394.1. EXAMPLE 56
(5)-N-(4-AMINO-l-(3,5-DIMETHYLPHENYL)-3,4-DIOXOBUTAN-2-YL)-3 -METHYL-5- -4- C ARB OX AMIDE (97)
[0743] A mixture of compound 97A (1.0 g, 3.41 mmol), compound N,0- dimethylhydroxylamine (400 mg, 4.09 mmol, HC1) , HOBt (460 mg, 3.41 mmol) and NMM (1.03 g, 10.23 mmol, 1.12 mL) in CHC1 3 (20 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (980 mg, 5.12 mmol) was added in portions. The mixture was stirred at 25 °C for 20 h under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (20 mL), and then diluted with DCM (10 mL). The combined organic layers were washed with IN HC1 (15 mL x 2), saturated aqueous NaHC0 3 (15 mL x 2) and brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give the compound 97B (1.13 g, yield: 98.5%) was obtained as a white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 7.08 (br d, = 8.2 Hz, 1H), 6.82 (s, 3H), 4.55 (br s, 1H), 3.71 (br s, 3H), 3.09 (s, 3H), 2.82 - 2.72 (m, 1H), 2.68 - 2.58 (m, 1H), 2.22 (s, 6H), 1.32 (s, 9H).
[0744] To a solution of LAH (255 mg, 6.72 mmol) in THF (10 mL) was degassed and purged with N 2 for 3 times at 0 °C , and the mixture of compound 97B (1.13 g, 3.36 mmol) in THF (20 mL) was added dropwise, and then the mixture was stirred at 0 °C for 2 h under N 2 atmosphere. The reaction mixture was quenched by addition EtOAc (10 mL), then added IN HCl (50 mL), and then diluted with EtOAc (20 mL), dried over Na 2 S0 4 , and stirred for 30 min, then filtered to give the organic layers. The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 97C (860 mg, yield: 92.3%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 7.24 (br d, J = 7.7 Hz, 1H), 6.85 - 6.73 (m, 3H), 4.08 - 3.94 (m, 1H), 3.04 - 2.91 (m, 1H), 2.70 - 2.57 (m, 1H), 2.20 (s, 6H), 1.39 - 1.19 (m, 9H).
[0745] To a solution of compound 97C (860 mg, 3.10 mmol) in DCM (10 mL) was added compound 2-hydroxy-2-methylpropanenitrile (530 mg, 6.20 mmol, 570 μί) and Et 3 N (470 mg, 4.65 mmol, 650 μί). The mixture was stirred at 25 °C for 22 h. The reaction mixture was quenched by addition IN HCl (20 mL), and then diluted with H 2 0 (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 97D (930.00 mg, yield: 98.6%) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) S 7.19 - 6.99 (m, 1H), 6.91 - 6.78 (m, 3H), 6.77 - 6.51 (m, 1H), 4.66 - 4.34 (m, 1H), 3.84 (br s, 1H), 2.99 - 2.81 (m, 1H), 2.75 - 2.60 (m, 1H), 2.27 (br s, 6H), 1.40 - 1.20 (m, 9H).
[0746] To a solution of compound 97D (930 mg, 3.63 mmol) and K 2 C0 3 (850 mg, 6.11 mmol) in DMSO (10 mL) was added H 2 0 2 (3.46 g, 30.55 mmol, 2.94 mL, purity: 30%). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H 2 0 (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was stirred in DCM (3 mL) and PE (25 mL) for 30 min and filtered to give the compound 5 (970 mg, yield: 98.32%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.42 - 7.08 (m, 1H), 6.86 - 6.45 (m, 3H), 6.21 - 5.49 (m, 1H), 4.06 - 3.82 (m, 1H), 3.31 (s, 1H), 2.72 - 2.52 (m, 2H), 2.26 - 2.13 (m, 6H), 1.40 - 1.18 (m, 9H).
[0747] To a solution of compound 97E (970 mg, 3.01 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 5 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with PE (20 mL), filtered and concentrated under reduced pressure to give the compound 97F (370 mg, yield: 43.7%, HCl) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.09 - 7.89 (m, 3H), 7.58 (br s, 2H), 6.96 (br s, 2H), 6.89 (s, 1H), 4.26 (br s, 1H), 3.89 (br s, 1H), 3.69 - 3.57 (m, 1H), 2.91 - 2.73 (m, 2H), 2.30 (br s, 6H). MS (ESI) m/z (M+H) + 223.1.
[0748] A mixture of compound 97F (310 mg, 1.18 mmol, HCl), compound 6A (200 mg, 984.30 umol), HOBT (133 mg, 984.30 umol) and DIEA (520 uL, 2.95 mmol) in DCM (15 mL) was added EDCI (285 mg, 1.48 mmol), and then the mixture was stirred at 25°C for 18 h. The reaction mixture was washed with H 2 0 (20 mL x 2). The combined organic layers were washed with HCl (IN, 30 mL), saturated aqueous NaHC0 3 (30mL) and brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was stirred in Petroleum Ether (5 mL) and DCM (1 mL) for 30 min and filtered to give the compound 97G (270 mg, yield: 61.9%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.59 - 8.24 (m, 1H), 7.64 - 7.51 (m, 2H), 7.49 - 7.28 (m, 5H), 6.89 - 6.77 (m, 3H), 5.98 - 5.63 (m, 1H), 4.61 - 4.49 (m, 1H), 4.11 - 3.86 (m, 1H), 2.86 - 2.59 (m, 2H), 2.21 - 2.03 (m, 9H). MS (ESI) m/z (M+H) + 408.1.
[0749] To a solution of compound 97G (100 mg, 245.42 umol) in DCM (10 mL) was added DMP (320 mg, 736.26 umol) at 0 °C. The mixture was stirred at 25°C for 7 h. The reaction mixture was quenched by addition saturated aqueous Na 2 S 2 0 3 (15 mL) and saturated aqueous NaHC0 3 (15mL), the mixture was stirred for 0.2 h, and then diluted with DCM (10 mL) and extracted with H 2 0 (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was stirred in Petroleum Ether (15 mL) and EtOAc (1 mL) for 30 min and filtered to give the compound 97 (60 mg, yield: 60.3%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.01 (br d, 7 = 7.5 Hz, 1H), 8.18 (br s, 1H), 7.90 (br s, 1H), 7.64 (br d, 7=7.3 Hz, 2H), 7.53 - 7.46 (m, 1H), 7.45 - 7.38 (m, 2H), 6.92 - 6.81 (m, 3H), 5.40 (br t, 7 = 7.3 Hz, 1H), 3.15 (br d, 7=10.6 Hz, 1H), 2.72 - 2.58 (m, 1H), 2.18 (s, 6H), 2.11 (s, 3H). MS (ESI) m/z (M+H) + 406.1. EXAMPLE 57
[0750] To a solution of compound 98A (1.0 g, 2.99 mmol) and N- methoxymethanamine (321 mg, 3.29 mmol, HCl) in CHC1 3 (30 mL) was added HOBt (404 mg, 2.99 mmol,) and EDCI (803 mg, 4.19 mmol). Then NMM (1.3 mL, 11.96 mmol) was added into the reaction mixture. After addition, the reaction mixture was stirred at 28 °C for 14 h. The reaction mixture was concentrated in vacuum and the residue was dissolved into 80 mL of EtOAc. The mixture was washed with IN HCl (30 mL x 2) and saturated aqueous NaHC0 3 (30 mL x 2), then brine (30 mL). The mixture was dried over Na 2 S0 4 and concentrated in vacuum to afford compound 98B (1.1 g, yield 82.9%) as white solid. 1H NMR (400MHz, DMSO-i¾) δ 7.44 (s, 1H), 7.34 - 7.19 (m, 3H), 4.55 (br s, 1H), 3.71 (br s, 3H), 3.17 - 3.00 (m, 3H), 2.90 - 2.80 (m, 1H), 2.76 - 2.67 (m, 1H), 1.29 (s, 8H). MS (ESI) m/z (M-56) + 320.9.
[0751] To a solution of LiAlH 4 (122 mg, 3.21 mmol) in THF (10 mL) was added a solution of compound 98B (1.1 g, 2.92 mmol) in THF (20 mL) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for lh. 2 mL of EtOAc was added into the reaction mixture at 0 °C and the mixture was stirred for 10 min. Then 2 mL of IN HCl was added into the reaction mixture slowly. After addition, the mixture was diluted with 80 mL of EtOAc and the mixture was washed with 1 N HCl (30 mL x 2), brine (30 mL). Then the mixture was dried over Na 2 S0 4 and concentrated in vacuum to afford compound 98C (800 mg, yield 80.9%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) S 9.52 (s, 1H), 7.53 - 7.17 (m, 4H), 4.20 - 4.08(m, 1H), 3.19 -3.08 (m, 1H), 2.72 - 2.63 (m, 1H), 1.37 - 1.27 (m, 9H).
[0752] To a solution of compound 98C (800 mg, 2.51 mmol) in MeOH (10 mL) was added dropwise a solution of NaHS0 3 (261 mg, 2.51 mmol) in H 2 0 (15 mL) at 0-5 °C. After that, the reaction mixture was stirred at 25 °C for 5h. NaCN (129 mg, 2.64 mmol) in H 2 0 (20 mL) was added into the reaction mixture followed by EtOAc (40 mL). After that, the reaction mixture was stirred at 25 °C for 14h. The organic layer was separated and washed with brine (30 mL), then dried over Na 2 S0 4 .The mixture was concentrated to afford compound 98D (800 mg, yield 92.33%) as light yellow gum. 1H NMR (400MHz, DMSO-d 6 ) δ 7.46 - 7.22 (m, 3H), 7.16 - 7.02 (m, 1H), 6.89 - 6.70 (m, 1H), 4.65 - 4.30 (m, 1H), 3.95 - 3.76 (m, 1H), 3.07 - 2.87 (m, 1H), 2.76 -2.55 (m, 1H), 1.32 - 1.20 (m, 8H).
[0753] To a solution of compound 98D (800 mg, 2.32 mmol) and K 2 C0 3 (641 mg, 4.64 mmol) in DMSO (8 mL) was added H 2 0 2 (2 mL, 22.25 mmol, 30% purity) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for lh. The reaction mixture was diluted with ice water (20 mL) and 50 mL of saturated aqueous Na 2 S0 3 . The mixture was extracted with EtOAc (50 mL x 3) and the combined extracts were washed with saturated aqueous Na 2 S0 3 (50 mL x 2). The organic layer was dried over Na 2 S0 4 and concentrated to afford crude compound. The crude compound was diluted with MTBE (5 mL) and filtered to afford compound 98E (800 mg, yield 94.9%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.48 - 7.12 (m, 5H), 6.73 - 6.20 (m, 1H), 5.86 - 5.63 (m, 1H), 4.04 - 3.71 (m, 2H), 2.86 - 2.54 (m, 1H), 1.34 - 1.19 (m, 9H). MS (ESI) m/z (M +23) + 384.9.
[0754] To a solution of compound 98E (800 mg, 2.20 mmol) in EtOAc (10 mL) was added HCl/EtOAc (4M, 55 mL). After addition, the reaction mixture was stirred at 26 °C for lh. 20 mL of Petroleum ether was added into the reaction mixture and the mixture was filtered to afford compound 98F (400 mg, yield 58.87%, HCl) as white solid. 1H NMR (400MHz, DMSO- d 6 ) δ 8.35 (br s, 1H), 8.14 (br s, 1H), 7.62 - 7.41 (m, 3H), 7.33 (d, 7=1.8 Hz, 1H), 6.90 - 6.50 (m, 1H), 4.28 (br s, 1H), 3.94 - 3.84 (m, 1H), 3.77 - 3.56 (m, 1H), 3.03 - 2.80 (m, 2H).
[0755] To a solution of compound 7 (100 mg, 492.15 umol) and compound 98F (162 mg, 541.37 umol, HCl) in DMF (10 mL) was added HOBT (67 mg, 492.15 umol) and DIEA (340 uL, 1.97 mmol), then EDCI (133 mg, 689.01 umol) was added. After addition, the reaction mixture was stirred at 26 °C for 14h. The mixture was diluted with 30 mL of EtOAc. The mixture was washed with IN HC1 (15 mL x 2) and saturated aqueous NaHC0 3 (15 mL x 3), then brine (20 mL). The residue was dried over Na 2 S0 4 and concentrated in vacuum. The residue was diluted with 4 mL of EtOAc and filtered to afford compound 98G (110 mg, yield 45.87%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.65 - 8.26 (m, 1H), 7.60 - 7.30 (m, 9H), 7.28 - 7.17 (m, 1H), 6.04 - 5.65 (m, 1H), 4.73 - 4.56 (m, 1H), 4.11 - 4.06 (m, 0.5H), 4.01 - 3.95 (m, 0.5H), 3.01 - 2.70 (m, 2H), 2.18 - 2.09 (m, 3H). MS (ESI) m/z (M +H) + 448.1.
[0756] To a solution of compound 98G (110 mg, 245.37 umol) in DCM (30 mL) and DMSO (4 mL) was added DMP (416 mg, 981.48 umol). After addition, the reaction mixture was stirred at 26 °C for 2h. 10 mL of saturated aqueous Na 2 S 2 0 3 and 10 mL of saturated aqueous NaHC0 3 was added into the reaction mixture, and the mixture was stirred for 20 min. Then the mixture was separated, the organic layer was washed with 10 mL of saturated aqueous Na 2 S 2 0 3 and 10 mL of saturated aqueous NaHC0 3 , then water (20 mL) and brine (20 mL). The mixture was dried over Na 2 S0 4 and concentrated in vacuum to afford compound 98 (30 mg, yield 24.66%) as light yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.08 (d, 7=7.5 Hz, 1H), 8.21 (s, 1H), 7.94 (s, lH), 7.68 - 7.58 (m, 2H), 7.54 - 7.42 (m, 4H), 7.34 (d, 7=1.8 Hz, 2H), 5.45 - 5.33 (m, 1H), 3.28 - 3.19 (m, 1H), 2.83 - 2.73 (m, 1H), 2.12 (s, 3H). MS (ESI) m/z (M +H) + 446.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(6-METHOXYPYR IDIN-2- -3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (99)
[0757] A mixture of compound 2-chloro-6-methoxypyridine (5.0 g, 34.83 mmol) in
ΝΗ 2 ΝΗ 2 Ή 2 Ο (17.44 g, 348.30 mmol, 16.93 mL) was stirred at 120 °C for 16h. The reaction mixture was concentrated under reduced pressure to give a residue .then diluted with ¾0 (30 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O 2 , Petroleum ether/Ethyl acetate = 5:1 to 1: 1) to give compound 99B (1.06 g, 21.87% yield) as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.41 (t, J=7.8 Hz, IH), 6.24 - 6.08 (m, 2H), 5.73 (br s, IH), 3.86 (s, 3H), 3.83 - 2.75 (m, 2H). MS (ESI) m/z (M+H) + 140.1.
[0758] A mixture of compound 99B (1.00 g, 7.19 mmol) and ethyl 2- (methoxyimino)-4-oxopentanoate (1.35 g, 7.19 mmol) in HOAc (20.00 mL) was stirred at 120 °C for 16h. The reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with H 2 0 (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1:0 to 5: 1) and further purified by preparatory-HPLC (TFA condition) to give compound 99C (487.00 mg, 25.87% yield) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.70 (t, =7.9 Hz, IH), 7.21 (d, =7.5 Hz, IH), 6.71 (d, =8.2 Hz, IH), 6.66 (s, IH), 4.27 (q, =7.2 Hz, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.25 (t, =7.2 Hz, 3H). MS (ESI) m/z (M+H) + 261.9.
[0759] To a solution of compound 99C (487.00 mg, 1.99 mmol) in THF (15.00 mL) was added LiOH H 2 0 (417.50 mg, 9.95 mmol) in H 2 0 (5.00 mL). The mixture was stirred at 28 °C for 16h. The reaction mixture was diluted with H 2 0 (10 mL) and extracted with MTBE (15 mL x 2), the water phase was added IN HC1 to pH = 3-4, extracted with EA (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 99D (396 mg, 91.61% yield) as a white solid. Compound 99D: 1H NMR (400MHz, DMSO- 6 ) δ 7.86 (t, =7.8 Hz, IH), 7.26 (d, =7.5 Hz, IH), 6.80 (d, =8.2 Hz, IH), 6.67 (s, IH), 3.80 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z (M+H) + 234.1.
[0760] Compound 99 (10.00 mg, 13.78% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 99D. Compound 99: 1H NMR (400MHz, CDC1 3 ) δ 7.68 (br t, =7.9 Hz, IH), 7.26 - 7.18 (m, 4H), 7.12 - 7.01 (m, 3H), 6.73 (br s, IH), 6.68 - 6.60 (m, IH), 6.65 (br d, =8.2 Hz, IH), 6.50 (s, IH), 5.73 - 5.64 (m, IH), 5.50 (br s, IH), 3.67 (s, 3H), 3.45 - 3.35 (m, IH), 3.25 - 3.11 (m, IH), 2.33 (s, 3H). MS (ESI) m/z (M+H) + 408.1. EXAMPLE 59
COMPOUNDS 101, 493
(5)-N-(4-((3,4-DICHLOROBENZYL)AMINO)-3,4-DIOXO-l-PHENYLBUTAN -2-YL)-3- ME -5-PHENYLISOXAZOLE-4-CARBOXAMIDE (101)
[0761] To a solution of compound 23A (20.00 g, 98.43 mmol) in THF (300 mL) was added l-hydroxypyrrolidine-2,5-dione (12.46 g, 108.27 mmol) and EDCI (22.64 g, 118.12 mmol) with DCM (200 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and diluted with ethyl acetate (200 mL). Then the mixture was washed with HCl (1M, 200 mL), saturated aqueous NaHC0 3 (200 mL), dried over Na2S04 and concentrated. Compound 101A (28.00 g, crude) was obtained as a yellow oil. 1H NMR (400MHz, DMSO-de) δ 7.94 - 7.88 (m, 2H), 7.69 - 7.63 (m, 1H), 7.62 - 7.56 (m, 2H), 2.87 (br s, 4H), 2.50 - 2.48 (m, 3H).
[0762] To a solution of compound 101A (28.00 g, 93.25 mmol) in DMF (200 mL) was added (2S)-2-amino-3-phenyl-propan- l-ol (15.51 g, 102.57 mmol). The mixture was stirred at 25 °C for 12 hour. The mixture was diluted with H 2 0 (1000 mL), extracted with ethyl acetate (1000 mL), the organic layer was washed with HCl (aqueous 1000 mL), NaHC0 3 (aqueous 1000 mL), dried over Na 2 S0 4 and concentrated. Compound 3 (20.00 g, yield 63.8%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.45 (br d, = 8.8 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.53 - 7.40 (m, 3H), 7.32 - 7.18 (m, 5H), 4.97 - 4.92 (m, 1H), 4.33 - 4.23 (m, 1H), 3.54 - 3.41 (m, 2H), 3.01 - 2.97 (m, 1H), 2.69 - 2.57 (m, 1H), 2.06 (s, 3H).
[0763] To a solution of compound 101B (3.00 g, 8.92 mmol) in DCM (100 mL) was added DMP (5.67 g, 13.38 mmol). The mixture was stirred at 25 °C for 3 hour. The mixture quenched with 10% Na 2 S203 (aqueous): saturated NaHC0 3 (aqueous) (1: 1, 200 mL), extracted with DCM (200 mL) and washed with brine (200 mL x 3). The combined organic layers were dried over Na 2 S0 4 and concentrated. Compound 101C (2.70 g, yield 90.5%) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.66 (s, 1H), 8.91 (d, = 8.4 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.53 - 7.47 (m, 1H), 7.46 - 7.40 (m, 2H), 7.29 - 7.19 (m, 5H), 4.79 - 4.72 (m, 1H), 3.37 - 3.32 (m, 1H), 2.81 - 2.72 (m, 1H), 2.09 (s, 3H).
[0764] To a solution of compound 101C (500.0 mg, 1.50 mmol) in DCM (20 mL) was added TMSCN (223.2 mg, 2.25 mmol, 280 uL) and TEA (15.2 mg, 150.00 umol, 20 uL). The mixture was stirred at 0 °C for 3 hours. The mixture was concentrated, diluted with ethyl acetate (20 mL), washed with water (20 mL), brine (20 mL), dried over Na 2 S0 4 and concentrated to obtain compound 101D (600.0 mg, crude) as colorless oil.
[0765] To a solution of compound 101D (600.0 mg, 1.41 mmol) in THF (10 mL) was added HCl (10 mL). The mixture was stirred at 60 °C for 12 hours. The mixture was diluted with H 2 0 (200 mL), extracted with ethyl acetate (100 mL), the organic layer was washed with NaHC0 3 (aqueous 100 mL), the water phase was added HCl (1M) until pH ~ 1, then extracted with ethyl acetate (100 mL), the organic layer was washed with brine (100 mL), dried over Na 2 S0 4 and concentrated. Compound 101E (240.0 mg, crude) was obtained as a colorless oil and used in next step directly.
[0766] To a solution of compound 101E (200.0 mg, 526 umol) in THF (10.00 mL) was added (3,4-dichlorophenyl)methanamine (92.6 mg, 525.78 umol, 70 uL), DIEA (203.85 mg, 1.58 mmol, 275.48 uL), HOBt (71.04 mg, 525.78 umol) and EDCI (120.95 mg, 630.93 umol). The mixture was stirred at 25 °C for 4 hours. The mixture was concentrated and diluted with ethyl acetate (50 mL), washed with HCl (1M, 50 mL), saturated NaHC0 3 (aqueous 50 mL), brine (50 mL x 3), dried over Na 2 S0 4 and concentrated. The mixture was triturated with CH 3 CN (5 mL) and filtered. Compound 101F (70.0 mg, yield 24.7%) obtained as a white solid. 1H NMR (400MHz, DMSO-de) δ 8.63 - 8.53 (m, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.58 - 7.10 (m, 13H), 6.20 - 5.94 (m, 1H), 4.68 - 4.57 (m, 1H), 4.32 - 4.16 (m, 2H), 4.08 - 3.99 (m, 1H), 2.97 - 2.67 (m, 2H), 2.07 - 1.96 (m, 1H), 2.07 - 1.96 (m, 2H).
[0767] To a solution of compound 101F (60.0 mg, 111.44 umol,) in DCM (10 mL) and DMSO (1.00 mL) was added DMP (141.8 mg, 334.32 umol). The mixture was stirred at 25 °C for 3 hours. The mixture quenched with 10% Na 2 S203 (aqueous): saturated NaHC0 3 (aqueous) (1: 1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 S0 4 and concentrated. Compound 101 (33.2 mg, yield 55.5%) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.52 - 9.43 (m, 1H), 9.12 (d, = 7.6 Hz, 1H), 7.69 - 7.38 (m, 7H), 7.35 - 7.20 (m, 6H), 5.53 - 5.42 (m, 1H), 4.40
- 4.32 (m, 2H), 3.31 - 3.19 (m, 1H), 2.93 - 2.71 (m, 1H), 2.12 - 2.00 (m, 3H). MS (ESI) m/z (M+H) + 536.1.
(5)-N-(4-(((lH-BENZO[rf]IMIDAZOL-5-YL)METHYL)AMINO)-3,4-DIOX O-l- PHENYLBUTAN-2-YL)-3-METHYL-5-PHENYLISOXAZOLE-4-CARBOXAMIDE (493)
[0768] Compound 493 (20 mg, 23.4% yield, yellow solid) was prepared as in compound 101 from the corresponding intermediate carboxylic acid, compound 101E and (l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[<i]imidazol-5-yl) methanamine followed by removal of the 2-(trimethylsilyl)ethoxy)methyl group to obtain compound 493. Compound 493: 1H NMR (400MHz, DMSO-i¾) δ 8.07 (s, 1H), 7.67 - 7.59 (m, 3H), 7.56 (br s, 1H), 7.52 - 7.38 (m, 4H), 7.30 (br s, 1H), 7.25 - 7.14 (m, 4H), 6.89 (br d, = 6.2 Hz, 2H), 6.12 (br d, = 6.8 Hz, 1H), 5.72
- 5.63 (m, 1H), 4.62 (br d, = 5.5 Hz, 2H), 3.37 (br dd, = 4.7, 14.0 Hz, 1H), 2.99 (br dd, = 7.9, 14.3 Hz, 1H), 2.33 (s, 3H). MS (ESI) m/z (M+H) + 378.1.
(5 l-(lH-INDAZOL-3-YL)-N-(l-OXO-3-PHENYLPROPAN-2-YL)-lH-IMIDAZO LE-5- ARBOXAMIDE (102)
[0769] To a solution of lH-indazol-3-amine (8.7 g, 65.3 mmol) in MeOH (90 mL) was added ethyl 2-oxoacetate (20 g, 98.01 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated to give crude product 102A (15 g, crude) as brown solid, which was used for the next step without purification.
[0770] To a solution of 102A (15 g, 69.1 mmol) in EtOH (400 mL) was added K 2 C0 3 (14.5 g, 104 mmol) and TosMIC (11.6 g 59.4 mmol). The mixture was stirred at 90 °C for 0.5 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1 :0 to 1 : 1) to give compound 102B (2.9 g, yield: 16.4%) as yellow solid. 1H NMR (400MHz, CDCI 3 ) δ 11.04 (br s, 1H), 7.98 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.48 - 7.41 (m, 3H), 7.25 - 7.19 (m, 1H), 4.24 - 4.14 (m, 2H), 1.14 (t, 7 = 7.1 Hz, 3H).
[0771] To a solution of 102B (2.9 g, 11.3 mmol) in THF (40 mL) and H 2 0 (8 mL) was added NaOH (905 mg, 22.6 mmol). The mixture was stirred at 25 °C for 10 hours. The mixture was concentrated under reduced pressure to remove the organic solvent, and extracted with EtOAc (20 mL). The aqueous layer was acidified with 1M HC1 to pH ~ 5 and then extracted with EtOAc (30 mL x 3). The combined organic layer was washed with H 2 0 (40 mL), brine (40 mL), dried over Na 2 S0 4 , filtered and concentrated to give 102C (1.5 g, yield: 58.1%) as yellow solid. 1H NMR (400MHz, OMSO-d 6 ) δ 13.35 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.20 - 7.15 (m, 1H). MS (ESI) m/z (M+H) + 228.9.
[0772] Compound 102 (20 mg, yield 52.9%, pale yellow solid) was prepared as in Example 6 from the corresponding intermediate compounds 102C and 21G ((5)-2-amino-3- phenylpropan- l-ol). Compound 102: 1H NMR (DMSO-i¾ , 400 MHz) δ 13.22 (s, 1H), 9.48 (s, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.72 (s, 1H), 7.59 - 7.51 (m, 1H), 7.42 - 7.40 (m, 1H), 7.31 - 7.24 (m, 2H), 7.24 - 7.18 (m, 4H), 7.12 - 7.06 (m, 1H), 7.06 - 7.06 (m, 1H), 4.34 - 4.23 (m, 1H), 3.19- 3.15 (m, 1H), 2.77 - 2.74(m, 1H). MS (ESI) m/z (M+H) + 360.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3'- METHYL- [l,l'-B -3-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (105)
[0773] To a mixture of compound 103A (150 mg, 0.33 mmol) and m-tolylboronic acid (89 mg, 0.66 mmol) in THF (50 mL) was added H 2 0 (10 mL), Na 2 C0 3 (70 mg, 0.66 mmol) and Pd(PPh 3 )4 (38 mg, 0.033 mmol) in one portion at 25 °C under N 2 . The mixture was stirred at 80 °C for 12h. The reaction mixture was added H 2 0 (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with saturated aqueous NaHC0 3 (150 mL x 3), brine (150 mL x 3), dried over Na 2 S0 4 and concentrated. The crude product was treated with i- propyl ether/CH 3 CN (10/1, 10 mL). The solid was collected and dried in vacuo to afford compound 2A (72.7 mg, yield 42.70%) as gray solid. Compound 105A: 1H NMR (DMSO- 6, 400 MHz) δ 8.51 - 8.10 (m, 1H), 7.60 - 7.52 (m, 2H), 7.47 - 7.38 (m, 2H), 7.36 - 7.28 (m, 3H), 7.26 - 7.12 (m, 7H), 7.03 - 6.93 (m, 1H), 6.57 (d, J = 3.3 Hz, 1H), 5.93 - 5.73 (m, 1H), 4.49 - 4.29 (m, 1H), 4.04 - 3.86 (m, 1H), 2.90 - 2.81 (m, 1H), 2.81 - 2.72 (m, 1H), 2.35 (s, 3H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 469.2.
[0774] To a mixture of compound 105A (65 mg, 0.14 mmol) in DCM (10 mL) and DMSO (1 mL) was added DMP (177 mg, 0.42 mmol) in one portion at 0 °C. The mixture was stirred at 0 °C for 10 min, then temperature to 25 °C and stirred for 2 hours. The reaction was quenched by 20 mL of 10 % Na 2 S 2 0 3 aquoeus solution and 20 mL of saturated aqueous NaHC0 3 solution and then extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (40 mL x 3), dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuo. The residue was purified by preparatory-HPLC (basic condition) to afford compound 105 (35.0 mg, yield 53.6%) as white solid. 1H NMR (DMSO-d 6, 400 MHz) δ 9.08 (d, = 7.7 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.84 (br s, 1H), 7.60 - 7.52 (m, 2H), 7.45 - 7.37 (m, 3H), 7.36 -7.30 (m, 1H), 7.28 - 7.25 (m, 3H), 7.23 - 7.16 (m, 3H), 7.12 - 7.06 (m, 1H), 6.60 (br s, 1H), 5.29 (br s, 1H), 3.22 - 3.14 (m, 1H), 2.86 - 2.76 (m, 1H), 2.35 (s, 3H), 2.28 - 2.22 (m, 3H). MS (ESI) m/z (M+H) + 467.2.
COMPOUNDS 103, 106, 216-218, 214
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4 , -FLUORO-[l,l'- BIPHENYL -3-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (103)
[0775] Compound 103B (110 mg, yield 70.98%, off-white solid) was prepared as in Example 49 from the corresponding intermediate compounds 103A and (4-fluorophenyl)boronic acid. Compound 103B: 1H NMR (DMSO-d 6, 400 MHz) δ 8.45 (d, = 9.0 Hz, 0.5H), 8.15 (d, = 9.0 Hz, 0.5H), 7.68 - 7.52 (m, 4H), 7.40 - 7.13 (m, 10H), 7.02 (br d, = 8.4 Hz, 0.5H), 6.94 (br d, = 7.9 Hz, 0.5H), 6.59 (d, = 2.4 Hz, 1H), 5.93 - 5.74 (m, 1H), 4.49 - 4.32 (m, 1H), 4.02 - 3.88 (m, 1H), 2.95 - 2.66 (m, 2H), 2.26 - 2.19 (m, 3H).
[0776] Compound 103 (78 mg, yield 68.93%, pale yellow solid) was prepared as in Example 61 from the corresponding intermediate compounds 103B. Compound 103: 1H NMR (DMSO- e , 400 MHz) δ 9.09 (d, = 7.7 Hz, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.65 (dd, = 5.4, 8.7 Hz, 2H), 7.58 (br d, = 7.7 Hz, 1H), 7.52 (s, 1H), 7.41 (t, = 7.8 Hz, 1H), 7.32 - 7.25 (m, 6H), 7.23 - 7.19 (m, 1H), 7.11 (br d, =7.9 Hz, 1H), 6.60 (s, 1H), 5.35 - 5.25 (m, 1H), 3.18 (dd, = 3.5, 13.7 Hz, 1H), 2.81 (dd, = 10.4, 13.7 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 471.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3 , -FLUORO-[l,l'-
BIPHENYL]-3-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (106)
[0777] Compound 106 (18.7 mg, yield 46.2%, light yellow solid) was prepared as in Example 61 from the corresponding starting materials, compound 103A and (3- fluorophenyl)boronic acid. Compound 106: 1H NMR (DMSO-d 6, 400 MHz) δ 9.08 (br d, = 7.7 Hz, 1H), 8.05 (br s, 1H), 7.85 (br s, 1H), 7.69 - 7.62 (m, 1H), 7.60 - 7.56 (m, 1H), 7.52 - 7.43 (m, 3H), 7.43 - 7.37 (m, 1H), 7.33 - 7.24 (m, 4H), 7.24 - 7.15 (m, 2H), 7.13- 7.05 (m, 1H), 6.62 (s, 1H), 5.35 - 5.25 (m, 1H), 3.20 - 3.15 (m, 1H), 2.86 - 2.76 (m, 1H), 2.28 - 2.21 (m, 3H). (ESI) m/z (M+H) + 471.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3 , -FLUORO-[l,l'- BIPHEN -4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (216)
[0778] Compound 216 (26 mg, yield 16.7%, yellow solid) was prepared as in Example 62 from the corresponding starting materials, compound 83D and (3- fluorophenyl)boronic acid. Compound 216: 1H NMR (CDC1 3 400ΜΗζ) δ 7.59 (br d, J = 7.7 Hz, 2H), 7.47 - 7.35 (m, 4H), 7.33 - 7.27 (m, 4H), 7.05 (br d, J = 6.4 Hz, 3H), 6.75 (br s, 1H), 6.49 (s, 1H), 6.42 - 6.33 (m, 1H), 5.66 - 5.50 (m, 2H), 3.39 (br dd, J = 5.0, 13.8 Hz, 1H), 3.16 (br dd, / = 7.4, 14.0 Hz, 1H), 2.40 - 2.29 (m, 3H). MS (ESI) m/z (M+H) + 471.1.
[0779] Compound 217 was prepared as in Example 62 from the corresponding starting materials, compound 83D and (2-fluorophenyl)boronic acid. Compound 217 (13 mg, yield 14.49%, yellow solid): 1H NMR (CDC1 3 400ΜΗζ) δ 7.59 (d, = 7.3 Hz, 2H), 7.49 - 7.39 (m, 3H), 7.37 - 7.26 (m, 3H), 7.24 - 7.13 (m, 3H), 7.02 (br d, = 6.0 Hz, 2H), 6.72 (br s, 1H), 6.49 (s, 1H), 6.37 - 6.29 (m, 1H), 5.62 - 5.49 (m, 2H), 3.36 (dd, = 5.3, 14.1 Hz, 1H), 3.11 (dd, = 7.4, 14.0 Hz, 1H), 2.38 - 2.29 (m, 3H). MS (ESI) m/z (M+H) + 471.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3'- METHYL- [l,l'-BIPHENYL]-4-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (218)
[0780] Compound 218 was prepared as in Example 62 from the corresponding starting materials, compound 83D and m-tolylboronic acid. Compound 218 (yield 36.1%, yellow solid): 1H NMR (CDCl 3 400MHz) δ 9.16 (d, = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.60 (d, = 8.6 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.38 - 7.28 (m, 5H), 7.26 - 7.21 (m, 3H), 7.18 (br d, = 7.5 Hz, 1H), 6.54 (s, 1H), 5.28 - 5.18 (m, 1H), 3.20 (br dd, = 3.6, 13.8 Hz, 1H), 2.83 (dd, = 10.6, 13.7 Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H).
[0781] Compound 214 was prepared as in Example 62 from the corresponding starting materials, compound 103A and (2-fluorophenyl)boronic acid. Compound 214 (20 mg, yield 29.5%, white solid): 1H NMR (CDC1 3, 400 MHz) δ 7.62 - 7.55 (m, 2H), 7.52 - 7.43 (m, 2H), 7.41 - 7.30 (m, 2H), 7.26 - 7.22 (m, 3H), 7.21 - 7.13 (m, 2H), 7.03 - 6.94 (m, 2H), 6.65 (br s, 1H), 6.49 (s, 1H), 6.33 - 6.26 (m, 1H), 5.56 - 5.52 (m, 1H), 5.37 (br s, 1H), 3.38 - 3.31 (m, 1H), 3.17 - 3.09 (m, 1H), 2.36 - 2.30 (m, 3H). MS (ESI) m/z (M+H) + 471.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-PHENYLFURAN-2 -
[0782] To a solution of i-Pr 2 NH (3 mL , 18.71 mmol) in anhydrous THF ( 13 mL) was added n-BuLi (7 mL,18.71 mmol) dropwise at -78 °C and stirred at 0 °C for 30 min. Then a solution of 3-bromofuran (2.5 g, 17.01 mmol) in THF (13 mL) was added to the mixture drop wise at -78 °C and the mixture was stirred at -78 °C for 30 minutes. Anhydrous C0 2 was poured into the solution at -78 °C for 30 minutes. The reaction was quenched with H 2 0 (20 mL) and extracted with ethyl acetate (20 mL), then water phase was treated with HC1 until pH ~ 3. The precipitation was filtered and dried under reduced pressure. Compound 104A (1.8g, crude) was obtained as yellow solid. 1H NMR (DMSO-d 6 , 400MHz) S 7.96 (d, = 1.8 Hz, 1H), 6.89 (d, = 1.8 Hz, 1H).
[0783] Cs 2 C0 3 (2.13 g, 6.55 mmol) was added to a solution of compound 104A (500 mg, 2.62 mmol) in DMF (10 mL). Then Mel (652.43 uL, 10.48 mmol) was added to the mixture. The mixture was stirred at 25 °C for 13h. The mixture was diluted with ethyl acetate (35 mL) and H 2 0 (30 mL). The organic layer was separated and the aqueous layer was washed extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed brine (30 mL), dried over MgS04, filtered and concentrated. The residue was purified by Flash column chromatography (Petroleum Ether/Ethyl Acetate = 15/1). Compound 104B (250 mg, yield 46.54%) was obtained as white solid. 1H NMR (CDC1 3 , 400MHz) δ 7.50 (d, = 2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 3.94 - 3.92 (m, 3H)
[0784] To a solution of Compound 104B (221 mg, 1.08 mmol) in THF (4 mL) and H 2 0 (2 mL) was added phenylboronic acid (263 mg, 2.16 mmol) and Cs 2 C0 3 (553 mg, 1.70 mmol), followed by Pd(PPh 3 ) 4 (125 mg, 108.00 umol), then the mixture was heated to 80 °C and stirred for 12h. The reaction mixture was cooled to the room temperature and H 2 0 (6 mL) was added to quenched the reaction. The mixture was extracted with ethyl acetate (lOmL x 2). The combined organic layer was washed with H 2 0 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered, evaporated under reduced pressure. The residue was purified by FCC (PE/EA: 0 to 10/1). Compound 104C (180 mg, yield 82.42%) was obtained as yellow oil. 1H NMR (CDC1 3 , 400MHz) δ 7.61 - 7.55 (m, 3H), 7.45 - 7.35 (m, 3H), 6.64 (d, = 1.8 Hz, 1H), 3.86 (s, 3H)
[0785] To a solution Compound 104C (170 mg, 840.71 umol) in MeOH (5 mL) was added NaOH (2 M, 2 mL) dropwise, then the mixture was stirred at 25 °C for 2h. The reaction was diluted with H 2 0 (5 mL) and removed solvent under reduced pressure, then the mixture was extracted with MTBE (5 mL). The water phase was treated with HC1 (1 M) until pH ~ 3, then water phase was extracted with ethyl acetate (5 mL x 3). The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , evaporated under reduced pressure. Compound 104D (120 mg, yield 75.85%) was obtained as white solid which was used directly in next step. 1H NMR (DMSO-i¾ , 400MHz) δ Ί .90 (d, = 1.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.39 - 7.28 (m, 3H), 6.80 (d, / = 1.8 Hz, 1H) [0786] Compound 104 (35 mg, yield 44.0%, yellow solid) was prepared as in
Example 5 from the corresponding intermediate carboxylic acid, compound 104D. Compound 104: 1H NMR (DMSO-d 6, 400MHz) δ 8.56 (d, = 7.5 Hz, 1H), 8.07 (s, 1H), 7.88 (d, = 1.8 Hz, 1H), 7.81 (s, 1H), 7.61 - 7.54 (m, 2H), 7.36 - 7.29 (m, 3H), 7.29 - 7.25 (m, 4H), 7.21 - 7.17 (m, 1H), 6.90 - 6.83 (m, 1H), 5.39 - 5.29 (m, 1H), 3.21 - 3.12 (m, 1H), 3.01 - 2.92 (m, 1H). MS (ESI) m/z (M+H) + 363.1
COMPOUNDS 107, 243, 253, 265, 168, 459, 460, 475
(5)-N-(4-AMINO-l-(4-FLUOROPHENYL)-3,4-DIOXOBUTAN-2-YL)-2-MET HYL-4-
PHENYLOXAZOLE-5-CARBOXAMIDE (107)
(5)-N-(l-AMINO-l,2-DIOXOPENTAN-3-YL)-2-METHYL-4-PHENYLOXAZOL E-5-
(5)-N-(l-AMINO-5-METHYL-l,2-DIOXOHEXAN-3-YL)-2-METHYL-4- PHENYLOXAZOLE-5-CARBOXAMIDE (253)
(5)-N-(l-AMINO-l,2-DIOXOHEPTAN-3-YL)-2-METHYL-4-PHENYLOXAZOL E-5- ARBOXAMIDE (265)
[0787] Compounds 107, 243, 253 and 265 were prepared as in Example 5 from the corresponding starting materials, respectively— compound 107B and compound 58F, 47A, 253A or 62E.
[0788] Compound 107 (77.3 mg, 51.80% yield, white solid): 1H NMR (400 MHz, CDC1 3 ) S 8.12 - 8.05 (m, 2H), 7.46 - 7.36 (m, 3H), 7.12 - 7.05(m, 2H), 7.00 - 6.94 (m, 2H), 6.79 - 6.70 (m, 2H), 5.72 - 5.64 (m, 1H), 5.53 (br s,lH), 5.57 - 5.47 (m, 1H), 3.46 - 3.38 (m, 1H), 3.24
- 3.16 (m„ 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H) + 396.1.
[0789] Compound 243 (52.8 mg, 42.87% yield, yellow solid): 1H NMR (400 MHz, CDC1 3 ): S 8.13 (d, 7 = 6.8 Hz, 2H), 7.47 - 7.33 (m, 3H), 6.91 -6.81 (m, 1H), 6.75 (br s, 1H), 5.53
- 5.36 (m, 2H), 2.58 (s, 3H), 2.20 - 2.08 (m, 1H),1.88 - 1.76 (m, 1H), 0.99 (t, 7 = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 316.1.
[0790] Compound 253 (6.5 mg, 6.42% yield, white solid): 1H NMR (CDCI3, 400 MHz): δ 8.19 - 8.09 (m, 2H), 7.50 - 7.34 (m, 3H), 6.84 - 6.68 (m, 2H), 5.55 - 5.38 (m, 2H), 2.60 (s, 3H), 1.87 - 1.74 (m, 2H), 1.63 - 1.58 (m, 1H), 1.04 (d, 7 = 6.4 Hz, 3H), 0.98 (d, 7 = 6.4 Hz, 3H). MS (ESI) m/z (M+H) + 344.1.
[0791] Compound 265 (79.7 mg, 94.04% purity, white solid): 1H NMR (400MHz, DMSO-i¾) δ 8.73 (d, 7=6.8 Hz, 1H), 8.13 - 8.03 (m, 3H), 7.79 (s, 1H), 7.45 - 7.35 (m, 3H), 5.17 - 5.10 (m, 1H), 2.56 (s, 3H), 1.87 - 1.76 (m, 1H), 1.73 - 1.60 (m, 1H), 1.45 - 1.26 (m, 4H), 0.93 - 0.83 (m, 3H). MS (ESI) m/z (M+H) + 344.1.
(5)-N-(4-AMINO-l-(4-FLUOROPHENYL)-3,4-DIOXOBUTAN-2-YL)-l-MET HYL-3- PHENYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (168)
[0792] Prepared as in Example 64 from the corresponding starting materials, compounds 32F and 58F. Compound 168 (21.3 mg, yield: 45.1%, light yellow solid): 1H NMR (400MHz, DMSO-d 6 ) δ 8.38 (br d, 7 = 7.7 Hz, 1H), 8.12 - 7.99 (m, 2H), 7.81 (s, 1H), 7.54 (br d, 7 = 3.7 Hz, 2H), 7.36 - 7.24 (m, 5H), 7.12 (br t, 7 = 8.7 Hz, 2H), 5.30 - 5.20 (m, 1H), 3.89 (s, 3H), 3.19 - 3.09 (m, 1H), 2.87 - 2.74 (m, 1H). MS (ESI) m/z (M+H) + 395.1.
N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METH YL-4- PHENYLOXAZOLE-5-CARBOXAMIDE (459)
[0793] Prepared as in compound 107 from the corresponding starting materials, compounds 107B and 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride. Compound 459 (210 mg, yield: 65.2%, white solid): 1H NMR (400MHz, DMSO-d 6 ) δ 8.88 - 8.79 (m, 2H), 8.06 - 7.99 (m, 2H), 7.43 - 7.34 (m, 3H), 7.33 - 7.26 (m, 4H), 7.25 - 7.18 (m, 1H), 5.48 - 5.35 (m, 1H), 3.26 - 3.17 (m, 1H), 3.05 - 2.94 (m, 1H), 2.82 - 2.71 (m, 1H), 2.55 (s, 3H), 0.70 - 0.52 (m, 4H). MS (ESI) m/z (M+H) + 418.2. N-(l-(CYCLOPROPYLAMINO)-l,2-DIOXOHEPTAN-3-YL)-2-METHYL-4- PHENYLOXAZOLE-5-CARBOXAMIDE (460)
[0794] Prepared as in compound 107 from the corresponding starting materials, compounds 107B and 3-amino-N-cyclopropyl-2-hydroxyheptanamide hydrochloride. Compound 460 (180 mg, yield: 53.3%, white solid): 1H NMR (400MHz, OMSO-d 6 ) δ 8.76 (br s, 2H), 8.10 (br s, 2H), 7.40 (br s, 3H), 5.12 (br s, 1H), 2.77 (br s, 1H), 2.56 (br s, 3H), 1.81 (br s, 1H), 1.68 (br s, 1H), 1.32 (br s, 4H), 0.88 (br s, 3H), 0.70 - 0.52 (m, 4H). MS (ESI) m/z (M+H) + 384.2.
(5)-N-(4-FLUORO-3-OXO-l-PHENYLBUTAN-2-YL)-2-METHYL-4- PHENYLOXAZOLE-5-CARBOXAMIDE (475)
[0795] Prepared as in compound 107 from the corresponding starting materials, compounds 107B and (2S,3S)-3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride. Compound 475 (75 mg, yield: 50.28%, white solid): 1H NMR (400MHz, CDC1 3 ) δ 8.13 - 8.08 (m, 2H), 7.47 - 7.38 (m, 3H), 7.36 - 7.28 (m, 3H), 7.18 (d, =6.6 Hz, 2H), 6.81 - 6.76 (m, 1H), 5.31 - 5.22 (m, 1H), 5.05 - 4.89 (m, 1H), 4.88 - 4.72 (m, 1H), 3.29 - 3.22 (m, 1H), 3.17 - 3.10 (m, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H) + 367.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(QUI NOLIN-5- -lH-PYRAZOLE-5-CARBOXAMIDE (108)
[0796] A mixture consisting of quinolin-5-amine (5 g, 34.68 mmol) in cone. HCI (20 mL) at 0 °C was added NaN0 2 (2.63 g, 38.15 mmol) dropwise and the resultant mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was warmed to 25 °C over 0.5 hour, and then cooled to 0 °C. The SnCl 2 « 2H 2 0 (15.65 g, 68.36 mmol, in 20 mL cone. HCI) was added dropwise to the reaction mixture, and stirred at 0 °C for 0.5 hour. The resulting mixture was allowed to warm to 25 °C with vigorous stirring over 4 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with ethanol 90 mL (30 mL x 3), filtered and concentrated under reduced pressure to afford compound 108A (5.2 g, 76.64% yield, HC1) as a yellow solid. 1H NMR (DMSO-i¾ , 400 MHz): δ 9.98 (br s, 1H), 9.26 - 9.15 (m, 2H), 8.07 - 7.97 (m, 2H), 7.89 (d, / = 8.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H).
[0797] To a mixture of compound 108A (2 g, 12.56 mmol, HC1) and ethyl 2- (methoxyimino)-4-oxopentanoate (1.91 g, 10.22 mmol) in AcOH (20 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 110 °C for 2h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with CH 2 C1 2 (100 mL), adjusted to pH - 7 - 8 with saturated aqueous NaHC0 3i and then extracted with CH 2 C1 2 (40 mL x 2). The organic phase was dried over anhydrous Na 2 S0 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1 :0 to 0: 1) to give compound 108B (1.2 g, 41.78% yield) as a yellow solid and compound 108C (150 mg, 5.22% yield) as a yellow solid. Compound 108B: 1H NMR (CDC1 3 , 400 MHz): δ 8.93 (d, J = 4.0 Hz, 1H), 8.23 (d, = 8.4 Hz, 1H), 7.78 (t, = 8.0 Hz, 1H), 7.64 (d, = 8.4 Hz, 1H), 7.56 (d, = 7.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 4.05 (q, = 7.2 Hz, 2H), 2.41 (s, 3H), 1.00 (t, = 7.2 Hz, 3H).
[0798] Compound 108C: 1H NMR (CDC1 3 , 400 MHz): δ 1H NMR (400MHz, DMSO-d 6 ) δ 8.98 - 8.87 (m, 1H), 8.27 (d, = 8.8 Hz, 1H), 7.83 - 8.77(m, 1H), 7.68 - 7.56 (m, 2H), 7.45 - 7.40 (m, 1H), 6.85 (s, 1H), 4.42 (q, = 7.2 Hz, 2H), 2.13 (s, 3H), 1.40 (t, = 7.2 Hz, 3H).
[0799] To a mixture of 108B (250 mg, 888.7 umol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH » H 2 0 (149.2 mg, 3.55 mmol) in one portion and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 108D (200 mg, 88.03% yield) as a white solid. 1H NMR (DMSO- 6, 400 MHz): δ 8.97 (d, = 4.0 Hz, 1H), 8.17 (d, = 8.8 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.67 - 7.62 (m, 1H), 7.61 - 7.52 (m, 2H), 6.96 (s, 1H), 5.76 (s, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+l) + 253.9. [0800] Compound 108 (21.2 mg, 23.11 % yield, white solid) was prepared as in Example 107 from the corresponding intermediate compounds 108D and 12G. Compound 108: 1H NMR (CDC1 3 , 400 MHz): δ 8.95 (d, = 2.8 Hz, 1H), 8.22 (d, = 8.8 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.50 (d, = 7.2 Hz, 1H), 7.39 (d, = 8.4 Hz, 1H), 7.24 - 7.18 (m, 3H), 6.89 (d, = 5.6 Hz, 2H), 6.63 (s, 2H), 6.28 (d, J = 7.2 Hz, 1H), 5.53 - 5.39 (m, 2H), 3.24 (d, J = 14 A Hz, 1H), 3.03 (d, J = 14 A Hz, 1H), 2.39 (s, 3H). MS (ESI) m/z (M+H) + 428.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(PYRIDIN-2-YL )THIAZOLE- -CARBO 09)
[0801] A mixture of ethyl 4-bromothiazole-5-carboxylate (500 mg, 2.12 mmol), 2- (tributylstannyl)pyridine (858.5 mg, 2.33 mmol), Pd(PPh 3 )4 (122.5 mg, 106 umol) in dioxane (15 mL) was stirred at 105 °C for 14h. The mixture was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=3: l to 1 : 1) to afford compound 109A (221 mg, 44.05% yield) as yellow oil. MS (ESI) m/z (M+H) + 235.0.
[0802] To a solution of compound 109A (221 mg, 943.36 umol) in MeOH (10 mL) and water (2 mL) was added LiOH.H 2 0 (99 mg, 2.36 mmol, 2.5 eq). The mixture was stirred at 32 °C for 0.5 hr. MeOH was evaporated. To the residue was added water (20 mL). The mixture was extracted with MTBE (5 mL) and separated. The aqueous layer was acidified to pH ~ 3 with IN HC1 and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na 2 S0 4 and concentrated to afford compound 109B (155 mg, 79.68% yield) as white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.37 (s, 1H), 8.84 (br d, J = 4.8 Hz, 1H), 8.57 (d, = 8.0 Hz, 1H), 8.34 (br t, = 7.4 Hz, 1H), 7.78 (t, = 6.2 Hz, 1H).
[0803] Compound 109 (5.7 mg, 13.91% yield, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 109B. Compound 109: MS (ESI) m/z (M+H) + 381.0. 1H NMR (400MHz, CDC1 3 ) δ 13.47 - 13.34 (m, 1H), 8.85 (s, 1H), 8.43 (d, 7 = 8.0 Hz, 1H), 8.03 (d, 7 = 5.2 Hz, 1H), 7.96 - 7.79 (m, 1H), 7.26 - 7.22 (m, 1H), 7.20 - 7.06 (m, 5H), 6.81 (br s, 1H), 5.94 - 5.86 (m, 1H), 5.68 (br s, 1H), 3.49 - 3.33 (m, 2H).
(5)-l-(4-(OXAZOL-2-YL)PYRIDIN-2-YL)-N-(l-OXO-3-PHENYLPROPAN- 2-YL)-lH- -5-CARBOXAMIDE (110)
[0804] A mixture of 4-bromopyridin-2-amine (20 g, 115.60 mmol) and ethyl 2- oxoacetate (30.7 g, 150.28 mmol) in MeOH (300 mL) was heated to 80 °C for 3 h. The mixture was concentrated, the residue was purified by silica gel column (Petroleum ether : Ethyl acetate = 20: 1). Compound 110A (28.9 g, yield: 86.5%, yellow solid): 1H NMR (400 MHz, CDC1 3 ) δ 7.96 (d, 7 = 5.2 Hz, 1 H), 6.86 (dd, 7 = 5.2, 1.75 Hz, 1 H), 6.77 (d, 7 = 1.3 Hz, 1 H), 5.75 (br s, 1 H), 5.61 (d, 7 = 8.3 Hz, 1 H), 4.29 (q, 7 = 7.0 Hz, 2 H), 3.41 (s, 3 H), 1.37 - 1.31 (m, 3 H).
[0805] A mixture of 110A (15 g, 51.9 mmol) and K 2 C0 3 (21.5 g, 156 mmol) in EtOH (300 mL) was stirred at 80 °C for 0.5 hr, then l-(isocyanomethylsulfonyl)-4-methyl- benzene (15.2 g, 77.82 mmol) was added, the resulting mixture was stirred at 80 °C for another 2 h. Most of ethanol was removed and a precipitate was formed, the solid was filtered and washed with water (100 mL x 2), the solid was dried and concentrated to give HOB (6.4 g, yield: 41.7%), as yellow solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.38 (d, 7 = 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.85 (s, 1 H), 7.61 (s, 1 H), 7.56 (dd, 7 = 5.26, 1.3 Hz, 1 H), 4.27 (q, 7 = 7.02 Hz, 2 H), 1.29 (t, 7 = 7.02 Hz, 3 H).
[0806] HOB (3 g, 10.13 mmol), Pin 2 B 2 (2.57 g, 10.13 mmol), KOAc (2.98 g, 30.4 mmol) and Pd(dppf)Cl 2 (741 mg, 1.01 mmol) in dioxane (100 mL) was de-gassed and then heated at 70 °C for 4 hours under N 2 . The mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel chromatography (DCM: Methanol = 5: 1) to give HOC (1.70 g, crude) as black solid.
[0807] HOC (300 mg, 1.15 mmol), 2-iodooxazole (157 mg, 805.00 umol), Pd(dppf)Cl 2 (84.1 mg, 115.00 umol) and Na 2 C0 3 (244 mg, 2.30 mmol) in toluene (2 mL), EtOH (2 mL), H 2 0 (1 mL) was degassed and then heated to 120 °C for 1 hour under microwave condition. LCMS showed desired MS, the mixture was added water (5 mL) and extracted with ethyl acetate (10 mL x 2), the organic phases were dried and concentrated, the residue was purified by preparatory- TLC (Petroleum ether : Ethyl acetate = 1: 1) to give HOD (80 mg, yield: 24.5%), as yellow solid.
[0808] A mixture of HOD (80 mg, 281.42 umol) and LiOH.H 2 0 (17.7 mg, 422.13 umol) in THF (5 mL), H 2 0 (1 mL) was stirred at 25 °C for 12 h. LCMS showed desired MS, THF was removed under vacuum, the water layer was extracted with ethyl acetate (10 mL x 2), the water layer was adjusted to pH ~ 6 with IN HC1 and lyophilized, the residue was purified by prep-HPLC (FA) to give HOE (35 mg, yield: 48.5%), as white solid. 1H NMR (400MHz, methanol-^) δ 8.70 (d, 7 = 5.3 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 8.08 (d, 7 = 5.1 Hz, 1H), 7.81 (s, 1H), 7.46 (s, 1H).
[0809] Compound 110 (38 mg, yield: 58.8%, white solid) was prepared as in Example 6 from the corresponding intermediate compounds HOE and 21G ((5)-2-amino-3- phenylpropan-l-ol). Compound 110: 1H NMR (400MHz, CDC1 3 ) δ 9.69 (s, 1H), 8.52 (d, 7 = 5.1 Hz, 1H), 7.98 (br d, 7 = 9.9 Hz, 2H), 7.92 (br d, 7 = 5.1 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.52 (br d, 7 = 5.3 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.17 (m, 4H), 7.13 (br d, 7 = 7.1 Hz, 2H), 4.84 (q, 7 = 6.5 Hz, 1H), 3.33 - 3.18 (m, 2H). MS (ESI) m/z (M+H) + 388.1.
COMPOUNDS 111-112
[0810] Compound lllE (60 mg, crude, grey solid) was prepared as in Example 110 from the corresponding starting materials, 5-bromopyridin-2-amine. Compound lllE: MS (ESI) m/z (M+H) + 257.0. Compound 111 (55 mg, yield: 76.9%, white solid) was prepared as in Example 21 from the corresponding intermediate compounds HIE and 21G ((5)-2-amino-3- phenylpropan- l-ol). Compound 111: 1H NMR (400MHz, CDC1 3 ) δ 9.71 (s, 1H), 9.05 (d, J = 1.5 Hz, 1H), 8.42 (dd, J = 2.2, 8.4 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.34 (br d, J = 6.4 Hz, 1H), 7.31 (s, 1H), 7.28 - 7.24 (m, 2H), 7.22 - 7.17 (m, 1H), 7.14 (br d, = 7.1 Hz, 2H), 4.87 (q, = 6.5 Hz, 1H), 3.24 (d, = 6.4 Hz, 2H). MS (ESI) m/z (M+H) + 388.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(5-(OXAZOL-2- YL)PYRIDIN- 2-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (112)
[0811] Compound 112 (20 mg, yield: 48.2%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds lllE and 12G. 1H NMR (400MHz, DMSO-d 6 ) δ 9.06 (d, J = 7.5 Hz, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.39 (dd, J = 2.4, 8.4 Hz, 1H), 8.34 (s, 1H), 8.26 - 8.21 (m, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.34 (d, = 8.4 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 7.24 - 7.16 (m, 1H), 5.28 - 5.13 (m, 1H), 3.18 (dd, J = 3.7, 13.9 Hz, 1H), 2.85 (dd, J = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 431.1. EXAMPLE 69
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(5- PHENYLTHIAZOL-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (113)
[0812] 5-phenylthiazol-2-amine (850 mg, 4.82 mmol) was added to concentrated hydrochloric acid (5 mL). While being stirred at 0 °C, the aqueous solution of NaN0 2 (998 mg, 14.5 mmol) in H 2 0 (3 mL) was dropped slowly into the mixture, and the mixture was stirred for lhr. Then hydrochloric acid solution of SnCl 2 .2H 2 0 (3.26 g, 14.4 mmol) was added drop-wise slowly, and the mixture was stirred at 25 °C for 3h. LCMS showed 5-phenylthiazol-2-amine was consumed completely and one peak with desired MS was detected. The reaction mixture was filtered. The filtered cake was wash with water (20 mL), and concentrated under reduced pressure to give the product 113A (1 g, crude) as a yellow solid. MS (ESI) m/z (M+H) + 191.9.
[0813] A mixture of compound 113A (1 g, 5.23 mmol), methyl 2,4-dioxopentanoate (754 mg, 5.23 mmol) in HOAc (15 mL) was stirred at 120 °C for lhr. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and adjusted the pH to 8 ~ 9 with the saturated aqueous NaHC0 3 . Then the mixture was extracted with Ethyl acetate (60 mL x 3). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. Firstly, the residue was purified by column chromatography (Petroleum ether : Ethyl acetate = 50: 1 to 10: 1) to give the pure compound 113C (300 mg) and the mixture of 113B & 113C (300 mg). And then the mixture of 113B & 113C (300 mg) was purified by preparatory-HPLC (TFA condition) to give 113B (30 mg) and 113C (120 mg) both as a yellow solid.
[0814] Compound 113B: 1 H NMR (400MHz, CDC1 3 ) δ 7.79 (br s, 1H), 7.60 - 7.51 (m, 2H), 7.46 - 7.38 (m, 2H), 7.38 - 7.29 (m, 1H), 6.75 (br s, 1H), 4.05 - 3.71 (m, 3H), 2.54 - 2.16 (m, 3H). MS (ESI) m/z (M+H) + 300.0.
[0815] Compound 113C: 1H NMR (400MHz, CDC1 3 ) δ 7.74 (s, 1H), 7.58 - 7.53 (m, 2H), 7.46 - 7.40 (m, 2H), 7.38 - 7.32 (m, 1H), 7.26 (s, 1H), 6.72 (d, = 0.7 Hz, 1H), 3.96 (s, 3H), 2.75 (s, 3H). MS (ESI) m/z (M+H) + 300.0.
[0816] To a solution of 113B (30 mg, 100 umol) in THF (5 mL), H 2 0 (1 mL) was added LiOH.H 2 0 (6.31 mg, 150 umol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was added aqueous HC1 to adjust the pH ~ 5. Then the mixture was freezed. Compound 113D (35 mg, crude) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.07 (s, 1H), 7.68 (d, = 7.3 Hz, 2H), 7.49 - 7.41 (m, 2H), 7.40 - 7.32 (m, 1H), 6.79 (s, 1H), 2.25 (s, 3H).
[0817] Compound 113 (20 mg, yield: 66.4%, white solid) was prepared as in Example 5 from the corresponding intermediate compounds 113D and 12G. Compound 113: 1H NMR (400MHz, CDCI 3 ) δ 11.73 (br d, J = 5.5 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.42 (br t, = 7.3 Hz, 2H), 7.38 - 7.31 (m, 1H), 7.23 (br dd, / = 3.9, 8.0 Hz, 6H), 7.03 (s, 1H), 6.80 (br s, 1H), 5.87 - 5.70 (m, 1H), 5.58 (br s, 1H), 3.43 (br dd, = 4.5, 14.2 Hz, 1H), 3.22 (br dd, = 8.2, 14.3 Hz, 1H), 2.31 (s, 3H). MS (ESI) m/z (M+H) + 460.1.
[0818] Following the procedure as used for compound 113, compound 115 (62.0 mg, yield: 68.3%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 115A. Compound 115: 1H NMR (400MHz, CDCI 3 ) δ 7.71 (s, 1H), 7.56 (d, = 7.3 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.39 - 7.33 (m, 2H), 7.33 - 7.27 (m, 2H), 7.26 (s, 1H), 7.19 (br d, = 6.8 Hz, 2H), 6.76 (br s, 1H), 6.65 (s, 1H), 5.77 - 5.62 (m, 1H), 5.52 (br s, 1H), 3.43 (dd, = 5.5, 13.9 Hz, 1H), 3.26 (dd, = 7.1, 13.9 Hz, 1H), 2.71 (s, 3H). MS (ESI) m/z (M+23) + 460.1. EXAMPLE 70
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-l-(5- -2-YL)-lH-PYRAZOLE-3-CARBOXAMIDE (114)
[0819] To a solution of 5-phenyloxazole (800 mg, 5.51 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 2.76 mL) drop-wise at -78 °C and stirred for 30 min, then hexachloroethane (1.96 g, 8.27 mmol) in THF (2 mL) was added, the reaction mixture was slowly warmed to 25 °C and stirred for 12 h. The mixture was poured into ice- water (20 mL) and extracted ethyl acetate (10 mL x 2), the organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated, the residue was purified by silica gel column (Petroleum ether: Ethyl acetate = 10: 1) to give 114A (900 mg, yield: 90.9%) as yellow oil. 1H NMR (400MHz, CDCI 3 - ) δ 7.58 (d, = 7.3 Hz, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.31 (m, 1H), 7.27 (s, 1H).
[0820] A mixture of 114A (90 mg, 501 umol), ethyl 3-methyl- lH-pyrazole-5- carboxylate (92.7 mg, 601 umol) and K 2 C0 3 (103 mg, 752 umol) in CH 3 CN (3 mL) was stirred at 120 °C for 2 hr under microwave condition. The mixture was diluted with ethyl acetate (20 mL) and water (20 mL), the organic phase was dried over Na 2 S0 4 , filtered and concentrated, the residue was purified by preparatory-TLC (Petroleum ether: Ethyl acetate = 5: 1) to give 114B (0.14 g, yield: 60.4%) as yellow oil, 1H NMR (400MHz, CDC1 3 ) δ 7.76 - 7.67 (m, 2H), 7.47 - 7.41 (m, 2H), 7.39 - 7.32 (m, 2H), 6.75 (d, = 0.9 Hz, 1H), 4.44 (q, = 7.2 Hz, 2H), 2.67 (d, = 0.7 Hz, 3H), 1.43 (t, 7 = 7.2 Hz, 3H).
[0821] A mixture of 114B (140 mg, 471 umol) and LiOH.H 2 0 (39.5 mg, 942 umol) in THF (5 mL), H 2 0 (1 mL) was stirred at 25 °C for 2 h. The organic solvent was removed under vacuum, the water layer was adjusted to pH ~ 5 with IN HC1 and filtered, the water layer was extracted with DCM (10 mL x 3), the organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated, the residue combined the filtrate cake to give 114C (120 mg, crude), as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.88 (s, IH), 7.81 - 7.71 (m, 2H), 7.52 (t, 7 = 7.7 Hz, 2H), 7.46 - 7.40 (m, IH), 6.81 (d, 7 = 0.7 Hz, IH), 2.62 (s, 3H).
[0822] Compound 114 (53 mg, yield: 66.5%, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 114C. Compound 114: 1H NMR (400MHz, DMSO-i¾) δ 8.59 (d, 7 = 7.7 Hz, IH), 8.10 (s, IH), 7.87 (s, IH), 7.84 (s, IH), 7.76 (d, 7 = 7.3 Hz, 2H), 7.52 (t, 7 = 7.7 Hz, 2H), 7.45 - 7.38 (m, IH), 7.31 - 7.22 (m, 4H), 7.19 (qd, 7 =
4.3, 8.8 Hz, IH), 6.72 (d, 7 = 0.7 Hz, IH), 5.49 - 5.40 (m, IH), 3.25 - 3.17 (m, IH), 3.06 (dd, 7 =
9.4, 14.0 Hz, IH), 2.57 (s, 3H). MS (ESI) m/z (M+H) + 444.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(ISOQUINOLIN- l-YL)-3- -1H-PYRAZOLE-5-CARBOXAMIDE (119)
[0823] To a mixture of 1-chloroisoquinoline (5.0 g, 30.56 mmol) in dioxane (10.00 mL) was added ΝΗ 2 ΝΗ 2 Ή 2 0 (305.62 mmol, 15 mL). The mixture was stirred at 80 °C for 16h. The reaction mixture was washed with H 2 0 (100 mL). The reaction mixture diluted with MTBE and filtered to give compound 119A (4.27 g, 87.77% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.16 (d, 7=8.3 Hz, IH), 7.87 (d, 7=5.8 Hz, IH), 7.72 - 7.65 (m, IH), 7.64 - 7.56 (m, IH), 7.48 - 7.41 (m, IH), 6.90 (d, 7=5.8 Hz, IH). MS (ESI) m/z (M+H) + 160.1.
[0824] A mixture of compound 119A (4.20 g, 26.38 mmol ) and ethyl 2- (methoxyimino)-4-oxopentanoate (4.94 g, 26.38 mmol) in HOAc (40.00 mL) was stirred at 120 °C for 48h. The reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with H 2 0 (20 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (40 mL), dried over Na 2 S0 4 , concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=10/l to 0: 1) to give compound 119B (238.00 mg, 3.08% yield) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 8.46 (br d, 7=5.5 Hz, IH), 7.92 (d, 7=8.2 Hz, IH), 7.79 (d, 7=5.5 Hz, IH), 7.72 (t, 7=7.4 Hz, IH), 7.67 - 7.53 (m, 2H), 6.92 (s, IH), 4.06 (q, 7=7.1 Hz, 2H), 2.43 (s, 3H), 0.99 (t, 7=7.2 Hz, 3H). MS (ESI) m/z (M+H) + 282.
[0825] To a solution of compound 119B (238.00 mg, 846.04 umol) in THF (6.00 mL) was added LiOH ' H 2 0 (177.50 mg, 4.23 mmol) in H 2 0 (2.00 mL). The mixture was stirred at 28 °C for 16h. The reaction mixture was diluted with H 2 0 (10 mL) and extracted with MTBE (15 mL x 2), the water phase was added IN HC1 to pH ~ 3-4, extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 119C (201.00 mg, 92.87% yield) as a yellow solid. Compound 119C: 1H NMR (400MHz, DMSO-d 6 ) δ 8.42 (d, 7=5.5 Hz, IH), 8.12 (d, 7=8.2 Hz, IH), 8.01 (d, 7=5.7 Hz, IH), 7.85 (t, 7=7.2 Hz, IH), 7.69 (t, 7=7.4 Hz, IH), 7.56 (d, 7=8.4 Hz, IH), 6.92 (s, IH), 2.32 (s, 3H). MS (ESI) m/z (M+H) + 254.1.
[0826] Compound 119 (20.00 mg, 35.64% yield, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 119C. Compound 119: 1H NMR (400MHz, CDC1 3 ) δ 8.23 (br d, 7=6.2 Hz, IH), 7.94 - 7.85 (m, 3H), 7.75 (br t, 7=7.8 Hz, IH), 7.69 (br d, 7=5.3 Hz, IH), 7.62 (br t, 7=7.7 Hz, IH), 7.12 (br d, 7=7.1 Hz, IH), 7.09 - 7.03 (m, 2H), 6.92 (br d, 7=7.1 Hz, 2H), 6.73 (s, IH), 6.67 (br s, IH), 5.65 - 5.59 (m, IH), 5.51 (br s, IH), 3.36 - 3.28 (m, IH), 3.21 - 3.14 (m, IH), 2.41 (s, 3H). MS (ESI) m/z (M+H) + 428.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(5- METHYLPYRIDI -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (120)
[0827] A mixture of 2-fluoro-5-methylpyridine (10.00 g, 89.99 mmol, 9.35 mL) in ΝΗ 2 ΝΗ 2 .Η 2 0 (53.00 g, 899.93 mmol, 51.5 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 120 °C for 15 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 0 (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 120A (6.09 g, yield: 54.9%) was obtained as a light pink solid. 1H NMR (400MHz, CDC1 3 ) δ 7.95 (s, 1H), 7.32 (dd, = 2.0, 8.4 Hz, 1H), 6.63 (d, = 8.4 Hz, 1H), 5.68 (br s, 1H), 2.20 (s, 3H).
[0828] A mixture of compound 120A (2 g, 16.24 mmol), ethyl 2-(methoxyimino)-4- oxopentanoate (3.04 g, 16.24 mmol) in HO Ac (20 mL) was stirred at 120 °C for 20 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 0 (15 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with NaHC0 3 (20 mL x 3), and then washed with brine (20 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparatory-HPLC (HCl condition) to give the compound 120B (340 mg, yield: 8.5%) was obtained as a white solid. Compound 120B: 1H NMR (400MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.82 (dd, 7 = 1.8, 8.3 Hz, 1H), 7.58 (d, = 8.3 Hz, 1H), 6.77 (s, 1H), 4.19 (q, = 7.0 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H).
[0829] To a solution of compound 120B (340 mg, 1.39 mmol) in THF (10 mL) was added LiOH.H 2 0 (291 mg, 6.95 mmol) in H 2 0 (3 mL). The mixture was stirred at 25 °C for 30 h. The reaction mixture was diluted with H 2 0 (15 mL) and extracted with MTBE (10 mL). The combined water layers were adjusted to pH ~ 6 by adding IN HCl, and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 120D (300 mg, yield: 99.4%) was obtained as a white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 13.50 (br s, 1H), 8.26 (s, 1H), 7.79 (dd, J = 1.8, 8.2 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 6.73 (s, 1H), 2.33 (s, 3H), 2.24 (s, 3H).
[0830] Compound 120 (15 mg, yield: 54.1% light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 120D. Compound 120: 1H NMR (400MHz, OMSO-d 6 ) δ 9.21 (d, = 7.3 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.73 (dd, = 1.6, 8.2 Hz, 1H), 7.44 (d, = 8.3 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.53 (s, 1H), 5.35 - 5.26 (m, 1H), 3.16 (dd, 7 = 4.0, 14.1 Hz, 1H), 2.87 (dd, = 9.8, 14.1 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H). EXAMPLE 73
COMPOUNDS 121-122, 445
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(5-
METHYLPYRIDI -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (121)
[0831] Intermediate compound 121D (650 mg, yield: 89.8%, white solid) was prepared as in Example 120 from the corresponding starting materials, compound 121A and 2- chloro-5-(trifluoromethyl)pyridine. Compound 121A: 1H NMR (400MHz, DMSO-d 6 ) δ 13.55 (br s, 1H), 8.86 (s, 1H), 8.39 (dd, J = 2.3, 8.5 Hz, 1H), 7.91 (d, = 8.4 Hz, 1H), 6.81 (s, 1H), 2.27 (s, 3H).
[0832] Compound 121 (35.9 mg, yield: 55.2%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 121D. Compound 121: 1H NMR (400MHz, OMSO-d 6 ) δ 9.15 (d, = 7.3 Hz, 1H), 8.45 (s, 1H), 8.29 (dd, = 2.1, 8.7 Hz, 1H), 8.11 (s, 1H), 7.88 - 7.80 (m, 2H), 7.28 - 7.24 (m, 4H), 7.22 - 7.17 (m, 1H), 6.51 (s, 1H), 5.36 - 5.28 (m, 1H), 3.14 (dd, = 3.6, 14.0 Hz, 1H), 2.81 (dd, = 9.9, 14.1 Hz, 1H), 2.27 (s, 3H).
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(5-(TRIFLUOROMETHYL)PYRIDIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMID E
[0833] Compound 122 (54.1 mg, yield: 87.9%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 121D. Compound 122: 1H NMR (400MHz, DMSO-d 6 ) δ 9.16 (d, = 7.3 Hz, 1H), 8.85 (d, = 5.1 Hz, 1H), 8.42 (s, 1H), 8.30 (dd, 7 = 2.1, 8.7 Hz, 1H), 7.83 (d, = 8.6 Hz, 1H), 7.29 - 7.23 (m, 4H), 7.22 - 7.16 (m, 1H), 6.51 (s, 1H), 5.38 - 5.30 (m, 1H), 3.14 (dd, J = 3.7, 14.1 Hz, 1H), 2.86 - 2.72 (m, 2H), 2.27 (s, 3H), 0.68 - 0.55 (m, 4H). N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(5- (TRIFLUOROMETHYL)PYRIDIN-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (445)
[0834] Compound 445 (140 mg, yield: 47.4%, white solid) was prepared as in compound 121 from the corresponding intermediates 121D and 274D. Compound 445: 1H NMR (400MHz, DMSO-d 6 ) δ 9.16 (d, = 7.5 Hz, 1H), 8.50 - 8.43 (m, 1H), 8.31 (dd, = 2.2, 8.8 Hz, 1H), 8.12 (s, 1H), 7.90 - 7.81 (m, 2H), 7.29 - 7.18 (m, 4H), 6.53 (s, 1H), 5.38 - 5.29 (m, 1H), 3.16 (dd, J = 4.0, 14.1 Hz, 1H), 2.83 (dd, J = 9.9, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 446.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4,6-DIMETHYL PYRIDIN-2- YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (123)
[0835] Intermediate compound 123C (210 mg, yield: 78.29%, white solid) was prepared as in Example 120 from the corresponding starting materials, compound 123A and 2- chloro-5-(trifluoromethyl)pyridine. 1H NMR (400MHz, DMSO-d 6 ) δ 7.38 (s, 1H), 7.14 (s, 1H), 6.77 (s, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z (M +H) + 232.0.
[0836] Compound 123 (40 mg, yield: 38.78%, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 123C. Compound 123: 1H NMR (400MHz, DMSC fc) δ 9.13 (d, = 7.3 Hz, 1H), 8.04 (s, 1H), 7.81 (s, lH), 7.28 - 7.18 (m, 6H), 6.99 (s, 1H), 6.44 (s, 1H), 5.41 - 5.21 (m, 1H), 3.12 (dd, J = 4.0, 13.9 Hz, 1H), 2.82 (dd, J = 9.7, 13.9 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z (M +H) + 406.1. (5 N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METH YL- 4-PHENYLTHIAZOLE-5-CARBOXAMIDE (124) [0837] Compound 124 (40 mg, yield: 57.35%, white solid) was prepared as in Example 41 from the corresponding carboxylic acid, 2-methyl-4-phenylthiazole-5-carboxylic acid. 1H NMR (400MHz, CDC1 3 ) δ 7.58 - 7.50 (m, 2H), 7.49 - 7.36 (m, 3H), 7.22 - 7.13 (m, 3H), 6.84 (br s, 1H), 6.80 - 6.69 (m, 2H), 6.22 (br d, J = 6.3 Hz, 1H), 5.58 - 5.46 (m, 1H), 3.26 (dd, J = 4.9, 14.2 Hz, 1H), 2.89 (dd, J = 7.5, 14.1 Hz, 1H), 2.79 (qt, J = 3.8, 7.4 Hz, 1H), 2.71 (s, 3H), 0.94 - 0.82 (m, 2H), 0.66 - 0.55 (m, 2H). MS (ESI) m/z (M +H) + 434.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5- METHYL- l-(4-PHENYLTHIAZ -2-YL)-lH-PYRAZOLE-3-CARBOXAMIDE (127)
[0838] Intermediate compound 127B (150 mg, 94.78% yield, white solid) was prepared as in Example 85 from compound 127A. Compound 127B: 1H NMR (400 MHz, DMSO-d 6 ): δ 9.20 (s, 1H), 8.99 (s, 2H), 6.94 (s, 1H), 2.27 (s, 3H).
[0839] Compound 127 (55.3 mg, 45.18% yield, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 127B. Compound 127: 1H NMR (400 MHz, CDC1 3 ): δ 9.15 (s, 1H), 8.76 (s, 2H), 7.35 - 7.28 (m, 3H), 7.13 - 7.09 (m, 2H), 6.95 (br s, 1H), 6.66 - 6.60 (m, 1H), 6.47 (s, 1H), 5.60 - 5.54 (m, 1H), 3.46 - 3.38 (m, 1H), 3.20 - 3.13 (m, 1H), 2.87 - 2.77 (m, 1H), 2.35 (s, 3H), 0.92 - 0.87 (m, 2H), 0.66 - 0.61 (m, 2H). MS (ESI) m/z (M+l) + 419.1.
(5 N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-lH-PYRAZOL E-5-
[0840] To a solution of NaH (1.46 g, 36.59 mmol, 60% purity) in THF (80 mL) was added methyl 4-bromo- lH-pyrazole-3-carboxylate (5.00 g, 24.39 mmol) ith THF (20 mL) at 0°C. After addition, the mixture was warmed to 25°C and stirred for 2h. Then the mixture was cooled to 0°C and a solution of SEM-C1 (4.47 g, 26.83 mmol, 4.8 mL) in THF (100 mL). The mixture was stirred at 25°C for 12h. The mixture was diluted with H 2 0 (200 mL), the organic layer was washed with HCI (1M, 100 mL), saturated NaHC0 3 (100 mL), brine (100 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1 to 3: 1). Compound 129A (3.40 g, yield 41.6%) was obtained as a colorless oil. 1H NMR (400MHz, OMSO-d 6 ) δ 8.39 (s, 1H), 5.51 (s, 2H), 3.87 (s, 3H), 3.62 - 3.56 (m, 2H), 0.95 - 0.81 (m, 2H), 0.07 - -0.07 (m, 9H).
[0841] A mixture of compound 2 (3.40 g, 10.14 mmol), phenylboronic acid (1.48 g, 12.17 mmol), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (660.9 mg, 1.01 mmol), K 3 P0 4 (6.46 g, 30.42 mmol) in dioxane (30 mL) and H 2 0 (10 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 70 °C for 1 hour under N 2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=10/l to 3: 1). Compound 129B (3.00 g, crude) was obtained as a brown oil. 1H NMR (400MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.51 - 7.32 (m, 5H), 5.53 (s, 2H), 3.78 (s, 3H), 3.67 - 3.59 (m, 2H), 0.94 - 0.82 (m, 2H), 0.06 - -0.07 (m, 9H). [0842] To a solution of compound 129B (3.00 g, 9.02 mmol) in MeOH (100 mL) and THF (100 mL) was added NaOH (2M, 90 mL). The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated and diluted with H 2 0 (200 mL), the mixture was extracted with ethyl acetate (200 mL), the water phase was added HCl (1M) until pH ~ 3, then the mixture was extracted with ethyl acetate (200 mL), the organic layer was washed with brine (200 mL), dried over Na 2 S0 4 and concentrated. Compound 129C (300.0 mg, yield 10.4%) was obtained as a brown oil. 1H NMR (400MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.51 - 7.47 (m, 2H), 7.43 - 7.37 (m, 2H), 7.35 - 7.30 (m, 1H), 5.50 (s, 2H), 3.67 - 3.61 (m, 2H), 0.92 - 0.87 (m, 2H), 0.03 - -0.03 (m, 9H).
[0843] Intermediate compound 129E (70.0 mg, crude, colorless oil) was prepared as in Example 5 from the corresponding carboxylic acid, compound 129C. Compound 129E: 1H NMR (400MHz, DMSO-i¾) δ 8.45 (d, J = 7.6 Hz, 1H), 8.25 - 8.21 (m, 1H), 8.20 - 8.13 (m, 1H), 7.90 (s, 1H), 7.44 - 7.38 (m, 2H), 7.36 - 7.19 (m, 8H), 5.51 - 5.43 (m, 3H), 3.68 - 3.60 (m, 2H), 3.26 - 3.18 (m, 1H), 3.08 - 2.99 (m, 1H), 0.95 - 0.87 (m, 2H), 0.06 - -0.05 (m, 9H).
[0844] To a solution of compound 129E (70.0 mg, 142.09 umol) in ethyl acetate (10 mL) was added HCl/EtOAc (4M, 710 uL). The mixture was stirred at 25 °C for 3 hours. The mixture was concentrated. The residue was purified by prep-HPLC (HCl condition). Compound 129 (20.0 mg, HCl, yield 34.4%) was obtained as a white solid. 1H NMR (400MHz, D 2 0) δ 7.74 - 7.61 (m, 1H), 7.41 - 7.33 (m, 2H), 7.30 - 7.09 (m, 10H), 4.54 - 4.53 (m, 1H), 3.00 - 2.92 (m, 2H). MS (ESI) m/z (M+H) + 363.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- (PHENO -lH-PYRAZOLE-5-CARBOXAMIDE (131)
[0845] To a mixture of ethyl 3-methyl-lH-pyrazole-5-carboxylate (250 mg, 1.62 mmol), [4-(phenoxymethyl)phenyl]boronic acid (554.7 mg, 2.43 mmol), 4A° MS (8 g) and pyridine (141 mg, 1.78 mmol, 0.15 mL) in DCM (50 mL) was added Cu(OAc) 2 (383 mg, 2.11 mmol), the mixture was stirred at 25 °C for 16h under 0 2 balloon (15 psi). The reaction mixture was filtered to get rid of 4A° MS and catalyst, and then the filtrate was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1) and by preparatory- TLC (Si0 2 , Petroleum ether/Ethyl acetate = 5/1).
[0846] Compound 131A (69.3 mg, yield: 13.03%) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.99 - 7.93 (m, 2H), 7.91 - 7.82 (m, 2H), 7.80 - 7.68 (m, 2H), 7.46 - 7.40 (m, 3H), 5.59 (s, 2H), 4.68 (q, J = 1.1 Hz, 2H), 2.81 (s, 3H), 2.05 (s, 1H), 1.69 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 337.1.
[0847] To a solution of compound 131A (69.3 mg, 206.02 umol), in THF (5 mL) and H 2 0 (3 mL) was added LiOH.H 2 0 (26 mg, 618.06 umol). After stirred at 25 °C for 3h, the reaction mixture was added H 2 0 (10 mL) and extracted with MTBE (20 mL).The organic layer was washed with H 2 0 (10 mL). The combined aqueous layer was acidified to pH ~ 1-2 with IN HC1, extracted with ethyl acetate (20 mL x 3), dried over Na 2 S0 4 , filtered and concentrated. Compound 131C (70 mg, crude, white solid): 1H NMR (400MHz, DMSO-d 6 ) δ 13.23 (br s, 1H), 7.57 - 7.51 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.05 (d, J = 7.8 Hz, 2H), 6.96 (t, J = 7.3 Hz, 1H), 6.83 (s, 1H), 5.17 (s, 2H), 2.26 (s, 3H).
[0848] Compound 131 (37.2 mg, yield: 45.9%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 131C. Compound 131: 1H NMR (400MHz, DMSO-i¾) δ 9.12 (br d, J = 7.5 Hz, 1H), 8.11 (br s, 1H), 7.86 (s, 1H), 7.39 (br d, J = 8.2 Hz, 2H), 7.33 - 7.26 (m, 6H), 7.23 (br d, J = 6.4 Hz, 1H), 7.17 (br d, J = 8.2 Hz, 2H), 7.01 (br d, J = 8.2 Hz, 2H), 6.93 (t, = 7.4 Hz, 1H), 6.56 (s, 1H), 5.31 - 5.22 (m, 1H), 5.09 (s, 2H), 3.19 (br dd, = 3.2, 13.8 Hz, 1H), 2.82 (br dd, = 10.9, 13.6 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 483.1. EXAMPLE 78
(5 /V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(ISOQUINOLIN-4-Y L)-3- - 1H-PYRAZOLE-5-CARBOXAMIDE (133)
[0849] To a solution of isoquinolin-4-amine (1.4 g, 9.71 mmol ) in 5N aqueous hydrochloric acid (12 mL) at 0 °C was added a solution of NaN0 2 (670 mg, 9.71 mmol) in deionized water (1 mL). The reaction mixture was stirred at 0 °C for 0.5h and a solution of SnCl 2 *2H 2 0 (5.48 g, 24.28 mmol) dissolved in concentrated hydrochloric acid (5 mL) was added dropwise. The mixture was stirred at 25 °C for 2h. The mixture was adjusted to pH - 12 - 14 with 20 % aqueous NaOH. The mixture was extracted with 2: 1 CHCl 3 /iPrOH (200 mL). The organic layer was dried (Na 2 S0 4 ), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1/0 to 0: 1) and then dried under reduced pressure to afford compound 133A (720 mg, 46.55 % yield) as a brown solid. 1H
NMR (DMSO- e , 400 MHz): δ 9.95 (br s, 1H), 9.25 - 9.13 (m, 2H), 8.04 - 7.95 (m, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.28 - 7.23 (m, 1H).
[0850] To a mixture of compound 133A (620 mg, 3.89 mmol) and ethyl 2,4- dioxopentanoate (615.9 mg, 3.89 mmol) in AcOH (5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 120 °C for 2 hours under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with EtOAc 10 mL and adjusted with saturated NaHC0 3 and then finally extracted with EtOAc (30 mL x 3). The combined organic layers were dried by Na 2 S0 4 , filtered and concentrated under reduced pressure to give a crude product. The reaction solution was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=l/0 to 0/1) to give compound 133B (600.00 mg, 45.16% yield) as a yellow oil. Compound 133B: 1H NMR (CDC1 3 , 400 MHz): δ 9.34 (s, 1H), 8.54 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.72 - 7.61 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+l) + 282.1. [0851] To a mixture of 133B (200 mg, 711 umol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH » H 2 0 (119.3 mg, 2.84 mmol) in one portion and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (5 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 133D (150 mg, 75.43% yield) as a yellow solid. 1 H NMR (DMSO- 6, 400 MHz): 09Λ5 (s, 1H), 8.54 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.86 - 7.73 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 2.33 (s, 3H). MS (ESI) m/z (M+l) + 254.0.
[0852] Compound 133 (22.2 mg, 31.49% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 133D. Compound 133: 1H NMR (CDC1 3 , 400 MHz): δ 9.30 (s, 1H), 8.46 (s, 1H), 8.06 (d, = 8.0 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.47 (d, = 8.4 Hz, 1H), 7.26 - 7.24 (m, 3H), 6.97 - 6.95 (m, 2H), 6.66 (br s, 1H), 6.59 (s, 1H), 6.48 (d, J = 7.2 Hz, 1H), 5.65 (br s, 1H), 5.41 - 5.36 (m, 1H), 3.28 - 3.24 (m, 1H), 3.11 - 3.06 (m, 1H), 2.40 (s, 3H). MS (ESI) m/z (M+H) + 428.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYR IDIN-3-YL)-
1H-P -5-CARBOXAMIDE (136)
[0853] To a solution of ethyl 3-methyl- l-(pyridin-3-yl)-lH-pyrazole-5-carboxylate (2.0 g, 12.97 mmol) and pyridin-3-ylboronic acid (1.59 g, 12.97 mmol) in pyridine (30 mL) was added Cu(OAc) 2 (1.18 g, 6.49 mmol) .The mixture was stirred at 55 °C for 18 hrs. The mixture filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). Compound 136A (850 mg, 28.34% yield, white solid): 1H NMR (400MHz, CDC1 3 ): δ 8.69 (d, = 2.0 Hz, 1H), 8.65 - 8.62 (m, 1H), 7.80 - 7.77 (m, 1H), 7.42 - 7.38 (m, 1H), 6.86 (s, 1H), 4.27 - 4.21 (m, 2H), 2.37 (s, 3H), 1.27 - 1.23 (m, 3H). [0854] Compound 136C (160 mg, 60.57% yield, white solid) was prepared as in Example 85. Compound 136C: 1H NMR (400 MHz, DMSO-d 6 ): δ 8.65 - 8.55 (m, 2H), 7.91 - 7.85 (m, 1H), 7.53 - 7.47 (m, 1H), 6.88 (s, 1H), 2.26 (s, 3H).
[0855] Compound 136 (46.2 mg, 54.66% yield, yellow solid) was prepared as in Example 5 from the corresponding intermediate compounds 136C and 12G. Compound 136: 1H NMR (400 MHz, CDC1 3 ) δ 8.61 (d, = 2.4 Hz, 1H), 8.58 - 8.55 ( m, 1H), 7.74 - 7.69 (m, 1H), 7.36 - 7.28 (m, 4H), 7.12 - 7.07 (m, 2H), 6.79 (br s, 1H), 6.55 - 6.48(m, 1H), 6.43 (s, 1H), 5.69 (br s, 1H), 5.56 - 5.49 (m, 1H), 3.43 - 3.36 (m, 1H), 3.20 - 3.13 (m, 1H), 2.33 (s, 3H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYR IMIDIN-5- -lH-PYRAZOLE-5-CARBOXAMIDE (138)
[0856] To a solution of pyrimidin-5-ylboronic acid (5.00 g, 40.35 mmol) in MeOH (32 mL) was added Cu(OAc) 2 (732.8 mg, 4.04 mmol) and DBAD (9.29 g, 40.35 mmol). The resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to 25°C, concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (80 mL x 3). The extract was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to give the title compound as yellow oil, which was used in the next step without purification. Compound 138A (9.00 g, 71.87% yield) was obtained as a yellow oil. 1H NMR (400 MHz, CDC1 3 ) δ 8.96 (s, 1H), 8.89 (br s, 1H), 1.53 - 1.50 (m, 18H).
[0857] To a solution of compound 138A (9.00 g, 25.00 mmol) in 1,4-dioxane (60 mL) was added 4M HCl 1,4-dioxane (60 mL) and the mixture was stirred at room-temperature for 30 hours. The suspension was filtered, and the residue was washed with ethyl acetate (100 mL x 2) and dried under reduced pressure to afford the title compound (3.45 g, crude), which was used in the next step without purification. Compound 138B (3.45 g, 81.17% yield, HC1) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.80(s, 1H), 8.61(s, 2H).
[0858] To a solution of compound 138B (800.0 mg, 5.46 mmol, HC1) in CH 3 COOH (12 mL) was added ethyl 2-(methoxyimino)-4-oxopentanoate (1.02 g, 5.46 mmo), then the mixture was stirred at 120 °C for 2 hours. The mixture was diluted with CH 2 CI 2 (70 mL) and washed by saturated sodium bicarbonate (20 mL x 2) and saturated brine (20 mL x 2), the organic layer was dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was purified by flash column chromatography (Si0 2 , petroleum ether : ethyl acetate = 10/1 to 3/1). Compound 138C (250.0 mg, 19.72% yield) was obtained as a white solid.
[0859] To a solution of compound 138C (50.0 mg, 215.29 umol) in THF (3.00 mL) was added TMSOK (55.2 mg, 430.58 umol), then the mixture was stirred at 25 °C for 0.5 hour. The mixture was diluted with petroleum ethyl (20 mL) and the precipitate was filtered to give intermediate compound 138D (45.0 mg, 86.27% yield) as a white solid. MS (ESI) m/z (M+l) + 204.9.
[0860] Compound 138 (10.0 mg, 14.63% yield) was prepared as in Example 5from the corresponding intermediate carboxylic acid, compound 138D. Compound 138: 1 H NMR (400 MHz, CDCI 3 ): δ 9.15(s, 1H), 8.78(s, 2H), 7.35-7.31(m, 3H), 7.13(d, = 6.4 Hz, 2 H), 6.82(s, 1H), 6.58(d, = 7.2 Hz, 1H), 6.47(s, 1H), 5.57-5.52(m, 1H), 5.46-5.58(m, 1H), 3.45-3.40(m, 1H), 3.21-3.15(m, 1H), 2.35(s, 3H). MS (ESI) m/z (M+l) + 379.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-(2H-INDAZOL-2 -YL)-3- METHYLI XAZOLE-4-CARBOXAMIDE (139)
[0861] To a solution of diethyl 2-acetylmalonate (5 g, 24.7 mmol) in EtOH (50 mL) was added NH 2 OH.HCl (1.9 g, 27.2 mmol) and Na 2 C0 3 (1.3 g, 12.4 mmol) in one portion, the mixture was stirred at 90 °C for 2 hours. Then the contents were poured into ice-cold water (6 mL), and then filtered to give intermediate compound 139A (3.2 g, yield: 75.6%) as a pale yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 4.37 (q, J = 7.0 Hz, 2H), 2.43 - 2.37 (m, 3H), 1.38 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 126.2.
[0862] To compound 139A (3 g, 17.5 mmol) was added POCl 3 (21.5 g, 140.2 mmol, 13 mL) in one portion. Then TEA (1.8 g, 17.5 mmol) were added. The mixture was stirred at 110 °C for 24 hours under N 2 . Then ice water (15 mL) was added in to the mixture, and the aqueous phase was extracted with EtOAc (25 mL x 3), the combined organic layer was washed with brine, dried over Na 2 S0 4 , and concentrated to give intermediate compound 139B (2.6 g, 13.7 mmol, yield: 78.2%) as brown oil. 1H NMR (400MHz, CDC1 3 ) δ 4.36 (q, = 7.1 Hz, 2H), 2.48 (s, 3H), 1.38 (t, 7 = 7.2 Hz, 5H).
[0863] To a mixture of compound 139B (400 mg, 2.1 mmol) and 2H-indazole (299 mg, 2.5 mmol) in DMF (3 mL) was added K 2 C0 3 (1.2 g, 8.4 mmol) in one portion. The mixture was stirred at 80 °C for 12 hours. Then H 2 0 (9mL) was added into the mixture, and the aqueous phase was extracted with EtOAc (15 mL x 3), and the combined organic layer was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 300: 1 to 40: 1) to give compound 139C (340 mg, yield: 59.4%) as a pale yellow solid. 1H NMR (400MHz, CDC1 3 ) S 8.33 (s, 1H), 7.82 (d, = 7.9 Hz, 1H), 7.68 (d, = 8.8 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.13 (t, = 7.2 Hz, 3H).
[0864] To a solution of compound 139C (100 mg, 368.6 umol) in THF (2 mL) and H 2 0 (500 uL) was added LiOH.H 2 0 (15.5 mg, 368.6 umol) in one portion. The mixture was stirred at 25 °C for 12 hours. Then the pH of the aqueous phase was adjusted to about 5 by adding HCl (1M), and the residue concentrated on a rotary evaporator to give intermediate compound 139D (83 mg, yield: 92.6%) as a white solid. 1H NMR (400MHz, DMSO-J6) δ 8.62 (s, 1H), 7.94 (d, = 7.9 Hz, 1H), 7.59 (d, = 3.5 Hz, 2H), 7.41 - 7.35 (m, 1H), 3.30 (br s, 3H). MS (ESI) m/z (M+H) + 243.9.
[0865] Compound 139 (18 mg, yield: 24.8%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 139D. Compound 139: 1H NMR (400MHz, CDCI 3 ) δ 10.32 (br d, 7 = 5.7 Hz, 1H), 8.17 (d, / = 8.6 Hz, 1H), 7.93 (s, 1H), 7.81 (d, = 7.9 Hz, 1H), 7.65 (t, = 7.4 Hz, 1H), 7.43 (t, = 7.5 Hz, 1H), 7.19 - 7.12 (m, 5H), 6.77 (br s, 1H), 5.77 - 5.69 (m, 1H), 5.49 (br s, 1H), 3.42 (dd, 7 = 5.1, 14.3 Hz, 1H), 3.20 (dd, J = 7.9, 14.3 Hz, 1H), 2.57 (s, 3H). MS (ESI) m/z (M+H) + 418.0.
METHYL (5)-(3-(5-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)- 3- -lH-PYRAZOL-l-YL)BENZYL)CARBAMATE (140)
[0866] To a solution of 3-hydrazinylbenzonitrile (30.0 g, 176.9 mmol , HCl salt) in HOAc (500 mL) was added ethyl 2-methoxyimino-4-oxo-pentanoate (33.1 g, 176.9 mmol). The mixture was stirred at 100 °C for 12 hours. The mixture was concentrated, diluted with ethyl acetate (200 mL), washed with NaHC0 3 (aqueous, 200 mL), brine (200 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1 :0 to 5: 1). The product obtained was triturated with Petroleum ether/Ethyl acetate = 10: 1 (100 mL) and filtered. Compound 140A (20.0 g, yield 44.3%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.05 - 8.02 (m, 1H), 7.93 - 7.88 (m, 1H), 7.83 - 7.78 (m, 1H), 7.70 - 7.63 (m, 1H), 6.94 (s, 1H), 4.21 - 4.13 (m, 2H), 2.26 (s, 3H), 1.19 - 1.11 (m, 3H).
[0867] To a solution of compound 140A (9.00 g, 35.26 mmol) in MeOH (500 mL) was added Raney-Ni (1.51 g) and NH 3 .H 2 0 (4 mL). The mixture was stirred at 25 °C under H 2 at 40 psi for 12 hours. The mixture was concentrated, diluted with ethyl acetate (500 mL), washed with HCl (500 mL), the water phase was added NaHC0 3 (aqueous) until pH ~ 11. Then the mixture was extracted with ethyl acetate (500 mL), washed with brine (500 mL), dried over Na 2 S0 4 and concentrated to afford intermediate compound 140B (15 g, crude) as a yellow oil.
[0868] To a solution of compound 140B (9.6 g, 37.06 mmol) in DCM (100 mL) was added TEA (7 mL, 55.6 mmol), then Boc 2 0 (9 mL, 40.77 mmol) was added to the mixture and the mixture was stirred at 25°C for 12h. The reaction was washed with citric acid (10%, 100 mL), extracted with DCM (100 mL x 2), washed with H 2 0 (100 mL), dried over anhydrous Na 2 S0 4 , filtered, evaporated under reduced pressure. The crude product was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate =5/1) to afford compound 140C (8.5 g, yield 63.8%) as yellow oil. 1H NMR (DMSO-i¾ , 400MHz) S 7.50 - 7.44 (m, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.24 (m, 3H), 6.88 (s, 1H), 4.20 - 4.13 (m, 4H), 2.27 (s, 3H), 1.37 (s, 9H), 1.20 - 1.14 (m, 3H).
[0869] To a suspension of compound 140C (4.5 g, 13.03 mmol) in EA (350 mL) was added HCl/EtOAc (4 M, 35 mL) and the mixture was stirred at 25 °C for 2 h. The reaction was evaporated under reduced pressure to afford compound 140D (3.3 g, yield 89.9%, HCl) as white solid, which was used directly in next step.
[0870] To a solution of compound 140D (1 g, 3.4 mmol, HCl) in DCM (20 mL) was added TEA (1.4 mL, 10.1 mmol), followed by compound methylchloroformate (1.6 mL, 20.1 mmol), then the mixture was stirred at 25°C for lh. The reaction was diluted with H 2 0 (10 mL), the mixture was extracted DCM (20 mL x 2). The organic layer was collected, washed with brine (20 mL x 3), dried over anhydrous Na 2 S04, filtered, and concentrated under reduced pressure. The product was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate, 0 to 10/1) to afford compound 140E (400 mg, yield 37.3%) was obtained as white solid. 1 H NMR (DMSO-i¾ , 400MHz) δ 7.77 (br t, J = 6.2 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.33 - 7.25 (m, 3H), 6.88 (s, 1H), 4.23 (d, J = 6.2 Hz, 2H), 4.16 (q, J = 1.1 Hz, 2H), 3.55 (s, 3H), 2.26 (s, 3H), 1.14 (t, 7 = 7.1 Hz, 3H).
[0871] Compound 140F (230 mg, yield 64.6%, white solid) was prepared as in Example 85 from the intermediate compound 140E. 1H NMR (DMSO-i¾ , 400MHz) δ 7.76 (br t, = 6.1 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.31 - 7.22 (m, 3H), 6.82 (s, 1H), 4.23 (br d, J = 6.2 Hz, 2H), 3.55 (s, 3H), 2.25 (s, 3H)
[0872] Compound 140 (35 mg, yield 21.1%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 140F. Compound 140: 1H NMR (CD 3 CN 400MHz) δ 7.40 - 7.17 (m, 10H), 7.07 (br d, J = 18.3 Hz, 2H), 6.47 (br s, 1H), 6.26 (br s, 1H), 6.09 (br s, 1H), 5.34 (br s, 1H), 4.29 (br s, 2H), 3.60 (br s, 3H), 3.27 (br d, J = 9.5 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.27 (br s, 3H). MS (ESI) m/z (M+H) + 464.2.
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3- (BENZAMIDOMETHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE
[0873] To a solution of compound 140D (300 mg, 1.22 mmol) and benzoic acid (150 mg, 1.22 mmol) in DCM (10 mL) was added HOBt (330 mg, 2.44 mmol), DIEA (0.5 mL, 3.05 mmol) and EDCI (470 mg, 2.44 mmol). The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (20 mL), washed with IN HC1 (20 mL). The organics were collected, washed with saturated NaHC0 3 (20 mL). The organics were collected, washed with brine (20 mL), dried with Na 2 S0 4 , filtered and concentrated to afford compound 141A (400 mg, crude) as yellow oil. MS (ESI) m/z (M+H) + 364.0.
[0874] To a solution of compound 141A (400 mg, 1.14 mmol) in THF (5 mL) and H 2 0 (5 mL) was added LiOH.H 2 0 (241 mg, 5.72 mmol). The mixture was stirred at 25°C for 12h. The reaction was acidified with IN HC1 to pH ~ 4, extracted with EtOAc (15 mL x 2). The organics were collected and concentrated. The residue was purified by preparatory-HPLC (Neutral conditions) to afford compound 141B (100 mg, yield: 26.16%) as white solid. MS (ESI) m/z (M+Na) + 358.0.
[0875] Compound 141 (4.4 mg, yield: 14.40%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 141B. Compound 141: MS (ESI) m/z (M+H) + 510.0. 1H NMR (400MHz, DMSO-d 6 ) 8.86 - 8.68 (m, 2H), 7.94 - 7.88 (m, 2H), 7.84 - 7.57 (m, 2H), 7.54 - 7.20 (m, 11H), 7.11 - 6.99 (m, 1H), 6.55 (s, 1H), 5.33 - 5.24 (m, 1H), 4.56 - 4.48 (m, 2H), 3.26 - 3.18 (m, 1H), 2.95 - 2.86 (m, 1H), 2.25 (s, 3H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3-( (3- PHENYLPROPANAMIDO)METHYL)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE
[0876] To a solution of compound 140D (500 mg, 2.04 mmol) and 3- phenylpropanoic acid (310 mg, 2.04 mmol) in DCM (20 mL) was added DIEA (0.9 mL, 5.10 mmol), HOBt (552 mg, 4.08 mmol) and EDCI (783 mg, 4.08 mmol). The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with IN HC1 (30 mL). The organics were collected, washed with saturated (30 mL), brine (30 mL), dried with Na 2 S0 4 , filtered, collected and dried in vacuo to afford intermediate compound 22 (700 mg, crude) as yellow oil. MS (ESI) m/z (M+Na) + 414.0. [0877] To a solution of compound 142A (700 mg, 1.85 mmol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (390 mg, 9.27 mmol). The mixture was stirred at 25°C for 12h. The residue was acidified with IN HC1 to pH ~ 4. The solution was extracted with EtOAc (20 mL x 2). The organics were collected and concentrated. The residue was purified by preparatory-HPLC (Neutral) to afford compound 142B (210 mg, yield: 31.24%) as white solid. MS (ESI) m/z (M+Na) + 386.0.
[0878] Compound 142 (49.5 mg, yield: 37.88%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 142B. Compound 142: MS (ESI) m/z (M+H) + 538.2. 1H NMR (400MHz, DMSO-d 6 ) 8.80 - 8.68 (m, 1H), 8.18 - 8.08 (m, 1H), 7.88 - 7.54 (m, 2H), 7.33 - 7.02 (m, 15H), 6.59 - 6.49 (m, 1H), 5.33 - 5.26 (m, 1H), 4.32 - 4.25 (m, 2H), 3.26 - 3.20 (m, 1H), 2.95 - 2.90 (m, 1H), 2.90 - 2.85 (m, 2H), 2.49 - 2.45 (m, 2H), 2.28 - 2.22 (m, 3H).
(5)-l-(3-(ACETAMIDOMETHYL)PHENYL)-N-(4-AMINO-3,4-DIOXO-l- PHENYLBUTAN-2-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (143)
[0879] To a solution of compound 140D (500 mg, 2.04 mmol) and acetyl chloride (160 mg, 2.04 mmol) in DCM (20 mL) was added TEA (0.7 mL, 5.10 mmol). The mixture was stirred at 25°C for 12 h. The reaction was washed with IN HQ (10 mL). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 143A (580 mg, crude) as yellow oil. MS (ESI) m/z (M+Na) + 323.9.
[0880] To a solution of compound 143A (580 mg, 2.02 mmol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (424 mg, 10.09 mmol). The mixture was stirred at 25 °C for 12h. The reaction was acidified with IN HC1 to pH ~ 4. The solution was extracted with EtOAc (20 mL x 2). The organics were collected and concentrated. The residue was purified by preparatory-HPLC (Neutral) to afford compound 26 (100 mg, yield: 18.11%) as white solid. MS (ESI) m/z (M+Na) + 295.9.
[0881] Compound 143 (6.2 mg, yield: 12.26%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 143B. Compound 143: MS (ESI) m/z (M+H) + 448.1. 1H NMR (400MHz, DMSO-d 6 ) 8.78 - 8.67 (m, 0.6H), 8.19 - 8.05 (m, 1H), 7.85 - 7.72 (m, 1H), 7.67 - 7.53 (m, 0.6H), 7.36 - 6.87 (m, 10H), 6.59 - 6.46 (m, 1H), 6.30 - 5.89 (m, 1H), 5.33 - 5.23 (m, 0.6H), 4.52 - 4.40 (m, 0.6H), 4.32 - 4.22 (m, 2H), 3.27 - 3.19 (m, 0.5H), 2.96 - 2.85 (m,0.6H), 2.77 - 2.66 (m, 1H), 2.29 - 2.19 (m, 3H), 1.89 (s, 3H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3-( (2- PHENYLA -lH-PYRAZOLE-5-CARBOXAMIDE (144)
[0882] To a solution of compound 140D (500 mg, 2.04 mmol) and 2-phenylacetic acid (278 mg, 2.04 mmol) in DCM (20 mL) was added DIEA (0.9 mL, 5.10 mmol), HOBt (552 mg, 4.08 mmol) and EDCI (783 mg, 4.08 mmol). The mixture was stirred at 25 °C for 12h. The solvent was removed in vacuo. The residue was dissolved in EtOAc (30 mL), washed with IN HC1 (30 mL). The organics were collected, washed with saturated NaHC0 3 (30 mL). The organics were collected, washed with brine (30 mL). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 144A (700.00 mg, crude) as yellow oil. MS (ESI) m/z (M+H) + 378.0.
[0883] To a solution of compound 144A (700 mg, 1.93 mmol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (405 mg, 9.63 mmol). The mixture was stirred at 25 °C for 12h. The reaction was acidified with IN HC1 to pH ~ 4. The solution was extracted with EtOAc (15 mL x 2). The organics were collected and concentrated. The residue was purified by preparatory-HPLC (Neutral) to give compound 144B (260 mg, yield: 38.56%) as yellow oil. MS (ESI) m/z (M+H) + 349.9. [0884] Compound 144 (36 mg, yield: 45.17%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 144B and 12G. Compound 144: MS (ESI) m/z (M+H) + 524.2. 1H NMR (400MHz, DMSO-d 6 ) δ 9.07 (d, = 7.6 Hz, 1H), 8.66 - 8.49 (m, 1H), 8.08 (br. s, 1H), 7.84 (br. s, 1H), 7.34 - 7.10 (m, 13H), 6.94 - 6.86 (m, 1H), 6.53 (s, 1H), 5.27 - 5.16 (m, 1H), 4.32 - 4.16 (m, 2H), 3.44 (s, 2H), 3.22 - 3.10 (m, 1H), 2.85 - 2.73 (m, 1H), 2.22 (s, 3H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3- (PHENYLSULFONAMIDOMETHYL)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE
[0885] To a mixture of compound 140D (300 mg, 1.1 mmol, HCl salt) in DCM (20 mL) was added TEA (0.44 mL, 3.2 mmol) in one portion. Benzenesulfonyl chloride (0.15 mL, 1.2 mmol) was added dropwise to the mixture at 0 °C for 30 min and then stirred at 25 °C for lh. The reaction mixture was washed with 0.5 N HCl (10 mL), saturated aqueous NaHC0 3 (10 mL) and brine (10 mL). The separated organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was triturated with CH 3 CN (2 mL). The solid was collected and dried in vacuum to afford compound 145A (330 mg, yield 79.2%) as white solid. MS (ESI) m/z (M+H) + 386.0.
[0886] To a mixture of compound 145A (150 mg, 0.39 mmol) in MeOH (10 mL) and H 2 0 (0.5 mL) was added LiOH.H 2 0 (81.6 mg, 1.9 mmol) in one portion. The mixture was stirred at 25 °C for 12h. The reaction mixture was concentrated under reduced pressure to move MeOH. Then the residue was diluted with water (15 mL) and extracted with ethyl acetate (10 mL), the aqueous phase was acidified with aqueous HCl (1M) till pH ~ 6-7 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL) and dried over Na 2 S04, filtered and concentrated to afford intermediate compound 145B (140 mg, crude) as white solid. 1 H NMR (DMSO-i¾ , 400 MHz): δ 8.29 - 8.22 (m, 1H), 7.85 - 7.78 (m, 2H), 7.65 - 7.54 (m, 3H), 7.38 - 7.23 (m, 4H), 6.82 (s, 1H), 4.04 (d, J = 6.0 Hz, 2H), 2.26 (s, 3H).
[0887] Compound 145 (30 mg, yield 46.8%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 145B. Compound 145: 1H NMR (CDC1 3, 400 MHz): δ 7.86 - 7.81 (m, 2H), 7.58 - 7.46 (m, 3H), 7.37 - 7.26 (m, 5H), 7.15 - 7.06 (m, 5H), 6.41 (s, 1H), 6.24 - 6.18 (m, 1H), 6.16 - 6.10 (m, 2H), 5.38 - 5.31 (m, 1H), 4.20 - 4.08 (m, 2H), 3.34 - 3.27 (m, 1H), 3.10 - 3.03 (m, 1H), 2.30 (s, 3H). MS (ESI) m/z (M+H) + 546.1.
ETHYL (5)-(3-(5-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)- 3- MET -lH-PYRAZOL-l-YL)BENZYL)CARBAMATE (147)
[0888] To a solution of compound 140D (1 g, 3.38 mmol, HC1 salt) in DCM (20 mL) was added TEA (1.4 mL, 10.14 mmol), ethylchloroformate (1.9 mL, 20.27 mmol,) dropwise, then the mixture was stirred at 25 °C for lh. The reaction was diluted with H 2 0 (10 mL), the mixture was extracted DCM (20 mL x 2). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na 2 S0 4 , filtered, concentrated under reduced pressure. The product was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate: 0 to 10/1) to afford compound 147A (570 mg, yield 50. 9%) as white solid. 1H NMR (DMSO-i¾ , 400MHz) δ 7.72 (br t, = 6.1 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.25 (m, 3H), 6.88 (s, 1H), 4.23 (br d, = 6.2 Hz, 2H), 4.15 (q, = 7.1 Hz, 2H), 4.03 - 3.97 (m, 2H), 2.26 (s, 3H), 1.16 - 1.12 (m, 6H).
[0889] To a solution of compound 147A (560 mg, 1.69 mmol) in MeOH (15 mL) was added LiOH (2 M, 5mL) dropwise and then the mixture was stirred at 25°C for lh. The reaction was diluted with H 2 0 (10 mL) and concentrated under reduced pressure. The mixture was extracted with TBME (10 mL) and the water phase was treated with HC1 (1M) until pH ~ 5. The mixture was extracted with ethyl acetate (15 mL x 3), the combined organic layer was washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered, concentrated under reduced pressure to afford compound 147B (420 mg, yield 81.9%) was obtained as white solid, which was used directly in next step. 1H NMR (DMSO-d 6, 400MHz) δ 7.69 (br t, = 6.2 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.27 - 7.20 (m, 3H), 6.78 (s, 1H), 4.19 (br d, J = 6.2 Hz, 2H), 3.97 (q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.16 - 1.10 (m, 3H).
[0890] Compound 147 (45mg, yield 27.4%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 147B. Compound 147: 1H NMR (CD 3 CN 400MHz) δ Ί .31 - 7.22 (m, 9H), 7.10 (br d, J = 7.7 Hz, 2H), 6.49 (s, 1H), 6.33 (br s, 1H), 6.10 (br s, 1H), 5.40 - 5.31 (m, 1H), 4.31 (br d, J = 6.2 Hz, 2H), 4.08 (q, J = 1.1 Hz, 2H), 3.29 (dd, J = 4.5, 14.0 Hz, 1H), 2.93 (dd, J = 9.4, 14.0 Hz, 1H), 2.29 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 478.2.
(5)-N-(4-((3,4-DICHLOROBENZYL)AMINO)-3,4-DIOXO-l-PHENYLBUTAN -2-YL)-3- -1-PHENYL-1H-PYRAZOLE-5-CARBOXAMIDE (149)
[0891] To a solution of phenylhydrazine (1.00 g, 9.25 mmol, 910 uL) in HOAc (20 mL) was added ethyl 2,4-dioxopentanoate (1.46 g, 9.25 mmol, 1.3 mL). The mixture was stirred at 100 °C for 12 hours. The mixture was concentrated and diluted with ethyl acetate (50 mL), washed with NaHC0 3 (aqueous, 50 mLx3), brine (50 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by preparatory-HPLC (TFA condition). Compound 149A (700.0 mg, yield 32.9%) was obtained as a yellow oil. Compound 149B (1.00 g, yield 46.9%) was obtained as a yellow oil.
[0892] Compound 149A: 1H NMR (400MHz, DMSO-i¾) δ 7.48 - 7.36 (m, 5H), 6.87 (s, 1H), 4.18 - 4.10 (m, 2H), 2.25 (s, 3H), 1.16 - 1.11 (m, 3H). [0893] Compound 149B: 1H NMR (400MHz, DMSO-i¾) δ 7.61 - 7.44 (m, 5H), 6.75 (s, 1H), 4.31 - 4.23 (m, 2H), 2.31 (s, 3H), 1.30 - 1.24 (m, 3H).
[0894] To a solution of compound 149A (700.0 mg, 3.04 mmol) in THF (20 mL) and MeOH (20mL) was added NaOH (2M, 30) .The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated, diluted with H 2 0 (20 mL), extracted with ethyl acetate (20 mL), the water phase was added HC1 (1M) until pH ~ 1, then the mixture was extracted with ethyl acetate (20 mL), the organic layer was washed with brine (20 mL), dried over Na 2 S0 4 and concentrated. Compound 149C (600.0 mg, yield 97.6%) was obtained as a colorless oil. 1H NMR (400MHz, DMSO-i¾) δ 13.21 (br s, 1H), 7.49 - 7.31 (m, 5H), 6.81 (s, 1H), 2.24 (s, 3H).
[0895] To a solution of compound 149C (600.0 mg, 2.97 mmol) in THF (20 mL) was added DIEA (1.54 g, 11.88 mmol, 2 mL), (2S)-2-amino-3-phenyl-propan-l-ol (448.7 mg, 2.97 mmol), HOBt (401.3 mg, 2.97 mmol) and EDCI (683.2 mg, 3.56 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated and diluted with ethyl acetate (50 mL), washed with HC1 (1M, 50 mL), saturated NaHC0 3 (aqueous, 50 mL), brine (50 mLx3), dried over Na 2 S0 4 and concentrated. Compound 149D (600.0 mg, yield 60.2%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.38 (d, = 8.8 Hz, 1H), 7.32 - 7.17 (m, 8H), 7.12 - 7.07 (m, 2H), 6.50 (s, 1H), 4.89 - 4.83 (m, 1H), 4.10 - 3.99 (m, 1H), 3.48 - 3.35 (m, 2H), 2.95 - 2.87 (m, 1H), 2.68 - 2.59 (m, 1H), 2.21 (s, 3H).
[0896] To a solution of compound 149D (600.0 mg, 1.79 mmol) in DCM (200 mL) was added DMP (1.14 g, 2.69 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture quenched with 10% Na 2 S 2 0 3 (aqueous): saturated NaHC03 (aqueous) (1: 1, 200 mL), extracted with DCM (100 mL) and washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 S0 4 and concentrated. Compound 149E (500.0 mg, yield 83.8%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.58 (s, 1H), 9.03 (d, = 8.0Hz, 1H), 7.36 - 7.13 (m, 10H), 6.57 (s, 1H), 4.56 - 4.49 (m, 1H), 3.28 - 3.21 (m, 1H), 2.81 - 2.72 (m, 1H), 2.25 - 2.17 (m, 3H).
[0897] To a solution of compound 149E (500.0 mg, 1.50 mmol) in DCM (10 mL) was added TEA (15.2 mg, 150.00 umol, 20 uL) and TMSCN (223.2 mg, 2.25 mmol, 280 uL). The mixture was stirred at 0 °C for 3 hours. The mixture was washed with H 2 0 (100 mL), brine (100 mL), dried over Na 2 S0 4 and concentrated to obtain intermediate compound 149F (600.0 mg, crude) as a colorless oil.
[0898] To a solution of compound 149F (600.0 mg, 1.39 mmol) in THF (30 mL) was added HC1 (10 mL). After stirred at 60 °C for 12 hours, the mixture was diluted with H 2 0 (100 mL), extracted with ethyl acetate (50 mL). The organic layer was washed with NaHC0 3 (aq, 50 mL). The water phase was added HC1 (1M) until pH ~ 1, and then extracted with ethyl acetate (500 mL). The organic layer was washed with brine (50 mL), dried over Na 2 S0 4 and concentrated to obtain intermediate compound 149G (500.0 mg, crude) as colorless oil.
[0899] To a solution of compound 149G (500.0 mg, 1.32 mmol) in THF (10 mL) was added (3, 4-dichlorophenyl)methanamine (255.6 mg, 1.45 mmol, 190 uL), HOBt (178.4 mg, 1.32 mmol), DIEA (682.4 mg, 5.28 mmol, 920 uL) and EDCI (303.7 mg, 1.58 mmol) with DCM (10 mL). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated and diluted with ethyl acetate (30 mL), washed with HC1 (1M, 30 mL), saturated NaHC0 3 (aqueous, 30 mL), brine (30 mL), dried over Na 2 S0 4 and concentrated. The crude product was purified by preparatory-HPLC (TFA condition). The product obtained (70 mg) was triturated with CH 3 CN (5 mL) and filtered. Compound 149H (30.0 mg, 4.23%) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.67 - 8.50 (m, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.39 - 7.34 (m, 1H), 7.32 - 7.14 (m, 9H), 7.07 - 6.96 (m, 2H), 6.47 - 6.36 (m, 1H), 4.46 - 4.36 (m, 1H), 4.34 - 4.10 (m, 2H), 4.06 - 3.99 (m, 1H), 2.95 - 2.71 (m, 2H), 2.26 - 2.13 (m, 2H), 2.26 - 2.13 (m, 1H).
[0900] To a solution of compound 149H (30.0 mg, 55.82 umol) in DCM (10 mL) and DMSO (1 mL) was added DMP (47.4 mg, 111.64 umol). The mixture was stirred at 25 °C for 48 hours. The mixture was quenched with 10% Na 2 S 2 0 3 (aqueous): saturated NaHC0 3 (aqueous) (1: 1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mL x 3). The combined organic layers were dried over Na 2 S0 4 and concentrated. The crude product was triturated with CH 3 CN (3 mL) and filtered. Compound 149 (15.0 mg, yield 40.0%) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.36 - 9.30 (m, 1H), 9.11 (br d, 7 = 7.6 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.33 - 7.19 (m, 9H), 7.13 (br d, 7=6.6 Hz, 2H), 6.52 (s, 1H), 5.29 - 5.22 (m, 1H), 4.34 - 4.28 (m, 2H), 3.22 - 3.15 (m, 1H), 2.89 - 2.80 (m, 1H), 2.26 - 2.18 (m, 3H). MS (ESI) m/z (M+H) + 535.1.
(S)-N-(3,4-DIOXO-l-PHENYL-4-((3- (TRIFLUOROMETHOXY)BENZYL)AMINO)BUTAN-2-YL)-3-METHYL-5- PHENYLIS -4-CARBOXAMIDE (150)
[0901] To a solution of compound 101E (500.0 mg, 1.31 mmol) in THF (10 mL) was added [3-(trifluoromethoxy)phenyl]methanamine (251.3 mg, 1.31 mmol), DIEA (509.6 mg, 3.94 mmol, 690 uL), HOBt (177.6 mg, 1.31 mmol) and EDCI (302.4 mg, 1.58 mmol) with DCM (5 mL). After stirred at 25 °C for 12 hours, the mixture was concentrated and diluted with ethyl acetate (50 mL), washed with HCl (1M, 50 mL), saturated aqueous NaHC0 3 (50 mL), brine (50 mL x 3), dried over Na 2 S04 and concentrated. The crude product (0.30 g) was triturated with CH 3 CN (5 mL) and filtered. Compound 150A (140.0 mg, yield 19.3%, white solid): 1H NMR (400MHz, DMSO-i¾) δ 8.75 - 8.53 (m, 1H), 8.31 (d, 7 = 9.6 Hz, 1H), 7.59 - 7.08 (m, 14H), 6.21 - 5.91 (m, 1H), 4.71 - 4.56 (m, 1H), 4.40 - 4.24 (m, 2H), 4.22 - 4.01 (m, 1H), 2.98 - 2.67 (m, 2H), 2.09 - 1.96 (m, 3H).
[0902] To a solution of compound 150A (60.0 mg, 108.40 umol) in DCM (10 mL) and DMSO (1 mL) was added DMP (137.9 mg, 325.20 umol). After stirred at 25 °C for 4 hour, the mixture was quenched with 10% Na 2 S 2 0 3 (aqueous): saturated aq. NaHC0 3 (1 : 1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mLx3). The combined organic layers were dried over Na 2 S0 4 and concentrated. The crude product was triturated with CH 3 CN (3 mL) and filtered. Compound 150 (50.0 mg, yield 82.8%, white solid): 1H NMR (400MHz, DMSO- d 6 ) δ 9.54 - 9.45 (m, 1H), 9.11 (d, = 7.6 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.54 - 7.36 (m, 4H), 7.34 - 7.18 (m, 8H), 5.52 - 5.43 (m, 1H), 4.40 (br d, = 6.0 Hz, 2H), 3.27 - 3.18 (m, 1H), 2.84 - 2.72 (m, 1H), 2.04 (s, 3H). MS (ESI) m/z (M+H) + 552.1.
(5)-3-METHYL-N-(4-((4-(METHYLSULFONYL)BENZYL)AMINO)-3,4-DIOX O-l-
PHENYLBUTAN-2-YL)-5-PHENYLISOXAZOLE-4-CARBOXAMIDE (151) (5)-3-METHYL-N-(4-((3-(METHYLSULFONYL)BENZYL)AMINO)-3,4-DIOX O-l-
PHENYLBUTAN-2-YL)-5-PHENYLISOXAZOLE-4-CARBOXAMIDE (152)
[0903] Compounds 151 and 152 were prepared as in Example 150 from compound 101E and the corresponding amine, respectively. Compound 151 (40.0 mg, 63.6% yield, white solid): 1H NMR (400MHz, DMSO-i¾) δ 9.58 - 9.51 (m, 1H), 9.12 (d, = 7.2 Hz, 1H), 7.86 (d, = 8.4 Hz, 2H), 7.65 - 7.59 (m, 2H), 7.56 - 7.38 (m, 5H), 7.31 - 7.19 (m, 5H), 5.53 - 5.44 (m, 1H), 4.48 - 4.42 (m, 2H), 3.29 - 3.21 (m, 1H), 3.20 - 3.10 (m, 3H), 2.83 - 2.73 (m, 1H), 2.08 - 1.96 (m, 3H). MS (ESI) m/z (M+H) + 546.1.
[0904] Compound 152 (42.0 mg, 68.8% yield, white solid): 1H NMR (400MHz, DMSO- e) δ 9.59 - 9.51 (m, 1H), 9.11 (d, = 7.6 Hz, 1H), 7.91 - 7.78 (m, 2H), 7.67 - 7.57 (m, 4H), 7.53 - 7.37 (m, 3H), 7.34 - 7.17 (m, 5H), 5.53 - 5.45 (m, 1H), 4.46 (br d, = 6.4 Hz, 2H), 3.29 - 3.21 (m, 1H), 3.20 - 3.10 (m, 3H), 2.83 - 2.72 (m, 1H), 2.09 - 1.98 (s, 3H). MS (ESI) m/z (M+H) + 546.1
BENZYL (5)-(4-(5-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)- 3- METHY -lH-PYRAZOL-l-YL)BENZYL)CARBAMATE (153)
[0905] To a solution of 4-hydrazinylbenzonitrile (20 g, 117.92 mmol, HC1) in HOAc (200 mL) was added ethyl 2-methoxyimino-4-oxo-pentanoate (23.18 g, 123.82 mmol), then the mixture was heated to 110 °C and stirred for 12h and then removed the solvent under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and treated with NaHC0 3 until pH ~ 8 and then the organic layer was collected and evaporated under reduced pressure. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 15/1 to 3/1) to give compound 153B (5 g, yield: 16.61%) as a white solid. Compound 153B: 1H NMR (400MHz, CDC1 3 ) δ 7.71 (dd, = 7.9 Hz, 2H), 7.53 (br d, J = 7.5 Hz, 2H), 6.84 (s, 1H), 4.23 (q, 7 = 7.0 Hz, 2H), 2.33 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 255.9.
[0906] To a solution of compound 153B (6.5 g, 25.46 mmol) in MeOH (70 mL) was added Raney-Ni (1.09 g, 12.73 mmol) and NH 3 .H 2 0 (2.68 g, 76.38 mmol, 3 mL) under argon. The suspension was degassed under vacuum and purged with H 2 3 times. The mixture was stirred at 30 °C for 16h under H 2 (40 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate compound 153D (6.6 g, crude) as a yellow oil. 1H NMR (400MHz, DMSO-d 6 ) δ 7.46 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 6.87 (s, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 2.26 (s, 3H). [0907] To a mixture of compound 153D (3.3 g, 13.45 mmol) in DCM (40 mL) was added Et 3 N (2.04 g, 20.17 mmol, 2.8 mL) and Boc 2 0 (3.52 g, 16.14 mmol, 3.7 mL) in portion at 25 °C under N 2 . The mixture was stirred at 25 °C for 1.5h. The reaction mixture was diluted with DCM (20 mL), and washed with H 2 0 (50 mL). The organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layers was washed with brine (30 mL x 2), dried over anhydrous Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1 to 2/1) to give compound 153E (3.3 g, yield: 64.86%) as yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.37 (s, 4H), 6.80 (s, 1H), 4.38 (dd, = 5.1 Hz, 2H), 3.78 (s, 3H), 2.36 (s, 3H), 1.47 (s, 9H). MS (ESI) m/z (M+H) + 346.1.
[0908] To a mixture of compound 153E (3.3 g, 9.55 mmol) in ethyl acetate (20 mL) was added HCl/EtOAc (4M, 20 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2h. The mixture was concentrated to give intermediate compound 153F (2.7 g, crude, HC1) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 8.62 (s, 1H), 7.63 (dd, = 7.9 Hz, 2H), 7.40 (dd, = 7.5 Hz, 2H), 6.80 (s, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 2.34 (s, 3H).
[0909] To a mixture of compound 153F (300 mg, 1.06 mmol, HC1) in DCM (20 mL) was added Et 3 N (268.15 mg, 2.65 mmol, 0.4 mL) and benzyl carbonochloridate (181 mg, 1.06 mmol, 0.2 mL) in portion at 25 °C and stirred for 1.5h. The reaction mixture was treated with DCM (20 mL), added with H 2 0 (30 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound 153G (350 mg, yield: 87.03%) as off-white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.42 - 7.29 (m, 9H), 6.82 - 6.78 (m, 1H), 5.16 (s, 2H), 4.45 (dd, J = 6.2 Hz, 2H), 3.80 - 3.77 (m, 3H), 2.39 - 2.34 (m, 3H). MS (ESI) m/z (M+H) + 380.0.
[0910] To a mixture of compound 153G (350 mg, 922.48 umol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (116 mg, 2.77 mmol) in portion at 25 °C and stirred for 1.5h. The mixture was diluted with H 2 0 (10 mL) and concentrated to remove THF, then, the water was extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with IN HC1, then, the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 153H (300 mg, yield: 89.04%) as white solid. 1H NMR (400MHz, CDC1 3 ) S 7.35 (dd, = 5.3, 8.2 Hz, 6H), 7.30 - 7.16 (m, 2H), 7.14 - 6.98 (m, 1H), 6.90 - 6.82 (m, 1H), 5.15 (s, 2H), 4.47 - 4.30 (m, 2H), 2.46 - 2.28 (m, 3H). MS (ESI) m/z (M+H) + 366.1.
[0911] Compound 153 (35 mg, yield: 50.19%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 153H. Compound 153: 1H NMR (400MHz, DMSO-i¾) δ 9.04 (d, = 7.7 Hz, 1H), 8.09 (s, 1H), 7.84 (br s, 2H), 7.38 - 7.17 (m, 12H), 7.09 (d, = 8.2 Hz, 2H), 6.53 (s, 1H), 5.27 (t, = 7.5 Hz, 1H), 5.04 (s, 2H), 4.20 (d, = 6.0 Hz, 2H), 3.19 (dd, = 3.3, 14.1 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.22 (s, 3H). MS (ESI) m/z (M+H) + 540.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4- (BENZAMIDOMETHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE
[0912] To a mixture of compound 153F (300 mg, 1.06 mmol, HCl), benzoic acid (155 mg, 1.27 mmol, 0.2 mL), HOBt (286 mg, 2.12 mmol) and DIEA (343 mg, 2.65 mmol, 0.5 mL) in DCM (20 mL) was added EDCI (406 mg, 2.12 mmol) in portion at 25 °C and stirred for 4h. The reaction mixture was treated with DCM (10 mL), washed with H 2 0 (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic layer was washed with 0.5N HCl (20 mL x 2), NaHC0 3 (20 mL x 2) and brine (30 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound 154A (280 mg, yield: 75.61%) as offwhite solid. 1H NMR (400MHz, CDC1 3 ) δ 7.81 (dd, = 6.4 Hz, 2H), 7.58 - 7.40 (m, 7H), 6.85 - 6.78 (m, 1H), 6.48 (br s, 1H), 4.72 (br d, = 5.1 Hz, 2H), 3.84 - 3.77 (m, 3H), 2.41 - 2.34 (m, 4H). MS (ESI) m/z (M+Na) + 372.0.
[0913] To a mixture of compound 154A (280 mg, 801.42 umol) in MeOH (10 mL) and H 2 0 (10 mL) was added NaOH (2M, 2 mL) in portion at 25 °C and stirred for 3h. The mixture was concentrated to remove MeOH and then the water was extracted with MTBE (30 mL x 2). The water layer were acidized to pH ~ 2 with IN HC1, then the solution extracted with ethyl acetate (20 mL x 2). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 154B (200 mg, yield: 74.41%) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.79 (dd, = 8.2 Hz, 2H), 7.50 - 7.31 (m, 7H), 6.78 (s, 1H), 4.62 (s, 2H), 2.31 (s, 3H). MS (ESI) m/z (M+H) + 336.0.
[0914] Compound 154 (20 mg, yield: 29.53%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 154B. Compound 154: 1H NMR (400MHz, DMSO- 6 ) δ 9.11 - 9.04 (m, 2H), 8.11 (s, 1H), 7.96 - 7.91 (m, 2H), 7.86 (s, 1H), 7.56 - 7.47 (m, 3H), 7.30 (d, = 4.4 Hz, 3H), 7.27 (d, = 8.6 Hz, 2H), 7.23 - 7.19 (m, 1H), 7.12 (d, = 8.4 Hz, 2H), 6.55 (s, 1H), 5.32 - 5.26 (m, 1H), 4.51 (br d, J = 5.7 Hz, 2H), 3.21 (dd, J = 3.5, 13.9 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 510.1.
[0915] Following the procedure as used for compound 154B, intermediate compound 155B (200 mg, yield: 74.41%, white solid) was prepared from compound 153F through 155A. Compound 155B: 1H NMR (400MHz, CDCI 3 ) δ 7.28 - 7.12 (m, 8H), 6.94 (s, 1H), 6.78 (s, 1H), 4.42 - 4.31 (m, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H). MS (ESI) m/z (M+H) + 364.1.
[0916] Compound 155 (20 mg, yield: 27.16%, light yellow solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 155B. Compound 155: 1H NMR (400MHz, DMSC fc) δ 9.06 (d, J = 7.7 Hz, 1H), 8.38 (t, J = 5.8 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.33 - 7.29 (m, 4H), 7.27 (d, J = 7.5 Hz, 2H), 7.24 - 7.18 (m, 3H), 7.13 - 7.07 (m, 4H), 6.56 (s, 1H), 5.30 (dd, = 2.6 Hz, 1H), 4.27 (d, = 5.7 Hz, 2H), 3.25 - 3.19 (m, 1H), 2.87 - 2.83 (m, 2H), 2.53 (d, J = 2.0 Hz, 1H), 2.49 - 2.44 (m, 2H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 538.2.
[0917] Following the procedure as used for compound 154B, intermediate compound 156B (250 mg, yield: 86.48%, white solid) was prepared from compound 153F through 156A. Compound 156B: 1H NMR (400MHz, CDC1 3 ) δ 7.85 (dd, = 7.7 Hz, 2H), 7.61 - 7.43 (m, 3H), 7.29 - 7.20 (m, 4H), 6.78 (s, 1H), 4.09 (s, 2H), 2.30 (s, 3H). MS (ESI) m/z (M+H) + 372.0.
[0918] Compound 156 (45 mg, yield: 78.05%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 156B. Compound 156: 1H NMR (400MHz, DMSO-i¾) δ 9.10 - 9.01 (m, 1H), 8.19 (br s, 1H), 8.09 (s, 1H), 7.86 - 7.79 (m, 3H), 7.63 - 7.56 (m, 3H), 7.32 - 7.25 (m, 5H), 7.19 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.52 (s, 1H), 5.26 (br s, 1H), 3.97 (d, J = 5.3 Hz, 2H), 3.23 - 3.13 (m, 1H), 2.87 - 2.75 (m, 1H), 2.22 (s, 3H). MS (ESI) m/z (M+H) + 546.1. (5)-l-(4-(ACETAMIDOMETHYL)PHENYL)-N-(4-AMINO-3,4-DIOXO-l- P -2-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (157)
[0919] Following the procedure as used for compound 154B, intermediate compound 157B (162 mg, yield: 94.62%, white solid) was prepared from compound 153F through 157A. Compound 157B: 1 H NMR (400MHz, DMSO-d 6 ) δ 13.20 (br s, 1H), 8.43 (br t, 7 = 5.8 Hz, 1H), 7.37 - 7.25 (m, 4H), 6.79 (s, 1H), 4.29 (d, 7 = 6.0 Hz, 2H), 2.23 (s, 3H), 1.88 (s, 3H).
[0920] Compound 157 (17 mg, yield: 33.13%, gray solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 157B. Compound 157: 1H NMR (400MHz, DMSO-d 6 ) δ 8.71 (br d, 7 = 7.5 Hz, 1H), 8.12 (br s, 1H), 7.83 - 7.54 (m, 2H), 7.31 - 7.18 (m, 9H), 6.55 (s, 1H), 5.35 - 5.27 (m, 1H), 4.28 (d, 7 = 6.0 Hz, 2H), 3.25 (d, 7 = 4.3 Hz, 0.5H), 3.21 (d, 7 = 4.0 Hz, 0.5H), 2.94 (s, 0.5H), 2.91 (d, 7=4.3 Hz, 0.5H), 2.25 (s, 3H), 1.91 (s, 3H). MS (ESI) m/z (M+H) + 448.1.
[0921] Following the procedure as used for compound 154B, intermediate compound 158B (150 mg, yield: 62.91%, white solid) was prepared from compound 153F through 158A. Compound 158B: 1H NMR (400MHz, CDC1 3 ) δ 7.36 - 7.28 (m, 4H), 6.78 (s, 1H), 4.36 (s, 2H), 3.67 (s, 3H), 2.34 - 2.30 (m, 3H). MS (ESI) m/z (M+H) + 289.9. [0922] Compound 158 (12 mg, yield: 22.68%, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 158B. Compound 158: 1H NMR (400MHz, DMSO-d 6 ) δ 9.08 (dd, 7 = 7.5 Hz, 1H), 8.13 (s, 1H), 7.87 (br s, 1H), 7.74 (s, 1H), 7.35 - 7.17 (m, 7H), 7.16 - 7.07 (m, 2H), 6.54 (s, 1H), 5.34 - 5.24 (m, 1H), 4.19 (dd, 7 = 6.0 Hz, 2H), 3.57 (s, 3H), 3.28 - 3.18 (m, 1H), 2.82 (dd, 7 = 10.9, 13.3 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 464.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4-( (2- PHENYLACETAMI -lH-PYRAZOLE-5-CARBOXAMIDE (159)
[0923] To a mixture of compound 153F (300 mg, 1.06 mmol, HC1) and 2- phenylacetic acid (173 mg, 1.27 mmol, 0.16 mL) in DMF (10 mL) was added DIEA (548 mg, 4.24 mmol, 0.75 mL) and HBTU (603 mg, 1.59 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 1.5h. The mixture was diluted with 30 mL ethyl acetate and 20 mL H 2 0, the organic layer was separated and washed with IN HC1 (20 mL x 2), saturated NaHC0 3 (20 mL x2) and brine (20 mL), the organic layer was dried with over Na 2 S0 4 , and filtered and organic layer was concentrated in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 4/1). Compound 159A (190 mg, yield: 49.32%) was obtained as a yellow oil. 1H NMR (400MHz, DMSO-d 6 ) δ 8.62 (br t, 7 = 5.8 Hz, 1H), 7.36 - 7.14 (m, 9H), 6.91 - 6.78 (m, 1H), 4.31 (d, 7 = 6.0 Hz, 2H), 3.69 (s, 3H), 3.48 (s, 2H), 2.24 (s, 3H).
[0924] To a solution of compound 159A (190 mg, 522.83 umol) in MeOH (8 mL) and H 2 0 (5 mL) was added NaOH (84 mg, 2.09 mmol). The mixture was stirred at 25 °C for 2h.
The reaction mixture was concentrated and added 10 mL of water and the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (10 mL x 2), the organic phase was dried over Na 2 S0 4 , and concentrated to give a residue. Compound 159B (143 mg, yield: 78.28%) was obtained as a white solid, which was used for next step directly. 1H NMR (400MHz, DMSO-i¾) δ 8.62 (br t, = 5.7 Hz, 1H), 7.34 - 7.24 (m, 8H), 7.24 - 7.19 (m, 1H), 6.76 (s, 1H), 4.30 (d, J = 5.7 Hz, 2H), 3.48 (s, 2H), 2.22 (s, 3H).
[0925] Compound 159 (25 mg, yield: 33.34%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 159B. Compound 159: 1H NMR (400MHz, DMSO-d 6 ) δ 8.31 (br s, 1H), 7.40 - 7.05 (m, 17H), 6.56 (s, 1H), 5.31 (dd, = 4.3, 9.8 Hz, 1H), 4.31 (d, = 4.3 Hz, 2H), 3.52 (s, 2H), 3.23 (dd, = 4.3, 14.1 Hz, 1H), 2.91 (dd, 7 = 10.0, 13.8 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 524.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4-((4- FLUOROBENZAMIDO)METHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-
[0926] Compound 496 (246.9 mg, yield: 80.2%, white solid) was prepared as in compound 154 using intermediate 153F and 4-fluorobenzoyl chloride and the resulting product was subjected to reactions as in compound 12 to obtain compound 496. Compound 496: 1H NMR (400MHz, DMSO-d 6 ) δ 99.20 - 9.05 (m, 2H), 8.13 (s, 1H), 8.05 - 7.96 (m, 2H), 7.87 (s, 1H), 7.40 - 7.16 (m, 9H), 7.16 - 7.08 (m, 2H), 6.54 (s, 1H), 5.32 - 5.22 (m, 1H), 4.55 - 4.45 (m, 2H), 3.22 - 3.14 (m, 1H), 2.83 -2.73 (m, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 526.2.
METHYL (S)-(4-(5-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)- 3-
METHYL-lH-PYRAZOL-l-YL BENZYL)CARBAMATE (161)
[0927] To a mixture of compound 153F (450 mg, 1.60 mmol, HC1) in DCM (15.00 mL) was added TEA (485 mg, 4.79 mmol, 0.7mL) and ethyl carbonochloridate (452 mg, 4.17 mmol, 0.4 mL) in portion at 25 °C and stirred for 2h. The reaction mixture was treated with DCM (20 mL), washed with H 2 0 (30 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous NaS0 4 , filtered and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1 to 1/1) to give compound 161A (400 mg, yield: 52.81%) as offwhite solid. 1H NMR (400MHz, CDC1 3 ) δ 7.37 (br s, 4H), 6.80 (dd, 7 = 3.5 Hz, 1H), 4.43 (s, 2H), 4.20 - 4.09 (m, 2H), 3.79 (d, 7 = 3.7 Hz, 3H), 2.36 (dd, 7 = 3.5 Hz, 3H), 1.27 (td, 7 = 3.5, 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 318.0.
[0928] To a mixture of compound 161A (400 mg, 1.26 mmol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (159 mg, 3.78 mmol) in portion at 25 °C and stirred for 0.5h. The mixture was diluted with H 2 0 (10 mL) and concentrated to remove THF, then, the water was extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with IN HC1, then, the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 161B (300 mg, yield: 78.50%) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.33 (s, 4H), 6.79 (s, 1H), 4.35 (s, 2H), 4.23 - 4.03 (m, 2H), 2.38 - 2.27 (m, 3H), 1.41 - 1.19 (m, 4H). MS (ESI) m/z (M+H) + 304.0.
[0929] Compound 161 (25 mg, yield: 22.8%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 161B. Compound 161: 1H NMR (400MHz, DMSO-d 6 ) δ 9.07 (dd, 7 = 8.2 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H), 7.42 - 7.27 (m, 5H), 7.20 (dd, 7 = 7.9 Hz, 2H), 7.16 - 7.06 (m, 2H), 6.54 (s, 1H), 5.34 - 5.24 (m, 1H), 4.18 (dd, 7 = 5.5 Hz, 2H), 4.02 (q, 7 = 7.1 Hz, 2H), 3.21 (dd, 7 = 2.9, 13.2 Hz, 1H), 2.92 - 2.77 (m, 1H), 2.24 (s, 3H), 1.18 (br t, 7 = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 478.1.
PHENYL (S)-(4-(5-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)- 3- METHYL-lH-PYRAZOL-l-YL BENZYL)CARBAMATE (162)
[0930] To a mixture of compound 153E (300 mg, 868.58 umol) in THF (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (109 mg, 2.61 mmol) in portion at 25 °C and stirred for 12h. The mixture was diluted with H 2 0 (10 mL) and concentrated to remove THF, then, the water was extracted with MTBE (30 mL x 2). The water layers were acidified to pH ~ 2 with IN HC1, then, the solution extracted with ethyl acetate (30 mL x 3). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 162A (250 mg, yield: 86.86%) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.41 - 7.30 (m, 2H), 7.27 - 7.04 (m, 2H), 6.86 (s, 1H), 4.43 - 4.26 (m, 2H), 2.46 - 2.32 (m, 3H), 1.60 - 1.40 (m, 9H). MS (ESI) m/z (M+H) + 332.0.
[0931] To a mixture of compound 12G (209 mg, 905.33 umol, HC1) and compound 162A (250 mg, 754.44 umol) in DMF (10 mL) was added DIEA (244 mg, 1.89 mmol, 0.3 mL) and HBTU (343 mg, 905.33 umol) in portion at 25 °C and stirred for 1.5h. The reaction mixture was treated with ethyl acetate (40 mL), washed with H 2 0 (50 mL x 2). The organic layer was washed with brine (30 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo. The residue was triturated in DCM (2 mL) and petroleum ether (10 mL), the solid was collected and was dried in vacuo to give compound 162B (300 mg, yield: 75.76%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.72 - 8.41 (m, 1H), 7.95 (s, 1H), 7.45 - 7.20 (m, 7H), 7.12 (dd, = 8.4 Hz, 2H), 7.02 - 6.91 (m, 2H), 6.70 - 6.48 (m, 1H), 6.08 (d, = 5.5 Hz, 1H), 4.45 (s, 1H), 4.12 - 3.98 (m, 2H), 2.89 (s, 1H), 2.87 - 2.80 (m, 1H), 2.73 (s, 1H), 2.28 - 2.14 (m, 3H), 1.52 -
1.33 (m, 9H). MS (ESI) m/z (M-56) + 452.1.
[0932] To a mixture of compound 162B (300 mg, 591.04 umol) in EA (10 mL) was added HCl/EtOAc (4M, 10 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2h. The mixture was concentrated to give intermediate compound 162C (250 mg, yield: 95.28%, HC1) as white solid. 1H NMR (400MHz, DMSO-d 6 ) <5 8.71 - 8.64 (m, 2H), 7.53 - 7.35 (m, 3H),
7.34 - 7.17 (m, 7H), 7.03 (dd, = 8.4 Hz, 2H), 6.65 (s, 1H), 4.59 - 4.30 (m, 1H), 4.15 (s, 2H), 2.88 (s, 1H), 2.83 (dd, = 11.9 Hz, 1H), 2.72 (s, 1H), 2.22 (s, 3H).
[0933] To a mixture of compound 162C (120 mg, 270.31 umol, HC1) in DCM (10 mL) was added Et 3 N (68 mg, 675.78 umol, 0.1 mL) and phenyl carbonochloridate (51 mg, 324.38 umol, 0.1 mL) in portion at 25 °C and stirred for lh. The reaction mixture was treated with DCM (20 mL), added with H 2 0 (30 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous NaS0 4 , filtered and concentrated. The residue was purified by preparatory-HPLC (HC1 condition) to give compound 162D (70 mg, yield: 47.71%) as off- white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.36 (s, 1H), 8.50 (dd, J = 9.0 Hz, 1H), 7.41 - 7.11 (m, 14H), 7.08 (s, 1H), 7.02 (dd, = 8.4 Hz, 1H), 6.99 (dd, = 8.4 Hz, 1H), 6.78 - 6.72 (m, 2H), 6.57 - 6.50 (m, 1H), 4.43 (s, 1H), 4.31 - 4.22 (m, 2H), 3.99 (s, 1H), 2.87 - 2.75 (m, 2H), 2.74 - 2.65 (m, 2H), 2.27 - 2.20 (m, 3H). MS (ESI) m/z (M+H) + 528.1.
[0934] To a mixture of compound 162D (40 mg, 75.82 umol) in DMSO (3 mL) and DCM (15 mL) was added DMP (96 mg, 227.46 umol) in one portion at 25 °C under N 2 . The mixture was stirred at 25 °C for 1.5h. The reaction mixture was diluted with DCM (10 mL), NaHC0 3 (5 mL) and Na 2 S 2 0 3 (10 mL), then stirred for 10 min and layers were separated. The organic layers were washed with water (50 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was triturated in DCM (2 mL) and petroleum ether (10 mL), the solid was collected and was dried in vacuo to give compound 162 (25 mg, yield: 51.13%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.15 (d, = 8.0 Hz, 1H), 8.39 (t, J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.41 - 7.19 (m, 11H), 7.14 (dd, 7 = 8.0 Hz, 3H), 6.68 - 6.51 (m, 1H), 5.41 - 5.22 (m, 1H), 4.29 (dd, = 6.0 Hz, 2H), 3.21 (dd, = 3.5, 13.6 Hz, 1H), 2.85 (dd, 7 = 10.8, 13.8 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 526.1. EXAMPLE 95
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-( n-TOLYL)-lH- -4-CARBOXAMIDE (163)
[0935] To a solution of i-BuONO (3.8 niL, 30.94 mmol) in CH 3 CN (60 mL) was added CuBr 2 (6.91 g, 30.94 mmol). The mixture was stirred at 25 °C for lh under N 2 . Then ethyl 3-amino- lH-pyrazole-4-carboxylate (4 g, 25.78 mmol) was added in portions. The mixture was then heated to 70 °C and stirred for 12h. The reaction was washed with H 2 0 (100 mL), extracted with EtOAc (100 mL x 2). The organic s were collected, dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 163A (6 g, crude) as black oil. MS (ESI) m/z (M+2) + 220.9.
[0936] To a solution of compound 163A (10 g, 45.65 mmol) and Cs 2 C0 3 (29.75 g,
91.30 mmol) in DMF (250 mL) was added Mel (19.44 g, 136.95 mmol, 8.53 mL). The mixture was stirred at 25 °C for 16h. The mixture was filtered, the filtrate was diluted with H 2 0 (500 mL), and extracted with ethyl acetate (100 mL x 3), dried over Na 2 S0 4 , concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 163B (2.5 g, yield: 23.50%) was obtained as a yellow oil, and
Compound 163C (5.5 g, yield: 51.70%) was obtained as a white solid. [0937] Compound 163B: 1H NMR (400MHz, CDC1 3 ) S 7.93 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.95 - 3.87 (m, 3H), 1.36 (t, J = 7.1 Hz, 3H).
[0938] Compound 163C: 1H NMR (400MHz, CDCI3) δ 7.82 (s, 1H), 4.30 (q, = 7.1 Hz, 2H), 3.99 - 3.77 (m, 3H), 1.35 (t, J = 7.2 Hz, 3H).
[0939] To a solution of compound 163B (600 mg, 2.57 mmol) in MeOH (10 mL) and H 2 0 (10 mL) was added NaOH (514 mg, 12.85 mmol). The mixture was stirred at 25 °C for 3h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (20 mL x 2), the organic phase was dried over Na 2 S0 4 , concentrated to give a residue. Compound 163D (480 mg, yield: 91.05%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 12.65 (s, 1H), 8.13 (s, 1H), 3.82 (s, 3H).
[0940] To a solution of Compound 163D (450 mg, 2.20 mmol), (3S)-3-amino-2- hydroxy-4-phenyl-butanamide 12G (761 mg, 3.30 mmol, HC1) and HOBT (445 mg, 3.30 mmol) in DCM (20 mL) was added DIEA (1.14 g, 8.80 mmol, 1.54 mL) and EDCI (843 mg, 4.40 mmol). The mixture was stirred at 25 °C for 16h. The mixture was diluted with CHCI 3 : z ' PrOH = 3: 1 (50 mL), washed with IN HC1 (30 mL), saturated aqueous NaHC0 3 (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na 2 S0 4 and concentrated in vacuo. The solid was triturated in ethyl acetate (30 mL), filtered. Compound 163E (550 mg, yield: 61.64%) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.09 - 7.95 (m, 1H), 7.78 (d, = 8.8 Hz, 0.6H), 7.46 (d, = 9.0 Hz, 0.4H), 7.38 - 7.07 (m, 6H), 6.01 - 5.86 (m, 1H), 4.54 - 4.33 (m, 1H), 4.00 (dd, = 3.4, 5.2 Hz, 1H), 3.85 - 3.74 (m, 4H), 2.93 - 2.67 (m, 1H), 2.62 (dd, = 2.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 381.0.
[0941] To a solution of compound 163C (2.6 g, 11.16 mmol) in MeOH (10 mL) and H 2 0 (10 mL) was added LiOH.H 2 0 (2.34 g, 55.80 mmol). The mixture was stirred at 25 °C for 12h. The reaction mixture was concentrated and added 20 mL of water and the mixture was extracted with MTBE (20 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (30 mL x 2), the organic phase was dried over Na 2 S0 4 and concentrated to give a residue. Compound 163F (2.2 g, yield: 96.16%) was obtained as a gray solid, which was used for next step directly. 1H NMR (400MHz, DMSO- 6 ) δ 12.55 (br s, 1H), 8.24 (s, 1H), 3.81 (s, 3H). [0942] To a mixture of compound 163F (2.2 g, 10.73 mmol) and compound 12G (2.97 g, 12.88 mmol HC1) in DMF (20 mL) and HOBt (2.17 g, 16.10 mmol) and DIEA (4.16 g, 32.19 mmol, 5.62 mL) and EDCI (4.11 g, 21.46 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 12h. The reaction mixture was diluted with H 2 0 (40 mL) and extracted with CHC1 3 : isopropanol (v: v = 3: 1 ; 30 x 3 mL), then the organic phase was washed with IN HC1 (20 mL x 2) and saturated aqueous NaHC0 3 (20 mL x 2). The mixture was dried over Na 2 S0 4 and concentrated. The residue was diluted with EtOAc (15 mL) the solid was collected and dried in vacuo. Compound 163G (2.9 g, yield: 68.06%) was obtained as a white solid. 1H NMR (400MHz, DMSO- e) δ 8.18 (s, 1H), 7.61 (br d, J = 8.8 Hz, 1H), 7.31 (br d, J = 2.4 Hz, 2H), 7.24 - 7.13 (m, 5H), 5.89 (d, J = 5.7 Hz, 1H), 4.51 - 4.40 (m, 1H), 4.00 - 3.97 (m, 1H), 3.79 (s, 3H), 2.80 - 2.76 (m, 1H), 2.65 - 2.58 (m, 1H). MS (ESI) m/z (M+H) + 381.0.
[0943] Compound 163G (200 mg, 525 umol), m-tolylboronic acid (85.6 mg, 629 umol), Pd(dppf)Cl 2 (38.4 mg, 52.5 umol) and K 2 C0 3 (145 mg, 1.05 mmol) in dioxane (5 mL) was de-gassed and then heated to 100 °C for 12 hours under N 2 . The mixture was filtered and concentrated, the residue was purified by prep-TLC (Dichloromethane: Methanol = 10: 1) to give compound 163H (100 mg, yield: 48.6%), as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.99 (d, J = 19.4 Hz, 1H), 7.37 (br s, 1H), 7.31 - 7.06 (m, 11H), 5.76 (br s, 1H), 4.52 - 4.31 (m, 1H), 3.98 (br s, 1H), 3.83 (s, 3H), 3.80 (br s, 1H), 2.87 - 2.72 (m, 1H), 2.71 - 2.56 (m, 1H), 2.26 (d, = 6.8 Hz, 3H).
[0944] A mixture of compound 163H (100 mg, 255 umol) and DMP (432 mg, 1.02 mmol) in DCM (10 mL), DMSO (2 mL) was stirred at 25°C for 1 hr. The mixture was diluted DCM (20 mL), quenched with saturated aqueous NaHC0 3 (20 mL), saturated aqueous Na 2 S 2 0 3 (20 mL) and stirred for 20 min, the mixture was extracted with DCM (20 mL x 2), the combined organic phase was washed with water (20 mL), brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated, the residue was stirred in DCM and n-hexane for 20 min, the solid was filtered and dried to give 163 (43.5 mg, yield: 43.7%) as white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 8.23 (br d, = 7.3 Hz, 1H), 8.08 - 7.97 (m, 2H), 7.78 (s, 1H), 7.38 (s, 1H), 7.31 (br d, = 7.5 Hz, 1H), 7.28 - 7.13 (m, 6H), 7.11 - 7.05 (m, 1H), 5.31 - 5.21 (m, 1H), 3.85 (s, 3H), 3.12 (dd, J = 3.7, 13.9 Hz, 1H), 2.79 (dd, / = 9.7, 13.9 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 391.1. EXAMPLE 96
COMPOUNDS 164, 169, 480-488, 498-518, 530, 548, 567-573, 585, 587, 591, 593, 597, 601-
605, 607, 611, 613-617, 620-621, 624-629
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-( PYRIDIN-2-YL)- -PYRAZOLE-4-CARBOXAMIDE (164)
[0945] To the mixture of 163E (200 mg, 527 umol) and tributyl(2-pyridyl)stannane (388 mg, 1.05 mmol) in toluene (5 mL) was added Pd(PPh 3 ) 4 (60.9 mg, 52.7 umol) under N 2 (15 psi). After stirred at 110 °C for 10 h, the mixture was concentrated in vacuum to get residue. The residue was purified by preparatory-HPLC (acid) to get compound 164A (85 mg, yield: 42.5%) as light yellow solid. 1H NMR (400 MHz, CDC1 3 - ) δ 8.97 (br d, J = Ί .06 Hz, 1H), 8.72 (br d, = 7.28 Hz, 1H), 8.55 (dd, = 17.64, 4.85 Hz, 1H), 8.03 - 7.95 (m, 1H), 7.88 - 7.79 (m, 1H), 7.43 - 7.31 (m, 2H), 7.13 - 6.99 (m, 6H), 5.49 (br d, = 10.14 Hz, 1H), 4.27 - 4.17 (m, 2H), 3.89 (d, = 3.53 Hz, 3H), 3.26 - 2.91 (m, 2H).
[0946] Compound 164 (31 mg, yield: 41.6%, white solid) was prepared as in Example 105 from the intermediate compound 164A. Compound 164: 1H NMR (400MHz, CDC1 3 - ) δ 8.51 (br d, = 6.4 Hz, 1H), 8.43 (d, = 5.1 Hz, 1H), 8.01 (s, 1H), 7.84 (br t, = 7.8 Hz, 1H), 7.49 (d, =7.9 Hz, 1H), 7.32 (dd, 7 = 5.3, 7.1 Hz, 1H), 7.21 - 7.09 (m, 3H), 6.96 (br d, = 5.7 Hz, 2H), 6.75 (br s, 1H), 5.70 - 5.60 (m, 2H), 3.89 (s, 3H), 3.33 (dd, J = 5.1, 14.3 Hz, 1H), 3.15 (dd, J = 7.1, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR IDIN-2-YL)-
1H-PYRAZOLE-4-CARBOXAMIDE (169)
[0947] Compound 169 (20 mg, yield: 48.2%, white solid) was prepared as in compound 163 from the corresponding starting materials, compound 163G and tributyl(2- pyridyl)stannane. 1H NMR (400MHz, OMSO-d 6 ) δ 11.88 (br d, J = 7.9 Hz, 1H), 8.32 (br d, J = 5.3 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.74 (br s, 1H), 7.52 (br s, 1H), 7.40 - 7.32 (m, 1H), 7.20 - 7.05 (m, 5H), 5.64 - 5.47 (m, 1H), 3.91 (s, 3H), 3.27 (dd, = 4.8, 14.5 Hz, 1H), 3.12 - 3.07 (m, 1H). MS (ESI) m/z (M+H) + 378.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,3-DIFLUOROPHEN YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (480)
[0948] Compound 480 (60 mg, yield: 48.13%, white solid) was prepared as in compound 163 from the corresponding starting materials, compound 163G and (2,3- difluorophenyl)boronic acid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.39 (d, = 7.3 Hz, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.45 - 7.34 (m, 1H), 7.33 - 7.13 (m, 7H), 5.28 - 5.22 (m, 1H), 3.92 (s, 3H), 3.13 (dd, = 3.6, 13.8 Hz, 1H), 2.83 (dd, = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 413.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(6-CYANOPYRIDIN-3 -YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (481)
[0949] Compound 481 (15 mg, yield: 37.47%, white solid) was prepared as in compound 163 from the corresponding starting materials, compound 163G and (6-cyanopyridin- 3-yl)boronic acid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.91 (d, = 1.8 Hz, 1H), 8.67 (d, = 7.3 Hz, 1H), 8.25 (s, 1H), 8.15 (dd, = 2.0, 8.2 Hz, 1H), 8.08 (s, 1H), 7.97 (d, = 8.2 Hz, 1H), 7.81 (s, 1H), 7.27 (d, = 4.4 Hz, 4H), 7.24 - 7.17 (m, 1H), 5.27 (t, = 3.0 Hz, 1H), 3.94 (s, 3H), 3.15 (dd, = 3.7, 13.9 Hz, 1H), 2.86 - 2.74 (m, 1H). MS (ESI) m/z (M+H) + 403.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(lH-INDAZOL-3-YL) -l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (482)
[0950] Compound 482 (18 mg, yield: 14.77%, white solid) was prepared as in compound 163 from the corresponding starting materials, compound 163C and 3-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- IH-indazole and the final compound 482 was obtained by removal of the 2-(trimethylsilyl)ethoxy)methyl group. 1H NMR (400MHz, DMSO-d 6 ) δ 11.10 (br s, 1H), 9.57 (br s, 1H), 8.44 (d, = 8.0 Hz, 1H), 8.08 (s, 1H), 7.46 - 7.38 (m, 2H), 7.24 (s, 6H), 6.84 (br s, 1H), 5.70 (br s, 1H), 5.50 (br s, 1H), 3.97 (s, 3H), 3.42 - 3.32 (m, 1H), 3.26 - 3.20 (m, 1H). MS (ESI) m/z (M+H) + 417.0. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-BENZYL-l-METHYL-l H-
[0951] Compound 483 (65 mg, yield: 66.57%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate and 2-benzyl-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane and the final compound 483 was obtained by removal of the 2- (trimethylsilyl)ethoxy)methyl group. 1H NMR (400MHz, OMSO-d 6 ) δ 8.33 (d, = 7.1 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.31 - 7.23 (m, 4H), 7.20 - 7.07 (m, 6H), 5.31 - 5.23 (m, 1H), 4.05 (s, 2H), 3.77 (s, 3H), 3.20 - 3.09 (m, 1H), 2.91 - 2.80 (m, 1H). MS (ESI) m/z (M+H) + 391.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUOROPHENYL)- l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (484)
[0952] Compound 484 (3.35 g, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound 163C and (2- fluorophenyl)boronic acid and the final compound 484 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.30 (d, = 7.3 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.41 - 7.11 (m, 9H), 5.30 - 5.18 (m, 1H), 3.90 (s, 3H), 3.12 (dd, = 3.6, 14.0 Hz, 1H), 2.83 (dd, = 9.8, 13.8 Hz, 1H). MS (ESI) m/z (M +H) + 395.0.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-FLUOROPHENYL)- l- METHYL-l -PYRAZOLE-4-CARBOXAMIDE HYDROCHLORIDE (485)
[0953] Compound 485 was synthesized from intermediate 590 which was synthesized using 163H. Compound 485 (3.1 g, yield: 79.85% white solid) was prepared from intermediate 590 using the procedures similar to compound 163 from the corresponding starting materials and the final compound 485 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.51 (d, = 7.3 Hz, 1H), 8.12 (s, 2H), 7.85 (br s, 1H), 7.46 (d, = 8.3 Hz, 2H), 7.39 - 7.28 (m, 5H), 7.25 - 7.20 (m, 1H), 7.14 (t, = 8.0 Hz, 1H), 5.43 - 5.25 (m, 1H), 3.18 (dd, = 3.4, 13.7 Hz, 1H), 2.84 (dd, = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 395.1..
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,6-DIFLUOROPHEN YL)-l- METHYL- 1H-PYRAZOLE-4-CARBOXAMIDE (486)
[0954] Compound 486 (60 mg, yield: 43.0% light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound 163C and (2,6-difluorophenyl)boronic acid and the final compound 486 was obtained. 1H NMR (400MHz, CDC1 3 ) δ 7.94 (s, 1H), 7.41 - 7.33 (m, 1H), 7.22 - 7.17 (m, 3H), 6.99 - 6.93 (m, 2H), 6.88 (dd, = 3.0, 6.3 Hz, 2H), 6.67 (br s, 1H), 6.01 (br d, = 7.1 Hz, 1H), 5.63 - 5.57 (m, 1H), 5.53 (br s, 1H), 3.97 (s, 3H), 3.27 (dd, = 5.3, 14.1 Hz, 1H), 3.09 (dd, = 6.6, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 413.1
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(6-METHOXYPYRIDIN -2-YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (487)
[0955] Compound 487 (10 mg, yield: 20.06% white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound 163C and 2-methoxy-6-(tributylstannyl)pyridine and the final compound 487 was obtained. 1H NMR (400MHz, CD 3 CN) δ 11.02 (d, = 5.5 Hz, 1H), 8.01 (s, 1H), 7.81 (t, = 7.9 Hz, 1H), 7.60 (d, = 7.5 Hz, 1H), 7.14 - 7.06 (m, 5H), 7.00 - 6.88 (m, 1H), 6.81 (d, = 8.2 Hz, 1H), 6.23 - 6.01 (m, 1H), 5.21 - 5.15 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.27 (dd, = 4.4, 13.9 Hz, 1H), 2.97 (dd, = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 408.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-BENZYL-l-METHYL-l H-
[0956] Compound 488 (35.6 mg, yield: 35.57%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 5-iodo-l-methyl-lH-pyrazole-4-carboxylate and 2-benzyl-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane and the final compound 488 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.40 (d, = 7.8 Hz, 1H), 8.03 (br. s, 1H), 7.92 (s, 1H), 7.77 (br. s, 1H), 7.31 - 7.03 (m, 10H), 5.32 - 5.23 (m, 1H), 4.36 - 4.24 (m, 2H), 3.58 (s, 3H), 3.19 - 3.10 (m, 1H), 2.89 - 2.79 (m, 1H). MS (ESI) m/z (M+H) + 391.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(5-METHY LFURAN- 2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (498)
[0957] Compound 498 (70 mg, yield: 54.1%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (5-methylfuran-2-yl)boronic acid and the final compound 498 was obtained. 1H NMR (400MHz, OMSO-d 6 ) δ 8.38 - 8.22 (m, 1H), 8.20 - 8.01 (m, 2H), 7.91 - 7.71 (m, 1H), 7.31 - 7.17 (m, 5H), 6.90 (d, J = 3.1 Hz, 1H), 6.08 (d, J = 2.2 Hz, 1H), 5.47 - 5.20 (m, 1H), 3.87 (s, 3H), 3.17 (dd, J = 3.9, 13.8 Hz, 1H), 2.88 (dd, J = 9.7, 14.1 Hz, 1H), 2.29 - 2.19 (m, 3H). MS (ESI) m/z (M+H) + 381.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,5-DIMETHYLTHIO PHEN-3- YL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (499)
[0958] Compound 499 (110 mg, yield: 64.9%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2,5-dimethyl-3-thienyl)boronic acid and the final compound 499 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.14 - 8.00 (m, 2H), 7.87 - 7.73 (m, 2H), 7.34 - 7.12 (m, 5H), 6.58 (d, J = 1.1 Hz, 1H), 5.28 (ddd, J = 4.0, 7.3, 9.5 Hz, 1H), 3.91 - 3.79 (m, 3H), 3.14 (dd, J = 4.0, 13.9 Hz, 1H), 2.77 (dd, 7 = 9.4, 14.0 Hz, 1H), 2.33 (s, 3H), 2.22 - 2.12 (m, 3H). MS (ESI) m/z (M+H) + 411.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(FURAN-2-YL)-l-ME THYL-lH-
[0959] Compound 500 (55 mg, yield: 91.2%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo- l-methyl-lH-pyrazole-4-carboxylate and 2-furylboronic acid and the final compound 500 was obtained. 1H NMR (400MHz, OMSO-d 6 ) δ 8.37 (d, = 7.1 Hz, 1H), 8.14 (s, 1H), 8.07 (br s, 1H), 7.81 (br s, 1H), 7.61 (s, 1H), 7.28 (s, 4H), 7.20 (br s, 1H), 6.99 (d, = 2.9 Hz, 1H), 6.48 (br s, 1H), 5.37 - 5.28 (m, 1H), 3.88 (s, 3H), 3.18 (dd, J = 3.5, 13.7 Hz, 1H), 2.86 (dd, J = 9.7, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 367.1 N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-CHLOROTHIOPHEN -3-YL)-l- METHYL-1H-PYRAZOLE-4-CARBOXAMIDE (501)
[0960] Compound 501 (110 mg, yield: 68.3%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2-chlorothiophen-3-yl)boronic acid and the final compound 501 was obtained. 1H NMR (400MHz, OMSO-d 6 ) δ 8.13 (s, 1H), 7.80 - 7.46 (m, 3H), 7.35 (d, J = 5.8 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.23 - 7.16 (m, 3H), 6.98 (d, J = 5.8 Hz, 1H), 5.31 (m, 1H), 3.89 (s, 3H), 3.17 (dd, J = 4.4, 13.9 Hz, 1H), 2.88 (dd, J = 8.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 417.1.
[0961] Compound 502 (160 mg, yield: 63.78%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo- l-methyl-lH-pyrazole-4-carboxylate and furan-3-ylboronic acid and the final compound 502 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.35 (d, J = 7.6 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.13 (s, 1H), 8.04 (br. s, 1H), 7.76 (br. s, 1H), 7.61 - 7.57 (m, 1H), 7.31 - 7.14 (m, 5H), 6.80 - 6.75 (m, 1H), 5.32 - 5.23 (m, 1H), 3.85 (s, 3H), 3.19 - 3.11 (m, 1H), 2.88 - 2.78 (m, 1H). MS (ESI) m/z (M+H) + 367.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(THIOPHE N-3-YL)-
[0962] Compound 503 (65 mg, yield: 47.7%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and thiophen-3-ylboronic acid and the final compound 503 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.37 (d, J = 7.3 Hz, 1H), 8.04 (s, 2H), 7.92 (s, 1H), 7.77 (br s, 1H), 7.50 - 7.34 (m, 2H), 7.30 - 7.22 (m, 4H), 7.18 (dd, J = 4.4, 8.6 Hz, 1H), 5.38 - 5.18 (m, 1H), 3.84 (s, 3H), 3.22 - 3.08 (m, 1H), 2.81 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 383.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(4- METHYLTHIOPHEN-2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (504)
[0963] Compound 504 (100 mg, yield: 65.93%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate and (4-methylthiophen-2-yl)boronic acid and the final compound 504 was obtained. 1H NMR (400MHz, DMSO- 6 ) δ 8.37 (d, =
7.2 Hz, 1H), 8.09 (s, 1H), 8.06 (br. s, 1H), 7.78 (br. s, 1H), 7.57 - 7.54 (m, 1H), 7.29 - 7.23 (m, 4H), 7.22 - 7.15 (m, 1H), 6.99 - 6.95 (m, 1H), 5.34 - 5.27 (m, 1H), 3.83 (s, 3H), 3.19 - 3.10 (m, 1H), 2.88 - 2.77 (m, 1H), 2.14 (s, 3H). MS (ESI) m/z (M+H) + 397.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(5- METHYLTHIOPHEN-2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (505)
[0964] Compound 505 (130 mg, yield: 61%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4-carboxylate and (5-methylthiophen-2-yl)boronic acid and the final compound 505 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.68 (s, 1H), 8.57 (d, = 7.5 Hz, 1H), 8.53 - 8.48 (m, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.92 - 7.86 (m, 1H), 7.81 (s, 1H), 7.34 - 7.25 (m, 4H), 7.23 - 7.18 (m, 1H), 5.36 - 5.28 (m, 1H), 3.94 (s, 3H), 3.17 (dd, J = 3.9, 14.0 Hz, 1H), 2.83 (dd, / = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 396.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(5-FLUOROPYRIDIN- 3-YL)-l- METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (506)
[0965] Compound 506 (35 mg, yield: 20.4%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate and (5-fluoropyridin-3-yl)boronic acid and the final compound 506 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.40 (d, = 7.3 Hz, 1H), 8.16 -
8.03 (m, 2H), 7.81 (s, 1H), 7.54 (d, = 3.5 Hz, 1H), 7.29 (d, = 4.2 Hz, 4H), 7.24-7.19 (m, 1H), 6.66 (dd, = 1.0, 3.6 Hz, 1H), 5.34-5.29 (m, 1H), 3.85 (s, 3H), 3.17 (dd, = 3.7, 13.9 Hz, 1H), 2.84 (dd, = 9.9, 13.9 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z (M+H) + 397.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUORO-5- METHOXYPHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (507)
[0966] Compound 507 (34 mg, yield: 15.75%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2-fluoro-5-methoxyphenyl)boronic acid and the final compound 507 was obtained. 1H NMR (400MHz, OMSO-d 6 ) δ 8.14 (s, 1H), 7.68 (br d, J = 7.0 Hz, 2H), 7.51 (br s, 1H), 7.30 - 7.15 (m, 5H), 7.10 - 7.01 (m, 1H), 6.98 - 6.87 (m, 2H), 5.28 (ddd, J = 4.6, 7.3, 8.8 Hz, 1H), 3.90 (s, 3H), 3.75 (s, 3H), 3.15 (dd, / = 4.5, 14.1 Hz, 1H), 2.87 (dd, = 8.9, 14.2 Hz, 1H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -124.53 (br d, = 88.69 Hz, 1 F). MS (ESI) m/z (M+Na) + 447.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3- (DIFLUOROMETHYL)PHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE
[0967] Compound 508 (140 mg, yield: 69.98%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (3-(difluoromethyl)phenyl)boronic acid and the final compound 508 was obtained. 1H NMR (400MHz, OMSO-d 6 ) δ 8.43 (d, = 7.6 Hz, 1H), 8.09 (s, 1H), 8.02 (br. s, 1H), 7.85 - 7.81 (m, 1H), 7.78 (br. s, 1H), 7.73 - 7.67 (m, 1H), 7.51 - 7.46 (m, 1H), 7.44 - 7.39 (m, 1H), 7.30 - 7.16 (m, 5H), 7.15 - 6.84 (m, 1H), 5.32 - 5.23 (m, 1H), 3.89 (s, 3H), 3.19 - 3.11 (m, 1H), 2.87 - 2.76 (m, 1H). MS (ESI) m/z (M+H) + 427.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUORO-3- METHOXYPHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (509)
[0968] Compound 509 (190 mg, yield: 66.92%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2-fluoro-3-methoxyphenyl)boronic acid and the final compound 509 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 8.13 (d, = 7.6 Hz, 1H), 7.96 (br. s, 1H), 7.73 (br. s, 1H), 7.30 - 7.16 (m, 5H), 7.14 - 7.01 (m, 2H), 6.87 - 6.79 (m, 1H), 5.27 - 5.16 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.14 - 3.06 (m, 1H), 2.84 - 2.74 (m, 1H). MS (ESI) m/z (M+H) + 425.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,2- DIFLUOROBENZO[rf][l,3]DIOXOL-4-YL)-l-METHYL-lH-PYRAZOLE-4-
[0969] Compound 510 (70 mg, yield: 34%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2,2-difluorobenzo[<i] [ 1 ,3]dioxol-4-yl)boronic acid and the final compound 510 was obtained. 1H NMR (400MHz, DMSO- 6 ) δ 8.44 (d, = 7.5 Hz, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.35 (d, = 7.8 Hz, 1H), 7.31 - 7.12 (m, 7H), 5.34 - 5.21 (m, 1H), 3.93 (s, 3H), 3.14 (dd, J = 3.6, 13.9 Hz, 1H), 2.82 (dd, J = 9.9, 14.2 Hz, 1H). MS (ESI) m/z (M+H) + 457.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-METHOXYPHENYL) -l- METHYL- 1H-PYRAZOLE-4-CARBOXAMIDE (511)
[0970] Compound 511 (23 mg, yield: 8.04%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (2-methoxyphenyl)boronic acid and the final compound 511 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.04 (s, 1H), 7.72 (br s, 1H), 7.55 (br s, 1H), 7.37 (br t, J = 7.9 Hz, 1H), 7.28 - 7.10 (m, 5H), 7.08 - 6.90 (m, 4H), 5.30 (br d, = 4.3 Hz, 1H), 3.91 - 3.81 (m, 3H), 3.66 - 3.54 (m, 3H), 3.12 (br d, J = 4.3 Hz, 1H), 2.76 (dd, J = 8.8, 14.1 Hz, 1H). MS (ESI) m/z (M+Na) + 407.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-FLUORO-2- (TRIFLUOROMETHYL)PHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE
[0971] Compound 512 (60 mg, yield: 21.65%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and 2-(3-fluoro-2-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl- l,3,2-dioxaborolane and the final compound 512 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.67 - 7.59 (m, 1H), 7.52 - 7.43 (m, 1H), 7.31 - 7.17 (m, 5H), 7.05 (d, J = 7.7 Hz, 1H), 5.25 - 5.16 (m, 1H), 3.90 (s, 3H), 3.11 (dd, J = 3.6, 14.0 Hz, 1H), 2.79 (dd, J = 10.0, 14.0 Hz, 1H). 19 F NMR (376MHz, DMSO- d 6 ) δ -55.03 (d, = 18.3 Hz, 3F), - 114.43 (tdd, = 6.1, 12.3, 18.7 Hz, IF). MS (ESI) m/z (M+Na) + 463.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(2- (TRIFLUOROMETHYL)PHENYL)-lH-PYRAZOLE-4-CARBOXAMIDE (513)
[0972] Compound 513 (45 mg, yield: 54.58%, white solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo- l-methyl-lH-pyrazole-4-carboxylate and (2-(trifluoromethyl)phenyl)boronic acid and the final compound 513 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.25 (s, 1H), 7.99 (br d, = 7.1 Hz, 2H), 7.80 - 7.69 (m, 2H), 7.62 - 7.52 (m, 2H), 7.30 - 7.17 (m, 6H), 5.20 (ddd, = 3.9, 7.4, 9.7 Hz, 1H), 3.89 (s, 3H), 3.17 - 3.03 (m, 1H), 2.78 (dd, = 9.7, 13.9 Hz, 1H). 19 F NMR (376MHz, DMSO- d 6 ) δ -57.15 (s, 3F). MS (ESI) m/z (M+H) + 445.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(BENZO[rf][l,3]DI OXOL-4-YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (514)
[0973] Compound 514 (92 mg, yield: 34.71%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo- l-methyl-lH-pyrazole-4-carboxylate and benzo[<i][l,3]dioxol-4-ylboronic acid and the final compound 514 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 2.82 (dd, = 13.89, 9.48 Hz, 1 H) 3.12 (dd, = 14.00, 4.08 Hz, 1 H) 3.88 (s, 3 H) 5.16 - 5.34 (m, 1 H) 5.77 (s, 1 H) 5.87 (s, 1 H) 6.76 - 6.90 (m, 3 H) 7.18 - 7.31 (m, 5 H) 7.77 (s, 1 H) 8.00 (s, 1 H) 8.07 (s, 1 H) 8.11 (d, / = 7.28 Hz, 1 H). MS (ESI) m/z (M+H)+ 421.1.
[0974] Compound 515 (60 mg, yield: 20.6%, yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate and (5-methoxypyridin-3-yl)boronic acid and the final compound 515 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.50 (d, = 7.5 Hz, 1H), 8.39 (d, = 1.5 Hz, 1H), 8.22 (d, = 2.6 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.59 (dd, 7 = 1.8, 2.9 Hz, 1H), 7.29 (d, = 4.4 Hz, 4H), 7.24 - 7.18 (m, 1H), 5.35 - 5.26 (m, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.16 (dd, J = 3.6, 13.8 Hz, 1H), 2.83 (dd, J = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 408.2. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUORO-3- (TRIFLUOROMETHYL)PHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE
[0975] Compound 516 (85 mg, yield: 78.65%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4-carboxylate and (2-fluoro-3-
(trifluoromethyl)phenyl)boronic acid and the final compound 516 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.42 (d, 7 = 7.5 Hz, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.79 - 7.72 (m, 2H), 7.63 (br t, 7 = 7.1 Hz, 1H), 7.37 (t, 7 = 7.7 Hz, 1H), 7.31 - 7.18 (m, 5H), 5.29 - 5.19 (m, 1H), 3.93 (s, 3H), 3.13 (dd, 7 = 3.5, 14.1 Hz, 1H), 2.82 (dd, 7 = 10.1, 13.9 Hz, 1H). 19 F NMR (376MHz, DMSO-d 6 ) δ -59.92 (s, IF), -59.96 (s, IF), -116.72 -116.79 (m, 1 F), -116.80 - 116.86 (m, IF). MS (ESI) m/z (M+H)+ 463.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUORO-3-
METHYLPHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (517)
[0976] Compound 517 (170 mg, yield: 53.97%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate and (2-fluoro-3- methylphenyl)boronic acid and the final compound 517 was obtained. 1H NMR (400MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 8.13 (d, 7 = 7.5 Hz, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.31 - 7.20 (m, 6H), 7.15 - 7.10 (m, 1H), 7.07 - 7.02 (m, 1H), 5.25 (ddd, 7 = 3.9, 7.3, 9.5 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.13 (dd, 7 = 4.0, 13.9 Hz, 1H), 2.82 (dd, 7 = 9.7, 13.9 Hz, 1H). 2.21 (d, 7 = 1.5 Hz, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -116.59 - 120.74 (m, IF). MS (ESI) m/z (M+H) + 409.2.
[0977] Compound 518 (35.9 mg, yield: 24.08%, light yellow solid) was prepared using the procedures similar to compound 163 from the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate and (2,5-difluorophenyl)boronic acid and the final compound 518 was obtained. 1H NMR (400MHz, DMSO- 6 ) δ 8.33 (d, 7 = 7.3 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.31 - 7.17 (m, 8H), 5.29 - 5.21 (m, 1H), 3.92 (s, 3H), 3.13 (dd, 7 = 3.6, 14.0 Hz, 1H), 2.82 (dd, 7 = 9.8, 13.8 Hz, 1H). 19 F NMR (376 MHz, DMSO-i¾) δ -119.41(tdd, / = 4.8, 8.7, 17.7 Hz, IF), -119.69 -120.11 (m, IF). MS (ESI) m/z (M+H) + 413.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(lH-INDAZOL-l-YL) -l- METHYL-1H-PYRAZOLE-4-CARBOXAMIDE (530)
[0978] Compound 530 (85 mg, yield: 39.2%, light yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate and lH-indazole and alkylated using K 3 PO 4 , Cul, and (IR,2R)-NI,N2- dimethylcyclohexane-l,2-diamine, followed by subjecting the nresulting intermediate to procedures such as in compound 12 to obtain compound 530. 1H NMR (400MHz, δ 9.41 (d, = 5.8 Hz, 1H), 8.28 (d, = 2.3 Hz, 2H), 8.00 (d, = 8.5 Hz, 1H), 7.91 (d, = 8.0 Hz, 1H), 7.79 (br s, 1H), 7.68 - 7.48 (m, 2H), 7.33 (t, = 7.4 Hz, 1H), 7.19 - 7.04 (m, 5H), 5.47 (dt, =4.8, 7.7 Hz, 1H), 3.95 (s, 3H), 3.23 (dd, = 4.6, 14.2 Hz, 1H), 2.94 (dd, = 8.4, 14.2 Hz, 1H). MS (ESI) m/z (M+H) + 417.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,2-
DIFLUOROBENZO[rf][l,3]DIOXOL-5-YL)-l-METHYL-lH-PYRAZOLE-4 -
[0979] Compound 548 (130 mg, yield: 53.1%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and (2,2-difluorobenzo[<i][l,3]dioxol-5-yl)boronic acid, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 548. 1H NMR (400MHz, DMSO-d 6 ) δ 8.48 (d, = 7.5 Hz, 1H), 8.14 - 8.04 (m, 2H), 7.82 (s, 1H), 7.57 (d, = 1.5 Hz, 1H), 7.46 (dd, = 1.8, 8.4 Hz, 1H), 7.36 - 7.17 (m, 5H), 5.38 - 5.19 (m, 1H), 3.90 (s, 3H), 3.17 (dd, = 4.0, 13.9 Hz, 1H), 2.83 (dd, = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 457.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(BENZO[rf][l,3]DI OXOL-5-YL)-l- METHYL-1H-PYRAZOLE-4-CARBOXAMIDE (567)
[0980] Compound 567 (125 mg, yield: 72.7%, yellow solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and benzo[<i][l,3]dioxol-5-ylboronic acid, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 567. 1H NMR (400MHz, DMSO-d 6 ) δ 8.29 (d, = 7.5 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.80 (s, 1H), 7.32 - 7.19 (m, 5H), 7.16 - 7.08 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.01 (s, 2H), 5.33 - 5.24 (m, 1H), 3.86 (s, 3H), 3.16 (dd, = 4.1, 13.8 Hz, 1H), 2.82 (dd, = 9.9, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 421.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l,2 , -DIMETHYL-lH,2 , H-[3,3'-
BIPYRAZOLE]-4-CARBOXAMIDE (568)
[0981] Compound 568 (24 mg, yield: 12.0%, white solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4-carboxylate (198A) and (1 -methyl- lH-pyrazol-5-yl)boronic acid, followed by subjecting the nresulting intermediate to procedures such as in compound 12 to obtain compound 568. 1H NMR (400MHz, DMSO-d 6 ) δ 8.28 - 8.10 (m, 1H), 7.99 - 7.69 (m, 2H), 7.59 (br s, 1H), 7.40 - 7.10 (m, 6H), 6.42 - 6.29 (m, 1H), 5.31 (br s, 1H), 3.98 - 3.85 (m, 3H), 3.77 - 3.57 (m, 3H), 3.19 (br d, = 13.6 Hz, 1H), 2.92 - 2.81 (m, 1H). MS (ESI) m/z (M+H) + 381.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(NAPHTHA LEN-l- YL)-lH-PYRAZOLE-4-CARBOXAMIDE (569)
[0982] Compound 569 (125 mg, yield: 72.0%, off-white solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate (198A) and naphthalen-l-ylboronic acid, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 569. 1H NMR (400MHz, DMSO-d 6 ) δ 8.32 (s, 1H), 8.02 (s, 1H) 8.03 - 7.89 (m, 3H), 7.82 (d, = 7.3 Ηζ,ΙΗ), 7.76 (s, 1H), 7.68 (d, = 8.4 Ηζ,ΙΗ), 7.53 - 7.44 (m, 2H), 7.40 (dt, = 1.1, 7.6 Hz ,1H), 7.35 (dd, = 1.1, 7.1 Hz ,1H), 7.28 - 7.15 (m, 3H), 7.08 - 7.00 (m, 2H), 5.15 (ddd, = 4.0, 7.4, 9.4 Hz ,1H), 3.96 (s, 3H), 3.04 (dd, = 3.5, 13.9 Hz ,1H), 2.67 (dd, = 9.7, 13.7 Hz ,1H). MS (ESI) m/z (M+H) + 427.2..
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2,3- DIHYDROBENZO[6][l,4]DIOXIN-5-YL)-l-METHYL-lH-PYRAZOLE-4-
[0983] Compound 570 (41.8 mg, yield: 45.3%, off-white solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate (198A) and (2,3-dihydrobenzo[b][l,4]dioxin-5-yl)boronic acid, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 570. 1H NMR (400MHz, OMSO-d 6 ) δ 8.09 - 7.93 (m, 2H), 7.83 - 7.69 (m, 2H), 7.31 - 7.10 (m, 5H), 6.88 - 6.73 (m, 3H), 5.34 - 5.22 (m, 1H), 4.15 - 4.06 (m, 2H), 4.02 - 3.93 (m, 1H), 3.91 - 3.82 (m, 4H), 3.11 (dd, J = 4.0, 13.9 Hz, 1H), 2.79 (dd, J = 9.3, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 435.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(NAPHTHA LEN-2- YL)-lH-PYRAZOLE-4-CARBOXAMIDE (571)
[0984] Compound 571 (41.8 mg, yield: 45.3%, off-white solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl- lH-pyrazole-4- carboxylate (198A) and naphthalen-2-ylboronic acid, followed by subjecting the nresulting intermediate to procedures such as in compound 12 to obtain compound 571. 1H NMR (400MHz, DMSO-d 6 ) δ 8.45 (d, = 7.3 Hz, 1H), 8.18 - 8.06 (m, 3H), 7.92 - 7.81 (m, 4H), 7.72 (dd, 7 = 1.4, 8.5 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.33 - 7.19 (m, 5H), 5.36 - 5.27 (m, 1H), 3.94 (s, 3H), 3.17 (dd, J = 3.9, 14.0 Hz, 1H), 2.84 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 427.1.
[0985] Compound 572 (110 mg, yield: 40.9%, light yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl- lH-pyrazole-4- carboxylate (198A) and l-bromo-2-(difluoromethyl)benzene and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) in presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 572. 1H NMR (400MHz, DMSO-d 6 ) δ 8.31 - 8.21 (m, 2H), 8.03 (s, 1H), 7.79 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.33 - 7.17 (m, 6H), 7.00 - 6.66 (m, 1H), 5.30 - 5.18 (m, 1H), 3.92 (s, 3H), 3.13 (dd, = 3.6, 13.7 Hz, 1H), 2.79 (dd, = 10.0, 13.8 Hz, 1H). 19 F NMR (376MHz, DMSO-d 6 ) δ -107.64 - 110.93 (m, 2F). MS (ESI) m/z (M+H) + 396. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CYCLOHEXYL-l-METH YL-lH-
[0986] Compound 573 (172 mg, yield: 81.1%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate (198A) and 2-(cyclohex- l-en- l-yl)-4,4,5,5-tetramethyl- l,3,2-dioxaborolane followed by hydrogenolysis of the resulting product which then followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 573. 1H NMR (400MHz, DMSO-d 6 ) δ 8.11 (d, J = 7.3 Hz, 1H), 8.02 (s, 2H), 7.76 (s, 1H), 7.28 - 7.21 (m, 4H), 7.20 - 7.11 (m, 1H), 5.24 (ddd, = 3.6, 7.1, 10.3 Hz, 1H), 3.74 (s, 3H), 3.11 (dd, = 3.7, 13.9 Hz, 1H), 3.05 - 2.96 (m, 1H), 2.79 (dd, J = 10.0, 13.8 Hz, 1H), 1.76 - 1.55 (m, 5H), 1.39 - 1.05 (m, 5H). MS (ESI) m/z (M+ H) + 383.3.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(ISOQUINOLIN-6-YL )-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (585)
[0987] Compound 585 (120 mg, yield: 60.0%, light yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl- lH-pyrazole-4- carboxylate (198A) and isoquinolin-7-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 585. 1H NMR (400MHz, DMSO-d 6 ) δ 9.28 (s, 1H), 8.56 (d, J = 7.3 Hz, 1H), 8.48 (d, J = 5.8 Hz, 1H), 8.20 (s, 1H), 8.16 - 8.08 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.90 - 7.77 (m, 3H), 7.29 (d, J = 4.3 Hz, 4H), 7.25 - 7.18 (m, 1H), 5.38 - 5.25 (m, 1H), 3.95 (s, 3H), 3.18 (dd, J = 3.8, 14.1 Hz, 1H), 2.85 (dd, J = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+ H) + 428.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(QUINOLI N-2-YL)-
[0988] Compound 587 (70 mg, yield: 49.7%, light pink solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate (198A) and 2-bromoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) in presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 587. 1H NMR (400MHz, DMSO-i¾) δ 12.08 (br d, = 8.0 Hz, 1H), 8.50 (br d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 8.26 (br d, J = 8.8 Hz, 1H), 8.14 (br s, 1H), 8.02 (br d, J = 7.5 Hz, 1H), 7.84 (br s, 1H), 7.74 - 7.59 (m, 3H), 7.07 - 6.90 (m, 5H), 5.75 - 5.66 (m, 1H), 3.98 (s, 3H), 3.31 - 3.26 (m, 1H), 3.18 - 3.08 (m, 1H). MS (ESI) m/z (M+H) + 428.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(ISOQUINOLIN-4-YL )-l- METHYL-1H-PYRAZOLE-4-CARBOXAMIDE (591)
[0989] Compound 591 (35 mg, yield: 56.3%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and 4-isoquinolylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 591. 1H NMR (400MHz, DMSO- g) δ 9.26 (s, 1H), 8.36 - 8.30 (m, 2H), 8.25 - 8.21 (m, 1H), 8.14 - 8.09 (m, 1H), 7.93 (s, 1H), 7.71 (br s, 1H), 7.68 - 7.60 (m, 3H), 7.27 - 7.20 (m, 2H), 7.19 - 7.13 (m, 3H), 5.17 - 5.09 (m, 1H), 3.95 (s, 3H), 3.09 - 3.02 (m, 1H), 2.77 - 2.69 (m, 1H). MS (ESI) m/z (M+H) + 428.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(QUINOLI N-
6-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (593)
[0990] Compound 593 (30 mg, 29.9% yield; pale yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate (198A) and quinolin-6-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 593. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.86 (br s, 1H), 8.50 (br.d, = 6.6 Hz, 1H), 8.31 (br.d, = 7.9 Hz, 1H), 8.20 (br.s, 1H), 8.09 (br.d, = 9.5 Hz, 2H), 7.93(br.s, 2H), 7.81 (br s, 1H), 7.53 - 7.47 (m, 1H), 7.30 - 7.15 (m, 5H), 5.29 (br.s, 1H), 3.92 (s, 3H), 3.16 (br.d, 7 = 11.5 Hz, 1H), 2.88 - 2.78 (m, 1H). MS (ESI) m/z (M+H) + 428.1
[0991] Compound 597 (20 mg, yield: 25.1%, yellow solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and quinolin-5-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 597. 1H NMR (400MHz, DMSO-ifo) δ 8.88 (dd, J = 1.8, 4.0 Hz, 1H), 8.34 - 8.19 (m, 1H), 8.17 - 7.97 (m, 2H), 7.81 - 7.35 (m, 6H), 7.27 - 7.03 (m, 5H), 5.29 - 5.11 (m, 1H), 4.02 - 3.90 (m, 3H), 3.07 - 3.0 (m, 1H), 2.80 - 2.74 (m, 1H). MS (ESI) m/z (M+ H) + 428.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(ISOQUINOLIN-3-YL )-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (602)
[0992] Compound 602 (55 mg, yield: 36.3%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and 3-bromoisoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) in presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 602. 1H NMR (400MHz, DMSO-ifc) δ 12.07 (d, = 7.1 Hz, 1H), 8.98 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 7.5 Hz, 3H), 7.89 - 7.79 (m, 2H), 7.75 - 7.67 (m, 1H), 7.15 - 7.06 (m, 4H), 7.04 - 6.97 (m, 1H), 5.64 - 5.53 (m, 1H), 4.03 -
3.84 (m, 3H), 3.27 (dd, = 5.0, 14.0 Hz, 1H), 3.10 (dd, = 7.7, 14.1 Hz, 1H). MS (ESI) m/z (M+ H) + 428.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-CHLOROPHENYL)- l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (604)
[0993] Compound 604 (120 mg, yield: 58.6%, pale yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate (198A) and (2-chlorophenyl)boronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 604. 1H NMR (400MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 8.03 (d, = 7.3 Hz, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.39 - 7.15 (m, 9H), 5.24 - 5.19 (m, 1H), 3.87 (s, 3H), 3.08 (dd, = 3.6, 14.0 Hz, 1H), 2.76 (dd, = 9.8, 14.0 Hz, 1H). MS (ESI) m/z (M+ H) + 411.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(QUINOLI N-3-YL)- lH-PYRAZOLE-4-CARBOXAMIDE (605)
[0994] Compound 605 (140 mg, yield: 55.6%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and quinolin-3-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 605. 1H NMR (400MHz, DMSO- g) δ 9.08 (s, 1H), 8.65 - 8.45 (m, 2H), 8.23 (s, 1H), 8.08 (br s, 1H),7.99 (dd, J = 8.3, 12.7 Hz, 2H),
7.85 - 7.70 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.34 - 7.13 (m, 5H), 5.36 - 5.20 (m, 1H), 4.05 - 3.89 (m, 3H), 3.18 - 2.78 (m, 2H). MS (ESI) m/z (M+ H) + 428.2. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(ISOQUINOLIN-5-YL )-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (607)
[0995] Compound 607 (50 mg, yield: 34.6%, white solid) was prepared using the corresponding starting materials, compound ethyl 3 -iodo-1 -methyl- lH-pyrazole-4-carboxylate (198A) and isoquinolin-5-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 607. 1H NMR (400MHz, DMSO- g) δ 9.41 - 9.21 (m, 1H), 8.52 - 8.27 (m, 2H), 8.23 - 7.93 (m, 3H), 7.81 - 7.48 (m, 4H), 7.32 - 7.09 (m, 5H), 5.22 - 5.10 (m, 1H), 4.06 - 3.90 (m, 3H), 3.09 (dd, 7 = 3.2, 13.8 Hz, 1H), 2.76 (dd, 7 = 9.8, 13.8 Hz, 1H). MS (ESI) m/z (M+ H) + 428.1.
[0996] Compound 611 (55 mg, yield: 78.2%, light yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl-lH-pyrazole-4- carboxylate (198A) and quinolin-4-ylboronic acid followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 611. 1H NMR (400MHz, DMSO-d 6 ) δ 8.86 - 8.76 (m, 1H), 8.41 - 8.34 (m, 1H), 8.07 - 7.88 (m, 2H), 7.85 - 7.58 (m, 3H), 7.49 (t, 7 = 7.8 Hz, 1H), 7.33 - 7.11 (m, 7H), 5.21 - 5.11 (m, 1H), 4.30 (br s, 1H), 4.04 - 3.93 (m, 3H), 3.10 (dd, 7 = 3.5, 14.1 Hz, 1H), 2.78 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+ H) + 428.1.
[0997] Compound 615 (122 mg, yield: 73.0%, white solid) was prepared using the corresponding starting materials, compound l-methyl-3-(thiophen-2-yl)-lH-pyrazole-4- carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 615. 1H NMR (400MHz, DMSO-ifc) δ 8.42 (d, 7 = 7.3 Hz, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.73 (d, 7 = 3.5 Hz, 1H), 7.41 (dd, 7 = 1.1, 5.1 Hz, 1H), 7.28 (d, 7 = 4.2 Hz, 4H), 7.24 - 7.18 (m, 1H), 6.97 (dd, 7 = 3.6, 5.0 Hz, 1H), 5.49 - 5.20 (m, 1H), 3.85 (s, 3H), 3.16 (dd, 7 = 3.5, 13.9 Hz, 1H), 2.83 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+ H) + 383.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CYCLOPROPYL-l-MET HYL-
[0998] Compound 616 (120 mg, yield: 71.5%, white solid) was prepared using the corresponding starting materials, compound 3 -cyclopropyl- 1 -methyl- lH-pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 616. 1H NMR (400MHz, DMSO-d 6 ) δ 8.08 (d, 7 = 7.5 Hz, 1H), 8.04 (s, 1H), 8.03 (br s, 1H), 7.77 (s, 1H), 7.27 (d, 7 = 4.4 Hz, 4H), 7.20 - 7.16 (m, 1H), 5.31 - 5.26 (m, 1H), 3.71 (s, 3H), 3.15 (dd, 7 = 3.9, 13.8 Hz, 1H), 2.84 (dd, 7 = 9.9, 13.9 Hz, 1H), 2.41 - 2.35 (m, 1H), 0.77 - 0.70 (m, 2H), 0.69 - 0.65 (m, 2H). MS (ESI) m/z (M+H) + 341.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(TETR AHYDRO-2H- PYRAN-4-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (617)
[0999] Compound 617 (55 mg, yield: 34.4%, white solid) was prepared using the corresponding starting materials, compound l-methyl-3-(tetrahydro-2H-pyran-4-yl)-lH-pyrazole- 4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 617. 1H NMR (400MHz, δ 8.20 (d, 7 = 7.5 Hz, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.30 - 7.21 (m, 4H), 7.19 - 7.14 (m, 1H), 5.31 - 5.15 (m, 1H), 3.80 (d, 7 = 9.5 Hz, 2H), 3.76 (s, 3H), 3.29 - 3.20 (m, 3H), 3.11 (dd, 7 = 3.5, 13.9 Hz, 1H), 2.79 (dd, 7 = 10.0, 13.8 Hz, 1H), 1.65 - 1.52 (m, 4H). MS (ESI) m/z (M+H) + 385.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CYCLOPENTYL-l- METHYL- lH-PYRAZOLE-4-CARBOXAMIDE (620)
[1000] Compound 620 (70 mg, yield: 53.1%, white solid) was prepared using the corresponding starting materials, compound 3 -cyclopentyl-1 -methyl- lH-pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 620. 1H NMR (400MHz, DMSO-d 6 ) δ 8.14 (br d, 7 = 7.3 Hz, 1H), 8.06 - 8.02 (m, 2H), 7.77 (br.s, 1H), 7.29 (d, 7 = 4.3 Hz, 4H), 7.24 - 7.17 (m, 1H), 5.29 - 5.21(m, 1H), 3.77 (s, 3H), 3.42 (br.t, 7 = 8.0 Hz, 1H), 3.14 (br.dd, 7 = 3.5, 13.8 Hz, 1H), 2.83 (br.dd, 7 = 10.2, 13.4 Hz, 1H), 1.80 (br.d, 7 = 7.8 Hz, 2H), 1.69 - 1.45 (m, 6H). MS (ESI) m/z (M+H) + 369.2. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(5-CHLOROTHIOPHEN -2-YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (621)
[1001] Compound 621 (25 mg, yield: 25.1%, pale-yellow solid) was prepared using the corresponding starting materials, compound 3-(5-chlorothiophen-2-yl)-l-methyl-lH- pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 621. 1H NMR (400MHz, DMSO- g) δ 8.53 (br d, J = 6.8 Hz, 1H), 8.22 - 8.04 (m, 2H), 7.87 - 7.61 (m, 2H), 7.35 - 6.97 (m, 6H), 5.33 (br s, 1H), 3.88 (br s, 3H), 3.19 (br d, J = 14.1 Hz, 1H), 2.92 - 2.79 (m, 1H). MS (ESI) m/z (M+H) + 417.0.
TERT-BUTYL 3-(4-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)-l- METHYL-lH-PYRAZOL-3-YL)PIPERIDINE-l-CARBOXYLATE (624)
[1002] Compound 624 (100 mg, yield: 33.04%, white solid) was prepared using the corresponding starting materials, compound 3-(l-(ieri-butoxycarbonyl)piperidin-3-yl)-l-methyl- lH-pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 624. 1H NMR (400MHz, DMSO- d 6 ) δ 8.27 - 8.18 (m, 1H), 8.12 (s, 1H), 8.02 (d, = 2.9 Hz, 1H), 7.78 (s, 1H), 7.32 - 7.13 (m, 5H), 5.29 (s, 1H), 4.02 - 3.85 (m, 2H), 3.82 - 3.75 (m, 3H), 3.20 - 3.09 (m, 2H), 3.19 - 2.99 (m, 1H), 2.99 - 2.78 (m, 2H), 2.73 - 2.64 (m, 1H), 1.84 (s, 1H), 1.62 (s, 1H), 1.48 (d, = 11.9 Hz, 1H), 1.39 - 1.27 (m, 10H). MS (ESI) m/z (M+H) + 484.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3,4-DIHYDRO-2H- BENZO[6][l,4]DIOXEPIN-7-YL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMI DE (625)
[1003] Compound 625 (70 mg, yield: 58.6%, yellow solid) was prepared using the corresponding starting materials, compound 3-(3,4-dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-l- methyl-lH-pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 625. 1H NMR (400MHz, DMSO-d 6 ) δ 8.29 (d, = 7.3 Hz, 1H), 8.09 - 7.94 (m, 2H), 7.80 (s, 1H), 7.32 - 7.14 (m, 7H), 6.90 - 6.83 (m, 1H), 5.39 - 5.22 (m, 1H), 4.16 - 4.07 (m, 4H), 3.88 - 3.82 (m, 3H), 3.16 (dd, = 4.0, 13.7 Hz, 1H), 2.82 (dd, = 9.8, 13.8 Hz, 1H), 2.13 - 2.06 (m, 2H). MS (ESI) m/z (M+H) + 449.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l,l , -DIMETHYL-lH,l , H-[3,4'-
BIPYRAZOLE] -4-CARBOXAMIDE (626)
[1004] Compound 626 (55 mg, yield: 34.4%, white solid) was prepared using the corresponding starting materials, compound 1,1 '-dimethyl- 1H,1'H- [3, 4'-bipyrazole]-4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 626. 1H NMR (400MHz, DMSO-d 6 ) δ 8.06 (d, = 17.6 Hz, 2H), 7.94 (s, 1H), 7.76 - 7.45 (m, 3H), 7.31 - 7.23 (m, 4H), 7.23 - 7.15 (m, 1H), 5.37 - 5.28 (m, 1H), 3.83 (d, = 8.3 Hz, 6H), 3.22 (dd, = 4.1, 13.7 Hz, 1H), 2.95 (dd, = 8.9, 14.4 Hz, 1H). MS (ESI) m/z (M+H) + 381.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-
(TETRAHYDROFURAN-3-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (627)
[1005] Compound 627 (40 mg, yield: 25.1%, pale yellow solid) was prepared using the corresponding starting materials, compound l-methyl-3-(tetrahydrofuran-3-yl)-lH-pyrazole- 4-carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 627. 1H NMR (400MHz, δ 8.06 (s, 1H), 8.00 - 7.87 (m, 1H), 7.69 (s, 0.5H), 7.57 - 7.44 (m, 0.7H), 7.30 - 7.03 (m, 6H), 5.33 - 5.23 (m, 1H), 3.92 (dt, = 2.6, 7.7 Hz, 1H), 3.86 - 3.81 (m, 1H), 3.79 (s, 3H), 3.77 - 3.73 (m, 1H), 3.71 (d, = 7.8 Hz, 1H), 3.62 - 3.54 (m, 1H), 3.20 (dd, = 4.3, 14.1 Hz, 1H), 2.96 - 2.88 (m, 1H), 2.09 (q, = 7.3 Hz, 2H). MS (ESI) m/z (M+H) + 371.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(BENZOFURAN-3-YL) -l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (628)
[1006] Compound 628 (143 mg, yield: 98.6%, white solid) was prepared using the corresponding starting materials, compound 3-(benzofuran-3-yl)-l-methyl-lH-pyrazole-4- carboxylic acid and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 628. 1H NMR (400MHz, DMSO-ifc) δ 8.56 (d, = 7.3 Hz, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.63 (d, = 6.8 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.33 - 7.15 (m, 7H), 5.36 (ddd, = 3.9, 7.3, 9.8 Hz, 1H), 3.94 (s, 3H), 3.24 - 3.14 (m, 1H), 2.87 (dd, = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 417.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(ISOQUINOLIN-3-YL )-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (629)
[1007] Compound 629 (25 mg, yield: 50.14%, pale yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-iodo-l-methyl- lH-pyrazole-4- carboxylate (198A) and 7-bromoisoquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) in presence of palladium catalyst, followed by subjecting the resulting intermediate to procedures such as in compound 12 to obtain compound 629. 1H NMR (400MHz, DMSO-d 6 ) δ 9.27 (s, 1H), 8.54 (d, = 7.5 Hz, 1H), 8.49 (d, = 5.7 Hz, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 8.00 - 7.94 (m, 1H), 7.92 - 7.87 (m, 1H), 7.85 - 7.78 (m, 2H), 7.30 - 7.17 (m, 5H), 5.36 - 5.26 (m, 1H), 3.95 (s, 3H), 3.18 (dd, J = 4.0, 13.9 Hz, 1H), 2.85 (dd, = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+ H) + 428.2.
BENZYL 4-(4-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)-l- ME -lH-PYRAZOL-3-YL)PIPERAZINE-l-CARBOXYLATE (601)
[1008] To the solution of compound 198A (500 mg, 1.79 mmol) and benzyl piperazine- l-carboxylate (590 mg, 2.68 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc) 2 (40 mg, 0.18 mmol), Cs 2 C0 3 (116 mg, 3.57 mmol) and Sphos (147 mg, 0.36 mmol) under N 2 atmosphere. The reaction was stirred at 100 °C for 16 h. The reaction mixture was filtered and washed with EtOAc (10 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified on Combi flash (eluent: PE ~ 10% ~ 30% EtOAc/PE) to afford the compound 601A (183 mg, yield 25.7%) as a yellow oil.
[1009] Compound 601 (55 mg, yield: 78.8%, pink solid) was prepared using the corresponding starting materials, compound benzyl 4-(4-(ethoxycarbonyl)-l -methyl- lH-pyrazol-
3-yl)piperazine-l-carboxylate (601A) and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 601. 1H NMR (400MHz, DMSO-d 6 ) δ 8.28 - 8.15 (m, 2H), 8.03 (s, 1H), 7.92 (s, 1H), 7.43 - 7.33 (m, 5H), 7.28 - 7.21 (m, 2H), 7.19 - 7.13 (m, 1H), 7.06 (d, J = 7.0 Hz, 2H), 5.53 (q, J = 6.3 Hz, 1H), 5.13 - 5.04 (m, 2H), 3.79 - 3.68 (m, 3H), 3.33 - 3.18 (m, 5H), 3.17 - 3.08 (m, 1H), 2.86 (br s, 2H), 2.81 - 2.75 (m, 2H). MS (ESI) m/z (M+H) + 519.2.
TERT-BUTYL 4-(4-((4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)CARBAMOYL)-l- METHYL-lH-PYRAZOL-3-YL)PIPERAZINE-l-CARBOXYLATE (603)
[1010] Intermediate 603A was prepared using the same procedure as for intermediate 601A using ie/ -butyl piperazine-l-carboxylate.
[1011] Compound 603 (18 mg, yield: 41.6%, white solid) was prepared using the corresponding starting materials, compound ie/ -butyl 4-(4-(ethoxycarbonyl)-l -methyl- 1H- pyrazol-3-yl)piperazine-l-carboxylate (603A) and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 603. 1H NMR (400MHz, DMSO-i¾) δ 8.07 (d, J = 7.5 Hz, 1H), 7.98 - 7.81 (m, 2H), 7.80 - 7.61 (m, 1H), 7.30 - 7.24 (m, 2H), 7.22 - 7.19 (m, 1H), 7.13 (d, = 7.5 Hz, 2H), 5.56 - 5.45 (m, 1H), 3.76 - 3.67 (m, 3H), 3.42 (br s, 1H), 3.35 - 3.28 (m, 2H), 3.27 - 3.21 (m, 2H), 3.15 - 3.13 (m, 1H), 2.88 (d, J = 6.3 Hz, 2H), 2.84 - 2.77 (m, 2H), 1.44 (s, 9H). MS (ESI) m/z (M+H) + 485.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(l,l- DIOXIDOTHIOMORPHOLINO)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE
[1012] Intermediate 613A was prepared using the same procedure as for intermediate 601A using thiomorpholine 1,1 -dioxide.
[1013] Compound 613 (70 mg, yield: 33.7%, light yellow solid) was prepared using the corresponding starting materials, compound ethyl 3-(l,l-dioxidothiomorpholino)-l-methyl- lH-pyrazole-4-carboxylate (613A) and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 613. 1H NMR (400MHz, DMSO-d 6 ) δ 8.15 (d, J = 7.0 Hz, 2H), 8.05 (s, 1H), 7.87 (s, 1H), 7.31 - 7.26 (m, 2H), 7.23 (br d, 7 = 7.0 Hz, 1H), 7.16 (d, J = 6.8 Hz, 2H), 5.48 - 5.31 (m, 1H), 3.75 (s, 3H), 3.42 (m, 4H), 3.25 - 3.20 (m, 1H), 3.14 - 3.07 (m, 2H), 3.06 - 2.98 (m, 3H). MS (ESI) m/z (M+H) + 434.1. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-MORPHOLI NO-lH-
[1014] Intermediate 614A was prepared using the same procedure as for intermediate 601A using morpholine.
[1015] Compound 614 (45 mg, yield: 86.3%, yellow solid) was prepared using the corresponding starting materials, compound ethyl l-methyl-3-morpholino- lH-pyrazole-4- carboxylate (614A) and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride using the procedures such as in compound 12 to obtain compound 614. 1H NMR (400MHz, DMSO-dg) δ 8.21 - 8.11 (m, 2H), 7.98 (s, 1H), 7.91 - 7.84 (m, 1H), 7.26 - 7.21 (m, 2H), 7.18 (s, 1H), 7.07 (d, J = 6.8 Hz, 2H), 5.52 - 5.44 (m, 1H), 3.71 (s, 3H), 3.55 - 3.47 (m, 2H), 3.46 - 3.39 (m, 2H), 3.23 (dd, = 5.3, 14.1 Hz, 1H), 3.06 (dd, 7 = 7.1, 14.1 Hz, 1H), 2.89 - 2.82 (m, 2H), 2.80 - 2.75 (m, 2H). MS (ESI) m/z (M+H) + 386.2.
COMPOUNDS 165-167, 170-173, 176-190, 315, 407, 408, 446, 447 (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-(PYR IDIN-4-YL)- -PYRAZOLE-4-CARBOXAMIDE (165)
[1016] To a mixture of compound 163E (200 mg, 525 umol), 4-pyridylboronic acid (129 mg, 1.05 mmol) and K 2 C0 3 (218 mg, 1.57 mmol) in dioxane (9 mL) and H 2 0 (1 mL) was added Pd(dppf)Cl 2 (76.8 mg, 105 umol) under N 2 . The mixture was stirred at 130 °C under microwave conditions for 2h. The solvent was removed under vacuum. The residue was purified by prep-TLC (Dichloromethane: Methanol = 10: 1, R f = 0.5) to give 165A (90 mg, yield: 45.2%) as a white solid. Compound 165A: 1H NMR (400 MHz, OMSO-d 6 ) δ 8.55 - 8.70 (m, 2H), 7.96 (br dd, = 15.55, 5.40 Hz, 1H), 7.79 (br d, J = 7.94 Hz, 1H), 7.03 - 7.44 (m, 10H), 5.74 - 5.87 (m, 1H), 4.25 - 4.45 (m, 1H), 3.75 - 4.02 (m, 1H), 3.68 (br t, = 5.40 Hz, 3H), 2.57 - 2.91 (m, 3H). [1017] Compound 165 was prepared as in Example 61 from the corresponding intermediate compound 165A. Compound 165: 1H NMR (400 MHz, DMSO-d 6 ) δ 8.60 - 8.65 (m, 2H), 8.40 (d, = 7.50 Hz, 1H), 8.00 (s, 2H), 7.77 (s, 1H), 7.32 - 7.36 (m, 2H), 7.18 - 7.31 (m, 5H), 5.14 - 5.25 (m, 1H), 3.68 (s, 3H), 3.14 (dd, J = 13.89, 3.75 Hz, 1H), 2.83 (dd, J = 13.67, 10.14 Hz, 1H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(p-T OLYL)-lH-
[1018] Compound 166 (17.5 mg, yield: 27.9%, off-white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and /?-tolylboronic acid. Compound 166: 1H NMR (400MHz, OMSO-d 6 ) δ 8.28 (d, = 7.3 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.81 (br s, 1H), 7.46 (d, = 8.2 Hz, 2H), 7.33 - 7.19 (m, 5H), 7.11 (d, = 7.9 Hz, 2H), 5.33 - 5.23 (m, 1H), 3.93 - 3.81 (m, 3H), 3.15 (dd, J = 3.6, 13.8 Hz, 1H), 2.82 (dd, J = 10.0, 13.8 Hz, 1H), 2.30 (s, 3H). MS (ESI) m/z (M+H) + 391.1.
[1019] Compound 167 (40.0 mg, yield: 66.9%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163E and /?-tolylboronic acid. Compound 167: 1H NMR (400MHz, DMSO-d 6 ) δ 7.98 - 7.91 (m, 2H), 7.89 (s, 1H), 7.73 (s, 1H), 7.30 - 7.08 (m, 9H), 5.24 - 5.11 (m, 1H), 3.58 (s, 3H), 3.08 (dd, J = 3.6, 14.0 Hz, 1H), 2.77 (dd, J = 9.8, 13.6 Hz, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+H) + 391.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR IDIN-4- YL)-lH-PYRAZOLE-4-CARBOXAMIDE (170)
[1020] Compound 170 (15.6 mg, yield: 17.3%, off-white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and 4-pyridylboronic acid. Compound 170: 1H NMR (400 MHz, OMSO-d 6 ) δ 8.61 (br d, J = 7.50 Hz, 1H), 8.49 (d, = 4.85 Hz, 2H), 8.03 - 8.15 (m, 2H), 7.82 (br s, 1H), 7.56 (d, J = 4.85 Hz, 2H), 7.19 - 7.34 (m, 5H), 5.22 - 5.36 (m, 1H), 3.87 - 3.96 (m, 3H), 3.18 (br dd, = 14.00, 3.42 Hz, 1H), 3.12 - 3.22 (m, 1H), 2.83 (br dd, J = 13.56, 10.25 Hz, 1H). MS (ESI) m/z (M+H 2 0+H) + 396.1. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(o-T OLYL)-lH-
[1021] Compound 171 (16 mg, 41 umol, yield: 14.6%, purity: 100.0%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and o-tolylboronic acid. Compound 171: 1H NMR (400MHz, CDC1 3 ) δ 7.95 (s, 1H), 7.38 - 7.33 (m, 1H), 7.30 - 7.26 (m, 1H), 7.25 - 7.21 (m, 2H), 7.19 - 7.12 (m, 3H), 6.75 - 6.71 (m, 2H), 6.68 (br s, 1H), 5.81 (br d, J = 5.7 Hz, 1H), 5.57 (br s, 1H), 5.47 - 5.39 (m, 1H), 3.94 - 3.87 (m, 3H), 3.15 (dd, J = 4.4, 14.1 Hz, 1H), 2.62 (dd, J = 8.5, 14.2 Hz, 1H), 2.11 (s, 3H). MS (ESI) m/z (M+H) + 391.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-( n-TOLYL)-lH-
[1022] Compound 172 (25.3 mg, yield: 21.2%, yellow solid) was prepared as in Example 97 from the corresponding starting materials, compound 163E and m-tolylboronic acid. Compound 172: 1H NMR (400MHz, OMSO-d 6 ) δ 7.98 (br s, 1H), 7.91 (s, 1H), 7.88 (br d, J = 7.3 Hz, 1H), 7.75 (br s, 1H), 7.33 - 7.21 (m, 4H), 7.20 - 7.10 (m, 4H), 7.07 (br d, = 7.3 Hz, 1H), 5.19 (br s, 1H), 3.58 (s, 3H), 3.09 (br dd, = 3.3, 13.7 Hz, 1H), 2.77 (br dd, = 9.7, 13.7 Hz, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+H) + 391.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR IMIDIN-5- YL)-lH-PYRAZOLE-4-CARBOXAMIDE (173)
[1023] Compound 173 (6.9 mg, yield: 18.6%, light yellow solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and pyrimidin-5- ylboronic acid. Compound 173: 1H NMR (400MHz, DMSO-d 6 ) δ 9.15 - 9.06 (m, 1H), 8.97 - 8.77 (m, 1H), 8.62 (d, = 7.5 Hz, 1H), 8.34 - 8.22 (m, 1H), 8.09 (s, 1H), 7.86 - 7.62 (m, 1H), 7.40 - 7.07 (m, 6H), 5.36 - 5.25 (m, 1H), 3.98 - 3.90 (m, 3H), 3.17 (dd, J = 4.0, 13.7 Hz, 1H), 2.83 (br dd, 7 = 10.3, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 379.1.
[1024] Compound 176 (15 mg, yield: 12.19%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163E and pyrimidin-5- ylboronic acid. 1H NMR (400MHz, CD 3 CN) δ 9.24 - 9.17 (m, 1H), 8.77 - 8.68 (m, 1H), 7.87 (s, 1H), 7.61 (s, 1H), 7.34 - 7.18 (m, 5H), 6.97 (br s, 2H), 6.24 - 6.09 (m, 1H), 5.38 - 5.33 (m, 1H), 3.73 (s, 3H), 3.25 (dd, 7 = 5.0, 14.0 Hz, 1H), 2.92 (dd, 7 = 9.0, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 379.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-METHOXYPHE NYL)-l- METHYL- 1H-PYRAZOLE-4-CARBOXAMIDE (177)
[1025] Compound 177 (46 mg, yield: 74.2%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and (3-methoxyphenyl) boronic acid. Compound 177: 1H NMR (400MHz, DMSO-i¾) δ 8.02 (s, 1H), 7.85 (br d, 7 = 7.3 Hz, 1H), 7.78 - 7.65 (m, 1H), 7.54 (br s, 1H), 7.30 - 7.25 (m, 3H), 7.24 - 7.18 (m, 5H), 6.92 - 6.87 (m, 1H), 5.38 -5.31 (m, 1H), 3.89 (s, 3H), 3.78 - 3.74 (m, 3H), 3.20 (dd, 7=4.5, 14.1 Hz, 1H), 2.90 (dd, 7=9.0, 14.1 Hz, 1H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-FLUOROPHEN YL)-l- METHYL-1H-PYRAZOLE-4-CARBOXAMIDE (178)
[1026] Compound 178 (26 mg, yield: 49.4% white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.46 (br d, 7 = 7.3 Hz, 1H), 8.07 (s, 2H), 7.80 (br s, 1H), 7.42 (d, 7 = 8.2 Hz, 2H), 7.36 - 7.31 (m, 1H), 7.30 - 7.25 (m, 4H), 7.22 - 7.18 (m, 1H), 7.11 (br t, 7 = 8.3 Hz, 1H), 5.33 - 5.25 (m, 1H), 3.88 (s, 3H), 3.15 (br dd, 7 = 3.5, 13.7 Hz, 1H), 2.80 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 395.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(4-FLUOROPHEN YL)-l- METHYL- 1H-PYRAZOLE-4-CARBOXAMIDE (179)
[1027] Compound 179 (15 mg, yield: 36.7%, light yellow solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO-ifc) δ 8.42 (d, 7 = 7.5 Hz, 1H), 8.07 (s, 2H), 7.81 (s, 1H), 7.61 (dd, 7 = 5.7, 8.8 Hz, 2H), 7.34 - 7.19 (m, 5H), 7.12 (br t, 7 = 8.9 Hz, 2H), 5.37 - 5.22 (m, 1H), 3.89 (s, 3H), 3.16 (br dd, 7 = 3.5, 14.1 Hz, 1H), 2.82 (br dd, 7 = 10.1, 13.7 Hz, 1H). MS (ESI) m/z (M+H) + 395.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-ISOPROPYLP HENYL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (180)
[1028] Compound 180 (58 mg, yield: 60.95%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO-^) δ 8.29 (d, 7 = 7.5 Hz, 1H), 8.11 - 7.98 (m, 2H), 7.81 (s, 1H), 7.48 (s, 1H), 7.37 - 7.16 (m, 9H), 5.38 - 5.23 (m, 1H), 3.89 (s, 3H), 3.15 (dd, 7 = 3.6, 14.0 Hz, 1H), 2.91 - 2.77 (m, 3H), 1.18 (d, 7 = 6.8 Hz, 6H). MS (ESI) m/z (M+H) + 419.2..
[1029] Compound 181 (46 mg, yield: 70.7%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO-ifo) δ 8.26 - 8.16 (m, 2H), 8.01 (s, 1H), 7.77 (s, 1H), 7.43 - 7.07 (m, 9H), 5.28 - 5.18 (m, 1H), 3.96 - 3.85 (m, 3H), 3.12 (dd, 7 = 3.6, 14.0 Hz, 1H), 2.81 (dd, 7 = 9.7, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 395.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-ETHYLPHENY L)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (182)
[1030] Compound 182 (24 mg, yield: 65.4%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.13 (s, 1H), 7.94 (br d, 7 = 7.0 Hz, 1H), 7.60 (s, 1H), 7.52 (d, 7 = 7.8 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.26 (m, 6H), 5.48 - 5.43 (m, , 1H), 4.01 (s, 3H), 3.30 (dd, 7 = 4.5, 14.1 Hz, 1H), 3.00 (dd, 7 = 9.0, 14.1 Hz, 1H), 2.74 (q, 7 = 7.5 Hz, 3H), 1.32 (t, 7 = 7.7 Hz, 4H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(3- (TRIFLUOROMETHYL)PHENYL)-lH-PYRAZOLE-4-CARBOXAMIDE (183)
[1031] Compound 183 (38 mg, yield: 61.9%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.51 (d, 7 = 7.5 Hz, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.84 (br d, 7 = 7.9 Hz, 1H), 7.80 (s, 1H), 7.63 (br d, 7 = 7.7 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.26 (d, 7 = 4.2 Hz, 4H), 7.21 - 7.16 (m, 1H), 5.32 - 5.25 (m, 1H), 3.89 (s, 3H), 3.17 - 3.11 (m, 1H), 2.83 - 2.76 (m, 1H). MS (ESI) m/z (M+H) + 445.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(3- (TRIFLUOROMETHOXY)PHENYL)-lH-PYRAZOLE-4-CARBOXAMIDE (184)
[1032] Compound 184 (18 mg, yield: 53.5%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO-^) δ 8.48 (d, 7 = 7.7 Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.64 - 7.56 (m, 2H), 7.41 (t, 7 = 8.2 Hz, 1H), 7.30 - 7.24 (m, 5H), 7.12 - 7.16 (m, 1H), 5.33 - 5.27 (m, 1H), 3.89 (s, 3H), 3.15 (dd, 7 = 3.9, 13.8 Hz, 1H), 2.81 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 461.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-CYANOPHENY L)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (185)
[1033] Compound 185 (20 mg, yield: 43.2%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.65 (dd, 7 = 7.3 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.89 (dd, 7 = 7.5 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, 7 = 8.2 Hz, 1H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.31 - 7.19 (m, 5H), 5.31 (dd, 7 = 6.8 Hz, 1H), 3.91 (s, 3H), 3.16 (dd, 7 = 9.9 Hz, 1H), 2.91 - 2.81 (m, 1H). MS (ESI) m/z (M+H) + 402.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3- CYCLOPROPYLPHENYL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (186)
[1034] Compound 186 (30 mg, yield: 53.72%, yellow solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.36 (dd, 7 = 6.8 Hz, 1H), 8.14 - 8.01 (m, 2H), 7.82 (s, 1H), 7.30 - 7.14 (m, 8H), 6.99 (dd, 7 = 7.5 Hz, 1H), 5.28 (s, 1H), 3.88 (s, 3H), 3.14 (dd, 7 = 11.0 Hz, 1H), 2.87 - 2.80 (m, 1H), 1.89 (s, 1H), 0.92 (dd, 7 = 6.6 Hz, 2H), 0.62 (s, 2H). MS (ESI) m/z (M+H) + 417.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-CHLOROPHEN YL)-l- METHYL- 1H-PYRAZOLE-4-C ARBOXAMIDE (187)
[1035] Compound 187 (35 mg, yield: 53.0%, white solid) was prepared as in Example 97 from the corresponding starting materials. 1H NMR (400MHz, DMSO- e) δ 8.52 - 8.44 (m, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.74 - 7.65 (m, 1H), 7.60 - 7.50 (m, 1H), 7.39 - 7.33 (m, 2H), 7.30 - 7.28 (m, 3H), 7.25 - 7.18 (m, 2H), 5.38 - 5.25 (m, 1H), 3.90 (s, 3H), 3.17 (dd, 7 = 3.6, 14.0 Hz, 1H), 2.89 - 2.80 (m, 1H). MS (ESI) m/z (M+H) + 411.1..
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR IDIN-3- YL)-lH-PYRAZOLE-4-C ARBOXAMIDE (188)
[1036] Compound 188 (15.8 mg, yield: 26.5%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163G and pyridin-3-ylboronic acid. Compound 188: 1H NMR (400MHz, DMSO-d 6 ) δ 8.77 (d, 7 = 1.6 Hz, 1H), 8.53 - 8.47 (m, 2H), 8.19 (s, 1H), 8.06 (br s, 1H), 7.92 (td, 7 = 1.9, 7.9 Hz, 1H), 7.80 (br s, 1H), 7.34 (dd, 7 = 5.1, 7.6 Hz, 1H), 7.32 - 7.28 (m, 4H), 7.26 - 7.18 (m, 1H), 5.35 - 5.26 (m, 1H), 3.93 (s, 3H), 3.18 (dd, 7 = 3.8, 13.8 Hz, 1H), 2.84 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-( PYRIDIN-3-YL)-
[1037] Compound 189 (16 mg, 42.4 umol, yield: 30.9%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163E and pyridin-3- ylboronic acid. Compound 189: 1H NMR (400MHz, CDC1 3 ) δ 8.74 (br d, 7 = 4.2 Hz, 1H), 8.60 (s, 1H), 7.86 (s, 1H), 7.69 (br d, 7 = 7.9 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.25 (br d, 7 = 3.3 Hz, 2H), 6.94 (br d, 7 = 3.5 Hz, 2H), 6.74 (br s, 1H), 5.93 (br d, 7 = 6.6 Hz, 1H), 5.63 (br s, 1H), 5.52 (q, 7 = 6.5 Hz, 1H), 3.73 (s, 3H), 3.32 (dd, 7 = 5.3, 13.9 Hz, 1H), 3.08 (dd, 7 = 6.8, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-(o-T OLYL)-lH-
PYRAZOLE-4-CARBOXAMIDE(190)
[1038] Compound 190 (28.4 mg, yield: 30.7%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163E and o-tolylboronic acid. Compound 190: 1H NMR (400MHz, DMSO-d 6 ) δ 7.94 (d, 7 = 4.8 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.30 - 7.15 (m, 5H), 7.15 - 7.05 (m, 4H), 5.30 - 5.19 (m, 1H), 3.48 (s, 3H), 3.12 (dd, 7 = 4.4, 14.0 Hz, 1H), 2.76 (ddd, 7 = 4.8, 9.0, 13.8 Hz, 1H), 1.96 (d, 7 = 10.1 Hz, 3H). MS (ESI) m/z (M+H) + 391.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(6- (TRIFLUOROMETHYL PYRIDIN-3-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (315)
[1039] To a mixture of 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (1.35 g, 5.86 mmol, HCl) and compound 163F (1 g, 4.88 mmol), HOBt (659 mg, 4.88 mmol) in DMF (20 mL) was added DIEA (1.58 g, 12.20 mmol, 2 mL) and EDCI (1.4 g, 7.32 mmol) in portion at 20 °C and stirred for 16h. The reaction mixture was treated with EA (40 mL), washed with H 2 0 (50 mL x 2). The organic layer was washed with 0.5N HC1 (40 mL), saturated aqueous NaHC0 3 (40 mL) and brine (30 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo. The residue was triturated with DCM (2 mL) and PE (10 mL), the precipitate was formed, the solid was collected and was dried in vacuo to give compound 315A (900 mg, yield: 45.38%) as yellow solid. 1H NMR (400MHz, DMSO-i¾) δ 8.25 (s, 1H), 7.85 - 7.42 (m, 1H), 7.35 (dd, = 7.3 Hz, 1H), 7.28 - 7.18 (m, 5H), 6.15 (d, = 6.2 Hz, 1H), 5.95 (d, = 5.5 Hz, 1H), 4.56 - 4.32 (m, 1H), 3.86 - 3.78 (m, 4H), 2.95 - 2.84 (m, 1H), 2.82 - 2.73 (m, 1H), 2.69 - 2.58 (m, 1H). MS (ESI) m/z (M+H) + 381.0.
[1040] Compound 315 (30 mg, yield: 28.27%, white solid) was prepared as in Example 97 from the corresponding intermediate compounds, 315A and (6- (trifluoromethyl)pyridin-3-yl)boronic acid and through intermediate compound 315B. Compound 315: 1H NMR (400MHz, DMSO-d 6 ) δ 8.92 (s, 1H), 8.65 (dd, = 7.3 Hz, 1H), 8.26 (s, 1H), 8.20 (dd, = 8.4 Hz, 1H), 8.05 (s, 1H), 7.88 - 7.76 (m, 2H), 7.28 (d, = 3.7 Hz, 4H), 7.24 - 7.16 (m, 1H), 5.27 (t, = 3.1 Hz, 1H), 3.94 (s, 3H), 3.16 (dd, = 3.7, 14.1 Hz, 1H), 2.83 (dd, = 10.4, 13.7 Hz, 1H). MS (ESI) m/z (M+H) + 446.1.
[1041] Compound 407 (3.9 g, yield: 94.15%, white solid) was prepared as in Example 97 from the corresponding starting materials, compound 163C, (3-methoxyphenyl) boronic acid, and 274D. Compound 407: 1H NMR (400MHz, DMSO-d 6 ) δ 8.44 - 8.25 (m, 1H), 8.15 - 7.97 (m, 2H), 7.84 (br s, 1H), 7.37 - 7.11 (m, 8H), 6.96 - 6.80 (m, 1H), 5.44 - 5.19 (m, 1H), 3.90 (br s, 3H), 3.73 (br s, 3H), 3.26 - 3.07 (m, 1H), 2.92 - 2.72 (m, 1H). MS (ESI) m/z (M+H) + 407.1.
3-((lH-PYRAZOLO[4,3-c]PYRIDIN-l-YL)METHYL)-N-(4-AMINO-3,4 -DIOXO-l- PHENYLBUTA -2-YL)-l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (408)
[1042] A mixture of compound 163C (2 g, 8.58 mmol), MeB(OH) 2 (2.05 g, 34.3 mmol), Pd(PPh 3 ) 4 (793 mg, 687 umol), K 2 C0 3 (2.37 g, 17.2 mmol) in dioxane (50 mL) and H 2 0 (10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 120 °C for 12 hour under N 2 atmosphere. The reaction mixture was extracted with Ethyl acetate 50 mL (50 mL x 2). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 100: 1 to 80: 1). Compound 408A (1.4 g, yield: 97.0%) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 7.87 - 7.73 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.91 - 3.75 (m, 3H), 2.51 - 2.40 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H).
[1043] A mixture of compound 408A (1.2 g, 7.13 mmol), NBS (1.9 g, 10.7 mmol), AIBN (586 mg, 3.57 mmol) in CC1 4 (30 mL) was stirred at 80 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 98: 1 to 90: 1). Compound 408B (600 mg, yield: 34.1%) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.76 (s, 1H), 4.66 (s, 2H), 4.30 - 4.21 (m, 2H), 3.90 - 3.79 (m, 3H), 1.38 - 1.22 (m, 3H).
[1044] To a mixture of lH-pyrazolo [4,3-c]pyridine (797 mg, 6.69 mmol) in DMF
(20 mL) was added KOH (501 mg, 8.92 mmol). The mixture was stirred at 15 °C for 30min.
And then to the mixture was added compound 408B (550 mg, 2.23 mmol) in DMF (10 mL) drop- wise at 0 °C over 10 min, and the mixture was stirred at 0 °C for 2hr. The desired product was confirmed by NOE. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparatory-HPLC (basic condition). Compound 408C (300 mg, yield: 47.2%) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 9.14 - 8.99 (m, 1H), 8.40 (d, J = 6.2 Hz, 1H), 8.15 (s, 1H), 7.92 - 7.75 (m, 1H), 7.51 (d, J = 6.0 Hz, 1H), 5.85 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.93 - 3.75 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H).
[1045] Compound 408 (24.1 mg, yield: 40.4%, white solid) was prepared as in Example 95 from the corresponding starting materials, compound 408C and 274D.
[1046] Compound 408: 1H NMR (400MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.91 (br d, J = 5.5 Hz, 1H), 8.46 (br d, J = 5.5 Hz, 1H), 7.93 (s, 1H), 7.69 (s, 1H), 7.59 (br d, J = 5.5 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.23 (br s, 2H), 7.25 - 7.15 (m, 1H), 6.79 (br s, 1H), 5.69 - 5.51 (m, 1H), 5.73 - 5.38 (m, 1H), 5.49 - 5.37 (m, 1H), 5.50 - 5.37 (m, 1H), 5.74 - 5.33 (m, 1H), 3.79 (s, 3H), 3.56 - 3.42 (m, 1H), 3.17 (br dd, J = 9.5, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 432.3.
N-(4-AMINO-3-HYDROXY-4-OXO-l-PHENYLBUTAN-2-YL)-3-(4-FLUOR OPHENYL)- l-METHYL-lH-PYRAZOLE-4-CARBOXAMIDE (446) and N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(4-FLUOROPHENYL)- l-
METHYL-lH-PYRAZ LE-4-CARBOXAMIDE (447)
[1047] Compound 446A was treated with (4-fluorophenyl)boronic acid using procedure as in compound 163E followed by subjecting the resulting product to ester hydrolysis using sodium hydroxide and coupling with intermediate 274D using the procedures as in compound 12 to yield compounds 446 and compound 447. Compound 446 (550 mg, yield:
75.9%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.08 - 8.00 (m, 1H),
7.75 (d, J = 9.0 Hz, 1H), 7.56 (dd, J = 5.6, 8.7 Hz, 2H), 7.33 - 7.08 (m, 8H), 5.83 (d, J = 5.7 Hz,
1H), 4.59 - 4.37 (m, 1H), 4.00 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H), 2.80 - 2.73 (m, 1H), 2.68 (s, 1H), 2.66 (d, = 5.1 Hz, 1H). MS (ESI) m/z (M+H) + 397.1. Compound 447 (80 mg, yield: 39.9%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.42 (d, = 7.3 Hz, 1H), 8.11 - 8.03 (m, 2H), 7.81 (s, 1H), 7.65 - 7.57 (m, 2H), 7.32 - 7.18 (m, 5H), 7.12 (t, = 8.8 Hz, 2H), 5.27 (d, = 3.1 Hz, 1H), 3.89 (s, 3H), 3.30 - 3.12 (m, 1H), 2.83 (dd, / = 9.9, 13.7 Hz, 1H). MS (ESI) m/z (M+H) + 395.1.
COMPOUNDS 174-175, 191-193, 313, 293
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR IMIDIN-5- -lH-PYRAZOLE-4-CARBOXAMIDE (174)
163E 174A
[1048] To a solution of Compound 163E (150 mg, 393.47 umol) and tributyl(pyrazin- 2-yl)stannane (217 mg, 590.21 umol) in dioxane (15 mL) was added palladium;tritert- butylphosphane (100 mg, 196.74 umol). The mixture was stirred at 90 °C for 16h. The mixture was quenched with aqueous KF (20 mL), filtered, washed with ethyl acetate (20 mL), the filtrate was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over Na 2 S0 4 , concentrated to give a residue. The residue was purified by preparatory-HPLC (basic condition) and by preparatory-TLC (Si0 2 , DCM: MeOH = 10: 1). Compound 174A (70 mg, yield: 45.6%) was obtained as a white solid. 1H NMR (400MHz, MeOD) δ 8.77 - 8.69 (m, 1H), 8.66 - 8.54 (m, 2H), 7.94 - 7.78 (m, 1H), 7.25 - 7.12 (m, 5H), 4.63 - 4.58 (m, 1H), 4.26 - 4.02 (m, 1H), 3.91 - 3.84 (m, 3H), 3.01 - 2.83 (m, 2H). MS (ESI) m/z (M+H) + 381.1.
[1049] Compound 174 (25 mg, yield: 34.93%, white solid) was prepared as in Example 61 from the intermediate compound 174A. Compound 174A: 1H NMR (400MHz, DMSO- e) δ 8.75 (d, = 1.5 Hz, 1H), 8.71 (dd, / = 1.6, 2.6 Hz, 1H), 8.66 - 8.64 (m, 1H), 8.31 (d, = 7.5 Hz, 1H), 7.99 (s, 1H), 7.70 (br s, 1H), 7.51 (br s, 1H), 7.28 - 7.23 (m, 4H), 7.22 - 7.17 (m, 1H), 5.33 - 5.28 (m, 1H), 3.83 (s, 3H), 3.20 (dd, = 4.5, 14.1 Hz, 1H), 2.93 (dd, = 9.3, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 379.1. (5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-(PYR IMIDIN-4- YL)-lH-PYRAZOLE-4-CARBOXAMIDE (175)
[1050] Compound 175 (35 mg, yield: 47.75%, white solid) was prepared as in Example 98 from the corresponding starting materials, compound 163E and tributyl(pyrimidin-4- yl)stannane. Compound 175: 1H NMR (400MHz, DMSO-d 6 ) δ 9.24 (d, 7 = 1.1 Hz, 1H), 8.82 (d, 7 = 5.3 Hz, 1H), 8.71 (d, 7 = 7.5 Hz, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.54 (dd, 7 = 1.3, 5.3 Hz, 1H), 7.27 - 7.17 (m, 6H), 5.28 - 5.19 (m, 1H), 3.85 (s, 3H), 3.15 (dd, 7 = 4.0, 13.9 Hz, 1H), 2.83 (dd, 7 = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 379.1.
[1051] Compound 191 (20 mg, yield: 38.77%, white solid) was prepared as in Example 98 from the corresponding starting materials, compound 163E and tributyl(pyrimidin-2- yl)stannane. Compound 191: 1H NMR (400MHz, DMSO-d 6 ) δ 9.63 (d, 7 = 6.3 Hz, 1H), 8.86 (d, 7 = 5.0 Hz, 2H), 7.90 (s, 1H), 7.81 - 7.56 (m, 2H), 7.55 (t, 7 = 4.9 Hz, 1H), 7.21 - 7.14 (m, 3H), 7.12 - 7.06 (m, 2H), 5.47 (t, 7 = 5.1, 7.5 Hz, 1H), 4.05 (s, 3H), 3.24 (dd, 7 = 5.1, 14.2 Hz, 1H), 3.05 - 3.00 (m, 1H). MS (ESI) m/z (M+H) + 379.1.
[1052] Compound 192 (15 mg, yield: 29.82%, white solid) was prepared as in Example 98 from the corresponding starting materials, compound 163G and 4- (tributylstannyl)pyrimidine. Compound 192: 1H NMR (400MHz, CD 3 CN) δ 11.76 - 11.65 (m, 1H), 8.81 - 8.73 (m, 2H), 8.14 (s, 1H), 8.07 (dd, 7 = 1.1, 5.3 Hz, 1H), 7.59 (s, 1H), 7.15 (s, 4H), 7.04 (s, 1H), 6.24 (s, 1H), 5.65 - 5.59 (m, 1H), 3.93 (s, 3H), 3.33 (dd, 7 = 5.1, 14.1 Hz, 1H), 3.14 (dd, 7 = 7.7, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 379.1.
[1053] Compound 193 (25 mg, yield: 54.29%, white solid) was prepared as in Example 98 from the corresponding starting materials, compound 163G and tributyl(pyrimidin- 2-yl)stannane. Compound 193: 1H NMR (400MHz, DMSO-d 6 ) δ 11.24 (d, 7 = 7.3 Hz, 1H), 8.69 (d, 7 = 4.9 Hz, 2H), 8.29 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.47 (t, 7 = 4.9 Hz, 1H), 7.16 - 7.09 (m, 3H), 7.07 - 7.03 (m, 2H), 5.61 - 5.49 (m, 1H), 3.92 (s, 3H), 3.23 (dd, J = 5.1, 14.1 Hz, 1H), 3.07 (dd, J = 7.3, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 379.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(PYR AZIN-2- -lH-PYRAZOLE-4-CARBOXAMIDE (313)
[1054] Compound 313 was prepared as in Example 98 from the corresponding starting materials, compound 163G and 2-(tributylstannyl)pyrazine, through intermediate compound 313A. Compound 313 (70 mg, yield: 69.7%, white solid): 1H NMR (400MHz, CD 3 CN) δ 11.26 (d, = 6.0 Hz, 1H), 9.34 (d, = 1.3 Hz, 1H), 8.54 (d, = 2.6 Hz, 1H), 8.23 - 8.10 (m, 2H), 7.17 - 7.11 (m, 5H), 7.01 (br s, 1H), 6.19 (br s, 1H), 5.67 - 5.55 (m, 1H), 3.94 (s, 3H), 3.33 (dd, = 5.3, 14.1 Hz, 1H), 3.13 (dd, = 7.7, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 379.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(6-
M -2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (316)
[1055] Compound 316 was prepared as in Example 98 from the corresponding starting materials, compound 315A and 2-methyl-6-(tributylstannyl)pyridine, through intermediate compound 316A. Compound 316 (20 mg, yield: 21.64%, white solid): 1H NMR (400MHz, DMSO-i¾) δ 11.79 (d, = 7.7 Hz, 1H), 8.24 (s, 1H), 8.02 (s, 1H), 7.92 - 7.86 (m, 1H), 7.84 - 7.78 (m, 1H), 7.75 (s, 1H), 7.24 (d, = 7.7 Hz, 1H), 7.15 - 7.08 (m, 3H), 7.08 - 7.02 (m, 2H), 5.52 (t, = 5.2, 8.1 Hz, 1H), 3.89 (s, 3H), 3.22 (dd, = 4.7, 13.8 Hz, 1H), 2.99 (dd, = 8.4, 13.7 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 392.2. EXAMPLE 99
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-(6- (TRIFLUOROMETHYL) -2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (194)
[1056] To a mixture of 2-bromo-6-(trifluoromethyl)pyridine (3 g, 13.27 mmol) and 1,1, 1,2,2,2-hexamethyldistannane (5.7 g, 17.40 mmol) in 1,4-dioxane (96 mL) was added Pd(PPh 3 )4 (3.07 g, 2.65 mmol) at 25 °C under nitrogen atmosphere and the resultant mixture was stirred at 100 °C for 6 hours. The reaction mixture was cooled to room temperature, and filtered through a thin layer of celite. The filter cake was washed with DCM. The filtrate was concentrated in vacuum to give a dark solid, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 100: 1 to 10: 1) to afford crude compound 194A (3.2 g, 26.46% purity by LCMS) as a white solid. MS (ESI) m/z (M+H) + 311.8.
[1057] Compound 194 (32.1 mg, 62.15% yield, white solid) was prepared as in Example 98 from the corresponding starting materials, intermediate compounds 163E and 194A. Compound 194: 1H NMR (400MHz, CDC1 3 ): δ 7.98 - 7.91 (m, 1H), 7.85 (d, = 7.6 Hz, 1H), 7.75 (s, 1H), 7.72 (d, = 7.6 Hz, 1H), 7.26 - 7.21 (m, 3H), 7.07 - 7.02 (m, 2H), 6.74 (br s, 1H), 6.63 - 6.56 (m, 1H), 5.60 - 5.54 (m, 1H), 5.51 (br s, 1H), 3.94 (s, 3H), 3.41 - 3.31 (m, 1H), 3.14 - 3.06 (m, 1H). MS (ESI) m/z (M+H) + 446.0.
EXAMPLE 100
N-(l-AMINO-l,2-DIOXOHEX-5-EN-3-YL)-l-METHYL-3-PHENYL-lH-PYRA ZOLE-4-
[1058] To a solution of compound 163B (2 g, 8.58 mmol) and phenylboronic acid (1.26 g, 10.30 mmol) in dioxane (30 mL) and H 2 0 (10 mL) was added Pd(dtbpf)Cl 2 (280 mg, 0.43 mmol) and K 3 P0 4 (5.46 g, 25.74 mmol). The mixture was stirred at 70 °C under N 2 for 3h. The reaction was washed with H 2 0 (20 mL), extracted with EtOAc (15 mL x 2). The organics were collected and concentrated. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 10: 1) to afford compound 195A (1.9 g, yield: 96.17%) as yellow oil.
[1059] To a solution of compound 195A (1.9 g, 8.25 mmol) in THF (20 mL) and H 2 0 (20 mL) was added LiOH.H 2 0 (1.73 g, 41.25 mmol). The mixture was stirred at 25 °C for 24h. The reaction was acidified with IN HC1 to pH ~ 4. The mixture was extracted with EtOAc (25 mL x 2). The organics were collected, washed with brine (30 mL), dried with Na 2 S0 4 , filtered and concentrated to afford compound 195B (1.3 g, yield: 77.93%) as light yellow solid. MS (ESI) m/z (M+l) + 202.9.
[1060] To a solution of compound 195B (800 mg, 3.96 mmol) and (S)-2-amino-N- methoxy-N-methylpent-4-enamide hydrochloride (926 mg, 4.75 mmol) in DCM (20 mL) was added DIEA (1.73 mL, 9.90 mmol), HOBt (1.07 g, 7.92 mmol) and EDCI (1.52 g, 7.92 mmol). The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The reaction was diluted with EtOAc (30 mL), washed with IN HC1 (20 mL). The organics were collected and concentrated. The residue was purified by column chromatography (Petroleum Ether: Ethyl Acetate = 1: 1) to afford compound 195C (1.2 g, yield: 88.50%) as colorless oil. MS (ESI) m/z (M+l) + 343.1.
[1061] To a solution of compound 195C (1 g, 2.92 mmol) in THF (10 mL) at -40°C was added LiAlH 4 (1M, 3.1 mL) dropwise. After addition, the mixture was stirred at 0°C for lh. The reaction was quenched with IN HC1 (30 mL) dropwise, extracted with EtOAc (20 mL x 3). The organics were collected, washed with brine (30 mL), dried with Na 2 S0 4 , filtered and concentrated to afford intermediate compound 195D (800 mg, crude) as white solid. MS (ESI) m/z (M+l) + 284.0.
[1062] To a solution of compound 195D (280 mg, 0.99 mmol) and 2-hydroxy-2- methylpropanenitrile (0.54 mL, 5.88 mmol) in DCM (20 mL) was added TEA (0.17 mL, 1.19 mmol). The mixture was stirred at 25°C for 12h. The solvent was removed in vacuo. The residue was purified by column (Petroleum Ether: Ethyl Acetate = 1: 1) to give compound 195E (200 mg, yield: 65.21%) as yellow oil. MS (ESI) m/z (M+l) + 311.0.
[1063] To a solution of compound 195E (736 mg, 2.37 mmol) in DMSO (5 mL) at 0 °C was added K 2 C0 3 (656 mg, 4.74 mmol). Then H 2 0 2 (2.28 mL, 23.72 mmol, 30% purity) was added dropwise. The mixture was stirred at 25°C for lh. The reaction was quenched with 10% aq. Na 2 S 2 0 3 (30 mL) dropwise. The mixture was extracted with EtOAc (20 mL x 3). The organics were collected, washed with brine (30 mL), dried with Na 2 S0 4 , filtered and concentrated. The residue was washed with CH 3 CN (5 mL). The solid was filtered, collected and dried in vacuo to afford compound 195F (200 mg, yield: 25.60%) as white solid. 1H NMR (DMSO-de, 400 MHz): δ 8.09 (s, 1H), 7.72 - 7.61 (m, 2H), 7.48 - 7.42 (m, 1H), 7.40 - 7.26 (m, 3H), 7.25 - 7.12 (m, 2H), 5.81 - 5.60 (m, 2H), 5.12 - 4.93 (m, 2H), 4.33 - 4.17 (m, 1H), 3.96 - 3.93 (m, 1H), 3.86 (s, 3H), 2.34 - 2.05 (m, 2H). MS (ESI) m/z (M+l) + 329.0.
[1064] To a solution of compound 195F (200 mg, 609.07 umol) in DCM (15 mL) and DMSO (5 mL) was added DMP (775 mg, 1.83 mmol). The mixture was stirred at 25°C for 30 min. The reaction was diluted with DCM (20 mL), quenched with a solution of 10% aqueous Na 2 S 2 0 3 and saturated NaHC0 3 (v/v = 1/1) (40 mL). The organics were collected, washed with brine (30 mL x 3). The organics were collected, dried with Na 2 S0 4 , filtered and concentrated. The residue was washed with CH 3 CN (5 mL). The solid was filtered, collected and dried in vacuo to afford 195 (38 mg, yield: 18.72%) as white solid. 1H NMR (DMSO-i¾ , 400 MHz): δ 8.23 (d, J = 6.8 Hz, 1H), 8.13 (s, 1H), 7.98 (br. s, 1H), 7.73 (br. s, 1H), 7.68 - 7.61 (m, 2H), 7.38 - 7.25 (m, 3H), 5.89 - 5.71 (m, 1H), 5.11 - 4.98 (m, 3H), 3.88 (s, 3H), 2.57 - 2.50 (m, 1H), 2.40 - 2.31 (m, 1H). MS (ESI) m/z (M+l) + 327.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-BROMO-l-METHY L-lH-
[1065] Compound 196 (54 mg, yield: 50.44%, white solid) was prepared as in Example 61 from the corresponding intermediate compound 163G. Compound 196: 1H NMR (400MHz, DMSO- e) δ 8.21 - 8.15 (m, 2H), 8.06 (br s, 1H), 7.80 (br s, 1H), 7.28 - 7.23 (m, 4H), 7.20 - 7.16 (m, 1H), 5.33 - 5.26 (m, 1H), 3.82 (s, 3H), 3.15 (br dd, J = 3.7, 13.9 Hz, 1H), 2.83 (br dd, J = 9.8, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 379.0 & 381.0.
[1066] To a cold (0 °C), stirred solution of 3-bromo-lH-indazole (5 g, 25.38 mmol) in DMF (130 mL) was added NaH (1.22 g, 50.76 mmol) in portions. After 0.2h, SEM-C1 (5.08 g, 30.46 mmol) was added and then the mixture was stirred at 25 °C for 6 hours under N 2 atmosphere. The reaction was quenched with a saturated aqueous solution of NH 4 CI and the resulting layer was extracted with EtOAc (100 mL x 2). The combined organic layers were dried, filtered and concentrated under reduced pressure to leave a residue. The residue which was purified by flash chromatography on silica (elution with 100: 1 to 10: 1 Petroleum Ether : EtOAc ) to give compound compound 197A (5.5 g, 66.21% yield) as an oil. 1H NMR (CDC1 3, 400 MHz): δ 7.71 - 7.69 (m, 1H), 7.65 - 7.60 (m, 1H), 7.57 - 7.51 (m, 1H), 7.37 - 7.29 (m, 1H), 5.76 (d, = 3.2 Hz, 2H), 3.70 - 3.55 (m, 2H), 1.02 - 0.87 (m, 2H), 0.00 (d, = 3.2 Hz, 9H). MS (ESI) m/z (M+H) + 338.3.
[1067] To a mixture of compound 197A (2 g, 6.11 mmol), compound 4,4,4\4\5,5,5\5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.86 g, 7.33 mmol), KOAc (2.4 g, 24.44 mmol), Pd (dppf) Cl 2 (894.3 mg, 1.22 mmol) in dioxane (80 mL) was heated at 80 °C for 12 hours under N 2 atmosphere. Compound 197B (crude) was obtained as a solution (15.8 mg/mL in dioxane).
[1068] To a mixture of compound 197B (461.6 mg, 1.23 mmol, 30 mL in dioxane), compound 163E (100 mg, 262.3 umol), Pd(dtbpf)Cl 2 (34.19 mg, 52.46 umol) and K 3 PO 4 (111.4 mg, 524.6 umol) in H 2 0 (2 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 70 °C for 2 hours under N 2 atmosphere. The reaction solution was purified by preparatory-HPLC (basic condition) to give compound 197D (50 mg, 16.54% yield)as a brown solid. 1H NMR (CDC1 3, 400 MHz): δ 8.14 - 8.02 (m, 1H), 8.01 - 7.82 (m, 1H), 7.70 - 7.63 (m, 1H), 7.58 (t, = 7.6 Hz, 1H), 7.51 (d, = 8.4 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.02 - 6.89 (m, 1H), 6.88 - 6.69 (m, 5H), 6.42 (br s, 1H), 5.70 - 5.48 (m, 2H), 5.34 (br s, 1H), 4.39 - 4.27 (m, 1H), 4.24 - 4.08 (m, 1H), 3.84 (s, 3H), 3.58 (t, = 8.0 Hz, 2H), 3.04 - 2.74 (m, 2H), 0.92 - 0.87 (m, 2H), -0.07 (s, 9H). MS (ESI) m/z (M+H) + 549.2.
[1069] A mixture of compound 197D (50 mg, 91.12 umol) in DCM (10 mL) was added DMP (116 mg, 273.4 umol) in one portion at 0 °C under N 2 , and then the mixture was stirred at 0 °C for 1 hour under N 2 atmosphere. The mixture was quenched with saturated aqueous NaHC0 3 (15 mL) and saturated aqueous Na 2 S 2 0 3 (15 mL), and stirred for 20 min, then diluted with dichloromethane (100 mL). The mixture was stirred for 20 mins and washed with water (2 x 20 mL). The combined organic layers were dried over Na 2 S0 4 and concentrated under reduced pressure to give the crude product. The residue was purified by preparatory-HPLC (basic condition) to give compound 197E (30 mg, 55.67% yield) as white solid. 1H NMR (CDC1 3, 400 MHz): δ 8.23 (s, 1H), 7.98 (d, = 6.8 Hz, 1H), 7.74 (d, = 8.8 Hz, 1H), 7.70 - 7.60 (m, 2H), 7.48 - 7.38 (m, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.89 - 6.75 (m, 3H), 6.74 - 6.67 (m, 2H), 5.84 - 5.75 (m, 1H), 5.63 (d, J = 11.6 Hz, 2H), 5.45 (d, J = 11.2 Hz, 1H), 4.01 - 3.87 (m, 3H), 3.78 - 3.57 (m, 2H), 3.39 - 3.12 (m, 2H), 1.02 - 0.92 (m, 2H), 0.16 - 0.07 (m, 9H). MS (ESI) m/z (M+ H) + 547.2.
[1070] A mixture of compound 197E (30 mg, 54.88 umol) in HCl/EtOAc (4 M, 1.50 mL) was stirred at 25 °C for 78 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparatory-HPLC (basic condition) to afford compound 197 (1.6 mg, 6.68% yield) as a white solid. 1H NMR (400 MHz, CDCI 3 ): δ 10.35 (br s, 1H), 8.12 (s, 1H), 7.77 (br s, 1H), 7.61 - 7.50 (m, 3H), 7.34 - 7.28 (m, 1H), 7.10 - 7.04 (m, 1H), 6.98 - 6.90 (m, 2H), 6.84 - 6.68 (m, 3H), 5.62 - 5.42 (m, 2H), 3.83 (s, 3H), 3.29 - 3.19 (m, 1H), 3.08 - 2.97 (m, 1H). MS (ESI) m/z (M+H) + 417.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-3-(6- (TRIFLUOROMETHYL)PYRIDIN-2-YL)-lH-PYRAZOLE-4-CARBOXAMIDE (198)
[1071] A mixture of compound ethyl 3 -iodo- 1 -methyl- lH-pyrazole-4-carboxylate (200 mg, 714.13 umol) and compound 194A (1.91 g, 856.96 umol) in dioxane (3 mL) was added Pd(t-Bu 3 P)2 (110 mg, 214.24 umol) under nitrogen atmosphere. The mixture was stirred at 90 °C for 48 hours. The mixture was diluted with CH 2 C1 2 (30 mL), filtered to remove the precipitate and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (Petroleum Ether: Ethyl Acetate = 10/1 to 5/1) to afford compound (175.00 mg, 77.93% yield) as brown solid. 1H NMR (400 MHz, CDC1 3 ) S 8.01 - 7.91 (m, 3H), 7.72 - 7.67 (m, 1H), 4.26 - 4.20 (m, 2H), 4.00 (s, 3H), 1.25 - 1.19 (s, 3H).
[1072] To a mixture of compound 198B (170 mg, 568.09 umol) in MeOH (8 mL) and H 2 0 (4 mL) was added LiOH ' H 2 0 (191 mg, 4.54 mmol) in one portion and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (20 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 198C (150 mg, 97.36% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s 1H), 8.25 (d, 7 = 4 Hz, 1H), 8.00 - 7.98 (m, 2H), 3.95 (s, 3H).
[1073] Compound 198 (94.2 mg, 63.09% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 198C. Compound 198: 1H NMR (400 MHz, CDCI 3 ) δ 10.92 (d, 7 = 6.80 Hz, 1H), 8.39 (d, 7 = 8.40 Hz, 1H), 8.08 (s, 1 H) 7.92 - 8.02 (m, 1 H), 7.65 (d, 7=8.00 Hz, 1 H), 7.06 - 7.23 (m, 5 H), 6.72 (s, 1 H), 5.51 (br s, 1 H), 5.31 - 5.43 (m, 1 H), 3.93 (s, 3 H), 3.38 - 3.49 (m, 1 H), 2.96 - 3.11 (m, 1 H). MS (ESI) m/z (M+l) + 446.1.
[1074] Compound 199 (35.0 mg, yield 53.6%, white solid) was prepared as in Example 61 from the corresponding starting materials, compound 103A and m-tolylboronic acid. Compound 199: 1H NMR (DMSO-d 6, 400 MHz) δ 9.08 (d, 7 = 7.7 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.84 (br s, 1H), 7.60 - 7.52 (m, 2H), 7.45 - 7.37 (m, 3H), 7.36 -7.30 (m, 1H), 7.28 - 7.25 (m, 3H), 7.23 - 7.16 (m, 3H), 7.12 - 7.06 (m, 1H), 6.60 (br s, 1H), 5.29 (br s, 1H), 3.22 - 3.14 (m, 1H), 2.86 - 2.76 (m, 1H), 2.35 (s, 3H), 2.28 - 2.22 (m, 3H). MS (ESI) m/z (M+H) + 467.2. EXAMPLE 105
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(6-PHENYLPYRI DAZIN-3- Y -lH-IMIDAZOLE-5-CARBOXAMIDE (200)
[1075] To a mixture of 6-bromopyridazin-3-amine (10 g, 57 mmol) and phenylboronic acid (10.5 g, 86 mmol) in toluene (150 mL) and EtOH (150 mL) was added LiCl (7.3 g, 172.4 mmol). Then Na 2 C0 3 (1M, 155 mL) was added, followed by Pd(PPh 3 ) 2 Cl 2 (403 mg, 0.57 mmol). The mixture was heated to reflux for 16h. The mixture was filtered through Celite. The filtrate was diluted with H 2 0 (15 mL), extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (15 mL), dried over MgS0 4 , filtered and concentrated. The residue was triturated with TBME/ethyl acetate (v/v = 1/1, 50 mL). The cake was dried in vaccum to afford compound 2 (4.4 g, yield 44.7%) as off-white solid. 1H NMR (DMSO- e , 400 MHz) δ 7.94 (d, = 7.2 Hz, 2H), 7.79 (d, = 9.2 Hz, 1H), 7.46 -7.42 (m, 2H), 7.38 - 7.36 (m, 1H), 6.86 (d, J = 9.2 Hz, 2H), 6.52 (s, 2H). MS (ESI) m/z (M+H) + 172.0.
[1076] Ethyl 2-oxoacetate (26 mL, 128.50 mmol) was added to a solution of compound 200A (4.4 g, 25.7 mmol) in MeOH (100 mL). The mixture was heated to 65 °C and stirred for 15h. The mixture was concentrated. The residue was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate = 3/1) to afford compound 200B (5.5 g, yield 52%, 69.8% purity) as brown oil. MS (ESI) m/z (M+H) + 288.1.
[1077] K 2 C0 3 (6.61 g, 47.85 mmol) was added to a solution of compound 200B (5.5 g, 19.14 mmol) and tosylmethyl isocyanide (5.04 g, 25.84 mmol) in EtOH (190 mL). The mixture was heated to 65 °C and stirred for 3h. The mixture was concentrated in vacum and the residue was treated with Ethyl Acetate (100 mL) and H 2 0 (75 mL). The organic layer was separated and the aqueous layer was extracted with Ethyl Acetate (50 mL x2). The combined organic layer was washed with brine (100 mL), dried over MgS0 4 , filtered and concentrated. The residue was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate = 5/1 to 1/1) to afford (1.80 g, yield 30%) as yellow solid. 1 H NMR (CDC1 3, 400 MHz) δ 8.22 (s, IH), 8.12 -8.10 (m, 2H), 8.01 (d, 7 = 7.2 Hz, IH), 7.94 , (s, IH), 7.76 - 7.74 (m, IH), 7.56 -7.54 (m, 3H), 4.29 (q, 7 = 6.8 Hz, 2H), 1.33 (t, 7 = 6.8 Hz, 3H). MS (ESI) m/z (M+H) + 295.0.
[1078] LiOH.H 2 0 (114 mg, 2.72 mmol) was added to a solution of compound 200C (100 mg, 0.34 mmol,) in MeOH (5 mL). Then H 2 0 (0.5 mL) was added. The mixture was stirred at 25 °C for 3h. The mixture was diluted with H 2 0 (25 mL) and the volatile solvent was evaporated in vacuum. The residue was acidified to pH ~ 3 with IN HC1. The mixture was extracted with Ethyl Acetate (25 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgS0 4 , filtered and concentrated to afford compound 200D (90 mg, yield 99.5%) as yellow solid, which was used for next step directly. 1H NMR (DMSO- e , 400 MHz) δ 8.50 (d, 7=9.3 Hz, IH), 8.38 (d, 7=1.0 Hz, IH), 8.24 (dd, 7=1.9, 7.7 Hz, 2H), 8.13 (d, 7=9.0 Hz, IH), 7.85 (d, 7=1.0 Hz, IH), 7.66 - 7.55 (m, 3H).
[1079] Compound 200 (35 mg, yield 35.2%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 200D. Hydrate was observed in 1H NMR. Compound 200: 1H NMR (DMSO-i¾ , 400 MHz) δ 8.83 (br s, IH), 8.34 - 8.25 (m, 2H), 8.19 (dd, 7 = 1.8, 7.8 Hz, 2H), 7.81 (br s, IH), 7.75 (s, IH), 7.66 - 7.48 (m, 5H), 7.34 - 7.20 (m, 5H), 5.32 - 5.23 (m, IH), 3.24 (dd, 7 = 4.3, 14.1 Hz, IH), 2.94 (dd, 7 = 9.7, 13.9 Hz, IH). MS (ESI) m/z (M+H) + 441.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l- (6- PHENYLPYRIDAZIN-3-YL)-lH-IMIDAZOLE-5-CARBOXAMIDE (201)
[1080] Compound 201 (89 mg, yield 54.5%, yellow solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 200D. Hydrate was observed on 1H NMR. Compound 201: 1H NMR (DMSO-d 6, 400 MHz) δ 8.82 (br s, 0.8H), 8.51 (br s, 0.9H), 8.31 - 8.22 (m, 2.7H), 8.20 - 8.14 (m, 2.3H), 7.93 (s, 0.9H), 7.79 - 7.70 (m, 1.7H), 7.69 - 7.64 (m, 1.7H), 7.63 - 7.54 (m, 5.7H), 7.37 (br d, 7=8.5 Hz, 0.9H), 7.31 (d, 7=4.5 Hz, 3.6H), 7.28 - 7.17 (m, 5.2H), 5.35 - 5.28 (m, IH), 4.42 - 4.35 (m, 0.9H), 3.23 (dd, 7=4.0, 14.1 Hz, 0.7H), 3.07 (br s, 1.7H), 2.97 - 2.89 (m, 1.1H), 2.80 - 2.74 (m, 1.7H), 2.68 - 2.64 (m, 1.0H), 0.71 - 0.63 (m, 2.0H), 0.62 - 0.55 (m, 3.2H), 0.48 (br s, 1.6H). MS (ESI) m/z (M+H) + 481.1. EXAMPLE 107
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(2' -METHYL- [l,l'- -4-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (202)
[1081] To a solution of compound 83D (150 mg, 0.33 mmol) in THF (6 mL) and H 2 0 (3 mL) was added Cs 2 C0 3 (168mg, 0.51 mmol,) and o-tolylboronic acid (89 mg, 0.66 mmol), followed by Pd(PPh 3 )4 (38 mg, 0.033 mmol). Then the mixture was heated to 80 °C and stirred for 12h. The reaction mixture was cooled to the room temperature and H 2 0 (10 mL) was added to quenched the reaction and then the mixture was evaporated under reduced pressure. The water phase was extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with NaHC0 3 (10 ml), H 2 0 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered, evaporated under reduced pressure. The crude product was triturated with isopropyl ether/acetonitrile(10/l, 5 mL) to afford compound 202A (50 mg, yield 32.5%) as yellow solid. 1H NMR (DMSO-i¾, 400MHz) δ 8.54 (br d, J = 9.3 Hz, 1H), 8.20 (br d, J = 9.7 Hz, 1H), 7.66 - 7.46 (m, 1H), 7.38 (br s, 1H), 7.35 - 7.19 (m, 12H), 7.14 (br d, = 8.4 Hz, 1H), 6.61 - 6.51 (m, 1H), 6.01 - 5.66 (m, 1H), 4.45 (br s, 1H), 4.04 - 3.90 (m, 1H), 3.00 - 2.62 (m, 2H), 2.37 - 2.17 (m, 6H).
[1082] To a solution of compound 202A (46 mg, 98.2 umol) in DCM (10 mL) was added DMP (125 mg, 294.5 umol) and the mixture was at 25 °C for 2h. The reaction mixture was diluted with DCM (10 mL) and quenched with NaHC0 3 /Na 2 S 2 0 3 (1/1, 20 mL), then the mixture was stirred for 0.25h. The mixture was extracted with DCM(10 mL x 2), the combined organic layer was washed with NaHC0 3 (10 mL x 3) and brine (10 mL x 3), dried over anhydrous Na 2 S0 4 , filtered, evaporated under reduced pressure. The crude product was purified by preparatory-HPLC (base) to afford 202 (30 mg, yield 60.65%) was obtained as white solid. 1H NMR (CDC1 3 , 400MHz) δ 7.43 - 7.39 (m, 2H), 7.39 - 7.35 (m, 2H), 7.30 - 7.28 (m, 3H), 7.26 - 7.21 (m, 4H), 7.03 (dd, J = 1.9, 7.6 Hz, 2H), 6.72 (br s, 1H), 6.52 (s, 1H), 6.37 (br d, J = 7.5 Hz, 1H), 5.66 - 5.60 (m, 1H), 5.55 (br s, 1H), 3.38 (dd, J = 5.4, 14.2 Hz, 1H), 3.16 (dd, J = 7.3, 14.3 Hz, 1H), 2.36 (s, 3H), 2.29 - 2.27 (m, 3H). MS (ESI) m/z (M+H) + 467.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(6-METHYL-4-(TRIFLUOROMETHYL)PYRIDIN-2-YL)-lH-PYRAZOLE-5-
[1083] To a solution of 2-hydrazinyl-6-methyl-4-(trifluoromethyl)pyridine (500 mg, 2.62 mmol) in CH 3 COOH (10 mL) was added ethyl 2-(methoxyimino)-4-oxopentanoate (490.4 mg, 2.62 mmol), then the mixture was stirred at 120 °C for 2 hours. The mixture was diluted with CH 2 CI 2 (100 mL) and washed by saturated sodium bicarbonate (30 mL x 2 ) and saturated brine (30 mL x 2 ), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was purified by flash column chromatography (S1O 2 , Petroleum Ether : Ethyl Acetate = 10/1 to 3/1). Compound 206A (200.0 mg, 24.37% yield) was obtained as white solid. 1H NMR (400 MHz, CDCI 3 ) δ 7.72 (s, 1H), 7.33(s, 1H), 6.68(s, 1H), 4.33 - 4.28(m. 2H), 2.60(s, 3H), 3.23(s, 3H), 1.31 - 1.20(m, 3H).
[1084] To a mixture of compound 206A (180.0 mg, 574.58 umol) in MeOH (6 mL) and H 2 O (3 mL) was added LiOH » H 2 0 (96.4 mg, 2.30 mmol) in one portion and the mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. Then the mixture was diluted with ¾0 (10 mL) and the pH was adjusted to ~ 3 with IN HC1 and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 206B (145.0 mg, 88.48% yield) as white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (s, 1H), 7.73(s, 1H), 6.79(d, = 4 Hz, 1H), 2.56(s, 3H), 2.29(s, 3H). [1085] Compound 206 (52.0 mg, 52.16% yield, pale yellow solid) was prepared as in Example 41 from the corresponding intermediate carboxylic acid, compound 206B. Compound 206: 1H NMR (400 MHz, CDC1 3 ) δ 8.65 (J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.22 (s, 1H), 7.18 - 7.16 (m, 3H), 7.04 - 7.03 (m, 2H), 6.88 (s, 1H), 6.70 (s, 1H), 5.77 - 5.72 (m, 1H), 3.46-3.41 (m, 1H), 3.35-3.30 (m, 1H), 2.83 - 2.79 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 0.91 - 0.86 (m, 2H), 0.63-0.60 (m, 2H). MS (ESI) m/z (M+l) + 500.2.
[1086] A mixture of ethyl 2-(methoxyimino)-4-oxopentanoate (558.2 mg, 2.98 mmol) and 6-hydrazinylnicotinonitrile (400 mg, 2.98 mmol) in AcOH (5 mL) was stirred at 118 °C for 5 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue, which was diluted with CH 2 CI 2 (100 mL). The organic phase was washed with saturated aqueous NaHC0 3 (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1 :0 to 5: 1) to afford compound 208A (160 mg, 19.09% yield) as a white solid, but structure (proposed structure) could not be confirmed by N-H HMBC. 1H NMR (400 MHz, CDC1 3 ): δ 8.66 (dd, = 0.8, 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 8.4 Hz, 1H), 7.88 (dd, J = 0.8, 8.4 Hz, 1H), 6.67 (s, 1H), 4.35 (q, J = 6.8 Hz, 2H), 2.37 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+l) + 257.1.
[1087] To a solution of compound 208A (100 mg, 390.23 umol) in THF (4 mL) was added KOTMS (100 mg, 780.46 umol), then the mixture was stirred at 25 °C for 0.3 hour. The mixture was diluted by petroleum ether (20 mL), the precipitate was filtered to afford the residue. The mixture was diluted by petroleum ether (20 mL), the precipitate was filtered to afford intermediate compound 208B (80 mg, 76.98% yield) as white solid.
[1088] Compound 208 (13.5 mg, 27.13% yield, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 208B and 12G. Compound 208: 1H NMR (400 MHz, DMSO-d 6 ): δ 9.09 (d, = 7.2 Hz, 1H), 8.49 (d, = 1.6 Hz, 1H), 8.40 - 8.36 (m, 1H), 8.10 (br s, 1H), 7.86 (br s, 1H), 7.82 (d, = 8.4 Hz, 1H), 7.31 - 7.23 (m, 5H), 6.51 (s, 1H), 5.35 - 5.29 (m, 1H), 3.19 - 3.13 (m, 1H), 2.84 - 2.76 (m, 1H). MS (ESI) m/z (M+l) + 403.1.
COMPOUNDS 209, 439-441, 443-444
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-( PYRIDIN-4-YL)-
[1089] To a solution of ethyl 3-methyl-lH-pyrazole-5-carboxylate (3.0 g, 19.46 mmol), pyridin-4-ylboronic acid (5.98 g, 48.65 mmol) in Pyridine (40 mL) was added Cu(OAc) 2 (1.8 g, 9.73 mmol). The mixture was stirred at 55 °C for 18 hrs. The mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). Compound 209A (850 mg, 18.91% yield) was obtained as white solid. Compound 209B (850 mg, 18.91% yield) was obtained as white solid. Compound 209A (850 mg, 18.91% yield, white solid): 1H NMR (400MHz, CDC1 3 ) δ 8.75 - 8.65 (m, 2H), 7.42 (d, = 6.0 Hz, 2H), 6.87 (s, 1H), 4.33 - 4.25 (m, 2H), 2.36 (s, 3H), 1.32 - 1.28 (m, 3H). [1090] To a mixture of compound 209A (600 mg, 2.59 mmol) in EtOH (5 mL) was added aq. NaOH (1 M, 2.59 mL) in one portion and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (200 mL x 4). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure to afford intermediate compound 209C (390 mg, 74.10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.63 (br s, 2H), 7.50 (br d, J = 5.2 Hz, 2H), 6.90 (s, 1H), 2.26 (s, 3H).
[1091] Compound 209 (27.1 mg, 25.46% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 209C. Compound 209: 1H NMR (400MHz, OMSO-d 6 ) δ 9.33 (d, J = 7.8 Hz, 1H), 8.55 - 8.49 (m, 2H), 8.17 (s, 1H), 7.92 (s, 1H), 7.37 - 7.27 (m, 5H), 7.22 - 7.18 (m, 2H), 6.60 (s, 1H), 5.33 (s, 1H), 3.28 - 3.21 (m, 1H), 2.88 - 2.79 (m, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 378.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- PHENOXYPHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE (439)
[1092] Compound 439 (65 mg, yield: 61.4%, yellow solid) was prepared from ethyl 3-methyl-lH-pyrazole-5-carboxylate which was subjected to coupling with (4- phenoxyphenyl)boronic acid as in compound 209 followed by ester hydrolysis and coupling with intermediate 274D using procedures as in compound 12 to obtain compound 439. Compound 439: 1H NMR (400MHz, DMSO-i¾) δ 9.08 (br d, J = 7.3 Hz, 1H), 8.12 (br s, 1H), 7.87 (br s, 1H), 7.44 (br t, = 7.4 Hz, 2H), 7.31 - 7.13 (m, 8H), 7.06 (br d, = 7.9 Hz, 2H), 6.93 (br d, = 8.4 Hz, 2H), 6.57 (s, 1H), 5.26 (br s, 1H), 3.20 (br d, = 14.6 Hz, 1H), 2.81 (br t, = 12.3 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 469.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4-((TET RAHYDRO- 2H-PYRAN-4-YL)OXY)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE (440)
[1093] Compound 440 (90 mg, yield: 58%, white solid) was prepared from ethyl 1- (4-hydroxyphenyl)-3-methyl- lH-pyrazole-5-carboxylate which was subjected to mitsunobu coupling with tetrahydro-2H-pyran-4-ol followed by ester hydrolysis and coupling with intermediate 274D using procedures as in compound 12 to obtain compound 440. Compound 440: 1H NMR (400MHz, DMSO-i¾) δ 9.03 (d, = 7.8 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.35 - 7.23 (m, 5H), 7.07 (d, 7 = 8.8 Hz, 2H), 6.92 (d, 7 = 9.0 Hz, 2H), 6.53 (s, 1H), 5.27 - 5.14 (m, 1H), 4.59 - 4.54 (m, 1H), 3.89 - 3.82 (m, 2H), 3.49 (t, 7 = 9.3 Hz, 2H), 3.19 (dd, 7 = 3.1, 13.9 Hz, 1H), 2.81 (dd, 7 = 10.8, 13.8 Hz, 1H), 2.23 (s, 3H), 1.97 (d, 7 = 12.0 Hz, 2H), 1.58 (d, 7 = 7.8 Hz, 2H). MS (ESI) m/z (M+H) + 477.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4-(4- ((DIETHYLAMINO)METHYL)PHENOXY)PHENYL)-3-METHYL-lH-PYRAZOLE-5 -
C ARB OX AMIDE HYDROCHLORIDE (441)
[1094] Compound 441 (14 mg, yield: 26.21%, white solid) was prepared from ethyl l-(4-hydroxyphenyl)-3-methyl-lH-pyrazole-5-carboxylate which was subjected to coupling with (4-((diethylamino)methyl)phenyl)boronic acid as in compound 209 followed by ester hydrolysis and coupling with intermediate 274D using procedures as in compound 12 to obtain compound 441. Compound 441: 1H NMR (400MHz, DMSO-i¾) δ 11.55 (br. s, 1H), 7.77 - 7.71 (m, 2H), 7.37 - 7.15 (m, 8H), 7.12 - 7.06 (m, 2H), 6.99 (d, 7 = 9.0 Hz, 2H), 6.57 (s, 2H), 6.13 - 5.96 (m, 1H), 4.72 - 4.63 (m, 1H), 4.23 - 4.13 (m, 2H), 3.27 - 3.18 (m, 1H), 3.13 - 2.92 (m, 5H), 2.28 (s, 3H), 1.34 (t, 7 = 3.5, 7.3 Hz, 6H). MS (ESI) m/z (M+H) + 554.3.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4-(2-(2-
METHOXYETHOXY)ETHOXY)PHENYL)-3-METHYL-lH-PYRAZOLE-5-
[1095] Compound 443 (75 mg, yield: 61.3%, white solid) was prepared from ethyl 3- methyl-lH-pyrazole-5-carboxylate which was subjected to coupling with (4- (benzyloxy)phenyl)boronic acid as in compound 209 followed by hydrogenolysis to yield the phenolic derivative which was subjected to mitsunobu coupling with 2-(2-methoxyethoxy)ethan- l-ol followed by ester hydrolysis and coupling with intermediate 274D using procedures as in compound 12 to obtain compound 443. Compound 443: 1H NMR (400MHz, DMSO-i¾) δ 9.02 (br d, 7 = 7.8 Hz, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.37 - 7.20 (m, 5H), 7.08 (br d, 7 = 8.8 Hz, 2H), 6.89 (br d, 7 = 9.0 Hz, 2H), 6.53 (s, 1H), 5.28 - 5.17 (m, 1H), 4.16 - 4.06 (m, 2H), 3.80 - 3.71 (m, 2H), 3.65 - 3.56 (m, 2H), 3.51 - 3.44 (m, 2H), 3.25 (s, 3H), 3.21 - 3.14 (m, 1H), 2.81 (br dd, 7 = 10.7, 13.7 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 495.2. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3-(2-(2- METHOXYETHOXY)ETHOXY)PHENYL)-3-METHYL-lH-PYRAZOLE-5-
[1096] Compound 444 (60 mg, yield: 39.58%, white solid) was prepared from ethyl 3-methyl-lH-pyrazole-5-carboxylate which was subjected to coupling with (3- (benzyloxy)phenyl)boronic acid as in compound 209 followed by hydrogenolysis to yield the phenolic derivative which was subjected to mitsunobu coupling with 2-(2-methoxyethoxy)ethan- l-ol followed by ester hydrolysis and coupling with intermediate 274D using procedures as in compound 12 to obtain compound 444. Compound 444: 1H NMR (400MHz, DMSO- 6 ) δ 9.07 (d, J = 7.3 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.35 - 7.18 (m, 6H), 6.93 - 6.81 (m, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.54 (s, 1H), 5.28 (s, 1H), 4.05 (s, 2H), 3.72 (s, 2H), 3.57 (d, J = 4.2 Hz, 2H), 3.46 (d, J = 4.2 Hz, 2H), 3.24 (s, 3H), 3.18 (s, 1H), 2.88 - 2.77 (m, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 495.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-5-(3-P HENYL-lH- PYRA -l-YL)ISOXAZOLE-4-CARBOXAMIDE (211)
[1097] To a mixture of ethyl 5-chloro-3-methylisoxazole-4-carboxylate (400 mg, 2.1 mmol) and 3 -phenyl- lH-pyrazole (365 mg, 2.5 mmol) in DMF (3 mL) was added K 2 CO 3 (1.2 g,
8.4 mmol) in one portion. Then the mixture was stirred at 80 °C for 12 hours. Then H 2 0 (9 mL) was added into the mixture, and the aqueous phase was extracted with EtOAc (15 mL x 3), and the combined organic layer was concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 300: 1 to 30: 1). Compound
211A (256 mg, yield: 40.8%, pale yellow solid): 1H NMR (400MHz, CDCI 3 ) δ 8.62 (d, = 2.6
Hz, 1H), 7.93 (d, J = 6.8 Hz, 2H), 7.49 - 7.37 (m, 3H), 6.86 (d, J = 2.6 Hz, 1H), 4.37 (q, J = 1.1
Hz, 2H), 2.53 (s, 3H), 1.40 - 1.34 (m, 2H), 1.41 - 1.33 (m, 1H). [1098] To a solution of compound 211A (150 mg, 504.5 umol) in THF (2 mL) and H 2 0 (500 uL) was added LiOH.H 2 0 (31.8 mg, 756.8 umol) in one portion. Then the mixture was stirred at 25 °C for 3 hours. TLC (Petroleum ether: Ethyl acetate = 1 : 1, R f ~ 0.45) indicated compound 211A was consumed completely and one new main spot formed. The pH of the aqueous phase was adjusted to around 5 by adding HC1 (1M), and then the residue was concentrated on a rotary evaporator to give intermediate compound 211B (92 mg, yield: 67.7%) as a white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 9.39 (br s, 1H), 7.92 (d, = 7.0 Hz, 2H), 7.50 - 7.43 (m, 2H), 7.42 - 7.36 (m, 1H), 7.02 (s, 1H), 2.51 - 2.51 (m, 3H). MS (ESI) m/z (M+H) + 269.9.
[1099] Compound 211 (20 mg, yield: 44.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 21 IB. Compound 211: 1H NMR (400MHz, CDC1 3 ) δ 10.59 (br d, J = 6.8 Hz, 1H), 8.19 (d, = 2.6 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.45 - 7.38 (m, 3H), 7.12 - 7.05 (m, 3H), 7.03 - 6.98 (m, 2H), 6.89 (d, = 2.4 Hz, 1H), 6.72 (br s, 1H), 5.73 - 5.64 (m, 1H), 5.47 (br s, 1H), 3.38 (dd, = 5.3, 14.1 Hz, 1H), 3.06 (dd, / = 8.4, 13.9 Hz, 1H), 2.56 (s, 3H). MS (ESI) m/z (M+H) + 444.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(5- PH -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (212)
[1100] A solution of 2-chloro-5-phenyloxazole (compound 114A) (560 mg, 3.12 mmol) and ΝΗ 2 ΝΗ 2 .Η 2 0 (468 mg, 9.35 mmol) in dioxane (10 mL) was heated to reflux for 3hr. The mixture was concentrated to give compound 212A (610 mg, crude) as yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.27 (br s, 1H), 7.48 (br d, = 7.9 Hz, 1H), 7.36 (br t, = 7.7 Hz, 2H), 7.29 (s, 1H), 7.19 (br t, = 7.4 Hz, 2H), 4.53 - 4.12 (m, 1H), 4.35 (br s, 1H).
[1101] A solution of O-methylhydroxylamine (1.74 g, 20.8 mmol) in H 2 0 (20 mL) was added dropwise to a solution of methyl 2,4-dioxopentanoate (5 g, 34.7 mmol) in ethanol (45 mL), Η 2 0 (25 mL), the mixture was stirred at 25 °C for 12 hrs. The organic solvent was removed under vacuum, the water layer was extracted with ethyl acetate (20 mL x 2), the combined organic layer was washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated, the residue was purified by silica gel chromatography to give compound 212B (3.3 g, yield: 54.9%), as yellow oil. 1H NMR (400MHz, CDCI 3 - ) δ 4.06 (s, 3H), 3.87 (s, 3H), 3.72 (s, 2H), 2.21 (s, 2H).
[1102] A mixture of compound 212B (360 mg, 2.05 mmol) and compound 212A (355 mg, 2.05 mmol) in dioxane (5 mL) was heated to 110 °C for 12 hrs. The mixture was concentrated, the residue was purified by TLC (Petroleum ether: Ethyl acetate = 5: 1) to give compound 212C (140 mg, yield: 24.1%) as yellow oil.
[1103] A mixture of compound 212C (140 mg, 494 umol) and LiOH.H 2 0 (31.1 mg, 741 umol) in THF (5 mL), H 2 0 (1 mL) was stirred at 25°C for 2 hrs. TLC (Petroleum ether: Ethyl acetate = 1 : 1, R f ~ 0) showed the reaction was complete, the organic solvent was removed under reduced pressure, the water layer extracted with ethyl acetate (3 mL), then the water layer was adjusted to pH ~ 3 with IN HC1 to give a precipitate, the solid was filtered and dried to give compound 212D (100 mg, yield: 75.2%) as yellow solid. 1H NMR (400MHz, OMSO-d 6 ) δ 7.85 (s, 1H), 7.74 - 7.69 (m, 2H), 7.48 (t, = 7.7 Hz, 2H), 7.44 - 7.37 (m, 1H), 6.91 (s, 1H), 2.28 (s, 3H).
[1104] Compound 212 (34 mg, yield: 52.6%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 212D. Compound 212: 1H NMR (400MHz, DMSO-d 6 ) δ 9.17 (br d, J = 7.5 Hz, 1H), 8.08 (br s, 1H), 7.83 (br s, 1H), 7.73 (s, 1H), 7.62 (br d, J = 7.5 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.40 - 7.34 (m, 1H), 7.25 (s, 4H), 7.19 (br d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 5.28 (br d, J = 7.7 Hz, 1H), 3.16 (br dd, = 3.0, 14.0 Hz, 1H), 2.81 (br dd, 7 = 10.6, 13.7 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) + 444.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CHLORO-5- -4-CARBOXAMIDE (213)
96B 213F
[1105] A mixture of (ieri-butoxycarbonyl)-L-phenylalanine (50 g, 188.47 mmol), N- methoxymethanamine (20 g, 207.32 mmol, HCl), NMM (57 g, 565.41 mmol) and HOBT (25 g, 188.47 mmol) in CHC1 3 (700 mL) was degassed and purged with N 2 for 3 times at 0 °C, then EDCI (54 g, 282.71 mmol) was added in portions. The mixture was stirred at 25 °C for 16h under N 2 atmosphere. The reaction mixture was quenched by addition H 2 0 (500 mL). The organic layer was separated, washed with IN HCl (300 mL x 2), saturated aqueous NaHC0 3 (300 mL x 3), and brine (300 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was dissolved with petroleum ether (300 mL) and stirred for 2h, filtered and concentrated under reduced pressure to give compound 213A (46 g, yield: 79.15%) as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 1.21 - 7.13 (m, 5H), 5.26 - 4.85 (m, 2H), 3.64 (s, 3H), 3.15 (br s, 3H), 3.04 (br dd, =5.8, 13.6 Hz, 1H), 2.91 - 2.81 (m, 1H), 1.37 (s, 9H). MS (ESI) m/z (M +23) + 331.0.
[1106] To a solution of LiAlH 4 (5.32 g, 140.09 mmol) in THF (1L) was added a solution of compound 213A (36 g, 116.74 mmol) in THF (500 mL) at 0 °C. After addition, the reaction mixture was stirred for lh at 0 °C. The reaction mixture was quenched by addition ethyl acetate (200 mL) and IN HC1 (200 mL), and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with IN HC1 (300mL x 2), saturated aqueous NaHC0 3 (300mLx 3), and brine (300 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 213B (25.3 g, yield: 86.93%) as a white solid. 1H NMR (400MHz, CDC1 3 ) (5 9.61 (s, 1H), 7.33 - 7.24 (m, 3H), 7.16 (br d, 7 = 7.1 Hz, 2H), 5.16 - 5.03 (m, 1H), 4.40 (q, 7 = 6.6 Hz, 1H), 3.10 (br d, 7 = 5.3 Hz, 2H), 1.42 (s, 9H).
[1107] To a solution of compound 213B (32 g, 128.36 mmol) in MeOH (250 mL) was added dropwise a solution of NaHS0 3 (13.5 g) in H 2 0 (400 mL) at 0-5 °C. After that, the reaction mixture was stirred at 28 °C for 5h. NaCN (6.6 g, 134.78 mmol) in H 2 0 (600 mL) was added into the reaction mixture followed by EtOAc (1.2 L). After that, the reaction mixture was stirred at 28 °C for 14h. The mixture was separated and the organic layer was washed with brine (500 mL). The mixture was dried over Na 2 S0 4 and concentrated to afford compound 213C (35 g, yield: 98.68%) as a light yellow gum. 1H NMR (400MHz, DMSO-d 6 ) δ 7.26 - 7.14 (m, 6H), 6.82 - 6.70 (m, 1H), 4.57 - 4.28 (m, 1H), 3.88 - 3.72 (m, 1H), 3.01 - 2.58 (m, 2H), 1.31 - 1.22 (m, 9H). MS (ESI) m/z (M -55) + 220.9.
[1108] To a solution of compound 213C (35 g, 126.66 mmol) and K 2 C0 3 (35 g, 253.32 mmol,) in DMSO (400 mL) was added H 2 0 2 (148 g, 4.35 mol) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 2h. The reaction mixture was filtered to give a residue. The residue was washed with saturated aqueous Na 2 S 2 0 3 (100 mL x 2) and H 2 0 (100 mL), dissolved with toluene (200 mL), concentrated under reduced pressure to remove H 2 0. The filtrate was quenched with saturated aqueous Na 2 S0 3 slowly at 0 °C. The mixture was extracted with EtOAc (200 mL x 3) and the combined extracts were washed with saturated aqueous Na 2 S0 3 (300 mL x 3), brine (200 mL). The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 213D (37.5 g, yield: 88.51%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.29 - 7.16 (m, 7H), 6.64 - 6.09 (m, 1H), 5.74 - 5.61 (m, 1H), 4.09 - 3.67 (m, 2H), 2.86 - 2.56 (m, 2H), 1.36 - 1.22 (m, 9H). MS (ESI) m/z (M -100+H) + 194.9.
[1109] To a solution of compound 213D (41 g, 139.29 mmol) in EtOAc (300 mL) was added HCl/EtOAc (4M, 696.45 mL) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 2h. The reaction mixture was filtered to give a residue. The residue was washed with ethyl acetate (30 mL), concentrated under reduced pressure to give compound 12G (26 g, yield: 66.35%, HC1) as a brown solid. 1H NMR (400MHz, DMSO-i¾) δ 8.42 - 7.95 (m, 3H), 7.60 - 7.43 (m, 2H), 7.37 - 7.12 (m, 6H), 4.38 - 3.79 (m, 2H), 3.73 - 3.62 (m, 1H), 3.03 - 2.73 (m, 2H). MS (ESI) m/z (M + H) + 195.1.
[1110] To a 100 mL round-bottom placed compound 96B (2.00 g, 9.06 mmol) was added H 2 SO 4 (27.60 g, 281.40 mmol) dropwise, and stirred at 135 °C for lh. Then, the mixture was added NaN0 2 (907 mg, 13.14 mmol) in H 2 0 (10 mL) dropwise at 0 °C. The resulting solution was stirred at 50 °C for 0.5h. The reaction mixture was diluted with H 2 0 (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were extracted with 10% NaOH (50 mL x 2). The aqueous phase was adjusted to 3 with IN HC1, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brines (50 mL), dried Na 2 S0 4 , filtered and concentrated under reduced pressure to give a compound 213F (1.17 g, yield: 49.13%) as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.55 (d, 7=1.3 Hz, 5H). MS (ESI) m/z (M +H) + 239.9.
[1111] Compound 213 (65 mg, yield: 40.23%, gray solid) was prepared as in Example 5 from the corresponding starting materials, compounds 12G and 213F. 1H NMR (400MHz, DMSO- e) δ 9.35 (d, 7=7.3 Hz, 1H), 8.19 (br s, 1H), 7.91 (br s, 1H), 7.51 - 7.32 (m, 5H), 7.27 - 7.17 (m, 5H), 5.71 - 5.21 (m, 1H), 3.17 (dd, 7 = 3.4, 14.2 Hz, 1H), 2.72 (dd, 7 = 10.4, 14.1 Hz, 1H). MS (ESI) m/z (M +H) + 414.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(THI AZOL-2- -lH-PYRAZOLE-5-CARBOXAMIDE (215)
[1112] A mixture of 2-hydrazinylthiazole hydrochloride (600 mg, 3.9 mmol, HC1 salt) and ethyl 2-(methoxyimino)-4-oxopentanoate (815 mg, 4.35 mmol) in AcOH (15 mL) was stirred at 110 °C for 2h. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was treated with H 2 0 (50 mL) and ethyl acetate (50 mL), and then the mixture was acidified with saturated aqueous NaHC0 3 till the aqueous phase pH - 7 - 8. The separated aqueous layer was extracted with ethyl acetate (80 mL x 3), the combined organic layers were washed with saturated aqueous. NaCl (100 mL), dried over Na 2 S0 4 , filtered under reduced pressure to give crude product, which was purified by Flash Column Chromatography (petroleum ethenethyl acetate = 1-9) to afford compound 215A (138 mg, yield 12.6%) as white solid. Compound 215A: 1 H NMR (DMSO-i¾ , 400 MHz) δ 7.71 - 7.69 (m, 1H), 7.66 (d, J=3.5 Hz, 1H), 6.87 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 2.26 (s, 3H), 1.20 - 1.15 (m, 3H). MS (ESI) m/z (M+H) + 237.9.
[1113] To a mixture of compound 215A (130 mg, 0.55 mmol) in MeOH (10 mL) was added NaOH (2M, 1.4 mL) in one portion at 25 °C. After stirred at 25 °C for 1.5h, the reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was added H 2 0 (10 mL) and extracted with ethyl acetate (10 mL), the separated aqueous phase was acidified with 1M HC1 till pH - 5 - 6. The solid was separated and filtered under reduced pressure to afford compound 215B (70 mg, crude) as white solid. Compound 215B: 1H NMR (CDC1 3, 400 MHz) δ 7.56 (d, J = 3.7 Hz, 1H), 7.21 - 7.17 (m, 2H), 2.37 (s, 3H).
[1114] Compound 215 (10 mg, yield 53.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 215B. Compound 215: 1H NMR (CDC1 3, 400 MHz) δ 11.76 (s, 1H), 7.27 - 7.18 (m, 5H), 7.17 - 7.12 (m, 1H), 7.10 - 7.00 (m, 2H), 6.78 (s, 1H), 5.83 - 5.74 (m, 1H), 5.50 (s, 1H), 3.48 - 3.40 (m, 1H), 3.28 - 3.18 (m, 1H), 2.32 (s, 3H). MS (ESI) m/z (M+H) + 384.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-l-(THI AZOL-2-
YL)-lH-PYRAZOLE-3-CARBOXAMIDE (219)
[1115] To a solution of 2-hydrazinylthiazole hydrochloride (700 mg, 4.39 mmol, HCI salt) in CH 3 COOH (15 mL) was added ethyl 2,4-dioxopentanoate (632 uL, 4.48 mmol) drop wise , then the mixture was heated to 120 °C and stirred for 2h. Remove the solvent under reduced pressure, the residue was dissolve in ethyl acetate (5 mL) and treated with NaHC0 3 until pH ~ 8. The organic layer was collected and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography (Petroleum Ether/Ethyl Acetate = 1/ 0 to 10/1) to afford compound 219A (160 mg, yield 15.4%) as white solid. Compound 219A: 1 H NMR (CDC1 3 , 400MHz) 31.60 (d, 7=3.5 Hz, 1H), 7.18 (d, 7 = 3.5 Hz, 1H), 6.70 (d, 7 = 0.9 Hz, 1H), 4.42 (q, 7 = 7.1 Hz, 2H), 2.74 (d, 7 = 0.9 Hz, 3H), 1.42 (t, 7 = 7.1 Hz, 3H).
[1116] To a solution of compound 219A (160 mg, 674.31 umol) in MeOH (10 mL) was added NaOH (2M, 2.00 mL) dropwise and then the mixture was stirred at 25°C for 2h. The reaction mixture was diluted with H 2 0 (5 mL), evaporated under reduced pressure and then the water phase was extracted with MBTE (5 mL). The water phase (acidified with HC1, pH ~ 3) was extracted with Ethyl Acetate (10 mL x 3), then the organic (Ethyl Acetate) was collected, washed with saturate brine, dried over anhydrous Na 2 S0 4 and filtered concentrated under reduced pressure. Compound 219B (110 mg, yield 78%, white solid): 1H NMR (DMSO- e, 400MHz) δ 7.72 (d, 7=3.5 Hz, 1H), 7.64 (d, 7=3.5 Hz, 1H), 6.77 (d, 7=0.7 Hz, 1H), 2.67 (s, 3H).
[1117] Compound 219 (15 mg, yield 31.8%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 219B. Compound 219: 1H NMR (DMSO- e , 400MHz) δ 7.58 (d, 7 = 3.5 Hz, 1H), 7.37 - 7.26 (m, 3H), 7.26 - 7.24 (m, 1H), 7.22 - 7.15 (m, 3H), 6.78 (br s, 1H), 6.65 (s, 1H), 5.73 - 5.64 (m, 1H), 5.58 (br s, 1H), 3.43 (dd, 7 = 5.4, 14.0 Hz, 1H), 3.26 (dd, 7 = 6.9, 14.2 Hz, 1H), 2.71 (s, 3H). MS (ESI) m/z (M+H) + 384.1.
(2S,4R)-N-((S)-4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(BENZ YLOXY)-l- NYLPYRROLIDINE-2-CARBOXAMIDE 220)
[1118] A mixture of (2S,4R)-4-(benzyloxy)-l-(tert-butoxycarbonyl)pyrrolidine-2- carboxylic acid (500 mg, 1.56 mmol) in MeOH (3 mL), HCI/MeOH (15 mL) was stirred at 20 °C for 12 hours. LCMS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with aqueous NaHC0 3 , adjusted the H ~ 7, and extracted with DCM (30 mL x 2). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. Compound 220A (340 mg, crude, yellow oil): 1H NMR (400MHz, CDC1 3 ) δ 7.37 - 7.20 (m, 5H), 4.52 - 4.41 (m, 2H), 4.12 (br s, 1H), 4.00 (br t, = 7.6 Hz, 1H), 3.77 - 3.62 (m, 3H), 3.11 (br s, 2H), 2.66 (br s, 1H), 2.29 (br dd, = 7.8, 13.1 Hz, 1H), 1.98 (td, = 6.6, 13.4 Hz, 1H). MS (ESI) m/z (M+H) + 236.1.
[1119] A mixture of compound 220A (240 mg, 1.02 mmol), phenylboronic acid (249 mg, 2.04 mmol), Cu(OAc) 2 (278 mg, 1.53 mmol), pyridine (161 mg, 2.04 mmol) and 4A° MS (400 mg) in DCE (20 mL) was degassed and purged with 0 2 for 3 times, and then the mixture was stirred at 60 °C for 12 hours under 0 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 50: 1 to 10: 1). Compound 220B (130 mg, yellow oil): 1H NMR (400MHz, CDCI3) δ 7.36 - 7.16 (m, 5H), 7.16 - 7.06 (m, 2H), 6.68 - 6.57 (m, 1H), 6.42 (d, = 8.1 Hz, 2H), 4.45 (s, 2H), 4.39 - 4.25 (m, 2H), 3.77 - 3.67 (m, 1H), 3.66 - 3.56 (m, 3H), 3.34 (dd, J = 4.4, 9.5 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.28 - 2.15 (m, 1H). MS (ESI) m/z (M+H) + 312.0.
[1120] A mixture of compound 220B (130 mg, 418 umol), LiOH.H 2 0 (26.3 mg, 626 umol) in THF (5 mL), H 2 0 (2 mL) was stirred at 20 °C for 12 hours. The reaction mixture was added aqueous HC1 to adjust the pH ~ 5. And then the mixture was filtered, and the filter cake was dried by freeze dryer. Compound 220C (130 mg, crude, white solid: 1H NMR (400MHz, DMSO-d 6 ) δ 7.36 - 7.15 (m, 6H), 7.13 - 6.98 (m, 2H), 6.57 - 6.47 (m, 1H), 6.40 (br d, = 7.9 Hz, 2H), 4.48 - 4.40 (m, 2H), 4.28 (br s, 1H), 4.15 - 4.05 (m, 1H), 3.29 - 3.26 (m, 1H), 3.27 - 3.17 (m, 1H), 2.33 - 2.22 (m, 1H), 2.21 - 2.09 (m, 1H). MS (ESI) m/z (M+H) + 298.2.
[1121] Compound 220 (18.6 mg, yield: 70.3%, brown solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 220C. Compound 220: 1H NMR (400MHz, CDC1 3 ) δ 7.33 - 7.07 (m, 11H), 6.93 (br s, 2H), 6.84 - 6.70 (m, 2H), 6.59 (br s, 1H), 6.49 (br d, J = 8.4 Hz, 2H), 5.35 (br s, 1H), 5.30 - 5.13 (m, 1H), 4.50 - 4.29 (m, 2H), 4.01 (br dd, J = 4.2, 9.0 Hz, 1H), 3.95 - 3.85 (m, 1H), 3.62 (dd, J = 5.8, 8.9 Hz, 1H), 3.30 (br dd, 7 = 5.0, 14.0 Hz, 1H), 3.17 (dd, 7 = 6.4, 9.0 Hz, 1H), 2.80 (dd, 7 = 9.0, 13.9 Hz, 1H), 2.31 - 2.17 (m, 1H), 2.16 - 2.03 (m, 1H). MS (ESI) m/z (M+H) + 472.2. EXAMPLE 117
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-lH-IMI DAZOLE-2-
[1122] To a mixture of ethyl lH-imidazole-2-carboxylate (5 g, 35.7 mmol) and phenylboronic acid (8.7 g, 71.4 mmol) in DCE (150 mL) was added Cu(OAc) 2 (7.13 g, 39.25 mmol), pyridine (5.64 g, 71.36 mmol, 5.76 mL), 4A° MS (3 g). The mixture was stirred at 60 °C for 16 hours under 0 2 . The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography eluted with Petroleum ether: Ethyl acetate = 10: 1, 4: 1 to give compound 221A (3 g, 13.9 mmol, yield: 38.9%) as a yellow solid. Compound 221A: 1H NMR (400MHz, CDCI 3 δ 7.43 - 7.39 (m, 3H), 7.27 - 7.23 (m, 2H), 7.22 - 7.19 (m, 1H), 7.11 (d, / = 1.0 Hz, 1H), 4.22 (q, = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).
[1123] To a mixture of compound 221A (300 mg, 1.39 mmol) in THF (3 mL) and H 2 0 (1 mL) was added LiOH.H 2 0 (52 mg, 1.25 mmol). The mixture was stirred at 25 °C for 12 hours. The residue was extracted with ethyl acetate (5 mL x 2). The mixture was adjusted to pH ~ 5 with aqueous HC1 (1M) and concentrated by lyophilization to give intermediate compound 221B (550 mg, crude) as a white solid.
[1124] Compound 221 (17.1 mg, yield: 30.9%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 221B.
[1125] Compound 221: 1H NMR (400MHz, CDCI 3 ) δ 7.76 (br d, J = 7.9 Hz, 1H), 7.35 (br d, J = 2.6 Hz, 3H), 7.24 - 7.16 (m, 5H), 7.12 (br d, J = 7.1 Hz, 2H), 7.08 (s, 1H), 7.04 (s, 1H), 6.67 (br s, 1H), 5.60 - 5.47 (m, 2H), 3.32 (dd, = 4.9, 13.9 Hz, 1H), 3.08 (dd, = 7.4, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 363.1. EXAMPLE 118
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-2-
PHENYLTHIOPHENE-3-CARBOXAMIDE (222)
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-(2H-INDAZOL-2-YL) -5- METHYLTHIOPHENE-3-CARBOXAMIDE (428), and N-(4-AMINO-3,4-DIOXO-l- PHENYLBUTAN-2-YL)-2-(lH-BENZO[rf]IMIDAZOL-2-YL)-5-METHYLTHIO PHENE- -CARBOXAMIDE (429)
[1126] A mixture of ethyl 2-amino-5-methylthiophene-3-carboxylate (9 g, 48.6 mmol) and CuBr 2 (13 g, 58.3 mmol) in MeCN (150 mL) was stirred at 0 °C - 5 °C. t-BuONO (5.5 g, 53.5 mmol) was added dropwise. The reaction mixture was stirred for 0.5 hour at 0-5 °C and 2 hours at 20 °C. The reaction mixture was diluted with EtOAc (400 mL), washed with water (100 mL) and brine (100 mL), dried over MgS0 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 100: 1) to give compound 222A (2 g, yield: 16.5%) as yellow oil. Compound 222A: 1H NMR (400MHz, CDC1 3 - d) δ 7.01 (s, 1H), 4.30 (q, 7 = 7.1 Hz, 2H), 2.38 (s, 3H), 1.40 - 1.29 (m, 3H).
[1127] To a mixture of compound 222A (400 mg, 1.61 mmol) and phenylboronic acid (393 mg, 3.22 mmol), Cs 2 C0 3 (1.05 g, 3.22 mmol) in dioxane (20 mL) and H 2 0 (2 mL) was added Pd(dppf)Cl 2 (118 mg, 161 umol) under N 2 . T he mixture was stirred at 110 °C for 12 hours under N 2 . The reaction mixture was filtered and the filter was concentrated. The residue was purified by preparatory- TLC (Si0 2 , Petroleum ether: Ethyl acetate = 5: 1) to give compound 222B (350 mg, yield: 88.3%) as a white solid. Compound 222B: 1H NMR (400MHz, CDC1 3 ) δ 7.48 (br s, 2H), 7.38 (br s, 3H), 7.19 (br s, 1H), 4.19 (q, 7=6.9 Hz, 2H), 2.50 (br s, 3H), 1.23 - 1.15 (m, 3H).
[1128] To a mixture of compound 222B (350 mg, 1.42 mmol) in EtOH (10 mL) and H 2 0 (5 mL) was added NaOH (142 mg, 3.55 mmol). The mixture was stirred at 80 °C for 3 hours. The mixture was concentrated to remove solvent and adjusted to pH ~ 5 with aqueous HC1 (1M). The mixture was filtered and the solid was washed with H 2 0 (3 mL) to give intermediate compound 222C (250 mg, yield: 81.0%) as a white solid. Compound 222C: 1H NMR (400MHz, DMSO-d 6 ) δ 12.47 (br s, 1H), 7.43 - 7.38 (m, 2H), 7.37 - 7.32 (m, 3H), 7.10 (d, = 0.9 Hz, 1H), 2.41 (s, 3H).
[1129] Compound 222 (15.7 mg, yield: 29.6%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 222C. Compound 222: 1H NMR (400MHz, CDC1 3 ) δ 7.36 - 7.30 (m, 4H), 7.19 (s, 1H), 7.13 - 7.07 (m, 3H), 6.97 (s, 1H), 6.71 - 6.60 (m, 3H), 5.89 (br d, J = 5.3 Hz, 1H), 5.49 - 5.34 (m, 2H), 3.10 (dd, J = 5.0, 14.0 Hz, 1H), 2.81 (dd, J = 7.9, 13.9 Hz, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H) + 393.1.
[1130] Compound 428 (44.7 mg, yield: 40.5%, white solid) was prepared using intermediate 222A to synthesize the intermediate carboxylic acid, 2-(2H-indazol-2-yl)-5- methylthiophene-3 -carboxylic acid which was converted to compound 428 using the procedures as for compound 12. Compound 428: 1H NMR (400MHz, CDCI 3 ) δ 9.17 (br d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.70 (br d, J = 8.3 Hz, 1H), 7.61 (br d, = 8.7 Hz, 1H), 7.34 (br t, = 7.5 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.00 (br s, 3H), 6.85 (br s, 2H), 6.69 (br s, 1H), 5.69 - 5.58 (m, 1H), 5.43 (br s, 1H), 3.27 (br dd, = 4.8, 14.0 Hz, 1H), 2.95 (br dd, = 7.3, 14.1 Hz, 1H), 2.48 (s, 3H). MS (ESI) m/z (M+H) + 433.1.
[1131] Compound 429 (31.6 mg, yield: 35.7%, yellow solid) was prepared using intermediate 222A to synthesize the intermediate carboxylic acid, 5-methyl-2-(l-((2- (trimethylsilyl)ethoxy)methyl)- lH-benzo[<i]imidazol-2-yl)thiophene-3-carboxylic acid which was converted to compound 429 using the procedures as for compound 12. Compound 429: 1H NMR (400MHz, CDC1 3 ) δ 12.80 (br s, 1H), 10.05 (br d, = 6.8 Hz, 1H), 8.18 (br s, 1H), 7.85 (br s, 1H), 7.66 - 7.57 (m, 2H), 7.32 - 7.19 (m, 7H), 7.17 - 7.11 (m, 1H), 5.44 (br s, 1H), 3.27 (br s, 1H), 3.03 - 2.93 (m, 1H). MS (ESI) m/z (M+H) + 433.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-METHYL-l-PHEN YL-lH-
PYRA -5-CARBOXAMIDE (223)
[1132] To a mixture of ethyl 4-methyl- lH-pyrazole-5-carboxylate (2.00 g, 12.97 mmol), phenylboronic acid (2.37 g, 19.45 mmol), Py (1.13 g, 14.27 mmol, 1.2 mL) in DCM (40.00 mL) was added 4A° MS (10.00 g)(activated 4A° MS) and Cu(OAc) 2 (2.59 g, 14.27 mmol), the mixture was stirred at 40 °C for 63h. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE: EA=1 :0 to 5: 1) to give the compound 223A (725 mg, yield: 24.3%) was obtained as a colorless oil. Compound 223A: 1H NMR (400MHz, OMSO-d 6 ) δ 8.44 (s, 1H), 7.83 (d, = 7.7 Hz, 2H), 7.52 (t, = 7.9 Hz, 2H), 7.43 - 7.32 (m, 1H), 4.31 (q, = 7.1 Hz, 2H), 2.27 (s, 3H), 1.32 (t, = 7.1 Hz, 3H).
[1133] To a solution of compound 223A (720 mg, 3.13 mmol) in THF (20.00 mL) was added LiOH.H 2 0 (700 mg, 16.68 mmol) in H 2 0 (6.00 mL). The reaction was stirred at 25 °C for 27h and then a solution of NaOH (626 mg, 15.65 mmol) in H 2 0 (5.00 mL) and MeOH (4.00 mL) was added in the mixture. The mixture was stirred at 25 °C for 3.5h. The reaction mixture was diluted with H 2 0 (25 mL) and extracted with MTBE (15 mL). The aqueous layers were adjusted pH ~ 3 by addtion IN HC1, and then the aqueous layer was extracted with EA (20 mL x 3). The combine organic layer was washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 223C (526 mg, yield: 83.1%) was obtained as a white solid. Compound 223C: 1H NMR (400MHz, DMSO- 6 ) δ Ί .63 (s, 1H), 7.51 - 7.28 (m, 5H), 2.25 (s, 3H).
[1134] Compound 223 (34 mg, yield: 68.3%, white solid) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 223C. Compound 223: 1H NMR (400MHz, DMSO- 6 ) δ 9.18 (d, J = 7.8 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.37 - 7.22 (m, 10H), 5.46 - 5.36 (m, 1H), 3.26 (br dd, = 3.0, 13.8 Hz, 1H), 2.78 (dd, = 11.2, 13.9 Hz, 1H), 2.00 - 1.93 (m, 3H).
224A 225A
(5)-N-(3,4-DIOXO-l-PHENYL-4-((PYRIDIN-3-YLMETHYL)AMINO)BUTAN -2-YL)-3- METHYL-5-PHENYLISOXAZOLE-4-CARBOXAMIDE (224)
(5)-N-(4-((BENZO[£ ) ][l,3]DIOXOL-5-YLMETHYL)AMINO)-3,4-DIOXO-l- PHENYLBUTAN-2-YL)-3-METHYL-5-PHENYLISOXAZOLE-4-CARBOXAMIDE (225)
[1135] To a solution of compound 101E (350.0 mg, 920.11 umol) in DMF (10 mL) was added 3-pyridylmethanamine (119.4 mg, 1.10 mmol, 110 uL), DIEA (0.5 mL), HOBt (124.33 mg, 920.11 umol) and EDCI (211.66 mg, 1.10 mmol). After stirred at 25 °C for 48h, the mixture was added HBTU (418.7 mg, 1.10 mmol) and DIEA (0.5 mL), and then stirred at 25°C for 12h. The mixture was diluted with H 2 0 (100 mL), extracted with EA (30 mL), washed with HCl (1M, 30 mL), saturated NaHC0 3 (aq, 30mL), brine (30 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=5/l to 0: 1) to give compound 224A.
[1136] Compound 224A (60.0 mg, yield 13.9%, white solid): 1H NMR (400MHz, DMSO-i¾) δ 8.67 - 8.50 (m, 1H), 8.48 - 8.45 (m, 1H), 8.42 - 8.37 (m, 1H), 8.30 - 8.24 (m, 1H), 7.73 - 7.33 (m, 6H), 7.31 - 7.09 (m, 6H), 6.14 - 5.86 (m, 1H), 4.69 - 4.55 (m, 1H), 4.36 - 4.14 (m, 2H), 4.08 - 4.01 (m, 1H), 2.97 - 2.87 (m, 1H), 2.77 - 2.66 (m, 1H), 2.08 - 1.96 (m, 3H). MS (ESI) m/z (M+H) + 471.2.
[1137] Compound 225A (130.0 mg, 27.5% yield, white solid) was synthesiszed as shown above for 224A from the corresponding amine. Compound 225A: 1H NMR (400MHz, DMSO-i¾) δ 8.35 - 8.28 (m, 1H), 8.26 - 8.21 (m, 1H), 7.57 - 7.51 (m, 2H), 7.48 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 7.29 - 7.12 (m, 5H), 6.89 - 6.79 (m, 1H), 6.79 - 6.68 (m, 2H), 5.94 - 5.88 (m, 2H), 5.87 - 5.81 (m, 1H), 4.66 - 4.57 (m, 1H), 4.23 - 4.09 (m, 2H), 4.04 - 3.99 (m, 1H), 4.04 - 3.99 (m, 1H), 2.95 - 2.86 (m, 1H), 2.78 - 2.66 (m, 1H), 2.07 - 1.98 (m, 3H). MS (ESI) m/z (M+H) + 514.2.
[1138] To a solution of compound 225 A (120.0 mg, 233.67 umol) in DMSO (10 mL) and DCM (1 mL) was added DMP (297.3 mg, 701.01 umol). After stirred at 25 °C for 1 hour, the mixture was quenched with 10% Na 2 S 2 0 3 (aqueous): saturated aqueous NaHC0 3 (1 : 1, 50 mL), the organic layer was washed with brine (50 mLx3). The combined organic layers were dried over Na 2 S0 4 and concentrated. The crude product was triturated with CH 3 CN (5 mL) and filtered to obtain compound 225 (62.0 mg, yield 51.9%) as yellow solid. Compound 225: 1H NMR (400MHz, DMSO-i¾) δ 9.41 - 9.32 (m, 1H), 9.10 (d, = 7.6 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.53 - 7.48 (m, 1H), 7.46 - 7.40 (m, 2H), 7.33 - 7.23 (m, 5H), 6.89 - 6.83 (m, 2H), 6.79 - 6.76 (m, 1H), 5.98 (s, 2H), 5.54 - 5.47 (m, 1H), 4.27 (d, = 6.4 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.83 - 2.74 (m, 1H), 2.09 - 2.06 (m, 3H). MS(ESI) m/z (M+H) + 512.2.
[1139] Compound 224 was synthesiszed from the corresponding intermediate compound 224A as shown above for compound 225. Compound 224 (25.0 mg, 50.2% yield) has been obtained as white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.53 - 9.45 (m, 1H), 9.11 (d, = 7.6 Hz, 1H), 8.54 (s, 1H), 8.49 - 8.46 (m, 1H), 7.72 - 7.67 (m, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.48 (m, 1H), 7.46 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 7.32 - 7.23 (m, 5H), 5.54 - 5.47 (m, 1H), 4.40 (d, =6.3 Hz, 2H), 3.30 - 3.23 (m, 1H), 2.83 - 2.75 (m, 1H), 2.09 - 2.05 (m, 3H). MS(ESI) m/z (M+H) + 469.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-ETHYL-4- -5-CARBOXAMIDE (226)
[1140] To a mixture of iodobenzene (5 g, 24.51 mmol) and 2,4- dinitrobenzenesulfonic acid (7.83 g, 29.41 mmol, H 2 0) in CHC1 3 (20 mL), was added m-CPBA (4.23 g, 24.51 mmol). The mixture was stirred for 2 hours at 25 °C under an N 2 atmosphere. After the reaction, MTBE (20 mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid was washed with MTBE (30 mL) and compound 226A ( 8.9 g, 77.6% yield ) was obtained as a white solid. Compound 226A: 1H NMR (CDC1 3, 400 MHz): δ 9.76 (br s, 1H), 8.57 (d, = 2.4 Hz, 1H), 8.43 - 8.40 (m, 1H), 8.23 (d, = 7.6 Hz, 2H), 8.10 (d, = 8.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.66 - 7.59 (m, 2H).
[1141] Ethyl 3-oxo-3-phenylpropanoate (1.3 g, 6.76 mmol) and compound 226A (4.12 g, 8.79 mmol) in CH 3 CN (50 mL) were stirred at 80 °C for lh, and propanamide (5.93 g, 81.1 mmol) was added to the mixture, then the mixture was stirred at 120 °C for 0.2 hour under microwave irradiation. After being cooled to 25 °C, the suspension was diluted with saturated NaHC0 3 solution (30 mL), extracted with EtOAc (100 mL x 2), dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1) to obtain compound 226B (200 mg, 11.22% yield) as white solid. Compound 226B: 1H NMR (CDC1 3, 400 MHz): δ 8.03 - 7.96 (m, 2H), 7.46 - 7.35 (m, 3H), 4.36 (q, = 7.2 Hz, 2H), 2.88 (q, = 7.6 Hz, 2H), 1.40 (t, = 7.6 Hz, 3H), 1.35 (t, = 7.2 Hz, 3H).
[1142] Compound 226C (170 mg, 93.71% yield, yellow solid) was prepared as in Example 51 from the corresponding intermediate compound 226B. Compound 226C: 1H NMR (CDC1 3, 400 MHz): δ 7.99 - 7.97 (m, 2H), 7.47 - 7.35 (m, 3H), 2.83 (q, = 7.6 Hz, 2H), 1.27 (t, = 7.6 Hz, 3H). MS (ESI) m/z (M+H) + 217.9.
[1143] Compound 226 (59.7 mg, 58.17% yield, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 226C. Compound 226: 1H NMR (CDC1 3, 400 MHz): δ 8.12 - 8.04 (m, 2H), 7.45 - 7.35 (m, 3H), 7.32 - 7.23 (m, 3H), 7.13 (d, = 6.4 Hz, 2H), 6.81 - 6.68 (m, 2H), 5.74 - 5.59 (m, 2H), 3.46 - 3.41 (m, 1H), 3.26 - 3.21 (m, 1H), 2.91 - 2.80 (m, 2H), 1.40 (t, = 7.6 Hz, 3H). MS (ESI) m/z (M+ H) + 392.1.
IMIDAZOLE-5-CARBOXAMIDE (268)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-PHEN YL-lH- -4-CARBOXAMIDE (269)
[1144] Sulfuryl chloride (33.7 g, 250 mmol) was added drop wise to ethyl 3-oxo-3- phenylpropanoate (40 g, 208 mmol,) in CHC1 3 (200 mL) at 0 °C. The mixture was warmed to 25 °C for 30 min, and then heated to 80 °C for 3.5h. TLC (Petroleum ether: Ethyl acetate = 10: 1, R f ~ 0.45) showed the reaction was complete. LCMS showed desired MS after cooling to room temperature, the reaction mixture was diluted with chloroform (40 mL), washed with NaHC0 3 (aqueous; 40 mL x 2), water (40 mL) and then brine (30 mL) successively. The organic phase was dried over Na 2 S0 4 , filtered and evaporated to give the crude product compound 268A (48 g, crude), as yellow oil. Compound 268A: 1H NMR (400MHz, CDC1 3 - ) δ 8.10 - 7.96 (m, 2H), 7.73 - 7.58 (m, 1H), 7.57 - 7.39 (m, 2H), 5.62 (s, 1H), 4.39 - 4.25 (m, 2H), 1.32 - 1.13 (m, 3H).
[1145] A solution of compound 268A (20 g, 88.2 mmol), formamide (39.7 g, 882 mmol) and H 2 0 (3.18 g, 176 mmol) was heated to 180 °C for 3.5h. After cooling, the mixture was added water (100 mL) and extracted with DCM (50 mL x 3), the organic phase give a precipitate, the solid was filtered and dried to give compound 268B (1.45 g, yield: 7.6%), as off white solid. Compound 268B: 1H NMR (400MHz, DMSO-d 6 ) δ 13.26 - 12.66 (m, 1H), 7.96 - 7.78 (m, 1H), 7.81 (s, 1H), 7.63 (br d, J = 7.2 Hz, 1H), 7.53 - 7.26 (m, 3H), 4.33 - 4.09 (m, 2H), 1.33 - 1.13 (m, 3H).
[1146] To a solution of NaH (277 mg, 6.94 mmol, 60% purity) in DMF (5 mL) was added compound 268B (1.25 g, 5.78 mmol) in portions and stirred for 30 min, then CH 3 I (903 mg, 6.36 mmol) was added, the mixture was stirred at 15 °C for 2h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 3), the organic phases were dried over Na 2 S0 4 , filtered and concentrated, the residue was purified by prep-HPLC (neutral) to give compounds 268Cand 268D. Compound 268C (430 mg, yield: 64.7%, yellow solid): 1H NMR (400MHz, CDC1 3 - ) δ 7.67 (br d, = 7.1 Hz, 2H), 7.57 (s, 1H), 7.43 - 7.30 (m, 3H), 4.25 (q, = 7.1 Hz, 2H), 3.93 (s, 3H), 1.22 (t, = 7.2 Hz, 3H).
[1147] Compound 268D (380 mg, yield: 57.1%, yellow solid): 1H NMR (400MHz, CDC1 3 - ) δ 7.54 (s, 1H), 7.52 - 7.44 (m, 3H), 7.41 - 7.34 (m, 2H), 4.24 (q, J = 1.1 Hz, 2H), 3.50 (s, 3H), 1.25 (t, 7 = 7.2 Hz, 3H).
[1148] A mixture of compound 268C (200 mg, 869 umol) and NaOH (69.5 mg, 1.74 mmol) in THF (5 mL), H 2 0 (1 mL) was stirred at 15 °C for 12 h. TLC (ethyl acetate, R f ~ 0) showed the reaction was complete, the organic solvent was removed under vacuum, the water layer was adjusted to pH ~ 5 with 1NHC1 to give a precipitate, the solid was filtered and dried to give compound 268E (120 mg, yield: 68.3%) as white solid. Compound 268E: 1H NMR (400MHz, DMSO-i¾) δ 12.90 (br s, 1H), 7.86 (s, 1H), 7.62 (br d, J = 7.1 Hz, 2H), 7.38 - 7.21 (m, 3H), 3.80 (s, 3H).
[1149] Compound 268 (40.2 mg, yield: 27.2%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 268E. Compound 268: 1H NMR (400MHz, OMSO-d 6 ) δ 8.96 (d, = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.66 (s, 1H), 7.55 (d, = 6.8 Hz, 2H), 7.31 - 7.18 (m, 8H), 5.52 (ddd, = 3.5, 7.4, 10.5 Hz, 1H), 3.40 (s, 3H), 3.21 (dd, J = 3.5, 14.1 Hz, 1H), 2.75 (dd, J = 10.6, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 377.1.
[1150] Following the procedure used for intermediate compound 268E and compound 268, intermediate compound 269A and compound 269 were prepared. Compound 269A (130 mg, yield: 74%, white solid): 1H NMR (400MHz, OMSO-d 6 ) δ 7.76 (s, 1H), 7.47 - 7.30 (m, 5H), 3.40 (s, 3H). Compound 269 (32.4 mg, yield: 37.5%, white solid): 1H NMR (400MHz, CDCI 3 - ) δ 7.67 (br d, 7 = 7.2 Hz, 1H), 7.51 - 7.43 (m, 4H), 7.42 - 7.35 (m, 2H), 7.32 - 7.29 (m, 1H), 7.28 (s, 1H), 7.26 - 7.23 (m, 1H), 7.22 - 7.18 (m, 2H), 6.72 (br s, 1H), 5.64 (dt, 7 = 5.3, 7.5 Hz, 1H), 5.44 (br s, 1H), 3.51 (s, 3H), 3.41 (dd, 7 = 5.3, 14.1 Hz, 1H), 3.20 (dd, 7 = 7.4, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 377.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4- (ETHOXYMETHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (227)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(4- ((BENZYLOXY)METHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMID E
228B: R = CH 2 P ^ι^. κ - α
228C: R = CH 2 Ph
[1151] To a solution of ethyl 3-methyl-lH-pyrazole-5-carboxylate (2 g, 12.97 mmol), [4-(hydroxymethyl)phenyl]boronic acid (3.94 g, 25.94 mmol) in NMP (200 mL) was added pyridine (2.05 g, 25.94 mmol, 2.09 mL), Cu(OAc) 2 (3.53 g, 19.45 mmol), 4A° MS (20 g, 12.97 mmol). After stirred at 25 °C for 24h, the mixture was filtered. The filtrate was washed with H 2 0 (500 mL), extracted with ethyl acetate (50 mL x 3). The organic phase was washed brine (500 mL), dried over Na 2 S0 4 , concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1 to 3/1) to obtain intermediate Compound 227A (1 g, yield: 29.62%) as white solid. Compound 227A: 1H NMR (400MHz, CDCI 3 ) δ 7.41 - 7.34 (m, 4H), 6.80 (s, 1H), 4.71 (s, 2H), 4.22 (q, 7 = 7.1 Hz, 2H), 2.35 (s, 3H), 1.24 (t, 7 = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 261.0.
[1152] To a solution of compound 227A (350 mg, 1.34 mmol) and benzyl bromide (458 mg, 2.68 mmol, 318 uL) in DMF (10 mL) was added NaH (160 mg, 4.02 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for lh. The mixture was quenched with NH 4 C1 (1 mL), diluted with H 2 0 (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phase was combined, washed with NaCl (50 mL x 2), dried over Na 2 S0 4 , and concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10/1 to 5: 1) to obtain compound 228B (350 mg, yield: 64.85%, yellow oil). Compound 228B: 1H NMR (400MHz, CDC1 3 ) δ 7.47 - 7.28 (m, 9H), 6.87 - 6.78 (m, 1H), 4.66 - 4.60 (m, 2H), 4.56 (s, 2H), 4.23 (q, J = 1.1 Hz, 2H), 2.36 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 351.0.
[1153] To a solution of compound 228B (350 mg, 998.83 umol) in MeOH (10 mL) and H 2 0 (10 mL) was added NaOH (119 mg, 3.00 mmol). The mixture was stirred at 25 °C for 3h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (20 mL x 2), the organic phase was dried over Na 2 S0 4 , concnetrated to give a residue. Compound 228C (270 mg, yield: 83.86%, white solid): 1H NMR (400MHz, DMSO-i¾) δ 13.58 - 12.95 (m, 1H), 7.45 - 7.24 (m, 9H), 6.79 (s, 1H), 4.57 (d, = 6.8 Hz, 4H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 323.0.
[1154] Compound 228 (37.6 mg, yield: 51.78%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 228C. Compound 228: 1H NMR (400MHz, DMSO-i¾) δ 9.09 (d, = 7.9 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.39 - 7.21 (m, 12H), 7.14 (d, = 8.2 Hz, 2H), 6.58 - 6.50 (m, 1H), 5.33 - 5.17 (m, 1H), 4.53 (d, = 6.0 Hz, 4H), 3.18 (dd, = 3.2, 13.6 Hz, 1H), 2.80 (dd, = 10.8, 13.7 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 497.2.
[1155] Intermediate compound 227C (300 mg, yield: 95.04%) was obtained as a white solid using the same procedure as for compound 228C. Compound 227C: 1H NMR (400MHz, DMSO-i¾) δ 13.20 (br s, 1H), 7.47 - 7.24 (m, 4H), 6.79 (s, 1H), 4.49 (s, 2H), 3.50 (q, = 7.0 Hz, 2H), 2.23 (s, 3H), 1.16 (t, 7 = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 261.0.
[1156] Compound 227 (31 mg, yield: 54.75%, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 227C. Compound 227: 1H NMR (400MHz, DMSO-i¾) δ 9.07 (d, = 7.7 Hz, 1H), 8.11 (d, = 3.1 Hz, 1H), 7.87 - 7.84 (m, 1H), 7.31 - 7.24 (m, 7H), 7.13 (br d, J = 8.2 Hz, 2H), 6.53 (s, 1H), 5.25 (t, = 7.4 Hz, 1H), 4.44 (s, 2H), 3.52 - 3.44 (m, 2H), 3.19 (dd, = 3.0, 13.6 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.23 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H). MS (ESI) m/z (M+H) + 435.1.
(S)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3- ( -3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (229)
[1157] To ethyl 3-methyl-lH-pyrazole-5-carboxylate (3 g, 19.46 mmol), [3- (hydroxymethyl)phenyl]boronic acid (4.44 g, 29.19 mmol), 4A° MS (8 g) and Pyridine (1.69 g, 21.41 mmol, 1.8 mL) in DCM (70 mL) was added Cu(OAc) 2 (4.59 g, 25.30 mmol), the mixture was stirred at 25 °C for 16h under 0 2 balloon (15 psi). The reaction mixture was filtered to get rid of 4A° MS and catalyst, and then the filtrate was concentrated. The residue was purified by preparatory-HPLC (TFA condition). Compound 229A (1.8 g, yield: 35.54%) was obtained as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 7.48 - 7.35 (m, 3H), 7.32 - 7.28 (m, 1H), 6.81 (s, 1H), 4.71 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H).
[1158] To a solution of compound 229A (465 mg, 1.79 mmol) and iodoethane (1.4 g, 8.95 mmol, 0.75 mL) in dry DMF (10 mL) was added NaH (214.8 mg, 5.37 mmol, 60% purity) at 0 °C, then the mixture was reaction at 25 °C for 2h. The reaction mixture was quenched with 50 mL saturated NH 4 C1 at 0 °C, extracted with ethyl acetate (30 mL x 2), the organic phase was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 229B (443 mg, yield: 85.83%) was obtained as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 7.43 - 7.36 (m, 3H), 7.33 - 7.28 (m, 1H), 6.80 (s, 1H), 4.56 (s, 2H), 4.21 (q, J = 7.3 Hz, 2H), 3.54 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.23 (t, J = 2.4, 7.1 Hz, 6H).
[1159] To a solution of compound 229B (443 mg, 1.54 mmol) in MeOH (10 mL) and H 2 0 (6 mL) was added NaOH (184.8 mg, 4.62 mmol). The mixture was stirred at 25 °C for 2h. The reaction mixture was concentrated and added 20 mL of water and the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2 to 3 at 0 °C, and extracted with EtOAc (10 mL x 2), the organic phase was dried over Na 2 S0 4 , filtered and concentrated to give a residue. Compound 229C (400 mg, yield: 99.79%) was obtained as a white solid, which was used for next step directly. 1H NMR (400MHz, DMSO- e) δ 7.43 - 7.37 (m, 1H), 7.35 - 7.26 (m, 3H), 6.79 (s, 1H), 4.48 (s, 2H), 3.48 (q, 7 = 6.9 Hz, 2H), 2.23 (s, 3H), 1.16 - 1.12 (m, 3H).
[1160] Compound 229 (30.1 mg, yield: 47.21%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 229C. Compound 229: 1H NMR (400MHz, DMSO-i¾) δ 9.07 (br d, 7 = 7.7 Hz, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.32 - 7.22 (m, 8H), 6.99 (br d, 7 = 7.5 Hz, 1H), 6.54 (s, 1H), 5.31 - 5.20 (m, 1H), 4.42 (s, 2H), 3.47 - 3.43 (m, 2H), 3.17 (br dd, 7 = 3.4, 13.8 Hz, 1H), 2.80 (br dd, 7 = 10.6, 13.7 Hz, 1H), 2.23 (s, 3H), 1.11 (t, 7=6.9 Hz, 3H). MS (ESI) m/z (M+H) + 435.1.
[1161] To a solution of compound 229A (472 mg, 1.81 mmol) and bromomethylbenzene (1.55 g, 9.05 mmol, 1.1 mL) in dry DMF (15 mL) was added NaH (218 mg, 5.43 mmol, 60% purity) at 0 °C and then the mixture was reaction at 25 °C for 2h. The reaction mixture was quenched with 50 mL saturated NH 4 C1 at 0 °C, extracted with ethyl acetate (30 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 230A (623 mg, yield: 98.23%) was obtained as a colorless oil. 1H NMR (400MHz, CDC1 3 ) δ 7.43 - 7.41 (m, 3H), 7.37 - 7.34 (m, 5H), 7.31 (d, = 2.0 Hz, 1H), 6.81 (s, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.23 - 4.18 (m, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).
[1162] To a solution of compound 230A (623 mg, 1.78 mmol) in MeOH (15 mL) and H 2 0 (8 mL) was added NaOH (214 mg, 5.34 mmol). The mixture was stirred at 25 °C for 2h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (10 mL x 2), the organic phase was dried over Na 2 S0 4 , concentrated to give a residue. Compound 230B (569 mg, yield: 99.16%) was obtained as a white solid, which was used for next step directly. 1H NMR (400MHz, DMSO-d 6 ) δ 7.45 - 7.23 (m, 10H), 6.80 (s, 1H), 4.57 (s, 2H), 4.54 (s, 2H), 2.24 (s, 3H).
[1163] Compound 230 (33.3 mg, yield: 54.97%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 230B. Compound 230: 1H NMR (400MHz, DMSO-d 6 ) δ 9.08 (d, = 7.7 Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.35 - 7.25 (m, 12H), 7.23 - 7.20 (m, 1H), 7.03 - 6.98 (m, 1H), 6.55 (s, 1H), 5.30 - 5.21 (m, 1H), 4.51 (d, = 2.9 Hz, 4H), 3.17 (dd, = 3.4, 13.8 Hz, 1H), 2.80 (dd, = 10.6, 13.7 Hz, 1H), 2.23 (s, 3H). MS (ESI) m/z (M+H) + 497.1.
COMPOUNDS 231, 438, 442
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(3- (PHENOXYM -lH-PYRAZOLE-5-CARBOXAMIDE (231)
[1164] To a suspended solution of compound 229A (400 mg, 1.54 mmol) and phenol (174 mg, 1.85 mmol) in dry THF (10 mL) was added PPh 3 (605 mg, 2.31 mmol) and then slowly added DIAD (467 mg, 2.31 mmol, 449 uL) under N 2 . The mixture was reaction at 25 °C for 12h under N 2 . The reaction mixture dissolved in DCM (30 mL) and H 2 0 (20 mL), then extracted with DCM (20 mL x 2), the organic layer was combined and the mixture was dried over Na 2 S04, filtered and concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 4/1). Compound 231A (489.7 mg, yield: 94.53%) was obtained as a colorless oil. 1H NMR (400MHz, DMSO-i¾) δ 7.51 - 7.43 (m, 3H), 7.36 (d, 7 = 7.7 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.13 (t, 7 = 7.8 Hz, 1H), 7.00 (d, 7 = 7.7 Hz, 2H), 6.87 (s, 1H), 5.14 (s, 2H), 4.13 (q, 7 = 7.1 Hz, 2H), 2.25 (s, 3H), 1.11 (t, 7 = 7.1 Hz, 3H).
[1165] To a solution of compound 231A (551 mg, 1.64 mmol) in MeOH (5 mL) and H 2 0 (5 mL) was added NaOH (262 mg, 6.56 mmol). The mixture was stirred at 25 °C for lh. The reaction mixture was concentrated and added 10 mL of water and the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (10 mL x 2), the organic phase was dried over Na 2 S0 4 , filtered and concentrated to give a residue. Compound 231B (490 mg, yield: 96.90%) was obtained as a white solid, which was used for next step directly. 1H NMR (400MHz, DMSO- e) δ 7.50 - 7.42 (m, 3H), 7.36 - 7.32 (m, 1H), 7.31 - 7.25 (m, 2H), 7.01 (dd, 7 = 1.0, 8.7 Hz, 2H), 6.95 - 6.90 (m, 1H), 6.81 (s, 1H), 5.13 (s, 2H), 2.24 (s, 3H).
[1166] Compound 231 (68 mg, yield: 65.87%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 231B. Compound 231: 1H NMR (400MHz, DMSO-i¾) δ 9.08 (d, 7 = 7.7 Hz, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.40 - 7.23 (m, 10H), 7.21 - 7.17 (m, 1H), 7.04 - 6.95 (m, 3H), 6.91 (br t, 7 = 7.3 Hz, 1H), 6.55 (s, 1H), 5.28 - 5.20 (m, 1H), 5.08 (s, 2H), 3.17 (dd, 7 = 3.3, 13.9 Hz, 1H), 2.80 (br dd, 7 = 10.5, 13.8 Hz, 1H), 2.22 (s, 3H).
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(3- ((BENZYLOXY)METHYL)PHENYL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMID E
[1167] Compound 438 (2.9 g, yield: 86.54%, white solid) was prepared from the corresponding intermediate compound 229A by alkylating with benzyl bromide followed by ester hydrolysis and coupling with intermediate 274D as in compound 12. Compound 438: 1H NMR (400MHz, DMSO-i¾) δ 9.10 (d, 7 = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.39 - 7.23 (m, 13H), 7.10 - 6.99 (m, 1H), 6.58 (s, 1H), 5.28 (s, 1H), 4.53 (d, 7=3.1 Hz, 4H), 3.32 - 3.16 (m, 1H), 2.83 (dd, 7 = 10.6, 13.7 Hz, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 497.2. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- (MORPHOLINOMETHYL)PHENYL)-lH-PYRAZOLE-5-CARBOXAMIDE (442)
[1168] Compound 442 (50 mg, yield: 50.01%, yellow solid) was prepared from the corresponding intermediate compound 229A by converting it to the morpholino derivative via the mesylate. The morpholino derivative was subjected to ester hydrolysis and coupling with intermediate 274D as in compound 12. Compound 442: 1H NMR (400MHz, CD 3 CN) δ 7.34 - 7.15 (m, 11H), 7.07 - 6.96 (m, 1H), 6.50 (s, 1H), 6.24 (s, 1H), 5.39 (dd, J = 4.6, 8.0, 9.4 Hz, 1H), 3.64 - 3.60 (m, 4H), 3.50 (s, 2H), 3.30 - 3.25 (m, 1H), 2.89 (dd, = 9.4, 14.0 Hz, 1H), 2.40 (s, 4H), 2.26 (s, 3H). MS (ESI) m/z (M+H) + 476.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2,6-DIMETHYL PYRIMIDIN- -Y -5-METHYL-lH-PYRAZOLE-3-CARBOXAMIDE (232)
[1169] To a solution of 4-chloro-2,6-dimethylpyrimidine (3.0 g, 21.04 mmol) and ΝΗ 2 ΝΗ 2 .Η 2 0 (10.5 g, 210.40 mmol) in EtOH (40 mL). The mixture was stirred at 70 °C for 2 hours. The mixture was cooled to room-temperature and concentrated under reduced pressure to afford intermediate compound 232A (2.30 g, 62.60% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6 ): δ 6.33 (br s, 1H), 2.24 (s, 3H), 2.15 (s, 3H).
[1170] To a solution of compound 232A (2.30 g, 13.17 mmol, HC1) and ethyl 2,4- dioxopentanoate (2.08 g, 13.17 mmol,) in AcOH (30 mL). The mixture was stirred at 100 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove AcOH, then diluted with H 2 0, the pH was adjusted to around 9 by progressively adding NaHC0 3 , then partitioned between EtOAc (20 mL x 3), dried over Na 2 S0 4 . The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ethergradient @ 30 mL/min), then the residue was purified by preparatory-HPLC (basic condition). Compound 232C (50 mg, 1.46% yield) was obtained as a white solid. Compound 232C: 1H NMR (400MHz, CDC1 3 ) δ 7.76 - 7.71 (m, 1H), 6.72 - 6.66 (m, 1H), 4.48 - 4.37 (m, 2H), 2.82 - 2.74 (m, 3H), 2.73 - 2.66 (m, 3H), 2.58 - 2.52 (m, 3H), 1.47 - 1.38 (m, 3H)[1169] . Compound 232D (38 mg, 85.18% yield, white solid) was prepared as in Example 85 from the corresponding intermediate compound 232C. 1H NMR (400MHz, DMSO- d 6 ) δ 7.63 (s, 1H), 6.74 (s, 1H), 2.68 (s, 3H), 2.60 (s, 3H), 2.50 (s, 3H).
[1171] Compound 232 (48.4 mg, 57.40% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 232D. Compound 232: 1H NMR (400MHz, CDC1 3 ) δ 7.53 (s, 1H), 7.40 (br d, J = 7.2 Hz, 1H), 7.33 - 7.23 (m, 3H), 7.21 - 7.15 (m, 2H), 6.80 (br s, 1H), 6.66 (s, 1H), 5.77 - 5.69 (m, 2H), 3.49 - 3.40 (m, 1H), 3.34 - 3.24 (m, 1H), 2.75 (s, 3H), 2.69 (s, 3H), 2.58 (s, 3H). MS (ESI) m/z (M+H) + 407.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(6- PHE -3-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (233)
[1172] To a solution of 3-chloro-6-phenylpyridazine (1.00 g, 5.25 mmol) in EtOH (20 mL) was added N 2 H 4 .H 2 0 (2.63 g, 52.46 mmol, 2.55 mL). After stirred at 78 °C for 10 hours, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with petroleum ether 30 mL, stirred for 30 min, and then filtered to give crude intermediate product 233A as grey residue. 1H NMR (400 MHz, DMSO- 6 ): δ 1.96 (d, = 7.2 Hz, 1H), 7.85 (d, = 9.6 Hz, 1H), 7.47 - 7.43 (m, 2H), 7.39 - 7.35 (m, 1H), 7.09 (d, = 9.2 Hz, 1H).
[1173] To a solution of compound 233A (1.30 g, 6.98 mmol) in CH 3 COOH (12 mL) was added ethyl 2,4-dioxopentanoate (1.10 g, 6.98 mmol, 985.61 uL), then the mixture was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with solvent ethyl acetate (70 mL) and washed with solvent saturated aqueous NaHC0 3 solution (20 mL x 3), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum Ether: Ethyl Acetate = 30/1 to 10/1) to afford a residue. The crude was further separated by preparatory-HPLC (Acid condition). Compound 233B was obtained as a white solid (270.00 mg, 875.69 umol, 12.55% yield).
[1174] To a mixture of compound 233B (180.0 mg, 583.79 umol) in MeOH (6 mL) and H 2 0 (3.00 mL) was added LiOH.H 2 0 (73.5 mg, 1.75 mmol) in one portion and the mixture was stirred at 25 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (20 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 233D (160.00 mg, 97.78% yield) as a white solid. 1H NMR (400
MHz, DMSO-d 6 ) δ 8.52 (d, = 9.2 Hz, 1H), 8.27 - 8.22 (m, 2H), 7.63 - 7.56 (m, 2H), 6.85 (s, 1H), 2.73 (s, 3H).
[1175] Compound 233 (67.0 mg, 63.93% yield white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 233D. Compound 233: 1H NMR (400 MHz, CDC1 3 ) δ 8.16 (d, = 9.2 Hz, 1H), 8.13 - 8.11 (m, 2H), 8.03 (d, = 9.2 Hz, 1H), 7.59 - 7.54 (m, 3H), 7.42 (d, = 7.2 Hz, 1H), 7.32 - 7.27 (m, 3H), 7.20 - 7.18 (m, 1H), 6.77 (s, 1H), 6.75 (d, J = 0.4 Hz, 1H), 5.76 - 5.71 (m, 1H), 5.55 (s, 1H), 3.49 - 3.44 (m, 1H), 3.32 - 3.27 (m, 1H), 2.85 (s, 3H). MS (ESI) m/z (M+l) + 455.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(6-M ETHYL-4- (TRIFLUOR -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (234)
[1176] To a solution of 2-hydrazineyl-6-methyl-4-(trifluoromethyl)pyridine (400 mg, 2.09 mmol) in CH 3 COOH (4 mL) was added ethyl 2-(methoxyimino)-4-oxopentanoate (391 mg, 2.09 mmol), then he mixture was stirred at 120 °C for 2 hours. The mixture was diluted with CH 2 C1 2 (70 mL) and washed by saturated sodium bicarbonate (20 mL x 2) and saturated brine (20 mL x 2), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was purified by flash column chromatography (Si0 2 , Petroleum Ether: Ethyl Acetate = 10: 1 to 3: 1) to afford proposed compound 3 (150 mg, 22.91% yield) as white solid. 1H NMR (400 MHz, CDC1 3 ): S 8.08 (s, 1H), 7.32 (s, 1H), 6.72 (s, 1H), 4.46 - 4.36 (m, 2H), 2.72 (s, 3H), 2.65 (s, 3H), 1.44 - 1.41 (m, 3H).
[1177] To a solution of compound 234A (100 mg, 319.21 umol) in MeOH (4 mL) and H 2 0 (2 mL) was added LiOH » H 2 0 (53 mg, 1.28 mmol), then the mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure to afford intermediate compound 234B (80 mg, 87.87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ): δ 7.79 (s, 1H), 7.72 (s, 1H), 6.79 (s, 1H), 2.56 (s, 3H), 2.28 (s, 3H).
[1178] Compound 234 (24.1 mg, 34.58% yield, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 234B. Compound 234: 1H NMR (400 MHz, DMSO-d 6 , t = 80 °C) δ 8.81 (d, = 6.4 Hz, 1H), 7.75 (br s, 1H), 7.67 (s, 1H), 7.59 (br, s, 1H), 7.52 (s, 1H), 7.27 - 7.19 (m, 5H), 6.53 (s, 1H), 5.43 - 5.35 (m, 1H), 3.23 - 3.16 (m, 1H), 2.96 - 2.87 (m, 1H), 2.39 (s, 3H), 2.30 (s, 3H). MS (ESI) m/z (M+l) + 460.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(BENZO[D]OXAZ OL-2-YL)- 3-ME -1H-PYRAZOLE-5-CARBOXAMIDE (238)
[1179] A solution of 2-chlorobenzo[<i]oxazole (2.5 g, 16.3 mmol) in dioxane (4 mL) was added to a solution of Ν 2 Η 4 .Η 2 0 (4.07 g, 81.4 mmol) in dioxane (20 mL) dropwise keeping the reaction temperature below 30 °C. The reaction mixture was stirred at 20 °C for lhr. The solvent was evaporated. Water (50 mL) was added and the mixture was stirred for lOmin. The solid was collected by filtration and the cake was washed by water (50mL). The cake was dried to give pure product 238A (2g, yield: 82.4%) as a white solid. 1H NMR (400MHz, DMSO- 6 ) δ 8.76 (br s, 1H), 7.31 (d, 7 = 7.7 Hz, 1H), 7.22 (d, 7 = 7.3 Hz, 1H), 7.09 (dt, 7 = 1.0, 7.7 Hz, 1H), 6.95 (dt, 7 = 1.1, 7.7 Hz, 1H), 4.47 (br s, 2H).
[1180] A mixture of compound 238A (1 g, 6.70 mmol) and methyl 2, 4- dioxopentanoate (966 mg, 6.70 mmol) in AcOH (5 mL) was stirred at 120 °C for 16hrs. The solvent was evaporated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate= 20: 1-3: 1) to give compound 238B (900 mg, crude) as off-white solid.
[1181] A solution of compound 238B (200 mg, 777 umol) in toluene (5 mL) was added TMSOK (199 mg, 1.55 mmol). The reaction mixture was stirred at 80 °C for 5hrs. The reaction mixture was poured into saturated NH 4 C1 (5mL). The product was extracted with EtOAc (10 mL x 3). The combined organic layer was purified by preparatory-HPLC (HCOOH) to give compound 238C (30 mg, yield: 15.9%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 13.30 (br s, 1H), 7.80 (td, 7 = 4.2, 8.4 Hz, 2H), 7.52 - 7.37 (m, 2H), 6.83 (s, 1H), 5.72 (s, 1H), 2.69 (s, 3H).
[1182] Compound 238 (21 mg, yield: 70%, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 238C. Possible isomer could not confirmed by 2DNMR. Compound 238: 1H NMR (400MHz, CDCI 3 ) δ 7.78 - 7.69 (m, 1H), 7.61 (dd, 7 = 3.2, 5.8 Hz, 1H), 7.51 (br d, 7 = 7.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.32 - 7.16 (m, 6H), 6.80 - 6.70 (m, 2H), 5.81 - 5.71 (m, 1H), 5.55 (br s, 1H), 3.45 (dd, 7 = 5.4, 14.0 Hz, 1H), 3.22 (dd, 7 = 7.3, 14.1 Hz, 1H), 2.75 (s, 3H). MS (ESI) m/z (M+H) + 418.1.
COMPOUNDS 239-242, 469-474
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ETHYL-3-PHENY L-lH-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ISOPROPYL- 3-PHENYL-lH-
[1183] A solution of /?-TsOH.H 2 0 (61.3 g, 322.27 mmol) in H 2 0 (20 mL) was added to a suspension of compound 1 (20.0 g, 128.91 mmol) in CH 3 CN (400 mL) at 0 °C. The mixture turned clear. The mixture was stirred at 0 °C for 30 min. Then a solution of NaN0 2 (13.3 g, 193.4 mmol) and KI (32.1 g, 193.4 mmol) in H20 (20 mL) was added dropwise to the mixture at 0 °C. After addition, the mixture was stirred at 20 °C for lh. The mixture was quenched by the addition of saturated Na 2 S0 3 (-100 mL) at 0 °C. The black mixture turned yellow. The mixture was concentrated to 200 mL and then extracted with DCM (75 mL x 3). The combined organic layer was washed with brine (75 mL x 2), dried over MgS0 4 , filtered and concentrated. The residue was treated with 100 mL ethyl acetate. The insoluble substance was removed off by filter. The filtrate was concentrated and purified by FCC (PE/EA = 1/1) to afford compound 239A (17.50 g, yield 48.4%) as white solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 13.01 - 12.65 (m, 1H), 8.13 -8.11 (m, 1H), 4.38 - 4.32 (m, 2H), 1.41 - 1.37 (m, 3H). MS (ESI) m/z (M+H) + 266.8.
[1184] Cs 2 C0 3 (7.35 g, 22.56 mmol) was added to a solution of compound 239A (2.0 g, 7.52 mmol) in DMF (15 mL). Then EtI (1.50 mL, 18.8 mmol,) was added. The mixture was stirred at 25 °C for 2.5h. The mixture was treated with EA (50 mL) and H 2 0 (50 mL). The organic layer was separated and the aqueous layer was extracted with EA (25 mL x 2). The combined organic layer was washed brine (30 mL x 3), dried over MgS0 4 , filtered and concentrated. The residue was purified by FCC (PE/EA = 8/1) to afford compound 239B (1.31 g, yield 59.2%) as colorless oil. Compound 239B (R f = 0.24, PE/EA = 8/1): 1H NMR (DMSO-d 6 , 400 - 4.12 (m, 4H), 1.34 (t, 7=7.3 Hz, 3H), 1.25 (t, 7=7.1 Hz, 3H).
[1185] Na 2 C0 3 (360 mg, 3.4 mmol) was added to a solution of compound 239B (500 mg, 1.7 mmol) and phenylboronic acid (311 mg, 2.6 mmol) in dioxane (10 mL). Then H 2 0 (2 mL) was added, followed by Pd(dppf)Cl 2 (124 mg, 0.17 mmol). The mixture was de-gassed 3 times and heated to 80 °C and stirred for 22h at 80 °C. The mixture was filtered through a pad of Celite, the solid was washed with EA (25 mL x 3). The organic layer was separated from the filtrate, and then washed with brine (30 mL x 2), dried over MgS0 4 , filtered and concentrated. The residue was purified by FCC (PE/EA = 10/1) to afford compound 239D (380 mg, yield 91.5%) as pale yellow oil. 1 H NMR (CDC1 3 , 400 MHz): δ 7.99 (s, 1H), 7.76 (dd, 7 = 1.5, 7.9 Hz, 2H), 7.44 - 7.32 (m, 3H), 4.28 - 4.17 (m, 4H), 1.55 (t, 7 = 7.3 Hz, 3H), 1.27 (t, 7 = 7.2 Hz, 3H).
[1186] To a solution of compound 239D (380 mg, 1.56 mmol) in MeOH (15 mL) was added a solution of KOH (875 mg, 15.6 mmol) in H 2 0 (3 mL). The mixture was stirred at 70 °C for 2h. The mixture was diluted with H 2 0 (15 mL), and then the volatile solvent was removed by evaporation. The residue was acidified to pH ~ 2 with IN HC1. The precipitate was collected by filter and dried in vacuum to afford compound 239E (250 mg, yield 74.1%) was obtained as white solid, which was used for next step directly. 1H NMR (DMSO-i¾ , 400 MHz): δ 12.19 (br.s., 1H), 8.32 (s, 1H), 7.72 (dd, 7 = 1.4, 7.8 Hz, 2H), 7.41 - 7.24 (m, 3H), 4.17 (q, 7 = 7.3 Hz, 2H), 1.39 (t, 7 = 7.3 Hz, 3H).
[1187] Compound 239 (80 mg, yield 51.3%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 239E. Compound 239: 1H NMR (CDCI 3, 400 MHz): δ 8.32 (d, 7 = 7.2 Hz, 1H), 8.07 (s, 1H), 8.05 (br.s., 1H), 7.79 (br.s., 1H), 7.62 - 7.51 (m, 2H), 7.32 - 7.17 (m, 8H), 5.32 - 5.22 (m, 1H), 4.16 (q, 7 = 7.2 Hz, 2H), 3.14 (dd, 7 = 4.0, 14.0 Hz, 1H), 2.81 (dd, 7 = 10.0, 14.0 Hz, 1H), 1.40 (t, 7 =7.2 Hz, 3H). MS (ESI) m/z (M+H) + 391.1.
[1188] Following the procedure used for compound 239, intermediate compounds 242A, 242C and 242D were successively prepared. Compound 242A (1.41 g, yield 60.9%, colorless oil): 1H NMR (DMSO-d 6 , 400 MHz): δ 8.31 (s, 1H), 4.60 - 4.53 (m, 1H), 4.22 (q, 7 = 7.2 Hz, 2H), 1.41 (d, 7 = 6.4 Hz, 6H), 1.28 (t, 7 = 7.2 Hz, 3H).
[1189] Compound 242C (318 mg, yield 76.0%, colorless liquid): 1H NMR (DMSO- de , 400 MHz): δ 8.39 (s, 1H), 7.73 - 7.67 (m, 2H), 7.42 - 7.34 (m, 3H), 4.64 - 4.52 (m, 1H), 4.16 (q, 7 = 7.0 Hz, 2H), 1.46 (d, 7 = 6.8 Hz, 6H), 1.21 (t, 7 = 7.2 Hz, 3H). Compound 242D (119 mg, crude, white solid): 1H NMR (DMSO-i¾ , 400 MHz): δ 12.19 (s, 1H), 8.33 (s, 1H), 7.76 - 7.71 (m, 2H), 7.41 - 7.32 (m, 3H), 4.61 - 4.51 (m, 1H), 1.46 (d, 7 = 6.8 Hz, 3H). [1190] Compound 242 (47 mg, yield 46.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 242D. Compound 242: 1H NMR (CDC1 3 , 400 MHz): δ 7.99 (s, 1H), 7.55 - 7.49 (m, 2H), 7.47 - 7.37 (m, 3H), 7.23 - 7.14 (m, 3H), 6.85 - 6.78 (m, 2H), 6.73 (s, 1H), 6.13 - 6.05 (m, J = 6.2 Hz, 1H), 5.57 - 5.42 (m, 2H), 4.51 (spt, = 6.7 Hz, 1H), 3.25 (dd, / = 4.7, 14.0 Hz, 1H), 2.90 (dd, / = 8.0, 14.2 Hz, 1H), 1.53 (d, = 6.6 Hz, 6H). MS (ESI) m/z (M+H) + 405.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ETHYL-3-(2-FLUORO PHENYL)-
[1191] Compound 469 (130 mg, yield 49%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, l-ethyl-3-(2-fluorophenyl)- lH-pyrazole-4-carboxylic acid which was prepared using procedure similar to compound 239E. Compound 469: 1H NMR (DMSO-i¾ , 400 MHz): δ 8.21 (s, 1H), 7.89 - 7.45 (m, 3H), 7.43 - 7.31 (m, 2H), 7.30 - 7.10 (m, 7H), 5.33 - 5.22 (m, 1H), 4.20 (q, = 7.1 Hz, 2H), 3.22 - 3.15 (m, 1H), 2.92 - 2.82 (m, 1H), 1.45 (br t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 409.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ETHYL-3-(3-FLU OROPHENYL)-
[1192] Compound 470 (140 mg, yield 66.8%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, l-ethyl-3-(3-fluorophenyl)- lH-pyrazole-4-carboxylic acid which was prepared using procedure similar to compound 239E. Compound 470: 1H NMR (DMSO-i¾ , 400 MHz): δ 8.44 (d, = 7.5 Hz, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.29 (m, 1H), 7.28 - 7.23 (m, 4H), 7.22 - 7.16 (m, 1H), 7.14 - 7.07 (m, 1H), 5.35 - 5.25 (m, 1H), 4.21 - 4.11 (m, 2H), 3.15 (dd, = 3.9, 14.0 Hz, 1H), 2.81 (dd, = 9.9, 13.9 Hz, 1H), 1.40 (t, = 7.3 Hz, 3H). MS (ESI) m/z (M+H) + 409.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ETHYL-3-(4-FLU OROPHENYL)- lH-PYRAZOLE-4-CARBOXAMIDE (471)
[1193] Compound 471 (90 mg, yield 32.9%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, l-ethyl-3-(4-fluorophenyl)- lH-pyrazole-4-carboxylic acid which was prepared using procedure similar to compound 239E. Compound 471: 1H NMR (DMSO-d 6 , 400 MHz): δ 8.37 (d, = 7.5 Hz, 1H), 8.08 (s, 1H), 8.05 - 7.96 (m, 1H), 7.77 (s, 1H), 7.63 - 7.52 (m, 2H), 7.31 - 7.14 (m, 5H), 7.13 - 7.01 (m, 2H), 5.31 - 5.16 (m, IH), 4.24 - 4.03 (m, 2H), 3.18 - 3.06 (m, IH), 2.87 - 2.75 (m, IH), 1.38 (t, J = 7.3 Hz, 3H). MS (ESI) m/z (M+H) + 409.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2-FLUOROPHENYL)- l- ISOPROPYL-1H-PYRAZOLE-4-CARBOXAMIDE (472)
[1194] Compound 472 (88 mg, yield 45.8%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, 3-(2-fluorophenyl)-l- isopropyl-lH-pyrazole-4-carboxylic acid which was prepared using procedure similar to compound 242D. Compound 472: 1H NMR (DMSO-i¾ , 400 MHz): δ 8.25 (s, IH), 8.17 (d, = 7.5 Hz, IH), 7.96 (s, IH), 7.73 (s, IH), 7.40 - 7.05 (m, 9H), 5.26 - 5.16 (m, IH), 4.52 (td, = 6.8, 13.2 Hz, IH), 3.09 (br, dd, = 3.9, 14.2 Hz, IH), 2.78 (br.dd, = 9.7, 13.9 Hz, IH), 1.48 - 1.39 (m, 6H). MS (ESI) m/z (M+H) + 423.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(3-FLUOROPHENYL)- l- ISOPROPYL-lH-PYRAZOLE-4-CARBOXAMIDE (473)
[1195] Compound 473 (51 mg, yield 41.2%, pale yellow solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, 3 -(3 -fluorophenyl)- 1- isopropyl-lH-pyrazole-4-carboxylic acid which was prepared using procedure similar to compound 242D. Compound 473: 1H NMR (DMSO-d 6 , 400 MHz): δ 8.42 (d, = 7.3 Hz, IH),
8.14 (s, IH), 8.07 - 8.01 (m, IH), 7.78 (s, IH), 7.51 - 7.42 (m, 2H), 7.36 - 7.29 (m, IH), 7.28 - 7.24 (m, 4H), 7.22 - 7.16 (m, IH), 7.14 - 7.05 (m, IH), 5.34 - 5.25 (m, IH), 4.60 - 4.48 (m, IH),
3.15 (dd, = 4.0, 14.1 Hz, IH), 2.82 (dd, =9.8, 14.0 Hz, IH), 1.44 (d, =6.4 Hz, 6H). MS (ESI) m/z (M+H) + 423.2.
[1196] Compound 474 (80 mg, yield 52.6%, white solid) was prepared as in compound 12 from the corresponding intermediate carboxylic acid, 3-(4-fluorophenyl)-l- isopropyl-lH-pyrazole-4-carboxylic acidwhich was prepared using procedure similar to compound 242D. Compound 474: 1H NMR (DMSO-d 6 , 400 MHz): δ 8.10 (s, IH), 7.97 (s, IH), 7.85 - 7.39 (m, 4H), 7.34 - 7.17 (m, 5H), 7.15 - 7.03 (m, 2H), 5.37 - 5.27 (m, IH), 4.59 - 4.47 (m, IH), 3.26 - 3.16 (m, IH), 2.97 - 2.87 (m, IH), 1.49 (d, = 6.8 Hz, 6H). MS (ESI) m/z (M+H) + 423.2. EXAMPLE 132
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-ETHYL-3-PHEN YL-lH-
(S)-^V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-4-PHE NYL-lH- -3-CARBOXAMIDE (241)
[1197] To a mixture of methyl 4-bromo- lH-pyrazole-3-carboxylate (15.0 g, 73.2 mmol,) and Cs 2 C0 3 (59.6 g, 182.9 mmol) in DMF (150 mL) was added Mel (14.7 mL, 236.0 mmol) drop-wise at 0°C under N 2 . The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, the cake washed with ethyl acetate (200 mL x 2). The filtrate was washed with water (70 mL x 4) and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated to dryness under reduced pressure to dryness. The crude product which was purified by FCC (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound 240A (8.3 g, yield 51.8%) as a white solid and the title compound 240B (7.0 g, yield 43.7%) as white solid. Compound 240A: 1 H NMR (400MHz, CDC1 3 ): δ 7.48 (s, 1H), 4.15 (s, 3H), 3.93 (s, 3H). MS (ESI) m/z (M+H) + 219.0. Compound 240B: 1 H NMR (400MHz, CDC1 3 ): δ 7.47 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z (M+H) + 219.0.
[1198] Compound 240A (2.0 g, 9.1 mmol), phenylboronic acid (1.3 g, 11.0 mmol), Cs 2 C0 3 (8.9 g, 27.4 mmol) and Pd(PPh 3 ) 4 (211 mg, 183 umol) in DMF (30 mL) was de-gassed and then heated to 80°C for 16 hours under N 2 . The reaction mixture was filtered, the cake washed with ethyl acetate (30 mL x 2). The filtrate was washed with water (20 mL x 4) and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic extracts were dried over Na 2 S0 4 , filtered and concentrated to dryness under reduced pressure to dryness. The crude product which was purified by FCC (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford the title compound 240C (1.0 g, yield 47.3%) as a light yellow solid. Compound 240C: 1H NMR (400MHz, CDC1 3 ): δ 7.52 (s, 1H), 7.40 - 7.36 (m, 4H), 7.35 - 7.31 (m, 1H), 4.20 (s, 3H), 3.76 (s, 3H). MS (ESI) m/z (M+H) + 217.0.
[1199] A solution of NaOH (370 mg, 9.2 mmol) in H 2 0 (10 mL) was added to a solution of compound 240C (1.0 g, 4.6 mmol) in THF (10 mL) and MeOH (10 mL) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was adjusted to pH ~ 6 with IN HC1 (10 mL) at 25 °C, and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over Na 2 S0 4 , filtered, and concentrated to afford compound 240D (900 mg, yield 94.1%) as light yellow solid. Compound 240D: 1H NMR (400MHz, CD 3 OD): δ 7.54 - 7.49 (m, 1H), 7.44 - 7.38 (m, 2H), 7.37 - 7.27 (m, 3H), 4.14 (s, 3H). MS (ESI) m/z (M+H) + 202.9.
[1200] Compound 240 (68.6 mg, yield 41.4%) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 240D. Compound 240: 1H NMR (400MHz, DMSO-d 6 ): δ 7.46 - 7.39 (m, 4H), 7.39 - 7.34 (m, 2H), 7.20 - 7.13 (m, 3H), 6.73 - 6.68 (m, 2H), 6.14 - 6.07 (m, 1H), 5.57 - 5.46 (m, 2H), 4.09 (s, 3H), 3.19 (dd, J = 4.8, 14.0 Hz, 1H), 2.80 (dd, 7 = 8.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 377.1.
[1201] Following the procedure used for compound 240, compound 241 (90 mg, yield 58.5%, white solid) was prepared from intermediate compound 241B. Compound 241: 1H NMR (400MHz, CDCI 3 ): δ 7.53 - 7.47 (m, 2H), 7.41 (s, 1H), 7.37 - 7.27 (m, 6H), 7.19 - 7.13 (m, 2H), 6.72 (br s, 1H), 5.69 - 5.62 (m, 1H), 5.43 (br s, 1H),3.94 (s, 3H), 3.42 (dd, J = 5.2, 14.0 Hz, 1H), 3.20 (dd, J = 7.6, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 377.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(2- METHYLPYRIMIDIN-4-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (244)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(PYR IMIDIN-4-
[1202] A mixture of 4-chloro-2-methylpyrimidine (5.00 g, 38.89 mmol) and Ν 2 Η 4 .Η 2 0 (22.91 g, 388.90 mmol, 22.24 mL, 85% purity) in EtOH (100 mL) was degassed and purged with N 2 for 3 times, then the mixture was stirred at 70 °C for 2 hour under N 2 atmosphere. The mixture was concentrated under reduced pressure to give a crude, the crude was washed by PE (50 mL) and filtered, the residue was purified by column chromatography (DCM: CH 3 OH=10: 1) to obtain compound 244A (1.60 g, 33.14% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.99 (d, = 5.6 Hz, 1H), 6.48 (br s, 1H), 4.31 (br s, 2H), 2.30 (s, 3H).
[1203] To a solution of compound 244A (900.0 mg, 7.25 mmol) in CH 3 COOH (12 mL) was added ethyl 2-(methoxyimino)-4-oxopentanoate (1.36 g, 7.25 mmol), then the mixture was stirred at 120 °C for 2 hours. The residue was diluted with solvent EtOAc (70 mL) and washed with solvent satutaed NaHC0 3 solution (20 mL x 3), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE: EA = 30/1 to 10/1) to afford crude. The crude was further separated by preparatory-HPLC (Basic condition) to give compound 244B (158.0 mg, 8.85% yield) as a white solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.66 (d, 7 = 5.6 Hz, 1H), 7.53 (d, 7 = 3.6 Hz, 1H), 6.59 (s, 1H), 4.39 - 4.33 (m, 2H), 2.66 (s, 3H), 2.35 (s, 3H), 1.35 - 1.32 (m, 3H). MS (ESI) m/z (M+l) + 247.1.
[1204] To a mixture of compound 244B (130.0 mg, 527.90 umol) in MeOH (8 mL) and H 2 0 (4 mL) was added L1OH.H 2 O (88.6 mg, 2.11 mmol) in one portion and the mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (10 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 244D (HO.OOmg, 95.49% yield) as a white solid. 1H NMR (400 MHz, DMSO-i¾) δ 8.77 (d, 7 = 5.6 Hz, 1H), 7.56 (d, 7 = 3.6 Hz, 1H), 6.76 (s, 1H), 2.65 (s, 3H), 2.27 (s, 3H). MS (ESI) m/z (M+l) + 219.1.
[1205] Compound 244 (40.0 mg, 33.17% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 244D. Compound 244: 1H NMR (400 MHz, CDCI3) δ 9.48 (d, 7 = 5.2 Hz, 1H), 8.66 (d, 7 = 4.8 Hz, 1H), 7.70 (d, 7 = 5.2 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.10 (s, 2H), 6.84 (s, 1H), 6.78 (s, 1H), 5.81 (d, 7 = 6.0Hz, 1H), 5.58 (s, 1H), 3.47 - 3.38 (m, 1H), 3.39 - 3.34 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H). MS (ESI) m/z (M+l) + 393.1.
[1206] Following the procedure used for compound 244A, compound 245A (1.80 g, 49.37% yield, brown solid) was obtained from 4-chloropyrimidine and NH 2 NH 2 .H 2 0. Compound 245A: 1H NMR (400 MHz, DMSO-d 6 ): δ 8.32 (s, 2H), 8.06 (d, 7 = 5.2 Hz, 1H), 6.65 (s, 1H), 4.32 (m, 2H).
[1207] Following the procedure used for compound 244B, compound 245B (586.0 mg, 2.52 mmol, 17.39 % yield) was obtained as a white solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.92 (s, 1H), 8.71 (d, 7 = 5.6 Hz, 1H), 7.70 - 7.69 (m, 1H), 6.56 (s, 1H), 4.34 - 4.38 (m, 2H), 2.29 (s, 1H), 1.31 - 1.24 (m, 3H). MS (ESI) m/z (M+l) + 233.1.
[1208] Following the procedure for compound 244D, compound 245D (476.0 mg, 2.33 mmol, 93.30% yield) was obtained as white solid. 1H NMR (400 MHz, DMSO-i¾) δ 9.04 (s, 1H), 8.90 (d, 7 = 5.2 Hz, 1H), 7.81 (d, 7 = 5.6 Hz, 1H), 6.79 (s, 1H), 2.27 (s, 3H). [1209] Compound 245 (35.0 mg, 28.33% yield, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 245D. Compound 245: 1H NMR (400 MHz, DMSO- e) δ 9.18 (d, J = 1.2 Hz, 1H), 8.83 (d, 7 = 5.6 Hz, 1H), 8.74 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.73 (d, 7 = 4.8 Hz, 1H), 7.28 - 7.23 (m, 5H), 6.50 (s, 1H), 5.38 (s, 1H), 3.19 - 3.16 (m, 1H), 2.88 - 2.82 (m, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+l) + 379.1.
[1204] Compounds 246, 431-437, 448
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2-CHLOROPYRI MIDIN-4- YL -3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (246)
[1210] To a solution of 2,4-dichloropyrimidine (10 g, 67.12 mmol) and Et 3 N (10.2 mL, 73.83 mmol) in EtOH (120 mL) was added NH 2 NH 2 .H 2 0 (4.6 mL, 80.54 mmol) at 0-5 °C. The mixture was stirred at 5 °C for 1.5h. The mixture was concentrated. The residue was triturated in EtOH (15 mL) and water (15 mL) to afford compound compound 246A (4 g, 41.22% yield) as yellow oil. 1H NMR (400MHz, DMSO- 6 ) δ 9.00 - 8.79 (m, 1H), 8.09 - 7.63 (m, 1H), 6.82 - 6.59 (m, 1H), 4.82 - 4.30 (m, 2H).
[1211] A mixture of ethyl 2,4-dioxopentanoate (4.38 g, 27.67 mmol), compound
246A (4 g, 27.67 mmol) in AcOH (60 mL) was stirred at 118 °C for lh. The mixture was in
DCM (50 mL). The organic layer was washed with water (10 mL), NaHC0 3 to pH - 8-9 and dried over Na 2 S0 4 and concentrated. The residue was purified by column chromatography (Si0 2 ,
Petroleum ether/Ethyl acetate=10/l to 5: 1). Compound 246B (650 mg, 8.81% yield) was obtained as white solid. Compound 246C (240 mg, 3.25% yield) was obtained as white solid.
Compound 246B: 1H NMR (400MHz, DMSO- 6 ) δ 8.87 (d, 7=5.6 Hz, 1H), 7.98 (d, 7=5.6 Hz, 1H), 6.89 (s, 1H), 4.34 (q, 7=7.2 Hz, 2H), 2.71 (s, 3H), 1.32 (t, 7=7.2 Hz, 3H). Compound 246C: 1H NMR (400MHz, DMSO- d 6 ) δ 8.84 (d, 7=5.6 Hz, 1H), 7.86 (d, 7=5.6 Hz, 1H), 6.91 (s, 1H), 4.32 (q, 7=7.2 Hz, 2H), 2.31 (s, 3H), 1.30 - 1.20 (m, 3H).
[1212] A mixture of compound 246B (300 mg, 1.12 mmol) in THF (36 mL) and H 2 0 (12 mL) was added LiOH.H 2 0 (27.1 mg, 645.87 umol). The mixture was stirred at 31 °C for lh. The mixture was concentrated and acidified to pH ~ 5 with 1M HC1, then extracted with chloroform: isopropyl alcohol = 10 : 1 (10 ml x 2). This combined organic phase was washed with saturated aqueous NaCl and dried over Na 2 S0 4 , filtered and the solvent was removed in vacuo to give compound 246D (200 mg, 74.83% yield) as white solid. 1H NMR (400 MHz, DMSO-i¾): δ 14.19 - 13.39 (m, 1H), 8.83 (d, 7 = 5.4 Hz, 1H), 7.83 (d, 7=5.6 Hz, 1H), 6.84 (s, 1H), 2.28 (s, 3H).
[1213] Compound 246 (2.7 mg, yield, 12.35%, white solid) was prepared as in Example 5 from the corresponding carboxylic acid, compound 246D. Compound 246: 1H NMR (400MHz, DMSO-i¾): (59.16 - 9.11 (m, 1H), 8.77 - 8.72 (m, 1H), 8.03 (br s, 1H), 7.80 (br s, 1H), 7.73 - 7.68 (m, 1H), 7.23 (br s, 4H), 7.21 - 7.17 (m, 1H), 6.53 (s, 1H), 5.42 (br s, 1H), 3.17 - 3.13 (m, 1H), 2.88 - 2.84 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) + 413.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2-ISOPROPYLPYRIM IDIN-4- YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (431)
[1214] Compound 431 (65 mg, yield, 87.0%, white solid) was prepared using intermediate 246B which was subjected to suzuki coupling using 4,4,5,5-tetramethyl-2-(prop-l- en-2-yl)- l,3,2-dioxaborolane followed by ester hydrolysis using procedure as for compound 12 and hydrogenation and coupling with intermediate 274D as in compound 12 to obtain compound 431. Compound 431: 1H NMR (400MHz, DMSO-d 6 ): δ 9.11 (d, 7 = 7.5 Hz, 1H), 8.74 (d, 7 = 5.5 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.52 (d, 7 = 5.5 Hz, 1H), 7.32 - 7.20 (m, 5H), 6.47 (s, 1H), 5.52 - 5.41 (m, 1H), 3.16 (dd, 7 = 3.6, 13.8 Hz, 1H), 2.80 - 2.75 (m, 1H), 2.29 (s, 3H), 1.04 (dd, 7 = 6.9, 12.2 Hz, 6H). MS (ESI) m/z (M+H) + 421.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2-ETHYNYLPYRIMID IN-4-YL)- 3-METHYL-1H-PYRAZOLE-5-CARBOXAMIDE (432)
[1215] Compound 432 (35 mg, yield, 43.5%, white solid) was prepared using intermediate 246B which was subjected to coupling with 4ethynyltrimethylsilane followed by removal of trimethylsilyl group and then ester hydrolysis using procedure as for compound 12 and coupling with intermediate 274D as in compound 12 to obtain compound 432. Compound 432: 1H NMR (400MHz, DMSO-d 6 ): δ 9.14 (d, 7 = 7.0 Hz, 1H), 8.82 (d, 7 = 5.5 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.70 (d, 7 = 5.5 Hz, 1H), 7.31 - 7.17 (m, 5H), 6.55 (s, 1H), 5.46 - 5.35 (m, 1H), 4.39 (s, 1H), 3.19 (dd, 7 = 4.8, 14.1 Hz, 1H), 2.93 (dd, 7 = 9.0, 14.1 Hz, 1H), 2.29 (s, 3H). MS (ESI) m/z (M+H) + 403.1.
(5)-l-(2-ETHYNYLPYRIMIDIN-4-YL)-N-(4-FLUORO-3-OXO-l-PHENYLBU TAN-2- YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (433)
[1216] Compound 433 (35 mg, yield, 43.5%, white solid) was prepared using intermediate 246B which was subjected to coupling with 4ethynyltrimethylsilane followed by removal of trimethylsilyl group and then ester hydrolysis using procedure as for compound 12 and coupling with (2S,3S)-3-amino- l-fluoro-4-phenylbutan-2-ol hydrochloride using procedure as in compound 12 to obtain compound 433. Compound 433: 1H NMR (400MHz, DMSO- e): δ 9.24 (d, 7 = 7.8 Hz, 1H), 8.85 (d, 7 = 5.5 Hz, 1H), 7.78 (d, 7 = 5.5 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.29 - 7.21 (m, 3H), 6.38 s, 1H), 5.50 - 5.21 (m, 2H), 4.73 - 4.64 (m, 1H), 4.45 (s, 1H), 3.19 (dd, 7 = 4.9, 13.9 Hz, 1H), 2.93 (dd, 7 = 9.8, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 392.1.
N-(4-AMINO-3-HYDROXY-4-OXO-l-PHENYLBUTAN-2-YL)-l-(2-
CHLOROPYRIMIDIN-4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (434)
[1217] Compound 434 (80 mg, yield, 15.2%, white solid) was prepared using intermediate 246B which was subjected to coupling with intermediate 274D using procedure as in compound 12 to obtain compound 434. Compound 434: 1H NMR (400MHz, DMSO- e): δ 8.76 (t, 7 = 5.6 Hz, 1H), 8.63 (d, 7 = 8.8 Hz, 1H), 8.36 (d, 7 = 9.0 Hz, 1H), 7.68 (dd, 7 = 5.5, 19.6 Hz, 1H), 7.39 - 7.14 (m, 7H), 6.55 - 6.41 (m, 1H), 4.57 - 4.31 (m, 1H), 4.19 (d, 7 = 3.3 Hz, 1H), 3.85 (d, 7 = 2.4 Hz, 1H), 3.04 - 2.66 (m, 2H), 2.28 (d, 7 = 5.5 Hz, 3H). MS (ESI) m/z (M+H) + 415.0.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2- CHLOROPYRIMIDIN-4-YL)-5-METHYL-lH-PYRAZOLE-3-CARBOXAMIDE (435)
[1218] Compound 435 (160 mg, yield, 46.02%, white solid) was prepared using intermediate 246C which was subjected to coupling with intermediate 12G using procedure as in compound 12 to obtain compound 435. Compound 435: 1H NMR (400MHz, DMSO- 6 ): δ 8.88 (d, 7 = 5.7 Hz, IH), 8.09 (d, 7 = 5.5 Hz, IH), 7.82 (d, 7 = 9.3 Hz, IH), 7.42 (s, IH), 7.27 (d, 7 = 4.4 Hz, 4H), 7.23 - 7.13 (m, IH), 6.72 (s, IH), 6.21 (s, IH), 4.49 (d, 7 = 7.3 Hz, IH), 3.88 (d, 7 = 2.4 Hz, IH), 3.02 - 2.87 (m, IH), 2.86 - 2.74 (m, IH), 2.68 (s, 3H). MS (ESI) m/z (M+H) + 415.0.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2- METHOXYPYRIMIDIN-4-YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (436)
[1219] Compound 436 (25 mg, yield, 57.7%, white solid) was prepared using intermediate 246D which was subjected to treatment with sodium methoxide and coupling with intermediate 274D using procedure as in compound 12 to obtain compound 436. Compound 436: 1H NMR (400MHz, DMSO-d 6 ): δ 9.14 (d, 7 = 7.5 Hz, IH), 8.60 (d, 7 = 5.3 Hz, IH), 8.15 (s, IH), 7.91 (s, IH), 7.34 (d, 7 = 5.3 Hz, IH), 7.30 - 7.19 (m, 5H), 6.50 (s, IH), 5.45 - 5.36 (m, IH), 3.48 (s, 3H), 3.16 (dd, 7 = 3.3, 13.9 Hz, IH), 2.77 (dd, 7 = 10.1, 13.9 Hz, IH), 2.29 (s, 3H). MS (ESI) m/z (M+H) + 409.2.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(2-CYANOPYRIMIDIN -4- YL)-3-METHYL-lH-PYRAZOLE-5-CARBOXAMIDE (437)
[1220] Compound 437 (30 mg, yield, 81.32%, white solid) was prepared using intermediate 246D which was subjected to treatment with zinc cyanide using palladium catalyzed coupling conditions followed by coupling with intermediate 274D using procedure as in compound 12 to obtain compound 437. Compound 437: 1H NMR (400MHz, DMSO- 6 ): δ 9.13 (d, 7 = 7.3 Hz, IH), 8.96 (d, 7 = 5.5 Hz, IH), 8.05 - 7.93 (m, 2H), 7.84 (s, IH), 7.27 - 7.15 (m, 5H), 6.57 (s, IH), 5.51 - 5.31 (m, IH), 3.15 (dd, 7 = 4.2, 13.9 Hz, IH), 2.79 (dd, 7 = 9.4, 14.0 Hz, IH), 2.30 - 2.24 (m, 3H). MS (ESI) m/z (M+H) + 404.1.
[1221] To a solution of compound 246D (400 mg, 1.68 mmol) in 2-methylpropan-2- ol (6.2 g, 83.65 mmol, 8.00 mL) and THF (10 mL) was added pyridine (928 mg, 11.73 mmol, 947 uL) and then added p-TsCl (799 mg, 4.19 mmol) in one portion at 0 °C. The mixture was stirred at 25 °C for 48 h. The reaction was quenched with sat. NaHC0 3 at 0 °C, the mixture was extracted with EA (20 mL x 2), dried over Na 2 S0 4 , filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO ® ; 24g SepaFlash ® Silica Flash Column, eluent of 0-10% -20% Ethyl acetate/Petroleum ethergradient @ 35 mL/min). Compound 448A (400 mg, yield 81.0%) was obtained as a white solid. 1 H NMR (400MHz, CDC1 3 ) δ 8.63 (d, J = 5.3 Hz, 1H), 7.80 - 7.63 (m, 1H), 6.59 (s, 1H), 2.34 (m, 3H), 1.59 (m, 9H). MS (ESI) m/z (M+H) + 295.1.
[1222] To a solution of compound 448A (400 mg, 1.36 mmol) in DMF (13 mL) was added KF (788 mg, 13.57 mmol) and Dicyclohexano-18-crown-6 (51 mg, 135.71 umol). The mixture was stirred at 120 °C for 3 h under N 2 . The reaction was cooled to rt and added ice- water (80 mL), white precipitate was formed. The solid was collected by filtration. The residue was purified by preparatory- HPLC (HC1 condition). Column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (0.05%HC1)-ACN]; B%: 55%-85%, 9.5min. Compound 448B (130 mg, yield: 34.4%) was obtained as a white solid. 1 H NMR (400MHz, CDC1 3 ) δ 8.63 (dd, / = 2.0, 5.3 Hz, 1H), 7.72 (dd, / = 3.2, 5.4 Hz, 1H), 6.57 (s, 1H), 2.36 (s, 3H), 1.59 (s, 9H). MS (ESI) m/z (M+H) + 279.1.
[1223] To a solution of compound 448B (130 mg, 467.15 umol) in DCM (15 mL) was added TFA (2.31 g, 20.26 mmol, 1.5 mL). The mixture was stirred at 25 °C for 5 h. The reaction was concentrated to give a residue. The residue was used to the next step without purification. Compound 448C (105 mg, crude) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-de) δ 8.84 (dd, J = 2.1, 5.4 Hz, 1H), 7.81 (dd, J = 3.5, 5.5 Hz, 1H), 6.89 - 6.78 (m, 1H), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 222.9.
[1224] Compound 448 (35 mg, yield, 69.7%, white solid) was prepared using intermediate 246D and 448C using procedure as in compound 12 to obtain compound 448. Compound 448: 1H NMR (400MHz, DMSO-d 6 ): δ 9.14 (d, = 7.3 Hz, 1H), 8.76 (dd, = 2.0, 5.5 Hz, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.70 (dd, J = 3.5, 5.5 Hz, 1H), 7.27 - 7.17 (m, 5H), 6.53 (s, 1H), 5.42 - 5.37 (m, 1H), 3.14 (dd, J = 4.0, 14.1 Hz, 1H), 2.82 (dd, J = 9.3, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M+H) + 397.1.
(S)-N-(3,4-DIOXO-l-PHENYL-4-((4- (TRIFLUOROMETHOXY)BENZYL)AMINO)BUTAN-2-YL)-3-METHYL-5- -4-CARBOXAMIDE (247)
[1225] To a solution of compound 101E (500.0 mg, 1.31 mmol) in DMF (10 mL) was added [4-(trifluoromethoxy)phenyl]methanamine (250.4 mg, 1.31 mmol, 200 uL), DIEA (507.9 mg, 3.93 mmol, 690 uL), HOBt (53.1 mg, 393.00 umol) and EDCI (301.4 mg, 1.57 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with H 2 0 (100 mL), extracted with EA (30 mL), washed with HCl (1M, 30 mL), saturated NaHC03 (aq, 30mL), brine (30 mL), dried over Na 2 S0 4 and concentrated. The residue was purified by preparatory-HPLC (basic condition). Compound 247A (80.0 mg, crude) was obtained as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 8.46 - 8.20 (m, 1H), 7.57 - 7.11 (m, 15H), 5.90 - 5.64 (m, 1H), 4.71 - 4.56 (m, 1H), 4.10 - 3.90 (m, 2H), 2.99 - 2.89 (m, 1H), 2.86 - 2.74 (m, 1H), 2.11 - 2.01 (m, 3H).
[1226] To a solution of compound 247A (80.0 mg, 144.53 umol) in DCM (10 mL) and DMSO (lmL) was added DMP (183.9 mg, 433.59 umol). The mixture was stirred at 25 °C for 3 hours. The mixture quenched with 10% Na 2 S203 (aqueous): saturated NaHC0 3 (aqueous) (1: 1, 20 mL), extracted with DCM (10 mL) and washed with brine (20 mLx3). The combined organic layers were dried over Na 2 S0 4 and concentrated. The crude product was triturated with CH 3 CN (5 mL) and filtered. Compound 247 (20.0 mg, yield 25.1%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.50 - 9.43 (m, 1H), 9.12 - 9.06 (m, 1H), 7.66 - 7.57 (m, 2H), 7.51 - 7.36 (m, 5H), 7.34 - 7.19 (m, 7H), 5.53 - 5.45 (m, 1H), 4.41 - 4.16 (m, 2H), 3.27 - 3.20 (m, 1H), 2.82 - 2.72 (m, 1H), 2.10 - 2.01 (m, 1H), 2.05 (s, 2H). MS (ESI) m/z (M+H) + 552.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(4-FLUOROPHEN YL)-2- -5-CARBOXAMIDE (248)
[1227] A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (8 g, 38.06 mmol) and NH 4 OAc (5.87 g, 76.12 mmol) in EtOH (450 mL) was stirred at 78 °C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (60 mL) and then extracted with EtOAc (100 mL x 3). The combined organic phase was washed with sat. NaHC0 3 (50 mL x 3) and brine (50 mL), dried over anhydrous Na 2 S0 4 , filtered and the solvent was removed under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , petroleum ether/ethyl acetate = 100: 1 to 10: 1) to afford compound 248A (7.10 g, 89.16% yield) as a light yellow oil. 1H NMR (400 MHz, CDC1 3 ): δ 7.56 - 7.48 (m, 2H), 7.12 - 7.04 (m, 2H), 4.90 (s, 1H), 4.16 (q, = 7.2 Hz, 2H), 1.32 - 1.24 (m, 3H). [1228] To a mixture of compound 248A (9 g, 43.02 mmol) in DCE (90 mL) was added PhI(OAc)2 (18.0 g, 55.93 mmol) in three portions at 0 °C under N 2 , the mixture was stirred at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated aqueous NaHC0 3 (200 mL) and extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4i filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , petroleum ether/ethyl acetate = 20: 1 to 5: 1) to afford compound 248B (6.0 g, 52.19% yield) as a yellow oil. 1H NMR (400 MHz, CDC1 3 ): δ 7.49 - 7.35 (m, 2H), 7.12 - 7.00 (m, 2H), 4.27 - 4.16 (m, 2H), 1.93 (s, 3H), 1.27 (t, = 7.2 Hz, 3H).
[1229] A mixture of ethyl compound 248B (6.0 g, 22.45 mmol) in DCE (30 mL) and AcOH (15 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room- temperature and then concentrated to dryness under reduced pressure to afford a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=100:l to 10: 1) to afford compound 248C (2.80 g, 50.04% yield) as a white solid. 1H NMR (400 MHz, CDC1 3 ): δ 8.10 - 8.00 (m, 2H), 7.11 (t, = 8.4 Hz, 2H), 4.38 (q, = 7.2 Hz, 2H), 2.57 (s, 3H), 1.37 (t, = 7.2 Hz, 3H).
[1230] To a mixture of compound 248C (1 g, 4.01 mmol) in MeOH (30 mL) and H 2 0 (15 mL) was added LiOH » H20 (505.1 mg, 12.03 mmol) in one portion and the mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was adjusted to pH ~ 3 with IN HC1, diluted with water (30 mL) and then extracted with EtOAc (100 mL x 4). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 248D (820 mg, 92.45% yield) as a white solid. 1H NMR (400 MHz, CDC1 3 ): δ 8.10 - 8.00 (m, 2H), 7.17 - 7.07 (m, 2H), 2.60 (s, 3H).
[1231] Compound 248 (36.1 mg, 24.19% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 248D. Compound 248: 1H NMR (400 MHz, CDC1 3 ): δ 8.19 - 8.12 (m, 2H), 7.34 - 7.26 (m, 3H), 7.17 - 7.11 (m, 2H), 7.10 - 7.03 (m, 2H), 6.80 - 6.71 (m, 2H), 5.74 - 5.68 (m, 1H), 5.58 (br s, 1H), 3.48 - 3.40 (m, 1H), 3.28 - 3.19 (m, 1H), 2.53 (s, 3H). MS (ESI) m/z (M+H) + 396.0. EXAMPLE 137
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-PHENYLBENZOFU RAN-3-
[1232] To a mixture of ethyl 3-oxo-3-phenylpropanoate (2 g, 10.41 mmol, 1.8 mL), phenol (2.94 g, 31.23 mmol, 2.75 mL), and FeCl 3 .6H 2 0 (281 mg, 1.04 mmol) was added DCE (70 mL) under nitrogen at 25°C. Then di-tert-butylperoxide (3.04 g, 20.82 mmol, 3.85 mL) was dropped into the mixture under nitrogen. The reaction temperature was raised to 100 °C for 3h. The temperature of the reaction was cooled to room temperature. The resulting reaction solution was quenched with 30 mL of saturated NaHC0 3 and extracted with DCM (20 mL x 3). The extract was washed with 100 mL of saturated NaHC0 3 and 100 mL of 10 % Na 2 S 2 0 3 . The extract was dried over Na 2 S0 4 . The solvent was evaporated in vacuo to afford the crude products. The residue was purified by column chromatography (Si0 2 , PE ~ Petroleum ether/Ethyl acetate = 10/1) to give compound 249A (1.5 g, yield: 54.08%) as a yellow oil. 1 H NMR (400MHz, CDC1 3 ) δ 8.09 - 7.99 (m, 3H), 7.57 - 7.45 (m, 4H), 7.39 - 7.32 (m, 2H), 4.41 (q, 7 = 7.1 Hz, 2H), 1.43 - 1.39 (m, 3H). MS (ESI) m/z (M+H) + 267.0..
[1233] To a solution of compound 249A (600 mg, 2.25 mmol) in MeOH (30 mL) and H 2 0 (15 mL) was added NaOH (270 mg, 6.75 mmol). The mixture was stirred at 25 °C for 16h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (20 mL x 2), the organic phase was dried over Na 2 S0 4 , concentrated to give a residue. Compound 249B (330 mg, yield: 61.78%) was obtained as a white solid, which was used to the next step without purification. 1H NMR (400MHz, DMSO- e) δ 13.10 (br s, 1H), 8.05 - 7.92 (m, 3H), 7.72 - 7.62 (m, 1H), 7.57 - 7.47 (m, 3H), 7.41 - 7.34 (m, 2H). MS (ESI) m/z (M+H) + 239.0. [1234] Compound 249 (65 mg, yield: 60.09%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 249B. Compound 249: 1 H NMR (400MHz, DMSO-d 6 ) δ 9.08 (d, = 7.3 Hz, 1H), 8.23 (br s, 1H), 7.94 (br s, 1H), 7.69 (br s, 2H), 7.63 (d, = 7.9 Hz, 1H), 7.40 (br s, 3H), 7.39 - 7.20 (m, 8H), 5.56 (br s, 1H), 3.26 (br s, 1H), 2.79 (t, J = 12.2 Hz, 1H). MS (ESI) m/z (M+H) + 413.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-CYCLOPROPY L-3-PHENYL-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(CYCLOPROP YLMETHYL)- -PHENYL-1H-PYRAZOLE-4-CARBOXAMIDE (251)
[1235] To a mixture of compound 239A (2.0 g, 7.5 mmol) and cyclopropylboronic acid (1.29 g, 15.0 mmol) in DMF (40 mL) was added Cu(OAc) 2 (2.05 g, 11.28 mmol), 4A° MS (20 g) and pyridine (1.2 mL 15.0 mmol) at 25 °C under 0 2 (15 psi). The mixture was stirred at 25 °C for 38h. Additional cyclopropylboronic acid (1.29 g, 15.04 mmol) was added to the mixture, which was stirred at 70 - 80 °C for 20h. The reaction mixture was added Cu(OAc) 2 (2.05 g, 11.28 mmol) and stirred at 70 - 80 °C for 22h. The mixture was filtered, the filtrate was diluted with H 2 0 (200 mL), extracted with EA (150 mL x 3), the combined organic phase was washed with brine (100 mL), dried over Na 2 S0 4 and concentrated to give a residue. The residue was purified by FCC (Si0 2 , Petroleum ether/Ethyl acetate=l :0 to 10: 1) to afford compound 250A (552 mg, yield 24.0%) as white solid. Compound 250A: 1H NMR (DMSO-d 6, 400 MHz): δ 8.32 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.82 (tt, 7 = 3.8, 7.4 Hz, 1H), 1.27 (t, 7 = 7.1 Hz, 3H), 1.12 - 1.07 (m, 2H), 1.00 - 0.94 (m, 2H). MS (ESI) m/z (M+H) + 307.0.
[1236] To a mixture of compound 250A (544 mg, 1.7 mmol) and phenylboronic acid (434 mg, 3.5 mmol) in dioxane (50 mL) and H 2 0 (10 mL) was added Pd(dppf)Cl 2 (130 mg, 0.18 mmol) and Na 2 C0 3 (377 mg, 3.5 mmol) at 25 °C under N 2 . The mixture was stirred at 80 °C for 12h. The mixture was filtered over Celite. The filtrate was added EA (150 mL), and then washed with H 2 0 (100 mL x 3). The organic layer was dried over Na 2 S0 4 and concentrated. The residue was purified by FCC (Si0 2 , Petroleum ether/Ethyl acetate=l:0 to 5: 1) to afford compound 250C (431 mg, yield 94.5%) as light yellow liquid. 1H NMR (DMSO-d 6 , 400 MHz): δ 8.42 (s, 1H), 7.71 - 7.65 (m, 2H), 7.42 - 7.36 (m, 3H), 4.16 (q, 7 = 7.1 Hz, 2H), 3.85 (tt, 7 = 3.8, 7.4 Hz, 1H), 1.21 (t, 7 = 7.1 Hz, 3H), 1.18 - 1.13 (m, 2H), 1.04 - 0.96 (m, 2H). MS (ESI) m/z (M+H) + 257.0.
[1237] To a mixture of compound 250C (425 mg, 1.7 mmol) in MeOH (10 mL) was added the mixture of KOH (931 mg, 16.6 mmol) and H 2 0 (2 mL) in one portion at 25 °C. The mixture was stirred at 70 °C for lh 40 mins. The reaction mixture was concentrated under reduced pressure to move MeOH, the aqueous phase was acidified with aqueous HCl (0.5M) till pH - 4 - 5. The precipitate was filtered and dried to afford compound 250D (333 mg, crude) as white solid, which was used directly for the next step without purification. 1H NMR (DMSO-i¾ , 400 MHz): δ 12.24 (s, 1H), 8.35 (s, 1H), 7.73 - 7.69 (m, 2H), 7.41 - 7.34 (m, 3H), 3.83 (tt, 7 = 3.7, 7.5 Hz, 1H), 1.17 - 1.12 (m, 2H), 1.02 - 0.97 (m, 2H).
[1238] Compound 250 (70.0 mg, yield 46.3%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 250D. Compound 250: 1H NMR (DMSO- 6 , 400 MHz): δ 8.09 (s, 1H), 7.95 - 7.86 (m, 1H), 7.81 - 7.46 (m, 4H), 7.42 - 7.12 (m, 8H), 5.33 (s, 1H), 3.79 (s, 1H), 3.25 - 3.16 (m, 1H), 2.96 - 2.84 (m, 1H), 1.16 - 0.97 (m, 4H). MS (ESI) m/z (M+H) + 403.1.
[1239] Following the procedure used for compound 250D, compound 251D (150 mg, yield 95.64%, white solid) was prepared from the corresponding starting materials, compound 239A and bromomethylcyclopropane. Compound 251D: 1H NMR (DMSO- 6, 400MHz) δ 8.33 (s, 1H), 7.73 (dd, 7 = 1.5, 7.9 Hz, 2H), 7.40 - 7.34 (m, 3H), 4.01 (d, 7 = 7.1 Hz, 2H), 1.31 (br d, 7 = 7.7 Hz, 1H), 0.57 - 0.52 (m, 2H), 0.42 - 0.37 (m, 2H). [1240] Compound 251 (70 mg, yield 43.27%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 251D. Compound 251: 1 H NMR (DMSO-d 6 400MHz) δ 8.40 (br d, J = 7.3 Hz, 1H), 8.15 - 8.05 (m, 2H), 7.82 (br s, 1H), 7.62 - 7.52 (m, 2H), 7.30 (br s, 4H), 7.28 - 7.20 (m, 4H), 5.33 - 5.24 (m, 1H), 4.06 - 3.95 (m, 2H), 3.17 (br dd, = 3.5, 13.9 Hz, 1H), 2.84 (br dd, = 9.9, 13.7 Hz, 1H), 1.34 - 1.18 (m, 1H), 0.58 (br d, = 6.8 Hz, 2H), 0.42 (br d, = 4.4 Hz, 2H). MS (ESI) m/z (M+H) + 417.2.
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(PHENYLETHYN YL)-lH-
I DOLE-3-CARBOXAMIDE (252)
[1241] To a solution of methyl lH-indole-3-carboxylate (5.0 g, 28.55 mmol) in toluene (50 mL) was added Na 2 C0 3 (1.2 g, 11.42 mmol), CuCl 2 (153 mg, 1.14 mmol), pyridine (922 uL, 11.42 mmol), then ethynylbenzene (627 uL, 5.71 mmol) was added to the mixture. The mixture was heated to 70 °C and stirred for 4h under 0 2 atmosphere. The reaction was diluted with H 2 0 (15 mL) and EA (15 mL), filtered. The mixture was extracted with EA (15 mL x 2), the organic layer was collected and washed with NaHC0 3 (25 mL x 2), washed with brine(20 mL), dried over anhydrous Na 2 S0 4 , filtered, concentrated under reduced pressure. The product was purified by FCC (PE/EA:0 to 10/1) to afford compound 252A (630 mg, yield 40.08%) as light red solid. 1H NMR (DMSO- 6, 400MHz) δ 8.46 (s, 1H), 8.09 (d, = 7.7 Hz, 1H), 7.75 (d, = 7.9 Hz, 1H), 7.68 - 7.65 (m, 2H), 7.49 - 7.44 (m, 4H), 7.43 - 7.38 (m, 1H), 3.86 (s, 3H).
[1242] To a solution of compound 252A (300 mg, 1.09 mmol) in MeOH (10 mL) was added KOH (611mg, 10.90 mmol) and then the mixture was stirred at 70 °C for 3h. The reaction was diluted with H 2 0 (5 mL) and evaporated under reduced pressure, the water phase was extracted with TBME (5 mL) and then the water phase was treat with HC1 (1 M) until pH ~ 4. The mixture was extracted with EA (10 mL x 3), the organic layer was collected, washed with brine (10 mL), dried over anhydrous Na 2 S04, filtered and concentrated under reduced pressure. Compound 252B (240 mg, yield 84.27%) was obtained as white solid. 1H NMR (DMSO- 6, 400MHz) δ 8.37 (s, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.50 - 7.45 (m, 4H), 7.45 - 7.36 (m, 2H).
[1243] Compound 252 (70 mg, yield 24.39%, yellow solid) was prepared as in Example 5 from intermediate compound 252B. Compound 252: 1H NMR (DMSO-^OOMHz) δ 8.61 (d, = 7.5 Hz, 1H), 8.45 (s, 1H), 8.14 - 8.05 (m, 2H), 7.85 (s, 1H), 7.73 (d, = 8.2 Hz, 1H), 7.67 (dd, = 2.4, 7.3 Hz, 2H), 7.50 - 7.46 (m, 3H), 7.42 (t, = 7.7 Hz, 1H), 7.38 - 7.35 (m, 2H), 7.33 - 7.29 (m, 3H), 7.23 - 7.19 (m, 1H), 5.47 - 5.36 (m, 1H), 3.23 (dd, = 3.6, 14.0 Hz, 1H), 2.91 (dd, 7 = 10.0, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 436.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(3-FLUOROPHEN YL)-2- METHYL XAZOLE-5-CARBOXAMIDE (254)
[1244] To a solution of ethyl 3-(3-fluorophenyl)-3-oxopropanoate (3.00 g, 14.27 mmol) in EtOH (40 mL) was added CH 3 COONH 4 (2.20 g, 28.54 mmol), then the mixture was stirred at 78 °C for 9 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EA (100 mL) and washed with sat. NaHC0 3 solution (30 mL x 3) and saturated aqueous NaCl (30 mL x 3). The organic layer were dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified flash column chromatography (PE: EA=20/1 to 10: 1). Compound 254A (2.40 g, 80.39% yield) was obtained as yellow oil. 1H NMR (400 MHz, CDC1 3 ): δ 7.38 - 7.35 (m, 1H), 7.35 - 7.32 (m, 1H), 7.22(d, = 9.6 Hz, 1H), 7.13 - 7.09 (m, 1H), 4.93 (s, 1H), 4.19 - 4.13 (m, 2H), 1.29 - 1.26 (m, 3H). MS (ESI) m/z (M+l) + 210.1.
[1245] To a mixture of compound 254A (2.00 g, 9.56 mmol) in DCE (25 mL) was added PhI(OAc)2 (4.00 g, 12.43 mmol) at 0 °C under N 2 in five portions, the mixture was stirred at 0 °C for 3h and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 0.5h. The reaction mixture was quenched with saturated aqueous NaHC0 3 (150 mL) at 0 °C, warmed to 25 °C slowly, and extracted with DCM (70 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4i filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20: 1 to 10: 1). Compound 254B (1.24 g, 48.53% yield) was obtained as white solid. 1H NMR (400 MHz, CDC1 3 ): δ 1.31 - 7.34 (m, 1H), 7.22 - 7.00 (m, 1H), 7.17 - 7.13 (m, 1H), 7.12 - 7.09 (m, 1H), 4.23 - 4.18 (m, 2H), 1.94 (s, 3H), 1.29 - 1.26 (m, 3H). MS (ESI) m/z (M+l) + 268.1.
[1246] A mixture of compound 254B (1.20 g, 4.49 mmol) in DCE (20 mL) and CH 3 COOH (10 mL) was stirred at 90 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove the solvent and to give the residue. The residue was purified by flash column chromatography (PE:EA = 20/1 to 10/1). Compound 544 (360.0 mg, 32.07% yield) was obtained as a white solid. 1H NMR (400 MHz, CDC1 3 ) δ 7.87 - 7.86 (m, 1H), 7.83 - 7.80 (m, 1H), 7.41 - 7.39 (m, 1H), 7.13 - 7.09 (m, 1H), 4.43 - 4.37 (m, 2H), 2.58 (s, 3H), 1.40 - 1.37 (m, 3H). MS (ESI) m/z (M+l) + 250.1.
[1247] To a mixture of ethyl compound 544 (350.0 mg, 1.40 mmol)in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH.H 2 0 (235.0 mg, 5.60 mmol) in one portion and the mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (20 mL), adjusted to pH ~ 3 with IN HC1, and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 254D (300.0 mg, 96.88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6 ) δ 1.92 - 7.87 (m, 1H), 7.52 - 7.46 (m, 1H), 7.29 - 7.24 (m, 1H), 2.51 (s, 3H).
[1248] Compound 254 (90.3 mg, 58.91% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 254D. Compound 254: 1H NMR (400 MHz, CDC1 3 ) S 7.98 - 7.95 (m, 1H), 7.94 - 7.91 (m, 1H), 7.39 - 7.35 (m, 1H), 7.33 - 7.30 (m, 1H), 7.29 - 7.26 (m, 2H), 7.15 - 7.13 (m, 2H), 7.09 - 7.04 (m, 1H), 6.79 (d, = 7.2 Hz, 1H), 6.76(s, 1H), 5.74 - 5.69 (m, 1H), 5.53 (s, 1H), 3.47 - 3.42 (m, 1H), 3.27 - 3.22 (m, 1H), 2.54 (s, 3H). MS (ESI) m/z (M+l) + 396.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-2- (TRIFLUORO -5-CARBOXAMIDE (2
[1249] To a mixture of ethyl (E)-3-amino-3-phenylacrylate (1.5 g, 7.84 mmol) in DCE (400 mL) was added phenyliodine bis(2,2,2-trifluoroacetate) (4.38 g, 10.19 mmol) in three portions at 45 °C under N 2 , the mixture was stirred at 45 °C for 2 hours. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 100: 1 to 10: 1) to afford compound 255A (650 mg, 28.43% yield) as a white solid. 1H NMR (400 MHz, CDC1 3 ): δ 8.11 - 8.05 (m, 2H), 7.50 - 7.45 (m, 3H), 4.44 (q, = 7.2 Hz, 2H), 1.40 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 285.9.
[1250] Compound 255B (200 mg, 51.2% purity, yellow oil) was prepared as in Example 85 from compound 255A. Compound 255B: MS (ESI) m/z (M+H) + 258.0.
[1251] Compound 255 (7.0 mg, 9.89% yield, off-white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 255B. Compound 255: 1H NMR (400 MHz, CDC1 3 ): δ 8.17 - 8.08 (m, 2H), 7.48 - 7.41 (m, 3H), 7.34 - 7.28 (m, 3H), 7.17 - 7.10 (m, 2H), 6.88 - 6.80 (m, 1H), 6.77 (br s, 1H), 5.78 - 5.71 (m, 1H), 5.55 (br s, 1H), 3.50 - 3.42 (m, 1H), 3.27 - 3.20 (m, 1H). MS (ESI) m/z (M+H) + 432.2. EXAMPLE 142
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(BENZO[rf]OXA ZOL-2-YL)-5-
[1252] A mixture of 2-hydrazineylbenzo[d]oxazole (320 mg, 2.15 mmol) and methyl (E)-2-(methoxyimino)-4-oxopentanoate (447 mg, 2.58 mmol) in dioxane (10 mL) was heated to 110 °C for 12 hrs. The mixture was concentrated, the residue was purified by preparatory- TLC (Petroleum ether: Ethyl acetate = 2: 1) to give compound 256A (0.12 g, yield: 16.6%) as yellow oil.
[1253] A mixture of compound 256A (120 mg, 466 umol) and LiOH.H 2 0 (17.6 mg, 420 umol) in THF (5 mL), H 2 0 (1 mL) was stirred at 25 °C for 20 min. The organic solvent was removed under reduced pressure, the water layer was extracted with ethyl acetate (2 mL), and then adjusted to pH ~ 6 with IN HC1 to give a precipitate, the solid was filtered and dried to give compound 256B (90 mg, yield: 79.3%) as white solid. 1 H NMR (400MHz, OMSO-d 6 ) δ 8.02 - 7.87 (m, 2H), 7.61 (dq, 7 = 1.4, 7.7 Hz, 2H), 7.11 (s, 1H), 2.43 (s, 3H).
[1254] Compound 256 (22.2 mg, yield: 44.6%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 256B. Compound 256: 1H NMR (400MHz, OMSO-d 6 ) δ 8.97 (s, 1H), 7.82 (br s, 1H), 7.64 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.30 - 7.21 (m, 2H), 6.94 (q, 7 = 7.9 Hz, 4H), 6.90 - 6.83 (m, 1H), 6.64 (s, 1H), 5.37 (dd, 7 = 4.1, 8.0 Hz, 1H), 3.39 (dd, 7 = 4.1, 14.2 Hz, 1H), 2.83 (dd, 7 = 8.4, 14.1 Hz, 1H), 2.24 (s, 3H). MS (ESI) m/z (M+H) + 418.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-5-PHEN YL-lH-
PYRAZ LE-4-CARBOXAMIDE (257)
[1255] To a solution of ethyl 3-oxobutanoate (20.0 g, 153.7 mmol) in THF (150 mL) was added DMF-DMA (19.2 g, 161.4 mmol). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. To a solution of the crude product dissolving in EtOH (150 mL) was added drop-wise NH 2 NH 2 .H 2 O (9.2 g, 184.4 mmol). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with brine 80 mL and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over MgS0 4 , filtered and concentrated under reduced pressure to afford compound 257A (21.0 g, yield 87.8%) as light green solid. 1 H NMR (CDC1 3, 400 MHz): δ 7.96 (s, 1H), 4.29 (q, = 7.2 Hz, 2H), 2.55 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 154.8.
[1256] To a solution of compound 257A (12.0 g, 77.8 mmol) in AcOH (120 mL) was added NaOAc (19.2 g, 233.5 mmol) and Br 2 (12 mL, 233.5 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 hours under N 2 . The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water 150 mL and extracted with ethyl acetate (200 mL x 2). The combined organic extracts were washed with saturated aqueous NaHC0 3 (80 mL x 2), dried over Na 2 S0 4 , filtered and concentrated to dryness under reduced pressure to dryness. The crude product was purified by flash column (gradient eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to afford compound 257B (8.2 g, yield 43.3%) as light yellow solid. 1H NMR (CDC1 3, 400 MHz): δ 10.89 (br s, 1H), 4.34 (q, = 7.2 Hz, 2H), 2.64 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 235.1
[1257] To a solution of compound 257B (5.0 g, 21.5 mmol) in THF (50 mL) was added NaH (944 mg, 23.6 mmol, 60% purity) at 0 °C and the reaction stirred for 30 minutes. SEM-C1 (3.9 g, 23.6 mmol) was added, and the reaction stirred at 25°C for 16 hours. The reaction was quenched with water (30 ml) and extracted with ethyl acetate (50 mL x 3). The organic extract was dried over MgS0 4 and concentrated in vacuo. Compound 257C (6.2 g, yield 78.1%, colorless oil): 1H NMR (CDC1 3, 400 MHz): δ 5.52 - 5.39 (m, 2H), 4.35 (q, = 7.2 Hz, 2H), 3.62 (td, / = 8.4, 17.2 Hz, 2H), 2.66 - 2.44 (m, 3H), 1.40 (dt, = 2.4, 7.2 Hz, 3H), 0.92 (td, = 8.4, 13.6 Hz, 2H), 0.08 - -0.05 (m, 9H). MS (ESI) m/z (M+H) + 364.9.
[1258] To a solution consisting of compound 257C (2.0 g, 5.5 mmol), phenylboronic acid (871.8 mg, 7.2 mmol), Na 2 C0 3 (1.8 g, 16.5 mmol) in 1,4-dioxane (20 mL) and H 2 0 (4 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (89.9 mg, 110.0 umol) at 25 °C and the reaction mixture stirred for 10 minutes. The reaction mixture was heated to 80 °C for 16 hours under N 2 . The mixture was concentrated under reduced pressure at 40 °C. The reaction mixture was quenched with brine (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over Na 2 S0 4 , filtered, and concentrated to dryness under reduced pressure. The crude product was purified by flash column (Petroleum ether: Ethyl acetate=100: 0-1 : 1) to give compound 257D (1.6 g, yield 79.4%) as light yellow solid. 1H NMR (CDC1 3, 400 MHz): δ 7.62 - 7.53 (m, 1H), 7.48 - 7.34 (m, 4H), 5.48 (s, 1H), 5.18 (s, 1H), 4.25 - 4.06 (m, 2H), 3.62 (td, = 8.0, 15.6 Hz, 2H), 2.67 - 2.50 (m, 3H), 1.23 - 1.03 (m, 3H), 0.96 - 0.83 (m, 2H), 0.03 -0.07 (m, 9H). MS (ESI) m/z (M+H) + 361.1.
[1259] KOH (2.5 g, 44.4 mmol) was added to a solution consisting of compound 257D (1.6 g, 4.4 mmol), THF (10 mL), H 2 0 (5 mL) and MeOH (10 mL). The resultant mixture was stirred at 25 °C for 16 hours. The resultant mixture was stirred at 75 °C for 48 hours. The reaction solution was concentrated under reduced pressure. 2N HC1 (30 mL) was added, and extracted with EtOAc (30 mL x 3). Combined EtOAc extractions were washed with brine (20 mL), dried over MgS0 4 , filtered and concentrated. The crude product was purified by flash column (Petroleum ether: Ethyl acetate=100: 0-3:2) to give compound 257E (1.0 g, yield 62.8%) as a colorless oil. 1H NMR (CDC1 3, 400 MHz): δ Ί .63 - 7.58 (m, 1H), 7.48 - 7.36 (m, 4H), 5.49 (s, 1H), 5.17 (s, 1H), 3.62 (td, J = 8.4, 18.4 Hz, 2H), 2.66 (s, 1.5H), 2.52 (s, 1.5H), 0.95 - 0.83 (m, 2H), 0.00 - -0.06 (m, 9H). MS (ESI) m/z (M+H) + 333.2.
[1260] Intermediate compound 257G (150 mg, crude, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 257E. Compound 257G: 1H NMR (DMSO-d 6 , 400 MHz): δ 8.68 - 8.61 (m, 0.1H), 8.26 - 7.88 (m, 1H), 7.59 - 7.09 (m, 10H), 5.52 - 5.41 (m, 1H), 5.24 (s, 1H), 3.69 - 3.52 (m, 1H), 2.42 - 2.28 (m, 1H), 2.27 - 2.19 (m, 2H), 0.96 - 0.79 (m, 2H), 0.08 - 0.02 (m, 4.4H), 0.02 - -0.06 (m, 4.3H). MS (ESI) m/z (M+H)+ 507.2.
[1261] To a solution consisting of compound 257G (100 mg, 0.20 mmol), in EA (20 mL) was added HCl/EtOAc (4M, 2 mL) at 25 °C. The mixture was stirred at 25 °C under N 2 for 16 hours. The reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by preparatory-HPLC (0.05% ammonia hydroxide) to give 257 (15 mg, yield 19.3%) as a white solid. Compound 257: 1H NMR (DMSO-d 6 , 400 MHz): δ 12.67 (br.s., 1H), 7.85 - 7.72 (m, 2H), 7.64 - 7.57 (m, 1H), 7.57 - 7.49 (m, 2H), 7.38 - 7.17 (m, 8H), 5.45 - 5.32 (m, 1H), 3.21 (dd, J = 4.0, 14.0 Hz, 1H), 2.85 (dd, J = 9.2, 14.0 Hz, 1H), 2.19 (s, 3H). MS (ESI) m/z (M+H) + 377.1.
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-FLUORO-l-PHE NYL-lH- -5-CARBOXAMIDE (258)
[1262] To a mixture of ethyl lH-pyrazole-5-carboxylate (5.00 g, 35.68 mmol), phenylboronic acid (6.53 g, 53.52 mmol), Py (3.10 g, 39.25 mmol, 3.17 mL) in DCM (70 mL) was added 4A° MS (20.0 g) and Cu(OAc) 2 (7.13 g, 39.25 mmol), the mixture was stirred at 30°C for 20h. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (PE: EA=1:0 to 0: 1) to give the compound 258A (1.10 g, yield: 14.3%) was obtained as a rofous oil. Compound 258A: 1H NMR (400MHz, DMSO-d 6 ) δ 7.81 (d, = 2.0 Hz, 1H), 7.53 - 7.40 (m, 5H), 7.09 (d, = 2.0 Hz, 1H), 4.17 (q, = 7.0 Hz, 2H), 1.15 (t, 7 = 7.0 Hz, 3H).
[1263] To a solution of compound 258A (1.00 g, 4.62 mmol) in MeCN (60 mL) was added CH 3 COOH (20 mL), and then Select F (4.91 g, 13.86 mmol) was added in the mixture. The mixture was stirred at 105°C for 21h under N 2 atmosphere. The mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was purified by flash silica gel chromatography (PE:EA = 1:0 to 10: 1) to give the compound 258C (194 mg, yield: 17.9%)was obtained as a colorless oil. 1H NMR (400MHz, CHLOROFORM-d) δ 7.71 - 7.56 (m, 1H), 7.51 - 7.36 (m, 5H), 4.29 (q, = 7.2 Hz, 2H), 1.27 (t, = 7.1 Hz, 3H).
[1264] To a solution of compound 258C (190 mg, 811.17 umol) in THF (15 mL) was added LiOH.H 2 0 (170 mg, 4.06 mmol) in H 2 0 (5 mL). The mixture was stirred at 25°C for 20.3h. The reaction mixture was diluted with MTBE (15 mL) and extracted with H 2 0 (15 mL x 3). The combined aqueous layers were ajusted pH ~ 3 by addtion IN HC1, and then the aqueous layer was extracted with EA (20 mL x 3). The combine organic layer was washed with brine (15 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 258D (160 mg, yield: 95.7%) was obtained as a white solid. 1H NMR (400MHz, CHLOROFORM-d) δ 7.76 - 7.60 (m, 1H), 7.55 - 7.33 (m, 5H).
[1265] Compound 258 (25 mg, yield: 44.3%, light yellow solid) was prepared as in Example 5 from the corresponding starting materials, compounds 258D and 12G. Compound 258: 1H NMR (400MHz, DMSO-d 6 ) δ 9.33 (d, = 7.7 Hz, 1H), 8.18 (s, 1H), 8.00 - 7.85 (m, 2H), 7.39 - 7.36 (m, 2H), 7.33 - 7.27 (m, 5H), 7.26 - 7.19 (m, 3H), 5.42 - 5.28 (m, 1H), 3.22 (br dd, = 3.3, 14.1 Hz, 1H), 2.82 (br dd, = 10.5, 13.8 Hz, 1H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-5-PHEN YL-2H- l,2,3-TRIAZOLE-4-CARBOXAMIDE (259)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-5-PHEN YL-lH- l,2,3-TRIAZOLE-4-CARBOXAMIDE (260)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-METHYL-4-PHEN YL-lH- -TRIAZOLE-5-CARBOXAMIDE (261)
[1266] To a solution of benzaldehyde (5 g, 47.12 mmol, 4.76 mL) in DMF (100 mL) was added N,N-diethylethanamine;hydrochloride (19.46 g, 141.36 mmol) NaN 3 (9.19 g, 141.36 mmol) and ethyl 2-cyanoacetate (5.33 g, 47.12 mmol, 5.03 mL). The reaction mixture was heated at 70 C for 18h under nitrogen protection. After completion of the reaction, the mixture was poured into water (500 mL) and extracted with CHC1 3 : z ' -PrOH = 3: 1 (50 mL x 4). The organic layers were dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by chromatography (PE:EA = 5: 1). Compound 259A (4 g, yield: 38.3%) was obtained as a yellow oil. 1 H NMR (400MHz, CDC1 3 ) δ 7.81 (dd, = 2.9, 6.4 Hz, 2H), 7.49 - 7.38 (m, 3H), 4.38 (q, = 7.2 Hz, 2H), 1.43 - 1.26 (m, 3H). MS (ESI) m/z (M+H) + 217.9.
[1267] Mel (6.53 g, 46.03 mmol, 2.86 mL) was added to a solution of compound
259A (4 g, 18.41 mmol) and K 2 C0 3 (5.09 g, 36.82 mmol) in CH 3 CN (50 mL) and DMF (50 mL).
The reaction mixture was stirred at 25 °C for 16h. The mixture was filtered, the filtrate was added with H 2 0 (200 mL), extracted with EA (50 mL x 3). The organic phase was dried over Na 2 S0 4 , filtered and concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = PE ~ 10/1 to 2/1).
[1268] Compound 259B (1.8 g, yield: 41.9%, white solid): 1H NMR (400MHz, CDC1 3 ) δ 7.83 - 7.77 (m, 2H), 7.45 - 7.36 (m, 3H), 4.45 - 4.35 (m, 2H), 4.27 (s, 3H), 1.40 - 1.31 (m, 3H). Compound 259C (1.2 g, yield: 27.9%, white solid): 1H NMR (400MHz, CDCI 3 ) δ 7.75
- 7.67 (m, 2H), 7.48 - 7.38 (m, 3H), 4.37 - 4.30 (m, 5H), 1.27 (t, = 7.1 Hz, 3H). Compound 259D (700 mg, yield: 16.3%, white solid): 1H NMR (400MHz, CDCI 3 ) δ 7.55 - 7.48 (m, 3H), 7.40 - 7.35 (m, 2H), 4.36 - 4.25 (m, 2H), 3.95 (s, 3H), 1.31 - 1.23 (m, 3H).
[1269] To a solution of compound 259B (400 mg, 1.73 mmol) in MeOH (15 mL) and H 2 0 (15 mL) was added NaOH (345.95 mg, 8.65 mmol). The mixture was stirred at 25 °C for lh. The reaction mixture was acidified by IN HC1 to pH ~ 2-3 at 0 °C and white precipitate was formed. The solid was collected by filtration, the filtrate was extracted with EtOAc (20 mL x 2), the organic phase was dried over Na 2 S0 4 , filtered and concentrated to give a residue, the residue was combined with the solid to give compound 259E (337 mg, yield: 95.9%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.82 - 7.69 (m, 2H), 7.46 - 7.34 (m, 3H), 4.22 (s, 3H). MS (ESI) m/z (M+H) + 204.0.
[1270] Compound 259 (78 mg, yield: 77.2%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 259E. Compound 259: 1H NMR (400MHz, DMSO-d 6 ) δ 8.81 (br d, J = 7.5 Hz, 1H), 8.13 (br s, 1H), 7.87 (br s, 1H), 7.70 (br s, 2H), 7.38 (br s, 3H), 7.29 (br d, J = 4.0 Hz, 4H), 7.23 (br d, J = 4.3 Hz, 1H), 5.47 (br s, 1H), 4.25 (s, 3H), 3.21 (br d, J = 10.8 Hz, 1H), 3.04 - 2.91 (m, 1H). MS (ESI) m/z (M+H) + 378.1.
[1271] Following the procedure used for compound 259E, intermediate compounds 261A and 260A were prepared from compound 259C and 259D, respectively. Compound 261A (240 mg, yield: 91. 6%, white solid): 1H NMR (400MHz, CDCI 3 ) δ 7.69 - 7.63 (m, 2H), 7.38 - 7.29 (m, 3H), 4.26 (s, 3H). MS (ESI) m/z (M+H) + 203.9. Compound 260A (260 mg, yield: 98.5%, white solid): 1H NMR (400MHz, DMSO-d 6 ) δ 12.81 (br s, 1H), 7.60 - 7.42 (m, 5H), 4.02
- 3.74 (m, 3H). MS (ESI) m/z (M+H) + 204.0.
[1272] Following the procedure used for compound 259, compounds 261 and 260 were prepared from the corresponding intermediate carboxylic acid, compounds 261A and 260A, respectively. Compound 260 (75 mg, yield: 72.4%, white solid): 1H NMR (400MHz, DMSO- 6 ) δ 8.63 (d, 7 = 7.5 Hz, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.51 - 7.41 (m, 5H), 7.32 - 7.20 (m, 5H), 5.45 - 5.33 (m, 1H), 3.91 (s, 3H), 3.23 - 3.14 (m, 1H), 3.11 - 2.97 (m, 1H). MS (ESI) m/z (M+H) + 378.1.
[1273] Compound 261 (52 mg, yield: 59.5%, yellow solid): 1H NMR (400MHz, DMSO-i¾) δ 9.54 (dd, 7 = 7.9 Hz, 1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.60 (dd, 7 = 3.0, 6.5 Hz, 2H), 7.36 - 7.25 (m, 8H), 5.58 (dd, 7 = 3.3, 7.7, 10.9 Hz, 1H), 3.83 (s, 3H), 3.29 (dd, 7=3.3 Hz, 1H), 2.77 (dd, 7 = 10.9, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 378.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-PHENYL-lH-l,2 ,3- TRIAZOLE-4-CARBOXAMIDE (262)
[1274] Compound 262 (8.1 mg, 20.36% yield, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 204A. Compound 262: 1H NMR (400 MHz, OMSO-d 6 ) δ 8.38 - 7.89 (m, 2H), 7.87 - 7.69 (m, 2H), 7.63 - 7.34 (m, 4H), 7.31 - 7.06 (m, 6H), 5.55 - 5.42 (m, 1H), 3.32 - 3.24 (m, 1H), 3.12 - 3.06 (m, 1H). MS (ESI) m/z (M+H) + 364.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-lH-l,2 ,3- -5-CARBOXAMIDE (263)
[1275] To a solution of azidobenzene (0.5M, 11.8 mL) in toluene (20 mL) was added ethyl 3-(trimethylsilyl)propiolate (1 g, 5.87 mmol). The mixture was stirred at 100 °C for 12h. The solvent was removed in vacuo to afford a mixture of compound 263A and 263B (1.7 g, crude) as yellow oil, which was used directly for the next step without purification. MS (ESI) m/z (M+H) + 290.1.
[1276] To a mixture of 263A and 263B (1.7 g, 5.87 mmol) in THF (20 mL) was added TBAF (1M, 8.8 mL). The mixture was stirred at 25 °C for 12h. The reaction was washed with Η 2 0 (40 mL), extracted with EtOAc (20 mL x 3). The organics were collected and concentrated. The residue was purified by column (PE: EA = 5: 1) to give compound 263C (400 mg, yield: 31.37%) as yellow oil; 1H NMR (CDCI 3, 400 MHz): δ 8.26 (s, 1H), 7.56 - 7.47 (m, 5H), 4.29 (q, = 7.2 Hz, 2H), 1.28 (t, = 7.2 Hz, 3H).
[1277] To a solution of compound 263C (400 mg, 1.84 mmol) in H 2 0 (5 mL) and THF (5 mL) was added LiOH.H 2 0 (386 mg, 9.20 mmol). The mixture was stirred at 25 °C for 12h. The reaction was acidified with IN HC1 to pH ~ 3. The mixture was extracted with EtOAc (20 mL x 2). The organics were collected, washed with brine (20 mL), dried with Na 2 S0 4 , filtered and concentrated to afford compound 263E (340 mg, yield: 97.68%) as yellow solid. MS (ESI) m/z (M+l) + 189.9.
[1278] Compound 263 (6.5 mg, yield: 6.10%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 263E. Compound 263: MS (ESI) m/z (M+l) + 364.1. 1H NMR (DMSO-d 6, 400 MHz): δ 9.39 (d, = 8.0 Hz, 1H), 8.16 (s, 1H), 8.12 (br. s, 1H), 7.87 (br. s, 1H), 7.53 - 7.43 (m, 3H), 7.34 - 7.20 (m, 7H), 5.35 - 5.26 (m, 1H), 3.23 - 3.14 (m, 1H), 2.85 - 2.75 (m, 1H).
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-4-(PYR IDIN-2- -5-CARBOXAMIDE (266)
[1279] To a mixture of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (5 g, 25.88 mmol) in
EtOH (50 mL) was added NH 4 OAc (3.99 g, 51.76 mmol) and purged with N 2 for 3 times, and then the mixture was stirred at 80 °C for 15 hours under N 2 atmosphere. After removal of the solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100 mL x 2). This combined organic phase was washed with saturated aqueous NaHC0 3 (50 mL x 2) and brine (50 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 0: 1 to 10: 1) to give compound 266A (3.80 g, 69.23% yield) as a yellow solid. 1H NMR (CDC1 3 , 400 MHz): δ 8.62 (d, = 4.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.37 - 7.29 (m, 1H), 5.33 (s, 1H), 4.20 (q, = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 193.1.
[1280] To a mixture of iodosobenzene diacetate (2 g, 10.41 mmol) in DCE (21 mL) was added compound 266A (4.36 g, 13.53 mmol) in six portions at 0 °C under N 2 , the mixture was stirred at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was stirred at 25 °C for lh. The reaction mixture was quenched with saturated aqueous NaHC0 3 (60 mL) and extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20: 1 to 1: 1) to afford compound 266B (1.30 g, 49.90% yield) as a yellow oil. 1H NMR (400 MHz, CDC1 3 ): δ 8.72 - 8.61 (m, 1H), 7.81 - 7.69 (m, 2H), 7.36 - 7.29 (m, 1H), 4.24 (q, = 7.2 Hz, 2H), 2.13 (s, 3H), 1.29 (t, J = 1.2 Hz, 3H).
[1281] A solution of compound 266B (1.30 g, 5.19 mmol) in DCE (20 mL) and AcOH (10 mL) was stirred at 90 °C for 3 hours. The reaction mixture was cooled to room- temperature and the mixture concentrated under reduced pressure to give a residue which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 10: 1 to 0: 1) to afford compound 266C (300 mg, 23.06% yield) as a yellow solid. 1H NMR (400 MHz, CDC1 3 ): δ 8.78 - 8.73 (m, 1H), 8.13 - 8.08 (m, 1H), 7.80 - 7.74 (m, 1H), 7.33 - 7.28 (m, 1H), 4.40 - 4.34 (m, 2H), 2.60 (s, 3H), 1.37 - 1.33 (m, 3H). MS (ESI) m/z (M+ H) + 233.1.
[1282] To a mixture of compound 266C (300 mg, 1.29 mmol) in MeOH (10 mL) and H 2 0 (5 mL) was added LiOH » H 2 0 (162.4 mg, 3.87 mmol) in one portion and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was adjusted to pH ~ 3 with 1 N HC1, diluted with water (20 mL) and then extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to afford intermediate compound 266D (170 mg, 64.54% yield) as a yellow solid. 1H NMR (400 MHz, CDC1 3 : δ 8.59 (d, = 4.8 Hz, 1H), 8.31 (d, = 8.0 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.54 - 7.49 (m, 1H), 2.61 (s, 3H). MS (ESI) m/z (M+ H) + 204.8.
[1283] Compound 266 (15.3 mg, 14.91% yield, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 266D. Compound 266: 1H NMR (CDC1 3, 400 MHz): δ 12.79 (d, = 6.0 Hz, 1H), 8.17 (d, = 8.0 Hz, 1H), 8.00 (d, = 4.4 Hz, 1H), 7.82 (t, = 7.6 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.14 - 7.04 (m, 5H), 6.76 (br s, 1H), 5.89 (q, = 6.0 Hz, 1H), 5.56 (br s, 1H), 3.47 - 3.30 (m, 2H), 2.59 - 2.54 (m, 3H). MS (ESI) m/z (M+ H) + 379.1.
[1284] To a mixture of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (5 g, 25.88 mmol) in EtOH (50 mL) was added NH 4 OAc (3.99 g, 51.76 mmol) and purged with N 2 for 3 times, and then the mixture was stirred at 80 °C for 15 hours under N 2 atmosphere. After removal of the solvent, the residue was dissolved in water (50 mL), extracted with EtOAc (100 mL x 2). This combined organic phase was washed with saturated aqueous NaHC0 3 (50 mL x 2) and brine (50 mL), dried over Na 2 S0 4 , filtered and the solvent was removed in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 0: 1 to 10: 1) to give compound 266A (3.80 g, 69.23% yield) as a yellow solid. 1H NMR (CDC1 3, 400 MHz): δ 8.62 (d, = 4.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.37 - 7.29 (m, 1H), 5.33 (s, 1H), 4.20 (q, = 7.2 Hz, 2H), 1.31 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 193.1. [1285] To a mixture of iodosobenzene diacetate (2 g, 10.41 mmol) in DCE (21 mL) was added compound 266A (4.36 g, 13.53 mmol) in six portions at 0 °C under N 2 , the mixture was stirred at 0 °C for 3 hours and then warmed to 25 °C slowly. The mixture was stirred at 25 °C for lh. The reaction mixture was quenched with saturated aqueous NaHC0 3 (60 mL) and extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4i filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 20: 1 to 1: 1) to afford compound 266B (1.30 g, 49.90% yield) as a yellow oil. 1H NMR (400 MHz, CDC1 3 ): δ 8.72 - 8.61 (m, 1H), 7.81 - 7.69 (m, 2H), 7.36 - 7.29 (m, 1H), 4.24 (q, = 7.2 Hz, 2H), 2.13 (s, 3H), 1.29 (t, J = 1.2 Hz, 3H).
[1288] Compound 267 (15.3 mg, 14.91% yield, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 267D. Compound 267: 1H NMR (CDC1 3, 400 MHz): δ 12.79 (d, J = 6.0 Hz, 1H), 8.17 (d, / = 8.0 Hz, 1H), 8.00 (d, = 4.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.14 - 7.04 (m, 5H), 6.76 (br s, 1H), 5.89 (q, J = 6.0 Hz, 1H), 5.56 (br s, 1H), 3.47 - 3.30 (m, 2H), 2.59 - 2.54 (m, 3H). MS (ESI) m/z (M+ H) + 379.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-PHENYLTHIOPHE NE-3-
270A 270B
[1289] Ethyl 2-bromothiophene-3-carboxylate (2 g, 8.51 mmol), phenylboronic acid (1.35 g, 11.1 mmol), K 2 C0 3 (2.35 g, 17 mmol) and Pd(dppf)Cl 2 (622 mg, 851 umol) in dioxane (30 mL), H 2 0 (3 mL) was de-gassed and then heated to 100 °C for 6 hours under N 2 . The mixture was concentrated, the residue was purified by silica gel chromatography (Petroleum ether to Petroleum ether: Ethyl acetate = 25: 1) to give compound 270A (1.9 g, yield: 96.11%), as yellow oil. 1H NMR (400MHz, CDC1 3 - ) δ 7.53 (d, 7 = 5.4 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.44 - 7.38 (m, 3H), 7.25 (d, 7 = 5.4 Hz, 1H), 4.20 (q, 7 = 7.1 Hz, 2H), 1.19 (t, 7 = 7.1 Hz, 3H).
[1290] A mixture of 270A (150 mg, 646 umol) and NaOH (51.7 mg, 1.29 mmol) in THF (5 mL), EtOH (3 mL), H 2 0 (2 mL) was stirred at 15 °C for 12 hrs. TLC (petroleum ether/ethyl acetate = 10: 1) showed unreacted starting material and then the mixture was heated to 60 °C for another 3 hrs. The organic solvent was removed under reduced pressure, the water layer was adjusted to pH ~ 6 with IN HC1 to give a precipitate, the solid was filtered and dried to give 270B (100 mg, yield: 75.8%), as white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 12.63 (br s, 1H), 7.55 (d, 7 = 5.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.41 - 7.31 (m, 4H).
[1291] Compound 270 (16.00 mg, yield: 20.1%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 270B. Compound 270: 1H NMR (400MHz, DMSO-d 6 ) δ 8.73 (d, 7 = 7.5 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.58 (d, 7 = 5.3 Hz, 1H), 7.36 - 7.20 (m, 10H), 7.09 (d, 7 = 5.3 Hz, 1H), 5.29 (ddd, 7=3.6, 7.3, 10.4 Hz, 1H), 3.17 (dd, 7 = 3.6, 13.8 Hz, 1H), 2.80 (dd, 7 = 10.4, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 379.1. EXAMPLE 151
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-CHLORO-2-
PHENYLTHIOPHENE-3-CARB
[1292] To a solution of 270A (300 mg, 1.29 mmol) in DMF (5 mL) was added NCS (345 mg, 2.58 mmol) at 80 °C, and the mixture was stirred at 80 °C for 1.5 hrs. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2), the combined organic layer was washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether to Petroleum ether: Ethyl acetate = 20: 1) to give 271A (0.38 g, yield: 82.8%), as white solid (combined with page 158). 1H NMR (400MHz, CDC1 3 ) δ 7.50 - 7.44 (m, 2H), 7.43 - 7.37 (m, 3H), 7.34 (s, 1H), 4.19 (q, 7=7.1 Hz, 2H), 1.18 (t, 7=7.2 Hz, 3H).
[1293] A mixture of 271A (380 mg, 1.42 mmol) and NaOH (114 mg, 2.84 mmol) in THF (5 mL), EtOH (3 mL), H20 (2 mL) was stirred at 15°C for 12 hrs. The organic solvent was removed under vacuum, the water layer was adjusted to pH ~ 3 with IN HC1 and extracted with ethyl acetated (10 mL x 2), the organic layer was washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated to give 271B (330 mg, yield: 97.4%), as white solid. 1H NMR (400MHz, CDCI 3 - ) δ 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 3H), 7.28 (s, 1H).
[1294] Compound 271 (28.2 mg, yield: 30.4%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 271B. Compound 271: 1H NMR (400MHz, CDCI 3 ) δ 7.40 (br s, 5H), 7.19 (br s, 4H), 6.76 (br s, 2H), 6.66 (br s, 1H), 5.93 (br s, 1H), 5.44 (br d, 7 = 19.3 Hz, 2H), 3.18 (br d, 7 = 16.7 Hz, 1H), 2.94 - 2.81 (m, 1H). MS (ESI) m/z (M+H) + 413.0, 415.0. EXAMPLE 152
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CYANO-l-PHENY L-lH-
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-CYANO-l-PHENY L-lH- -3-CARBOXAMIDE (273)
[1295] To a solution of ethyl propiolate (4.30 g, 43.83 mmol) and 2- aminoacetonitrile hydrochloride (8.11 g, 87.67 mmol, HC1) in CHC1 3 (250 mL) and H 2 0 (10 mL) was added NaN0 2 (9.07 g, 131.50 mmol). The mixture was stirred for 14 h at 25 °C. Then, the reaction mixture was diluted with DCM (50 mL) and filtered. The filtrate was washed with H 2 0 (20 mL) and brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethylacetate/Petroleum ethergradient) to give 272A (1.40 g yield: 19.34%) as a white solid. 1 H NMR (400MHz, CHLOROFORM-d) δ 12.19 (br s, 1H), 7.21 (s, 1H), 4.45 (q, J = 1.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
[1296] To a mixture of 272A (1.40 g, 8.48 mmol), phenylboronic acid (1.55 g, 12.72 mmol), pyridine (737.60 mg, 9.32 mmol) in DCM (50 mL) was added 4A° MS (20 g) (activated 4A° MS) and Cu(OAc)2 (1.69 g, 9.32 mmol). After that, the mixture was stirred at 40 °C for 72 hours under 0 2 atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ethergradient) and then by prep-HPLC (HCl condition) to give 272B (170 mg, yield: 8.23%) and 272C (264 mg, yield: 12.78%) as white solid.
[1297] Compound 272B: 1H NMR (400MHz, CHLOROFORM-d) δ 1.13 (dd, 7 = 1.3, 8.3 Hz, 2H), 7.64 -7.46 (m, 4H), 4.46 (q, = 7.2 Hz, 2H), 1.42 (t, = 7.0 Hz, 3H). MS (ESI) m/z (M+H) + 241.9.
[1298] Compound 272C: 1H NMR (400MHz, CHLOROFORM-d) δ 7.55 - 7.47 (m, 3H), 7.45 - 7.39 (m, 2H), 7.37 (s, 1H), 4.27 (q, = 7.0 Hz, 2H), 1.25 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 241.9.
[1299] To a solution of 272B (170 mg, 704.69 umol) in THF (5 mL) and MeOH (5 mL) was added a solution of LiOH.H 2 0 (148 mg, 3.52 mmol) in H 2 0 (5 mL) at 0 °C. After addition, the reaction mixture was stirred for 3h at 25 °C, and then diluted with H 2 0 (10 mL) and extracted with MTBE (30 mL). The aqueous phase was neutralized by IN HCl to the pH - 4, and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. Compound 272D (98 mg, yield: 64.58%, white solid): 1H NMR (400MHz, CHLOROFORM-d) δ 7.76-7.74 (m, 2H), 7.61 - 7.52 (m, 4H), 2.83 (br s, 1H).
[1300] Compound 272 (40 mg, yield: 53.56%, white solid) was prepared as in Example 6 from the corresponding starting materials, compounds 272D and 12G. Compound 272: 1H NMR (400MHz, DMSO-d 6 ) δ 8.88 (br d, J = 7.8 Hz, 1H), 8.12 (br s, 1H), 7.91 - 7.74 (m, 4H), 7.71 - 7.57 (m, 3H), 7.31 - 7.15 (m, 5H), 5.47 (br s, 1H), 3.25 - 2.96 (m, 2H). MS (ESI) m/z (M + H) + 388.1.
[1301] Following the procedure used for compound 274, compound 273 (19 mg, yield: 44.44%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 273A. Compound 273A (201 mg, yield: 55.94%, white solid): 1H NMR (400MHz, CHLOROFORM-d) δ 7.58 - 7.53 (m, 1H), 7.46 - 7.42 (m, 5H), 4.05 (br s, 1H). Compound 273: 1H NMR (400MHz, DMSO-d 6 ) δ 9.43 (br d, J = 7.8 Hz, 1H), 8.15 (br s, 1H), 7.90 (br s, 1H), 7.44 (br d, = 8.5 Hz, 4H), 7.36 - 7.25 (m, 7H), 5.42 - 5.22 (m, 1H), 3.21 (br d, = 11.5 Hz, 1H), 2.90 - 2.75 (m, 1H). MS (ESI) m/z (M +H) + 388.1. EXAMPLE 153
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-BROMO-5-CHLORO-l- METHYL- 1H-PYRAZ LE-4-CARBOXAMIDE (274)
[1302] To a solution of ethyl 3-bromo-l-methyl-lH-pyrazole-4-carboxylate (500 mg, 2.15 mmol) and NCS (574 mg, 4.30 mmol) was stirred. The mixture was stirred at 160 °C for 3h under N 2 . The reaction mixture was added by addition of CC (20 mL), and then diluted with NaHC0 3 (30 mL). The mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparatory- TLC (Si0 2 , PE:EA = 5: 1). Compound 274A (180 mg, yield: 31.30%) was obtained as a yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 4.34 (q, = 7.1 Hz, 2H), 3.85 (s, 3H), 1.46 - 1.24 (m, 3H). MS (ESI) m/z (M+H) + 266.9.
[1303] To a solution of compound 274A (300 mg, 1.12 mmol) in MeOH (10 mL) and H 2 0 (10 mL) was added NaOH (134 mg, 3.36 mmol). The mixture was stirred at 25 °C for 3h. The reaction mixture was concentrated and added 20 mL of water, the mixture was extracted with MTBE (10 mL x 2), the aqueous layer was acidified by IN HC1 to pH ~ 2-3 at 0 °C, and extracted with EtOAc (20 mL x 2), the organic phase was dried over Na 2 S0 4 , filtered and concentrated to give a residue. Compound 274B (250 mg, yield: 93.22%) was obtained as a white solid, which was used to the next step without purification. 1H NMR (400MHz, CDC1 3 ) δ 4.02 - 3.72 (m, 3H). MS (ESI) m/z (M+H) + 238.9.
[1304] Compound 274 (70 mg, yield: 66.75%, light yellow solid) was prepared as in Example 5 from the corresponding starting materials, compounds 274B and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 274: 1H NMR (400MHz, DMSO-d 6 ) δ 8.41 - 8.27 (m, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.29 (dd, = 4.0 Hz, 4H), 7.22 (dd, = 4.0 Hz, 1H), 5.36 (s, 1H), 3.78 (s, 3H), 3.20 (dd, = 10.4 Hz, 1H), 2.90 - 2.81 (m, 1H). MS (ESI) m/z (M+H) + 415.0. N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-2-(3-PHENY L-lH- PYR -l-YL)THIOPHENE-3-CARBOXAMIDE (320)
[1305] Compound 320 (33.7 mg, yield: 51.5%, white solid) was prepared as in Example 153 from the corresponding carboxylic acid, compound 320A, and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 320: 1H NMR (400MHz, DMSO- 6 ) δ 8.88 (d, 7 = 7.6 Hz, 1H), 8.12 (s, 1H), 7.97 (d, 7 = 2.6 Hz, 1H), 7.85 (br d, 7 = 7.1 Hz, 3H), 7.50 - 7.42 (m, 2H), 7.41 - 7.34 (m, 1H), 7.33 - 7.19 (m, 5H), 6.92 (d, 7 = 2.6 Hz, 1H), 6.84 (d, 7 = 1.0 Hz, 1H), 5.40 - 5.31 (m, 1H), 3.19 (dd, 7 = 3.6, 14.0 Hz, 1H), 2.80 (dd, 7 = 10.3, 13.8 Hz, 1H), 2.44 (s, 3H). MS (ESI) m/z (M+H) + 459.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-PHEN YL-lH- -5-CARBOXAMIDE (276)
[1306] To a mixture of phenylhydrazine (50 g, 462.3 mmol) and ethyl 2,4- dioxopentanoate (76.8 g, 485.5 mmol) in AcOH (600 mL) at 25 °C. The mixture was stirred at 100 °C for 16h. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was added H 2 0 (200 mL) and EA (200 mL), and then the mixture was alkalized with saturated aqueous NaHC0 3 till the aqueous phase pH - 7 - 8. The separated aqueous layer was extracted with EA (150 mL x 3), the combined organic layers were washed with saturated aqueous NaHC0 3 (200 mL), saturated aqueous NaCl (200 mL), dried over Na 2 S0 4 , filtered under reduced pressure to give crude product. The crude product was purified by FCC (Si02, Petroleum ether: Ethyl acetate =1 : 0 ~ 3: 1). Compound 276A (39.0 g, yield: 36.7%, yellow solid): 1H NMR (DMSO-i¾ , 400 MHz): δ 7.50 - 7.37 (m, 5H), 6.88 (s, 1H), 4.16 (q, = 7.0 Hz, 2H), 2.26 (s, 3H), 1.14 (t, = 7.2 Hz, 3H).
[1307] To a mixture of compound 276A (250 mg, 1.1 mmol) in MeOH (10 mL) was added NaOH (2M, 3 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 2h. The reaction mixture was concentrated under reduced pressure to move MeOH. H 2 0 (10 mL) was added into the mixture, which was acidified with aqueous HC1 (1M) till pH - 3 - 4. The aqueous phase was extracted with EA (10 mL x 3). The combined organic phase was washed with saturated aqueous NaCl (15 mL x 2), dried over Na 2 S0 4 and filtered under reduced pressure to afford compound 276C (170 mg, crude) as yellow solid, which was used directly for next step without purification. 1H NMR (DMSO- 6, 400 MHz): δ 7.49 - 7.37 (m, 5H), 6.82 (s, 1H), 2.25 (s, 3H).
[1308] Compound 276 (100 mg, yield: 65.68%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 276C. Compound 276: 1H NMR (CDC1 3, 400 MHz): δ 9.14 - 9.00 (m, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.44 - 7.11 (m, 10H), 6.56 (s, 1H), 5.28 (s, 1H), 3.26 - 3.16 (m, 1H), 2.91 - 2.76 (m, 1H), 2.26 (s, 3H). MS (ESI) m/z (M+H) + 377.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(2- -4-CARBOXAMIDE (277)
[ 1309] To a suspension of 2-fluorobenzaldehyde (10 g, 80.6 mmol) and NH 2 OH.HCl
(6.2 g, 88.6 mmol) in EtOH (10 mL) and H 2 0 (20 mL) was added ice (50 g). Then an aqueous solution of NaOH (8 g, 201 mmol) in H 2 0 (25 mL) was added dropwise within a 10 min period where upon most of the solid dissolves. Then the mixture was stirred 2 hours at 16 °C. The resulting mixture was then acidified with HC1 (5N). The mixture was then extracted with dichioromethane ( 100 mL) for two times. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1: 0 to 200: 1) to give compound 277A (10 g, yield: 89.2%) as a pale yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 8.68 (s, 1H), 8.39 (s, 1H), 7.74 (br t, 7 = 7.5 Hz, 1H), 7.39 (q, 7 = 6.8 Hz, 1H), 7.18 (t, 7 = 7.4 Hz, 1H), 7.14 - 7.06 (m, 1H).
[1310] A solution of compound 277A (5 g, 35.9 mmol) in DMF (20 mL) was added l-chloropyrrolidine-2, 5-dione (5.3 g, 39.5 mmol ) followed by stirring at 20 °C for 3 hours. The reaction mixture was diluted with H 2 0 (60 mL), and extracted with ethyl acetate (100 mL x 2). The organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 277B (5 g, yield: 80.2%) as a yellow solid. 1H NMR (400MHz, CDCI3) δ 9.15 (s, 1H), 7.68 (br t, 7 = 7.5 Hz, 1H), 7.50 - 7.39 (m, 1H), 7.23 (t, 7 = 7.6 Hz, 1H), 7.20 - 7.13 (m, 1H).
[1311] To a solution of ethyl 3-(dimethylamino)acrylate (165 mg, 1.2 mmol) and TEA (233 mg, 2.3 mmol) in THF (15 mL) was added a solution of compound 277B (400 mg, 2.3 mmol) in THF (5 mL) drop-wise over 30 mins. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparatory-TLC (Si0 2 , Petroleum ether: Ethyl acetate = 1: 1) to give compound 277C (240 mg, yield: 44.4%) as a pale yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 8.94 (s, 1H), 7.51 - 7.36 (m, 2H), 7.21 - 7.14 (m, 1H), 7.13 - 7.04 (m, 1H), 4.17 (q, 7 = 7.1 Hz, 2H), 1.15 (t, 7 = 7.2 Hz, 3H).
[1312] A mixture of compound 277C (230 mg, 977.9 umol) in H 2 0 (2.00 mL), HOAc (1.5 mL) and HC1 (3 mL) was heated to 130 °C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound 277D (120 mg, yield: 59.2%) as a brown solid. The product was used into the next step without future purification. MS (ESI) m/z (M+H) + 208.1.
[1313] Compound 277 (33 mg, yield: 37.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 277D. Compound 277: 1H NMR (400MHz, DMSO-d 6 ) δ 9.43 (br s, 1H), 8.94 (br d, 7 = 6.8 Hz, 1H), 8.09 (br s, 1H), 7.83 (br s, 1H), 7.54 (br d, 7 = 5.3 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.36 - 7.16 (m, 9H), 5.31 (br s, 1H), 3.17 (br d, 7 = 13.5 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.89 - 2.75 (m, 1H). MS (ESI) m/z (M+H) + 382.1. EXAMPLE 156
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-PHENYL-5- (TR -4-CARBOXAMIDE (278)
[1314] To a mixture of N-hydroxybenzimidoyl chloride (1 g, 6.43 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (1.28 g, 7.71 mmol) in THF (10 mL) was added TEA (1.3 g, 12.9 mmol) at 25 °C. The mixture was stirred at 25°C for lh and H 2 0 (10 mL) was added to the mixture and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was purified by preparatory-TLC to get compound 278A (1 g, yield: 54.5%) as yellow oil. 1 H NMR (400MHz, CDC1 3 ) δ 7.68 (dd, J = 1.3, 7.9 Hz, 2H), 7.56 - 7.47 (m, 3H), 4.39 - 4.31 (m, 2H), 1.34 - 1.28 (m, 3H).
[1315] To a mixture of compound 278A (750 mg, 2.63 mmol) in HO Ac (2 mL) was added HC1 (12M, 939 uL). The mixture was stirred at 130 °C for 48h. TLC (dichloromethane: methanol = 10: 1, R f ~ 0.09) showed desired point. The mixture was concentrated to get crude product compound 278B (450 mg, crude) as yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.68 (br d, J = 7.9 Hz, 2H), 7.62 - 7.50 (m, 3H).
[1316] Compound 278 (15 mg, yield: 12.6%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 278B. Compound 278: 1H NMR (400MHz, OMSO-d 6 ) δ 9.17 (br d, J = 9.2 Hz, 1H), 7.55 - 7.48 (m, 3H), 7.43 - 7.36 (m, 4H), 7.28 - 7.14 (m, 5H), 5.88 (d, J = 5.3 Hz, 1H), 4.60 (br s, 1H), 4.04 (br s, 1H), 3.31 (s, 12H), 2.73 - 2.61 (m, 1H). MS (ESI) m/z (M+H) + 432.1. EXAMPLE 157
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-CHLORO-l-PHENYL-l H- -5-CARBOXAMIDE (280)
[[11331177]] TToo aa mmiixxttuurree ooff eetthhyyll llHH--ppyyrraazzoollee--55--ccaarrbbooxxyyllaattee ((1100..0000 gg,, 7711..3366 mmmmooll)),, pphheennyyllbboorroonniicc aacciidd ((1133..0055 gg,, 110077..0044 mmmmooll)),, PPyy ((88..8822 gg,, 111111..5500 mmmmooll,, 99..00 mmLL)) iinn DDCCMM ((112200 mmLL)) wwaass aaddddeedd 44AA°° MMSS ((4400..0000 gg)) aanndd CCuu((OOAAcc)) 22 ((1144..2266 gg,, 7788..5500 mmmmooll)),, tthhee mmiixxttuurree wwaass ssttiirrrreedd aatt 3300 °°CC ffoorr 115544hh.. TThhee rreeaaccttiioonn mmiixxttuurree wwaass ffiilltteerreedd,, tthhee ffiillttrraattee wwaass ccoonncceennttrraatteedd iinn vvaaccuuoo.. TThhee rreessiidduuee wwaass ppuurriiffiieedd bbyy ffllaasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ((PPEE:: EEAA == 11 ::00 ttoo 1100:: 11)) ttoo ggiivvee tthhee ccoommppoouunndd 228800AA ((33..1100 gg,, yyiieelldd:: 1199..11%%)) aass aa yyeellllooww ooiill.. CCoommppoouunndd 228800AA:: 1H1H NNMMRR ((440000MMHHzz,, DDMMSSOO--dd 66 )) δδ 77..8811 ((dd,, 77 == 22..00 HHzz,, 11HH)),, 77..5577 -- 77..3377 ((mm,, 55HH)),, 77..0099 ((dd,, 77 == 22..00 HHzz,, 11HH)),, 44..1177 ((qq,, 77 == 77..00 HHzz,, 22HH)),, 11..1155 ((tt,, 77 == 77..00 HHzz,, 33HH))..
[[11331188]] TToo aa ssoolluuttiioonn ooff ccoommppoouunndd 228800AA ((11..00 gg,, 44..6622 mmmmooll)) iinn CCHH 33 CCOOOOHH ((1155 mmLL)) wwaass aaddddeedd NNaaCCIIOO ((2244..22 gg,, 4477..1122 mmmmooll,, 2200..0000 mmLL,, 1144..55%% ppuurriittyy)).. TThhee mmiixxttuurree wwaass ssttiirrrreedd aatt 2255 °°CC ffoorr 2211hh uunnddeerr NN 22 aattmmoosspphheerree.. TThhee rreeaaccttiioonn mmiixxttuurree wwaass qquueenncchheedd bbyy aaddddiittiioonn HH 22 00 ((2255 mmLL)),, aanndd ddiilluutteedd wwiitthh EEAA ((2200 mmLL)) aanndd ssttiirrrreedd ffoorr 3300 mmiinn,, aanndd tthheenn eexxttrraacctteedd wwiitthh EEAA ((2255 mmLL)).. TThhee ccoommbbiinneedd oorrggaanniicc llaayyeerrss wweerree wwaasshheedd wwiitthh HH 22 00 ((2200 mmLL xx 22)),, aanndd tthheenn wwaasshheedd wwiitthh NNaaHHCC00 33 ((2200 mmLL xx 22)),, aanndd tthheenn wwaasshheedd wwiitthh bbrriinnee ((1155 mmLL xx 22)),, ddrriieedd oovveerr NNaa 22 SS00 44 ,, ffiilltteerreedd aanndd ccoonncceennttrraatteedd uunnddeerr rreedduucceedd pprreessssuurree ttoo ggiivvee aa rreessiidduuee.. TThhee rreessiidduuee wwaass ppuurriiffiieedd bbyy f fllaasshh ssiilliiccaa ggeell cchhrroommaattooggrraapphhyy ((PPEE:: EEAA == 11 ::00 ttoo 11 :: 11)) ttoo ggiivvee tthhee ccoommppoouunndd 228800CC ((332277 mmgg,, yyiieelldd:: 2288..11%%)) aass aa wwhhiittee ssoolliidd.. 1H1H NNMMRR ((440000MMHHzz,, CCHHLLOORROOFFOORRMM--d)) δδ 77..6699 ((ss,, 11HH)),, 77..5533 -- 77..3311 ((mm,, 55HH)),, 44..2277 ((qq,, 77 == 77..11 HHzz,, 22HH)),, 11..2222 ((tt,, 77 == 77..22 HHzz,, 33HH))..
[[11331199]] TToo aa ssoolluuttiioonn ooff ccoommppoouunndd 228800CC ((330000 mmgg,, 11..2200 mmmmooll)) iinn MMeeOOHH ((1155 mmLL)) wwaass aaddddeedd NNaaOOHH ((224400 mmgg,, 66..0000 mmmmooll)) iinn HH 22 00 ((55 mmLL)).. TThhee mmiixxttuurree wwaass ssttiirrrreedd aatt 2200 °°CC ffoorr 22hh.. TThhee rreeaaccttiioonn mmiixxttuurree wwaass ddiilluutteedd wwiitthh MMTTBBEE ((1155 mmLL)) aanndd HH 22 00 ((1155 mmLL)),, aanndd tthheenn ssttiirrrreedd ffoorr 1100 mmiinnss.. TThhee wwaatteerr llaayyeerr wwaass sseeppeerraatteedd,, aanndd tthhee oorrggaanniicc llaayyeerr wwaass eexxttrraacctteedd wwiitthh HH 22 00 ((1155 mmLL xx 22)).. TThhee ccoommbbiinneedd aaqquueeoouuss llaayyeerrss wweerree aajjuusstteedd ppHH ~~ 33 bbyy aaddddttiioonn IINN HHCC11,, aanndd tthheenn tthhee aaqquueeoouuss
-- 449933 -- layer was extracted with EA (20 mL x 3). The combine organic layer was washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the compound 280D (252 mg, yield : 94.1%) as a white solid. 1H NMR (400MHz, METHANOL-^) δ 7.76 (s, 1H), 7.52 - 7.38 (m, 5H).
[1320] Compound 280 (61 mg, yield: 61.2%, light yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 280D. Compound 280: 1H NMR (400MHz, DMSO-d 6 ) δ 9.46 (d, = 7.5 Hz, 1H), 8.20 (s, 1H), 7.97 - 7.86 (m, 2H), 7.41 - 7.24 (m, 10H), 5.48 - 5.35 (m, 1H), 3.21 (br dd, = 3.2, 14.0 Hz, 1H), 2.80 (dd, = 10.5, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 397.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CHLORO-l-PHEN YL-lH- -5-CARBOXAMIDE (281)
[1321] To EtOH (40 mL) was added Na (470 mg, 20.34 mmol) at 20°C. After all sodium was reacted, the mixture was heated to 78°C and phenylhydrazine (2.0 g, 18.49 mmol, 1.82 mL) was added, and stirred for O. lh and then diethyl maleate (3.5 g, 20.34 mmol, 3.27 mL) was added dropwise. The mixture was stirred at 78°C for 4h. After being cooled to 65°C, the reaction mixture was treated with AcOH (2.0 g, 33.28 mmol, 1.9 mL). The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H 2 0 (80 mL) and extracted with EtOAc (80 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=5/l to 1 : 1) to give the compound 281A (2.72 g, yield: 58.40%) as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 7.34 - 7.24 (m, 2H), 7.02 - 6.92 (m, 3H), 4.59 (dd, = 2.0, 9.7 Hz, 1H), 4.24 - 4.13 (m, 2H), 3.00 - 2.86 (m, 1H), 2.46 - 2.39 (m, 1H), 1.23 (t, = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 235.0. [1322] To a solution of Compound 281A (2.7 g, 11.53 mmol) in MeCN (50 mL) was added P0C1 3 (2.15 g, 14.02 mmol). The mixture was stirred at 85 °C for 5h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was neutralized by sat. NaHC0 3 to pH~8, then extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=10/l to 5: 1) to give the Compound 281B (1.9 g, yield: 65.21%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 7.31 - 7.17 (m, 2H), 6.98 (br d, 7 = 7.3 Hz, 2H), 6.89 (br t, 7 = 7.2 Hz, 1H), 4.86 - 4.60 (m, 1H), 4.34 - 4.14 (m, 2H), 3.62 - 3.37 (m, 1H), 3.33 - 3.17 (m, 1H), 1.37 - 1.11 (m, 3H). MS (ESI) m/z (M+H) + 252.9.
[1323] To a solution of Compound 281B (800 mg, 3.17 mmol) in MeCN (20 mL) was added H 2 S0 4 (620 mg, 6.34 mmol, 337.95 uL) and K 2 S 2 0 8 (1.29 g, 4.76 mmol). The mixture was stirred at 80 °C for 6h. The reaction mixture was concentrated under reduced pressure to remove most solvent. The residue was dropped in H 2 0 (30 mL), filtered and concentrated under reduced pressure to give a residue. The residue was washed with 30% MeCN (5 mL x 2). The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate=20/l to 15: 1) to give the compound 281C (190 mg, yield: 21.52%) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.47 (d, 7=1.3 Hz, 4H), 7.23 - 7.14 (m, 1H), 4.15 (q, 7=7.1 Hz, 2H), 1.12 (t, 7=7.2 Hz, 3H). MS (ESI) m/z (M+H) + 250.9.
[1324] To a solution of Compound 281C (150 mg, 598.37 umol) in THF/H 2 0 (5 mL/5 mL) was added NaOH (120 mg, 2.99 mmol). The mixture was stirred at 25 °C for 4h. The reaction mixture was diluted with H 2 0 (20 mL), then the mixture was concentrated under reduced pressure to remove THF, and extracted with MTBE (15 mL x 2). The water layers were neutralized by IN HC1 to pH ~ 3 and then extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give the Compound 281D (120 mg, yield: 90.08%) as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.50 - 7.34 (m, 5H), 6.97 (s, 1H).
[1325] Compound 281 (20 mg, yield: 40.20%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 281D. Compound 281: 1H NMR (400MHz, DMSO-d 6 ) δ 9.27 (d, 7 = 7.7 Hz, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.41 - 7.34 (m, 3H), 7.30 (br d, / = 7.1 Hz, 2H), 7.28 - 7.23 (m, 3H), 7.21 - 7.16 (m, 2H), 6.80 (s, 1H), 5.31 - 5.19 (m, 1H), 3.24 - 3.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3,5-DICHLORO-l-METH YL-lH-
[1326] To a solution of ethyl lH-pyrazole-4-carboxylate (5 g, 35.68 mmol) and Cs 2 C0 3 (23.25 g, 71.36 mmol) in DMF (100 mL) was added Mel (10.13 g, 71.36 mmol, 4.44 mL). The mixture was stirred at 25°C for 16h. The mixture was filtered, the filtrate was diluted with H 2 0 (500 mL), extracted with EA (50 mL x 3), dried over Na 2 S0 4 , filtered and concentrated to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 282A (4.5 g, yield: 81.81%) was obtained as a yellow oil. 1 H NMR (400MHz, CDC1 3 ) δ 7.84 (d, = 8.5 Hz, 2H), 4.24 (q, = 7.3 Hz, 2H), 4.03 - 3.70 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 155.0.
[1327] To a solution of compound 282A (1.5 g, 9.73 mmol) was added NCS (2.6 g, 19.46 mmol) under N 2 . The mixture was stirred at 160 °C for 3h. The reaction mixture was added CC1 4 (10 mL) and saturated aqueous NaHC0 3 (10 mL). The mixture was extracted with DCM (20 mL x 2), and then combined the organic layers and the organic phase was dried with over Na 2 S0 4 , filtered and the filtrate was concentrated in vacuum. Compound 282B (1.84 g, crude) was obtained as a brown oil, which was used for next step directly. MS (ESI) m/z (M+H) + 188.9.
[1328] To a solution of compound 282B (1.84 g, 9.76 mmol) was added NCS (2.61 g, 19.52 mmol) under N 2 and the mixture was stirred at 160 °C for 4h under N 2. To the reaction mixture was added CC1 4 (10 mL) and saturated aqueous NaHC0 3 (10 mL) and the mixture was extracted with DCM (20 mL x 2), and then combined the organic layers and the organic phase was dried with over Na 2 S0 4 , filtered and the filtrate was concentrated in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 5/1). Compound 282C (482 mg, yield: 22.14%) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) S 4.35 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 222.9.
[1329] To a mixture of compound 282C (480 mg, 2.15 mmol) in H 2 0 (5 mL) and MeOH (10 mL) was added NaOH (258 mg, 6.45 mmol) in portion at 20 °C and stirred for 2h. The mixture was concentrated to remove MeOH, then the mixture was diluted with H 2 0 (20 mL) and extracted with MTBE (50 mL x 2). The water layers were acidified to pH ~ 2 with IN HC1, then the solution was extracted with EA (50 mL x 3). The organic layers were dried over Na 2 S0 4 and concentrated to give intermediate compound 282D (390 mg, yield: 93.02%) as white solid. 1H NMR (400MHz, CDCI3) δ 1.21 (s, 1H), 3.77 (s, 3H). MS (ESI) m/z (M+H) + 194.8 & 196.8.
[1330] Compound 282 (50 mg, yield: 46.25%, off-white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 282D. Compound 282: 1H NMR (400MHz, DMSO-i¾) δ 8.32 (dd, = 7.7 Hz, 1H), 8.21 - 8.07 (m, 1H), 7.87 (s, 1H), 7.36 - 7.16 (m, 5H), 5.33 (s, 1H), 3.82 - 3.69 (m, 3H), 3.19 (dd, J = 13.2 Hz, 1H), 2.95 - 2.78 (m, 1H). MS (ESI) m/z (M+H) + 369.1 & 371.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-BENZYL-lH-PYRAZOL E-5-
[1331] To a mixture of ethyl lH-pyrazole-5-carboxylate (1 g, 7.14 mmol) and benzyl bromide (0.93 mL, 7.8 mmol) in DMF (30 mL) was added K 2 C0 3 (1.18 g, 8.6 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 14h. The reaction mixture was added H 2 0
(80 mL) and extracted by EA (50 mL x 3). The combined organic phase was washed with Sat. NaCl (50 niL x 2). The organic phase was dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by FCC (Si0 2 , Petroleum ether/Ethyl acetate=l/0 to 3/1) to afford compound 283A (523 mg, yield 31.7%) as colorless liquid and compound 283B (989 mg, yield 60.1%) as white solid.
[1332] Compound 283A: 1 H NMR (DMSO-d 6, 400 MHz) δ 7.65 (d, = 2.0 Hz, 1H), 7.36 - 7.23 (m, 3H), 7.13 (d, J = 7.0 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H), 5.72 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (M+H) + 231.0.
[1333] Compound 283B: 1H NMR (DMSO-i¾ , 400 MHz) δ 7.99 (d, J = 2.5 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.28 - 7.23 (m, 2H), 6.77 (d, J = 2.3 Hz, 1H), 5.43 (s, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H). MS (ESI) m/z (M+H) + 231.0.
[1334] To a mixture of compound 283A (517 mg, 2.2 mmol) in MeOH (10 mL) was added NaOH (2M, 6 mL, 12.0 mmol) in one portion at 25 °C. After stirred at 25 °C for 2h, the reaction mixture was concentrated under reduced pressure to move MeOH, the aqueous phase was acidified with aqueous HC1 (1M) till pH - 4 - 5. The precipitae was filtered and dried to afford compound 283C (389 mg, crude) as white solid, which was used directly for next step without purification. 1H NMR (DMSO- 6, 400 MHz) δ Ί .60 (d, J = 2.0 Hz, 1H), 7.34 - 7.22 (m, 3H), 7.15 - 7.08 (m, 2H), 6.88 (d, J = 2.0 Hz, 1H), 5.73 (s, 2H).
[1335] Compound 283 (177 mg, yield 89.0%) was prepared as in Example 12 from the corresponding intermediate carboxylic acid, compound 283C. Compound 283: 1H NMR (DMSO-i¾ , 400 MHz) δ 8.91 (d, J = 7.1 Hz, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.26 (s, 8H), 7.14 - 7.01 (m, 2H), 6.89 (s, 1H), 5.60 (s, 2H), 5.40 - 5.24 (m, 1H), 3.27 - 3.13 (m, 1H), 2.95 - 2.80 (m, 1H). MS (ESI) m/z (M+H) + 377.1.
[1336] Following the same procedure as is used for compound 283, compound 284 (35 mg, yield 35.7%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 284A. Compound 284: 1H NMR (DMSO- 6, 400MHz) δ 8.18 (br d, J = 7.5 Hz, 1H), 8.05 (br s, 1H), 7.94 - 7.79 (m, 2H), 7.40 - 7.30 (m, 3H), 7.28 - 7.18 (m, 7H), 6.64 (s, 1H), 5.40 (s, 3H), 3.19 (br dd, J = 3.7, 13.7 Hz, 1H), 3.04 (br dd, J = 8.9, 13.8 Hz, 1H). MS (ESI) m/z (M+H) + 377.1. EXAMPLE 161
(5)-3-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(PYRAZIN-2-YL)- lH- PYR -5-CARBOXAMIDE (285)
[1337] A mixture of 2-hydrazineylpyrazine (2 g, 18.16 mmol) and ethyl 2,4- dioxopentanoate (2.87 g, 18.16 mmol) in AcOH (40 mL) was stirred at 118 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with H 2 0 (8 mL), adjusted to pH ~ 7 with Na 2 C0 3 , and then extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). Compound 285A (1.5 g, 35.57% yield) was obtained as a white solid. Compound 285A: 1H NMR (400MHz, CDC1 3 ) δ 8.98 - 8.93 (m, 1H), 8.60 - 8.54 (m, 1H), 8.46 - 8.41 (m, 1H), 6.78 (s, 1H), 4.34 - 4.25 (m, 2H), 2.38 (s, 3H), 1.27 (t, =7.2 Hz, 3H).
[1338] Intermediate compound 285C (1.2 g, 92.84% yield, white solid) was deprotected as in Example 85 from compound 285A. Compound 285C: 1H NMR (400MHz, DMSO-d 6 ): δ 8.96 - 8.92 (m, 1H), 8.70 - 8.66 (m, 1H), 8.58 - 8.54 (m, 1H), 6.84 (s, 1H), 2.25 - 2.24 (m, 1H), 2.26 (s, 2H).
[1339] Compound 285 (143.0 mg, 53.28% yield, white solid) was prepared as in Example 6 from the corresponding intermediate compounds 285C and 21G ((S)-2-amino-3- phenylpropan- l-ol). Compound 285: 1H NMR (400MHz, CDC1 3 ) δ 9.74 (s, 1H), 9.19 - 9.16 (m, 1H), 9.03 - 8.96 (m, 1H), 8.48 - 8.43 (m, 1H), 8.06 - 8.03 (m, 1H), 7.27 - 7.25 (m, 1H), 7.24 - 7.20 (m, 3H), 7.17 - 7.12 (m, 2H), 6.80 (s, 1H), 5.00 - 4.91 (m, 1H), 3.39 - 3.31 (m, 1H), 3.30 - 3.23 (m, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H 2 0+H) + 354.2. EXAMPLE 162
(5)-3-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(PYRAZIN-2-YL)- lH- -5-CARBOXAMIDE (286)
[1340] To a solution of compound 270A (1 g, 4.30 mmol) in DMF (20 mL) was added NBS (1.53 g, 8.60 mmol) at 80 °C, and the mixture was stirred at 80 °C for 1.5 hrs. The mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic layer was washed with saturated NaHC0 3 (20 mL), brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether to Petroleum ether: Ethyl acetate = 20: 1) to give compound 286A (1.3 g, yield: 97.2%) as white solid. 1H NMR (400MHz, CDC1 3 ) δ 7.49 - 7.41 (m, 3H), 7.40 - 7.34 (m, 3H), 4.16 (q, = 7.2 Hz, 2H), 1.16 (t, 7 = 7.1 Hz, 3H).
[1341] A mixture of compound 286A (1 g, 3.21 mmol), Cul (1.22 g, 6.42 mmol) and sodium 2,2,2-trifluoroacetate (4.37 g, 32.1 mmol) in DMA (20 mL) was heated to 160 °C for 5 hrs. The mixture was added ethyl acetate (30 mL), water (50 mL), IN HCl (50 mL), the mixture was filtered, and the filtrate was separated. The organic solvent was washed with water (30 mL), brine (30 mL), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by MPLC (Petroleum ether to Petroleum ether: Ethyl acetate = 30: 1) to give compound 286B (210 mg, yield: 21.8%), as yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.85 (d, = 1.1 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.47 - 7.37 (m, 3H), 4.21 (q, = 7.2 Hz, 2H), 1.20 (t, = 7.1 Hz, 3H).
[1342] A mixture of compound 286B (210 mg, 699 umol) and NaOH (55.9 mg, 1.40 mmol) in THF (5 mL), EtOH (3 mL), H 2 0 (2 mL) was stirred at 10 °C for 12 hrs. The organic solvents was removed under vacuum, the water layer was adjusted to pH ~ 5 with IN HCl, and extracted with ethyl acetate (20 mL), the organic layer was dried over Na 2 S0 4 , filtered and concentrated to give compound 286C (160 mg, yield: 84%), as yellow solid. 1H NMR (400MHz, CDC1 3 ) (5 7.81 (d, / = 1.1 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.40 - 7.31 (m, 3H). [1343] Compound 286 (28.3 mg, yield: 45.5%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 286C and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 286: 1H NMR (400MHz, CDC1 3 ) δ 7.76 (s, 1H), 7.61 - 7.38 (m, 5H), 7.26 - 7.16 (m, 3H), 6.80 (br d, J = 5.6 Hz, 2H), 6.70 (br s, 1H), 6.01 (br d, J = 5.9 Hz, 1H), 5.61 - 5.47 (m, 2H), 3.24 (dd, = 5.0, 14.2 Hz, 1H), 2.93 (dd, = 7.6, 14.2 Hz, 1H). MS (ESI) m/z (M+H) + 447.1.
(5)-3-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-l-(PYRAZIN-2-YL)- lH- PYRAZ LE-5-CARBOXAMIDE (287)
[1344] To a solution of 6-(trifluoromethyl)picolinic acid (10 g, 52.33 mmol) in MeOH (150 mL) was added H 2 S0 4 (1.03 g, 10.47 mmol, 557.88 uL) dropwise. After stirred at 65 °C for 10 hours, the mixture was cooled to room temperature, neutralized with a saturated aqueous NaHC0 3 solution, and extracted with CH 2 C1 2 (70 mL x 3). The organic phases were combined, dried with anhydrous Na 2 S0 4 , and evaporated to afford crude intermediate compound 287A (9.20 g, 85.71% yield) as white solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.32 (d, = 8.0 Hz, 1H), 8.09 - 8.05 (m, 1H), 7.88 (d, = 8.0 Hz, 1H), 4.03 (s, 3H).
[1345] A solution of compound 287A (4.5 g, 21.94 mmol) in CH 3 COOC 2 H 5 (150 mL) was added i-BuOK (3.20 g, 28.52 mmol). The mixture was stirred for 0.25 hour at 25 °C. The mixture was quenched with H 2 0 (150 mL). The organic layer was separated and the aqueous was extracted with EA (70mL x 3). The organic phases were combined, dried with anhydrous Na 2 S0 4 , filtered and evaporated to afford intermediate compound 287B (3.95 g, 66.86% yield) as yellow oil. 1H NMR (400 MHz, CDC1 3 ) δ 8.24 (d, = 8.0 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.87 (d, = 7.2 Hz, 1H), 4.22 - 4.16 (m, 4H), 1.26 - 1.23 (m, 3H). [1346] To a solution of compound 287B (3.90 g, 14.93 mmol) in EtOH (80 mL) was added NH 4 OAc (5.75 g, 74.65 mmol), then the mixture was stirred at 78 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with EA (500 mL) and washed with saturated aqueous NaHC0 3 solution (30 mL x 3) and brine (30 mL x 3). The organic layer were dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (PE:EA=30/1 to 10/1) to afford compound 287C (2.52 g, 64.87% yield) as white solid. 1H NMR (400 MHz, CDC1 3 ) δ 7.94 - 7.93 (m, 2H), 7.73 - 7.71 (m, 1H), 5.38 (s, 1H), 4.23 - 4.18 (m, 2H), 1.33 - 1.29 (m, 3H).
[1347] To a mixture of compound 287C (2.5 g, 9.61 mmol) in DCE (60.00 mL) was added PhI(OAc) 2 (4.02 g, 12.49 mmol) at 0 °C under N 2 in four portions, the mixture was stirred at 0 °C for 6h and then warmed to 25 °C slowly. The mixture was then stirred at 25 °C for 0.5h. The reaction mixture was quenched with saturated aqueous NaHC0 3 (150 mL) at 0 °C, warmed to 25 °C slowly, and extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na 2 S0 4i filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (PE: EA=20/1 to 10/1) to afford compound 287D (650 mg, 21.23% yield) as yellow oil. 1H NMR (400 MHz, CDC1 3 ) δ 8.34 - 8.18 (m, 1H), 8.16 - 8.13(s, 1H), 7.96 - 7.90 (m, 1H), 4.28 - 4.23 (m, 2H), 2.13 (s, 3H), 1.28 - 1.23 (m, 3H).
[1348] A mixture of compound 287D (600 mg, 1.89 mmol) in DCE (5 mL) and CH 3 COOH (10 mL) was stirred at 90 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and to give the residue. The residue was purified by flash column chromatography (PE:EA=30/1 to 10/1) to afford compound 287E (120 mg, 221.31 umol, 11.71% yield, 55.37% purity)as yellow solid. 1H NMR (400 MHz, CDC1 3 ) δ 8.42 - 8.33 (m, 1H), 8.17 - 8.15 (m, 1H), 7.99 - 7.26 (m, 1H), 4.40 - 4.37 (m, 2H), 2.62 (s, 3H), 1.35 - 1.32 (m, 3H).
[1349] To a soluton of compound 287E (110 mg, 366.39 umol) in MeOH (6 mL) and H 2 0 (3mL) was added LiOH.H 2 0 (61 mg, 1.47 mmol), then the mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H 2 0 (20 mL), adjusted to pH ~ 3 with IN HC1, then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure to give intermediate compound 287F (86 mg, 59.17% yield) as a white solid. 1H NMR (400 MHz, OMSO-d 6 ) δ 8.45 - 8.26 (m, 2H), 8.10 - 8.07 (m, 1H), 2.58 (s, 3H).
[1350] Compound 287 (12.1 mg, 20.26% yield, off-white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 287F and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 287: 1H NMR (400 MHz, CDC1 3 ): δ 11.10 (d, 7=7.2 Hz, 1H), 8.46 (d, 7=8.0 Hz, 1H), 8.18 - 7.99 (m, 1H), 7.72 (d, 7=8.0 Hz, 1H), 7.23 - 7.04 (m, 5H), 6.70 (br s, 1H), 5.64 - 5.52 (m, 1H), 5.45 (br s, 1H), 3.57 - 3.47 (m, 1H), 3.10 - 2.94 (m, 1H), 2.55 (d, 7=0.80 Hz, 3H). MS (ESI) m/z (M+l) + 447.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(PYRIDIN-2- YL)ISOXAZOLE-4-CARBOXAMIDE (288)
[1351] NH 2 OH.HCl (156 mg, 2.24 mmol) and NaOAc (184 mg, 2.24 mmol) was added in a solution of picolinaldehyde (200 mg, 1.87 mmol) in EtOH (15 mL). The mixture was heated at 60 °C for 2 hours. The reaction mixture was concentrated. Dichloromethane (50 mL) was added. The organic phase was washed with H 2 0 (10 mL) and brine (10 mL), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to give intermediate compound 288A (180 mg, yield: 78.8%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 9.47 (br s, 1H), 8.57 (br d, J = 4.2 Hz, 1H), 8.50 (br d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 7.85 (t, = 7.7 Hz, 1H), 7.76 (d, = 7.9 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.40 - 7.32 (m, 1H), 7.26 - 7.17 (m, 1H).
[1352] To a mixture of compound 288A (180 mg, 1.47 mmol) in DMF (2 mL) was added NCS (216 mg, 1.62 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to give intermediate compound 288B (200 mg, yield: 87.1%) as a brown solid. 1H NMR (400MHz, CDC1 3 ) δ 10.79 (br s, 1H), 8.72 (d, = 4.2 Hz, 1H), 7.94 (d, = 8.2 Hz, 1H), 7.80 (dt, J = 1.7, 7.8 Hz, 1H), 7.39 (ddd, = 0.8, 5.0, 7.4 Hz, 1H), 2.79 (s, 1H).
[1353] To a mixture of ethyl 3-(dimethylamino)acrylate (92 mg, 639 umol), TEA (129 mg, 1.28 mmol) in THF (10 mL) was added a solution of compound 288B (200 mg, 1.28 mmol) in THF (10 mL) over a period of 20 min. The mixture was stirred at 20 °C and stirred for 12 hours. The reaction mixture was concentrated. The residue was purified by preparatory- TLC (Si0 2 , Petroleum ether: Ethyl acetate = 1 : 1) to give compound 288C (150 mg, yield: 53.8%) as yellow oil. 1H NMR (400MHz, CDCI 3 - ) δ 9.02 - 8.97 (m, 1H), 8.75 (d, = 4.6 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.45 - 7.36 (m, 1H), 4.27 (q, J = 7.3 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).
[1354] To a mixture of compound 288C (150 mg, 687 umol) in THF (5 mL) and H 2 0 (1 mL) was added LiOH.H 2 0 (58 mg, 1.4 mmol). The mixture was stirred at 15 °C for 12 hours. The mixture was concentrated to remove solvent. The mixture was adjusted to pH ~ 5 with aqueous HCl (1M) and concentrated to give intermediate compound 288D (130 mg, yield: 99.5%) as a brown solid. 1H NMR (400MHz, OMSO-d 6 ) δ 9.57 (s, 1H), 8.76 (d, = 4.9 Hz, 1H), 8.11 - 8.05 (m, 2H), 7.65 (dt, J = 3.1, 5.3 Hz, 1H).
[1355] Compound 288 (73.8 mg, yield: 81.7%, yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 288D. Compound 288: 1H NMR (400MHz, OMSO-d 6 ) δ 11.10 (br d, J = 7.0 Hz, 1H), 9.44 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.11 - 8.01 (m, 2H), 7.81 (br s, 1H), 7.65 - 7.51 (m, 2H), 7.17 - 7.08 (m, 5H), 5.62 - 5.52 (m, 1H), 3.27 (dd, J = 5.0, 13.8 Hz, 1H), 3.13 - 3.06 (m, 1H). MS (ESI) m/z (M+H) + 365.1.
[1356] Following the procedure used for compound 288, compound 289 (83.1 mg, yield: 70.9%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 289D. Intermediate compound 289D (100 mg, yield: 56.8%, white solid): 1H NMR (400MHz, DMSO-d 6 ) δ 9.55 (s, 1H), 7.89 - 7.81 (m, 2H), 7.39 - 7.28 (m, 2H). Compound 289: 1H NMR (400MHz, DMSC fc) δ 9.32 (s, 1H), 9.10 (d, 7 = 7.6 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.65 - 7.56 (m, 2H), 7.33 - 7.21 (m, 7H), 5.40 - 5.29 (m, 1H), 3.19 (dd, 7 = 3.9, 13.9 Hz, 1H), 2.84 (dd, 7 = 10.0, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 382.1.
[1357] A mixture of ethyl 2-chloro-3-oxobutanoate (16 g, 97.2 mmol), formamide (43.8 g, 972 mmol), H 2 0 (3.50 g, 194 mmol) in autoclave was stirred at 180 °C for 3.5 hours. The reaction mixture was filtered and the filtered cake was dissolved in DCM (200 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. Compound 290A (2 g, crude) was obtained as a yellow solid. MS (ESI) m/z (M+H) + 154.8.
[1358] A mixture of 290A (1.8 g, 11.7 mmol), phenylboronic acid (2.85 g, 23.4 mmol), Cu(OAc) 2 (3.18 g, 17.5 mmol), pyridine (1.85 g, 23.4 mmol) and 4A° MS (2 g) in DCE (60 mL) was degassed and purged with 0 2 for 3 times, and then the mixture was stirred at 60 °C for 12 hours under 0 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 50: 1 to 2: 1). Compound 290B (1.15 g, yield: 42.7%) was obtained as a yellow solid. 1H NMR (400MHz, CDC1 3 ) δ 7.53 (s, 1H), 7.45 - 7.35 (m, 3H), 7.27 - 7.16 (m, 2H), 4.18 - 4.05 (m, 2H), 2.53 (s, 3H), 1.10 (t, 7 = 7.1 Hz, 3H). MS (ESI) m/z (M+H) + 231.0 .
[1359] A mixture of 290B (300 mg, 1.30 mmol), LiOH.H 2 0 (109 mg, 2.60 mmol) in
THF (10 mL), H 2 0 (10 mL) was stirred at 15 °C for 12hrs. LCMS showed most of 290B was remained. To the mixture was added NaOH (416 mg, 10.4 mmol), and the mixture was stirred at
70°C for 12hrs. The reaction mixture was added aq. HC1 to adjust the pH ~5. And then the mixture was filtered, and the filter cake was concentrated to give the product. Compound 290C (300 mg, crude) was obtained as a yellow solid. 1H NMR (400MHz, DMSO-i¾) δ 7.90 (s, 1H), 7.50 - 7.37 (m, 3H), 7.36 - 7.28 (m, 2H), 2.39 (s, 3H). MS (ESI) m/z (M+H) + 203.1.
[1360] Compound 290 (15.3 mg, yield: 11.5%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 290C. Compound 290: 1H NMR (400MHz, DMSO-d 6 ) δ 8.23 (br d, = 7.0 Hz, 1H), 7.73 (s, 1H), 7.80 - 7.56 (m, 1H), 7.41 - 7.13 (m, 11H), 5.31 (br s, 1H), 3.20 (dd, =3.7, 13.8 Hz, 1H), 2.92 - 2.80 (m, 1H), 2.18 - 2.13 (m, 3H). MS (ESI) m/z (M+H) + 377.2.
(5)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-CHLORO-l-PHE NYL-lH- -5-CARBOXAMIDE (291)
[1361] A mixture of ethyl lH-imidazole-5-carboxylate (10 g, 71.4 mmol), phenylboronic acid (13.1 g, 107 mmol), Cu(OAc) 2 (19.4 g, 107 mmol), pyridine (11.3 g, 142.72 mmol) and 4A MS (4.0 g) in DCE (200 mL) was degassed and purged with 0 2 for 3 times, and then the mixture was stirred at 60 °C for 12 hours under 0 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 20: 1 to 5: 1). Compound 291A (2.8 g, yield: 18.2%) was obtained as a yellow solid. (Note: The structure was confirmed by NOE). 1H NMR (400MHz, CDC1 3 ) δ 7.79 (s, 1H), 7.63 (s, 1H), 7.47 - 7.33 (m, 3H), 7.32 - 7.22 (m, 2H), 4.14 (q, = 7.2 Hz, 2H), 1.16 (t, 7 = 7.1 Hz, 3H).
[1362] To a solution of 291A (1 g, 4.62 mmol) in CH 3 CN (20 mL) was added NCS
(925 mg, 6.93 mmol) at 80 °C. The mixture was stirred at 80 °C for 2hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM
(50 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether: Ethyl acetate = 80: 1 to
50: 1) and then purified by preparatory-TLC (Petroleum ether: Ethyl acetate= 3:1). Compound 291B (150 mg, yield: 13.0%) was obtained as a yellow oil. (Note: The structure was confirmed by HMBC). 1H NMR (400MHz, CDC1 3 ) δ 7.77 - 7.62 (m, 1H), 7.54 - 7.37 (m, 3H), 7.29 - 7.10 (m, 2H), 4.09 (q, 7 = 7.1 Hz, 2H), 1.11 (t, 7 = 7.2 Hz, 3H).
[1363] A mixture of 291B (150 mg, 598 umol), LiOH.H 2 0 (50.2 mg, 1.20 mmol) in THF (5 mL), H 2 0 (5 mL) was stirred at 15 °C for 12 hours. The reaction mixture was added aq. HC1 to adjust the pH ~ 5. And then the mixture was filtered, and the filter cake was concentrated to give the product. Compound 291C (130 mg, crude) was obtained as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 7.45 (br d, 7 = 2.2 Hz, 4H), 7.29 (br s, 2H). MS (ESI) m/z (M+H) + 222.8 .
[1364] Compound 291 (47.1 mg, yield: 47.6%, brown solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 291C. Compound 291: 1H NMR (400MHz, DMSO-d 6 ) δ 8.74 (br d, 7 = 7.7 Hz, 1H), 8.02 (br s, 1H), 7.79 (br s, 1H), 7.66 (s, 1H), 7.43 (br d, 7 = 4.0 Hz, 3H), 7.37 - 7.10 (m, 7H), 5.16 (br t, 7 = 6.8 Hz, 1H), 3.13 (br d, 7 = 10.8 Hz, 1H), 2.86 - 2.68 (m, 1H). MS (ESI) m/z (M+H) + 397.1 .
(25,4R)-/V-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-METHYL-l - P -2-CARBOXAMIDE (292)
[1365] To the mixture of l-(tert-butyl) 2-ethyl (25,4R)-4-methylpyrrolidine- l,2- dicarboxylate (2 g, 7.77 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4M, 20 mL) at 25 °C. The mixture was stirred at 25 °C for lOh. The mixture was concentrated to get residue and saturated aqueous Na 2 C0 3 (1.5 mL) was added to the residue, then DCM (200 mL) was added. Then the mixture was dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to get crude compound 292A (1.9 g, crude) as yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 8.76 (br s, 2H), 5.29 (s, 1H), 4.48 (dd, 7 = 4.1, 9.2 Hz, 1H), 4.27 (q, 7 = 7.2 Hz, 2H), 3.73 (dd, 7 = 7.4, 11.3 Hz, 1H), 2.95 (dd, 7 = 9.1, 11.3 Hz, 1H), 2.48 - 2.28 (m, 2H), 2.05 - 1.95 (m, 1H), 1.31 (t, 7 = 7.2 Hz, 3H), 1.13 (d, 7 = 6.6 Hz, 3H). [1366] To a mixture of compound 292A (1.9 g, 12.1 mmol) and phenylboronic acid (2.95 g, 24.2 mmol) in DCE (15 mL) was added 4A° MS (4 g), pyridine (1.91 g, 24.2 mmol), Cu(OAc) 2 (3.29 g, 18.1 mmol) in one portion at 25 °C. The mixture was stirred at 60°C for 10 h under 0 2 (15psi). The reaction was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100/1, 50/1) to get compound 292B (900 mg, yield: 31.9%) as light oil. 1H NMR (400MHz, CDC1 3 ) δ 7.42 - 7.32 (m, 2H), 7.29 - 7.17 (m, 3H), 4.28 - 4.08 (m, 3H), 3.67 (t, J = 8.0 Hz, 1H), 2.90 (t, J = 8.7 Hz, 1H), 2.69 - 2.55 (m, 1H), 2.24 - 2.14 (m, 1H), 1.96 - 1.83 (m, 1H), 1.24 (t, J = 1.1 Hz, 3H), 1.12 (d, 7 = 6.6 Hz, 3H).
[1367] To the mixture of compound 292B (300 mg, 1.29 mmol) in EtOH (5 mL) and H 2 0 (1 mL) was added NaOH (129 mg, 3.23 mmol) at 25 °C. The mixture was stirred at 25 °C for lOh. The reaction was concentrated and the aqueous phase was extracted with ethyl acetate (15 mL x 2). Then to the aqueous phase was added HC1 (1M) till pH ~ 3. Desired product was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to get crude compound 292C (100 mg, crude) as yellow oil.
[1368] Compound 292 (12.7 mg, yield: 25.5%, off-white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 292C. Compound 292: 1H NMR (400MHz, CDC1 3 ) δ 7.30 - 7.19 (m, 4H), 7.16 - 7.09 (m, 1H), 7.09 - 6.97 (m, 3H), 6.88 - 6.77 (m, 2H), 6.73 (br s, 1H), 6.55 (dd, J = 8.2, 18.3 Hz, 2H), 5.75 - 5.61 (m, 1H), 5.61 - 5.36 (m, 1H), 4.04 - 3.92 (m, 1H), 3.65 - 3.47 (m, 1H), 3.42 (dd, J = 5.0, 14.0 Hz, 1H), 3.23 - 3.02 (m, 1H), 2.90 (dd, J = 8.9, 14.0 Hz, 1H), 2.82 - 2.68 (m, 1H), 2.41 - 2.29 (m, 1H), 2.28 - 2.04 (m, 1H), 2.03 - 1.89 (m, 1H), 1.88 - 1.70 (m, 1H), 1.13 - 1.00 (m, 3H). MS (ESI) m/z (M+H) + 380.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-PHENYL-l,2,5- -3-CARBOXAMIDE (293)
[1369] To a solution of methyl cinnamate (1 g, 1 eq) in pyridine (20 mL) was added NOBF 4 (2.34 g, 3.2 eq) at 0°C. The reaction mixture was stirred at 0°C for 2 days. The solution was poured into ice water and extracted with EtOAc (3 times). The combined organic phase was washed with water, dried over NaS0 4 and concentrated under reduced pressure. The residue was purified on IS CO to afford compound 293 A.
[1370] The solution of compound 293A (0.5 g) in trimethyl phosphite (5 mL) was heated at 100°C under N 2 overnight. The reaction was cooled to room temperature and quenched with IN HC1 (10 mL). The mixture was extracted with EtOAc (3 times). The combined organic phase was washed with water, dried over NaS0 4 and concentrated under reduced pressure. The residue was purified on ISCO to afford compound 293B.
[1371] Compound 293 was prepared as in Example 5 from the corresponding acid, intermediate compound 293C, which was obtained by treating compound 293B (720mg) with LiOH in MeOH and water. 1H NMR (400 MHz, DMSO): δ 9.81 (d, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.6 - 7.2 (m, 10H), 5.53 (m, 1H), 3.25 (dd, 1H), 2.83 (dd, 1H) ppm. MS (ESI) m/z (M+Na) + 387.2.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(l-M ETHYL-lH- -2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (294)
[1372] Mel (6.1 mL, 98.3 mmol) was added to a mixture of 2-chloro-lH- benzo[ ]imidazole (5.0 g, 32.8 mmol) and K 2 C0 3 (13.6 g, 98.3 mmol) in DMF (20 mL). The mixture was stirred at 25 °C for lh. The insoluble substance was removed by filtration and the filtrate was treated with EA (50 mL), H 2 0 (50 mL). The organic layer was separated and the aqueous layer was extracted with EA (35 mL x 3). The combined organic layer was washed with H 2 0 (35 mL x 2), brine (35 mL x 2), dried over MgS0 4 , filtered and concentrated. The residue was triturated with TBME/PE (v/v = 1/1, -20 mL) to afford compound 294A (3.3 g, yield 60.38%) as pale yellow solid. 1H NMR (DMSO-i¾ , 400 MHz) δ Ί .60 - 7.56 (m, 2H), 7.31 - 7.24 (m, 2H), 3.80 (s, 3H). MS (ESI) m/z (M+H) + 167.0.
[1373] To a mixture of compound 294A (3.3 g, 19.8 mmol in EtOH (10 mL) was added N 2 H 4 .H 2 0 (5.8 g, 99.1 mmol, 85% purity) in one portion. The mixture was stirred at 110 °C for 12h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE (20 mL), the precipitate was filtered and dried in vacuum to afford compound 294B (2.4 g, yield 73.1%) as white solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 7.25 - 7.21 (m, 1H), 7.17 - 7.13 (m, 1H), 6.98 - 6.89 (m, 2H), 3.45 (s, 3H).
[1374] To a mixture of compound 294B (1.0 g, 6.17 mmol) and ethyl 2,4- dioxopentanoate (1.0 g, 6.48 mmol) in AcOH (20 mL) was stirred at 110 °C for 5h. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was added H 2 0 (50 mL) and EA (50 mL), and then the mixture was acidified with saturated aqueous NaHC0 3 till the aqueous phase pH ~ 7-8. The separated aqueous layer was extracted with EA (100 mL x 3), the combined organic layers were washed with saturated aqueous NaCl (150 mL), dried over Na 2 S0 4 , filtered under reduced pressure to give crude product. The crude product was purified by FCC (Si0 2 , Petroleum ether: Ethyl acetate =1: 0 ~ 3: 1) to afford compound 294C (494 mg, yield 27.9%) as yellow liquid.
[1375] Compound 294C: 1H NMR (DMSO- 6 , 400 MHz) δ 7.69 - 7.63 (m, 2H), 7.41 - 7.35 (m, 1H), 7.33 - 7.28 (m, 1H), 7.05 (s, 1H), 4.10 (q, = 7.1 Hz, 2H), 3.55 (s, 3H), 2.32 (s, 3H), 0.99 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 285.1.
[1376] To a mixture of compound 294C (645 mg, 2.3 mmol) in MeOH (10 mL) was added NaOH (2 M, 5.7 mL) in one portion at 25 °C. The mixture was stirred at 25 °C for 1.5h. The reaction mixture was concentrated under reduced pressure to move MeOH, the residue was added H 2 0 (10 niL) and acidified with IN HC1 solution till the aqueous phase pH - 6 - 7. The solid was separated and filtered under reduced pressure to afford compound 294E (482 mg, crude) as white solid, which was used directly for the next step without purification. 1H NMR (DMSO- de , 400 MHz) δ 13.58 (s, 1H), 7.69 - 7.61 (m, 2H), 7.40 - 7.34 (m, 1H), 7.33 - 7.26 (m, 1H), 6.96 (s, 1H), 3.54 (s, 3H), 2.31 (s, 3H). MS (ESI) m/z (M+H) + 257.0.
[1377] Compound 294 (27 mg, yield 57.7%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 294E. Compound 294: 1H NMR (CDC1 3, 400 MHz) δ 9.98 (d, J = 6.0 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.44 - 7.29 (m, 4H), 7.04 (m, 3H), 6.99 (m, 2H), 6.90 - 6.85 (m, 1H), 6.78 - 6.71 (m, 1H), 5.74 - 5.65 (m, 1H), 3.81 (s, 3H), 3.36 (m, 1H), 3.09 (m, 1H), 2.37 (s, 3H). MS (ESI) m/z (M+H) + 431.1.
(5)-N-(4-(CYCLOPROPYLAMINO)-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3- METHYL- l-(l-METHYL-lH-BENZO[rf]IMIDAZOL-2-YL)-lH-PYRAZOLE-5-CARBOXA MIDE
[1378] Compound 295 (50.0 mg, yield: 50.16%, white solid) was prepared as in Example 20 from the corresponding intermediate carboxylic acid, compound 294E. Compound 295: 1H NMR (CDCI 3, 400 MHz) δ 9.89 - 9.76 (m, 1H), 7.66 - 7.62 (m, 1H), 7.43 - 7.37 (m, 2H), 7.36 - 7.30 (m, 1H), 7.06 - 7.00 (m, 3H), 7.00 - 6.94 (m, 2H), 6.92 - 6.85 (m, 2H), 5.77 - 5.65 (m, 1H), 3.79 (s, 3H), 3.43 - 3.32 (m, 1H), 3.13 - 3.02 (m, 1H), 2.86 - 2.73 (m, 1H), 2.37 (s, 3H), 0.91 - 0.81 (m, 2H), 0.65 - 0.52 (m, 2H). MS (ESI) m/z (M+H) + 471.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-(6- METHOXYBENZO[rf]THIAZOL-2-YL)-5-METHYL-lH-PYRAZOLE-3-
[1379] HC1 (12 M, 5.50 mL) was added to NH 2 NH 2 .H 2 0 (6.9 mL, 120 mmol) with stirring at 0-5 °C, followed by ethylene glycol (30 mL). Then 6-methoxybenzo[<i]thiazol-2- amine (3.6 g, 20.0 mmol) was added in portions. The mixture was heated to 125 °C and stirred for 3h. After cooling to room temperature, the precipitate was collected by filtration. The cake was washed with EtOH (5 mL x 3) to afford compound 296A (3.0 g, 15.37 mmol, yield 76.8%) was obtained as pale green solid.
[1380] A mixture of compound 296A (1.0 g, 5.1 mmol) and ethyl 2,4- dioxopentanoate (0.7 mL, 5.1 mmol,) in HO Ac (20 mL) was heated to 120 °C and stirred for 3h. The mixture was concentrated. The residue was treated with MeOH (15 mL). The insoluble substance was removed by filter. The filtrate was concentrated and the residue was purified by preparatory- HPLC to afford compound 296C (670 mg, yield 41.2%) as pale yellow solid and compound 296B (74 mg, yield 4.6% ) as pink solid. The insoluble substance (0.5 g, impure) as pink solid was treated with DCM (50 mL). The insoluble substance was removed off by filtration. The filtrate was washed with saturated NaHC0 3 (15 mL x 3), brine (15 mL x 2), dried over MgS0 4 , filter and concentrated to afford compound 296B (0.35 g, yield 21.5%) as pink solid.
[1381] Compound 296B: 1H NMR (CDC1 3, 400 MHz) δ 7.80 (d, = 9.2 Hz, 1H), 7.30 (d, = 2.4 Hz, 1H), 7.06 (dd, = 2.4, 8.8 Hz, 1H), 6.72 (s, 1H), 4.42 (q, = 6.8 Hz, 2H), 3.89 (s, 3H), 2.82 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 317.9.
[1382] Compound 296C: 1H NMR (CDC1 3, 400 MHz) δ 7.80 (d, = 8.8 Hz, 1H), 7.30 (d, = 2.4 Hz, 1H), 7.80 (dd, = 2.0, 8.8 Hz, 1H) 6.71 (s, 1H), 4.37 (q, = 7.2 Hz, 2H), 3.88 (s, 3H), 2.37 (s, 3H), 1.30 (t, = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 317.9.
[1383] [1432] NaOH (2 M, 3.15 mL, 6.3 mmol) was added to a solution of compound 296C (400 mg, 1.26 mmol,) in MeOH (15 mL). The mixture was stirred at 25 °C for 12h. The mixture was diluted with H 2 0 (50 mL) and the volatile solvent was removed by evaporation. The resulting aqueous solution was acidified to pH ~ 3 with IN HC1. The precipitate was collected and azeotroped with toluene to afford compound 296D (320 mg, yield 87.8%) was obtained as white solid. 1H NMR (DMSO-i¾, 400MHz) δ 7.78 (d, = 9.0 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.11 (dd, = 2.5, 8.9 Hz, 1H), 6.86 (s, 1H), 3.82 (s, 3H), 2.28 (s, 3H).
[1384] Compound 296 (100 mg, yield 43.9%, pale yellow solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 296D. Compound 296: 1H NMR (DMSO-d 6 , 400MHz) δ 10.20 (br d, = 7.3 Hz, 1H), 8.12 (s, 1H), 7.86 (br s, 1H), 7.64 (d, =2.4 Hz, 1H), 7.56 (d, =9.0 Hz, 1H), 7.18 (q, = 7.8 Hz, 4H), 7.12 (br d, =6.8 Hz, 1H), 7.05 (dd, =2.6, 9.0 Hz, 1H), 6.73 (s, 1H), 5.59 - 5.49 (m, 1H), 3.81 (s, 3H), 3.22 (br dd, =4.5, 14.0 Hz, 1H), 3.02 (br dd, =8.5, 14.4 Hz, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) + 464.1.
[1385] Following the same procedure as is used for compound 296, compound 297 (30 mg, yield 54.3%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 297A. Compound 297: 1H NMR (DMSO-d 6 , 400MHz) δ 8.55 (br d, = 7.5 Hz, 1H), 8.12 (s, 1H), 7.88 - 7.80 (m, 2H), 7.72 (d, = 2.6 Hz, 1H), 7.31 - 7.25 (m, 4H), 7.22 - 7.17 (m, 1H), 7.11 (dd, = 2.6, 8.8 Hz, 1H), 6.76 (s, 1H), 5.45 - 5.35 (m, 1H), 3.83 (s, 3H), 3.22 (br dd, 7=4.1, 13.8 Hz, 1H), 3.04 (dd, 7=9.4, 13.8 Hz, 1H), 2.73 (s, 3H). MS (ESI) m/z (M+H) + 464.1.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-METHYL-l-(4- METHYLBENZO[rf]THIAZOL-2-YL)-lH-PYRAZOLE-5-CARBOXAMIDE (298)
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-5-METHYL-l-( 4- MET -2-YL)- -PYRAZOLE-3-CARBOXAMIDE (299)
[1386] HC1 (12M, 2.5 mL) was added to a mixture of 4-methylbenzo[<i]thiazol-2- amine (5.0 g, 30. 5 mmol) and NH 2 NH 2 .H 2 0 (19.2 mL, 335 mmol) in ethylene glycol (30 mL). The mixture was heated 120 °C and stirred for 5h. After cooling to room temperature, precipitation was observed. The precipitate was collected by filtration, and washed with EtOH (15 mL) to afford compound 298A (2.3 g, yield 41.7%) as white needle crystal. 1H NMR (DMSO-i¾, 400MHz) δ 8.98 (br.s., 1H), 7.46 (d, 7 = 8.0 Hz, 1H), 7.00 (d, 7 = 7.6 Hz, 1H), 6.88 - 6.84 (m, 2H), 4.98 (s, 2H), 2.38 (s, 3H). MS (ESI) m/z (M+H) + 179.8.
[1387] A mixture of compound 298A (1.7 g, 9.5 mmol) and ethyl 2,4- dioxopentanoate (1.5 g, 9.5 mmol) in AcOH (30 mL) was heated to 125 °C and stirred for 3h. The mixture was concentrated. The residue was treated with MeOH (15 mL). The insoluble substance was removed by filtration. The filtrate was concentrated and the residue was purified by prep-HPLC (FA) to afford compound 298B (260 mg, 9.1% yield) was obtained as yellow solid and compound 298C (1.12 g, yield 39.2%). The insoluble substance (1.4 g, impure) was treated with DCM (50 mL) and saturated aqueous NaHC0 3 (15 mL). The organic layer was separated, and then washed with saturated NaHC0 3 (15 mL x 2), brine (15 mL x 3), dried over MgS0 4 , filtered and concentrated. The residue was purified by FCC (PE/EA = 10/1) to afford compound 298B (620 mg, 21.7% yield) as yellow solid.
[1388] Compound 298B: 1 H NMR (CDC1 3 , 400MHz) δ 7.71 - 7.65 (m, 1H), 7.28 (d, 7 = 5.3 Hz, 2H), 6.74 (d, 7=0.9 Hz, 1H), 4.43 (q, 7 = 7.3 Hz, 2H), 2.87 (d, 7 = 0.9 Hz, 3H), 2.69 (s, 3H), 1.43 (t, 7 = 7.2 Hz, 3H). MS (ESI) m/z (M+H) + 302.0.
[1389] Compound 298C: 1H NMR (CDC1 3 , 400MHz) δ 7.681 - 7.66 (m, 1H), 7.30 - 7.26 (m, 2H), 6.66 (s, 1H), 4.39 (q, 7 = 7.2 Hz, 2H), 2.65 (s, 3H), 2.38 (s, 3H), 1.30 (t, 7 = 6.8 Hz, 3H). MS (ESI) m/z (M+H) + 301.9.
[1390] NaOH (2M, 2.5 mL, 5.0 mmol) was added to a solution of ethyl compound 298B (300 mg, 1.0 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2h. Thick white precipitate was observed. The mixture was diluted with H 2 0 (30 mL). And the volatile solvent was removed by evaporated. The residue was acidified to pH ~ 3 with IN HC1. The precipitate was collected and azeotroped with toluene to afford compound 298D (190 mg, yield 69.8%) as white solid. 1H NMR (DMSO-d 6 , 400MHz) δ 13.32 (br s, 1H), 7.93 - 7.87 (m, 1H), 7.37 - 7.31 (m, 2H), 6.83 (s, 1H), 2.79 (s, 3H), 2.62 (s, 3H).
[1391] Compound 298 (35 mg, yield 42.1%, white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 298D. Compound 298: 1H NMR (DMSO- e, 400 MHz) δ 8.60 (br d, 7 = 7.0 Hz, 1H), 8.14 (br s, 1H), 7.94 (br s, 1H), 7.88 (br s, 1H), 7.41 - 7.17 (m, 8H), 6.81 (s, 1H), 5.44 (br s, 1H), 3.23 (br s, 1H), 3.27 - 3.23 (m, 1H), 3.13 - 3.02 (m, 1H), 2.81 (br s, 3H), 2.65 (br s, 3H). MS (ESI) m/z (M+H) + 448.1.
[1392] Following the same procedure as is used for compound 298, compound 299 (30 mg, yield 25.0%, white solid) was prepared from the corresponding intermediate carboxylic acid, compound 299A. Compound 299: 1H NMR (DMSO-i¾ , 400 MHz) δ 11.49 (d, 7 = 6.8 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.32 - 7.28 (m, 1H), 7.26 - 7.21 (m, 1H), 7.20 - 7.04 (m, 6H), 6.73 (s, 1H), 5.56 - 5.43 (m, 2H), 3.55 - 3.47 (m, 1H), 3.25 - 3.16 (m, 1H), 2.39 (s, 3H), 2.36 (s, 3H). MS (ESI) m/z (M+H) + 448.1. EXAMPLE 173
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-CYCLOPROPY L-l-PHENYL- -PYRAZOLE-5-CARBOXAMIDE (306)
[1393] Compound 306 (25 mg, 24%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 306A and 12G. Compound 306: MS (ESI) m/z (M+H) + 403.
(5)-N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYL-lH-IND OLE-2-
[1394] Compound 307 was synthesized from the corresponding starting materials using same procedures as described earlier for compound 306.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-5-(PYRIDIN -2- -4-CARBOXAMIDE (314)
[1395] Na (29.55 mg, 1.29 mmol) was dissolved in MeOH (90 mg). The solution was added to a mixture of MeOH (10 mL) and DCM (90 mL) at 0 - 5 °C and 5 mins later, 2- chloroacetonitrile (10.2 mL, 160.7 mmol,) was added, and the mixture was stirred at 0 - 5 °C for 1.5 h. Then ethyl acetimidate hydrochloride (20 g, 128.55 mmol, HC1 salt) was added at 0 - 5 °C. The slurry was allowed to warm to 20 °C and stirred for 18h. H 2 0 (50 mL) was added to the mixture and the mixture was stirred for 15 mins to ensure the precipitate was dissolved. The organic layer was separated, washed with brine (30 mL), dried over MgS0 4 , filtered and concentrated to afford compound 314A (20.2 g, yield 88.5%) as clear oil, which was used for next step directly. 1H NMR (DMSO-i¾ , 400 MHz) δ 4.87 - 4.82 (m, 1H), 4.55 - 4.46 (m, 2H), 4.39 (s, 2H), 3.71 (s, 3H).
[1396] DBU (17.2 mL, 113.75 mmol) was added to a solution of compound 314A (20.2 g, 113.75 mmol) in DCM (lOOmL) slowly. The mixture was stirred at 25 °C for lh. The mixture was treated with 2N HC1 (40 mL). The organic layer was separated and then washed with H 2 0 (30 mL), brine (30 mL), dried over MgS0 4 , filtered and concentrated to afford compound 314B (13.5 g, yield 84.1%) as white solid, which was used for next step directly. 1H NMR (DMSO- e, 400 MHz) δ 8.68 (s, 1H), 3.76 (s, 3H), 2.42 (s, 3H).
[1397] Cs 2 C0 3 (4.6 g, 14.2 mmol) was added to a mixture of compound 314B (1.0 g, 7.1 mmol) and 2-iodopyridine (2.9 g, 14.2 mmol) in toluene (20.00 mL). Then P(o-tolyl) 3 (216 mg, 0.71 mmol) and Pd(OAc) 2 (80 mg, 0.35 mmol) was added. The mixture was de-gassed for 3 times. Then the mixture was heated to 110 °C and stirred for 18h. The mixture was filtered through Celite; the cake was washed with EA (15 mL x 2). The combined filtrates were concentrated. The residue was purified by Flash Column Chromatography (PE/EA = 10/1 to 1/1) to afford compound 314C (1.0 g, yield 64.6%) as pale yellow solid. 1H NMR (DMSO-i¾ , 400 MHz) δ 8.69 - 8.67 (m, 1H), 8.08 - 8.06 (m, 1H), 7.96 -7.91 (m, 1H), 7.48 - 7.45 (m, 1H), 3.77 (s, 3H), 2.50 (s, 3H).
[1398] To a mixture of compound 314C (500 mg, 2.3 mmol) in THF (10 mL) and H 2 0 (2 mL) was added KOH (1.28 g, 22.9 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 1.5h. The reaction mixture was concentrated under reduced pressure to move THF. The aqueous phase was acidified with aqueous HC1 (1M) till pH ~ 4-5, and then extracted with DCM (20 mL x 5). The combined organic phase was dried over Na 2 S0 4 , filtered and concentrated to afford compound 314D (600 mg, crude) as light yellow solid, which was used directly for next step without purification. 1H NMR (DMSO-d 6 , 400 MHz) δ 8.84 - 8.75 (m, 1H), 8.25 - 8.19 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.71 - 7.66 (m, 1H), 2.56 (s, 3H).
[1399] Compound 314 (30 mg, yield 26.2%, white solid) was prepared as in compound 12 from the corresponding starting materials, compounds 314D and 3-amino-2- hydroxy-4-phenyl-butanamide (274D). Compound 314: 1H NMR (CDC1 3, 400 MHz) δ 11.59 (d, 7 = 6.2 Hz, 1H), 8.14 - 8.09 (m, 1H), 8.03 - 7.98 (m, 1H), 7.87 - 7.80 (m, 1H), 7.26 - 7.22 (m, 1H), 7.18 - 7.05 (m, 5H), 6.81 (s, 1H), 5.86 - 5.78 (m, 1H), 5.64 (s, 1H), 3.50 - 3.41 (m, 1H), 3.37 - 3.29 (m, 1H), 2.58 (s, 3H). MS (ESI) m/z (M+H) + 379.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-5- PHENYLOXAZOLE-4-CARBOXAMIDE (494)
[1400] Compound 494 (40 mg, yield 25.1%, white solid) was prepared as in compound 314 from the corresponding starting materials, compounds 314B and iodobenzene followed by using procedures as in compound 12 to obtain compound 494. Compound 494: 1H NMR (CDCI 3, 400 MHz) δ 8.20 - 7.97 (m, 3H), 7.80 (br s, 1H), 7.61 (br d, 7=10.0 Hz, 1H), 7.49 - 7.34 (m, 3H), 7.31 - 7.04 (m, 5H), 6.22 (br s, 0.22H), 6.09 (br s, 0.22H), 5.46 (dt, 7=4.8, 8.0 Hz, 0.75H), 4.59 (dt, 7=3.0, 10.3 Hz, 0.28H), 3.27 (dd, 7=5.0, 14.1 Hz, 1H), 3.11 (br dd, 7=8.3, 14.1 Hz, 1H), 2.54 - 2.50 (m, 3H). MS (ESI) m/z (M+H) + 378.1.
(5)-l-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL)-3-PHENYL-lH-PYRAZ OLE-4-
[1401] To a mixture of ethyl 3-iodo-lH-pyrazole-4-carboxylate (30 g, 112.7 mmol) in DMF (200 mL) was added Cs 2 C0 3 (110.22 g, 338.28 mmol) in one portion at 25 °C. Then iodomethane (18.83 mL, 302.45 mmol) was added. The mixture was stirred at 25 °C for 3h. The reaction mixture was concentrated under reduced pressure to remove most of DMF. The mixture was treated with EA (100 mL) and H 2 0 (100 mL). The organic layer was separated and the aqueous layer was extracted with EA (50 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by FCC (Si0 2 , PE: EA = 1: 0 - 5: 1) to afford compound 317B (17.24 g, yield 54.59%) as white solid. Compound 317B: 1H NMR (DMSO-d 6 , 400 MHz) δ 8.25 (s, 1H), 4.20 (q, 7 = 7.1 Hz, 2H), 3.87 (s, 3H), 1.29 - 1.23 (m, 3H). [1402] To a mixture of compound 317B (10.0 g, 35.7 mmol) and phenylboronic acid (8.71 g, 71.4 mmol) in 1, 4-dioxane (300 mL) and H 2 0 (80 mL) was added K 2 C0 3 (9.87 g, 71.4 mmol) and Pd(dppf)Cl 2 (2.61 g, 3.57 mmol). The mixture was degassed and purged with N 2 for 3 times, and then stirred at 80 °C for 18h. The reaction mixture was concentrated under reduced pressure to move 1, 4-dioxane. The mixture was added EA (150 mL), and then washed with H 2 0 (100 mL x 3). The organic layer was dried over Na 2 S0 4 and concentrated. The residue was purified by Flash Column Chromatography (Si0 2 , Petroleum ether: Ethyl acetate=l : 0 to 3: 1) to afford compound 317C (8.30 g, crude) as light red solid. 1 H NMR (DMSO-i¾, 400 MHz) δ 8.34 (s, 1H), 7.71 - 7.64 (m, 2H), 7.41 - 7.33 (m, 3H), 4.20 - 4.06 (m, 2H), 3.88 (s, 3H), 1.26 - 1.12 (m, 3H). MS (ESI) m/z (M+H) + 231.0.
[1403] To a mixture of compound 317C (8.29 g, 36.0 mmol) in THF (15 mL) and MeOH (10 mL) was added the mixture of KOH (20.20 g, 360.0 mmol) and H 2 0 (10 mL) at 25 °C. The mixture was stirred at 70 °C for 1.5h. The reaction mixture was concentrated under reduced pressure to move MeOH and THF, the aqueous phase was acidified with concentrated HC1 (36-38 %) till pH - 3 - 4, precipitated solid was filtered and dried to afford compound 317D (5.95 g, yield 81.72%) as white solid, which was used directly for the next step without purification. 1H NMR (DMSO- 6 , 400 MHz) δ 8.29 (s, 1H), 7.75 - 7.70 (m, 2H), 7.42 - 7.30 (m, 3H), 3.89 (s, 3H).
[1404] Compound 317 (1.29 g, yield 63.83%) was prepared as in Example 6 from the corresponding intermediate compounds 317D and 21G ((S)-2-amino-3-phenylpropan- l-ol). Compound 317: 1H NMR (DMSO- 6 , 400 MHz) δ 9.56 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 7.60 - 7.48 (m, 2H), 7.34 - 7.13 (m, 8H), 4.51 - 4.37 (m, 1H), 3.87 (s, 3H), 3.26 - 3.15 (m, 1H), 2.90 - 2.76 (m, 1H). MS (ESI) m/z (M+H) + 334.1.
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-2-METHYL-l-PHENYL-l H-
DCE, 4A° MS
[1405] A mixture of N'-hydroxyacetimidamide (5 g, 67.5 mmol) and ethyl prop-2- ynoate (8.94 g, 91.1 mmol) in MeOH (50 mL) was stirred at 65 °C for 4h. Then the solvent was evaporated and Ph 2 0 (25 mL) was added. The reaction mixture was stirred at 250 °C for 4h. The mixture was cooled to 70 °C and poured into MTBE (100 mL) portion-wise. The mixture was stirred for 10 min. Filtered and the filter cake was collected. The solid was dissolved in EtOAc (200 mL) and MeOH (50 mL). Filtered and the filtrate was collected. The filtrate was concentrated to give the crude product as brown oil. The residue was suspended in MTBE (100 mL) and stirred for 10 mins. Filtered and the filter cake was collected to give compound 318A (2 g, yield: 19.2%) as a brown solid. 1 H NMR (400MHz, OMSO-d 6 ) δ 12.32 (br s, 1H), 7.72 - 7.49 (m, 1H), 4.25 - 4.10 (m, 2H), 3.33 (br d, J = 8.8 Hz, 1H), 2.33 - 2.23 (m, 3H), 1.25 (t, J = 7.2 Hz, 3H).
[1406] To a mixture of compound 318A (2 g, 13.0 mmol), phenylboronic acid (3.16 g, 25.9 mmol), pyridine (2.05 g, 25.9 mmol) and 4A° molecular sieve (2 g) in DCE (50 mL) was added Cu(OAc) 2 (3.53 g, 19.5 mmol). The mixture was stirred at 60 °C for 12h under 0 2 (15 psi). Filtered and the filtrate was purified by silica gel chromatography eluting with Petroleum ether: Ethyl acetate = 4: 1 to give the crude product. The crude product was then purified again by preparatory- TLC (EtOAc, R f ~ 0.5) twice to give compound 318B (160 mg, yield: 5.36%) as a yellow solid. 1H NMR (400 MHz, CDC1 3 ) δ 1.11 (s, 1H), 7.53 - 7.48 (m, 3H), 7.26 - 7.20 (m, 2H), 4.15 (q, 7 = 1.2 Hz, 2H), 2.24 (s, 3H), 1.19 (t, 7 = 7.1 Hz, 3H).
[1407] To a solution of compound 318B (100 mg, 434 umol) in THF (6 mL) and H 2 0 (2 mL) was added LiOH.H 2 0 (36.5 mg, 869 umol). The mixture was stirred at 15 °C for 24 hr. TLC (EtOAc, R f ~ 0) showed the reaction was completed. The pH of the mixture was adjusted to ~ 7.0 using IN HC1. Then solvent was removed under vacuum to give crude compound 318C (87.0 mg, crude) as yellow oil.
[1408] Compound 318 (30.3 mg, yield: 28.0%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 318C and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 318: 1H NMR (400MHz, CDC1 3 ) δ 7.57 - 7.39 (m, 5H), 7.30 (br s, 2H), 7.24 - 7.17 (m, 2H), 7.11 - 6.96 (m, 2H), 6.70 (br s, 1H), 6.13 (br s, 1H), 5.63 - 5.46 (m, 2H), 3.34 (dd, 7 = 5.5, 14.2 Hz, 1H), 3.12 (dd, 7 = 6.8, 14.1 Hz, 1H), 2.22 (s, 3H). MS (ESI) m/z (M+H) + 377.1. EXAMPLE 177
[1409] To a solution of 4-methyl- lH-imidazole (5 g, 60.9 mmol) in THF (100 mL) was slowly added NaH (2.68 g, 67 mmol) at 0 °C. The suspension was stirred at 0 °C for 30 mins and then SEM-C1 (12.2 g, 73.1 mmol) was added. The reaction mixture was stirred at 20 °C for 12 hours. The mixture was quenched with saturated aqueous NaHC0 3 (200 ml) and extracted with EtOAc (300 mL x 2). The combined organics were dried over Na 2 S0 4 , concentrated to give crude product. The crude product was purified by silica gel chromatography eluting with EtOAc to give a mixture of compound 319A and 319B (10 g, crude) as yellow oil.
[1410] To a solution of compound 319A and 319B (10 g, 47.1 mmol) in THF (40 mL) was added n-BuLi (2.5 M, 28.3 mL) at -78 °C. The mixture was stirred at -78 °C for lh. Ethyl carbonochloridate (7.67 g, 70.6 mmol) was added to the solution and stirred at 20 °C for 12h. The mixture was quenched with NH 4 C1 (aqueous; 200 ml), extracted with EtOAc (300 mL x 2). The combined organics were dried over Na 2 S0 4 , concentrated to give the crude product as orange oil. The crude product was purified by silica gel chromatography eluting with Petroleum ether: Ethyl acetate = 5: 1 to give a mixture of compound 319C and 319D (2.9 g, crude) as yellow oil.
[1411] A solution of 319C and 319D (2 g, 7.03 mmol) in HCl/EtOAc (50 mL) was stirred at 20°C for 24h. LCMS showed most 319C and 319D were consumed. The solvent was removed and the residue was extracted with EtOAc (50 ml) and water (50 mL). Then the pH of water layer was adjusted to ~ 8.0 using saturated aqueous NaHC0 3 and the residue was extracted with EtOAc (50 ml x 6). The combined organics were dried over Na 2 S0 4 , concentrated to give 319E (900 mg, crude) as a brown solid. The crude product was used directly in the next step. 1H NMR (400 MHz, CDC1 3 ) δ 10.42 (br s, 1H), 10.62 - 10.25 (m, 1H), 6.96 (s, 1H), 4.42 (q, J = 7.3 Hz, 2H), 2.33 (s, 3H), 1.41 (t, = 7.2 Hz, 3H).
[1412] To a mixture of compound 319E (405 mg, 2.63 mmol), phenylboronic acid (480 mg, 3.94 mmol), pyridine (416 mg, 5.25 mmol) and 4A° molecular sieve (500 mg) in DCE (30 mL) was added Cu(OAc) 2 (716 mg, 3.94 mmol). The mixture was stirred at 60 °C for 12h under 0 2 (15 psi). Filtered and the residue was purified by silica gel chromatography eluting with Petroleum ether: Ethyl acetate = 5: 1 to give compound 319F (400 mg, crude) as a clear oil. 1H NMR (400 MHz, CDC1 3 ) δ 7.49 - 7.44 (m, 3H), 7.33 - 7.28 (m, 2H), 6.93 (s, 1H), 4.30 (q, = 7.1 Hz, 2H), 2.35 (s, 3H), 1.31 (t, J = 7.1 Hz, 4H).
[1413] A solution of compound 319F (75 mg, 326 umol) and LiOH.H 2 0 (13.7 mg, 326 umol) in THF (3 mL) and H 2 0 (1 mL) was stirred at 15 °C for 12h. TLC (Petroleum ether: Ethyl acetate=l : l, R f ~ 0.01) and LCMS showed the reaction was completed. The pH of the mixture was adjusted to ~ 7.0 and THF was removed by N 2 . Then the residue was lyophilized to give crude compound 319G (130 mg, crude) as a white solid. The crude product was used directly in the next step. MS (ESI) m/z (M+H) + 202.8.
[1414] Compound 319 (38.3 mg, yield: 42.3%, off-white solid) was prepared as in Example 5 from the corresponding intermediate carboxylic acid, compound 319G. Compound 319: 1H NMR (400 MHz, CDC1 3 ) δ 7.80 (br s, 1H), 7.41 (br s, 3H), 7.33 - 7.28 (m, 2H), 7.21 (br d, J = 7.2 Hz, 4H), 6.85 (s, 1H), 6.70 (br s, 1H), 5.69 - 5.57 (m, 1H), 5.42 (br s, 1H), 3.39 (br dd, = 5.0, 14.2 Hz, 1H), 3.15 (br dd, = 7.6, 14.1 Hz, 1H), 2.28 (s, 3H). MS (ESI) m/z (M +H) + 377.2.
COMPOUNDS 321, 519-520
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-4-(3-FLUOROPHENYL)- l,2,5- -3-CARBOXAMIDE (321)
[1415] To a mixture of ethyl (E)-2-cyano-2-(hydroxyimino)acetate (25 g, 1.76 mol) in EtOH (100 mL) was added Pt0 2 (2 g, 8.8 mmol). The mixture was stirred at 25 °C for 12h under H 2 (50 psi). Filtered and the filtrate was concentrated to give compound 321A (44 g, crude) as red oil. The crude product was used directly in the next step.
[1416] To a solution of compound 321A (22 g, 172 mmol) in DMF (500 mL) was added chlorosulfanyl thiohypochlorite (69.6 g, 515 mmol). The mixture was stirred at 20 °C for 12h. The mixture was poured into ice-water (1000 mL), extracted with EtOAc (500 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with Petroleum ether: Ethyl acetate = 30: 1. Compound 321B (12 g, yield: 18.1%, yellow clear oil): 1H NMR (400MHz, CDC1 3 ) δ 4.50 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).
[1417] A mixture of compound 321B (1 g, 5.19 mmol) and (3-fluorophenyl)boronic acid (1.09 g, 7.79 mmol) in H 2 0 (2 mL) and toluene (20 mL) was added KF (603 mg, 10.38 mmol) and Pd(PPh 3 )4 (300 mg, 260 umol) under N 2 . Then the reaction mixture was stirred at 100 °C under N 2 for 16 h. The solvent was evaporated. The crude product was purified by preparatory-TLC (petroleum ether: ethyl acetate = 5: 1, R f = 0.69) to give compound 321C (100 mg, yield: 7.64%) as white solid.
[1418] A mixture of compound 321C (120 mg, 476 umol) in THF (4 mL) and H 2 0 (2 mL) was added LiOH.H 2 0 (39.9 mg, 951 umol). Then the reaction mixture was stirred at 20 °C for 16 h. 1M HC1 was added to the reaction mixture until pH ~ 6. The solvent was removed under vacuum to give crude compound 321D (100 mg, crude) as a white solid. The crude product was used in the next step without purification. 1H NMR (400MHz, CDC1 3 ) δ 7.70 - 7.50 (m, 3H), 7.36 - 7.33 (m, 1H).
[1419] Compound 321 (43.8 mg, yield: 61.6%, white solid) was prepared as in Example 6 from the corresponding starting materials, compounds 321D and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 321: 1H NMR (400MHz, DMSO-d 6 ) δ 9.39 (d, = 7.7 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.48 - 7.17 (m, 8H), 5.73 (s, 1H), 5.55 - 5.43 (m, 1H), 3.21 (dd, J = 3.6, 14.0 Hz, 1H), 2.85 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 399.1. 3-(2-FLUOROPHENYL)-l-METHYL-N-(2-OXO-l-(2- (TRIFLUOROMETHYL)PHENYL)ETHYL)-lH-PYRAZOLE-4-CARBOXAMIDE (519)
[1420] Compound 519 (50 mg, yield: 17.5%, white solid) was prepared as in compound 21 from the corresponding starting materials, 3-(2-fluorophenyl)-l-methyl-lH- pyrazole-4-carboxylic acid and 2-amino-2-(2-(trifluoromethyl)phenyl)ethan-l-ol. Compound 519: 1H NMR (400MHz, OMSO-d 6 ) δ 9.61 (s, 1H), 8.98 (d, = 6.8 Hz, 1H), 8.37 (s, 1H), 7.80 (d, = 8.0 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.62 - 7.56 (m, 2H), 7.49 - 7.40 (m, 2H), 7.26 - 7.17 (m, 2H), 5.77 (d, J = 6.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z (M+H) + 406.1.
3-(2-FLUOROPHENYL)-l-METHYL-N-(l-OXO-3-PHENYLPROPAN-2-YL) -lH-
[1421] Compound 520 (60 mg, yield: 39.6%, light yellow solid) was prepared as in compound 21 from the corresponding starting materials, 3-(2-fluorophenyl)-l-methyl-lH- pyrazole-4-carboxylic acid and 3-amino-2-hydroxy-4-phenyl-butanamide (274D). Compound 520: 1H NMR (400MHz, DMSO-d 6 ) δ 9.56 (s, 1H), 7.93 (s, 1H), 7.47 - 7.33 (m, 2H), 7.23 - 7.08 (m, 5H), 6.95 (dd, = 2.9, 6.6 Hz, 2H), 6.00 (d, = 6.2 Hz, 1H), 4.70 (q, = 6.7 Hz, 1H), 3.96 (s, 3H), 3.07 (d, = 6.4 Hz, 2H). MS (ESI) m/z (M+H) + 392.0.
[1422] To a suspension of 3-fluorobenzaldehyde (10 g, 80.6 mmol) and NH 2 OH.HCl (6.2 g, 88.6 mmol) in EtOH (10 mL) and H 2 0 (20 mL) was added ice (50 g). Then an aqueous solution of NaOH (8.1 g, 201.4 mmol) in H 2 0 (20 mL) was added dropwise over a period of 10 min where upon most of the solid dissolves. Then the mixture was stirred 2 hours at 16 °C. The resulting mixture was then acidified with HC1 (5N). The mixture was then extracted with dichloromethane (80 mL) for three times to give compound 323A (10 g, yield: 89.2%) as a light yellow solid. The product was used into the next step without future purification. 1H NMR (400MHz, CDCI 3 ) δ 8.13 (s, 1H), 7.95 (br s, 1H), 7.39 - 7.30 (m, 3H), 7.13 - 7.06 (m, 1H).
[1423] NCS (5.3 g, 39.5 mmol) was added to a solution of compound 323A (5 g, 35.9 mmol) in DMF (20 mL) followed by stirring at 20 °C for 3 hours. The reaction mixture was diluted with H 2 0 (60 mL), and extracted with Ethyl acetate (100 mL x 2). The organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give compound 323B (5.7 g, yield: 91.4%) as a yellow solid. The product was used into the next step without future purification. 1H NMR (400MHz, CDC1 3 ) δ 8.21 (s, 1H), 7.66 (d, = 7.9 Hz, 1H), 7.57 (br d, J = 10.1 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.16 (tt, J = 1.1, 8.3 Hz, 1H).
[1424] To a solution of ethyl 3-(dimethylamino)acrylate (825 mg, 5.8 mmol) and TEA (583 mg, 5.8 mmol) in THF (15 mL) was added a solution of compound 323B (1 g, 5.8 mmol) in THF (35 mL) dropwise over a period of 30 mins. The mixture was stirred at 16 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1 : 0 to 30: 1) to give compound 323C (800 mg, yield: 59%) as a pale yellow oil. 1H NMR (400MHz, CDCI 3 ) δ 9.03 (s, 1H), 7.62 - 7.51 (m, 2H), 7.45 (dt, = 5.8, 8.0 Hz, 1H), 7.25 - 7.17 (m, 1H), 4.32 (q, = 7.1 Hz, 2H), 1.33 (t, = 7.2 Hz, 3H).
[1425] To a mixture of compound 323C (224 mg, 952 umol) in THF (5 mL) and H 2 0 (1 mL) was added LiOH.H 2 0 (80 mg, 1.90 mmol). The mixture was stirred at 15 °C for 12 hours. The mixture was concentrated to remove solvent and adjusted to pH ~ 5 with aqueous HC1 (1M). The mixture was filtered and the solid was washed with H 2 0 (3 mL) to give intermediate compound 323D (200 mg, crude) as a white solid. 1H NMR (400MHz, DMSO-i¾) δ 9.40 (s, 1H), 7.74 (td, J = 1.9, 10.3 Hz, 1H), 7.66 (d, = 7.7 Hz, 1H), 7.52 (dt, = 6.2, 7.9 Hz, 1H), 7.34 (dt, = 2.2, 8.4 Hz, 1H).
[1426] Compound 323 (68.9 mg, yield: 66.0%, white solid) was prepared as in Example 5 from the corresponding starting materials, compounds 323D and 12G. Compound 323: 1H NMR (400MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 9.05 (br d, J = 7.5 Hz, 1H), 8.13 (br s, 1H), 7.87 (br s, 1H), 7.54 - 7.17 (m, 9H), 5.38 (br s, 1H), 3.26 - 3.15 (m, 1H), 2.81 (br dd, = 10.6, 13.2 Hz, 1H). MS (ESI) m/z (M+H) + 382.1. EXAMPLE 180
N-(4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-3-(PYRIMIDIN-2-YL)I SOXAZOLE- -CARBOXAMIDE (324)
[1427] A mixture of pyrimidine-2-carbonitrile (10 g, 95.2 mmol), NH 2 OH.HCl (6.94 g, 99.9 mmol) and CH 3 ONa (5.40 g, 99.9 mmol) in MeOH (100 mL) was heated to 70 °C for 2h. The mixture was concentrated, the residue was added water (50 mL) to give a precipitate, the solid was filtered, washed with water (5 mL x 2), MTBE (10 mL) to give compound 324A (10.4 g, yield: 79.1%) as white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 10.18 (s, 1H), 8.84 (d, = 4.9 Hz, 2H), 7.51 (t, J = 4.9 Hz, 1H), 5.84 (br s, 2H).
[1428] NaN0 2 (1.25 g, 18.1 mmol) in H 2 0 (7 mL) was added to a solution of compound 324A (2 g, 14.5 mmol) in HC1 (40 mL) at 0 °C, the mixture was stirred at 0 °C for 2h. The mixture was adjusted to pH ~ 6 with saturated aqueous NaHC0 3 to give a precipitate. The solid was filtered, washed with water (5 mL x 2) and dried to give compound 324B (1.40 g, yield: 61.4%), as white solid. 1H NMR (400MHz, OMSO-d 6 ) δ 12.95 (s, 1H), 8.92 (d, J = 4.9 Hz, 2H), 7.60 (t, J = 5.0 Hz, 1H).
[1429] A suspension of compound 324B (500 mg, 3.17 mmol) in THF (4 mL) was added in portions to a mixture of 3-amino-2-hydroxy-4-phenylbutanamide (454 mg, 3.17 mmol) and TEA (321 mg, 3.17 mmol) in THF (6 mL), the mixture was stirred at 10 °C for 12h. The mixture was filtered and the filtrate was concentrated, the residue was purified by preparatory- TLC (Petroleum ether: Ethyl acetate = 1 : 1) to give compound 324C (300 mg, yield: 43.2%) as yellow oil. 1H NMR (400MHz, CDC1 3 ) δ 7.46 - 7.39 (m, 1H), 7.39 - 7.32 (m, 2H), 7.30 - 7.27 (m, 1H), 7.25 - 7.19 (m, 4H), 7.05 - 7.00 (m, 2H), 6.87 (br s, 1H), 5.92 - 5.85 (m, 2H), 5.40 (br s, 1H), 4.22 (dd, J = 1.3, 4.9 Hz, 1H), 4.17 - 4.09 (m, 1H), 2.92 - 2.81 (m, 2H).
[1430] A mixture of compound 324C (150 mg, 684 umol) and LiOH.H 2 0 (43.1 mg, 1.03 mmol) in THF (5 mL), EtOH (3 mL), H 2 0 (2 mL) was stirred at 10 °C for 12h. LCMS showed desired MS, the organic solvent was removed under vacuum, the water layer was extracted with MTBE (5 mL) and then adjusted to pH ~ 4 with IN HC1, the mixture was concentrated to give crude compound 324D (130 mg, crude) as black solid.
[1431] Compound 324 (27.9 mg, yield: 62.3%, yellow solid) was prepared as in Example 6 from the corresponding starting materials, compounds 324D and 3-amino-2-hydroxy- 4-phenyl-butanamide (274D). Compound 324:. 1H NMR (400MHz, OMSO-d 6 ) δ 10.16 (d, 7 = 7.3 Hz, 1H), 9.56 (s, 1H), 8.84 (d, 7 = 5.1 Hz, 2H), 8.13 (s, 1H), 7.88 (s, 1H), 7.66 (t, 7 = 5.0 Hz, 1H), 7.27 - 7.05 (m, 5H), 5.51 (dt, 7 = 5.0, 7.6 Hz, 1H), 3.21 (dd, 7 = 4.9, 14.1 Hz, 1H), 3.00 (dd, 7 = 7.8, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 366.1.
(5)-N-((5)-4-AMINO-3,4-DIOXO-l-PHENYLBUTAN-2-YL)-l-PHENYLPYR ROLIDINE- -CARBOXAMIDE (308)
[1432] The mixture of L-proline (1.15 g, 1 eq) and iodobenzene (2.04 g, 1 eq), K 2 CO 3 (2.07 g, 1.5 eq) and Cul (0.19 g, 0.1 eq) in DMA (15 mL) was heated to 90 °C under N 2 atmosphere for 48 hours. The reaction mixture was diluted with ethyl acetate and water after cooling to room temperature and adjusted pH to ~ 3 with HC1. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 times). The combined organic layer was washed with brine, dried over Na 2 S0 4 and concentrated. The residue was purified on ISCO to afford compound acid 308A.
[1433] Compound 308 was prepared as in Example 5 from acid, intermediate compound 308A. 1H NMR (400 MHz, DMSO): 1H NMR (400 MHz, DMSO): δ 8.3 - 7.5 (m, 2H), 7.38 -7 (m, 7H), 6.7 -6.2 (m, 4 H), 5.2 (m, 0.5 H), 4.35 (m, 0.5H), 3.9-3.3 (m, 3H), 3.2 - 2.8 (m, 2H) 2.2 - 1.7 (m, 4H) ppm. MS (ESI) m/z (M+H) + 356.9. EXAMPLE 182
[1434] Compounds 325-327 were synthesized from the corresponding starting materials using same procedures as described earlier for compound 321.
[1435] Compound 325: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(M-tolyl)- l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO- 6 ) δ 9.42 (br d, J = 7.3 Hz, IH), 8.17 (br s, IH), 7.92 (br s, IH), 7.49 (s, IH), 7.39 - 7.13 (m, 8H), 5.55 - 5.43 (m, IH), 3.20 (br dd, J = 3.0, 14.2 Hz, IH), 2.85 (br dd, J = 10.0, 14.0 Hz, IH), 2.30 (s, 3H). MS (ESI) m/z (M+H) + 395.1.
[1436] Compound 326: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(o-tolyl)- l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 7.52 (br d, J = 7.7 Hz, IH), 7.39 - 7.32 (m, IH), 7.31 - 7.19 (m, 6H), 7.13 (br d, J = 6.6 Hz, 2H), 6.71 (br s, IH), 5.66 (dt, J = 5.3, 7.5 Hz, IH), 5.59 (br s, IH), 3.41 (dd, J = 5.1, 14.1 Hz, IH), 3.18 (dd, J = 7.3, 14.1 Hz, IH), 2.17 - 2.01 (m, 3H). MS (ESI) m/z (M+H) + 395.1.
[1437] Compound 327: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(2- fluorophenyl)-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 7.58 - 7.41 (m, 3H), 7.33 - 7.21 (m, 4H), 7.19 - 7.08 (m, 3H), 6.74 (br s, IH), 5.79 - 5.68 (m, IH), 5.65 (br s, IH), 3.50 - 3.37 (m, IH), 3.36 - 3.23 (m, IH). MS (ESI) m/z (M+H) + 399.1.
[1438] Compounds 328-329 were synthesized from the corresponding starting materials using same rocedures as described earlier for compound 317.
[1439] Compound 328 was synthesized using ethyl 3-bromo-l-methyl- lH-pyrazole-4- carboxylate and (3-f uorophenyl)boronic acid via intermediates 545 and 589 using the same procedures as in compound 317. Compound 328: (5)-3-(3-fluorophenyl)-l-methyl-N-(l-oxo-3- phenylpropan-2-yl)-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 9.57 (s, 1H), 8.51 (d, 7 = 8.0 Hz, 1H), 8.08 (s, 1H), 7.48 - 7.41 (m, 2H), 7.37 - 7.29 (m, 1H), 7.29 - 7.21 (m, 4H), 7.21 - 7.09 (m, 2H), 4.50 - 4.42 (m, 1H), 3.88 (s, 3H), 3.24 - 3.18 (m, 1H), 2.85 - 2.77 (m, 1H). MS (ESI) m/z (M+H) + 352.1.
[1440] Compound 329: (5)-l-methyl-N-(l-oxo-3-phenylpropan-2-yl)-3-(M-tolyl)- lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.56 (s, 1H), 8.35 (d, 7 = 7.2 Hz, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 7.32 (d, 7 = 7.6 Hz, 1H), 7.29 - 7.18 (m, 5H), 7.17 - 7.14 (m, 1H), 7.12 - 7.07 (m, 1H), 4.47 - 4.40 (m, 1H), 3.86 (s, 3H), 3.22 - 3.16 (m, 1H), 2.85 - 2.78 (m, 1H), 2.29 - 2.25 (m, 1H), 2.27 (s, 2H). MS (ESI) m/z (M+H) + 348.1.
COMPOUNDS 330
[1441] Compound 330 was synthesized from the intermediate 250D and using same procedures as described earlier for compound 317.
[1442] Compound 330: (5)-l-cyclopropyl-N-(l-oxo-3-phenylpropan-2-yl)-3- phenyl-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, CD 3 CN) δ 9.59 (s, 1H), 7.92 (s, 1H), 7.56 - 7.08 (m, 10H), 6.65 (s, 1H), 4.58 - 4.44 (m, 1H), 3.77 - 3.58 (m, 1H), 3.30 - 3.15 (m, 1H), 2.95 - 2.86 (m, 1H), 1.15 - 0.99 (m, 4H). MS (ESI) m/z (M+H) + 360.1.
[1443] Compounds 331-333 were synthesized from the intermediate 32F and using same procedures as described earlier for compound 168
[1444] Compound 331: (5)-N-(4-amino-3,4-dioxo-l-( n-tolyl)butan-2-yl)-l-methyl- 3-phenyl-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 8.25 (d, 7=7.3 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.80 (s, 1H), 7.61 - 7.56 (m, 2H), 7.40 - 7.22 (m, 3H), 6.85 (s, 3H), 5.28 (br s, 1H), 3.90 (s, 3H), 3.11 - 3.04 (m, 1H), 2.77 - 2.68 (m, 1H), 2.22 (s, 6H). MS (ESI) m/z (M+H) + 405.2. [1445] Compound 332: (S)-N-(l-amino-l,2-dioxopentan-3-yl)-l-methyl-3-phenyl- lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO- 6 ) δ 8.26 (br d, 7 = 6.8 Hz, 1H), 8.19 (s, 1H), 8.02 (br s, 1H), 7.76 (br s, 1H), 7.69 (br d, 7 = 7.0 Hz, 2H), 7.39 - 7.28 (m, 3H), 4.95 (br t, 7 = 10.0 Hz, 1H), 3.91 (s, 3H), 1.90 - 1.75 (m, 1H), 1.66 - 1.50 (m, 1H), 0.94 (t, 7 = 7.3 Hz, 3H). MS (ESI) m/z (M+H) + 315.1.
[1446] Compound 333: N-((35,4R)-l-amino-4-methyl-l,2-dioxohexan-3-yl)-l- methyl-3-phenyl-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 8.07 - 7.94 (m, 2H), 7.75 - 7.59 (m, 3H), 7.43 - 7.27 (m, 3H), 5.06 (t, 7 = 6.9 Hz, 1H), 3.90 (s, 3H), 2.11 - 1.88 (m, 1H), 1.36 (ddd, 7 = 3.9, 7.3, 13.7 Hz, 1H), 1.20 - 1.04 (m, 1H), 0.91 - 0.79 (m, 6H). MS (ESI) m/z (M +H) + 343.2.
[1447] Compound 415 (45 mg, yield: 60.98%): (5)-N-(l-amino-5-methyl-l,2- dioxohexan-3-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamide : 1H NMR (400MHz, DMSO- e) δ 8.24 (d, 7 = 6.8 Hz, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.66 (d, 7 = 7.4 Hz, 2H), 7.35 - 7.26 (m, 3H), 5.13 - 5.07 (m, 1H), 3.88 (s, 3H), 1.75 - 1.65 (m, 1H), 1.51 - 1.42 (m, 2H), 0.88 (d, 7 = 6.6 Hz, 6H). MS (ESI) m/z (M+H) + 343.1.
[1448] Compound 416 (25 mg, yield: 34.6%): (5)-N-(l-amino-5,5-dimethyl-l,2- dioxohexan-3-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamide : 1H NMR (400MHz, DMSO-d 6 ) δ 8.26 (d, 7 = 7.5 Hz, 1H), 8.13 - 8.09 (m, 1H), 8.04 (s, 1H), 7.78 - 7.66 (m, 3H), 7.38 - 7.28 (m, 3H), 5.19 (br t, 7 = 6.9 Hz, 1H), 3.93 - 3.87 (m, 3H), 1.61 - 1.46 (m, 2H), 0.95 (s, 9H). MS (ESI) m/z (M+H) + 357.2.
[1449] Compound 417 (25 mg, yield: 71.7%): N-(l-amino-l,2-dioxo-5- phenylpentan-3-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxami de: 1H NMR (400MHz, DMSO-d 6 ) δ 8.44 (d, 7 = 6.8 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.68 (d, 7 = 6.8 Hz, 2H), 7.36 - 7.23 (m, 5H), 7.22 - 7.14 (m, 3H), 4.99 - 4.91 (m, 1H), 3.90 (s, 3H), 2.79 - 2.69 (m, 1H), 2.67 - 2.59 (m, 1H), 2.10 - 1.99 (m, 1H), 1.87 - 1.76 (m, 1H). MS (ESI) m/z (M+H) + 391.2.
[1450] Compound 418 (25.1 mg, yield: 22.25%): N-(4-amino-l-(3,5- dichlorophenyl)-3,4-dioxobutan-2-yl)-l-methyl-3-phenyl-lH-py razole-4-carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 8.47 (d, 7 = 7.6 Hz, 1H), 8.05 (br. s, 1H), 7.98 (s, 1H), 7.79 (br. s, 1H), 7.55 - 7.44 (m, 3H), 7.32 - 7.21 (m, 5H), 5.25 - 5.17 (m, 1H), 3.87 (s, 3H), 3.19 - 3.11 (m, 1H), 2.88 - 2.77 (m, 1H). MS (ESI) m/z (M+H) + 445.0. [1451] Compound 419 (10 mg, yield: 17.6%): (S)-N-(l-amino-l,2-dioxoheptan-3- yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 8.23 (br d, J = 6.6 Hz, IH), 8.15 (s, IH), 8.00 (s, IH), 7.74 (s, IH), 7.65 (br d, J = 6.6 Hz, 2H), 7.36 - 7.25 (m, 3H), 5.07 - 4.93 (m, IH), 3.88 (s, 3H), 1.79 - 1.67 (m, IH), 1.57 - 1.44 (m, IH), 1.37 - 1.20 (m, 4H), 0.84 (br t, = 6.9 Hz, 3H). MS (ESI) m/z (M+H) + 343.2.
[1452] Compound 420 (25 mg, yield: 38.7%): (5)-N-(4-amino-l-(4- methoxyphenyl)-3,4-dioxobutan-2-yl)-l-methyl-3-phenyl-lH-pyr azole-4-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 8.04 (s, IH), 7.85 - 7.67 (m, 2H), 7.66 - 7.46 (m, 3H), 7.37 - 7.29 (m, 3H), 7.17 - 7.09 (m, 2H), 6.89 - 6.77 (m, 2H), 5.33 - 5.24 (m, IH), 3.94 - 3.85 (m, 3H), 3.76 - 3.71 (m, 3H), 3.16 - 3.10 (m, IH), 2.88 - 2.80 (m, IH). MS (ESI) m/z (M+H) + 407.1.
[1453] Compound 421 (10 mg, yield: 28.2%): (5)-N-(4-amino-l-(4- hydroxyphenyl)-3,4-dioxobutan-2-yl)-l-methyl-3-phenyl-lH-pyr azole-4-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.25 (s, IH), 8.25 (br d, = 7.3 Hz, IH), 8.06 (s, 2H), 7.80 (s, IH), 7.60 - 7.52 (m, 2H), 7.36 - 7.26 (m, 3H), 7.03 (d, = 8.6 Hz, 2H), 6.67 (d, = 8.6 Hz, 2H), 5.28 - 5.17 (m, IH), 3.92 - 3.85 (m, 3H), 3.03 (dd, = 4.1, 13.8 Hz, IH), 2.73 - 2.68 (m, IH). MS (ESI) m/z (M+H) + 393.1.
[1454] Compound 422 (20.3 mg, yield: 27.2%): N-(l-amino-6,6,6-trifluoro-l,2- dioxohexan-3-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamide : 1H NMR (400MHz, DMSO-d 6 ) δ 8.54 (br d, = 6.8 Hz, IH), 8.20 (s, IH), 8.03 (br s, IH), 7.78 (br s, IH), 7.68 (br d, = 7.6 Hz, 2H), 7.39 - 7.27 (m, 3H), 5.00 - 4.90 (m, IH), 3.91 (s, 3H), 2.43 - 2.36 (m, 2H), 2.12 - 1.98 (m, IH), 1.87 - 1.72 (m, IH). MS (ESI) m/z (M+l) + 383.1.
[1455] Compound 423 (23 mg, yield: 35.5%): (5)-N-(4-amino-l-(lH-indol-3-yl)- 3,4-dioxobutan-2-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxa mide: 1H NMR (400MHz, DMSO-d 6 ) δ 10.81 (s, IH), 8.18 (d, = 6.8 Hz, IH), 8.11 - 8.01 (m, 2H), 7.80 (s, IH), 7.62 (d, = 7.6 Hz, IH), 7.56 - 7.46 (m, 2H), 7.32 (d, = 7.6 Hz, IH), 7.28 - 7.21 (m, 3H), 7.14 - 7.08 (m, IH), 7.08 - 7.02 (m, IH), 6.99 - 6.93 (m, IH), 5.39 - 5.31 (m, IH), 3.85 (s, 3H), 3.30 - 3.23 (m, IH), 2.96 - 2.87 (m, IH). MS (ESI) m/z (M+H)+ 416.2.
[1456] Compound 424 (23.6 mg, yield: 24.48%): N-(5-amino-l,l,l-trifluoro-4,5- dioxopentan-3-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamid e: 1H NMR (400MHz, DMSO-d 6 ) δ 8.78 (d, = 7.2 Hz, IH), 8.14 - 8.02 (m, 2H), 7.81 (s, IH), 7.70 - 7.63 (m, 2H), 7.39 - 7.29 (m, 3H), 5.20 - 5.13 (m, 1H), 3.91 (s, 3H), 2.97 - 2.80 (m, 1H), 2.74 - 2.60 (m, 1H). MS (ESI) m/z (M+l) + 369.1.
[1457] Compound 317 was subjected to reaction conditions as used for converting intermediate 98C to 98D to obtain the intermediate 334A (1.82 g, yield 89.9%) as white solid, which was used directly for the next step without purification. 1H NMR (DMSO-i¾, 400 MHz) δ 8.17 - 8.05 (m, 1H), 8.03 - 7.89 (m, 1H), 7.51 - 7.40 (m, 2H), 7.29 - 7.13 (m, 8H), 6.89 - 6.76 (m, 1H), 4.69 - 4.42 (m, 1H), 4.40 - 4.26 (m, 1H), 3.85 (s, 3H), 3.10 - 2.94 (m, 1H), 2.84 - 2.60 (m, 1H). MS (ESI) m/z (M+H)+ 361.1.
[1458] To a mixture of compound 334A (1.82 g, 5.1 mmol) in MeOH (20 mL) was added HCl/MeOH (20 mL) at 25 °C. The mixture was stirred at 25 °C for 15h. After solvent of the reaction mixture was removed under reduced pressure, MeOH (25 mL) and ¾0 (25 mL) were added, and then the mixture was stirred at 25 °C for lh. The reaction mixture was concentrated under reduced pressure to remove solvents to afford compound 334B (2 g, crude) as white solid, which was used directly for next step without purification.
[1459] To a mixture of compound 334B (2 g, 5.1 mmol) in THF (15 mL) and MeOH
(15 mL) was added aqueous NaOH (2M, 13 mL) at 25 °C. The mixture was stirred at 25 °C for
6h. The reaction mixture was concentrated under reduced pressure to move MeOH and THF.
¾0 (10 mL) was added into the mixture, which was washed with TBME (10 mL x 2), and then the aqueous phase was acidified with aqueous HC1 (1M) till pH ~ 4-5. The precipitate was filtered and dried to afford compound 334C (1.33 g, yield 69.1%) as white solid, which was used directly for next step without purification. 1H NMR (DMSO-i¾ , 400 MHz) δ 12.55 (s, IH), 8.03 - 7.93 (m, IH), 7.90 - 7.39 (m, 3H), 7.32 - 7.14 (m, 8H), 5.74 - 5.25 (m, IH), 4.54 - 4.36 (m, IH), 4.10 - 3.94 (m, IH), 3.85 (d, J = 4.9 Hz, 3H), 2.92 - 2.71 (m, 2H). MS (ESI) m/z (M+H) + 380.1.
[1460] Compounds 334-340 were synthesized from the intermediate 334C and the corresponding amine and using same procedures as described earlier for compound 168.
[1461] Compound 334: (5)-l-methyl-N-(4-((oxazol-2-ylmethyl)amino)-3,4-dioxo- l-phenylbutan-2-yl)-3-phenyl-lH-pyrazole-4-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 7.90 (s, IH), 7.64 (s, IH), 7.54 - 7.33 (m, 6H), 7.22 - 7.12 (m, 3H), 7.10 (s, IH), 6.84 - 6.77 (m, 2H), 6.10 (d, = 6.0 Hz, IH), 5.60 - 5.46 (m, IH), 4.76 - 4.53 (m, 2H), 3.92 (s, 3H), 3.33 - 3.22 (m, IH), 2.96 - 2.87 (m, IH). MS (ESI) m/z (M+H) + 458.2.
[1462] Compound 335: (5)-N-(4-((2-(2-methoxyethoxy)ethyl)amino)-3,4-dioxo-l- phenylbutan-2-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamid e: 1H NMR (CDC1 , 400 MHz) δ 7.89 (s, IH), 7.53 - 7.45 (m, 2H), 7.44 - 7.29 (m, 4H), 7.18 (s, 3H), 6.80 (s, 2H), 6.09 (d, = 4.5 Hz, IH), 5.58 (d, = 4.8 Hz, IH), 3.91 (s, 3H), 3.68 - 3.48 (m, 8H), 3.38 (s, 3H), 3.28 (d, = 10.3 Hz, IH), 2.97 - 2.84 (m, IH) . MS (ESI) m/z (M+H) + 479.2.
[1463] Compound 336: (5)-l-methyl-N-(4-((2-(methylamino)-2-oxoethyl)amino)- 3,4-dioxo-l-phenylbutan-2-yl)-3-phenyl-lH-pyrazole-4-carboxa mide: 1H NMR (CDC1 3 400 MHz) δ 7.83 (s, IH), 7.58 - 7.32 (m, 6H), 7.18 (s, 3H), 6.82 (s, 2H), 6.32 (s, IH), 6.11 (s, IH), 5.31 (s, IH), 4.15 - 3.80 (m, 5H), 3.28 - 3.08 (m, IH), 2.93 - 2.64 (m, 4H). MS (ESI) m/z (M+H) + 448.2.
[1464] Compound 337: (5)-N-(4-((2-(dimethylamino)-2-oxoethyl)amino)-3,4- dioxo-l-phenylbutan-2-yl)-l-methyl-3-phenyl-lH-pyrazole-4-ca rboxamide: 1H NMR
(CDC1 3, 400 MHz) δ 7.92 - 7.79 (m, 2H), 7.52 - 7.44 (m, 2H), 7.44 - 7.33 (m, 3H), 7.21 - 7.11 (m, 3H), 6.85 - 6.74 (m, 2H), 6.09 (d, = 6.3 Hz, IH), 5.62 (q, = 6.5 Hz, IH), 4.18 - 3.99 (m, 2H), 3.91 (s, 3H), 3.31 - 3.22 (m, IH), 3.01 (d, = 3.3 Hz, 6H), 2.95 - 2.86 (m, IH). MS (ESI) m/z (M+H) + 462.2.
[1465] Compound 338: (S)-N-(4-((3-amino-3-oxopropyl)amino)-3,4-dioxo-l- phenylbutan-2-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamid e: 1H NMR (CDC1 , 400 MHz) δ 7.86 (s, IH), 7.52 - 7.46 (m, 2H), 7.45 - 7.35 (m, 4H), 7.21 - 7.13 (m, 3H), 6.86 - 6.74 (m, 2H), 6.08 (d, J = 5.8 Hz, IH), 5.71 (s, IH), 5.58 - 5.46 (m, IH), 5.34 (s, IH), 3.91 (s, 3H), 3.73 - 3.51 (m, 2H), 3.24 (dd, / = 4.8, 14.1 Hz, IH), 2.86 (dd, / = 7.8, 14.3 Hz, IH), 2.49 (t, / = 5.9 Hz, 2H). MS (ESI) m/z (M+H) + 448.2.
[1466] Compound 339: (5)-N-(4-((2-amino-2-oxoethyl)amino)-3,4-dioxo-l- phenylbutan-2-yl)-l-methyl-3-phenyl-lH-pyrazole-4-carboxamid e: 1H NMR (CDC1 3, 400 MHz) δ 7.83 (s, IH), 7.55 - 7.34 (m, 6H), 7.22 - 7.14 (m, 3H), 6.89 - 6.77 (m, 2H), 6.33 (s, IH), 6.14 (d, = 4.6 Hz, IH), 5.52 (s, IH), 5.37 - 5.19 (m, IH), 4.12 - 4.02 (m, IH), 3.99 - 3.94 (m, IH), 3.90 (s, 3H), 3.28 - 3.13 (m, IH), 2.99 - 2.77 (m, IH). MS (ESI) m/z (M+H) + 434.2.
[1467] Compound 340: Tert-butyl (5)-(2-(3-(l-methyl-3-phenyl-lH-pyrazole-4- carboxamido)-2-oxo-4-phenylbutanamido)ethyl)carbamate: 1H NMR (CDCl 3i 400 MHz) δ 7.89 (s, IH), 7.50 - 7.35 (m, 5H), 7.26 - 7.23 (m, IH), 7.20 - 7.13 (m, 3H), 6.86 - 6.70 (m, 2H), 6.09 (d, = 6.0 Hz, IH), 5.58 - 5.42 (m, IH), 4.97 - 4.82 (m, IH), 3.91 (s, 3H), 3.48 - 3.39 (m, 2H), 3.35 - 3.20 (m, 3H), 2.93 - 2.85 (m, IH), 1.44 (s, 9H). MS (ESI) m/z (M+H) + 520.3.
COMPOUND 341
[1468] Compounds 341C was synthesized from 2-hydrazinylpyrimidine and using same procedures as described earlier for compound 38.
[1469] Compound 341 was synthesized from 341C using same procedures as described earlier for compound 317. Compound 341: (5)-3-methyl-N-(l-oxo-3-phenylpropan- 2-yl)-l-(pyrimidin-2-yl)-lH-pyrazole-5-carboxamide: 1H NMR (400MHz, CDC1 3 ) S 9.75 (d, 7=1.8 Hz, IH), 8.70 - 8.60 (m, 3H), 7.28 - 7.26 (m, IH), 7.25 - 7.16 (m, 5H), 6.74 (s, IH), 5.00 - 4.94 (m, IH), 3.40 - 3.33 (m, IH), 3.32 - 3.24 (m, IH), 2.42 - 2.39 (m, 3H). MS (ESI) m/z (M+H 2 0+H) + 354.2.
[1470] Compounds 342 was synthesized from 2,2,3,3,3-pentafluoropropan-l-amine hydrochloride and using same procedures as described earlier for compound 272.
[1471] Compound 342: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-3- (perfluoroethyl)-l-phenyl-lH-pyrazole-5-carboxamide: 1H NMR (400MHz, OMSO-d6) δ 9.36 (d, J=7.7 Hz, IH), 8.10 (s, IH), 7.85 (s, IH), 7.48 - 7.34 (m, 4H), 7.32 - 7.18 (m, 9H), 5.31 - 5.24 (m, IH), 3.24 - 3.13 (m, IH), 2.85 - 2.69 (m, IH). MS (ESI) m/z (M+H) + 481.1.
[1472] Compound 343 was synthesized from ethyl l-(3-(aminomethyl)phenyl)-3- methyl-lH-pyrazole-5-carboxylate hydrochloride (343A) and using same procedures as described earlier for compound 153. Compound 343: Benzyl (5)-(3-(5-((4-amino-3,4-dioxo-l- phenylbutan-2-yl)carbamoyl)-3-methyl-lH-pyrazol-l-yl)benzyl) carbamate: 1H NMR
(400MHz, DMSO-iM) δ 9.14 - 9.05 (m, 0.4H), 8.16 - 8.00 (m, 0.9H), 7.93 - 7.82 (m, 1.3H), 7.59 - 7.06 (m, 14.2H), 7.00 - 6.87 (m, 0.5H), 6.77 - 6.64 (m, 0.5H), 6.31 - 6.50 (m, 0.9H), 6.49 - 6.40 (m, 0.4H), 6.29 - 6.17 (m, 0.4H), 5.34 - 5.23 (m, 0.4H), 5.04 (s, 1.9H), 4.53 - 4.34 (m, 0.5H), 4.31 - 4.09 (m, 1.9H), 3.24 - 2.99 (m, 0.8H), 2.90 - 2.63 (m, 1.4H), 2.30 - 2.16 (m, 3H). MS (ESI) m/z (M+H) + 540.2. EXAMPLE 190
[1473] Compound 344 was synthesized from ethyl \-{ -{{{tert- butoxycarbonyl)amino)methyl)phenyl)-3-methyl-lH-pyrazole-5-c arboxylate 344A and using same procedures as described earlier for compound 162. Compound 344: Phenyl (5)-(3-(5-((4- amino-3,4-dioxo-l-phenylbutan-2-yl)carbamoyl)-3-methyl-lH-py razol-l- yl)benzyl)carbamate: 1H NMR (400MHz, OMSO-d6) δ 9.14 - 9.08 (m, 1H), 8.40 - 8.33 (m, 1H), 8.13 - 8.04 (m, 1H), 7.87 (s, 1H), 7.45 - 7.09 (m, 13H), 6.99 - 6.71 (m, 1H), 6.60 - 6.20 (m, 1H), 5.31 - 5.23 (m, 1H), 4.46 - 3.97 (m, 2H), 3.26 - 3.01 (m, 1H), 2.90 - 2.68 (m, 1H), 2.31 - 2.19 (m, 3H). MS (ESI) m/z (M+H) + 526.2.
[1474] Compounds 345 and 346 were prepared from 2-hydrazinyl-3-methylpyridine and methyl 2,4-dioxopentanoate using procedures for compounds 38 and 317.
[1475] Compound 345: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-3-methyl-l-(3- methylpyridin-2-yl)-lH-pyrazole-5-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 8.36 (br d, = 4.0 Hz, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.18 - 7.05 (m, 5H), 6.67 (br s, 1H), 6.62 (s, 1H), 5.69 - 5.60 (m, 1H), 5.46 (br s, 1H), 3.35 (dd, J = 5.3, 14.0 Hz, 1H), 3.13 (dd, / = 7.2, 14.0 Hz, 1H), 2.19 (s, 3H), 2.12 (s, 3H).
[1476] Compound 346: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-5-methyl-l-(3- methylpyridin-2-yl)-lH-pyrazole-3-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 8.23 (br d, = 4.6 Hz, 1H), 7.67 (d, = 7.5 Hz, 1H), 7.33 (br d, = 7.3 Hz, 1H), 7.26 - 7.18 (m, 4H), 7.01 (br d, = 3.7 Hz, 2H), 6.68 (br s, 1H), 6.57 (s, 1H), 5.62 (q, = 6.5 Hz, 1H), 5.50 (br s, 1H), 3.34 (dd, = 5.3, 14.1 Hz, 1H), 3.17 (dd, = 6.5, 14.2 Hz, 1H), 2.34 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z (M+H) + 392.2. EXAMPLE 192
[1477] A mixture of 2-chloropyrimidine (10 g, 87.3 mmol), lH-pyrazole (7.73 g, 114 mmol) and K 2 C0 3 (24.1 g, 175 mmol) in DMF (150 mL) was heated to 120 °C for 12 hr. LCMS showed desired MS. TLC (Petroleum ether : Ethyl acetate = 3: 1, R f ~ 0) showed new point, after cooling the mixture was filtered and the filtrate was concentrated, the residue was purified by MPLC (Petroleum ether: Ethyl acetate = 1 : 1) to give Compound 347A (10.4 g, yield: 81.5%) as yellow solid. 1 H NMR (400MHz, CDC1 3 ) δ 8.76 (d, = 4.8 Hz, 2H), 8.60 (d, = 2.4 Hz, 1H), 7.84 (s, 1H), 7.21 (t, J = 4.8 Hz, 1H), 6.51 (s, 1H).
[1478] To a solution of compound 347A (500 mg, 3.42 mmol) in THF (10 mL) was added LDA (1M, 4.45 mL) dropwise at -70 °C and stirred for 10 min, then carbon dioxide was bubbled to the mixture for 30 min, the mixture was slowly warm to 15 °C for 20 min. The mixture was added MTBE (20 mL) and H 2 0 (20 mL), the water layer was adjusted to pH ~ 4 with IN HC1 and extracted with ethyl acetate (20 mL x 4), the organic layer was dried over Na 2 S0 4 , filtered and concentrated to give compound 347B (480 mg, yield: 73.8%) as brown solid. 1H NMR (400MHz, OMSO-d 6 ) δ 13.49 (br s, 1H), 8.94 (d, = 4.9 Hz, 2H), 7.83 (d, = 1.8 Hz, 1H), 7.63 (t, 7 = 4.9 Hz, 1H), 6.98 (d, / = 1.8 Hz, 1H).
[1479] A mixture of compound 347B (200 mg, 1.05 mmol) and NCS (154 mg, 1.16 mmol) in DMF (3 mL) was heated to 90 °C for 4 hr. LCMS showed desired MS, the mixture was purified by preparatory-HPLC (TFA) to give compound 347C (0.2 g , yield: 56.5%) as yellow solid. 1H NMR (400MHz, OMSO-d 6 ) δ 14.05 (br s, 1H), 8.96 (d, = 4.9 Hz, 2H), 8.07 (s, 1H), 7.66 (t, 7 = 4.9 Hz, 1H). [1480] Compound 347 was synthesized from 347C and using same procedures described earlier for converting compound 321D to compound 321. Compound 347: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-4-chloro-l-(pyrimidin-2- yl)-lH-pyrazole-5- carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 9.25 (d, = 7.3 Hz, 1H), 8.67 (d, = 4.9 Hz, 2H), 8.12 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.46 (t, J = 4.9 Hz, 1H), 7.32 - 7.15 (m, 5H), 5.50 - 5.38 (m, 1H), 3.13 (dd, J = 3.6, 14.2 Hz, 1H), 2.77 (dd, J = 9.9, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 399.1.
[1481] Compound 348 was synthesized from 2,3-difluoropyridine and using same procedures described earlier for Example 313. Compound 348: N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-l-(3-fluoropyridin-2-yl)-3-methyl-lH-pyraz ole-5-carboxamide: 1H NMR
(400MHz, DMSO-iM) δ 8.97 (d, = 7.5 Hz, 1H), 8.29 (d, = 4.6 Hz, 1H), 8.07 (s, 1H), 7.92 - 7.80 (m, 2H), 7.57 (td, = 4.2, 8.4 Hz, 1H), 7.32 - 7.25 (m, 4H), 7.21 (dt, = 2.5, 6.1 Hz, 1H), 6.91 (s, 1H), 5.26 - 5.17 (m, 1H), 3.16 (dd, J = 3.3, 13.9 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.27 (s, 3H). MS (ESI) m/z (M+H) + 396.1.
[1482] Compound 349B was prepared 3-(trifluoromethyl)- lH-pyrazole using the same procedure as described for Compound 347B.
[1483] Compound 349 was synthesized from 349B and using same procedures described earlier for converting compound 347C to compound 347. Compound 349: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-l-(pyrimidin-2-yl)-3-(tr ifluoromethyl)-lH-pyrazole-5- carboxamide: 1H NMR (400MHz, CDC1 3 ) S 8.69 (br s, 2H), 8.11 (br s, 1H), 7.33 (br s, 1H), 7.38 - 7.31 (m, 1H), 7.24 (br s, 4H), 7.15 - 7.08 (m, 1H), 7.15 - 7.08 (m, 1H), 7.15 - 7.01 (m, IH), 6.77 (br s, IH), 5.82 (br s, IH), 5.63 (br s, IH), 3.47 (br s, IH), 3.35 (br s, IH). MS (ESI) m/z (M+H) + 433.1.
COMPOUNDS 350 457
[1484] A mixture of 2-chloropyrimidine (15 g, 131 mmol), NH 2 NH 2 .H 2 0 (30 mL), K 2 C0 3 (15 g, 109 mmol) was stirred at 100 °C for 30 min. The mixture was ice cooled and the resulting crude crystals were collected by filtration. The crystals were washed with cold water, air dried, and recrystallized from Petroleum ether (150 mL) to give compound 350A (14.4 g, 131 mmol, yield: 99.8%) as a yellow solid. 1H NMR (400MHz, DMSO-i¾) δ 8.30 (d, = 4.8 Hz, 2H), 8.12 (br s, IH), 6.59 (t, J = 4.7 Hz, IH), 4.13 (s, 2H).
[1485] To a mixture of compound 350A (2 g, 18.2 mmol) and Na (1.46 g, 63.6 mmol) in EtOH (60 mL) was added diethyl maleate (3.75 g, 21.8 mmol) at 15 °C. The mixture was stirred at 60 °C for 3 hours. The reaction was cooled to 15 °C and quenched with acetic acid to pH ~ 7. The mixture was concentrated to give residue. The residue was purified by prep- HPLC (TFA condition) to give compound 350B (3.5 g, 14.8 mmol, yield: 81.6%) as brown oil. 1H NMR (400MHz, CDC1 3 ) δ 8.49 (d, = 4.9 Hz, 2H), 6.85 (t, = 5.0 Hz, 1H), 5.23 (dd, = 4.2, 11.0 Hz, 1H), 4.33 - 4.20 (m, 2H), 3.41 - 3.28 (m, 1H), 3.01 (dd, = 4.2, 17.6 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.32 - 1.21 (m, 3H).
[1486] To a mixture of compound 350B (3.5 g, 14.8 mmol) in MeCN (40 mL) was added POCl 3 (2.73 g, 17.8 mmol, 1.65 mL). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated. The residue was poured into saturated NaHC0 3 (30 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (50 mL x 4). The combined organic phase was dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 0: 1 to 1 : 1) to give compound 350C (900 mg, yield: 23.9%) as a yellow solid. 1H NMR (400MHz, CDC1 3 ) (5 8.44 (d, J = 4.9 Hz, 2H), 6.75 (t, J = 4.9 Hz, 1H), 5.11 (dd, 7 = 6.5, 12.7 Hz, 1H), 4.27 - 4.16 (m, 2H), 3.56 (dd, J = 12.7, 18.0 Hz, 1H), 3.21 (dd, J = 6.6, 18.1 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H).
[1487] To a mixture of compound 350C (900 mg, 3.53 mmol) in MeCN (15 mL) was added Mn0 2 (3.07 g, 35.3 mmol). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (Si0 2 , Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to give compound 350D (215 mg, yield: 24.1%) as brown oil. 1H NMR (400MHz, CDC1 3 ) δ 8.81 (d, J = 4.9 Hz, 2H), 7.36 (t, J = 4.9 Hz, 1H), 6.80 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
[1488] Compounds 350 were synthesized from the intermediate 350D and using same procedures as described earlier for converting compound 38B to compound 38. Compound 350: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-3-chloro-l-(pyrimid in-2-yl)-lH-pyrazole-5- carboxamide: 1H NMR (400MHz, OMSO-d 6 ) δ 9.23 (d, = 7.3 Hz, 1H), 8.78 (d, = 4.9 Hz, 2H), 8.09 (s, 1H), 7.85 (s, 1H), 7.55 (t, J = 4.9 Hz, 1H), 7.33 - 7.19 (m, 5H), 6.84 (s, 1H), 5.35 - 5.25 (m, 1H), 3.16 (dd, J = 3.6, 14.0 Hz, 1H), 2.82 (dd, J = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 399.1.
[1489] Compound 457 were synthesized from the intermediate 350E and 3-amino-N- cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride using same procedures as described earlier for compound 350. Compound 457 (70.21 g, yield: 70.32%): 3-chloro-N-(4- (cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-l-(pyrimidi n-2-yl)-lH-pyrazole-5- carboxamide: 1H NMR (400MHz, OMSO-d 6 ) δ 9.29 (d, = 7.5 Hz, IH), 8.84 (d, = 5.1 Hz, IH), 8.77 (d, J = 4.9 Hz, 2H), 7.56 (t, J = 4.7 Hz, IH), 7.32 - 7.20 (m, 5H), 6.90 (s, IH), 5.36 - 5.29 (m, IH), 3.16 (dd, J = 3.6, 14.0 Hz, IH), 2.83 (dd, J = 9.9, 13.9 Hz, IH), 2.79 - 2.72 (m, IH), 0.71 - 0.56 (m, 4H). MS (ESI) m/z (M+H) + 439.1.
[1490] Compound 351 was synthesized from 341C using same procedures as described earlier for converting compound 321D to compound 321. Compound 341: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-3-methyl-l-(pyrimidin-2- yl)-lH-pyrazole-5- carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.05 (d, J = 7.2 Hz, IH), 8.71 (d, J = 4.8 Hz, 2H), 8.07 (s, IH), 7.83 (s, IH), 7.47 - 7.42 (m, IH), 7.32 - 7.17 (m, 5H), 6.56 (s, IH), 5.29 - 5.21 (m, IH), 3.16 -3.08 (m, IH), 2.85 - 2.77 (m, IH), 2.25 (s, 3H). MS (ESI) m/z (M+H) + 379.0.
[1491] Compound 352 was prepared from 2-chloro-4-hydrazinylpyrimidine and ethyl 2,4-dioxopentanoate using procedures for compounds 345 and 321. Compound 352: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-l-(2-cyclopropylpyrimidi n-4-yl)-3-methyl-lH- pyrazole-5-carboxamide: 1H NMR (400MHz, DMSO- 6 ) δ 9.10 (br d, J = 7.0 Hz, IH), 8.62 (d, = 5.5 Hz, IH), 8.12 (br s, IH), 7.87 (br s, IH), 7.45 (d, = 5.5 Hz, IH), 7.35 - 7.19 (m, 5H), 6.44 (s, IH), 5.56 - 5.48 (m, IH), 3.18 (br dd, / = 3.8, 13.8 Hz, IH), 2.81 (br dd, / = 9.8, 13.8 Hz, IH), 2.28 (s, 3H), 2.00 - 1.90 (m, IH), 0.94 - 0.67 (m, 4H). MS (ESI) m/z (M+H) + 419.2.
[1492] Compound 353 was synthesized from 254D using same procedures as described earlier for synthesis of compound 322. Compound 353: (5)-4-(3-fluorophenyl)-2- methyl-N-(l-oxo-3-phenylpropan-2-yl)oxazole-5-carboxamide: 1H NMR (400MHz, CDC1 3 ) δ 9.71 (s, IH), 8.05 - 7.94 (m, 2H), 7.43 - 7.27 (m, 4H), 7.21 (br d, = 6.8 Hz, 2H), 7.13 - 7.05 (m, IH), 6.89 - 6.84 (m, IH), 4.98 - 4.90 (m, IH), 3.37 - 3.31 (m, IH), 3.29 - 3.20 (m, IH), 2.55 (s, 3H). MS (ESI) m/z (M+H 2 0+H) + 353.1.
[1493] Compound 354D was prepared using procedure for compound 213D. To a solution of compound 354D (2.50 g, 6.82 mmol) and 2,6-lutidine (6.36 mL, 54.56 mmol) in DCM (25 mL) was added trimethylsilyl trifluoromethane sulfonate (7.40 mL, 40.92 mmol) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 0.25 h, then stirred at 20 °C for 3h. The reaction mixture was cooled to 0 °C and added into cooled sat.NH 4 Cl (50 mL), then the mixture was extracted with EtOAc (100 mL x 2), the combined extracts were washed with sat.NaHC0 3 (100 mL), then the mixture was dried over Na 2 S0 4 and filtered, the filtrate was concentrated in vacuum to afford compound 354E (2.50 g, crude) as red oil. MS (ESI) m/z (M +H)+ 339.1.
[1494] To a solution of compound 354E (2.50 g, 7.39 mmol) in MeOH (40 mL) was added TMSCl (1.50 mL, 11.87 mmol) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 0.5 h. TEA was added into the reaction mixture to pH ~ 8, then the mixture was concentrated in vacuum to afford crude compound 354F (2.50 g, crude) as red solid. MS (ESI) m/z (M +H)+ 266.9..
[1495] To a solution of compound 107B (700 mg, 3.45 mmol), compound 354F (1.01 g, 3.80 mmol) and HBTU (1.57 g, 4.13 mmol) in DMF (40 mL) was added DIEA (2.41 mL, 13.78 mmol) at 0-10 °C. After addition, the reaction mixture was stirred at 20 °C for 2h. 5 mL of water was added into the reaction mixture and the mixture was concentrated in vacuum to remove the most of DMF. Then 100 mL of water and 80 mL of EtOAc were added into the mixture and stirred for 2 min. The mixture was separated and the aqueous layer was extracted with EtOAc (80 mL). The combined extracts were washed with 0.3N HC1 (80 mL x 2), sat.NaHC0 3 (80 mL x 2) and brine (80 mL). Then the mixture was dried over Na 2 S0 4 and filtered, the mixture was concentrated in vacuum to afford crude product. The residue was purified by preparatory-HPLC (neutral condition) to afford compound 354G (1.0 g, yield 63.55%) as white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.12 - 7.55 (m, 3H), 7.45 - 7.25 (m, 5H), 7.22 - 7.05 (m, 2H), 6.91 - 6.77 (m, 2H), 6.10 - 5.84 (m, 1H), 4.64 - 4.46 (m, 1H), 4.11 - 3.99 (m, 1H), 2.94 - 2.80 (m, 1H), 2.79 - 2.61 (m, 1H), 2.56 - 2.52 (m, 3H), 1.23 - 1.17 (m, 9H). MS (ESI) m/z (M +H)+ 452.1.
[1496] To a solution of compound 354G (863.1 mg, 1.91 mmol) in DCM (200 mL) was added DMP (3.24 g, 7.65 mmol) at 0 °C under N 2 atmosphere. After addition, the reaction mixture was stirred at 10 °C for lh. 50 mL of sat.Na 2 S 2 0 3 and 50 mL of NaHC0 3 was added into the reaction mixture, the mixture was stirred for 20 min. Then the mixture was separated, the organic layer was washed with 50 mL of sat.Na 2 S 2 0 3 and 50 mL of NaHC0 3 , then water (80 mL), brine (80 mL). The mixture was dried over Na2S04 and filtered, then the mixture was concentrated in vacuum to afford compound 354H (640 mg, yield 74.45%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.77 (d, J=7.5 Hz, 1H), 8.17 - 7.94 (m, 3H), 7.87 - 7.74 (m, 1H), 7.45 - 7.31 (m, 3H), 7.16 (d, J=8.4 Hz, 2H), 6.88 - 6.81 (m, 2H), 5.45 - 5.31 (m, 1H), 3.18 - 3.05 (m, 1H), 2.99 - 2.86 (m, 1H), 2.55 - 2.49 (m, 3H), 1.23 - 1.18 (m, 9H). MS (ESI) m/z (M +H)+ 448.2.
[1497] To a solution of compound 354H (440 mg, 978.87 umol) in DCM (30 mL) was added HCl/EtOAc (4M, 22 mL) at 0 °C. After addition, the reaction mixture was stirred at 10 °C for 2h. The reaction mixture was concentrated and the residue was dissolved into 80 mL of EtOAc, the mixture was washed with water (80 mL), 0.1% NaHC0 3 (80 mL) and brine (80 mL). Then the mixture was dried over Na 2 S0 4 and filtered, then concentrated in vacuum to afford compound 354. Compound 354 (650 mg, 1.49 mmol) was dissolved into 3 mL of CH 3 CN and 15 mL of 2-isopropoxypropane was added into the stirring mixture. After that, the mixture was filtered to afford pure compound 354 (450 mg, yield 71.40%) as light yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.25 (s, 1H), 8.70 (d, J=7.5 Hz, 1H), 8.11 (s, 1H), 8.07 - 8.00 (m, 2H), 7.84 (s, 1H), 7.42 - 7.36 (m, 3H), 7.08 (d, J=8.5 Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 5.45 - 5.29 (m, 1H), 3.13 - 3.05 (m, 1H), 2.93 - 2.84 (m, 1H), 2.56 (s, 3H). MS (ESI) m/z (M +H)+ 394.1.
[1498] To a solution of compound 354 (40 mg, 101.68 umol) and pyridine (19 mg, 233.86 umol) in DCM (2 mL) was added Tf 2 0 (34 mg, 122.02 umol) in DCM (0.5 mL) at 0 °C under N2 atmosphere. After addition, the reaction mixture was stirred at 0 °C for 4h. The reaction mixture was diluted with EtOAc (50 mL), the mixture was washed with 0.2 N HCl (20 mL), NaHC0 3 (20 mL) and brine (20 mL), then the mixture was dried over Na 2 S0 4 and filtered, the mixture was concentrated in vacuum to afford compound 355 (40 mg, yield 63.64%) as yellow solid. 1H NMR (400MHz, DMSO-d 6 ) δ 8.89 (d, J=7.5 Hz, 1H), 8.09 (s, 1H), 8.01 - 7.95 (m, 2H), 7.82 (s, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.38 (m, 2H), 7.37 - 7.32 (m, 3H), 5.44 - 5.28 (m, 1H), 3.26 - 3.21 (m, 1H), 3.06 - 2.96 (m, 1H), 2.52 (s, 3H). MS (ESI) m/z (M +H)+ 526.1.
[1499] To a solution of quinoxaline-2-carboxylic acid (6 g, 34.45 mmol) in MeOH (80 mL) was added con. H 2 SO 4 (675.8 mg, 6.89 mmol) dropwise, then the mixture was stirred at 65 °C for 10 hours. After cooling to room temperature, the mixture was neutralized with a sat. NaHC0 3 and extracted with DCM (60 mL x 3). The organic phases were combined, dried with anhydrous Na 2 S0 4 , and evaporated to afford compound 356A (5.80 g, yield: 89.47%) as a brown solid. The crude product was used directly in the next step without further purification. 1H NMR (CDC1 3 , 400 MHz) δ 9.56 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.97 - 7.84 (m, 2H), 4.13 (s, 3H).
[1500] A solution of compound 356A (2.5 g, 13.29 mmol) in CH 3 COOC 2 H 5 (60 mL) was added t-BuOK (1.94 g, 17.28 mmol). The mixture was stirred for 0.25 hour at 25°C. The mixture was quenched with H 2 0 (50 mL). The organic layer was separated and the aqueous was extracted with EA (50 mL x 3). The organic phases were combined, dried with anhydrous Na 2 S0 4 , filtered and evaporated. The residue was purified by flash chromatography (PE: EA =20/1 to 10/1) to afford compound 356B (2.45 g, 75.48% yield) as pale yellow solid. 1H NMR (CDCI3, 400 MHz) δ 9.57 - 9.33 (m, 1H), 8.19 - 8.06 (m, 2H), 7.96 - 7.74 (m, 2H), 4.35 - 4.26 (m, 2H), 4.24 - 4.13 (m, 2H), 1.28 - 1.18 (m, 3H).
[1501] A mixture of 2,4-dinitrobenzenesulfonic acid (7.83 g, 29.41 mmol, H 2 0) and iodobenzene (5 g, 24.51 mmol) in CHC1 3 (20 mL) was added m-CPBA (4.23 g, 24.51 mmol), the mixture was stirred at 25 °C for 2 hours under N 2 atmosphere. After the reaction, MTBE (20 mL) was added to the reaction mixture, and the resulting mixture was filtered and the solid was washed with MTBE (30 mL). The resulting mixture was filtered and the solid was washed with MTBE (30 mL) to give compound 356C (8.7 g, 75.82% yield) as a white solid. 1H NMR (400MHz, DMSO-d 6 ) δ 9.60 (br s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.39 - 8.36 (m, 1H), 8.18 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.63 - 7.55 (m, 2H).
[1502] A mixture of compound 356C (3.49 g, 7.45 mmol) and compound 356B (1.4 g, 5.73 mmol) were stirred at 80 °C for lh, and acetamide (4.06 g, 68.76 mmol) was added to the mixture, then the mixture was stirred at 120 °C for lh under microwave irradiation. The reaction mixture was concentrated under reduced pressure to remove solvent and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si0 2 , Petroleum ether/Ethyl acetate = 1/0 to 0: 1) to give compound 356D (300 mg, crude) as dull-red solid. MS (ESI) m/z (M+ H)+ 284.1.
[1503] Compound 356 was synthesized from 356D and using same procedures described earlier for converting compound 321C to compound 321. Compound 356: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-2-methyl-4-(quinoxalin-2 -yl)oxazole-5-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) i5 11.39 (d, = 8.4 Hz, 1H), 9.58 (s, 1H), 8.24 (br s, 1H), 8.12 (d, = 8.0 Hz, 1H), 7.95 (br s, 1H), 7.89 (t, = 7.6 Hz, 1H), 7.76 (t, = 7.6 Hz, 1H), 7.60 (d, = 8.4 Hz, 1H), 6.98 - 6.86 (m, 4H), 6.85 - 6.78 (m, 1H), 5.90 - 5.78 (m, 1H), 3.27 - 3.19 (m, 2H), 2.59 (s, 3H). MS (ESI) m/z (M+H) + 430.1.
[1504] Compound 357 was synthesized from 107B and using same procedures described earlier for converting compound 321D to compound 321. Compound 357: N-(4- amino-3,4-dioxo-l-phenylbutan-2-yl)-2-methyl-4-phenyloxazole -5-carboxamide: 1H NMR
(400 MHz, CDCI 3 ) δ 8.12 - 8.05 (m, 2H), 7.43 - 7.37 (m, 3H), 7.32 - 7.26 (m, 3H), 7.15 - 7.10 (m, 2H), 6.78 - 6.71 (m, 2H), 5.75 - 5.68 (m, 1H), 5.54 (br s, 1H), 3..50 - 3.38 (m, 1H), 3.29 - 3.18 (m, 1H), 2.55 (s, 3H). 1H NMR (400 MHz, OMSO-d 6 ) δ 8.82 (d, = 7.2 Hz, 1H), 8.15 - 7.92 (m, 3H), 7.86 (s, 1H), 7.41 - 7.35 (m, 3H), 7.32 - 7.26 (m, 4H), 7.25 - 7.17 (m, 1H), 5.48 -
5.38 (m, 1H), 3.27 - 3.15 (m, 1H), 3.06 - 2.93 (m, 1H), 2.55 (s, 3H). MS (ESI) m/z (M+l) + 378.1.
[1505] Compounds 358 and 359 were synthesized using same procedures described earlier for compound 255. Compound 358: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(2- fluorophenyl)-2-(trifluoromethyl)oxazole-5-carboxamide: 1H NMR (CDC1 3 , 400 MHz) δ 7.52 (t, J = 7.6 Hz, 1H), 7.45 - 7.35 (m, 1H), 7.28 - 7.20 (m, 3H), 7.19 - 7.07 (m, 2H), 7.02 (d, = 7.6 Hz, 2H), 6.68 (d, J = 4.8 Hz, 2H), 5.70 - 5.60 (m, 1H), 5.49 (br s, 1H), 3.42 - 3.32 (m, 1H), 3.24 - 3.14 (m, 1H). MS (ESI) m/z (M+H) + 450.1. Compound 359: N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-4-(o-tolyl)-2-(trifluoromethyl)oxazole-5-c arboxamide: 1H NMR (CDCl 3i 400 MHz) δ 7.43 - 7.34 (m, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.19 (m, 4H), 6.92 (br s, 2H), 6.69 (br s, 1H), 6.44 (d, J = 6.4 Hz, 1H), 5.66 - 5.58 (m, 1H), 5.50 (br s, 1H), 3.41 - 3.28 (m, 1H), 3.08 - 2.97 (m, 1H), 2.21 (s, 3H). MS (ESI) m/z (M+H) + 446.1.
[1506] Compound 360 was synthesized using same procedures described earlier for compound 26. Compound 360: N-((25)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2- methyl-4-phenyloxazole-5-carboxamide: 1H NMR (400 MHz, DMSO-d 6 ) δ 8.19 - 7.58 (m, 3H), 7.47 - 7.34 (m, 5H), 7.32 - 7.26 (m, 2H), 7.25 - 7.06 (m, 3H), 6.16 - 5.82 (m, 1H), 4.73 -
4.39 (m, 1H), 4.06 -3.88 (m, 1H), 3.04 - 2.65 (m, 2H), 2.59 - 2.53 (m, 3H). MS (ESI) m/z (M+l) + 380.0.
[1507] Compound 361 was synthesized from ethyl 3-(2,3-difluorophenyl)-3- oxopropanoate using same procedures described earlier for compound 267. Compound 361: N- (4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(2,3-difluorophenyl )-2-methyloxazole-5- carboxamide: 1H NMR (CDC1 3 , 400MHz) δ 7.36 - 7.27 (m, 3H), 7.26 - 7.17 (m, 2H), 7.15 - 7.06 (m, 3H), 6.78 - 6.63 (m, 2H), 5.74 - 5.62 (m, IH), 5.55 (br s, IH), 3.42 (dd, J = 5.5, 14.3 Hz, IH), 3.25 (dd, J = 6.6, 14.3 Hz, IH), 2.57 (s, 3H). MS (ESI) m/z (M+H)+ 414.1.
[1508] Compounds 362-377, 462-468 were synthesized from the corresponding intermediate or intermediate 321B and using same procedures as described earlier for compound 321.
[1509] Compound 362 (35.2 mg, 47.49% yield, 94% purity, EE%: 97%): (5)-N-(4- fluoro-3-oxo-l-phenylbutan-2-yl)-4-(4-((prop-2-yn-l-yloxy)me thyl)phenyl)-l,2,5- thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.50 - 9.40 (m, IH), 9.45 (d, 7=7.7 Hz, IH), 7.50 (d, 7=8.2 Hz, 2H), 7.38 - 7.22 (m, 7H), 5.44 - 5.14 (m, 2H), 4.99 - 4.88 (m, IH), 4.58 (s, 2H), 4.23 (d, 7=2.4 Hz, 2H), 3.53 (t, 7=2.3 Hz, IH), 3.21 (dd, 7=4.1, 14.2 Hz, IH), 2.89 (dd, 7=10.5, 14.0 Hz, IH). MS (ESI) m/z (M+H) + 438.1, (M+Na) + 460.0.
[1510] Compound 363 (39.2 mg, 36.85% yield, 94% purity): N-(4-amino-3,4-dioxo- l-phenylbutan-2-yl)-4-(4-((4-fluorobenzamido)methyl)phenyl)- l,2,5-thiadiazole-3- carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.44 (d, 7=7.7 Hz, IH), 9.14 (t, 7=6.0 Hz, IH), 8.21 (s, IH), 8.06 - 7.97 (m, 2H), 7.93 (s, IH), 7.51 (d, 7=8.2 Hz, 2H), 7.37 - 7.23 (m, 8H), 7.20 - 7.12 (m, IH), 5.60 - 5.44 (m, IH), 4.52 (d, 7=6.0 Hz, 2H), 3.24 (dd, 7=3.2, 14.0 Hz, IH), 2.85 (dd, 7=10.3, 14.0 Hz, IH). MS (ESI) m/z (M+H) + 532.2.
[1511] Compound 364 (27.5 mg, 26.56% yield, 96% purity): N-(4-amino-3,4-dioxo-
1- phenylbutan-2-yl)-4-chloro-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO- d 6 ) δ 9.24 (d, J=7.5 Hz, IH), 8.19 (s, IH), 7.92 (s, IH), 7.49 - 7.19 (m, 5H), 5.47 (ddd, J=3.9, 7.7, 9.6 Hz, IH), 3.24 (dd, J=3.9, 14.0 Hz, IH), 2.95 (dd, J=9.8, 14.0 Hz, IH). MS (ESI) m/z (M+H) + 339.0.
[1512] Compound 365 (60 mg, 39.4% yield): N-(4-amino-3,4-dioxo-l-phenylbutan-
2- yl)-4-(pyrazin-2-yl)-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-i/ 6 ) δ 9.23 (d, 7 = 7.3 Hz, IH), 9.06 (d, 7 = 1.5 Hz, IH), 8.69 (d, 7 = 2.4 Hz, IH), 8.51 (dd, 7 = 1.5, 2.4 Hz, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.29 - 7.14 (m, 6H), 5.47 (ddd, / = 4.1, 7.6, 9.3 Hz, 1H), 3.16 (dd, / = 4.0, 14.1 Hz, 1H), 2.87 (dd, / = 9.3, 14.3 Hz, 1H). MS (ESI) m/z (M+H) + 383.1.
[1513] Compound 366 (50 mg, 36.9% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-bromo-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.23 (d, = 7.5 Hz, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.35 - 7.17 (m, 4H), 5.54 - 5.41 (m, 1H), 3.23 (dd, = 3.9, 14.2 Hz, 1H), 2.95 (dd, = 9.7, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 383.0.
[1514] Compound 367 (50 mg, 18.43% yield): N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-4-(benzo[rf][l,3]dioxol-4-yl)-l,2,5-thiadi azole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 8.92 (d, = 8.0 Hz, 1H), 7.94 - 7.52 (m, 2H), 7.36 - 7.18 (m, 5H), 7.08 - 6.93 (m, 2H), 6.92 - 6.79 (m, 1H), 5.87 (d, = 10.0 Hz, 2H), 5.55 - 5.38 (m, 1H), 3.23 (dd, = 3.5, 14.1 Hz, 1H), 3.03 - 2.97 (m, 1H). MS (ESI) m/z (M+H) + 425.1.
[1515] Compound 368 (130 mg, 60.3% yield): N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-4-(2-fluoro-3-methylphenyl)-l,2,5-thiadiaz ole-3-carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 9.22 (d, = 7.7 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.39 (t, = 6.9 Hz, 1H), 7.31 - 7.19 (m, 6H), 7.17 - 7.10 (m, 1H), 5.42 (ddd, / = 3.7, 7.7, 9.7 Hz, 1H), 3.19 (dd, = 3.7, 14.1 Hz, 1H), 2.96 (dd, = 9.7, 13.9 Hz, 1H), 2.22 (d, = 2.0 Hz, 3H). MS (ESI) m/z (M+H) + 413.1.
[1516] Compound 369 (55 mg, 27.8% yield): N-(4-amino-3-hydroxy-4-oxo-l- phenylbutan-2-yl)-4-(4-((benzyloxy)methyl)phenyl)-l,2,5-thia diazole-3-carboxamide: 1H
NMR (400MHz, DMSO-d 6 ) δ 9.45 (d, = 7.5 Hz, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.63 - 7.52 (m, 2H), 7.44 - 7.16 (m, 12H), 5.54 - 5.49 (m, 1H), 4.62 - 4.56 (m, 4H), 3.24 (dd, = 3.6, 14.0 Hz, 1H), 2.86 (dd, = 10.1, 13.9 Hz, 1H). MS (ESI) m/z (M+H) + 501.1.
[1517] Compound 370 (55 mg, 20.1% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(3-((benzyloxy)methyl)phenyl)-l,2,5-thiadiazole-3-ca rboxamide: 1H NMR (400MHz, DMSO-i¾) δ 9.42 (d, = 7.7 Hz, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.49 - 7.43 (m, 2H), 7.42 - 7.33 (m, 5H), 7.32 - 7.24 (m, 5H), 7.24 - 7.19 (m, 1H), 6.49 - 6.39 (m, 1H), 5.55 - 5.48 (m, 1H), 4.55 (d, = 5.7 Hz, 4H), 3.22 (dd, = 3.6, 14.0 Hz, 1H), 2.88 (dd, = 9.9, 13.9 Hz, 1H). MS (ESI) m/z (M+H 2 0) + 518.2.
[1518] Compound 371 (90 mg, 63.2% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(pyridin-4-yl)-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.47 (d, J = 7.8 Hz, IH), 8.65 - 8.55 (m, 2H), 8.21 (s, IH), 7.95 (s, IH), 7.52 - 7.38 (m, 2H), 7.33 - 7.22 (m, 5H), 6.53 - 6.39 (m, IH), 5.55 - 5.47 (m, IH), 3.28 - 3.22 (m, IH), 2.92 - 2.83 (m, IH). MS (ESI) m/z (M+H) + 382.1.
[1519] Compound 372 (50 mg, 22.8% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(2,3-difluorophenyl)-l,2,5-thiadiazole-3-carboxamide : 1H NMR (400MHz, DMSO- d 6 ) δ 9.24 (d, = 7.6 Hz, IH), 8.12 (s, IH), 7.86 (s, IH), 7.59 - 7.50 (m, IH), 7.29 - 7.16 (m, 7H), 5.44 - 5.37 (m, IH), 3.21 - 3.14 (m, IH), 2.98 - 2.90 (m, IH). MS (ESI) m/z (M+H) + 417.1.
[1520] Compound 373 (85 mg, 44.6% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(pyridin-2-yl)-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.36 (d, = 7.1 Hz, IH), 8.42 (d, = 5.6 Hz, IH), 8.10 (s, IH), 7.97 - 7.79 (m, 3H), 7.50 - 7.34 (m, IH), 7.21 (s, 5H), 5.54 - 5.46 (m, IH), 3.20 - 3.11 (m, IH), 2.90 (dd, / = 8.8, 14.1 Hz, IH). MS (ESI) m/z (M+H) + 382.1.
[1521] Compound 374 (100 mg, 49.9% yield): N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-4-(pyrimidin-4-yl)-l,2,5-thiadiazole-3-car boxamide: 1H NMR (400MHz, DMSC fc) δ 9.27 (d, = 7.5 Hz, IH), 9.05 (d, = 1.3 Hz, IH), 8.94 (d, = 5.1 Hz, IH), 8.14 (s, IH), 7.94 - 7.83 (m, 2H), 7.28 - 7.16 (m, 5H), 5.50 (ddd, = 4.2, 7.5, 9.3 Hz, IH), 3.18 (dd, = 4.1, 14.2 Hz, IH), 2.88 (dd, = 9.5, 14.1 Hz, IH). MS (ESI) m/z (M+H) + 383.1.
[1522] Compound 375 (60 mg, 28.5% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(3-fluoro-2-methylphenyl)-l,2,5-thiadiazole-3-carbox amide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.19 (d, = 8.0 Hz, IH), 8.10 (s, IH), 7.84 (s, IH), 7.27 - 7.15 (m, 7H), 6.98 - 6.94 (m, IH), 5.39 - 5.31 (m, IH), 3.18 - 3.12 (m, IH), 2.93 - 2.85 (m, IH), 1.87 - 1.83 (m, 3H). MS (ESI) m/z (M+H) + 413.1.
[1523] Compound 376 (300 mg, 47.9% yield): (5)-N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-4-phenyl-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO- d 6 ) δ 9.46 (d, = 8.0 Hz, IH), 8.22 (s, IH), 7.95 (s, IH), 7.58 (d, = 6.8 Hz, 2H), 7.50 - 7.45 (m, IH), 7.44 - 7.38 (m, 2H), 7.35 - 7.24 (m, 5H), 5.56 - 5.49 (m, IH), 3.29 - 3.21 (m, IH), 2.93 - 2.83 (m, IH). (ESI) m/z (M+H) + 381.1.
[1524] Compound 377 (80 mg, 39.9% yield): N-(4-amino-3,4-dioxo-l-phenylbutan- 2-yl)-4-(pyridin-3-yl)-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.39 (d, = 7.7 Hz, IH), 8.82 (d, = 2.2 Hz, IH), 8.65 (dd, 7 = 1.5, 4.9 Hz, IH), 8.19 (s, IH), 7.96 - 7.82 (m, 2H), 7.43 (dd, J = 4.9, 7.9 Hz, 1H), 7.33 - 7.20 (m, 5H), 5.53 - 5.45 (m, 1H), 3.23 (dd, / = 3.6, 14.0 Hz, 1H), 2.90 (dd, / = 10.0, 14.0 Hz, 1H). MS (ESI) m/z (M+H) + 382.1.
[1525] Compound 462 (150 mg, 73.8% yield): N-(4-(cyclopropylamino)-3,4-dioxo- l-phenylbutan-2-yl)-4-phenyl-l,2,5-thiadiazole-3-carboxamide : 1H NMR (400MHz, DMSO- d 6 ) δ 9.45 (d, = 7.7 Hz, 1H), 8.91 (br d, / = 5.1 Hz, 1H), 7.57 (d, = 7.1 Hz, 2H), 7.50 - 7.43 (m, 1H), 7.42 - 7.34 (m, 2H), 7.34 - 7.25 (m, 5H), 5.59 - 5.48 (m, 1H), 3.24 (dd, = 3.1, 13.9 Hz, 1H), 2.93 - 2.76 (m, 2H), 0.72 - 0.59 (m, 4H). MS (ESI) m/z (M+H) + 421.1.
[1526] Compound 463 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-2-hydroxy-5-phenylpentanamide hydrochloride using same procedures as for compound 321. Compound 463 (120 mg, 35% yield): N-(l-amino- l,2-dioxo-5-phenylpentan-3-yl)-4-phenyl-l,2,5-thiadiazole-3- carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.49 (br d, = 7.1 Hz, 1H), 8.14 (br s, 1H), 7.91 - 7.78 (m, 3H), 7.56 - 7.45 (m, 3H), 7.33 - 7.25 (m, 2H), 7.22 - 7.15 (m, 3H), 5.15 (br t, = 6.6 Hz, 1H), 2.77 - 2.58 (m, 2H), 2.21 - 2.08 (m, 1H), 1.96 - 1.81 (m, 1H). MS (ESI) m/z (M+H) + 395.1.
[1527] Compound 464 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-4-(4-fluorophenyl)-2-hydroxybutanamide hydrochloride using same procedures as for compound 321. Compound 464 (120 mg, 47% yield): N-(4-amino-l-(4-fluorophenyl)-3,4-dioxobutan-2-yl)-4-phenyl- l,2,5-thiadiazole-3- carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.45 (d, = 6.4 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.56 (d, = 7.1 Hz, 2H), 7.50 - 7.37 (m, 3H), 7.31 (s, 2H), 7.18 - 7.05 (m, 2H), 5.47 (s, 1H), 3.29 - 3.15 (m, 1H), 2.91 - 2.78 (m, 1H). MS (ESI) m/z (M+H) + 399.0.
[1528] Compound 465 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-2-hydroxy-5-methylhexanamide hydrochloride using same procedures as for compound 321. Compound 465 (110 mg, 38.2% yield): N-(l- amino-5-methyl-l,2-dioxohexan-3-yl)-4-phenyl-l,2,5-thiadiazo le-3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.32 (d, = 6.6 Hz, 1H), 8.14 (s, 1H), 7.95 - 7.69 (m, 3H), 7.51 (s, 3H), 5.30 (s, 1H), 1.78 - 1.39 (m, 3H), 0.90 (dd, = 5.8, 15.3 Hz, 6H). MS (ESI) m/z (M+H) + 347.1.
[1529] Compound 466 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-4-(3,5-dimethylphenyl)-2-hydroxybutanamide hydrochloride using same procedures as for compound 321. Compound 466 (70 mg, 39.2% yield): N-(4-amino-l-(3,5-dimethylphenyl)-3,4-dioxobutan-2-yl)-4-phe nyl-l,2,5-thiadiazole- 3-carboxamide: 1H NMR (400MHz, DMSO-d 6 ) δ 9.40 (d, = 7.5 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 7.3 Hz, 2H), 7.53 - 7.35 (m, 3H), 6.89 (s, 3H), 5.56 - 5.40 (m, 1H), 3.20 - 3.08 (m, 1H), 2.85 - 2.71 (m, 1H), 2.21 (s, 6H). MS (ESI) m/z (M+H) + 409.1.
[1530] Compound 467 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-2-hydroxyheptanamide hydrochloride using same procedures as for compound 321. Compound 467 (80 mg, 73% yield): N-(l-amino-l,2- dioxoheptan-3-yl)-4-phenyl-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO- d 6 ) δ 9.31 (br d, = 7.0 Hz, 1H), 8.14 (br s, 1H), 7.94 - 7.69 (m, 3H), 7.58 - 7.43 (m, 3H), 5.30 - 5.15 (m, 1H), 1.82 (br d, = 7.5 Hz, 1H), 1.57 (br d, = 4.8 Hz, 1H), 1.40 - 1.39 (m, 1H), 1.36 - 1.22 (m, 1H), 1.36 - 1.20 (m, 3H), 0.88 - 0.81 (m, 3H). MS (ESI) m/z (M+H) + 347.1.
[1531] Compound 468 was prepared from the corresponding intermediates, 4-phenyl- l,2,5-thiadiazole-3-carboxylic acid and 3-amino-2-hydroxybutanamide hydrochloride using same procedures as for compound 321. Compound 468 (70 mg, 54.2% yield): N-(4-amino-3,4- dioxobutan-2-yl)-4-phenyl-l,2,5-thiadiazole-3-carboxamide: 1H NMR (400MHz, DMSO- 6 ) δ 9.40 (d, = 6.4 Hz, 1H), 8.12 (br s, 1H), 7.92 - 7.75 (m, 3H), 7.58 - 7.43 (m, 3H), 5.25 - 5.18 (m, 1H), 1.36 (d, = 7.3 Hz, 3H). MS (ESI) m/z (M+H) + 305.1.
COMPOUNDS 378 578, 599
[1532] To a solution of 6-bromoisoindolin-l-one (0.5 g, 2.36 mmol) in acetone (20 mL) was added BnBr (605 mg, 3.54 mmol, 0.420 mL), Cs 2 C0 3 (1.92 g, 5.90 mmol) and 18- crown-6 (62 mg, 235.80 umol), then the mixture was stirred at 70 °C for 16h. The reaction mixture was concentrated to remove solvent, then diluted with water (50 mL) and extracted with EA (40 mL x 2), and the organic layers were dried over Na 2 S0 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO ® ; 12 g SepaFlash ® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 30 mL/min). Compound 378A (0.46 g, yield: 59.5%) was obtained as white solid. 1 H NMR (400MHz, CDC1 3 ) δ 8.02 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 1.9, 8.0 Hz, 1H), 7.39 - 7.16 (m, 6H), 4.79 (s, 2H), 4.21 (s, 2H). MS (ESI) m/z (M+H) + 302.0.
[1533] To a solution of compound 378A (0.46 g, 1.52 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (580 mg, 2.28 mmol) in dioxane (20 mL) was added KOAc (299 mg, 3.04 mmol), and then Pd(dppf)Cl 2 (111 mg, 152.23 umol) was added under N 2 atmosphere, the mixture was stirred at 85 °C for 16 h. The reaction mixture was diluted with EA
(20 mL), then filtered and washed with EA (20 mL x 3), the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO ; 12 g SepaFlash Silica Flash Column, Eluent of 0 ~ 30 % Ethyl acetate/Petroleum ethergradient @ 30 mL/min). Then further purified by preparatory-TLC (PE:EA = 2: 1). Compound 378B (0.35 g, yield: 46.1%) was obtained as light yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.98 (t, J = 0.9 Hz, IH), 7.86 (dd, J = 1.1, 7.5 Hz, IH), 7.57 (dd, J = 0.9, 7.5 Hz, IH), 7.38 - 7.32 (m, 2H), 7.31 - 7.23 (m, 3H), 4.77 - 4.69 (m, 2H), 4.39 (s, 2H), 1.31 (s, 12H). MS (ESI) m/z (M+H) + 349.9.
[1534] To a solution of methyl 4-bromo-l,2,5-thiadiazole-3-carboxylate (186 mg, 835.17 umol) and compound 378B (0.35 g, 1.00 mmol) in dioxane (20 mL) and H 2 0 (2 mL) was added K 2 C0 3 (231 mg, 1.67 mmol), then Pd(dppf)Cl 2 (61 mg, 83.52 umol) was added under N 2 atmosphere, then the mixture was stirred at 85 °C for 16 h under N 2 atmosphere. The reaction mixture was diluted with EA (30 mL), then filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO ® ; 12 g SepaFlash ® Silica Flash Column, Eluent of 0-30 % Ethyl acetate/Petroleum ethergradient @ 30 mL/min). Compound 378C (0.13 g, yield: 37.3%) was obtained as a white solid. 1H NMR (400MHz, CDC1 3 ) δ 8.20 (d, J = 1.8 Hz, IH), 7.87 (dd, J = 1.8, 7.9 Hz, IH), 7.51 (d, J = 7.7 Hz, IH), 7.41 - 7.28 (m, 5H), 4.84 (s, 2H), 4.35 (s, 2H), 4.03 - 3.95 (m, 3H). MS (ESI) m/z (M+H)+ 366.0.
[1535] Compound 378 was synthesized from 378C and using same procedures described earlier for compound 321. Compound 378 (20 mg, 13.5% yield): N-(4-amino-3,4- dioxo-l-phenylbutan-2-yl)-4-(2-benzyl-3-oxoisoindolin-5-yl)- l,2,5-thiadiazole-3- carboxamide: 1H NMR (400MHz, DMSO-i¾) δ 9.07 (br s, IH), 8.20 - 8.00 (m, IH), 7.96 - 7.48 (m, 4H), 7.42 - 7.12 (m, 10H), 5.58 - 5.38 (m, IH), 4.78 (s, 2H), 4.45 (s, 2H), 3.26 (dd, J = 3.8, 14.3 Hz, IH), 2.98 (d, / = 14.1 Hz, IH). MS (ESI) m/z (M+H) + 526.1.
[1536] Compound 578 was synthesized by the coupling of methyl 4-bromo- 1,2,5- thiadiazole-3-carboxylate and (2,2-difluorobenzo[<i][l,3]dioxol-4-yl)boronic acid followed by subjecting the product to same procedures described earlier for compound 321. Compound 578 (100 mg, 57.9% yield): N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(2,2- difluorobenzo[rf][l,3]dioxol-4-yl)-l,2,5-thiadiazole-3-carbo xamide: 1H NMR (400MHz, DMSO-i¾) δ 9.36 - 9.32 (m, IH), 8.12 (s, IH), 7.88 (s, IH), 7.52 - 7.49 (m, IH), 7.28 - 7.17 (m, 7H), 5.50 - 5.43 (m, IH), 3.22 - 3.15 (m, IH), 2.94 - 2.86 (m, IH). MS (ESI) m/z (M+H) + 461.0. [1537] Compound 599 was synthesized by the coupling of methyl 4-bromo- 1,2,5- thiadiazole-3-carboxylate and (2,2-difluorobenzo[<i][l,3]dioxol-5-yl)boronic acid followed by subjecting the product to same procedures described earlier for compound 321. Compound 599 (140 mg, 69.6% yield): N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-4-(2,2- difluorobenzo[rf][l,3]dioxol-5-yl)-l,2,5-thiadiazole-3-carbo xamide: 1H NMR (400MHz, DMSO-i¾) δ 9 Λ0 (d, J = 1.1 Hz, 1H), 8.19 (s, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 0.9 Hz, 2H), 7.29 - 7.18 (m, 5H), 5.55 - 5.41 (m, 1H), 3.23 (dd, J = 3.5, 13.9 Hz, 1H), 2.86 (dd, J = 10.1, 14.1 Hz, 1H). MS (ESI) m/z (M+H) + 461.0.
[1538] Compounds 379-380 were synthesized from the corresponding intermediate 1- (difluoromethyl)-3-phenyl-lH-pyrazole-4-carboxylic acid using same procedures as described earlier for Example 5.
[1539] Compound 379 (240 mg, 76.2% yield): (5)-N-(4-amino-3,4-dioxo-l- phenylbutan-2-yl)-l-(difluoromethyl)-3-phenyl-lH-pyrazole-4- carboxamide: 1H NMR
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Broadband, BUSINESS, cloud, Local Business, Local news, NEWS, software, Technology, Technology November 29, 2018
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The Sims 3 Ambitions Guide
The Sims 3 Ambitions Walkthrough and Guide
Important Guide and Game Notes
The Sims 3 Ambitions Walkthrough
The Sims 3 Ambitions Unofficial Guide by CM Boots-Faubert for SuperCheats.com
Officially the second expansion pack (Stuff Packs do not really count) for the current series of The Sims -- The Sims 3 -- Ambitions was released in June of 2010 with much fanfare as, in addition to providing a major patch and update to the base game, it also introduced new career opportunities and an expanded control mechanism into the game that was long desired.
It would be simple enough to spew out the statistical facts about the game and be done with it for the purposes of an Introduction, but that would be a disservice to you -- and besides there are some significant (if not important) points to be commented on as part of the Introduction process!
Welcome to The Sims 3: Ambitions!
The first point is that the contents of Ambitions -- while it is widely considered to be the spiritual successor to The Sims 2: Open for Business -- are much deeper and progress in a different direction than that similar expansion did. In fact it is fair to say that while the basic idea is similar, the mechanisms that were chosen for this expansion and the ultimate results are very different indeed.
The Sims games have always been about playing God -- and controlling to one extent or another the lives of the imaginary people of the game who, quite on their own, become very real to gamers who consider themselves to number among the core audience. The fans if you will, but then it seems to me that using the word "fans" is somehow degrading to those very souls because, and let us be honest here, a great deal of imagination, time, and effort is spent by those gamers in creating the Sim families and their generations. So perhaps aficionado would be a more accurate and less insulting word?
What Ambitions brings to the table is, in part, the ability to exercise more control over the working life of your Sims -- as well as the additional career pathways to be sure -- and in so doing it attempts with some success to introduce a diversity of skill sets into the game that offer an expanding sense of freedom to most players and, not surprisingly, represents a massive expansion in player involvement in their Sims careers and lives that was simply absent in The Sims 3 base game. For those reasons alone this has turned out to be one of the most celebrated -- and important -- expansions of the game. In fact it is widely considered to be a mandatory expansion by most Simmers.
The dry and banal articles that cover it within the gaming press -- and some of the reviews for that matter -- declare Ambitions to be "A career-based expansion pack," and with that presume that they have told you everything that you need to know about that. While it is certainly true that Ambitions introduces new careers, it also has the effect of altering the standard work and career experience for most players once they move beyond the careers that were part of the base game and begin to explore the depth of these new careers and the interaction that they provide. The reality is that this expansion specifically changes the style of game play that is the foundation of the game series, a subject that warrants close examination by the players.
A focus on relationships is an important part of Ambitions
In the Sims 3 base game pretty much all of the careers present as a disappearance point for the Sims who are part of them -- in that when it came time to go to work, they run out of their home and jump into their work transport, disappearing from the game for eight or nine hours -- with any interactions that the player have with respect to those careers taking place as pop-up windows that appear only after their Sim has returned home from work -- and at least for most of the core careers this has not changed!
What has changed is that the new careers that are offered by the Ambitions expansion alter that setup, making the different careers a much more hand's-on process, allowing players to have more specific control over their Sims working lives -- and when the Sim chooses to be self-employed in a profession that allows them to work from home (or a "shop" though that mechanism from The Sims 2 has not been put in place here) that sense of control is intensified. Some of the careers have a much more personal impact on the other Sims in the game too, to the point of changing their appearance or even adding to it -- like the Tattoo Artist -- of altering their very world -- as is the case with the Architect.
Most gamers and serious Simmers will not be coming to Ambitions as their first dip in the water of the rich and addictive world of The Sims, and because of that will have already established their nascent dynasties and, for the most part, will desire to continue them. That being the case, perhaps the most obvious method for taking advantage of the new careers presented by this expansion (when your Sim has already invested time and effort in one of the old careers) is to get your Sims Ability to register at City Hall to be self employed in a "Skill Career" for the following skills: writing, painting, sculpting, inventing, photography, nectar making, gardening and fishing. to the point of retirement in their current (old) career and then move them into one of the new ones.
-- A Boon for Slackers --
In the world of The Sims there are more than a few clearly defined play styles, but for most gamers this world is neatly divided up into the traditional players who like to drink deeply of every aspect of the game, including putting their Sims to work in the traditional career role, and then the other half of the scene, which is made up of gamers who prefer to have their Sims lead a more Bohemian lifestyle, as Artists or Authors and the much less traditional roles of earning their livings. The former is generally thought of as the basic player, while the latter is generally thought of as Slacker-Play. Both have their advantages, to be sure, but if your Sim yearns for the freedom and independence that can only be had by being your own boss, well, the Slacker life it is!
Ambitions certainly brings a more hands-on effect to the new careers, but it also has the effect of allowing what have traditionally been considered the "Slacker" career paths (Artist, Author, and the like) a much more reasonable and predictable path to success! In fact often the Slacker path is the more profitable since it allows the player to have much more control over how much their Sims earn and when they earn it.
A non-traditional profession can be incredibly profitable
Wine making -- added by the World Adventures expansion -- can be an incredibly profitable career choice and is generally considered to be part of the Slacker careers -- and especially when the player has a Sim in the Vintners household who is an expert Green Thumb and thus can grow the special ingredients that the Wine making Sim requires.
Even if you happen to be a strong supporter of the traditional career-based Simming play, you should give serious thought to trying out the non-traditional roles of the self-employed for at least one of your Sims -- you may be surprised at how much you enjoy that!
-- The Nature of The Sims --
It is interesting to note that most gamers consider the constant expansion of the series to be a mixture of both blessing and curse, and in particular when each new Sims series is launched, because to the gamers who consider it one of the best games going -- when this third series was introduced it essentially wiped out the value of the accumulation of base game and expansions for the previous series (as it did for the first series) -- and while there was certainly an element of the gaming community who refused to adopt the new series immediately, preferring to retain the benefits that their ownership of their Sims 2 games provided, in the end the choice to embrace the newest series was really no choice at all...
Its vastly improved graphics, game play elements, and the new adventures to be had caused them to, one by one, become converts to the new series -- but that is really as it should be, and if you are still on the fence in that regard it may help to remember that whenever a new series is launched, they always include elements of all of the expansions from the previous series in the base game. Though admittedly those elements are little more than a breath of what was, as the expansion system and how it addresses each major element of play is a well-established tradition in the games.
Still most serious Simmers admit that the launch of Ambitions, combined with World Travels and the base game, brought a level of complexity and play options to the third series that made it the equal to all of the games in the second series combined, and that is to say that everything that follows in the expansion line of the third series will, therefore, enrich the game well beyond what existed at the very end of the second series. Which is widely held to be a good thing, and who are we to argue with that?
In the end as you embrace Ambitions you will find that having a guide to use as a reference will be of great help to you, because while much of the new content added by Ambitions is easy to find, there is a plethora of small and sparkling additions that can easily be missed if you do not know where to look for them. Fortunately that is what this guide is intended to do -- demonstrate where to look and what to expect when you find it... And perhaps to assist you in making the most of it when you do embrace this new game play goodness that is The Sims 3: Ambitions!
iOS | PC
18 comments, latest first.
Jul 26th 2017 Lily Hekimian
How do I get passed the preschool wth the kid that choses a toy?
Oct 19th 2015 Guest
i dont know how to win preaschool mini game
Sep 26th 2015 Guest
How do you get a kid do they grow to teens
Dec 29th 2013 Guest
How can you Get money fast
Aug 21st 2016 Guest
If u click comand click type in motherless it will give u 50,000 dollars u can do it as much as u want
Sep 2nd 2013 Guest
How much time dose it take for them to grow up on the iPod
And can u have more than 1 kid?
Aug 29th 2013 Guest
How do u get a kid
I was just wondering if you can have more than one child because I don't think I can.
May 5th 2013 Guest
can i have a baby on the iPad 2
Apr 28th 2013 Guest
I play on the Ipod touch and I want to know, what type of
relationship Comes after spouse?
Mar 12th 2016 Guest
Mar 21st 2013 Guest
I was just wondering how to have more than baby!!!!
Feb 25th 2013 Guest
How do i get the game can you play it on the i phone 5 or do you have to buy the game for the pc
I love this game and I've played it loads but the first comment is not tire cos its never happened 2 me.well maybe it did I and I didn't notice.ah well.xx
Nov 26th 2012 Guest
I have this game for my ipad and I was wondering if you can get a birthday cake and if yes then how?
Nov 1st 2012 Guest
rubish put more and shut up if you say the b word
Oct 31st 2012 Guest
^To October 29th:
If you adopt, a baby will be dropped off at your house, once you select your criteria.
If, however, you try for baby with a partner and you hear the jingles of success, you sim WILL experience symptoms for a day then become pregnant for a number of days. She'll give birth after thee days. If you choose to have your baby at home, you will see her scream and clutch her belly for a few hours, then she will twirl around and he baby will appear in her arms.
Jul 30th 2015 Guest
I have a partner in the game but I don't have the try for a baby option how do I get it?
Notable Additions
Practical Starting Strategies
Family Strategies and Creating an Optimal Family Group
Advanced Sim Creation
Lifetime Rewards
An Overview of the Sim Traits
Wishes and Desires
Choosing the Best Lifetime Wish
Collectibles and Collecting: Rocks and Gems
Collectibles and Collecting: Metals
Collectibles and Collecting: Beetles
Collectibles and Collecting: Butterflies
Collectibles and Collecting: Transmogrification
Careers Introduction
Architect Career (Ambitions)
Business Career (Base Game)
Criminal Career (Base Game)
Culinary Career (Base Game )
Education Career (Base Game )
Firefighter Career (Ambitions)
Ghost Hunter Career (Ambitions)
Journalism Career (Base Game )
Law Enforcement Career (Base Game )
Medical Career (Base Game & Ambitions)
Military Career (Base Game)
Music Career (Ambitions)
Political Career (Base Game )
Private Investigator Career (Ambitions)
Professional Sports Career (Base Game )
Science Career (Base Game )
Stylist Career (Ambitions)
Part-Time Bookstore Clerk (Ambitions)
Part-Time Day Spa Specialist (Ambitions)
Part-Time Day Spa Receptionist (Ambitions)
Part-Time Grocery Store Clerk (Ambitions)
Part-Time Mausoleum Helper (Ambitions)
The Slacker 411
Fisherman Profession
Gardener Profession
Inventor Profession
Nectar (Wine) Maker Profession
Painter Profession
Photographer Profession
Professional Collector Profession
Sculptor Profession
Writer Profession
Utility -- Ambrosia / Death Flower
Utility -- Martial Arts
Utility -- Magic Gnome Collections
Official Service Awards
Adventure Quest Worlds
Championship Manager 01/02
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Commentary - Best Products, or most hype?
Date Tue 11 December 2007 Tags important businessweek vista iphone products
In my usual lunchtime Digg reading, I came by a link to the BusinessWeek Most Important Products of 2007. Given the number of cars, it’s apparent that this is a very consumer-oriented listing. But I was a bit surprised - the first four products were all from Apple - the iPhone, MacBook Pro, OS X Leopard, and Apple TV. While some of these are definitely interesting, I really don’t think that any other than the iPhone could be considered truly important or groundbreaking. OS X Leopard and the MacBook Pro may be wonderful for Mac users, but they’re not really anything “new” in the sense of ideas - they’re just updated versions with more/better features. Given the amount of hype that surrounded it, it was clear that the iPhone would be on this list. And I will admit that, despite my moral objections to it (bricking phones that innocent users unlocked), the iPhone is very nicely done. But it’s not anything truly NEW. It’s a step in progression. There were phones with cameras, phones that were thin, phones with touchscreens, and phones that played MP3s. Apple just pulled all - and some extra - into a very nice package.
So what else was mentioned? The Dell XPS One, some Mac-ish all-in-one Media Center PC. It puts everything my computer has in one OEM package, and adds on Windows Media Center, just to make sure it won’t do everything you want. And it even puts the entire computer inside a monitor-sized enclosure, so if you crack the LCD, you have to send the whole thing back to Dell. Don’t even ask me how the Braun Pulsonic electric razor made it onto this list. Or a 30” Gateway LCD monitor. Yes, it’s a big monitor. And it has a TV tuner. That makes it one of the most important products of the year? Of course, there’s also a 60” Pioneer LCD TV, the Tivo HD DVR, and the Motorola Razr2. All jazzed-up versions of old ideas. And I’m not even going to mention Windows Vista, arguably Microsoft’s biggest flop (other than Windows ME), which appears on the list - though they do mention, “While many users hate it, there’s little question that the operating system is selling extremely well.”. They mention that Microsoft said, in October, that it had shipped 88 million copies of Vista. While I don’t totally doubt that figure, it doesn’t take into account the users who bought a Dell with Vista and then dumped it for Ubuntu. Or even the (I imagine rather large) number of users, like many of my friends, who bought that new computer with Vista and immediately loaded their old XP Pro disk.
So, after all of that nitpicking, what do I think is missing?
The desktop processor revolution, with 64-bit systems becoming quite common.
The Intel and AMD dual- and quad-core CPUs being put in consumer machines.
Intel VT hardware virtualization technology.
The Asus eeePC (well, this is still to be determined)
Motorola cellphones moving to Linux (as well as other companies)
The portion of the 700-MHz spectrum set for auction by the FCC. (well, not a consumer product, but it could revolutionize mobile communications if it falls into the right hands).
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The Radioactive Yak
What You Can Do With Your Modal Dialogs and Splash Screens (and the Horse They Rode In On)
Every time I'm presented with a splash screen, what I actually see is the app developer giving me the two fingered salute. The only thing more hostile is the use of a modal "loading" dialog: a UI metaphor used exclusively to save developers time at the expense of every single one of their users.
The apps which make me want to do something out of character start with a splash screen before segueing directly into a modal "loading" dialog. It's like they're spitting directly into my face. Why? Why do you hate me so much? I just want to use your app, I don't deserve this kind of hostility. No one does.
The 90s called, they'd like their UI metaphors back
Modal windows have always been a crutch. Windowed operating systems are by nature multithreaded, so to avoid apps "freezing" you execute time consuming tasks on background threads. This introduces complexity as the user can potentially interact with the UI between expected states.
The easiest solution for developers is to stick up a modal window that steals focus from the application and prevents users from interacting with the UI until the app completes the background task.
With great latency comes great responsibility
The ascent of the web as a platform largely eliminated these anachronisms. Page load times have a dramatic influence on how quickly people navigate away from a site. When page load latency is being measured in 10s or 100s of milliseconds, it's not surprising that splash screens and "loading" dialogs have all but disappeared.
The good news is that users have also gotten used to content being loaded dynamically. Most people won't bat an eyelid at a page which loads text first and updates the images afterwards. It's expected behaviour.
Users will use the time it takes getting past your splash screen uninstalling your app
It's ironic that a platform that has even less allowance for delay has seen the reintroduction of the dreaded "loading" dialog. Sadly too many devs have gotten lazy. It's harder to develop a UI that works smoothly and intuitively while data is loading or processing is being done, so many don't bother.
Don't be the lazy guy - "it's hard" isn't a valid excuse. Mobile users are incredibly impatient, phones are used on the move and users constantly switch between applications. To be successful you need to make startups and transitions fast and seamless.
Asynchronous tasks. Make sure anything that could take longer than a small fraction of a second happens in a background thread (use ASyncTasks to help). Use a Service to run tasks that should be completed even if the Activity is killed.
Branding fail. You want your app to seem an integral part of the device. Every time you show a splash screen you're reminding people that they're using an add-on -- an add-on they can replace with something less annoying.
Lazy loading. Loading data takes time, particularly if you need to download it first (particularly over a mobile network). It's important that you have something to show as quickly as possible, so take the browser approach by displaying what you can get quickly. Follow that up with slower items such as images. Load additional content as required when users start scrolling down your list, taking the same approach of text first, images later.
In-place updates. Don't clear all your data every time you pull an update from the server. Update, add, and remove items from your UI as new data becomes available. Same with updating existing layouts with images once they've been downloaded.
Pre-fetching. If you've got multiple tabs or even Activities within your app, there's no reason to wait until the user changes their selection to start loading data. Pre-fetch the first page of data so that it's ready when the user switches to it.
Save your state. Switching between apps should be seamless and instant. Save all your Activity state so your app can resume instantly.
Caching. There's no reason to download the same image multiple times. Likewise, it's often better to show out of date information and update it quickly than showing nothing at all.
Background loading. Use Services to perform updates and download data while your app isn't in the foreground. This can extend from small amounts of pre-fetching to regular updates, or complete offline support.
Visual "loading" elements. Use visual elements like progress bars to indicate that you're in the process of getting an update.
Disable unsupported actions. Some actions within your app might not make sense until all the data is loaded. Rather than block interactivity, disable actions that aren't possible.
To see some good examples of how to present no information (or updating information) without splash screens or loading dialogs check out the Gmail and News & Weather apps. Neither use a splash screen (or loading dialogs), and both begin with no information. Once they have data, updates and changes are integrated into the existing data being displayed.
If you're creating a fully immersive experience you may have good reason to use both splash screens and loading dialogs
There's always an exception. If you're engaging in an immersive experience (like a game or turn-by-turn navigation), you don't want to start until the environment is fully constructed. Developers can't use many of the tricks above like dynamic lazy loading, because users want to enjoy the complete experience right from the start. This is especially true of 3D environments like a FPS or Google Earth that rely on an OpenGL environment.
I remember playing California Games on a friends C64. It was loaded via the tape drive, so if anyone quit the game we'd spend the 15 minutes it took to reload in a diverting game of "beat the moron". While it's important to ensure the environment is fully complete before allowing users to explore it, there are still a few tricks you can use to ensure the wait isn't quite as painful.
Cache any downloaded content.
Dynamically pre-load as much data as possible during gameplay.
Save and cache as much state data as possible to ensure players can resume from where they left off.
Try to provide useful information (hints? instructions? cut scenes?) in inter-level "loading" screens or splash screens.
Delay the longest pauses as long as possible. I should be able to start the game, change the settings, and navigate to "load saved game" without a significant wait.
For most apps, splash screens and modal loading dialogs now belong in the 1990s with 9600 baud modems and pashminas. Embrace the now.
Posted 8/25/2010 06:12:00 pm
7 comments Labels: android, hostility
Beyond Mobiles: Android as a Universal Development Platform
Early next year GoogleTV will include the Android Market, meaning that it will be a compatible device. A GoogleTV is unlikely to include telephony support, or a camera, microphone, vibration, compass, GPS, or LED. And it likely won’t be the first Android device that isn’t a phone.
This suggests that there are some changes in store for the Android compatibility definition.
If you were an apps developer when the first desktop computer was released – what would you have built?
25 year ago, when I was writing code in my parents living room, I held little expectation that anyone but me would ever use any of it. Sharing an app meant copying it onto a 5.25” floppy disk and biking it over to a friends house where, CRC errors permitting, we’d run it.
There was also the issue of OS fragmentation. I had an IBM compatible PC-XT, my school housed a collection of BBC Micros and most of my friends had Amigas and C64s.
Over the next decade “IBM compatible” became “PC” and the Internet provided an unprecedented distribution mechanism that lets your apps span the globe in a heartbeat.
Right now there are more than 60 different compatible Android devices
Until recently the only way to get your mobile apps onto a phone was through a relationship with a carrier or device maker. Today, every day, 200,000 more people are activating Android compatible devices and searching the Market for your apps.
The open nature of Android means hardware manufacturers are using Android to power an increasingly diverse range of connected devices. At the same time, the Android Compatibility Program is expanding to make more of these devices compatible.
People talk a lot about the dangers of fragmentation
Where some might complain, I see a unique opportunity. Suddenly we’re presented with a blank slate on which to innovate, a rare opportunity to consider new ways for people to interact with devices with which they are already familiar.
If you, as a developer, want to avoid dealing with fragmentation it’s easily done. Pick a single device and develop only for that (I’d suggest the Motorola Droid). You’ll miss out on an order of magnitude of users, but you won’t have to make your apps resolution independent.
The same code will do the same thing on any compatible hardware
The Android Compatibility Program eliminates the real risks of hardware fragmentation. As a developer, all you need to do is make sure that your software doesn’t make assumptions about the underlying hardware.
So what are the assumptions you need to avoid?
Screen size, resolution, and aspect ratio.
The existence of particular hardware.
Screen size, resolution, and aspect ratio
Android developers have been accounting for different screen sizes since Android 1.6 and the release of the Verizon Droid and HTC Tattoo. There is an excellent writeup describing how to support multiple screen resolutions on the Android Developer Guide, aptly titled Supporting Multiple Screen Sizes.
At the risk of providing spoilers, it will tell you to:
Use density independent pixels rather than hard-coding pixel values in your code.
Use layouts such as Relative Layout, that don’t assume screen sizes, aspect ratios, or resolutions.
Provide alternative layouts (if required) for small, normal, or large screens.
Provide alternative drawable assets for low, medium, or high resolution displays.
Use the emulator to test, test, and test.
The existence of particular hardware
When it comes to hardware dependencies, there are two questions you need to address. Does your app:
Need any specific hardware in order to function?
Use some hardware features if they’re available, but which aren’t strictly necessary?
Apps like Layar aren’t very useful on a device without a camera and compass. If the answer to question one is yes, you need to create a manifest entry declaring the hardware features your app requires. The Android Market will then filter those apps out for devices that don’t have the required hardware.
<uses-feature android:name="android.hardware.sensor.compass"/>
<uses-feature android:name="android.hardware.camera"/>
As I described in Future Proofing Your Apps, the Market will make some aggressive guesses even if you don’t specify all the hardware you require, so if the answer to question two is yes, you need to tell the Market.
Specify optional hardware when you will use it if it’s available, but your app doesn’t depend on it.
Google Places uses cool compass arrows to show the direction of a place on interest. Even without the compass the app would still be useful on my TV, so it should declare the compass hardware as optional.
<uses-feature android:name="android.hardware.sensor.compass"
android:required="false" />
Within your app you will still need to find the code that uses the optional hardware and modify its behaviour accordingly.In this example, I’d want the app to simply hide the compass arrow if the compass isn’t available.
You can determine the availability of any hardware feature using the Package Manager and modify the UI or behaviour of your app accordingly.
PackageManager pm = getPackageManager();
pm.hasSystemFeature(PackageManager.FEATURE_SENSOR_COMPASS);
To make your life easier, all compatible devices will maintain the APIs used to monitor and control all supported hardware, they simply won’t return useful results when the required hardware doesn’t exist.
Be a launch partner for future Android devices
As an Android Advocate I’m regularly asked by developers how they can have their app available as a launch partner for future devices. You can consider this blog post as my answer.
5 comments Labels: android, developer
The Future of Mobile: Invisible, connected devices with infinite screens
The history of smartphones looks something like this: At the end of 2008 the very first Android handset was available on T-Mobile in the US. The iPhone has existed for 3 years. The very first Blackberry featuring push email came out in 2002.
From WAP and push email to iPhone in 5 years. From one iPhone to 60 different Android handsets in under 3 years. At that rate it's challenging to create a credible mobile roadmap that extends as far as 6 months - and the rate of change is increasing.
At the current rate, nearly anything is possible in 20 years
Lately a lot of people have asked me what I think is the future of mobile. Some people just want to know what device they should buy at Christmas, but others are looking for a 20 year outlook. 20 years! The first GSM network had barely launched 20 years ago! Predication at that scale is destined for failure and embarrassment. But I won't let that stop me.
Bigger screens are better
Mobile devices are morphing. Tablets have been talked about for years, and the iPad and Kindle provide the kind of experience people have been waiting for. Browsing pictures, watching videos, and reading books work really well on a screen that size.
Still, I find the iPad heavy and bulky. The ultimate device would be the size and weight of my mobile but include a screen that could be unfolded or rolled out to provide a better display for watching movies and playing games.
Actually, the ultimate device would be entirely virtual. I’d put on my glasses (or contact lenses) and look at any surface to see an augmented version of reality. Anything from interactive holographs, to augmented reality, or a cinema screen that stretches across the horizon. Everyone could see their own version of reality on a screen the size of their visual field.
1 year High res screens, tablet devices, and HD output from mobiles.
5 years Flexible displays and built in HD projectors.
10 years Transparent LCD patches that can be applied to regular glasses.
20 years Contact lenses that project a visual feed directly onto your retina.
Full keyboards are better. No keyboards is best
Keyboard designs (like the that on the SE Mini Pro) continue to improve, as do on-screen keyboards with technologies like Swype.
The Nintendo Wii and Microsoft's Kinect suggest that gestures might largely take the place of keyboards and touch screens for some interactions. Better multi-touch and increasingly accurate voice input will make physical keyboards almost entirely redundant.
For those who want to write something longer than an email, gesture recognition (capable of tracking fingers), combined with eye-focus tracking will provide virtual full-size keyboards.
If we’re thinking long-term, we can look forward to research like this letting us control our devices using our minds.
1 year Wireless keyboards, voice input, and gestures.
5 years Larger multitouch screens, better gesture input, and flawless voice recognition.
10 years Full virtual keyboards and voice input eliminate physical keyboards entirely.
20 years Mind control.
Smaller devices that last longer
The Sony Ericsson X10 Mini is a ridiculous 83x50x16mm and weighs less than 100g. When screens stop being a primary consideration for device size, the devices will shrink dramatically.
That leaves the problem of the battery. Mobile processors will become more efficient, and fuel cells may help battery life in the short term, but ultimately we’ll be powering mobile device using biology and ambient energy. Biokinetic and ambient energy will likely be the start, but the future suggests a move away from silicon and towards biological processors. The computer you inject is more likely to resemble a specialized virus than a tiny silicon chip.
1 year Lighter, thinner devices that last longer.
5 years Tiny devices powered by fuel cells.
10 years Devices small enough to embed into watches and jewellery that never need charging.
20 years You are the computer.
Connectivity will become ubiquitous
Cloud computing is already a reality. As even more of our data and processing is done in the cloud, continual and uninterrupted Internet connectivity will become increasingly critical.
The incredible growth of smartphones in countries with a mobile data infrastructure to support them is nothing short of phenomenal. It's easy to forget that the real powerhouses of mobile phone use are developing countries - countries that don't have a reliable infrastructure for traditional "wired" Internet access. Citizens there are likely to access the Internet exclusively via their mobile phones.
Over the next decade we'll see carriers (and new challengers) aggressively rolling out faster, more reliable networks and technologies that cover larger areas across the globe.
At the same time, you'll be using your mobile to control your TV, monitor your fridge, and start your car.
1 year 3G/4G and WiFi covers most of industrial world. Every mobile device comes with an unlimited (or high-cap) data plan. Mobiles start interacting with other consumer electronics and cars.
5 years 4G/5G and WiFi extend to cover the entire developing world.
10 years Whitespaces or similar technology means everyone everywhere is connected at all times.
20 years Connectivity is uninterrupted and ubiquitous. Losing connectivity is like losing power or running water.
What about calls!
Apparently some people use mobile phones to make and receive calls(!) As devices get smaller, keyboards become virtual, and screens move closer to your eyes, you'll need a separate piece of kit to sit near your mouth and ears. Bluetooth headsets will get smaller and more discrete, people apparently talking to themselves in public will become no less creepy or annoying.
Infinity screens, invisible devices, always connected
In 2030 you'll think of smart-phones as quaint anachronisms that died out about 10 years ago, now that all computing is mobile. You’ll be constantly connected to the Internet by a virus that lives in your bloodstream. Contact lenses will provide a truly infinite screen, and you’ll interact with your augmented environment through a combination of mental commands, physical gestures, and voice input.
We'll take all this for granted and complain that we still don't have jetpacks or flying cars.
23 comments Labels: android, mobile, predictions
I'm Reto Meier, I work for Google as the Tech Lead on the Android Developer Relations team. I'm also the author of Professional Android 4th Edition.
This blog covers technology and programming - particularly Android - but this is my personal blog. The views expressed on these pages are mine alone and not those of my employer.
Upcoming Public Appearances
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Android Location Protips Open Source Project
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Android Apps I've Built
When Offshoring Your Development Team Means Buying a Boat
When to Include an Exit Button in Android Apps (Hint: Never)
What You Can Do With Your Modal Dialogs and Splash...
Beyond Mobiles: Android as a Universal Development...
The Future of Mobile: Invisible, connected devices...
©2005-2011 Reto Meier
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The New SmartThings Experience and You
May 21, 2014 / Eliot / 26 Comments
Today is an exciting day for SmartThings customers and anyone who’s ever wanted to create a smart home. We’ve just unveiled an enhanced app experience that offers you one place to find, discover, and connect everything you need to customize a home that automatically reacts to your preferences.
Those of you who have followed us from our early Kickstarter days know that it’s always been our goal to create an open platform for the Internet of Things, and this announcement is a very important step toward realizing that long-term vision.
Here’s a look at what’s new:
The SmartThings App: Where Products, Developers, Services, and Customers Meet
Our enhanced app experience makes it easier than ever to monitor, control, and automate your home with an expanded list of uses and products. It also offers a single, streamlined way to integrate new devices, alerts, and actions via a brand-new section called SmartSetup.
Check out the below video for a full rundown of the new iOS app, which is now available for free download. The Android experience–which mirrors that of iOS–will be introduced in early June.
As you can see, the new SmartThings app experience establishes a single destination for smart home enthusiasts to create and customize a connected home that matches their needs. By embracing the innovative third-party applications and products on our open Platform, we hope to offer consumers greater flexibility and make it as easy as possible for anyone to create a smart home. To achieve this, we created three new things:
1. We’ve established an official certification program for device makers so that customers can choose from an expanded number of products that are compatible with SmartThings. (More on this here.)
2. We’ve made it possible for third-party developers in our growing community to publish SmartApps in the native SmartThings app so that all customers can access and use them. (More on this here.)
3. We’re creating a partner program for service providers so that third-party companies can offer solutions to assist SmartThings customers. (More on this here.)
Integrating New Products: The SmartThings Device-Certification Program
From locks and lighting solutions, to stereo systems and thermostats, there are already many companies inventing smart home devices. Some of the most valuable things that will one day fill our homes have likely not even been invented yet. At SmartThings, we’re embracing this wave of innovation and have created a new team lead by Kelly Liang to expand the list of devices that are certified as working with SmartThings.
The program introduces multiple levels of certification and compatibility with SmartThings and is designed to offer consumers greater confidence that the products they’re integrating with SmartThings will work properly. Once certified, these products will join our list of more than 100 approved and compatible devices from popular manufacturers like GE/Jasco, Honeywell, Kwikset, Aeon, and others that are discoverable within the SmartThings app.
And the list of SmartThings-compatible devices is growing. Today, we announced that Leviton, a leading manufacturer of lighting-control products is joining our ecosystem of compatible devices.
Additionally, we’re set to announce two new additions to SmartThings Labs very shortly: Jawbone, a smart wristband and app that helps you to understand how you sleep, move, and eat so that you can live better; and Life360, an app that allows you to view your family members on a map and effortlessly check in with them.
In addition, we’ve also partnered with CentraLite to introduce the next generation of elegant and easy-to-use ZigBee-based devices.
Interested device manufacturers who would like to learn more about how to qualify your smart device for the SmartThings Platform should please complete this form.
Discovering New Use Cases: Publishing SmartApps on the SmartThings Platform
As developers submit new and creative use cases to our Platform, we’ll publish these on our app for all customers to use.
Much like Apple’s iTunes platform or the Google Play Store, the SmartThings Platform will bring together developers from our growing community who make “platform applications” and consumers who want to use them.
With today’s announcement, we are rolling out the ability for third-party developers to publish their creations (“SmartApps”) within the SmartThings native app so that they may reach SmartThings’ rapidly growing user base. This means that SmartThings customers will be able to easily discover within the app a growing collection of new use cases, making it easier than ever to browse, set up, and customize these new SmartApps to fit their needs.
For instance, many of the recent SmartThings Labs integrations that we’ve recently announced or are set to announce (for instance: Quirky, TCP, and Jawbone) have been created by developers from our ecosystem of more than 5,000 developers. Today, these integrations are available for all SmartThings customers, and as the community continues to create and submit additional integrations, we’ll continue to publish them.
Developers, you can read more about how to access our integrated development environment (“IDE”), how to create and submit a SmartApp, and the details of our approval process on the SmartThings Community forums.
Offering Added Services: Matching Customers with Professionals
In addition to showcasing a growing number of compatible product options and sharing SmartApps created by third-party developers, the new SmartThings Platform will also offer customers the ability to choose service providers to deliver a variety of solutions.
As an example, today we announced that SmartThings and Cross Country Home Services, a provider of TotalProtect home service plans, have partnered to bring a full range of services to SmartThings customers. These services range from installation services for connected devices like locks, lighting and thermostats; to home maintenance and repair services for critical home systems; all the way up to full home-warranty services.
We expect to partner with additional home service providers moving forward. By giving SmartThings customers the option to access the services of these third-party providers, we hope to make it easier than ever for anyone who wants to create a smart home to do so.
Interested service providers who would like to join the SmartThings Platform can complete this form.
Android, iOS, New SmartThings Internet of Things Ecosystem, New SmartThings Product Experience, SmartThings App, SmartThings Certification Program, SmartThings Developers, SmartThings Product Experience, SmartThings SmartApps
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[VIDEO] Hello, Smart Home: Rob
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United Kingdom Tax Returns
UK daňové přiznání pro majitele nemovitostí
UK landlords are obliged to file an annual UK tax return
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Daňové přiznání pro britské pronajímatele
Landlords letting UK property need to file an annual tax return by 31st October if filing on paper or 31 January if e-filing. Speak to us today about our fast and efficient service and make sure you're claiming all deductible expenses. Our landlord tax return service starts from £195 and will make sure you're compliant with all your HMRC obligations.
A common misconception is that non-resident landlords letting UK property have no UK tax obligations. Speak to us today about our bespoke NRL service and let our team guide you through registering under HMRC's NRL Scheme and completing your annual tax return. Our tax return is priced at a flat fee so you will know exactly what you're paying from the outset.
If you also own property overseas, our sister company, Property Tax International, can assist you.
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UK Property Tax FAQ
?I rent out a number of properties in the UK. Do I have to file a tax return?
Yes. If you are in receipt of property income of £10,000 or more (before deducting allowable expenses), you are required by law to file a self-assessed tax return.
In other cases, HMRC should make an adjustment to your PAYE code to collect any tax due on such income. For more information about self-assessment or PAYE, check out the respective sections on our website.
?What is 'property income'?
Property income is income which comes from a property which is purely owned to generate revenue. Such properties include those which generate rent, such as houses and flats, land which generates revenue from hobbies carried out on it, such as an archery club or river for fishing or, if you are a UK-resident landlord, any overseas properties which generate revenue.
?What if I am a UK non-resident landlord?
Income received from non UK properties, will be exempt from UK tax.
If a tenant living in the UK rents a property from a landlord who lives outside the UK, the landlord will still pay UK tax on the rental income even if he / she doesn't live there because the property is situated in the UK.
?How are property business profits calculated?
For both UK and foreign properties – these work on a ‘rents receivable less expenses payable’ basis.‘Receivable' means the rents that relate to a tax year, which is not necessarily the same as cash physically received.
From rents receivable you deduct any allowable expenses payable. ‘Payable' means expenses that relate to the tax year. This may not necessarily be equal to cash physically spent.
?What are allowable expenses?
These are expenses which are deductible from rents only if those expenses are incurred ‘wholly and exclusively' for the business of letting. Examples of deductible expenses will include agent fees, commissions and genuine repair expenses. For example, if a tenant breaks a window and you repair that window this is a genuine repair and the cost can be deducted from rent.
Any water charges or council tax paid by a landlord are deductible expenses, as is any interest paid on a loan taken out to purchase the property in the first place. Insurance premiums are also deductible.
?What about capital expenditure?
Any expenditure of a capital nature cannot be deductible from rents – i.e. any expenditure that improves or enhances the value of the property.
E.g. if instead of simply repairing some broken roof tiles, a landlord takes the opportunity to replace his whole roof, there is obviously some degree of improvement here and the costs will not be deductible.
However, capital allowances (essentially depreciation tax relief) may be able to be claimed in respect of capital expenditure used in the rental business. For example capital allowances can be claimed in respect of tools such as ladders and lawnmowers which are used in the property business.
?How can I be compensated for dilapidation of furniture, furnishings etc?
A wear and tear allowance can be claimed in respect of furnished lettings. Basically, a deduction of 10% of the relevant rental amount is taken when calculating the profits of the property business. If a landlord does not want to claim wear and tear, there is an alternative called the renewals basis – which means that the landlord cannot claim a deduction for the initial costs of any furniture he buys, but when the furniture is replaced, the costs of replacements can be included as allowable expenses.
Where wear and tear allowance is claimed no other relief is available in respect of expenditure incurred on furniture and furnishings etc. Landlords must either adopt one basis or another – they cannot change between wear and tear and the renewals basis when it suits them
?What if I make a 'loss' on my property business?
Where expenses exceed income, a property business loss will arise. If you have several sources of UK property income, all profits and losses in the year are pooled together for these purposes to give an overall profit or loss for the year. If a taxpayer has a property business loss, that loss can only be carried forward and set against property income from a UK property business in future tax years. It cannot be set against non- rental income nor can it be carried back to a previous year.
You should note that an overseas property loss, eg a loss on a villa in Spain, cannot be set off against UK property business income. This also applies the other way around so there is never any mixing of UK and overseas property business profits and losses. If you have an overseas property business loss, that loss can only be carried forward and set against future overseas property business income.
?What is a Furnished Holiday Let?
A Furnished Holiday Let is a special type of property that can benefit from certain tax advantages.
?What is Rent-a-room relief?
If a landlord is letting out a room to a tenant in his home (i.e. his only or main residence) a special relief is available. Note here that the landlord and tenant will be living in the same property, so the tenant is a ‘lodger' of the landlord.
If the tenant pays the landlord a rent of say, £50 a week, this is strictly chargeable to tax as property income. However, where gross rents are not more than £4,250 a year, rent-a-room relief can apply and the rental income is exempt from tax.
?Are there any special rules for non-resident landlords?
HMRC has had difficulty in persuading taxpayers who live abroad to pay their tax bill on their UK rental income, so what they ask the tenant or letting agent to do is withhold basic rate tax from the rent paid. For example, if a landlord charges a tenant £1,000 a month to live in a UK property, he will receive £800 of this and £200 will be sent to HMRC. This is HMRC's way of getting some tax in, in the event that the non-resident landlord decides to ignore his UK tax obligations.
If the non resident landlord prefers, he or she can make an application to HMRC to receive this rental income gross. HMRC will agree to this if the non-resident landlord promises to file a self-assessment tax return and pay his income tax in the normal way. If the landlord has a good record and is up to date with his obligations etc, HMRC will agree to him receiving his rents gross. Contact us for further information on this.
We file tax returns for thousands of UK landlords every year
If you’re a landlord in the UK, you fall into the category of tax payer which is obliged by HMRC to complete an annual self-assessed tax return. At taxback.com, we understand that filing a return can be a complicated and costly business, especially if you have to engage the services of an accountant. We provide a simplified service which is tailored to your individual requirements whether you have UK or foreign property. We will file your UK tax return for a flat fee and provide a transparent, efficient service.
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.@kj_fetishmodel Wins Fan Contest, Joins Cast of ‘The Empire Strikes Back XXX’
Katrina Jade Wins Fan Contest, Joins Cast of ‘The Empire Strikes Back XXX: An Axel Braun Parody’
Best New Starlet Nominee Blows Away Competition in Online Contest!
LOS ANGELES (March 4, 2016) – Adult starlet Katrina Jade is the winner of an online casting contest, in which fans voted for their favorite star to join the cast of director Axel Braun’s The Empire Strikes Back XXX: An Axel Braun Parody, now the subject of an Indiegogo crowdfunding campaign.
The contest, launched two weeks ago, pinned 12 of the top adult stars against each other, with stars utilizing their social media skills to engage fans. Jade and her 242,000 Twitter followers came out on top, with Sasha Heart taking second place, and receiving an honorable mention for her incredibly sexy campaign videos.
The movie is the sequel to the bestselling adult movie of all time, Star Wars XXX: An Axel Braun Parody. When the crowdfunding drive for The Empire Strikes Back XXX succeeds, the movie will become the first feature adult film to be released free of charge across the world, on all platforms.
“I’m very happy to have Katrina on board,” said Braun. “She’s been in several of my movies, as she is a terrific actress and performer. She has a delightful attitude and true superstar potential, and she’s a fantastic addition to our stellar cast.”
Jade, who was nominated for Best New Starlet at the 2016 XBIZ Zwards, was recently featured on the cover of Axel Braun’s Inked.
The Empire Strikes Back XXX: An Axel Braun Parody includes returning cast members Allie Haze (Princess Leia), Lexington Steele (Darth Vader), Seth Gamble (Luke Skywalker), and superstars Dani Daniels, Casey Calvert, Riley Steele, Carter Cruise, Aiden Ashley, Lexi Belle, and Asa Akira, on special loan from Wicked Pictures.
Braun aims to make the production model of The Empire Strikes Back XXX a statement against piracy while giving back to fans with a movie, which is completely crowdfunded. Once the movie is completed, it will be 100% free-of-charge via online download.
Set up as a Fixed Funding effort through Indiegogo, the campaign will ensure all contributions will be automatically refunded if it does not meet its $500,000 funding goal by April 22.
To watch the Indiegogo campaign video, donate, or learn more about the crowdfunding drive, click here.
About Axel Braun:
The son of legendary porn-pioneer Lasse Braun, Axel Braun was born and raised in Italy, where he worked closely with his father before moving to Los Angeles to pursue his own career in 1990. Fluent in five languages, a member of MENSA, a film-school graduate, and the bearer of a Ph.D. in Psychology, Axel has a unique cultural background that sets him apart from the many other directors in the Adult industry. A second-generation AVN and XRCO Hall-of-Famer, over the span of his career he has won accolades all over the world for Directing, Producing, Screenwriting, Cinematography, and Editing, including four consecutive AVN Director Of The Year awards and six consecutive AVN Best Parody awards. For more information visit Facebook.com/AxelBraun and Twitter.com/AxelBraun
Axel Braun, The Empire Strikes Back XXX: An Axel Braun Parody, Star Wars XXX: A Porn Parody, crowdfunding, Indiegogo, vote, sexy role, donations, donors, Katrina Jade, Alaska, California, Nevada, adult entertainment, porn, porn star, adult industry, XXX, sex, men, women, parody, trailer, sponsorships, rewards, April 22, September 30.
Production Department:
Axel Braun Productions
Email: Info@AxelBraunProductions.com
Fine Ass Marketing
Email: Adella@AxelBraunProductions.com
Email: Chris@AxelBraunProductions.com
Posted on April 4, 2016 Author FAMCategories Adult Industry NewsTags adult entertainment, adult industry, Alaska, April 22, Axel Braun, California, crowdfunding, donations, donors, Indiegogo, Katrina Jade, men, Nevada, parody, porn, porn star, rewards, September 30, sex, sexy role, sponsorships, Star Wars XXX: A Porn Parody, The Empire Strikes Back XXX: An Axel Braun Parody, trailer, vote, women, XXX
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Future Presence
NarratorRoger Wayne
Non-fictionCulturePersonal DevelopmentSex & Sexuality
A Wired senior editor and virtual reality expert presents a captivating, candid glimpse into the future "realities" of this emerging technology: how we will use it to form previously impossible relationships, explore new frontiers of intimacy, and how it will forever change human connection.
Heralded as the most significant technological innovation since the smartphone, virtual reality is poised to transform our very notions of life and humanity. Though this tech is still in its infancy, to those on the inside, it is the future. VR will change how we work, how we experience entertainment, how we feel pleasure and other emotions, how we see ourselves, and most importantly, how we relate to each other in the real world. And we will never be the same.
Peter Rubin, senior culture editor for Wired and the industry’s go-to authority on the subject, calls it an "intimacy engine." While once we needed another person to feel the sensations of closeness, trust, vulnerability, confidence, and titillation, VR will give us the ability to induce these sensations by ourselves for the first time in human history. This metamorphosis, Rubin argues, is going to have a powerful impact on relationships that will ripple throughout our society and our individual lives.
A journey into this uncertain future and a glimpse at the cultural implications and promises of a new reality, Future Presence explores a host of complex questions about what makes us human, what connects us, and what is real. Offering a glimpse into the mind-blowing things happening in universities, labs, and tech companies around the world, Rubin leads readers on an entertaining tour of the weirdest, wildest corners of this fascinating new universe. Describing this book as "half travelogue and half crystal ball", Rubin will:
Introduce readers to the creators and consumers of VR technology
Show readers what an experience is like inside the current VR devices
Explain how this technology will upend everything we know about human connection in the future
At once the incredible, inevitable story of virtual reality’s rise and a look towards the future of our fantasies, Future Presence is a deeply personal examination of what connects us, and an analysis of what relationships, empathy, and sex could look like—sooner than we think.
PublisherHarperAudio
© HarperAudio (Audiobook)
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Careless Love
DCI Banks 25
Peter Robinson
Description - Careless Love by Peter Robinson
The twenty-fifth instalment of the Number One Bestselling DCI Banks series
'Robinson remains the master of the police procedural.' Mail on Sunday
'Robinson is prolific, but with each book he manages to ring the changes.' Guardian
A young local student has apparently committed suicide. Her body is found in an abandoned car on a lonely country road. She didn't own a car. Didn't even drive. How did she get there? Where did she die? Who moved her, and why?
Meanwhile a man in his sixties is found dead in a gully up on the wild moorland. He is wearing an expensive suit and carrying no identification. Post-mortem findings indicate he died from injuries sustained during the fall. But what was he doing up there? And why are there no signs of a car in the vicinity?
As the inconsistencies multiply and the mysteries proliferate, Annie's father's new partner, Zelda, comes up with a shocking piece of information that alerts Banks and Annie to the return of an old enemy in a new guise.
This is someone who will stop at nothing, not even murder, to get what he wants - and suddenly the stakes are raised and the hunt is on.
Buy Careless Love by Peter Robinson from Australia's Online Independent Bookstore, Boomerang Books.
Fiction & related items »
Imprint: Hodder & Stoughton Ltd
Publisher: Hodder & Stoughton General Division
Publish Date: 26-Jul-2018
Other Editions - Careless Love by Peter Robinson
Book Reviews - Careless Love by Peter Robinson
» Have you read this book? We'd like to know what you think about it - write a review about Careless Love book by Peter Robinson and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a Boomerang Books Account Holder - it's free to sign up and there are great benefits!)
Author Biography - Peter Robinson
Peter Robinson's DCI Banks is now a major ITV1 drama starring Stephen Tompkinson (Wild at Heart, Ballykissangel) as Inspector Banks, and Andrea Lowe (The Bill, Murphy's Law) as DI Annie Cabbot. Peter's standalone novel BEFORE THE POISON won the IMBA's 2013 Dilys Award as well as the 2012 Arthur Ellis Award for Best Novel by the Crime Writers of Canada. This was Peter's sixth Arthur Ellis award. His critically acclaimed DCI Banks novels have won numerous awards in Britain, the United States, Canada and Europe, and are published in translation all over the world. Peter grew up in Yorkshire, and now divides his time between Richmond and Canada. Peter keeps a website at www.inspectorbanks.com.
Boomerang Books customers who bought Careless Love by Peter Robinson also bought the following titles:
Trashing the Planet
Hardback, October 2017
What is Right and Wrong? Who Decides? Where Do Values Come From? And Other Big Questions
Hardback, March 2018
Paperback / softback, May 2018
Teacher: One Woman's Struggle to Keep the Heart in Teaching
Books By Peter Robinson
Sleeping in the Ground
Hardback, July 2017
Making Water & Rock Gardens
Gallows View
View All Books By Author Peter Robinson
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Mac Miller Honored With Moment of Silence at Pittsburgh Pirates Game
Mac Miller was undeniably a staple in the Pittsburgh community, which has mourned his untimely death wholeheartedly alongside family, friends and fans over the last few weeks. The city's baseball team, the Pittsburgh Pirates, made sure to remember their friend Mac with a moment of silence before their game on Monday (Sept. 17) against the Kansas City Royals, TMZ reports.
As the moment of silence among fans was held, a video montage played showing Mac's memorable moments at PNC Park, the local stadium, including when he once threw the first pitch at a game.
Over the loudspeaker, the announcer said, "Mac was a rapper, a singer, a producer and had a very bright future in the industry ahead of him. Locally, Mac is remembered as a hometown kid who sang about our city where his heart clearly remained. Our thoughts are with his parents, his grandmother and all of his family and friends who mourn his passing."
At their game the night before, one Pirates player in particular, James Conner, shouted Mac out in a special way—donning white cleats with a silhouette of Mac's face on them alongside the phrase, "Thank you Mac."
Mac Miller tragically passed away of a suspected overdose on Sept. 7. His exact cause of death is currently pending the results of a toxicology test.
The Pirates aren't the first in Mac's hometown to highlight his love for the city. Ahead of a vigil in his honor at Pittsburgh's Frick Park last week, Mayor Bill Peduto made a statement saying that he knew Mac well as someone who truly cared about bettering the city.
Watch the moment of silence and check out Conner's cleats below.
Justin Berl, Getty Images
See Photos of Mac Miller's Different Looks Over the Year
Source: Mac Miller Honored With Moment of Silence at Pittsburgh Pirates Game
Filed Under: mac miller
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The core populations and co-occurrence patterns of prokaryotic communities in household biogas digesters
Junpeng Rui†1, 2,
Jiabao Li†1, 2,
Shiheng Zhang1, 2,
Xuefeng Yan1, 2,
Yuanpeng Wang3 and
Xiangzhen Li1, 2Email author
Biotechnology for Biofuels20158:158
© Rui et al. 2015
Accepted: 9 September 2015
Household biogas digesters are widely used to harvest energy in rural areas of developing countries. Understanding core prokaryotic communities, their co-occurrence patterns, and their relationships to environmental factors is important to manage these small-scale anaerobic digestion systems effectively. In this study, 43 household biogas digesters were collected across eight provinces in China. Prokaryotic communities were investigated using 454 pyrosequencing of 16S rRNA genes.
Fourteen core genera and ten core OTUs were identified in household biogas digesters. They were mainly affiliated with the phylum Firmicutes, Synergistetes, Actinobacteria, Chloroflexi, and Spirochaetes. Core prokaryotic genera were mainly composed of Clostridium, Clostridium XI, Syntrophomonas, Cloacibacillus, Sedimentibacter, and Turicibacter. Prokaryotic communities in the 43 samples were clearly divided into two clusters. Cluster I was dominated by Clostridium, while Cluster II was dominated by members of Spirochaetes, Bacteroidales, Clostridia, and abundant syntrophs and methanogens. NH4 +-N and COD contributed significantly to the assembly of the prokaryotic community in Cluster I, while NH4 +-N, pH, and phosphate contributed significantly to Cluster II. Correlation-based network analysis showed that the prokaryotic communities in the biogas digesters were dominated by some functional modules. Cluster I was dominated by acetotrophic methanogenic modules and the Clostridium-driven primary fermentation module, while the network of Cluster II was dominated by hydrogenotrophic and acetogenic methanogenesis modules and multi-group-driven (Spirochaetes, Bacteroidales, and Clostridia) primary fermentation modules. The network of Cluster II was more complex and functionally redundant.
Prokaryotic communities identified in the household biogas digesters varied significantly and were affected by environmental factors, such as NH4 +-N, pH, and COD. However, core prokaryotic communities existed, and most of them were also dominant populations. Cosmopolitan OTUs tended to co-occur. Prokaryotic communities in biogas digesters were well organized by some functional modules. The modular structure of the prokaryotic community, which has functional redundancy, enhances the resistance against environmental stress and maintains digestion efficiency in the anaerobic digestion process.
Household biogas digesters
Prokaryotic community
Co-occurrence pattern
Manure digestion
Methanogenesis
Anaerobic digestion is an effective process for converting organic waste, e.g., animal manure and agricultural or food waste, into biogas containing 50–70 % methane [1, 2]. Generally speaking, digestion consists of four steps: substrate hydrolysis, acidogenesis, acetogenesis, and methanogenesis. The stable and efficient digestion process relies on multiple syntrophic relationships among a community of microbes, including hydrolyzing and fermenting bacteria, acidogenic and acetogenic bacteria, and methanogenic archaea [3, 4]. However, microbial populations in anaerobic manure digesters can be highly variable, even with the digestion of a common core substrate [5]. A deep analysis of the structure and variations of bioreactor microbial communities may potentially reveal their important assembly mechanisms.
Many factors affect the prokaryotic community structure in biogas digesters, including digester design, substrates, and operational conditions [1, 6, 7]. Compared to the large-scale digesters, household biogas digesters are usually small in size that most digesters have volume of less than 10 m3. Geographic difference is likely more important to influence anaerobic digestion process in household biogas digesters. For example, temperature is not controlled during the operation; therefore, the digestion process is affected by the seasonal variation of local climate. Mixed raw materials are usually used depending on their local availability, e.g., manures from livestock, humans, and grass residues. Substrate types and quality are often recognized as the primary driving factors shaping microbial communities in anaerobic biogas digesters [8]. As a digester is constantly re-inoculated by multiple substrates, variations in substrate quantity and quality may lead to different microbiomes. Further, microbiomes in the digesters reflect not only the variation of manure quality, but also differences in the digestive tracts of rumen and non-rumen animals. Swine manure is most often used for household biogas digestion in China. It usually contains high ammonium nitrogen (NH4 +-N) due to the high protein content [3]. High NH4 +-N is an inhibitor of methanogenesis, especially acetotrophic methanogens [9]. Therefore, the concentration of NH4 +-N may be a crucial factor affecting prokaryotic community structure in the household biogas digester.
A core OTU is usually defined as being present in most samples [10, 11]. Huse et al. reported that more OTUs will be detected but the differences are minor if using the definition of 90 % prevalence, compared to 95 %. The core microorganisms in this study are defined as those common to most digesters (90 % prevalence), while specific microorganisms exist only in a few or in one digester. The variations in both core and specific populations are related to changes in function (i.e., digestion efficiency) and environmental conditions (i.e., operating conditions). Core microorganisms may have a stronger ability to resist perturbation, while specific microorganisms respond rapidly to some changing conditions. Core and specific microorganisms have been identified, based on seven multiple types of digestion systems, using the clone library method [11]. However, the information is limited by the low throughput clone library method and the small number of digester samples. Moreover, core and specific microbial populations can be better identified by using a high throughput sequencing technique and a larger number of samples from biogas digesters.
The anaerobic methanogenic system is a representative model with a well-organized, closely interacting bacterial and archaeal community. Co-occurrence of prokaryotic populations in the system reflects their similar niche adaptation of the co-occurring species, or interspecies interactions, either by competition or by cooperation. In the anaerobic digestion system, nearly all acidogenic microorganisms also participate in hydrolysis, such as members of Clostridium, Ruminococcus, and Bacteroidetes [3]. Acetogenesis could be carried out by at least two groups of bacteria: homoacetogens and syntrophs. Acetogenic syntrophs, e.g., the butyrate oxidizer Syntrophomonas [12], and the benzoate oxidizer Syntrophus [13], can metabolize syntrophically with hydrogenotrophic methanogens. Through the syntrophic metabolism, H2 partial pressure is maintained at a very low level to keep anaerobic oxidation of organic matter energetically [4]. Homoacetogens could exergonically produce acetate, competing for substrates with primary fermenters, secondary fermenters, and hydrogenotrophic methanogens [14]. These interactions are also characterized by a co-occurrence network. The correlation-based co-occurrence network analysis can produce microbial functional modules, which enable us to reveal the interactions between different functional groups and environmental factors in various complex systems [15–19].
Household biogas digesters are widely used to harvest energy in rural China and other developing countries [20]. However, according to the literature review, there are few reports using a pyrosequencing technique to compare bacterial communities between various household biogas digesters operated at different geographic locations. The co-occurrence patterns of prokaryotic communities in the household biogas digesters were not revealed. In this study, we collected sludge samples from 43 household biogas digesters across eight provinces of China, and analyzed the variations and co-occurrence networks of prokaryotic communities based on 16S rRNA amplicon pyrosequencing data. The aims were to investigate (1) variations of the prokaryotic community structure, (2) core prokaryotic populations, and (3) the co-occurrence networks of prokaryotic communities in household biogas digesters.
Overall prokaryotic community structure and diversity
The prokaryotic communities in 43 household biogas sludge samples were separated into two clusters based on UniFrac distances (PerMANOVA p < 0.001) (Fig. 1). The prokaryotic communities were clustered independently on substrate types (Additional file 1: Figure S1), but related to different locations. Cluster I contained 16 samples, mainly from Pengzhou, Deyang, Jitian, Gejiu, and Lanzhou. Cluster II contained 27 samples mainly from the remaining 10 rural areas. The prokaryotic diversity indices based on the number of OTUs (operational taxonomic units), Chao1 richness, and Shannon’s and Simpson’s diversity indices, revealed that the prokaryotic diversity of Cluster I was significantly lower than that of Cluster II (p < 0.001) (Additional file 1: Figure S2, Additional file 2: Table S1).
Jackknife sample cluster analysis of prokaryotic communities based on weighted UniFrac distances. The internal nodes represent values of Jackknife support
The results of principal coordinate analysis (PCoA) showed that the community structures of Cluster I were strongly affected by NH4 +-N, while those of Cluster II were strongly affected by NH4 +-N, COD (chemical oxygen demand), and pH (Fig. 2). Variance partitioning analysis (VPA) was performed to quantify the relative contributions of different environmental variables to changes in the prokaryotic community structure (Additional file 2: Table S2). It showed that COD and NH4 +-N were the primary measured environmental factors to affect community structure in Cluster I, explaining 14.8 and 13.6 % of total observed variation, respectively (p < 0.05). NH4 +-N and pH explained 18.9 and 14.4 % of total observed variation in Cluster II, respectively, including 9.0 % shared between them (p < 0.01). Therefore, NH4 +-N was the primary environmental factor that influenced community structure in both clusters.
PCoA score plot based on weighted UniFrac metrics. Plots were ranked by the concentrations of a NH4 +-N (mg L−1), b pH, c COD (mg L−1) and d phosphate (mg L−1)
Core prokaryotic populations in biogas sludge
The 1641 OTUs were detected in these 43 samples based on 97 % identity of 16S rRNA gene sequences. The 961 OTUs were shared between Cluster I and II. A total of 61 OTUs (0.45 % of 1641 OTUs in relative abundance) were detected only in Cluster I, mainly affiliated with Clostridiales. The 619 OTUs (12.31 % of 1641 OTUs in relative abundance) were detected only in Cluster II, mainly affiliated with Bacteroidetes and Spirochaetes. Generally, the OTUs related to Clostridium, Clostridium XI, Turicibacter, Ruminococcaceae, and Anaerolinaceae were more abundant in Cluster I, while those affiliated with Bacteroidales, Sphaerochaeta, Candidatus Cloacamonas, Porphyromonadaceae, and Methanosaeta were more abundant in Cluster II.
OTUs distributed in >90 % of the 43 digesters were defined as core OTUs in this study. Results showed that there were 10 core OTUs, mainly affiliated with Firmicutes, such as Clostridium, Clostridium XI, Syntrophomonas, and Turicibacter (Table 1). Members of Cloacibacillus and Anaerolinaceae were also included. Generally, most of the core OTUs were also dominant OTUs with a relative abundance of >1 %, and the sum proportion of them was 45.1 and 16.1 % in Cluster I and II, respectively.
Core genera and core OTUs and their average relative abundances in household biogas digesters
Core genera/OTUs
Relative abundance (%)
Cluster I
Cluster II
Phylum Firmicutes
34.37 ± 4.26
Anaerovorax
0.72 ± 0.14
OTU1
Ruminococcus
OTU1200
Oscillospira
OTU24
Phylum Synergistetes
Clostridium XI
Cloacibacillus
Aminobacterium
Turicibacter
Phylum Actinobacteria
Corynebacterium
Syntrophomonas
Leucobacter
Phylum Spirochaetes
Sedimentibacter
Candidatus Cloacamonas
Phylum Chloroflexi
Tissierella
OTU10 (Anaerolinaceae)
OTUs distributed in >90 % of samples in each cluster were defined as sub-core OTUs excluding core OTUs. Fourteen sub-core OTUs were identified in Cluster I. They were mainly affiliated with Firmicutes (such as Clostridium, Trichococcus and Lachnospiraceae), Actinobacteria (Cloacibacillus, Leucobacter), and the aerobic Acinetobacter. These 14 OTUs were also presented in many Cluster II samples, but they were less abundant than those in Cluster I (2.3 vs. 6.4 %) (Additional file 2: Table S3).
Fourteen sub-core OTUs were also identified in Cluster II. They were mainly affiliated with Bacteroidetes (such as Bacteroidales and Porphyromonadaceae) and Spirochaetes (such as Sphaerochaeta, Candidatus Cloacamonas, and Treponema) (Additional file 2: Table S3). The amount of these 14 OTUs was much lower in Cluster I than in Cluster II (1.1 vs. 9.0 % in total), and some of them were not observed in Cluster I.
The definitions of core genera and sub-core genera were similar to those of core OTUs and sub-core OTUs. The 14 core genera were identified, and they were affiliated with Firmicutes, Synergistetes, Actinobacteria, and Spirochaetes. Among them, six core genera contained core OTUs (Table 1). Three sub-core genera in Cluster I and seven in Cluster II (Additional file 2: Table S3) were also identified. The communities of Cluster I mainly consisted of core genera (60.3 % in total), while those of Cluster II mainly consisted of core (31.0 %) and sub-core genera (10.7 %), indicating that prokaryotic communities were more diverse in Cluster II than in Cluster I.
At the phylum level, Firmicutes were most abundant in both Cluster I and II. Compared to Cluster II, Cluster I digesters had more abundant Firmicutes (75.2 vs. 33.1 %) and Chloroflexi (7.6 vs. 2.7 %), and less abundant Bacteroidetes (2.5 vs. 25.8 %), Spirochaetes (0.5 vs. 15.8 %), Euryarchaeota (1.0 vs. 4.2 %), and Tenericutes (0.6 vs. 1.8 %) (p < 0.01, Fig. 3a, Additional file 2: Table S4).
Taxonomic compositions of microbial communities in Cluster I and II. Relative abundances (% of total reads) of 16S rRNA gene a at the phylum level of prokaryote, b at the genus level of bacteria, and c at the genus/family level of methanogens. **Significant at p < 0.01, *significant at p < 0.05
At the genus level, Clostridium was most abundant in both Cluster I and II. Compared to Cluster II, Cluster I digesters had more abundant Clostridium (34.4 vs. 10.6 %), Clostridium XI (10.4 vs 2.1 %), Turicibacter (4.5 vs. 1.6 %), and Tissierella (1.7 vs. 0.5 %), and less Sphaerochaeta (0.07 vs. 7.1 %), Candidatus Cloacamonas (0.4 vs. 5.3 %), and Treponema (0.04 vs. 1.4 %) (p < 0.01, Fig. 3b, Additional file 2: Table S4). The relative abundances of Cloacibacillus (about 4 %) and Syntrophomonas (about 2 %) were similar in both clusters.
Methanogens were more abundant in Cluster II than in Cluster I (3.9 vs. 1.0 % in total reads, p < 0.01). Compared to Cluster I, Cluster II contained more Methanosaeta (1.61 vs. 0.22 %, p < 0.05), Methanoculleus (0.16 vs. 0.008 %, p < 0.05), and Methanospirillum (0.14 vs. 0.003 %, p < 0.01) (Fig. 3c). Besides, Methanosarcina, Methanocorpusculum, and Methanogenium were also abundant in several samples. In general, acetotrophic (Methanosaeta, Methanosarcina) and hydrogenotrophic methanogens (Methanocorpusculum, Methanogenium, Methanoculleus, Methanospirillum, Methanobrevibacter, etc.) accounted for 46 and 54 % of all methanogens in both clusters, respectively, without a significant difference.
Relationships of prokaryotic communities with environmental factors
Pearson’s correlation analysis indicated that the relative abundance of phylum Firmicutes was significantly correlated to phosphate concentration in Cluster I, while it was significantly correlated to pH in Cluster II (Additional file 2: Table S5). Euryarchaeota (e.g. Methanosaeta) and Syntrophus were negatively correlated with NH4 +-N, indicating that they were sensitive to NH4 +-N (Additional file 1: Figure S3). However, NH4 +-N was positively correlated to Spirochaetes and Tenericutes in Cluster II (p < 0.01).
Generally, more genera were significantly correlated to COD and NH4 +-N in Cluster I, while more were significantly correlated to pH, NH4 +-N, and phosphate in Cluster II (Additional file 2: Table S5). Sphaerochaeta showed a significant positive correlation with NH4 +-N, COD, phosphate, and pH in Cluster II. In Cluster II, the genus Clostridium showed positive correlations, while Syntrophus showed negative correlations to pH and NH4 +-N.
The dominant acetotrophic methanogens (genus Methanosaeta) and hydrogenotrophic methanogens (especially Methanoregulaceae) were significantly and negatively correlated with both NH4 +-N and pH, while Methanocorpusculum was only negatively correlated with pH (p < 0.05, Additional file 2: Table S6). In contrast to other methanogens, Methanoculleus were positively correlated with both NH4 +-N and pH (p > 0.05). COD was negatively correlated with Methanosaeta and Methanoregulaceae, while positively correlated with Methanobrevibacter (p < 0.05). These results indicated that different methanogens were susceptible to different environmental factors.
Network analysis of cosmopolitan OTUs
Cosmopolitan OTUs were defined as OTUs that occurred in more than half of the samples in the sample group. Cosmopolitan OTUs were identified in Cluster I, II, and in all samples. Nonrandom co-occurrence patterns were detected by the C-score test, with the observed C-scores (6.78, 24.29, and 65.30, respectively) being higher than the mean values (6.65, 23.56, and 63.42 respectively, p < 0.0001) expected under the null model, indicating that these cosmopolitans tended to co-occur more often than expected by chance.
Three correlation-based networks, named C1, C2, and AS, were constructed with these cosmopolitan OTUs for Cluster I, Cluster II, and all samples, respectively (Fig. 4, Additional file 1: Figure S4). Prokaryotic communities in Cluster II digesters showed different topological properties of co-occurring networks from those in Cluster I digesters (Additional file 2: Table S7). The network sizes were similar in AS and C1 (110 and 103 nodes respectively), but were much smaller than C2 (206 nodes). The total abundance of OTUs that occurred in these networks was 60.4, 73.0, and 65.8 %, respectively, indicating that most microorganisms in the sludge samples were affiliated with these cosmopolitan OTUs. Values of modularity, average clustering coefficient, and average path length in these empirical networks were higher than those in random networks, suggesting that the empirical networks had “small world” modularity and hierarchy properties [17, 21].
Networks of co-occurring prokaryotic OTUs in all sludge samples based on correlation analysis. Nodes were colored by a modularity class with labeled genera names, and b occurrence in networks of Cluster I (C1) and Cluster II (C2). A connection stands for a strong (Spearman’s ρ > 0.6) and significant (p < 0.01) correlation. For each panel, the size of each node is proportional to the number of connections (degree); the thickness of each connection between two nodes (edge) is proportional to the value of Spearman’s correlation coefficients, ranging from 0.60 to 0.93. Other: OTUs did not occur in networks of Cluster I or II
An important function of each module can be inferred based on the prokaryotic composition, PICRUSt prediction, and their known physiological functions [3, 22]. Cluster I contained eight modules, in which the function of five modules could be predicted confidently. 93 nodes (OTUs) belonged to the module C1M0, 1, 2, 4, and 6 (Table 2, Additional file 2: Table S8), mainly affiliated with Firmicutes (57.9 %), Chloroflexi (6.3 %), and Spirochaetes (4.2 %). The ammonium-sensitive methanogen Methanosaeta was in the module C1M1, while Methanosarcina was in the high NH4 +-N module C1M2 (positive correlation with NH4 +-N) (Table 3). Large modules C1M1 and C1M2 were predicted to be similar in their function, most likely conducting fermentation mainly with acetotrophic methanogens. C1M4 was also a high-NH4 +-N module, dominated by Clostridium for fermentation. The small module C1M6 included aerobic or facultative anaerobic Proteobacteria, e.g., Sphingomonas, Methylobacteriaceae, and Acinetobacter, which were likely involved in organic substrate degradation and oxygen consumption for the maintenance of anoxic environment. C1M4 had a positive relationship to C1M1, C1M2, and C1M6, reflecting their cooperative nature. The negative relationship between C1M1 and C1M2 reflected a certain competition (Additional file 2: Table S9).
Taxonomic information of dominant modules in the networks of all samples (AS), Cluster I (C1), and II (C2)
Number of nodes
Module hubs
Methanogens
Abundant phyla/classes
(1) AS
Bacteroidales, Sphaerochaeta, Treponema, Methanocorpusculum, etc.
Methanocorpusculum, Methanoculleus
Bacteroidetes, Spirochaetes
Clostridium, Clostridium XI
Clostridia
Bacteroidales, Parabacteroides, Desulfobulbus, Syntrophus
Methanosaeta
Bacteroidetes, Spirochaetes, Euryarchaeota
Sphaerochaeta, Bacteroidaceae, Porphyromonadaceae
Bacteroidetes, Spirochaetes, Clostridia
(2) C1
C1M0
Coriobacteriales, Leucobacter etc.
Clostridia, Actinobacteria, Synergistetes
Clostridium, Pirellulaceae, Gaiellales, etc.
Clostridia, Chloroflexi, Actinobacteria
Clostridium, Ruminococcaceae, Erysipelotrichaceae
Methanosarcina
Clostridium, Clostridia, Coriobacteriales, Syntrophomonas
Sphingomonas
Alphaproteobacteria, Gammaproteobacteria
Sphaerochaeta, Bacteroidales, Clostridium, Tissierella, Treponema, Cloacibacillus, etc.
Spirochaetes, Bacteroidetes, Clostridia
Coriobacteriales
Methanocorpusculum
Clostridia, Bacteroidetes, Spirochaetes
Clostridia, Sphaerochaeta, Bacilli, Actinobacteria
Bacteroidales, Syntrophus, Syntrophomonas, Treponema
Spirochaetes, Bacteroidetes, Deltaproteobacteria, Clostridia, Chloroflexi, Euryarchaeota
Methanogenium
Clostridia, Spirochaetes, Bacteroidetes
Spearman’s correlation of environmental variables to prokaryotic community structures of dominant modules in networks tested by partial Mantel test (permutations: 9999)
NH4 +-N
(1) All samples
0.223**
0.162*
−0.07
(2) Cluster I
(3) Cluster II
** Significant at p < 0.01, * significant at p < 0.05
When one environmental variable was analyzed by the partial Mantel test, the remaining three environmental variables were controlled
In the 10-module network C2, 198 nodes belonged to module C2M 0, 1, 2, 4, 5, 6, and 8 (Additional file 2: Table S10), which were composed mainly of Firmicutes (22.4 %), Bacteroidetes (19.1 %), and Spirochaetes (13.6 %). Among them, 7 functional modules were identified in C2, including three methanogenic fermentation modules. C2M2 and C2M6 were hydrogenotrophic methanogenic modules, with Methanocorpusculum and Methanogenium as the key methanogen, respectively. C2M5 was an acetotrophic methanogenic module, with Methanosaeta as the key methanogen. C2M1 and C2M8 were primary fermentation modules, including abundant Spirochaetes, Bacteroidetes, and Clostridia. These modules were likely regulated by NH4 +-N. Based on the relationships between its members and NH4 +-N, it is inferred that C2M1 preferred high NH4 +-N, while C2M2, 5, and 8 preferred low NH4 +-N.
C1 and C2 shared 53 nodes distributed in almost all modules. They were mainly affiliated with Clostridia and Anaerolinaceae (Additional file 2: Tables S8, S11). The remaining 53 nodes in C1 were mainly related to Clostridia. However, most of nodes in C1M6 belonged to aerobic Proteobacteria, such as Methylobacterium and Sphingomonas. The remaining 153 nodes in C2 were mainly affiliated with Spirochaetes and Bacteroidales, and they also included nodes belonging to hydrogenotrophic methanogens (Methanocorpusculum and Methanogenium) and syntrophs (Syntrophus and Syntrophomonas).
In the 11-module network AS, 93 nodes belonged to module AM1, 4, 5, 7, and 8 (Additional file 2: Table S11). These nodes were mainly affiliated with Firmicutes (relative abundance of 31.8 % in total OTUs), Bacteroidetes (9.8 %), and Spirochaetes (7.5 %). Hydrogenotrophic methanogens Methanocorpusculum and Methanoculleus were in AM1, and acetogenic Methanosaeta was in AM7. They mainly co-occurred with Bacteroidetes and Spirochaetes (Table 2). Members of AM4 and AM5 were mainly affiliated with Clostridia, especially the genus Clostridium. The network AS was a combination of C1 and C2, sharing 105 nodes with them (Additional file 1: Figure S5). Nodes in AM1, 7, and 8 were mainly shared with those in C2, while those in AM4 and 5 were mainly shared with both C1 and C2 (Fig. 4b).
Totally, 388, 330, and 771 pairs of nodes were positively correlated in AS, C1, and C2, respectively (Spearman’s ρ > 0.6, p < 0.01, Fig. 4), while only 46, 135, and 108 pairs of nodes were negatively correlated, respectively (Spearman’s ρ < −0.6, p < 0.01, not shown as edges in Fig. 4). Negative associations usually existed between Clostridium and Bacteroides/Syntrophus in AS, and Clostridium and Coriobacteriales/Facklamia/Cloacibacillus/Anaerolinaceae in C1, probably due to the high abundances of Clostridium in many samples (tradeoff or competition interactions). However, negative associations were more complex in C2 since the amount of Clostridium was much less in these samples. Negative associations usually existed between Clostridium/Tissierella/Bacteroidales and Syntrophus/Treponema, Sphaerochaeta, and Syntrophus/Bacteroidales in C2.
OTU23 (Methanocorpusculum), OTU142 (Methanoculleus), OTU14 (Methanosaeta) were three nodes belonging to methanogens in AS, with 20, 7, and 7 co-occurrents, respectively (Fig. 4). Their co-occurrents were mainly affiliated to Bacteroidetes and Spirochaetes, which were likely involved in hydrolysis and acidogenesis, and the production of precursors for methanogenesis. OTU14 also co-occurred with acetogenic syntrophs, e.g., Syntrophomonas and Syntrophus. Therefore, these co-occurrence relationships may reflect a food chain cascade or syntrophic interactions in the anaerobic digestion.
The partial Mantel test showed that NH4 +-N was significantly related to many modules in these three networks, such as AM5, 7 and 8, C1M2 and 4, C2M1, 2, 5, and 6 (Table 3). Modules significantly related to pH or COD were almost related to NH4 +-N as well. It was likely that nodes often shared among modules have the same ammonium preference in different networks. Therefore, NH4 +-N may be an important environmental factor in influencing microbial modularity.
Core prokaryotic communities in the biogas digesters
In this study, 14 core genera were identified, mainly affiliated with the phylum Firmicutes (9 genera), such as Clostridium, Clostridium XI, Syntrophomonas, Sedimentibacter, and Turicibacter. The others were affiliated with the phyla Synergistetes (Cloacibacillus and Aminobacterium), Actinobacteria, and Spirochaetes (Candidatus Cloacamonas). Ten core OTUs were identified, mainly affiliated with Firmicutes, such as Clostridium, Clostridium XI, Syntrophomonas and Turicibacter, Cloacibacillus, and Anaerolinaceae. Generally, most of the core OTUs were also dominant OTUs in biogas digesters, indicating their importance in biogas fermentation, regardless of the treatment process and geographic locations.
Core genera or OTUs identified in this study are also widely detected in various anaerobic digestion systems [11, 23]. Phylogeny-based empirical relationships can yield powerful correlations between community structure and function as observed in previous studies [24]. Core populations identified in this study have been recognized to play important roles in hydrolysis, fermentation, and syntrophic metabolism. The Genus Clostridium participates in both hydrolysis and acidogenesis, and it is especially dominant in the first two digestion phases. The Clostridium members decompose various substrates, such as starch, cellulose, amino acids, and fatty acids [3]. Members of Clostridium and Bacteroidetes are able to hydrolyze proteins to amino acids with proteases, and degrade amino acids to fatty acids and NH4 +-N [22]. Clostridium XI was more abundant in Cluster I. It is affiliated with the family Peptostreptococcaceae, which can ferment saccharides, alcohol, and cellulose [25]. Sphaerochaeta was more abundant in Cluster II, which could enhance the degradation of cellulose when grown in co-culture with Clostridium thermocellum [26]. Cloacibacillus could ferment amino acids (e.g., mucin in swine intestinal tract), and produce fatty acids [27]. Turicibacter is able to degrade carbohydrates, which is an important member of the gut microbiota [28]. Anaerolinaceae members were more abundant in Cluster I, and they could ferment carbohydrates and produce hydrogen and acetate [29]. The PICRUSt prediction further supported that the genes encoding enzymes involved in polysaccharides hydrolysis existed in some core populations such as Clostridium, Clostridium XI, Sphaerochaeta, Leucobacter, Turicibacter, Bacteroidetes, and Anaerolinaceae. Some of them also include genes encoding proteases, such as Clostridium, Clostridium XI, Sphaerochaeta, Candidatus Cloacamonas, Bacteroidetes, and Anaerolinaceae.
Each full-scale bioenergy system has a unique community structure with an unprecedented level of stability [24]. Core bacterial populations must be key players in maintaining the stability and function of an anaerobic digestion system. Bacterial community structures are resilient, and key populations will be rebounded following disturbances [24]. The aim of this study is to compare the general assembly rules of microbial community across different digesters. Thus, although we only collected a one-time sample from each of 43 digesters, it may represent the properties of a bacterial community structure in a specific biogas digester.
Significant variation of prokaryotic community
In this study, the prokaryotic communities of 43 mesophilic household biogas sludge samples were clearly divided into two clusters based on the UniFrac distances, independent of substrate types (Additional file 1: Figure S1B) or our measured environmental factors (pH, COD, NH4 +-N, and phosphate, p > 0.05). This indicated the different key factors in shaping the assemblies of prokaryotic communities. Previous work indicated that the prokaryotic communities of 19 full-scale anaerobic digestion installations were divided into two clusters driven by NH4 +-N concentration [30]. The low NH4 +-N cluster was dominant with Bacteroidales, while the high NH4 +-N cluster was dominant with Clostridiales. In this study, we observed more aerobic microbial organisms (e.g., Sphingomonas and Pseudomonas) and less abundant methanogens in Cluster I digesters. It might be caused by the recent re-inoculation or other disturbance to the digester system. These results possibly implicated poor performance in Cluster I digesters [31]. Clostridium was the main primary fermenter in Cluster I digesters, while more diversified primary fermenters occurred in Cluster II digesters, including Spirochaetes, Bacteroidetes, and Clostridia. The abundances of these bacteria were highly correlated with those of methanogens (Table 4).
Cosmopolitan methanogen OTUs and their significant (p < 0.01) co-occurrent OTUs in all samples
Co-occurrents
Spearman’s ρ
Co-occurrent affiliations
Co-occurrent affiliated phylum
Number of co-occurring samples
(a) OTU23 (Methanocorpusculum)
Parabacteroides
Bacteroidetes
Porphyromonadaceae
Bacteroidales
OTU128
Sphaerochaetaceae
Spirochaetes
Bacteroidaceae
Sphaerochaeta
Anaeroplasmataceae
Tenericutes
Treponema
Lachnospiraceae
Firmicutes
(b) OTU14 (Methanosaeta)
Syntrophus
Proteobacteria
(c) OTU142 (Methanoculleus)
Crenarchaeota
The genus Syntrophus is able to syntrophically oxidize benzoate with hydrogenotrophic methanogens, and produce acetate and H2 [13]. The genus Candidatus Cloacamonas is probably a hydrogen-producing syntroph present in many anaerobic digesters [32]. Both of these genera were significantly higher in Cluster II than in Cluster I, indicating active secondary fermentation in Cluster II digesters. Methanogenic activity appears in the acidogenic phase, but the number of methanogenic archaea obviously increases in the methanogenic phase [3]. Methanogens, especially Methanosaeta, Methanoculleus, and Methanospirillum, were more abundant in Cluster II than in Cluster I (p < 0.05), indicating methanogenesis was possibly more active in Cluster II digesters.
Selective inhibition of NH4 +-N affects prokaryotic community structure
Many environmental factors influence prokaryotic communities in the biogas digestion system, such as substrates, pH, inoculation, etc. [3, 33]. If one environmental factor predominates the microbial community structure, it may decouple the relationships between community structures and other factors. In this study, it is difficult to collect particular data for household biogas digesters, such as gas production rate, hydraulic retention time, exact substrate compositions, and so forth. Among our measured environmental parameters, the NH4 +-N, pH, and COD were observed to strongly influence prokaryotic communities in the household digesters. Phosphate, which was positively correlated to NH4 +-N (p < 0.01), had less effect on prokaryotic communities, except for module C1M4 and C1M6 dominant by Clostridium and aerobic Proteobacteria, respectively.
Swine manure as a main substrate used in the Chinese household digesters often contains high NH4 +-N. VPA analysis indicated that NH4 +-N is an important factor in influencing the prokaryotic community structure in both Cluster I and Cluster II. High NH4 +-N has an inhibiting effect, and may even be toxic to microbial communities because free ammonia could diffuse passively into cells, causing a proton imbalance and potassium deficiency [34, 35]. High NH4 + ion (>1500 mg L−1 NH4 +-N) also has an inhibiting effect on those species (e.g., methanogens) sensitive to pH [3, 34]. The NH4 +-N concentration of 25 samples were higher than 1500 mg L−1 in this study. Compared to bacteria, methanogenic archaea are more susceptible to NH4 +-N. Moreover, the tolerance of hydrogenotrophic methanogens to ammonium is usually higher than that of acetoclastic Methanosarcina and Methanosaeta [9]. In this study, the relative abundance of Euryarchaeota was negatively correlated with NH4 +-N in both clusters (p < 0.05), while only the most dominant methanogen Methanosaeta was inhibited in Cluster II (p < 0.05). This indicated that the keystone populations can be altered by NH4 +-N. The microbial community may select syntrophic acetate oxidation as a significant pathway for forming methane from acetate under high NH4 +-N concentration [36]. Besides NH4 +-N concentration, the degree of ammonia inhibition could also be influenced by temperature, pH, volatile fatty acids, and some other ions [34]. It is reported that some ions (e.g., Na+, Mg2+, and Ca2+) could be antagonistic to ammonia inhibition [37]. The adaptations of methanogens to ammonia were also observed [38]. The adaptations might be common for the microbial populations due to diverse substrates and long hydraulic retention time in household biogas digesters.
Core methanogen OTU was not observed, indicating that they are susceptible to environmental changes, e.g., NH4 +-N. Besides methanogens, this study observed that some bacteria were also inhibited by NH4 +-N, including Proteobacteria (e.g., Syntrophus) and Planctomycetes in Cluster II. However, some bacteria were positively correlated to NH4 +-N, including Clostridium and Sphaerochaeta, Erysipelothrix, and Tissierella. Therefore, the selection of different prokaryotic taxa by NH4 +-N would shift the community structure through the adjustment of species abundance (species sorting), in which those species genetically better adapted to high NH4 +-N may outcompete other less well-adapted species.
Co-occurrence patterns of prokaryotic communities
Co-occurrence network analysis is useful in revealing common system-level properties of prokaryotic communities in the biogas digestion systems. Co-occurrence analysis of microbial taxa from 43 household digesters in this study suggested strong within- and between-domain correlations between different groups of microorganisms within the digesters. It also showed that the prokaryotic communities in biogas digesters are well organized by some functional modules. Significant and positive correlations between members within the modules indicated they may co-occur with mutualism interactions, such as an exchange of metabolic intermediates. Methanogenesis is a central metabolic process in the anaerobic biogas digestion. As abundant methanogens in the household biogas digesters, OTUs affiliated to hydrogenotrophic Methanocorpusculum and Methanoculleus and acetoclastic Methanosaeta tended to co-occur with fermentation bacterial Bacteroidetes, Spirochaetes, Tenericutes, and Firmicutes (Table 1). These bacteria participate in hydrolysis and produce intermediates, e.g., H2/CO2, formate, and acetate [3]. The occurrence of a modularity structure in the prokaryotic community further indicates the occurrence of multiple syntrophic metabolic pathways with functional redundancy of competition or cooperation populations in the biogas digesters. Besides the exchange of metabolic intermediates, multiple syntrophic interactions must be maintained between bacteria and methanogens, which consume H2 and maintain a low H2 partial pressure, so that the overall reaction in the system is exergonic [4]. This is further supported by the fact that the positive interactions of multi-group-driven primary fermentation modules with hydrogenotrophic methanogenic fermentation modules were much stronger than those with acetotrophic methanogenic fermentation modules (Additional file 1: Figure S6). The different co-occurrence networks were observed between Cluster I and Cluster II digesters in this study. It was speculated that different co-occurrence networks may influence the stability and performance of biogas digesters.
The assembly of microbial communities is controlled by neutral and deterministic processes [39]. Recent studies indicated that deterministic processes may play a larger role in the process of microbial community assembly in anaerobic digesters [40]. Interspecies interactions and environmental selections are proposed to be two relevant mechanisms of deterministic factors [41, 42]. The integrative effects of these environmental factors may create niche differentiation, and cause the variations in microbial community structure in various digesters. Further, the results in this study showed that cosmopolitan OTUs tended to co-occur, and microbial communities showed modularity properties in the biogas digesters. These modules and their inferred central functions are highly correlated to some environmental factors, e.g., NH4 +-N, pH, and COD. Thus, the modular structure of microbial interactions may be largely shaped by the deterministic processes.
The present study showed that 14 genera and 10 OTUs of prokaryotic populations were commonly shared by at least 90 % of all 43 samples. They were mainly affiliated with the phyla Firmicutes, Synergistetes, Actinobacteria, Chloroflexi, and Spirochaetes. Core prokaryotic genera were mainly composed of Clostridium, Clostridium XI, Syntrophomonas, Cloacibacillus, Anaerolinaceae, Sedimentibacter, and Turicibacter. Prokaryotic communities of the 43 samples showed high variations and were clearly separated into 2 clusters with different co-occurrence networks. Cluster I was dominated by Clostridium, while Cluster II was dominated by members of Spirochaetes, Bacteroidales, Clostridia, and abundant syntrophs and methanogens. NH4 +-N and COD contributed significantly to the assembly of the prokaryotic community in Cluster I, while NH4 +-N, pH, and phosphate contributed significantly to the community assembly in Cluster II. Correlation-based network analysis showed that the prokaryotic communities of biogas digesters are well organized by some functional modules. These modules and their inferred central functions are highly correlated to some environmental factors, such as NH4 +-N, pH, and COD. Anaerobic digestion is susceptible to various forms of perturbation because of its delicate balance between the different microbial consortia in the anaerobic digestion process. The modular structure of the prokaryotic community with functional redundancy in the biogas digestion system may provide the system with access to the total functional diversity and environmental specificity available in the community, thus, enhances the resistance against perturbation, and maintains the performance of biogas digesters.
Sample description and chemical property measurements
Forty-three sludge samples from household biogas digesters were collected in 15 rural areas across eight provinces in China (Additional file 2: Table S12). These digesters, which are also called hydraulic biogas digesters, were typically constructed using brick and concrete in a fixed-dome configuration. All digesters were operated in a temperature range from 18 to 35 °C without temperature control. The volume of most digesters ranged from 6 to 25 m3. Only one digester had a volume of 55 m3. The feeding substrates varied among individual digesters, including manures from swine, cattle, humans, poultry, and donkeys. Grass residue was used occasionally in some digesters. Usually three bottles of sludge samples from each digester were collected into sterile flasks, transported to the lab under ice, pooled and centrifuged under 8000 rpm, and stored at -20 °C until the genomic DNA were extracted. Chemical properties of sludge, including pH, chemical oxygen demand, NH4 +-N, and phosphate were measured as previously described [43, 44].
DNA extraction and pyrosequencing
Genomic DNA was extracted by the method described previously [45]. DNA quality was checked using a NanoDrop Spectrophotometer, subjected to electrophoresis, and visualized in a 0.8 % agarose gel. Extracted DNA was diluted to 10 ng μl−1 for downstream use. For pyrosequencing, the 16S rRNA gene was amplified with universal primers 515F (5′-GTGYCAGCMGCCGCGGTA-3′) and 909R (5′-CCCCGYCAATTCMTTTRAGT-3′). The detailed PCR conditions were described previously [44]. The barcoded amplicons were pooled with equal molar concentrations of the samples and sequenced using a GS FLX + pyrosequencing system (454 Life Sciences).
Sequencing data analysis
The raw sequences were sorted based on unique barcodes, trimmed for sequence quality, and clustered at 97 % identity for OTUs with USEARCH v7.0 (http://www.drive5.com/usearch/download.html) using UPARSE pipeline [46]. Chimeras and singletons were removed from clustered sequences with USEARCH. Re-sampling to the same sequence depth (2230 sequences per sample) was performed using daisychopper.pl (http://www.festinalente.me/bioinf/downloads/daisychopper.pl) prior to downstream analysis. Chao1 estimator of richness and Shannon’s and Simpson’s diversity indices were calculated using QIIME pipeline v1.7.0 (http://qiime.org/tutorials/tutorial.html) [47]. The phylogenetic affiliation of each sequence was analyzed by an RDP Classifier at a confidence level of 80 % [48]. Gene functions of dominant OTUs were predicted using PICRUSt [49], a tool that predicts the gene function of a microbial community using an existing database of microbial genomes. It is usually used well in predicting the function of microbiome from simple habitats, such as human and animal gut. Recently it is also used to study soil microbiome [50]. To predict the gene function of an OTU, the OTU representative sequence is assigned to a reference sequence in the GreenGenes database at 97 % identity using QIIME. Then, the functional profile of the reference sequence is found in COG and/or KEGG orthology databases using PICRUSt.
The original pyrosequencing data from this study were available at the European Nucleotide Archive by accession no. PRJEB10542 (http://www.ebi.ac.uk/ena/data/view/PRJEB10542).
Overall structural changes of prokaryotic communities were evaluated by PCoA in Fast UniFrac [51]. The statistical significance among datasets was assessed by PerMANOVA using the weighted PCoA scores in PAST (http://folk.uio.no/ohammer/past/). The partial Mantel test was applied to evaluate the correlations among prokaryotic communities with environmental variables. Variance partitioning analysis (VPA) was performed to quantify the relative contributions of environmental variables based on redundancy analysis (RDA) using the R package Vegan (http://cran.r-project.org/web/packages/vegan/index.html). One-way-analysis of variance (ANOVA), regression and correlation analysis between prokaryotic abundances and environmental factors were conducted using SPSS 21 software.
Co-occurrence network analysis
OTUs occurred in more than half of samples were used for network analysis. Non-random co-occurrence patterns of selected OTUs were tested with the checkerboard score (C-score) under a null model [15, 52]. Spearman’s rank correlations between selected OTUs were calculated [16]. A valid co-occurrence event was considered to be a robust correlation if the Spearman’s correlation coefficient was ρ > 0.6 with a significance of p < 0.01 [15]. Correlation networks were constructed with the robust correlations as weighted edges using Gephi software (https://gephi.github.io/). 10,000 Erdös-Réyni random networks with the same number of nodes and edges as the empirical networks were generated using the R package igraph (http://cran.r-project.org/web/packages/igraph/) [16].
Junpeng Rui and Jiabao Li contributed equally to this work
OTU:
operational taxonomic unit
PCoA:
principal coordinates analysis
PerMANOVA:
permutational multivariate analysis of variance
redundancy analysis
VPA:
variance partitioning analysis
JR and JL performed the experimental work, data analysis, and writing. JL and YW were involved in the experimental work. JL, SZ and XY participated in sample collections. XL was involved in the experimental design and writing. All authors read and approved the final manuscript.
We appreciate many volunteers who helped with sampling. This work was supported by 973 project (No. 2013CB733502), National Key Technology Support Program (2014BAD02B04) and the National Natural Science Foundation of China (31300447, 41371268, 41271260), CAS database project (XXH12504-3-18). The authors declare no conflict of interests.
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
13068_2015_339_MOESM1_ESM.docx Additional file 1: Figure S1. PCoA score plot based on weighted UniFrac metrics colored by (A) locations, and (B) substrates. P: swine manure; B: cattle manure; H: human manure; C: poultry manure; E: donkey manure; G: grass. Figure S2. Rarefaction curve of observed OTUs before re-sampling. Figure S3. Relationships between (A) NH4 +-N concentration and the relative abundance of Euryarchaeota in Cluster II, (B) the relative abundance of Clostridium and that of Euryarchaeota, and (C) the relative abundance of Bacteroidetes and that of Spirochaetes in all samples. Figure S4. Networks of co-occurring prokaryotic OTUs in (A) Cluster I and (B) Cluster II based on correlation analysis. OTUs were colored by modularity class with labeled genera names. A connection stands for a strong (Spearman’s ρ > 0.6) and significant (p < 0.01) correlation. For each panel, the size of each node is proportional to the number of connections (degree); the thickness of each connection between two nodes (edge) is proportional to the value of Spearman’s correlation coefficients ranging from 0.60 to 0.95. Ca.: Candidatus. Figure S5. Number of shared nodes (OTUs) among networks AS, C1, and C2. Figure S6. Relationships among functional modules of prokaryotic communities of (A) Cluster I and (B) Cluster II. The shapes of each module represent the main function of the module. The color of each module represents the correlation between the module and NH4 +-N concentration: black, positive correlation (p < 0.05); white, negative correlation (p < 0.05); grey, no significant correlation. The thickness of each solid line between modules is proportional to the sum of positive Spearman’s ρ between them in the networks (C1 and C2) ranging from 0.6 to 18.5; a dotted line represents over 10 couples of OTUs with significant negative correlations (Spearman’s ρ < −0.6, p < 0.01) between modules.
13068_2015_339_MOESM2_ESM.xlsx Additional file 2: Table S1. Prokaryotic diversity indices based on 97 % identity of 16S rRNA gene sequences and 2230 reads per sample. Table S2. The relative contributions (R square value) of each environmental factor to OTUs in all samples, Cluster I and II based on RDA analysis. Table S3. Relative abundances of core genera/OTUs in all 43 samples and sub-core genera/OTUs in Cluster I and II, and their correlation to environmental factors. Table S4. Relative abundances of the abundant phyla (average relative abundance >0.1%) and genera (average relative abundance >0.05 %). Table S5. Pearson’s correlation of abundant phyla and genera to environmental factors in Cluster I and II. Table S6. Pearson’s correlation of abundant methanogens to environmental factors in all samples. Table S7. Topological properties of co-occurring networks AS (43 samples), C1 (27 samples in Cluster I), and C2 (16 samples in Cluster II), generated with Gephi software. Table S8. Node information of 103 cosmopolitan OTUs in the network C1 (Cluster I). Table S9. Positive and negative interactions among modules in network AS, C1, and C2. Table S10. Node information of 206 cosmopolitan OTUs in the network C2 (Cluster II). Table S11. Node information of 110 cosmopolitan OTUs in the network AS (all samples). Table S12. Fermentation conditions and chemical properties in biogas digesters.
Key Laboratory of Environmental and Applied Microbiology, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
Environmental Microbiology Key Laboratory of Sichuan Province, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China
Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Fujian, 361005, China
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Are we off to see Der Fuhrer?
Philosophy in the Contemporary World: Totalitarianism in Our Time by Nathan Eckstrand (3-22-2018)
How do you kill 12 million people? Evil then and now: Recognizing & containing it
Why does God allow evil to exist?
The Dark Charisma of Donald Trump
Posted in DISPUTES & CONTROVERSIES, MINISTRY OF ENLIGHTENMENT, MY MOST POPULAR BLOG ENTRIES, PHILOSOPHY & SPIRITUALITY, politics, Problems in the Homeland (Empire)
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Tags: 1984, Alt-right, authoritarianisn, Der Fuhrer, dictator, Donald Trump, doomsday, Drittes Reich, dystopias, dystopic, end times, evil, fascism, Forth Reich, George Orwell, Hannah Arendt, Hitler, Mao, Nazi, Naziism, Pol Pot, right wing, Stalin, theodicy, Third Rerich, totalistarianism
Paul Harvey, Prophet (?)
Posted in MINISTRY OF ENLIGHTENMENT, PHILOSOPHY & SPIRITUALITY, PROPHECY, RELIGION
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Tags: evil, moral decay, Paul Harvey
Déjà Vu: Muslim extremist evils should sound familiar
Few reading this, I dare say, have any qualms about seeing religious extremists who believe they please the Almighty by dealing with nonbelievers, sinners, so-called apostates and “infidels” with intolerance and especially cruelty and butchery, contained and even eradicated (Mandated when an armed response is the lesser of 2 evils — kill or else have more innocents killed).
At the moment (October 2014) a coalition of nations including many predominately Muslin ones are involved in rolling back the Islamic State (ISIS, ISIL) whose atrocities and wanton evil are regularly showcased and discussed on TV and in newspapers, not to mention web, blog and social media outlets galore worldwide.
In the midst of all this most justifiable righteous indignation with extremist violence and monstrous wickedness, there is also a growing hostility towards Muslims in countries throughout the world in which peaceful, law-abiding ones are not only suspected of being sympathetic to Islamic extremists like IS/ISIS/ISIL but are thought to be fellow travelers, even members of planted “sleeper cells” who lurk in the shadows awaiting conditions to favor their popping out and engaging in terrorism.
And, even though Muslims including scholars have come out and denounced the extremist evil of IS including their cherry-picking of the Quran to support their beliefs and actions (Examples: Here & here), this is oftentimes ignored or eclipsed by our all-too-human in-group/out-group sentiments (wiring?) which in many instances has given rise to xenophobia and then paranoia. There is something both ironic and paradoxical in the fact that many who decry the intolerance and acts of cruelty championed by extremists began to treat anyone or anything that “smacks of the enemy” with intolerance and cruelty (ranging from subtle ostracism to physical violence).
It is also tempting to filter out contrary evidence within the Islamic world and conclude that IS/ISIS/ISIL actually reflects the heart and soul of Muslim beliefs and heartfelt convictions. It doesn’t help that stories and accounts come out of how many Muslims actually do believe that certain Islamic extremist groups, often dominated by clerics, are an antidote for deviating from a literal interpretation of the Quran or “creeping liberalism”. This sort of thing is naturally seized upon by those who argue that Muslims who bomb, shoot, crucify, bury alive, behead and otherwise dispatch “infidels” in bestial ways represent the real Islamic McCoy. Here is one of many posted articles on the Web that take this position (This one claims that the Oklahoma Muslim who beheaded an ex-coworker represents the “real Islam”): http://www.wnd.com/2014/09/oklahoma-beheader-represents-real-islam/
If this doesn’t should familiar, you’ve either forgotten your high school history lessons or slept through them. How so? At one time the Christian world, especially many of its leaders both religious and secular, sanctioned draconian measures against “infidels” which included torture, imprisonment, exile and cruel executions. What did these “defenders of the faith” base their actions on? They certainly didn’t need to make up scriptural justification for this sort of thing. The Bible provided them abundant material that when taken literally and narrowly applied, sometimes out-of-context and sometimes not, justified the cruelest imaginable treatment and horrific execution of gays, occultists, nonbelievers, heterodox believers (heretics), infidels (non-Christians) and more. Click to read a rundown of such verses.
Historic examples? Thankfully, a chap by the name of Mark Humphrys saved me having to dig out all the applicable historic incidents and practices and such, as he researched, organized and posted this to http://markhumphrys.com/christianity.killings.html (Readers are also encouraged to peruse what’s posted at http://www.heretication.info/_heretics.html).
Of course, most modern (Western) Christian believers and organizations including churches and denominations would never entertain taking verses such as Leviticus 20:10 as (ahem) gospel and acting on them: If a man commits adultery with another man’s wife, both the man and the woman must be put to death (Albeit some especially aggrieved wives or husbands might wish this was the law of the land)
But ask yourself: What stopped the waves of church-sanctioned persecution, torture and cruel execution of heretics and those declared apostates, sinners or such who would not repent or otherwise bend their knee to those who held their lives in-the-balance? History reveals no sudden turnabout. However, over time a number of shifts and changes occurred that gradually undermined and eroded intolerance and forced conformity to orthodoxy: Among these, the church lost secular power and influence while Biblical literalism and militant, extremist Christian policies and actions lost steam as more moderate views won the day (And these because to a great extent religious scholars and others critically examined archaic beliefs and practices and even the scriptures themselves in light of contrary or mitigating factual evidence and reasoning).
This is viewpoint is reflected in comments made by Southern Baptist Theological seminary faculty member Dr. Timothy Paul Jones to the Baptist Press which were incorporated in a July 2014 article titled “Why Christians killed and why Muslim violence continues” by David Roach:
“Christians used to kill with some frequency over matters of doctrine. There was the Spanish Inquisition, Calvin’s Geneva, England’s notorious Bloody Mary, the drowning of Anabaptists, the Crusades and more.”
Dr. Jones, the author of “Christian History Made Easy“, also stated that “it was the intermingling of church authority and civil authority that made it possible for persons who claimed to be Christians to have the state execute others who also professed Christ.”
But,…and this is a big but…..this shift was not without acrimonious debates, calls for a return to “that old time religion” (i.e., a church with secular power that punished heretics and others), fist fights and open warfare, and worse, in various quarters at various times.
Now ask yourself: Does all that’s happening in the Middle East — the theocratic Islamic governments who rely on oppression and cruelty and public executions to hold the pot lid down on dissent, the pitched battles (literal and figurative) between proponents of a Muslim religious worldview that is exclusivist literalist, and radically fundamentalist and those who champion the opposite, etc. — represent the kind of “Future Shock” cultural, social and religious clashes and upheavals that arose from and signaled the transition from a Europe that was ruled by clerics and which burned heretics to one of nations largely democratic and essentially tolerant? (But not without periodic lapses into darkness when conditions favored the eclipse of reason and tolerance by fear, hatred and bigotry). I tend to think so.
The question of whether such a complete transition will occur may not be one of if but when. But at what cost to the Muslim world and Israel, the EU, America, and other countries before the dust settles?
Beyond containing militant/radical Muslim extremists, there are other variables at play that could up the ante and the “dust” that gets kicked up before it settles to the ground. Assume for a moment that those who warn that Iran is dead set on building nuclear weapons — something underscored by alarming developments such as this — are right and they do. What happens if a major offensive is launched by one or more Arab countries against Israel and Iran joins this? If so, it is not inconceivable that Russia, which has longstanding ties to Iran (not to mention Assad’s Syria), might seize the opportunity to support such military adventurism. This would surely result in America rightfully jumping into the fray to help Israel repel this armed assault and intended invasion. Bingo, WWIII or, if not something this dire, surely a major regional conflagration that will come awfully close to unleashing it.
A major war in the Middle East, too, seems less a matter of if but when. Certainly a great many Jewish and Christian believers view this as inevitable based on prophecies in the books of Daniel and Ezekiel (Among others). Read my blog entry on this by clicking this link.
However, whether a great war hits the Middle East in the near future, later on or not at all, we can all expect a lot of craziness and bloodshed not only there but in Europe, the US, Canada, and elsewhere before the Muslim world breaks free of the forces of extremism, oppression and such.
Our challenge here in the US lies not just encouraging and waiting out the hoped for transition among Muslim countries, but also in preventing terrorist acts by Islamic extremists and their sympathizers in our midst, while at the same time avoiding letting their occasional successes drive us into the arms of authoritarian solutions…or worse.
Dr. Anthony G. Payne (Br. Anthony of the Resurrection)
Additional/supplemental reading penned by “yours truly”
Dark times and the allure of evil
Posted in EGO write proinde EGO sum, MINISTRY OF ENLIGHTENMENT, OP-ED, Philosophic & Religious Musings, PROPHECY, RELIGION, PHILOSOPHY & SPIRITUALITY
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Tags: antimessiah, antisemitisim, Arabs, beheading, bias, bigotry, bombings, Christianity, crucifixtion, Daniel, end times, evil, extremists, Ezekial, false prophet, Hamas, intolerance, Iran, Iranian bomb, IS, ISIL, ISIS, Israel, Jews, mark of the beast, militant Muslims, militants, Muslims, Revelations, Rood Awakening, shootings, suicide bombings, terrorism, terrorists, Tribulation, WW III
A world gone mad and what lies ahead
Also watch:
Posted in MINISTRY OF ENLIGHTENMENT, OP-ED, Philosophic & Religious Musings, PROPHECY, RELIGION, PHILOSOPHY & SPIRITUALITY
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Tags: Antichrist, antisemitism, Apocalyse, beheadings, Bob Shieffer, Book of Daniel, Caliphate, CBW, Daniel war, Dark Ages, Davidic messiah, dictators, earthquakes, economic collapse global warming, end times, eschatology, evil, Face the Nation, false prophet, Godfearers, IS, ISIS, Islam, Islamic, Islamic State, Israel, Jesus, last days, messiah, Middle East, nuclear war, prophecy, Revelations, sleeper cells, stonings, supercells, Temple Institute, terrorism, Tribulation, violence, Yehoshua
“Mein Fuhrer! I can walk!”
At the tail end of Stanley Kubrick’s satirical and brilliant 1964 anti-Cold War movie “Dr. Strangelove” the wheelchair bound German scientist (played by Peter Sellers) manages to stand up and take a step or two forward and then excitedly proclaim, “Mein Fuhrer! I can walk!” (This was reportedly an unscripted improvisation on the part of actor Peter Sellers) People in the throes of extreme excitement, passion or even religious ecstasy sometimes yell out to God, their mate or, in the case of Dr. Strangelove, to his leader (The American President whom he not infrequently calls “Mein Fuhrer” during the course of Kubrick’s cinematic masterpiece).
I suspect Sellers added the dramatic final touch not as an expression of the neurologic malady which landed his character in a wheelchair but, rather, as an upwelling of Dr. Strangelove’s impossible to suppress fascist sentiments and loyalty to Hitler.
In addition, I would offer a slightly different take on Dr. Strangelove’s outburst: I believe it was meant to represent the transcendent march of evil across time. That is, Seller’s was acting out the fact that evil, like death, haunts humankind and is impossible to totally suppress, manage or banish. Of course, we all know that those who do not resist and oppose evil not infrequently find their lives overshadowed by it.
The late writer-director-producer Rod Serling actually captured this theme very adroitly in a 1963 episode of the Twilight Zone titled “He’s Alive” (“He” being Hitler) that focuses on a “bush league Fuhrer” named Peter Vollmer.
Of course, we all are cognizant of the fact that evil permeates the human experience and has countless modern day incarnations. It is certainly one wheel that gets reinvented without ever showing much wear or loss of perpetrators and victims. Sometimes, though, the expressions are so continuous across time they appear to come out of some kind of historical-cosmic Xerox® machine. Click these links and reflect for a moment:
http://weirdthings.com/wp-content/uploads/2012/01/skitched-20120111-150835.jpg
http://theheartthrills.files.wordpress.com/2013/04/north-korean-soldiers-drilling-2.jpg
OK, so evil is perennial. What we can do about it? Laugh at and ponder comic portrayals such as Seller’s, yes, but never make the mistake of viewing evil people as clowns or easy to control (A mistake many German pre-Nazi leaders made with respect to Hitler and his cronies). But above all learn everything we can about the nature of evil and its subtlest expressions and then work to expose and oppose them.
How do you kill 12 million people? Evil then and now: Recognizing & containing it by Dr. Anthony G. Payne
The Science of Evil: On Empathy and the Origins of Cruelty by Dr. Simon Baron-Cohen
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Tags: Adolf Hitler, alien hand syndrome, doomsday, Dr. Strangelove, end times, evil, extremeists, goose steppers, goose stepping, He Live's, Hitler, intolerant, Nazi, Naziism, North Korea, Peter Sellers, Peter Vollmer, terrorism, terrorists
The dog you feed the most will dominate your life
In 1985 the Broadway hit “Agnes of God” was released as a movie directed by Normal Jewison. Marshall Fine tendered this review on Amazon.com:
This Broadway hit gets a solid film treatment by director Norman Jewison, but that can’t make up for the weaknesses of the script (which were as true onstage as they are here). Jane Fonda plays a chain-smoking shrink sent to a convent to do a psychological evaluation of a novice (Meg Tilly) who gave birth to a baby and then killed it in her little room. Was it a virgin birth? A miracle? And what of the bloody stigmata that seem to spontaneously appear on her hands? Fonda also finds herself clashing with the Mother Superior (Anne Bancroft) over the line between faith and science. But writer John Pielmeier can’t flesh this out beyond an idea; in the end, the solution is a disappointingly earthbound one that even the strong acting in this film can’t elevate.
OK, so the film isn’t flawless and has garnered more than its fair share of “1 or 2 thumbs down”. With this said, I like this flick. Why so? In-a-word it lays in the fact Agnes the novice nun somehow manages to interact with the world thorough a lens of innocence. That is, the unjaded aspects of her being for the most part dominate her day-to-day existence and how she perceives life and those around her.
Hollywood nonsense, you say? I might have agreed with you if this were early 1999. But not afterwards. What changed for me? I spent more than four years in Japan living and teaching classes of Japanese young people from pre-school through doctoral level plus many corporate classes filled with adult working professionals. What I discovered was that virtually all the young folks were, well, in some ways “Agnes of God” like. Mind you, I was aware that there were exceptions and many expats I shared sake and chat with were quick to point out their bad experiences with pretty jaded Japanese characters. But on-the-whole even they agreed most Japanese people they had encountered while teaching and in society at-large exhibited less of the cynicism and sheer nastiness that appeared commonplace back in the US and the West in general (Some of these expats came from the UK, New Zealand and Australia).
My then girlfriend and later (2001) wife thought I was seeing her people through rose colored glasses. This changed once we moved from Japan to southern California in early 2003. Having left being the corporate world in Japan (18 years work for a major multinational corporation in Tokyo), she pursued her long held dream of becoming a marriage and family therapist. This journey took her through the MS in Counseling program at Cal State Fullerton (she graduated with honors) and internships at a number of places including the Salvation Army residential program in Anaheim. While doing an internship at MiraCosta College in Oceanside, she happened to counsel a number of Japanese students who had come to the US in order to obtain specific educational credentials in an English language environment. What she discovered — and made a point of mentioning to me — is that her Japanese charges were very “unjaded” compared to the American students she counseled. Maybe my glasses were not so rose-colored after all.
At the very least, there seems to be at least a modicum of real world evidence that my original observation was spot on: The Japanese were and are on-a-whole less jaded (“more innocent”) than Americans.
Were Americans less jaded in the past? It seemed that way to me when I was a youngster. TV and movies in the late 1950s into the 1960s tended to reflect a certain un-worldliness (Less cynical, less nasty). This began to go out the window with the advance of the sexual revolution, Vietnam and all that entailed, and the general rejection of authority and conventional ways among many young folks of that era (including moi).
Can we ever recapture what we lost short of embarking on a 2nd childhood (individually and collectively)? Is the genie out of the bottle for good? Is there any way to truly be “as wise as serpents and as gentle as doves” (Rabbi Yehoshua’s admonition). Good questions, I think. We American Indians (Choctaws) have a saying that goes like this: “The dog you feed the most becomes biggest”. By this token if we as Americans feed ourselves on jaded & cynical things such as pornography, greed, pride, and other vices then the dogs that will steer our sled (lives) will be these vices. On the other hand, if we feed virtues and starve vices, well, we just might find ourselves less jaded and “wicked”. And while we may not become a nation of “Agnes of God” characters or even Japanese-like, we could inch a little closer to it.
Comments Off on The dog you feed the most will dominate your life
Tags: 1960s, Agnes of God, American Indians, Anne Bancroft, change, chastity, Choctaw, cuteness, cynical, cynicism, ESL in Japan, evil, expats, faith, jaded, Japanese, kawaii, Meg Tilly, Normal Jewison, pronography, purity, sin, Vietnam, wickedness
Color photo from TIME, Inc.
My good friend Jim Haverlock recently asked, “How do you kill 12 million people?” He was, of course, referring to the Shoah or Holocaust. He wasn’t asking about the nuts & bolts of pulling off mass executions but, rather, how did so many ordinary and even extraordinary men and women willingly take part in Hitler’s Endlösung (Final Solution). This is a question that has intrigued and haunted me since early boyhood actually. In fact, as part of my quest for answers I read all of Nazi propaganda minister Dr. Paul Joseph Goebbels diaries as a young man plus vol. 1 of “Mein Kampf” (Vol. 2 was unknown when I was a youngster), watched archival film of the Nuremberg & Doctor’s trials, and read just about every substantive book on Hitler, the Nazis and fascism that existed at the time (And everything worth reading on the subject since as well). As anyone reading this who ever took a course in World History knows, both Hitler and Goebbels stressed the use of propaganda and the “big lie” as integral to the creating and sustainment of the Greater Germania they envisioned. And both were extraordinary in their zeal and abilities to forge a monolithic state predicated on a shared national myth, and induce the German people to embrace it via lies, artful use of imagery and symbols, fear, rewards and appeals to entrenched biases that went back not just decades but centuries (Particularly in the case of antisemitism which sadly had its roots in early Christian teachings especially the Hellenized spin on Jesus and his message crafted & promulgated by Saul of Tarsus aka St. Paul. Learn more by reading Paul and Jesus: How the Apostle Transformed Christianity by scholar & historian Dr. James D. Tabor).
One place to turn for insight is historian Dr. Daniel Goldhagen’s books plus those of psychologist Dr. Philip Zimbardo. They do a smashing good job of laying out the historic, sociological, psychological and economic forces, currents and mechanisms that set the stage for the rise of the Nazis and then sustained them once they were in power.
But, even after you’ve read and mastered these works and others like them you likely find yourself still perplexed by the fact so many people down through the millennia and especially during the heyday of fascism could ignore and in many instances take an active hand in wanton cruelty. After nearly a lifetime of studying human cruelty and complicity in cruelty and evil I know there is no simple answer to “why”. Certainly lack of empathy or reduced or impaired empathy for targets/scapegoats is vital to evil and, yes, lies play a powerful role as well, but there is so much more that works to foster wickedness than lies and people’s failure to detect them or act on them or neglect to search them out and deal with them. However, with this said it certain behooves Americans to be vigilant and to call out wrongs and evil as soon as they come to light.
Things are complicated by the fact that evil and good rely on similar mechanisms and tools to govern (God, too, relies on these – see my op-ed piece on this subject titled “Hitler & HaShem at http://www.healingcare4u.org/hitler-hashem.pdf). Heaven knows our government has used lies of varying magnitude to govern across the years of our country’s existence. Probably Nixon and his “Imperial Presidency” took this to a whole new level and set certain wickedness in motion that has grown in scope to this day. In theory, yes, a super crisis or series of crises could lead to martial law and suspensions of Constitutional guarantees. During the Civil War (or as it is better known where I came from, “The War for Southern Independence”) Abraham Lincoln threw many folks who questioned his administration and policies into jail and kept them there, thanks to his having suspended the writ of habeas corpus. However, people rebelled, the press raised hell and the Supreme Court ultimately undid some of the more egregious acts of hegemony. I think any move to contain social disorder by imposition of a police or ultra-authoritarian state would, at the very least, result in the formation of tens of thousands of militias and resistance groups across the land that would make keeping the lid on the pot problematic if not impossible.
Naturally, best to act now and prevent a quasi-police or full-fledged police state then try to overthrow one that is in-place. Keeping our representatives working and honest is certainly part of that.
While no one has knows the full rhyme and reason behind human evil and its various incarnations, it helps to be aware of and reject ideas, movements, and acts that arise from and feed evil: Among them being intolerance, the marginalization and dehumanization of others especially minorities and other vulnerable groups, and unquestioned belief in authority figures and an unwillingness to call them out when they violate the very civil virtues and Constitutional guarantees they are charged with upholding.
I would add this: Although I’ve been a democratic socialist since 1985 I find some ideas and notions articulated by conservatives and even some right wingers of merit. As a Southerner whose ancestors go back to Revolutionary War times (and beyond) in South Carolina, Georgia and Mississippi, and whose paternal and maternal forbearers lived under the Stars & Bars (Confederacy) and in some instances fought for the C.S.A., I inherited a mix of ideas and notions, some worthy of consideration if not embrace, others that had no substance when they were articulated long ago and never will. Of those that I deemed worth hanging onto was the longstanding Southern distrust of a powerful central government running everything including many aspects of people’s everyday lives. Although you might think a democratic socialist would welcome an all powerful centralized government, I emphatically do not. History shows all too clearly that the concentration of power in the hands of strongmen leads to abuses and skullduggery of the worst sort. Actually there are at least a few liberal thinkers who would prefer to see a decentralization of power in the US and other countries, and even the break-up of powerhouse countries into small nation-states (Especially those that are unstable or might become so and with this attempt to retain order and stability by imposition of a police or authoritarian state). I’m sure a world comprised of small, less powerful nations, say, the size of Switzerland, would by no means avoid many of the ills that plague major powers today, but I can’t help think they would have less influence and thus less ability to work evil in the world. And for those that do, their neighbors could form temporary confederations and impose various kinds of sanctions or, when regrettably necessary, military containment (Hey, sometimes the only way to stop a thug is send in the police).
But until power shifts from Washington to the states (if it ever does), best to keep an eye on the politicians on Capital Hill and do everything possible to keep our representatives working, honest and limited in the evil they can do. The same applies to the press and other so-called sacred American institutions.
Dr. Anthony G. Payne (waxing philosophic from his porch swing)
RECOMMENDED ADDITIONAL READING
My spiritual watering hole website: http://summerclouds.weebly.com/
Why does God allow evil (Theodicy)? See Are you an atheist, religionist, deist, fideist or ???
CBN video presentation “God & Hitler”: http://www.cbn.com/700club/features/churchhistory/godandhitler/index.aspx
Supernormal Stimuli: How Primal Urges Overran Their Evolutionary Purpose by Deirdre Barrett, Ph.D.
Posted in EGO write proinde EGO sum, MINISTRY OF ENLIGHTENMENT, OP-ED, Psychology, THE HUMAN THING TO DO
Comments Off on How do you kill 12 million people? Evil then and now: Recognizing & containing it
Tags: "God & Hitler", Abraham Lincoln, abuse of power, Adolf Hitler, antisemitism, CBN, Christianity and antisemitism, Civil War, Confederacy, cruelty, CSA, Daniek Goldhagen, democratic socialism, Dr. Goebbels, Dr. Tabor, end times, Endsolung, evil, fascism, Final Solution, Gestapo, Goebbels, Hitler, Hitler & the Bible, Hitlerism, Holocaust, imperialism, James Tabor, James the Just, Lincoln, Mein Kampf, nationalism, Nazi, Naziism, Nixon, Nuremburg Trials, Paul and Jesus, rascism, Ray Comfort, right wing, science of evil, Shoah, Simon Baron-Cohen, South, Southern culture, Southerners, SS, Tea Party, the Holocaust, torture, War for Southern Independence, wickedness, willing executioners
Is an Attachment-Style Problem Complicating or Undermining Your Life?
Is an attachment style problem complicating or undermining your life? by Dr. Anthony G. Payne
Posted in BOOKS, EGO write proinde EGO sum, Philosophic & Religious Musings, Psychology
Comments Off on Is an Attachment-Style Problem Complicating or Undermining Your Life?
Tags: Abraham Maslow, Adolf Hitler, Alfred Adler, anthropology, attachment theory, attachment therapy, attachment therapy for adults, Carl Jung, Carl Rogers, cognitive dissonance, Darwinian psychology, depressed, evil, evolutionary psychology, faith, frustrated, hope, humanistic psychology, Jewish, Philip Zimbardo, psychiatry, psychology, sad, schools of psychological thought, Sigmund Freud, suicidal, toxic parents, transgenerational curse
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A new prize: Afghan woman of the year
Jean-Michel Marlaud - Kabul, Afghanistan - 17 March 2014
All the versions of this article: [English] [Español] [français]
During a working session with the political chancery team, we discussed the various cooperation projects that the Embassy was running to promote the rule of law: could we come up with an initiative that the general public would view as symbolic of the importance of human rights? The idea of a prize was mentioned.
July to September
The project began to take shape, as we discussed ideas with our partners to identify needs and avoid retreading old ground. It was widely agreed that the prize should be linked to women’s rights.
Since 2001 and the fall of the Taliban, huge progress has been made but there is still a long way to go. The statistics offer dry, mathematical proof of this, whether they map the rate of mortality or the level of female illiteracy. Statistics aside, the same can be observed simply by visiting the schools or health centres that we support. Moreover, although nothing has come of current debates on reintroducing death by stoning or prohibiting people from testifying against a family member (which would, in practice, prevent legal action in the case of domestic violence), they show that the most conservative sectors of society wish to undo some of the progress that has been made.
Throughout history, Afghanistan has been home to exceptional women: in literature, with Rabia Balkhi of medieval times, who sang of her love for a slave and became known as one of the first great poetic voices, but also in politics, with the powerful 15th-century queen Goharshad, whose tomb is still admired in Herat, not to mention all the women who taught in secret under the Taliban. Today, women are excelling in all areas of society: skilled street-artists and rappers, a regional public prosecutor, policewomen, fashion designers, not to mention those, like Chékéba Hachemi, author of L’insolente de Kaboul, who have returned to their country to set up schools for girls…
Discussions were held with the Embassy’s culture department, due to its familiarity with the intellectual sphere and, from a practical perspective, because it would be responsible for managing the financial aspect of the prize.
Final quarter of 2013
By now, we had a clear idea of what we wanted but several questions remained to be answered. The first concerned the prize itself. It would consist not only of a trophy, decorated by a calligrapher, but also a sum of money, which would enable to the prize-winner to carry out a project of her choice.
We also had to decide on the award criteria and we chose to define five areas: arts and culture, politics and government, social issues, science, and economics. Each year, a different field would be selected. We decided to start with arts and culture.
Only the final, most complex, decision remained: choosing the jury. After testing out ideas and discreetly gauging opinions, we opted for a scholarly combination of Afghan and international members. The chairperson of the jury would be an uncontested leader of the intellectual world and civil society: the chairperson of the Afghan Independent Human Rights Commission. She would be accompanied by the Minister of Women’s Affairs, the president of the Afghan Red Crescent Society (which was giving us access to the entire country) and the chairperson of a group of non-governmental organisations committed to promoting women. On the international side, in addition to the Embassy, we requested support from UN Women, a United Nations agency, and AFRANE, a French NGO specialising in education, which has thoroughly studied the reasons why girls drop out of school.
Photo : Amina Hassani
A meeting was organised with our German counterparts, as the German and French Ministries of Foreign Affairs were encouraging the Embassies to develop joint projects. We invited them to participate as observers. If they liked what they saw, they could join us in 2015. They reacted enthusiastically and were keen to get involved immediately, adopting the rules that we had established without reservations. From then on, the prize was called the “Franco-German prize for Afghan woman of the year”.
We officially launched the prize at the French Institute in Afghanistan, in the presence of journalists who were interested enough for the news to be shown on most television channels and even to appear on the front page of a daily newspaper.
As soon as the press conference was over, the jury met to select a prize-winner. The rules were simple: each participant was invited to put forward a name and had five minutes to explain the reasons for this choice. A vote could be held if necessary, but we hoped to reach a conclusion by consensus. After we had gone round the table, it was noticeable that the candidates put forward by the international members of the jury, although excellent, were already relatively well-known. Our Afghan colleagues, meanwhile, were suggesting women who had never been in the public eye. It was not easy to choose between these two options. Of course, it was tempting to break new ground. But if we awarded the prize to someone the public had never heard of, how would this be perceived? As just another instance of behind-the-scenes discussions leading to a decision influenced by personal, ethnic or local considerations? Or as proof of our ability to recognise talent without simply being dazzled by (modest) fame? We decided to trust our Afghan colleagues.
This did not shorten the debate, for it was a difficult decision to make. Aside from the candidates’ respective profiles, there was another fundamental issue to be considered: should we select someone who had already enjoyed a long career and as such, was deemed to be a moral leader, since she had a following, even if she had never been properly recognised? Or should we select a "young hopeful", giving her the support she needed now, at the risk of finding out in a few years’ time that she had been nothing more than a flash in the pan? Two names soon stood out, representing these two approaches, and an indicative vote showed us that the jury was evenly divided. So we decided to award the prize to two women instead of one; this was possible thanks to our German partnership, which had doubled the prize value.
Emotions were running high in the auditorium of the French Institute, where all 450 seats were filled and the cameras of 16 television channels were rolling. The chairperson of the jury announced the names of the two prize-winners: the first was Sharifa Danish Zaringar from Kandahar, a poet, miniaturist and sculptor who was already active under the Taliban. Her name is a point of reference in Afghan intellectual circles, but she lives modestly in Kabul on her teaching salary. The second, Amina Hassani, was a 22-year-old photographer, living in Bamiyan. She was orphaned when the Taliban killed her parents, then mistreated by the people who fostered her and her younger brother, but she dared to defend herself and took the case to court. Her photography focuses on her region and aims to show the reality of daily life, particularly that of women. Her approach is at once artistic and politically engaged.
Next year, the prize will be awarded for the second time, and we hope that it will gradually establish itself as a feature of the Afghan cultural landscape. Of course, it will not fundamentally alter the status of women in Afghanistan. But we hope, at least, to make a contribution towards lasting change.
Embassy of France in Afghanistan
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Kabul: Life in a submarine
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Primary Care For Your Eyes
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Dr. Robbins began his practice of optometry in 1982. He maintained offices in Portland and South Portland until 1997, when he joined with two neighboring practices to create Casco Bay EyeCare. He is a member of the Maine Optometric Association as well as the American Optometric Association, and has served as a preceptor at the University of New England and as a staff optometrist at Martin’s Point Health Care. He is also a past director and treasurer of the Maine Optometric Association. Dr. Robbins received his doctor of optometry degree from the New England College of Optometry after graduating from the University of Pennsylvania with a biology degree. In 2012 he was one of the first optometrists nationwide to become certified by the new American Board of Optometry. Dr. Robbins and his wife live in downtown Portland and spend much of their leisure time exploring the many and varied neighborhoods of our remarkable little city. On less ambitious days they are content to garden in their city-sized backyard and just BE.
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Cladding costs to fall on owners
Strata lawyer Tom Bacon says the Victoria Government seems more determined than ever to burden apartment owners with the cost of removing non-compliant cladding.
Planning Minister Richard Wynne on March 10 issued new ministerial guidelines to building surveyors, which ban the most dangerous types of combustible cladding from being used on Victorian buildings.
Aluminium Cladding Panels with a polyethylene core of more than 30 per cent will be banned on all multi-storey buildings. Expanded polystyrene will also be banned.
Mr Wynne has directed the Victorian Building Authority (VBA) to issue a product safety alert, and building practitioners who ignore this directive will face disciplinary action from the VBA.
But the minister also said if buildings were found to be non-compliant at a current state-wide audit, the VBA and municipal building surveyors will issue emergency orders.
“These orders are issued on building owners, which are the owners’ corporations,” Mr Bacon said.
“Because these orders are of an emergency nature, in extreme cases, the buildings could be declared uninhabitable until such time as the cladding is removed and replaced.”
“In other situations, the residents might be able to reside there, but only if interim safeguard measures are put in place and the cladding issues are fixed very, very quickly.”
“So it doesn’t leave OCs with much time to seek to join wrongdoers who might be responsible for why the cladding is there in the first place.”
“If the building is over a certain age, or if the legal risks of bringing a claim are too high, then OCs might well have to simply fix the cladding themselves via special levies.”
Mr Bacon said the government seemed determined to protect building surveyors who had originally approved the installation of non-compliant cladding.
“The problem is that if certifiers and building surveyors are hung out to dry, they might simply close their companies and hand back their licences,” Mr Bacon said.
“The state government faces a shortage of qualified surveyors already, and if the industry collapses then the state government and councils will need to step back in and start certifying buildings themselves again, which would be very expensive and then exposes them from a liability perspective.”
He said builders and developers were similarly also not in the firing line.
“The policy reason is that the government must keep ‘building conditions’ optimum for developers and builders so that they continue to build apartment blocks,” Mr Bacon said.
“It’s simple economics. The more apartments, the more stamp duty in the coffers, and it’s not worth upsetting builders and developers by placing the liability at their feet with the cladding issue, for fear that the builders and developers decide to ‘land bank’ and not develop their properties, or go to other states around Australia where it is easier for them to do business.”
Tags cladding
Flammable cladding: residents ignored
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Phone numbers in Bali (+62) 818-0550-3494
(+62) 821-4444-4094
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Bedugul & Beratan Lake Tour
If you thought Bali was only about sand and waves, then it’s time to be pleasantly surprised with a tour to Bali’s mountain lake resort area called Bedugul. Located in central-north region of the island in Tabanan Regency, Bedugul enjoys mild mountain weather due to its location of about 1,500 metres above sea level.
Surrounded by rolling hills and verdant greenery, major tourist’s attractions in Bedugul include Lake Beratan, Buyan and Tamblingan. Beratan, the largest of the three is perfect place for water sports such as parasailing, boating, jet skiing, water skiing, canoeing. Views of the lakes are captivating from the road above, so prepare your cameras! Other places of interest include beautiful Pura Ulun Danu Beratan, Taman Ayun Temple and Bali Botanic Garden. Bedugul’s fertile soil also produces abundance of fruits and vegetables which you can buy at the Bedugul vegetable market.
This tour will take approximately 8 hours and is inclusive of a professional English-speaking guide, an air-conditioned car and lunch at a local restaurant with a mesmerizing view of rice terraces to accompany your meal.
Besakih Tour
Besakih is a temple complex also known to the Balinese Hindu as the «Mother Temple». It is the biggest, holiest and most important temple in Bali that is located on the slopes of Mount Agung in East Bali. Built in 1284, there are 23 temples within the complex with the biggest being Pura Penataran Agung; each different but related temple features a different meaning and function according to the Balinese Hindu beliefs.
The grounds surrounding the temple are beautifully taken care of, and the air is cool as the temple is located 1000 metres above sea level. The temple is breathtaking with ancient carvings, temple buildings, statues, gates and entryways, so don’t forget your camera. On the way to Besakih, we’ll stop to visit a few places of interests including Kerta Gosa and Bukit Jambul. Lunch will be served at a local restaurant.
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Bluesdoodles CD Review News Desks
King King New Bass Player Announced
20th February 2019 20th February 2019 Liz Aiken 0 Comments Exile and Grace, King KIng, New Bass Player Zander Greenshields
Zander Greenshields confirmed as new Bass Player.
King King have confirmed their new bass player is Zander Greenshields. Zander replaces King King’s original bass player Lindsay Coulson, who was with the band for 10 years.
Greenshields is an old Glaswegian musician friend of Alan Nimmo who played with Alan in his first band Silvertrain, then joined the Nimmo Brothers and went on to play bass for the Blackwater Blues Band.
Greenshields also played with the late drummer Ted McKenna (The Sensational Alex Harvey Band, Rory Gallagher, Michael Schenker Group).
Zander will join King King on their upcoming European dates and will also enter the studio this summer to record King King’s fifth studio album. The new album will be the follow-up to King King’s 2017 album “Exile & Grace.”
King King tour France, Norway and the Netherlands from late March onwards. On May 11th, they play KK’s Steel Mill in Wolverhampton.
The band also join Joe Bonamassa’s Keeping the Blues Alive At Sea Mediterranean Blues Cruise which takes in Barcelona, Spain, Monte Carlo in Monaco and Valletta in Malta from August 16-21.
King King
Jonny Dyke – Zander Greenshields – Alan Nimmo – Wayne Proctor
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Asian Yearbook of Inte...
Asian Yearbook of International Law
Asian Yearbook of International Law, Volume: 22
Editors: Seokwoo Lee and Hee Eun Lee
Launched in 1991, the Asian Yearbook of International Law is a major internationally-refereed yearbook dedicated to international legal issues as seen primarily from an Asian perspective. It is published under the auspices of the Foundation for the Development of International Law in Asia (DILA) in collaboration with DILA-Korea, the Secretariat of DILA, in South Korea. When it was launched, the Yearbook was the first publication of its kind, edited by a team of leading international law scholars from across Asia. It provides a forum for the publication of articles in the field of international law and other Asian international legal topics.
The objectives of the Yearbook are two-fold. First, to promote research, study and writing in the field of international law in Asia; and second, to provide an intellectual platform for the discussion and dissemination of Asian views and practices on contemporary international legal issues.
Each volume of the Yearbook contains articles and shorter notes; a section on Asian state practice; an overview of the Asian states’ participation in multilateral treaties and succinct analysis of recent international legal developments in Asia; a bibliography that provides information on books, articles, notes, and other materials dealing with international law in Asia; as well as book reviews. This publication is important for anyone working on international law and in Asian studies.
Seokwoo Lee, D.Phil. (2001), Oxford, is Professor of Public International Law at Inha University Law School, Incheon, Korea. He is Founding Co-Editor-in-Chief of the Asia-Pacific Journal of Ocean Law and Policy (APJOLP) and the Executive Editor of the Korean Journal of International and Comparative Law (KJICL).
Hee Eun Lee, J.D., Syracuse University College of Law (honors, 1999), LL.M., New York University School of Law (2002). He is Associate Dean and Professor of Law at Handong International Law School.
Co-Editors-in-Chief:
Seokwoo LEE (Inha University Law School, Korea)
Hee Eun LEE (Handong International Law School, Korea)
Executive Editor:
Lowell BAUTISTA (University of Wollongong School of Law, Australia)
Editorial Board Members:
Jay BATONGBACAL (University of the Philippines, Philippines)
Tran Viet DUNG (Ho Chi Minh City University of Law, Vietnam)
V.G. HEGDE (Jawaharlal Nehru University, India)
Juwana HIKMAHANTO (Universitas Indonesia, Indonesia)
Kanami ISHIBASHI (Tokyo University of Foreign Studies, Japan)
Kitti JAYANGAKULA (Eastern Asia University, Thailand)
Sumaiya KHAIR (University of Dhaka, Bangladesh)
Jaclyn NEO (National University of Singapore, Singapore)
Jamal SEIFI (IranUnited States Claims Tribunal, The Netherlands)
Liann THIO (National University of Singapore, Singapore)
Dustin KuanHsiung WANG (National Taiwan Normal University, Taiwan)
Guifang Julia XUE (Shanghai Jiao Tong University, China)
Founding General Editors:
KO Swan Sik (Erasmus University at Rotterdam, The Netherlands)
Christopher W PINTO (IranUnited States Claims Tribunal, The Netherlands)
J.J.G. SYATAUW (Institute of Social Studies (ISS), The Netherlands) *Deceased
Key Editors for Previous Volumes:
B.S. CHIMNI (Jawaharlal Nehru University, India)
MIYOSHI Masahiro (Aichi University, Japan)
Javaid REHMAN (Brunel Law School, UK)
Surya SUBEDI (University of Leeds, UK)
Kevin YL TAN (National University of Singapore, Singapore)
Foundation for the Development of International Law in Asia ( DILA ) Editorial Note Seokwoo Lee and Hee Eun Lee Peaceful Uses of East Asian Seas: An Editorial Note Keyuan Zou
Maintaining Maritime Peace and the Law of the Sea
1 Peaceful Use of the Sea and the Rule of Law Miyoshi Masahiro 2 Peaceful Proposals and Maritime Cooperation between Mainland China, Japan, and Taiwan in the East China Sea: Progress Made and Challenges Ahead Yann-huei Song 3 The South China Sea Disputes: An Opportunity for the Cross Taiwan Strait Relationship Yen-Chiang Chang
Peaceful Uses of Marine Resources
4 Management of Fishery Resources: A Starting Point towards Cooperation in the East China Sea Kuan-Hsiung Wang 5 Framework for the Joint Development of Hydrocarbon Resources Robert Beckman and Leonardo Bernard 6 The International Legal Obligations of States in Disputed Maritime Jurisdiction Zones and Prospects for Co-operative Arrangements in the East China Sea Region David M. Ong 7 Joint Development in the South China Sea: Is the Time Ripe? Jianwei Li and Pingping Chen
Promotion of Marine Scientific Research for Peace
8 Peaceful Use of the Sea and Military Intelligence Gathering in the EEZ Keyuan Zou 9 Marine Data Collection: US Perspectives J Ashley Roach 10 Voluntary Observing Ship and Marine Scientific Research under the Law of the Sea Hong Chang
Peaceful Means for Maritime Dispute Resolution
11 Unilateral Actions and the Rule of Law in Maritime Boundary Disputes Anne Hsiu-An Hsiao 12 Search and Rescue as an Enabler to Stimulate Cooperation in Areas of Tension Erik Franckx 13 Natural Prolongation and Delimitation of the Continental Shelf beyond 200 nm: the Bangladesh/Myanmar Case Yao Huang and Xuexia Liao 14 China’s Air Defence Identification Zone: Towards a Crystallization of a New International Custom Matthias Vanhullebusch 15 Indonesia’s Practice in Combatting Illegal Fishing: 2015–2016 Arie Afriansyah 16 Participation in Multilateral Treaties Karin Arts 17 State Practice of Asian Countries in International Law 1 Bangladesh 2 Japan 3 Korea 4 Malaysia 5 Philippines 6 Singapore 7 Thailand 8 Vietnam 18 Book Review Sangmin Shim 19 International Law in Asia: A Bibliographic Survey—2016 Dila Events 20 2016 DILA International Conference and 2016 DILA Academy and Workshop Seokwoo Lee and Hee Eun Lee
All interested in International Law and Asian Law.
Asian Law, International Law, International Law: General Interest, International Law, General, Asian Studies
Brill | Nijhoff
xxii, 452 pp.
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West Side Glory
By Diana Maudslay Cross on Tuesday, May 14, 2019
Elizabeth Mistry sees Mexican actress Gabriela Garcia sing her heart out at Manchester’s Royal Exchange Theatre.
Pictures © Richard Davenport / The Other Richard
That there is a genuinely Latin American flavour to the new production of Leonard Bernstein and Stephen Sondheim’s 1957 musical West Side Story – currently showing at Manchester’s innovative Royal Exchange Theatre – is a testament to director Sarah Frankcom’s obvious commitment to making this Romeo and Juliet-inspired tale of doomed love relevant to a new generation of theatre goers.
That there is a genuinely Latin American flavour to the new production of Leonard Bernstein and Stephen Sondheim’s 1957 musical West Side Story – currently showing at Manchester’s innovative Royal Exchange Theatre – is a testament to director Sarah Frankcom’s obvious commitment to making this Romeo and Juliet-inspired revengers’ tragedy relevant to modern audiences.
While the ‘boy meets and falls in love with girl from boy’s enemy tribe’ theme is a storytelling staple, Frankcom brings the story bang up to date – leaving the audience in no doubt that intolerance, gang violence and inevitably, knife crime, are worryingly close to home as they were on the streets of New York’s Upper West Side less than a decade after Americans of all colours fought together during World War II.
The Sharks
The tension between two gangs (the Jets, made up mostly of the sons of white(r) first generation immigrants and the Sharks, predominantly composed of young Puerto Ricans) is observed helplessly by Tom Hodgkins’s benign seen-it-all-before drugstore proprietor and – more worryingly for younger audience members – by Jack Lord’s racist cop, Lieutenant Schrank.
The mutual disdain is clear from the slow burning opening number which sets the scene with a brooding portent of the inevitable, against Anna Fleischle’s minimalist set design. Never have simple white metal girders served so well as the urban jungle; the fire escapes and the mean streets, a hideaway for young lovers and a bridal boutique.
Both gangs are uniformly dressed – by Polly Sullivan – in 1950s inspired costumes with everyone kitted out in converse style trainers which surely makes the exuberant dancing much easier on the company. The show features new choreography for the first time since the original work opened and while the big numbers are enjoyable, it is the surprisingly poignant encounter between Jet leader Riff (Michael Duke) and Bernardo, the chief Shark played by Fernando Mariano, that stays in the mind.
Each actor combines the right amount of swagger and self belief with a semblance of affection for their families – both blood and chosen. It reminds us – fleetingly – why gang culture can seem so attractive. As one character says early on, “Without a gang you’re an orphan.”
The supremely talented UK-based Gabriela Garcia (born in Leon, Guanajuato) takes the leading role of Maria, a young girl newly arrived from Puerto Rico who is being lined up by her brother Bernardo as a potential bride for his young protege.
Garcia, who trained in England at the Arts Educational Schools, first rose to prominence following her standout performance in London a couple of years ago as Nina in In The Heights, an early musical from Lin-Manuel Miranda (a Nuyorican who also acknowledges some Mexican ancestry).
A decade ago, Miranda worked on a bilingual revival of West Side Story on Broadway and later went on to write ‘Hamilton.’
Much has been made of the decision to use new the choreography, specially commissioned from Aletta Collins for the Royal Exchange’s production. Her clever circular movements and formations make full use of the unique space constructed (and reconstructed 20 years ago by the appropriately named architectural practice LevittBernstein) inside the original Cotton Exchange which was once responsible for trading and exporting cotton from the mills of North West England to countries such as Mexico – where Frida Kahlo used material from Manchester in some of her famous Tehuana-style dresses.
The seven-sided theatre with just three tiers of seating makes for an incredibly intimate theatrical experience.
When Andy Coxon’s Tony, who has just met Maria at a dance organised to try and help overcome the visercal hatred between two gangs who are more alike in (in)dignity than they would ever realise or acknowledge, sings of his new passion for the Puerto Rican girl, some might find it cheesy. Coxon makes it ring true.
Both Coxon and Garcia are well matched with Coxon’s admirable vocal range perfectly suited to Sondheim’s music and an excellent foil to Garcia’s operatic style of singing which is more than strong enough to stand up to the technically brilliant (but occasionally over amplified) music coming from the Pit – for this production located in an acoustic cabin just outside the auditorium – under Mark Aspinall’s baton.
Gabriela García (Maria) and Andy Coxon (Tony)
There are several standout moments; Garcia’s rendition of ‘I Feel Pretty’ and perhaps the musical’s best known number ‘America’ which unlike the film version is not played as a face off between the Puerto Rican girls and boys but as a episode between the girls alone led by Jocasta Almgill’s feisty Anita (excellent as a woman torn between her loyalty to Bernardo and sympathy for Maria’s plight).
But on the night I saw the show, the moment my heart skipped a beat was when Emily Langham’s Anybodys – the tomgirl who desperately wants to be one of the Jet boys despite their generally callous treatment of her – sang ‘Somewhere’.
The decision to give her the opportunity to open the number was inspired; for the duration of the song, in a theatre which 20 years previously had been virtually destroyed by an IRA bomb representing desperation, hate and vengeance – in a city determined to show the world that it will continue to rise above the attack on concert goers less than two years ago – the audience collectively held their breath.
I can’t have been the only one who heard it as a plea for a place of greater safety for all those who need a refuge from the ills and intolerances of the world. It was my defining theatre moment of the year so far.
When the song finished there was a hush in the auditorium and a tear in the eye of this reviewer. In the silence that briefly followed, not a single clap was heard – which was – though the cast might not have realised it at the time, the greatest applause of all.
West Side Story runs at the Royal Exchange Manchester until 25 May.
While almost sold out, a few tickets are available and the production will also run from 18 April-23 May 2020.
For more information call the box office on 0161 833 9833
www.royalexchange.co.uk
Gabriela Garcia Manchester Royal Exchange West Side story
Diana Maudslay Cross
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The British Mexican Society (BMS) is a charity and the UK hub where we celebrate all aspects of Mexican culture, including its unique history and archaeology, its food & drink, its music and folkloric traditions and its ancient and modern arts & literature – in fact any cultural contribution that Mexico and its people make to the world, past and present.
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Outdoors Calendar
Jay Burney, chairman of the Friends of Times Beach Nature Preserve, says there is plenty of forage for deer to eat. He urges people not to feed them. (News file photo)
By Staff|Published Wed, Jan 31, 2018 |Updated Wed, Jan 31, 2018
Jan. 31 – Full Moon Snowshoe Tour with Buffalo Niagara Waterkeeper at the Stella Niagara Preserve, Lewiston , 5:30 p.m. Go to the website at www.bnwaterkeeper.org to register.
Jan. 31 – Free fly tying/fly fishing classes every Wednesday (formerly on Tuesday) at the Costello Room, Rockefeller Arts Center, SUNY Fredonia from 7 p.m. to 8:30 p.m. For more information contact Alberto Rey at 410-7003 or visit www.albertorey.com.
Jan. 31 – Final day for New York State Pistol Permit Recertification. Contact the county clerk or visit https://firearms.troopers.ny.gov for details.
Jan. 31 – Final day, varying hare rabbit hunting season in the Southern Tier. Check out www.dec.ny.gov for details.
Feb. 1 – Deadline for the New York State Outdoorsmen Hall of Fame nominations. For details go to http://nysohof.org.
Feb. 1 – Orvis Buffalo will be hosting former Buffalo Sabre Jim Lorentz for a book signing with “Atlantic Salmon: Moody and Mysterious” at 6 p.m.
Feb 3 – The Niagara Frontier Chapter of the NWTF will host its banquet on Feb. 3 at Banchetti’s on North Forest Road in Amherst. There will be live and silent auctions with raffles featuring 14 guns. For info call Al Gai at 937-3271.
Feb. 3 – Niagara River Anglers Assn. Roger Tobey Memorial Steelhead Contest in the lower Niagara River and Lake Ontario tributaries. Sign up at Creek Road Bait and Tackle, Lewiston, the Slippery Sinker in Olcott or at the launch ramp in Lewiston the morning of the contest.
Feb. 3 - Snowshoeing and Cocoa at the Darwin Martin House State Historic Site from 10 a.m. to 1 p.m. For more info or to register call 549-1050.
Feb. 3 – Superb Owl Saturday at the Buffalo Audubon’s Beaver Meadow Center in North Java from 2 to 5 p.m. There will also be an Owl Prowl from 6 p.m. to 8 p.m. that you must preregister for at 585-457-3228.
Feb. 3 – Niagara Frontier Chapter National Wild Turkey Federation Hunting Heritage Banquet at Banchetti’s Banquet Facility, Amherst. For more info contact Al Gai at 937-3271.
Feb. 3-4 – Kid Fest at WNED-TV (140 Lower Terrace, Buffalo starting at noon each day. Learn about birds, fish, animals and fun in the outdoors. $12 adults, $10 kids. Call 845-7000 Ext. 100 for more info.
Feb. 4 – Alabama Hunt Club monthly black powder shoot and meeting at the range and clubhouse located on Lewiston Road, Alabama starting at 9 a.m. for relay one and 11 a.m. for relay two. Contact John Szumagala at 714-5514 for more info.
Feb. 4 -- Winter trap league and open shooting continues at Allied Sportsmen Club 12846 Clinton St., Alden. The league will shoot every other Sunday 11 am-2 pm. Includes 50 birds/Sunday, total 300 targets. Unlimited shoot ahead & shoot back. Must be there for final Sunday for class shoot off. New shooters, public and non-league shooters welcome. Food will be available. Call Joe Truty for info. 867-1458.
Feb. 4 – Niagara Frontier Gun Show at the Alexander Fireman’s Rec Hall, 10708 Alexander Road, Alexander from 8 a.m. to 3 p.m. Visit www.nfgshows.com for other details.
Feb. 7 – Buffalo Audubon’s naturalist Mark Carra will be giving a hike with the theme “The Dynamic World beneath the Snow.” Pre-registration required at 585-457-3228. Cost is $5.
Feb. 8 - Orvis Buffalo will be hosting noted author Rick Kustich for a book signing and talk on local steelhead tactics, as well as a special screening of the DVD Spey Daze. It begins at 6 p.m.
Feb. 10 – Evangola State Park Forest to Lake Snowshoe Hike from 10 a.m. to noon. Call 549-1050 for information or to preregister.
Feb. 10 – Animal Tracks Snowshoe Tour at DeVeaux Woods State Park, Niagara Falls, 10 a.m. Go to the website at www.bnwaterkeeper.org to register.
Feb. 10 – Shoot N’ Hoot at North Forest Rod and Gun Club, Lockport for the ladies. NRA Training Class Part 1 with a Gun Safety Seminar and Power Point presented by NRA Women Instructors. Register by Feb. 7. Shooting to follow. Ammo is supplied. Register with Colleen Gaskill at 628-9023.
Feb. 10 – Buffalo Audubon will present “Everything Snowshoes” with naturalist Mark Carra at the Beaver Meadow Center in North Java from 10 a.m. to noon. Call 585-457-3228 to register. $5 for use of snowshoes.
Feb. 11 – Woodland Winter Walk at Knox Farm State Park from 10 a.m. to 12:30 p.m. For more info and to register call 549-1050.
Feb. 13 – Niagara County Second Amendment Forum monthly meeting at the Wilson Conservation Club, Wilson-Cambria Road, Wilson (Route 425), 7 p.m.
Feb. 15 – Southtowns Walleye Association of WNY monthly meeting at the clubhouse located at 5895 Southwestern Blvd., Hamburg, 7:30 p.m. Guest speaker will be Mike Steffes with Warrior Lures.
Feb. 15 – Erie County SCOPE will hold its monthly meeting at Harvey D. Morin Post, 965 Center Road, West Seneca, 7 p.m.
Feb. 17 – Harry Smith Installation Dinner and Dance with the Southtowns Walleye Association, 5895 Southwestern Blvd., Hamburg. Visit www.southtownswalleye.org for more info.
Feb. 17 – Youth/Adult Fly Tying Classes hosted by the Lake Erie Chapter of Fly Fishers International at the Reinstein Woods Educational Building, 93 Honorine Drive, Cheektowaga from 1 to 4:30 p.m. This is the first of four classes. For more info call 675-4766.
Feb. 17 – Winter Wonderland Ski Tour at Evangola State Park from 10 a.m. to noon. Cross-country skiing with the Buffalo Nordic Ski Club. Call 549-1050 to register or for more info.
Feb. 17 – Great Backyard Bird Count. Join Buffalo Audubon at Beaver Meadow in North Java. Free but you must preregister by calling 585-457-3228.
Feb. 17-18 – Niagara Frontier Gun Show at the Ridgeway Volunteer Fire Department, 11392 Ridge Road (Route 104), Medina, 9 a.m. each day. Visits www.nfgshows.com for more info.
Feb. 17 – Animals in Winter program with naturalist Mark Carra at Buffalo Audubon’s Beaver Meadow in N. Java. Pre-registration required. Fee is $5. Call 585-457-3228 to register. Times are 1 p.m. to 2:30 p.m.
Feb. 18 – Cross Country Ski Tour at Knox Farm State Park from 1-3 p.m. hosted by Buffalo Audubon. Bring your own skis. Call 585-457-3228 to register.
Feb. 22 – Junior Audubon Club – What do you wonder about birds? From 10 a.m. to noon. Held at Beaver Meadow in N. Java. Call 585-457-3228 to register.
Feb. 24 – Ice World Erie Exploration at Evangola State Park from 10 a.m. to noon. Call 549-1050 to register or for more info.
Feb. 24 – Birding on the River at Beaver Island State Park. Call 282-5154 to register or for more info.
Feb. 24 – Buffalo Niagara Waterkeeper will be hosting an Explore Water at its source in our headwaters forests at Hunters Creek County Park in Wales starting at 10 a.m. Register at www.bnwaterkeeper.org.
Feb. 25 – Orvis Buffalo will be hosting WNY guide Alberto Rey at noon for a fly tying demonstration of his “Cuban Flea” fly and discuss tactics for local steelhead. The shop is located at 4545 Transit Road, Williamsville.
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Daniel Green Home Ent Reviews
DVD Review: ‘Dawn of the Planet of the Apes’
Memories of Tim Burton’s woeful 2001 Planet of the Apes remake were thankfully replaced with far fonder recollections in 2011 following the release of Rupert Wyatt’s Rise of the Planet of the Apes. An earnest entry in the flagging sci-fi franchise and a surprise hit at the international box office, a sequel was quickly green-lit with Wyatt once again penned in to direct. After dropping out of the project due to a conflict in vision with 20th Century Fox, Wyatt was replaced by Matt Reeves (Cloverfield, Let Me In) who, with Dawn of the Planet of the Apes (2014), not only carries on the torch of series rejuvenation but has also crafted an eminently darker, grey matter-stimulating post-apocalyptic follow-up sure to please fans.
Ten years have passed since ape figurehead Caesar (Andy Serkis returning as the man behind the pixel mask), the unexpectedly enhanced product of genetic tests into a cure for Alzheimer’s by the nefarious Gen-Sys corporation, led a band of altered primates across the Golden Gate Bridge and into the relative safety of the redwood forest. Humanity has declined in the interim, teetering on the verge of extinction after the destruction ravaged by Simian Flu – a deadly aversion to the very drug that has given Caesar and their kin an evolutionary boost – and a decade of petty in-fighting. Fighting for their species’ existence are Malcolm (Jason Clarke) and Dreyfus (Gary Oldman), who have singled out a power station in ape territory as their only shot a survival. But will Caesar and his kind grant right of way?
An undoubted hindrance to Wyatt’s forebear was its largely underwhelming human cast, with only John Lithgow’s sympathetic turn as an Alzheimer’s sufferer able to match that of Serkis and his digital cohorts. This time around, Reeves makes the wise decision to sideline humanity from the off, with far more time spent focusing upon Caesar’s harmonious ape republic and the conflicts that inevitably arise once contact with their one-time masters is re-established. Besting even Serkis’ Caesar in terms of character complexity is the wonderful Koba (Toby Kebbell), unquestionably one of the most sophisticated creations yet offered up by motion capture technology. A Brutus-like figure, Koba wears his experiment scars proudly but finds himself unable to even consider peace between apes and humans (“Caesar loves humans more than apes!”, he claims, signalling the beginning of the end). This decorated general’s tumultuous relationship with his beloved captain is also, remarkably, one of the most compelling seen in any feature film this year.
A satisfying balance of family drama, political intrigue and all-out action (an ape cavalry charge has to be seen to be believed) do, in truth, only constitute half of the story, as Reeves’ sci-fi sequel is as much a technical triumph as a narrative one. It’s hard to believe that, only three years on from Rise, the digital creations of Dawn could look as photo-realistic as they do, and a huge amount of credit is due not only to the visual artists but also Serkis and his team of mocap actors. For every dopey line of human dialogue (“I don’t take orders from monkeys!”) there are a host of telling, non-verbal glances between the ape cast. The very fact that the film is so reliant on sign language (subtitled, naturally) is in itself a mainstream achievement comparable with that of Wall-E’s rightly lauded dialogue-less opening. Humanity may have been wiped out countless times on screen by all manner of plagues and wars, but rarely has the future after our reign looked so optimistic. However, with a third and final (?) prequel on the way, do expect a nuclear-powered finale.
This review was originally published on 16th July 2014 for the film’s theatrical release.
Daniel Green | @DanGreen1986
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Home / Single-trip in-bond: An Easy Solution
Single-trip in-bond: An Easy Solution
What is the easiest way to take advantage of an opportunity where, as a non-bonded highway carrier, you’re asked to pick up a load that needs to be traveled safely in-bond through Canada? The single-trip bond is your best alternative.
Issued by the Canadian Border Services Agency (CBSA), bonds, whether single way or annual, allow carriers to transport goods internally to a sufferance warehouse for eventual release or “in-transit” in Canada for release further down the line outside the country.
The CBSA require a carrier who wants to become annually bonded a carrier code, putting up financial responsibility for $25K as well as usual forms and signatures expected from an administrative application process. The thought of jumping through all the hoops may scare a few. But keep this in mind: obtaining a single-trip can be obtained on an as-needed basis, making it simpler and more accessible for carriers.
Obtaining the single-trip bond is doable via the CBSA or the First Port of Arrival using cash or a certified cheque to file for security. You may also want to opt for the services of a customs broker like Clearit that will help you navigate through the process and deal with security matters.
When moving goods during a single-bond trip, they are associated to a carrier code of the carrier responsible for the transport. A bond authorization number and a Cargo Control Number (CCN) are issued and included on a Cargo Control Document (CCD) which allows the CBSA to report, trace and acquit for all shipments. Because the CBSA believes that the process related to single-trip bond is declining, the administrative steps will remain paper based.
How to single-trip bond the movement of goods:
Cargo and conveyance data is transmitted by the highway carrier as a frontier release prior to arriving to the First Port of Call.
The driver will declare at the Primary Inspection Line that a single-trip authorization is required to move inland with the goods. He will then provide a lead sheet to the Borders Services Officer on which there is a barcode CRN or barcode CCN with a handwritten CRN.
The officer will refer the driver inside to apply for a single-trip bond.
A completed paper re-manifest (A8A) is presented to the officer who will stamp the A8A in order to allow the driver to continue on inland with the goods. Clearance is then granted and processed as an in-bond transport.
The copies of the A8A are split as they were pre-emanifest. The carriers will avoid being penalized for handwriting the CCN on the A8A used to re-manifest during a single-trip in-bond transit.
The goods being transported must reach destination that was approved by the CBSA as per the bond. Normally, the single-trip ends at the moment the goods have reached their destination.
Carriers are obligated to keep all records related to the single-trip bond for 3 years plus the current year.
To find out more about how Clearit can help single-trip bond the movement of your goods, Click Here
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Search The Clover Chronicle
During times of universal deceit, telling the truth becomes a revolutionary act
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Since 2008, The Nation Of Islam Has Been Receiving Federal Funds To Teach Prison Inmates…
By cloverchronicle on December 19, 2018
According to a recent Washington Examiner report, The Nation of Islam, a black nationalist group led by Louis Farrakhan, has received hundreds of thousands of dollars from the U.S. government to teach federal prison inmates about religion.
Per the report:
“The Nation of Islam preaches that white people are ‘blue-eyed devils’ and Jews are ‘the synagogue of Satan.’ Its leaders have received at least $364,500 in contracts and awards from the U.S. Bureau of Prisons and the Department of Justice between fiscal 2008 and fiscal 2019.”
Farrakhan’s institution has been labeled a hate group by the Anti-Defamation League and the Southern Poverty Law Center.
The Washington Examiner reached out to the Bureau of Prisons, but they declined to provide further details about its contracts with the NOI, including what exactly they are teaching inmates.
“Contracts are retained six years after final payment, so we are not able to provide details regarding the original contract on which the Nation of Islam began contracting with the Bureau of Prisons,” said a spokesperson.
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Geoscientist Online >
Online Debates >
The Great Plumes Debate (2003) >
A curate's egg
Geoscientist Cover Competition
Origin of the Caribbean Plate (2009)
The Great Chicxulub Debate (2004)
And Yet It Smokes
Keller et al's response
Still Smoking
Old Evidence, Partial Interpretation - Part 1
The Chicxulub Discussion Part 1
Not a single shred...
The Great Chicxulub Debate concludes - where next?
The Great Plumes Debate (2003)
If not plumes, what?
Making the evidence fit the plume
No plume under Iceland
Plumes - an alternative to the alternative
Plumes - shorter communications
Ptolemy, Piltdown, phlogiston, polywater and... plumes?
Revealing argument - but about what?
Sheth returns the ball
The emperor strikes back
The Great Plumes Debate - Part 2
Beyond the Plume Hypothesis - a student's eye view of the Penrose conference by Marc Davies - 2 October 2003
There are many ways to cook an egg, and it is equally probable that there are many ways to generate intraplate volcanism. It is hardly surprising therefore that the plume hypothesis, in its most rigid form, cannot account for every occurrence of volcanism away from plate boundaries. Should a model as such then be taken as a rigid framework that is discounted as soon as it is seen not to fit? Or should the essence of the model be developed to formulate a more appropriate model?
Picture- the author, suitably braced by scenery, weather and debate. Photo - Marc Davies
This was clearly not the preface of the recent Penrose Conference, Plume IV: Beyond the Plume Hypothesis since the statement of its objectives presented in the opening address was to explore alternatives to the plume model. Again, it is hardly surprising that it is difficult to find a unified theory, as was called for at the end of the meeting, if we are only looking for alternatives.
It is certainly apparent that structural features related to lithospheric architecture and stress can play an important role in controlling intraplate volcanism. O'Connor neatly demonstrated this with reference to the Foundation and Juan Fernandez seamount chains in the South Pacific. It is also conceivable that many such seamount chains that exhibit linear age progressions may be explained by propagating fractures as in the cases of the New England Seamounts (McHone), and the parallel chains in the Pacific, including Puka Puka Ridge (Natland). Similarly, those with non-linear age progressions, such as Louisville, Marshall-Gilbert, Line Island, and Cook-Austral-Marquesas chains, may be interpreted as leaky transforms (Smith). Furthermore, the concept of edge-driven convection may be invoked to explain the voluminous volcanism and melt anomaly tracks associated with the margins of ancient cratons, such as the Columbia River Basalts and the Yellowstone hotspot trail (Christiansen), and possibly the Azores (King).
All these considered, it still remains unclear how such shallow level mechanisms can account for the huge volumes, high melting temperatures and rapid rates of emplacement characteristic of large igneous provinces. Even if we accept that edge-driven convection generated by strong contrasts in lithospheric architecture is capable of producing large volumes of magma, oceanic plateaux and continental flood basalt provinces with no obvious cratonic association still remain unexplained without reference to plumes. If we go as far to accept that changes in lithospheric stress can release huge melt ponds trapped beneath the lithosphere to create large igneous provinces, we have to then come up with some evidence to substantiate the existence of such ponds and explain how such features can be maintained at sub-lithospheric depths for an appreciable length of time.
After three days of heated and often objective discussion on the origins of various seamounts and oceanic island chains, in between the inevitable argumentative discourse on Iceland and Hawaii, I found it disappointing that the response to the presentations on large igneous provinces in the penultimate session of the conference was subdued and largely inconsequential. The role of carbon dioxide in lowering the solidus temperature (Presnall) is not sufficient to discredit the anomalously high temperatures reported for provinces such as the Ontong Java Plateau (Fitton) and the Ethiopian Traps (Davies), and the role of water (Green) doesn?t even come into the equation since these melts are essentially anhydrous. A lower mantle source for plumes may be discounted on the basis that convection in the lower mantle is suppressed by pressure (Hofmeister), and there is growing evidence that primordial noble gas signatures evident in many large igneous provinces are not necessarily indicative of a deep lower mantle contribution. Similarly, osmium isotope data indicate that there is no contribution from the core in the Ethiopian Flood Basalt Province. By discrediting a lower mantle or core we still cannot explain high melting temperatures and anomalous buoyancy fluxes. I went to Iceland looking for something other than a plume to explain the origin of high-Ti flood basalts from the Ethiopian Plateau; I came back without an alternative, but with a more panoramic view of intraplate volcanism than I had before.
In the absence of a unified theory there were elements of commonality at the end of all this discussion. There seemed to be a consensus that the upper mantle is compositionally heterogeneous, and that the geochemical variation we see at ocean ridges (Bonatti, Dick) and in intraplate volcanism is a consequence of this heterogeneiity. The components of the geochemists' alphabet soup should no longer be viewed as representative of discreet mantle reservoirs but as numerical limits, defining compositional mixtures of recycled bits and bobs which themselves constitute upper mantle heterogeneiity. It was not discounted that Earth's rotation is capable of generating a westward drift of the lithosphere relative to the mantle sufficient to influence plate motion, create global asymmetries at rift and subduction zones, and possibly induce shear-melting as a result of decoupling between the lithosphere and underlying asthenosphere (Doglioni). A slower net westward drift of the mantle resulting from same mechanism may also influence patterns of convection in the mantle.
The way forward was encapsulated in a few presentations which considered both non-plume and plume ideas together to explain the observed data. With reference to tomographic sections across the Horn of Africa, Montagner proposed that the Afar upwelling originates at a boundary layer at the 660 km discontinuity. Alongside this he suggested that a series of shallow level parallel N - S trending high velocity regions to the west of Afar are a consequence of edge-driven convection emphasised by the northward movement of the African plate. Similarly, Wilson acknowledged that shear/wrench faulting, as a result of the periodic release of plate stresses, played an important role in controlling the development of the Walvis Ridge and the Rio Grande Rise, previously interpreted as simple hotspot trails.
Still it remains unclear whether or not there is any exchange of heat or material between the upper and the lower mantle, and the boundary layers from which plumes arise remain elusive. With growing evidence that the core-mantle boundary is an unlikely candidate for the origins of many deep mantle plumes, perhaps we should be asking ourselves do we really need a persistent boundary layer to generate a plume? After all, all we need is a compositional difference to generate convection, and there is a multitude of such differences in a heterogeneous mantle.
This great plume debate perhaps needs refocusing. The non-plume protagonists initiated a healthy debate which has encouraged us to consider mechanisms other than boundary generated plumes to explain intraplate volcanism. The issue has now become one of scale! Large igneous provinces are difficult to explain without deep, hot upwellings or plumes, whereas the range of smaller scale features generated by intraplate volcanism from localised and regional volcanic fields to chains of tiny seamounts may be explained within the context of global lithospheric architecture and stress by some variant between mini-plumes, edge effects, propagating fractures and shear melting. Where Iceland and Hawaii fit into this framework is still open to debate, but regardless of whether we are 'top-downists' or 'bottom-upists', there is room within the framework to accommodate our theories. Perhaps then we can ease off defending our preconceptions and concentrate on generating data to test our inferences.
It seems as difficult to attribute all intraplate volcanism to global lithospheric stress patterns, which generally encompass the range of presented alternatives, as it is to explain everything with plumes. With reference to the constellation paradox quoted to illustrate how the plume theory focuses on those features that fit (Anderson), we should be as careful not to focus so much on the stars in between that we lose focus on the constellations themselves. The emphasis throughout the conference on the numerous chains of seamounts and calderas which can be adequately explained by shallow level processes, almost to the exclusion of considering the mechanisms responsible for the generation of large igneous provinces, went some way toward losing this focus. Nevertheless, the convenors of Plume IV: Beyond the Plume Hypothesis should be complimented on staging a meeting that actively encouraged debate. There was a lesson to be learned here! Limiting the presentations to a few provocative keynotes, leaving aside enough time for spontaneous discussion, and limiting numbers so that it was not so daunting to contribute to the proceedings, was altogether a fine recipe for a productive conference. With a finer balance between 'believers' and 'non-believers' it would have been the perfect forum to scramble the egg.
Back to the Plume debate homepage
The bracketed names cited in the text refer to presenters at the conference. Their abstracts are published in the conference handbook and may be viewed on the website http://www.mantleplumes.org
I should like to thank my supervisors Nick Rogers and Ian Parkinson for their constructive comments on the content and arrangement of the text, and Gillian Foulger and Don Anderson for their thoughtful remarks on the first draft. Also I should like to thank The Open University, The Geological Society of London, The Geological Society of America for their financial assistance, without which I could not have attended the conference.
* Marc Davies (Research Student) Department of Earth Sciences, The Open University, Walton Hall, Milton Keynes MK7 6AA UK Marc.Davies@open.ac.uk
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September 4, 2017 by Mal and Rita
Indieterria meets Lost Tiger to the Wild
Lost Tiger to the Wild band logo
On September 22 2017, Worcester will be rocked by Musicians Against Homelessness campaign. The town will host an annual gig to raise funds for Crisis, an NGO that help vulnerable people. This year yours truly are involved and our role is to bring to light and attention of general public the amazing artists who will be playing for the fundraiser. We have already profiled nth cave for this blog. It`s time to meet Lost Tiger To The Wild.
Believe us or not, we found them via Twitter when they were still under a different name around a year and half ago, we have been in the first row on their debut gig, we may have passed a word about them to a DJ or two. It was a pleasure to watch this duo grow into confident artists. Now it is a pleasure to present them on this blog.
Hear us roar
Jokingly referred to as the rock and roll version of the Thompson Twins (who were not real twins mind you!) brothers Alfie and Zack Jeavons-Fellows are on the straight way to stardom. Their sudden appearance on Worcester music scene less than a year ago was a true musical knock out. Powerful riffs, rhythmic beats combined with talent for writing songs you cannot get out of your head, proved to be a winning combination. We have caught up with the skilled duo to speak about their early success, getting noticed and their upcoming music.
You are identical twins, we are not seeing double, are we?
Alfie Jeavons-Fellows: (laughing) Yes, we are identical twins; born a minute apart. I’m the older of us both.
Lost Tiger to the Wild is an interesting name for a band – half poetic and half cryptic. Can you explain where it came from?
Alfie Jeavons-Fellows: We found the phrase in a book. The quote read “We have lost a tiger to the wild”. We liked the way the words worked together, so we went with ‘Lost Tiger to the Wild’. For us the name is about being free and independent.
Alfie and Zac before their BBC Introducing session with Andrew Marston for BBC Hereford and Worcester Photo by Andy O`Hare https://www.facebook.com/andy.ohare1
Zac, you normally play the lead guitar and sing, while your brother Alfie is wreaking havoc behind his drum kit. However, you are known to switch places or play different instruments such as ukulele or keyboard during your performances. Is it hard to play only with your brother as a duo or do you prefer to keep it simple?
Zac Jeavons-Fellows: Playing as a duo is easier for us. We get on really well, have similar mindsets and share an approach to our music. Decision-making is much easier. And of course sorting rehearsals is simple. We are keeping it simple; it works for us at the moment.
Are you working with any other local musicians? Do you have a backing band that is supporting you on stage on special occasions?
Alfie Jeavons-Fellows: Yes, we do. We’ve added a bass and lead guitarist for a recent live gig, which was really good for us because we were able to experiment with the solid guitar sound that Lost Tiger is about.
Many young bands look up to your own musical heroes such as Arctic Monkeys, The Kooks, Kasabian, Oasis or Catfish and The Bottlemen and their influences can easily be heard. The music you make is hard to categorize – it is rhythmic and energetic, yet very original. What inspires you to write?
Zac Jeavons-Fellows: Song writing is all about the riff for me. The lyrics come after. I can’t really tell you where the inspiration comes from. We probably draw from blues, a bit of soul and plenty of guitar rock, although we do listen to lots of different music. Lyrics generally come from experiences – some of my own and some that I see other people going through.
Read to Rock! Photo from band archives.
BBC Introducing gave you one of the best recommendations we have seen in years. “Great guys, great melodies, great live shows, great future ahead of them”. It is not easy to impress people who listen to music for a living.
Alfie Jeavons-Fellows: (laughing again) People who listen to live music for a living are our best critics. Honest feedback is what helps us drive forwards. The BBC Introducing chaps were really good to work with, funnily enough we bumped in to Andrew Marston after our Coventry University gig and we see Andy O’Hare all over the place. Good blokes.
You are represented by prestigious Coalition Talent Entertainment Agency in London, responsible for shaping careers of well-known acts such as Shoala Ama, Pixie Lott, The Wombats or Artful Dodger. How did your partnership begin?
Alfie Jeavons-Fellows: Once our social media started to kick off, we found several agents were getting in touch. Rather than leap at the first offer we have received, we waited for a proven talent management team that could help push our careers on. Coalition got in touch in February, making some really positive noises so we met with them in London and soon agreed to work together. Being part of the Coalition stable gives us a chance to perform with lots of other professional artists.
We have to ask about our favourite track, Remember to Breathe. You played it at the BBC session at the Railway in Redditch to rave reviews and great compliments from the crowd. It is a powerful track with thoughtful lyrics. Tell us more about this song.
Zac Jeavons-Fellows: I have had the chorus riff for ages and loved the way it sounded with a decent fuzz pedal. Alf developed the song without lyrics a lot and it still sounds exactly the same. Coming up with lyrics to compliment the gritty sound was a struggle until I heard a bluesy song called “Remember to Breathe” written by Australian busker, Owen Campbell. It just clicked. With a little bit of tweaking, the lyrics fitted perfectly over my verse and chorus. We love it. Hope Owen will too, when he hears it.
Lost Tiger to the Wild – performing at the Marrs Bar on 5th May 2017 – their debut gig
Debut gig on May the 5th 2017 – force was definitely with the band
Lost Tiger was only founded in November 2016 and you have been performing extensively ever since. Your achievements are most impressive: on 17th of May you played at the sold out CUSU Summer Ball 2017 at the legendary Coventry University Students’ Union supporting Tinie Tempah; on the 10th of June you supported Lethal Bizzle at University of Essex and recently you headlined a gig for UNCOVER sessions night in Worcester. Where are you going to play next?
Alfie Jeavons-Fellows: Our next gig is the Monmouthshire Filthy Girl Mud Run After party at the beginning of September. We played the sister event in Derbyshire about a month ago which was great fun. The crowd was really up for it. Top gigs are all about the audience.
On 22nd of September you will return to Marrs Bar in Worcester to take part in Musicians Against Homelessness initiative in support of Crisis (charity combating homelessness). This nation-wide musical event is championed by Alan McGee, the founder of Creation Records and manager of Primal Scream, Oasis and The Libertines. Are you preparing anything special for the night?
Alfie Jeavons-Fellows: The Marrs Bar is the home of original music in Worcester so we’ll definitely be playing our own music. If everything goes well, we’re hoping to debut a couple of new tracks. We’re really pleased to be part of the event.
Debut gig at the Marrs Bar.
Outside of your musical careers, you are very keen on sports, especially rugby. You both play for Stourbridge RFC, also with great success. We hope you are not thinking about a sudden career-change.
Zac Jeavons-Fellows: No, don’t worry! We’re really into music; it’s what we really want to do.
Last but not least – the fun question. Tell us the most rock and roll thing that has happened to you so far.
Alfie Jeavons-Fellows: I think it’d be best if we keep that one to ourselves… if you ask us face to face we may answer differently.
You can follow Lost Tiger to the Wild at:
https://www.facebook.com/LostTigerBand/
https://twitter.com/LostTigerBand
https://www.youtube.com/channel/UCNcu1GbXFLTrl_UP-L9lHsw
https://www.instagram.com/LostTigerBand/
Lost Tiger to the Wild in Slap Magazine
You can read this interview in September issue of Slap Magazine:
http://www.slapmag.co.uk/issue-73/september-2017/
or you can download the copy here:
issue-73-september-2017
Musicians Against Homelessness charity concert will take place on September 22nd 2017 at Marrs Bar
If you want to see Lost Tiger to the Wild play Musicians Against Homelessness concert, tickets are a £5 and can be bought from the links below:
https://www.wegottickets.com/event/413506
http://www.marrsbar.co.uk/events/musicians-against-homelessness-2/
To find out more about MAH visit Musicians Against Homelessness on Facebook https://www.facebook.com/mahgigs/
We will see you soon enough for more music,
This entry was posted in Indieterria and tagged blog, blogger, blogging, British music, charity, concert, discover new music, gig, guitar music, independent music, independent scene, indie, indie music, indie pop, indie scene, Journalism, live music, local scene, Midlands, music, music artist, music blog, music blogger, music interview, Music journalism, music scene, music writer, Musicians Against Homelessness, new music, new music alert, new sound, rock, rock music, rock`n`roll, UK, West Midlands, Worcester, Worcestershire, writer. Bookmark the permalink.
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The 3 Best and 3 Worst Games of November 2018
Lillian King
3 Up, 3 Down – November 2018 Edition
With releases like Red Dead Redemption 2 and Spider-Man at our backs—two of the only eight games to ever earn a perfect score from COG—November has a lot to follow. While there were many good releases this month, sadly, some of the greats fell far in this chilly precursor to December (or, as I call it, the month before the Overwatch holiday event). With that in mind, let’s take us a gander at the three best and worst games of the month.
***Click here for our full review***
It’s the oldest game in the book—almost literally. This is both a blessing and a curse: everyone knows it, but why should we go out of our way to buy it, right? Wrong. Tetris Effect proves that an old dog can be taught new tricks, and this new and fun version of the classic is worth picking up for the great visuals and challenging gameplay. All in all, we said in our review that “Tetris Effect is, at times, unrecognizable – a project unfazed by its own history,” and “Tetris Effect acts as a launching platform for newcomers by coaxing them in with the simplicity of it all.”
Spinoffs have a tendency to be bad, but Thronebreaker: The Witcher Tales breaks the mold just as The Witcher did before it. Based on the game Gwent, originally a card mini-game you can play inside The Witcher 3, Thronebreaker takes this opportunity to launch into its own strategy game that utilizes and explores the world of a battlefield. With Meve the warrior queen to push the story forward and a host of genuinely difficult and well-written choices to be made, Gwent has never felt more fun. In fact, we said in our review that, “the intricately layered story and carefully crafted characters and writing are some of the best I’ve seen this year, and the card play is more rewarding than it’s ever been before. Whether or not you are a fan of the Witcher series, or even card games in general, Thronebreaker deserves your attention.”
428: Shibuya Scramble
Originally released in 2008, 428: Shibuya Scramble was released this year for the PS4 and PC, and we, along with many people, rediscovered a unique and creative visual novel. Shibuya Scramble uses live actors in short scenes with still image backgrounds to tell its harrowing story about a kidnapped girl named Maria whose freedom is as stake while Kano, a detective, hunts down the culprits. With four other quirky and compelling protagonists whose lives are linked so much that making one bad decision as a first character could lead to the death of the second. One of the greatest visual novels out there, we said in our review that “428: Shibuya Scramble is definitely a must-play for visual novel lovers and those newer to the genre. It is not only unique with well-developed protagonists, but the sophisticated story involving every character in the game creates a masterpiece that is hard to forget.”
Check out Page 2 for the games that didn’t fare so well in November 2018…
Rage 2 Is Getting Three New Game Modes This Month
DOOM Eternal’s Multiplayer Will Provide the Same Slayer Experience as the Campaign
Amazon Is All About Action This Week with Their PC Gaming Deals
The Developer Behind No Man’s Sky Offers Friendly Advice To Bethesda and EA
Bethesda Sees an Opportunity for Growth in the Nintendo Switch
Next 12 Great Stocking Stuffer Ideas for Gamers 2018
Previous Top 5 Video Games Arriving in December 2018
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Infinite Powers: How Calculus Reveals the Secrets of the Universe: Steven Strogatz
From preeminent math personality and author of The Joy of x, a brilliant and endlessly appealing explanation of calculus – how it works and why it makes our lives immeasurably better.
Without calculus, we wouldn’t have cell phones, TV, GPS, or ultrasound. We wouldn’t have tamed AIDS or discovered Neptune or figured out how to put 5,000 songs in your pocket.
Though many of us were scared away from this essential, engrossing subject in high school and college, Steven Strogatz’s brilliantly creative, down‑to‑earth history shows that calculus is not about complexity; it’s about simplicity. It harnesses an unreal number—infinity—to tackle real‑world problems, breaking them down into easier ones and then reassembling the answers into solutions that feel miraculous.
Infinite Powers recounts how calculus tantalized and thrilled its inventors, starting with its first glimmers in ancient Greece and bringing us right up to the discovery of gravitational waves (a phenomenon predicted by calculus). Strogatz reveals how this form of math rose to the challenges of each age: how to determine the area of a circle with only sand and a stick; how to explain why Mars goes “backwards” sometimes; how to make electricity with magnets; how to ensure your rocket doesn’t miss the moon; how to cure infectious diseases.
As Strogatz proves, calculus is truly the language of the universe. By unveiling the principles of that language, Infinite Powers makes us marvel at the world anew.
Source: www.amazon.com
Macroscopic dynamics and the collapse of urban traffic
The chaperone effect in scientific publishing
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1927.000m
Annual sea surface temperature difference from normal, 2002
This dataset was first added to MfE Data Service on 11 Feb 2016.
The ocean waters surrounding New Zealand vary in temperature from north to south. They interact with heat and moisture in the atmosphere and affect our weather. Long-term changes and short-term variability in sea-surface temperatures can affect marine processes, habitats, and species. Some species may find it hard to survive in changing environmental conditions.
This layer shows annual sea-surface temperature difference from normal for 2002 as part of the data series for years 1993 to 2013. "Normal" is defined as the average sea-surface temperature for 1993–2013.
NIWA’s sea-surface temperature archive is derived from the Advanced Very High Resolution Radiometer (AVHRR) satellite data it receives from the National Oceanic and Atmospheric Administration. The archive provides high spatial (approximately 1km) and high temporal (approximately 6-hourly in cloud-free locations) resolution estimates of sea-surface temperatures over the New Zealand region, dating from January 1993. Uddstrom and Oien (1999) and Uddstrom (2003) describe the methods used to derive and validate the data.
This dataset relates to the "Annual average sea-surface temperature" measure on the Environmental Indicators, Te taiao Aotearoa website.
Geometry: grid
Unit: percent
Further information can be found in:
Uddstrom, MJ (2003). Lessons from high-resolution satellite SSTs. Bulletin of the American Meteorological Society, 84(7), 896–897.
Uddstrom, MJ, & Oien, NA (1999). On the use of high resolution satellite data to describe the spatial and temporal variability of sea surface temperatures in the New Zealand region. Journal of Geophysical Research (Oceans) 104, chapter 9, 20729–20751.
1. Annual sea surface temperature difference from normal, 1993 2013 199 KB pdf
Environmental Reporting > Atmosphere & Climate > Sea temperatures influence on weather and climate
CLIMATE-AND-WEATHER, New Zealand, CLIMATE-AND-WEATHER-Climate-change, CLIMATE-AND-WEATHER-Temperature
Image/Raster
About 1927.000m
Catalog Service (CS-W), data.govt.nz Atom Feed
Imported on Feb. 11, 2016 from GeoTIFF in WGS 84.
<iframe src="https://data.mfe.govt.nz/layer/53030-annual-sea-surface-temperature-difference-from-normal-2002/?embed=1" width="400" height="350" frameborder="0" scrolling="no" marginheight="0" marginwidth="0" style="border: 1px solid #808080; overflow: hidden;"><a href="https://data.mfe.govt.nz/layer/53030-annual-sea-surface-temperature-difference-from-normal-2002/?source=embed">Annual sea surface temperature difference from normal, 2002</a> from <a href="https://data.mfe.govt.nz/">MfE Data Service</a></iframe><br /><small><a href="https://data.mfe.govt.nz/layer/53030-annual-sea-surface-temperature-difference-from-normal-2002/?source=embed" style="color:#00f;text-align:left">Annual sea surface temperature difference from normal, 2002</a> on <a href="https://data.mfe.govt.nz/" style="color:#00f;text-align:left">MfE Data Service</a></small>
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David R. Stokes
Author of Jake & Clara
“In this book David Stokes tells the J. Frank Norris story... It really happened.”
—Bob Schieffer, Emmy-winning broadcaster (CBS News)
Churchill dies. World leaders converge on London for his funeral. But not U.S. President Lyndon Johnson. Why? What does he know?
What will he do?
This sensational and scandalous story held the nation spellbound. Hollywood even made a movie about it—but they had to burn all the copies.
ABOUT DAVID STOKES
David R. Stokes writes books that are impeccably researched with a keen eye for historical detail and accuracy. His fiction reads like true life, and his nonfiction has the brilliant feeling that the story once appeared on the front page of the New York Times.
LATEST BLOG ENTRY…
DAVIDSTOKESLIVE.COM
https://davidstokeslive.wordpress.com/ … READ FULL POST
For information about how to get autographed/inscribed copies or discounts for groups, CLICK HERE.
Copyright © 2019 David R. Stokes | Site by AuthorBytes
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Mental health, Suicide/ self-harm July 27, 2017 August 4, 2017
Perfectionism as a risk factor for suicide – the most comprehensive test to date
According to the World Health Organisation, someone takes their own life every 45 seconds. To help prevent future tragedies, we need to know more about the factors that make some people especially vulnerable to suicidal thoughts and acting on those thoughts. One candidate is perfectionism: the tendency some people have to hold themselves to consistently impossible standards and/or feeling the need to meet or surpass the lofty expectations of others.
In 1995 the late psychologist Sidney Blatt highlighted the apparent link between perfectionism and suicide in an influential article for American Psychologist titled “The Destructiveness of Perfectionism” in which he profiled three highly talented, ambitious but harshly self-critical individuals all of whom took their own lives: Vincent Foster, a deputy counsel to President Bill Clinton; writer, singer and broadcaster Alasdair Clayre; and athlete and scholar Roger D Hansen.
“Because of the need to maintain a personal and public image of strength and perfection, [perfectionists] are constantly trying to prove themselves, are always on trial, feel vulnerable to any possible implication of failure or criticism, and often are unable to turn to others, even the closest of confidants, for help or to share their anguish” Blatt wrote.
However, since Blatt’s paper, research progress on the topic has been slow, hampered in part by a confusing multitude of definitions of perfectionism and a paucity of studies with the longitudinal methodology needed to establish that perfectionist tendencies increase suicidal risk. But now, writing in Journal of Personality, a team led by Martin Smith at the University of Western Ontario say there is enough data to conduct a “meta-analysis”, which is what they’ve done, producing “the most comprehensive test of the perfectionism-suicidality link to date”.
The researchers found 45 relevant, suitably robust studies involving collectively 54 samples, totalling 11,747 participants. Forty-eight of the samples were cross-sectional (measures were only taken at a single point in time) while six had the all-important longitudinal design, granting insight into whether perfectionism may precede suicidal thoughts or behaviours. Collectively, the studies covered 15 of the different definitions and ways of measuring perfectionism that exist, most falling under the main categories of either placing excessive expectations on oneself, feeling pressure from others (including parents or society at large), or holding other people to perfectionistic standards.
Overall, the analysis showed that 13 of the 15 different measures of perfectionism had associations with increased suicidal thoughts (in statistical terms the effect size was small to moderate). Aspects of perfectionism related to concerns about meeting others’ expectations were additionally associated with making more suicide attempts. Meanwhile, holding others to high standards, and being perfectionist in terms of tidiness and organisation, were not related to suicidal thoughts or attempts.
“Perfectionists,” the researchers explained, “are their own worst critics … locked in an endless loop of self-defeating over-striving in which each new task is another opportunity for harsh self-rebuke, disappointment, and failure.”
But the most pernicious form of perfectionism seems to be feeling the weight of meeting other people’s expectations – this was related to increased suicidal thoughts in longitudinal studies that followed the same participants over time and that controlled for their baseline levels of suicidal thought. “Our findings lend credence to the long-standing notion that feeling incapable of living up to the lofty standards of others is a part of the premorbid personality of people at risk for suicide,” the researchers said.
It’s notable that past research has found trait conscientiousness (one of the Big Five personality traits associated with self-discipline and orderliness) is associated with reduced risk of suicide. This suggests perfectionism as defined here – holding oneself to unrealistic standards, or seeking to meet the unrealistic standards of others – is not simply a form of excessive conscientiousness.
Although this is the most thorough examination of the links between perfectionism and suicide to date, and the data suggests that perfectionism is a relevant risk factor, it’s important to note that the research base is still lacking. There is especially a need for more longitudinal research, more research with diverse groups (most of the studies to date have involved White Western people) and more research that tests whether perfectionism adds risk even after other factors are taken into account, such as depression.
For now, the researchers said the data are consistent with “case histories and theoretical accounts suggesting people high in perfectionism appear to think, behave, perceive, and relate in ways that have suicidogenic consequences”. Perfectionism is associated with “intense psychological pain” they said. Perfectionists have a “harsh way of relating to a self they find deficient”. Their lives are typically stressful and they often have a “prickly, conflictual style of relating to others,” leaving them isolated and lacking support. “Amid such pain,” Smith and his colleagues conclude,” perfectionists may think about, or engage in, suicide as a means of escaping a life they find unbearable.”
—The Perniciousness of Perfectionism: A Meta-Analytic Review of the Perfectionism-Suicide Relationship
Booty more amusing than ass, according to first in-depth study of the funniness of English words
The researchers asked over 800 participants to rate the funniness of hundreds of individual words, all in the service of science. By Christian Jarrett
We adjust the pitch of our voice based on the status of who we’re talking to
Whether we raise or lower our voice in the company of a high status person depends on how confident and dominant we feel about ourselves. By Lexie Thorpe
9 thoughts on “Perfectionism as a risk factor for suicide – the most comprehensive test to date”
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really helpful and helped expand my thinking in different perspectives.
JF says:
I just want to add that not many perfectionist hold impossible standards.
Often time, even if you follow every little rules of society and he/she ensures that one has the necessary prerequisite on their endeavours,and yet get disadvantaged because of corruption in the system as a whole or a lot of other variables that are not taken into account when administering a test or attempting to run an experiment with regards to mental issues like depression.
In short, with all due respect,what Dr Jarette mentioned in his article has some essence of truth but couldn’t be completely more wrong than that.
The theory that Blatts it forward is accurate to certain extent; but for one to say that it’s the person’s own fault (because they hold themselves to a higher standard in the eyes of others) seem to a lacked of insight.
Sometimes, you play the game but it is already rig to begin with, naturally the response will be negative you one has tried over and over and over.
So it is not meeting other people expectation but your own expectation (aren’t someone allowed to have their own goal without having to be perceived as trying to meet someone’s expectation?)
Perhaps that is why suicide exist because no one ever truly tried to understand how it all come about.
The literature seem to be confirmed biased from what I read.
It makes good reading materials but it doesn’t truly reflect why people have suicide ideation or at least the very factors that lead to this point or perhaps death in many instances.
Your post is rather incoherent (maybe English is not your first language, so that’s understandable), but from what I gather, you are arguing that holding yourself to your own high standards is healthy, while holding yourself to high standards of others is not. Whilst some subjectivity is involved, surely it cannot be healthy to have impossibly high standards at all? Think of REBT and Albert Ellis’ works on irrational beliefs.
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appliedpyschologysolutions says:
“Shoulda woulda coulda” ! I come out high in ‘conscientiousness’ as a trait. Just as well, as I was driven to the point of suicide several times by religious zealots in the Church if England and it’s ‘evangelical’ Christian ‘cult’ satellites to whom we are all ‘sinners’ and can’t ever redeem ourselves without believing in their ridiculous fantasy about how the world is – or rather, how it was 2,000 years ago. The only thing that stopped me was knowing what it would do to my family. I have had to teach myself that it is ok to be less than perfect, that the world is not going to come to an end if I don’t achieve all I set out to, NOR all others think I should and that actually what I think is not that important – least of all to someone else! Perfectionism, for me WAS linked to my desire to die – the feeling of powerlessness and lack of control and the resulting ‘dissonance’ (Festinger), meant I had to adjust my beliefs so they were more in alignment with what was realistically achievable. Sometimes suicide feels like the only way of exerting control over a seemingly overwhelming situation. Its our job to provide an alternative. Its OK to be human – warts and all.
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Sana 2014
Great achievements in 2014
A 36% increase in visitors for a total of 43.500 visits, a 10% rise in exhibitors, and 40% more foreign exhibitors compared to the 2013 edition and 1.500 non-Italian buyers. These were the record attendance figures for SANA 2014, the 26th International Exhibition of Organic and Natural Products, that closed its door last Tuesday.
Not only were records broken for the number of halls, crowded exhibitor booths, visitors and buyers from Italy and all over the world. It was also a full house at the meetings, with an estimated 5.000 participants attending the very many general interest and scientific sidecar conferences. Topics ranged from the SANA Academy courses, organised by BolognaFiere, and meetings on health and professional or amateur sports, organised by the new section SANA Sport, to technical medical and scientific conferences on coeliac disease and dietary education in the third millennium, organised by the Foundation Istituto di Scienze della Salute. All these events confirmed that SANA is the premier Italian tradeshow covering the entire gamut of the natural and organic sector, every year increasing its international reach, and acknowledged as a key promoter in the world of Made-in-Italy organic produce. This was amply borne out by the large buyer delegations from Australia, Austria, China, Denmark, Germany, Greece, Japan, Latvia, Lithuania, Netherlands, Poland, Russia, Serbia, Slovenia, South Korea, Sweden, Switzerland, United Arab Emirates, and the United States as well as the 2.613 B2B meetings held in the International BuyerLounge between visiting foreign operators and SANA exhibitors.
Biofach-Vivaness 2014
FULL CLOSING REPORT February 2014
BIOFACH and VIVANESS 2014:
42,445 visitors at 25th anniversary of world’s leading exhibition
Continuity in national and international attendance
Exhibitors and visitors in the mood for celebrating
42,445* trade visitors from 135 countries (international share 44 %) were determined not to miss the 25th anniversary of BIOFACH and the eighth edition of VIVANESS. So the exhibition duo continues its high level of attendance from Germany and abroad. The World’s leading Trade Fair for Organic Food and the International Trade Fair for Natural Personal Care impressed once again with their four-day presentation of varied, innovative and high-quality products. 2,235 exhibitors from 76 countries (international share 70 %) presented their products for buyers from the food and cosmetic sectors on a net area of 42,328 m². The top 5 visiting countries were Germany, Austria, Italy, France and the Netherlands. The special focus in 2014 was on the future of the organic food industry and the key theme Organic 3.0.
Petra Wolf, Member of the Management Board of NürnbergMesse: “The past four intensive and inspiring days at the exhibition have confirmed it once again: BIOFACH in its 25th edition is still the organic exhibition highlight at the start of the year. An impressive sector that constantly inspires with its ecological view and also in terms of its economic and innovative power. The mood in the halls – at VIVANESS too – was really positive, and exhibitors and visitors were highly satisfied. We are already looking forward to seeing everyone again in 2015 and to the Netherlands as Country of the Year!”
* The figures for exhibitors and visitors are certified by the Society for Voluntary Control of Fair and Exhibition Statistics (FKM), Berlin.
Exhibitors and visitors highly satisfied with 25th anniversary edition
The anniversary guests offered their congratulations on the 25th edition and were full of praise for the exhibition duo. 91 % of the exhibitors – BIOFACH and VIVANESS together – rate their overall success positively, according to the result of the survey by an independent institute. 97 % of the visitors were satisfied with the products offered at the two exhibitions. Almost 93 % of the exhibitors reached their top target groups and made new business contacts. 86 % of the exhibiting companies assess the present economic situation in their sector favourably. 87 % of the BIOFACH and VIVANESS exhibitors expect good follow-up business. Almost 90 % of the buyers influence purchasing and procurement decisions in their companies. The exhibitors’ assessment of the quality of the visitors was correspondingly positive and well over 90 % of them praised the quality. 94 % of the visitors already know that they will travel to the organic sector’s first event of the year again in 2015.
Successful regrouping: highlights to the power of five!
The highlights of the complete global show for the organic market were rearranged for BIOFACH and VIVANESS 2014 into the five clusters of Trends & Innovations, Worlds of Experience, Fachhandelstreff, Generation Future and Congress. Exhibitors and visitors discovered Trends & Innovations concentrated on the two Novelty Stands, where 649 innovative and inspiring products could be experienced (BIOFACH Novelty Stand: 496, VIVANESS Novelties: 153). New in 2014 was a separate category for vegan food with 111 delicious products. Buyers discovered five Worlds of Experience at BIOFACH 2014: Cheese, Olive Oil, Wine, Fish and Coffee. Here traders were able to gather sound practical information about the respective range of products from recognized experts, try out the products and obtain inspiration for their own shop. The Fachhandelstreff with Forum and Club clearly confirmed its function as a central communication location for the German retail trade. The highlights of Generation Future were the Careers Centre and the Organic Food Research Award, which was presented for the first time. The Congress at the 25th anniversary edition of the exhibition duo attracted 6,550 participants to 104 individual events (including 30 company presentations).
Key theme Organic 3.0 exactly what the sector wants
Both at the congress and in the exhibition halls, exhibitors and visitors showed an intensive interest and commitment to the focus topic Organic 3.0, which was organized jointly by IFOAM, the international patron of the world’s leading exhibition, BÖLW (German Federation of the Organic Food Industry), the national supporting organization, and BIOFACH. The patron and supporting organization were agreed: the focus theme was exactly right and created impetus. Markus Arbenz, Executive Director of IFOAM: “With the Organic 3.0 theme in the 25th year of BIOFACH, the stakeholders created impetus for the next 25 years!” Stefan Zwoll, Managing Director, BÖLW: “In 2014 BIOFACH has sharpened its profile as a source of ideas and political think tank. The strong presence of stakeholders from politics, science and business emphasizes its high relevance.” The visiting professionals were also particularly interested in the key theme at the congress, where the nine presentations on this theme reached almost 1,000 people. The most popular was the congress paper on the Organic 3.0 Trend and Potential Study by future researcher Hanni Rützler, which was attended by 260 participants.
Prizewinners: awards presented to organic products at the world’s leading exhibition
Enjoyment and quality are top priority at BIOFACH. This year’s visitors were again delighted with the prize-winning organic products in the Best New Product Award competition, which tracked down the most convincing new products for the fourth time. Every visitor at the exhibition had the opportunity to choose his favourite product as the Best New Product in each of eight categories using his voting card. The winners were: Poesie Amelie from foodloose (category Trend vegan), Fresh Chilli Noodles from frizle (category Fresh), Schrozberger Frozen Raspberry Yoghurt on a Stick from Molkerei Schrozberg (category Frozen), Organic Pumpkin Ketchup from Georg Thalhammer Gesundes von Feld und Wald (category Grocery products – cooking & baking), Lovechock Rocks Mulberry/Hemp Seed from Lovechock (category Grocery products – snacks and sweets), Dirty Harry BBQ World Champion from Münchner Kind´l Senf (category Other grocery products), GingerVerde organic from Querdenker (category Drinks) and the Organic Garden Set for Young Explorers from Aries Umweltprodukte (category Non-Food).
VIVANESS: show of trends and products for natural cosmetics market
VIVANESS, the International Trade Fair for Natural Personal Care, took place in 2014 for the eighth time. This year 192 exhibitors from 30 countries presented their products on a net space of 4,874 m². The exhibitors once again included newcomers and niche brands as well as pioneering manufacturers. The top 3 exhibiting countries were Germany (63), France (41) and Italy (22). The highlights and visitor attractions included Breeze, Novelties and the premiere of the Meet & Talk communication platform.
One of the most important reasons for visiting both BIOFACH and VIVANESS every year is to discover inspiring new products. There was accordingly a lot to be experienced, tested and discovered by the trade buyers present from the international cosmetics sector, which in general is becoming greener and greener. The number of registrations for the VIVANESS Novelties rose from 101 to 191. Eleven manufacturers from seven countries also presented more brands than ever before in the special Breeze area.
Decision-makers from the retail trade (32 %), manufacturing (19 %), service sector (19 %) and wholesale/import & export (16 %) were also the main groups of visitors at this year's VIVANESS. Over 95 % of them were satisfied with the products, organization and service offered at the exhibition. The VIVANESS Forum as part of the BIOFACH und VIVANESS Congress attracted the usual keen interest in 2014 and almost 500 participants attended its seven events.
Save the date! The organic sector meets in Nürnberg next time from 11–14 February 2015.
Contact for press and media
Barbara Böck, Helen Kreisel-Gebhard, Ellen Damarowski
Tel +49 (0) 9 11. 86 06-83 28
Fax +49 (0) 9 11. 86 06-12 83 28
ellen.damarowski@nuernbergmesse.de
All press articles, more detailed information and photos are obtainable at:
www.biofach.de/press and www.vivaness.de/press
Market Research on Korea's Organic and Natural Products
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Il Mercato Coreano del Biologico [ ] 2377 Kb
Market Research on Korea's Organic and Natural Products [ ] 2434 Kb
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Article 13 must go: No desperate last-minute witchcraft can turn it into magic pixie dust3 months ago by Glyn Moody
Interview with Bernd Porr4 months ago by Glyn Moody
Anriette Esterhuysen Interview4 months ago by Glyn Moody
Article 13 is Not Just Criminally Irresponsible, It’s Irresponsibly Criminal5 months ago by Glyn Moody
Have You Heard? No One Wants the © Reform5 months ago by Herman Rucic
Article 13 must go: No desperate last-minute witchcraft can turn it into magic pixie dust
Interview with Bernd Porr
Article 13 is Not Just Criminally Irresponsible, It’s Irresponsibly Criminal
Anriette Esterhuysen Interview
Interview with Pamela Samuelson
#HumansOfCopyright: Interview with David Lopez, Lifelong Learning Platform
Have You Heard? No One Wants the © Reform
EU © Reform: Where Italy Makes Sense and the Germans Cave In
© Reform: Over 100 MEPs Call for Deletion of Article 11
Article 11: Driven by Rhetoric, not by Arithmetic
#CopyrightWeek – EC Withholds © Evidence (Again)
#CopyrightWeek: Online Platforms’ Catch 22 with the EU Data Protection Regulation
The 5 Fundamental Flaws of the TDM Provision
The 5 fundamental flaws of the Censorship filter
2018 New Year’s Greetings: Copy’s Christmas Story
The Myth of the Value Gap Simply Explained
Text & Data Mining (TDM) Simply Explained
Copyright Editorial EU Reform Featured
You Wouldn’t Steal a Meme: The Threat from Article 13
Glyn Moody 1 year ago
The computer experts are unanimous. The only way to implement Article 13‘s requirements is through a general filter of every user upload. The fact that the word “filter” is studiously avoided in the Copyright Directive’s text makes no difference to this unavoidable fact of digital life. After all, how would it be possible to make sure that no uploaded file contains copyright material unless every one were checked beforehand? The volume of uploads for major platforms is such that manual inspection is out of the question, which means filtering has to be automated. Since that is now clear to (almost) everyone, the argument around Article 13 has moved on to the practical implications of requiring top sites to install censorship machines for user-uploaded content.
One class of material particularly at risk involves memes. These are often topical ideas that take pre-existing texts, music, images, and videos, and use them with varying degrees of cleverness to make a witty comment or a political point. The vast majority of memes are likely to be blocked by Article 13’s upload filters, since a key feature of them is the use and subversion of other copyright material.
Few would argue that annihilating the Internet’s meme culture would be a good thing – memes may vary in their tastefulness, but they are undeniably a powerful and characteristic expression of 21st-century creativity. As a result, defenders of Article 13’s blanket filters have been forced to take another tack. Now, the argument is that memes won’t be caught by upload filters, because they are covered by exceptions to copyright that allow precisely this kind of parodic use. But there are a number of serious flaws in this line of reasoning.
First, it is not true that memes are covered by exceptions to copyright across the whole of the EU, an important fact the European Commission seems unaware of. There is no blanket “fair use” doctrine, as in the US, that would create a presumption that memes are to be excluded from filtering. Instead, Article 5 of the 2001 Directive on the “harmonisation of certain aspects of copyright and related rights in the information society” says that “Member States may provide for exceptions or limitations”, including “for the purpose of caricature, parody or pastiche”. Potentially, that would seem to cover memes.
However, the crucial word here is “may”: Member States have the option, but not the obligation, to grant an exception for uses that include memes. Only a minority of EU countries have taken advantage of that freedom. Germany and eighteen other Member States still have no parody exception, and thus none for memes either.
What this will mean in practice is that Article 13’s upload filters would need to encapsulate local laws when it comes to deciding whether or not to block material across the EU. And it’s not just local laws. A ruling by the EU’s highest court suggested that local standards of taste were also a factor in determining whether a parody was a legitimate use of copyright material. EU-wide upload filters already face an incredibly challenging task of deciding when material is covered by one of the existing exceptions to copyright, something that even courts struggle with. Add in the requirement that account must also be taken of local laws and sensibilities, and the job of implementing this correctly becomes impossible.
It is clear what is likely to happen. Because of the legal risks of not doing so, companies using upload filters will always err on the side of caution, and pro-actively block anything that might conceivably be infringing. As a result of the different rules in different Member States, the easiest option will be to apply the harshest national constraints across the whole of the EU, which means blocking all parodies and memes if they use any existing copyright material.
That situation will inevitably lead to huge quantities of perfectly legal material being censored. In the US, memes are frequent targets of takedown notices under the Digital Millennium Copyright Act. Existing upload filters already overblock, sometimes removing entire YouTube channels in error. In Germany, a video created by the feminist organisation Pinkstinks was blocked by Google’s ContentID filter for an alleged copyright infringement of material from the broadcaster RTL. In fact, it was not Pinkstinks who used content from RTL, but RTL who had used the organisation’s content in a broadcast without noting the source. The ContentID system assumed that Pinkstinks, not RTL, was in the wrong, and incorrectly blocked legal material. With Article 13 in place, assumptions that uploaders are guilty until proven innocent will become the rule.
Supporters of Article 13 insist that this, too, isn’t really a problem, because the online services will be obliged by the Copyright Directive to put back material that is wrongly blocked in this way. Once again, this reasoning is fallacious. The Pinkstinks experience demonstrates why that is the case. The video in question was part of a campaign by the organisation, and much of its impact depended on being timely. Even though the video was put back after eight hours, a crucial window for influencing people had been lost. This is a general problem, because memes are often extremely topical, and short-lived. They frequently refer to events in today’s news, and without that context, lose much of their power and point. Unblocking this kind of material after hours or days of invisibility may mean that it falls completely flat, or even is irrelevant. For many memes, time is of the essence.
Even for those memes with a longer shelf-life, the fact that people will need to challenge the blocking of their uploaded material will have a chilling effect on the whole culture. One of the great strengths of memes is that they can easily created by ordinary people, with no need for complex technical resources or prior artistic skill. Memes are the ultimate in democratic art. But members of the public are precisely those who are least likely to know how to challenge upload filter blocks, or even to be aware that this is possible.
Many will simply accept the result of the upload filtering, either because they don’t know that they can challenge it, or they don’t have the time and energy to do so. They may be so disheartened to find their attempts at memes are blocked repeatedly that they give up crafting them. The overall result will be an impoverishment of what can be considered an important new digital folk art. The Internet in the EU will be the poorer for it, and freedom of expression of European citizens will be seriously curtailed.
Breezy claims that Article 13 will not affect the Internet’s meme culture are untrue. There is no blanket exemption across the EU for meme-like material. Even where the exemption exists, implementing faithfully the local laws and standards in upload filters will be impossible. This will lead to overblocking of legal material. The much-vaunted “safety clause” is illusory. Most people will be unable or unwilling to go through the daunting process of appealing against the blocking of their creations. And for the few that are determined to get their material online, the delay in posting their memes may mean that they lose most or even all of their force.
The harm it will cause to memes is not the only reason to remove Article 13 from the Copyright Directive – many other domains will be adversely affected, as CopyBuzz has previously noted – but it is certainly a very good one.
Featured image based on video by エルエルLL.
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Writer (Rebel Code), journalist, blogger. on openness, the commons, copyright, patents and digital rights. [All content from this author is made available under a CC BY 4.0 license]
#SaveYourInternet – #DeleteArt13: Article 13 is About Filters!
#SaveYourInternet – #DeleteArt13: Big Businesses Fighting Each Other to the Detriment of Freedom
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debbiewritesreviewshere May 4, 2018 August 24, 2018 Television, Uncategorized
From the pilot episode of Superstition – a supernatural series now available on Netflix – its central themes and the main eco-activist message are clear. Set in the small town of La Rochelle, it follows the Hastings family, who act as protectors of their community from otherworldly spirits and demonic “infernos” through black magic, rituals, and superstitions.
The increasing number of evil attacks from the demons is linked directly by the protagonists to the negative impact human beings have had on the planet. These spirits are supposedly making an attempt to destroy humanity as a result of our indifference towards our environment.
A conversation between Isaac Hastings and his son Calvin conveys the environmental message of the show, in an exchange part-way through episode one:
Isaac – “Since you were a kid, we human beings have destroyed over half of the world’s wildlife. Instead of being good stewards of this earth, we are sucking it dry.”
Calvin – “I know this. What’s your point?”
I – “This imbalance is causing a rise in evil, among us and outside. It’s as if the infernos have come to put us in check.”
C – “You know Pop, after what I saw in Afganistan, I wonder if we’re even worth saving.”
Other themes such as fatherhood, racism, masculinity, and religion all play a part in building up the narrative surrounding Calvin and his family, providing them with personal problems, while fending off various forms of demonic infernos.
Calvin, recently returned from active duty, struggles with new-found fatherhood of a teenage daughter, as well as the family secrets surrounding his own father’s mysterious identity. Each episode develops the relationships between the Hastings, while the supernatural uprising of evil remains the central reason for violence throughout the series.
If humans are as doomed as Mayer Hillman claims in his recent interview with The Guardian, then the release of Superstition on UK Netflix can bring this issue to the forefront of our consciousness through an easy-to-swallow fantastical version of reality. Through the violent monsters in the show, La Rochelle’s future is filled with possible danger and death around every corner. The demons take up residency inside human bodies, hiding in plain sight, literally making people into their own worst enemies.
“We’re doing the reverse of what we should be doing, with everybody’s silent acquiescence, and nobody’s batting an eyelid.”
– Mayer Hillman, The Guardian
Masked as a supernatural-horror-mystery-drama, Superstition promotes conservation and lessening the damage on our surroundings, while it also presents the slight possibility of defeating the evil future our planet may face.
Otherworldly, demonic attacks force the protagonists to confront the damage caused by humans upon the environment in Superstition, while we await the consequences of climate change and pollution within planet earth’s narrative.
Images – SyFy / Netflix / MVPTV
Previous Gore & Gumption in ‘The Alienist’
Next ‘Avengers: Infinity War’ & Superhero Mortality (with spoilers)
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June 15, 2018 June 16, 2018 DisIsAfrica
World cup 2018: Russia disallowed Nigerian Fans from bringing live chicken to the stadium.
The supporters of the Nigerian team at the ongoing FIFA world cup in Russia have been denied a request by a group of fans to bring live chicken in to the football stadium.
According to a A local news reports from Russia, the Minister of Culture and Tourism of the Kaliningrad region where the team is based, Andrei Ermak denied the Super Eagles fans what he called an unusual request from certain group of the fans he told reporters
“Our information center MCH-2018 receives a lot of various questions: fans from Nigeria asked if it’s possible to go to the stadium with a chicken, it’s their symbol, the citizens are sick with them at all matches, we told them that to pass a live chicken, in any case, it is impossible “.
He however soften on his stance that if the fans really want to do that for their team then a solution can be worked out
At the same time, he noted that if the Nigerians are rooting for their team in other places, “we will, of course, advise them where the chicken can be bought.”
We are ready to satisfy the most eccentric inquiries,” the regional minister added.
Very colourful and ever happy Nigerian fans
The supporters club of the Super Eagles have been known to go into stadiums with a live chicken, which is one of the ways they cheer on the team to victory, the chicken are painted in the national colours to cheer the team.
Such is OK in Nigeria but could be classified as cruelty to animal in the western world and those fans could actually be prosecuted for such action, they could take painted chicken to football games in Nigeria but its a whole new ball game when the eyes of the world is upon them, international animal right group will have something to say about the behaviour of those fans.
Obviously the chicken will go through unprecedented stress and trauma within such a large crowed and the handling of the animal in such a super charged environment will be cruel.
At the world cup of 2010 in South Africa, Nigerian fans were refused entry into the stadium when they turned up with pimped up chicken in national colours.
We wait to see how the Russians deal with this unusual request.
Previous A cheating husband and his landlady got stuck together during sex. Video
Next Egyptian Goalkeeper made history as the oldest player in a world cup finals.
World Cups Bans Nigeria's Live 'Good Luck' Chickens From Football Stadium says:
[…] Although the gesture arose from roots of passion, the practice has received much flack from animal rights activists and event organizers. The chickens controversially have their feather dyed to match the Nigerian flag and endure egregious conditions throughout the matches, which are often very loud – especially when vuvuzelas are involved. Frequently, the chicken’s wings will be forcibly spread open as football supporters parade the animals throughout the relevant events. “Obviously the chicken will go through unprecedented stress and trauma within such a large crowd and the handling of the animal in such a super charged environment will be cruel,” wrote news outlet Dis Is Africa. […]
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Is Hyperconverged cost competitive with the cloud?
Home•Is Hyperconverged cost competitive with the cloud?
Hyperconverged infrastructure delivers upgrades in availability, performance and manageability over legacy infrastructure. By consolidating all IT, we can build a highly optimised environment that’s easy to manage. But how does hyperconverged compare with the cloud?
The cloud can also deliver big upgrades in availability, performance and manageability over legacy infrastructure, and it’s equally easy to manage.
Most enterprises have moved some of their IT processes into the cloud, such as web applications and commercial software. The affordability of this is the biggest draw and that affordability allows enterprises to adopt a multi-cloud approach to avoid vendor lock-in – an important benefit that mitigates risk.
But, the cloud isn’t necessarily more cost competitive than an in-house infrastructure.
HPE SimpliVity hyperconverged infrastructure can offer a lower Total Cost of Ownership with a significant cost differential over time.
In this report from Evaluator Group, Amazon Web Services (AWS) is compared against HPE SimpliVity hyperconverged infrastructure. It finds that HPE SimpliVity costs 22 to 49pc less than AWS over three years – a significant difference.
“Due to their [SimpliVity’s] comprehensive, low-cost hardware architectures and advanced efficiency and management features,” the report says, “hyperconverged infrastructure can cost significantly less than a comparable cloud solution.”
With the ability to deploy and expand hyperconverged systems quickly (you just add nodes, and they don’t need integrating) hyperconverged infrastructure offers the benefit of modularity over the cloud. Operating expenses are very low, because they’re designed with VM-centric management to simplify the day-to-day running.
The cloud has its place, of course. If your business experiences low usage with occasional activity spikes, the cloud will likely satisfy your needs. But when it comes to scaling up operations and delivering performance with intense activity, investing in hyperconverged infrastructure is a surefire way to reduce costs. It beats out the cloud’s TCO in this scenario and wins the race with performance. It’s as simple as that.
Paul Lyons2019-06-27T16:28:03+01:00
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A team of students at Mountaintop set out to determine if wearable technology could help in evaluating principals
Inside the cool, cavernous interior of Bay 2 on Lehigh's Mountaintop Campus, six students studied flowcharts and scrawled notes on whiteboards. Outside their roomy, makeshift cubicle, a fluorescent sign proclaiming their mission—Smart Schools—stood like a sentry amidst a sea of similar cubicles and similar markers.
The students set out to determine if wearable technology could help in evaluating how school principals, teachers and others spend their time and how they interact with their school environments. Their work in summer 2016 was part of Lehigh's Mountaintop program, which gives teams of undergraduate and graduate students from a variety of disciplines the freedom to pursue answers to open-ended questions.
"I was really impressed with how this group grew," said Abby Mahone, a graduate student in Educational Leadership who worked with the team. "The students had to teach themselves new skills to accomplish tasks they had never done before."
The team was adapting existing smart-wearable technology and creating mobile and desktop apps that could potentially be used to study school administrators' daily activities and behaviors. Each student brought different talents to the table—coding, cognitive science, design, business skills.
Mahone and her adviser, Craig Hochbein, assistant professor of Educational Leadership in the College of Education, mentored the students and allowed them to formulate their own ideas.
The project extended Hochbein's earlier work in tracking how principals use their time—and how that might correlate with student behavior/emotional risk. The students saw the recent explosion of biometric data-gathering devices as a golden opportunity to learn how the devices can improve the study and management of time use.
"After reviewing over 100 years of principals' time use research, we discovered that the daily activities of principals have been studied in only four ways—one-time surveys, observations, daily logs or event-sampling methodology," Mahone said. "We saw a huge opportunity to use data-collection technologies to improve the study of principals and created the team to explore it as a possibility. The hope is to have created a kit that principals or teachers can wear all year."
The team hoped the project would provide new insights into the challenges of administrators' jobs.
"We know very little about how they react to their environment right now," said Hochbein. "For example, which classrooms and spaces are principals visiting, and how are they reacting to those settings? Is the behavior of the principal influencing the school setting? Context matters, but it's very difficult to quantify how much it matters." The students took advantage of available smart-wearable technology that already accesses daily activities, to be able to examine heart rate and steps and floors climbed, and they conceived and built an app to track locations
"Context matters, but it's very difficult to quantify how much it matters."
Dr. Craig Hochbein, Professor of Educational Leadership
Students adapted existing smart-wearable technology and created mobile and desktop apps
The students wanted to outfit administrators with devices that would provide biometric data, including time spent walking, standing and sitting. The challenge was to be able to integrate data from multiple sources to paint a detailed, objective picture of how individuals respond physically and mentally, minute by minute, to their surroundings.
The students also developed the mobile and desktop applications that would allow principals to be contacted at random intervals with set questions to determine what they were doing and at "critical points," such as when the technology indicated heart rates were up. More research is needed to determine "critical points," Mahone said.
To find a technology that would yield data without being obtrusive to users, the students tried out a variety of wearable devices on themselves, other Mountaintop students and faculty. They narrowed their choices to three.
"One surprising thing we found was that not all the devices do what they say they will," said bioengineering major Dasom Ko '17. The students learned to be critical of technology while using it for a specific purpose. "Our kit of sensors had to make sense of what we needed to learn from educators," said Karen Huang '17, a cognitive science and design major.
The group also worked on software that integrates data from wearable devices with principals' answers to questions that are pinged to them. Common methods of data collection have used logs or beepers to record how people spend their time, but smart-wearable technology eliminates observer bias to yield more comprehensive data, Hochbein said.
Jordan Alam '19, a computer science and business major, created the mobile app that sends the queries to participants and allows them to input their answers.
"We want to know what the principal was doing [at a particular moment]," he said. Data return is more robust when an event-sampling methodology is used. Multiple forms of data come in at regular intervals—location, heart rate, position (such as standing or sitting). Adding data, such as when the program pings a principal for more information, provides a richer source of information, said Mahone.
Computer engineering student Sudipta Chowdhury '17 wrote the code for software to integrate multiple types of data into a single cohesive format. "We collected all the raw data in a database and had to make sure it could work with different devices so we could analyze it later," he said.
Dan Kramer '16, a computer science student, looked to take advantage of a school's WiFi network to figure out a principal's location at any given time. By grabbing the IDs of WiFi access points, he said, "we can see how much time they spend in a certain room or place."
Mahone said the project has "huge implications for education research."
Story by Manasee Wagh
Illustrations by Jordon Cheung.
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FE Week – Massive subcontracting top-slices finally revealed
Home / news / FE Week – Massive subcontracting top-slices finally revealed
Posted 2nd July 2018
In news, updates
FE Week – Massive subcontracting top-slices finally revealed2018-07-022018-07-02https://eevt.org/wp-content/uploads/2019/06/neweevtlogo.fw_.pngEEVThttps://eevt.org/wp-content/uploads/2019/06/neweevtlogo.fw_.png200px200px
Subcontracting top-slices exceeded £100 million last year, and 28 per cent of prime providers were charging more than 20 percent, FE Week can reveal.
The long-overdue subcontracting figures for 2016/17 have finally been published by the Education and Skills Funding Agency.
FE Week’s analysis of the data has shown that just under a third of primes were charging above the 20-per-cent best-practice threshold announced in March.
This threshold was agreed between the Association of Employment and Learning Providers, Holex and the Collab provider group. This represented 42 per cent of funding.
The Association of Employment and Learning Providers immediately criticised such “unacceptable fees”.
“There are some disgraceful & totally unacceptable fees here,” it tweeted. “@ESFAgov rules should now adopt @AELPUK @collabgrp@HOLEXPolicy 20% cap and hopefully this will feature in final report of current @CommonsEd inquiry”
A total of 407 prime providers charged an average top-slice of 19 per cent, of which 12 charged an average top-slice in excess of 30 per cent.
At 39 per cent, John Ruskin College had the highest average top-slice percentage (see tables below).
The biggest single deal was a £4.7 million (40 per cent) Learndirect top-slice taken from £11.9 million of adult education budget funding delivered by Go Train Limited.
“In reviewing its funding rules, the ESFA shouldn’t try to find a form of words to wheedle out of putting a 20-per-cent cap on management fees,” said AELP boss Mark Dawe. “
“There are some totally unacceptable and disgraceful figures among this data with millions of pounds being denied to frontline training as a result. The signals from the MPs on the select committee suggest that it is ready to take a tough stance when it reports on the apprenticeship reforms and the government must respond immediately.”
Top-slicing describes the level of funding that prime providers charge subcontractors in so-called “management fees”, in order to run training on their behalf.
Concern has mounted in recent years that certain lead providers were charging excessive rates, as an easy way of supplementing their incomes.
The ESFA revealed in April that subcontracting fees and charges are to be reviewed to ensure government funding is being used for “recognised costs”.
“In the coming months, we will be reviewing aspects of the subcontracting funding rules,” it said.
This will include “subcontracting fees and charges, so that we can be assured that our funding is being used for recognised costs”.
Any subsequent changes to subcontracting rules will come into force from August.
Ofsted has also taken a closer interest in subcontracting; it announced in February that it would be conducting two new types of monitoring visit.
The first are monitoring visits to a sample of new apprenticeship providers. The second are monitoring visits to directly funded providers to look specifically at subcontracted provision.
Individual lead providers used to have to publish their annual figures on their websites by the end of November every year.
This changed from 2016/17, when new rules dictated that providers had to inform the ESFA of their figures, which should then be published centrally.
But the agency came in for heavy criticism as November passed without any indication of when the full figures would be revealed for last academic year.
The sector finally got its answer in April, after Gordon Marsden, the shadow skills minister asked, through a written parliamentary question lodged, when the government planned to publish the fees.
The education minister Nadhim Zahawi replied this would be by the end of June – and they were finally published at 4.55pm on June 29.
The ESFA has been approached for comment.
FE Week Exclusive – Secrecy surrounds Ofsted’s decision to declare its 3aaa inspection ‘incomplete’news, updates
FE Week – Learndirect accuse PeoplePlus of ‘dirty tricks’ after entire senior executive team jumps shipnews, updates
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July 17, 2019 TEL: 07522 386235 info@EEVT.org LATEST NEWS:
Home / bids / Newsletter & Bids 4 2018
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Newsletter & Bids 4 20182018-01-282018-01-28https://eevt.org/wp-content/uploads/2019/06/neweevtlogo.fw_.pngEEVThttps://eevt.org/wp-content/uploads/2019/06/bids.jpg200px200px
This week’s newsletter Bids, Grants and Funds come to you in conjunction with our sponsors London Based Manley Summers Training. When we started we used to be called Elephant in a Room, we are now going out to 3,514 organisations in Training and Development. We will be known re the Newsletter as KPI Development Limited trading as 20/20 Vision which will be part of our other company KPI Development Limited. Company Number 01888963 – Incorporated on 22 February 1985.
This week we have some 44 pages of Information, News, Bids, Grants and Funds – use the download link below to get all the details!
Ok Clients that we have worked with or are working with I send out e-mails to update or warn them of items now most weeks I send out no one comes back to say Great or Thanks so this week I sent out with subject line Please Note From 25th of Jad and all of a sudden people e-mail me about that well many thanks but just checking to see if you read the e-mails.
From now on you need to be aware New Identity Checking Guidelines – Disclosure and Barring Service New identity (ID) checking guidelines have been introduced for standard and enhanced disclosure checks. The new guidelines have been running in parallel with previous guidelines since October 2017. However, the previous guidelines now cease to apply and you must use the new version. https://www.gov.uk/government/publications/dbs-identity-checking-guidelines The change is being introduced so that the DBS’s identity checking process is aligned with right to work checks. These state that employers must prevent illegal working in the UK by carrying out document checks on people before employing them to make sure they are allowed to work. If you have any questions about the changes: Contact customerservices@dbs.gsi.gov.uk.
Skills devolution needed to power economy: London and other parts of the country are experiencing severe skills shortages that could hinder economic growth and leave them vulnerable to the impact of Brexit, the All-Party Parliamentary Group for London (APPG for London) argued at Westminster Tuesday. In a specially convened Westminster Hall debate, Catherine West MP set out how the present skills system is unable to meet the growing demand for skilled employees, and made an urgent case for skills devolution to London and other major towns and cities such as Manchester, Leeds and Liverpool. Catherine West said: “I’m asking government to act now to free our skills system so it truly delivers the education and training employers are looking for. In London we want to respond to the needs of our growing population and dynamic business community but our powers are limited.”
Company for sale in Surrey on ROTO and ROTAP has Sub Contracts for Apprentices Year end 2016 the Turnover £212,939.00 with a Gross profit £152,959.00
Net profit (PBT) £66,875 (30%) Please note offers around £140,000.00 only.
The ESFA must be mad but here we go last year, as part of our continued customer experience work, we held interviews and workshops with a range of our customers.
In order to consider feedback and to enhance customer experience, we have set up improvement projects. As we progress these projects we want to talk with you again and will be doing 45 minute telephone interviews from 26 February to 9 March. We are also developing our online reference group and will be using this more to test our plans, ideas and services with you in a quick and simple way. If you are interested in being interviewed or joining the online group please email:josie.appleby@education.gov.uk.
TCHC on our NEETs contract in Northants have been given additional starts. If you are interested or know anyone that would be interested in funding to support young people progress into Education, Employment or Apprenticeships, let me know. Starts between now and end of March for delivery in reg or non reg. Short Pre Apprenticeship programme for 16-18 year olds, or other delivery and support that gets progressions for young people that they want! Email Dominic.wade@tchc.net
Ministry of Justice Commissioning of New Prison Education Contracts
Offender learning and Skills Service (OLASS) contracts come to an end in 2018, making way for a new era of prison governor-led education commissioning. Prisons are being given increasing flexibility and control over education budgets and the ability to commission a wide range of provision.
To stay up to date with announcements on this fast-moving area of reform, sign up to the Ministry of Justice (MoJ) online ‘Sourcing Portal’ here:
https://ministryofjusticecommercial.bravosolution.co.uk/web/login.html
ESFA tell us Employers are already making the switch to standards. As of 18 January 2018, there are 220 standards approved for delivery and employers are already recruiting apprentices onto those standards. In the academic year 2016 to 2017, we saw 24,600 starts on standards, up from 4,300 starts in the previous academic year. At this stage we are confident that standards are being taken up naturally.
Over the course of 2017, we sought feedback on a 4th and 5th batch of apprenticeship pathways and frameworks which our analysis suggested would be well covered by new apprenticeship standards. As a result of that feedback exercise, we are confident that there are a number of frameworks that are covered by standards that have been approved for delivery and are being taken up by employers. Those frameworks can be found on the removal of apprenticeship frameworks page https://lnkd.in/g3wdxyv However, recognising this is a time of significant change for the sector, we will not withdraw any further frameworks until 2020. For further information, refer to the removal of apprenticeship frameworks page https://lnkd.in/g3G27ZA contact the ESFA service desk.
We encourage employers and providers to let IAs know when they think that frameworks have become redundant. You can see which IAs manage which frameworks on the apprenticeship framework delivery list.
QAR 2016 to 2017 – re-release of provisional data for all providers Action
From the feedback received during the Qualification Achievement Rates provisional window, we will be applying some minor changes to the calculations. We will re-publish provisional data for all providers in the coming days and will communicate through both the Hub and the QAR FE connect blog once complete.
Although the changes do not affect the majority of providers, we still advise that you check your data. The BIRST dashboards will not be available while we update the data. We will communicate the outage through the HUB. Please ensure you check for these communications before raising an incident with the service desk.
You have until 5pm on Friday, 2 February to inform us of any further concerns about how we have implemented our published methodology; you cannot request fixes or adjustments to your 2016 to 2017 ILR data. If you have any queries, please contact the service desk.
For specific data queries, please complete the data queries form and email the form to the service desk.
Skills for Care annual conference 2018 Thursday 1 March 2018, ILEC Conference Centre, London Quality people, quality care Recruit, develop and lead for a sustainable service. A national conversation for leaders and managers in social care and health. book now for our national conference to take advantage of our early bird offer of £180+VAT – available until Friday 31 January 2018. Registered manager members can take advantage of a special membership price of £170+VAT.
This day-long conference focuses on the core themes of quality and sustainability. Showcasing best practice and the latest thinking from across the sector, the day is packed with high quality speakers and interactive workshops.
Come along to hear from Andrea Sutcliffe CBE, Chief Inspector of Adult Social Care at the Care Quality Commission (CQC) and Sir Andrew Dilnot CBE, a member of the Green Paper expert advisory group, as well as colleagues from:
The Outstanding Society
Royal College of Occupational Therapists
Wakefield New Models of Care Partnership (Connecting Care) – an NHS England Enhanced Care Home Vanguard.
https://events.skillsforcare.org.uk/skillsforcare/frontend/reg/thome.csp?pageID=84723&_cldee=amxhd3IyNDY2OEBhb2wuY29t&esid=5fe8723e-2301-e811-80d7-005056877cb9&eventID=292&recipientid=contact-82ef475c48aee61194120050568779ad-3e41f082a4a74bf4b84c032fb1cd1e2c&urlid=0&eventID=292&CSPCHD=003001000000tQF1it0kiwsGjNeYhhGoYo_TPfCE13Qc7lnoxU
Pitman Training Group has introduced a community category to its annual Super Achievers awards to recognise the excellent work done by local community groups across the country. Please share with your network to get recognition and the chance of £1,000 reward for your local groups. Nominations are open until 2nd March. Find out more at superachievers.pitman-training.com
Social Firms Wales is delighted to be celebrating the launch of The Bridge Project.
Barod CIC, Social Firms Wales and three partners would like to invite you to the launch of The Bridge Project on the 1 February at TechHub in Swansea. 2pm – 4.30 pm.
There will be a buffet tea and cake and the opportunity to come together as a community to share our experiences and build new friendships for the future. The Bridge project aims to change assumptions about work, business ownership and generating income for people with Learning difficulties. Booking is essential so that we can prepare your place at the table. Email: anne@barod.org to book your place advising of any dietary requirements. We hope to see you there. Please feel free to share this invitation to anyone you think would be interested in attending.
The CPD Standards Office tell us as part of their Campaigning for Excellence in Lifelong Learning tell us everywhere you look, there is great advice on how to run training courses, what to do and how to do it. But no one tells you what not to do – those things that are guaranteed to disappoint or detract from your training.
So here is the top list of 7 things to never do:
Don’t do Monday mornings or Fridays: Obvious really, but it’s amazing how often courses are agreed without checking which day of the week they are on.
Don’t create a 5 day course: Delegates simply won’t put aside a full week to attend your training course. Their boss simply won’t allow it and if they are the boss, they won’t want to take a week out. Condense your 5 days content into 3 days.
Don’t pin your hopes on public courses:You won’t get the take up you are expecting, the training market has moved on – sorry!
Don’t isolate your delegates: Introduce your delegates to each other, get them to network together and create ways they can carry on their conversations after your training. Share their contact details with each other – with their permission.
Don’t set overnight assignments: Rather start the next day with a summary of the previous day. You avoid embarrassing those that didn’t have time or were not staying over, forgot or could not be bothered.
Don’t immortalise one delegate: Constantly referencing one of your delegates because you happen to know they are good in an area is guaranteed to embarrass that person and alienate the rest of your audience.
Don’t overrun: With child care charges of up to £5 per minute for overtime, and on the run busy lives, you’re not making friends by overrunning. Finish 10 minutes early and offer your delegates the chance to join you for an informal coffee or drink.
The conference on Thursday at Coventry had the keynote speaker for this event which was Rt Hon Anne Milton MP – Minister of Skills & Apprenticeships, who discussed the importance of changing the way Apprenticeships are positioned, to be viewed as a mark of quality, and programmes which help people of all ages to achieve big dreams, but mentions that there’s still a long way to go. The question and answer session followed;
Q: In 2020 what will success look like in terms of apprenticeships?
A: We need to ensure the economy has all the skills needed post Brexit, therefore our focus is on skills over knowledge.
Q: Why have starts been so low?
A: Starts are a bit lower than expected because there was initial resistance from employers. Historically employers in general have put low amounts of money into skills development therefore the government was right to push ahead with the levy, simply a ring fenced ‘tax’, to fund the skills that employers need. It takes time to change mind-sets and understand / embed a new system. It has taken employers time to decide / plan what they want to spend their pot of money on. We’re now seeing much better understanding and uptake with the new Standards.
Q: The 20% off-the-job is an arbitrary requirement that emphasizes quantity over quality, which goes against what you have just said. Many learners have numerous opportunities outside of the workplace and outside of normal hours to attend events but at the moment, they cannot be counted or have to be given time-off-in-lieu.
A: We need to find a balance between people not abusing the system and being creative about the ways we can develop these skills. The minister is keen to have us send her suggestions as to how activities outside of the workplace and normal working hours (e.g. attending networking events) can be incorporated into the 20% requirement.
Q: is it right that organisations use this levy to upskill or super-skill their existing staff, particularly in areas like management development, rather than on bringing in new young staff?
A: Upskilling and super-skilling is a good thing for the economy, particularly where it is related to management where it has been demonstrated that better managers drive more effective businesses. The key however, is to get a balance between upskilling existing workers and ensuring there are still the opportunities for the young and those with other needs.
Taking fees for brokering apprenticeship funding is acceptable, according to correspondence from the Skills Funding Agency – as long as payments aren’t made directly from government funding.
The government recently promised to crack down on brokering, which can see subcontractors charged up to five per cent of their total contract funding in commission to be matched with a prime. The AELP now wants this loophole fixed for good, to “ensure the need for brokerage is eliminated”.
Funding rules were changed last year to prevent brokering, and state that “funds in an employer’s digital account or government-employer co-investment must not be used for… specific services not related to the delivery and administration of the apprenticeship”. But the director of a Yorkshire-based firm that openly offers a “subcontracting and brokerage service” on its website has denied any wrongdoing, and has correspondence from the body that became the Education and Skills Funding Agency to prove it. Please see:
https://feweek.co.uk/2018/01/27/government-loophole-allows-apprenticeship-brokerage-to-continue/
A huge college rocked by a string of senior leadership departures that’s currently rated ‘requires improvement’ by Ofsted has been revisited amid portents that standards could be slipping further.
Sheffield College lost its chief executive in November and its governing body chair in January, after both resigned with immediate effect. Its latest accounts, dated December 18, reveal an ongoing decline in achievement rates – particularly among 16- to 18-year-olds. However, the college denied there was any connection between these upheavals and Ofsted’s visit.
https://feweek.co.uk/2018/01/27/ofsted-revisits-grade-three-college-amid-signs-of-falling-standards/
Fake HMRC Text Messages: HMRC halts thousands of scam text messages. As part of Take Five to Stop Fraud Week, the tax authority explains its work to protect customers from text message scammers.
HM Revenue and Customs (HMRC) has stopped thousands of taxpayers from receiving scam text messages, with 90 percent of the most convincing texts now halted before they reach their phones. The milestone comes during Take Five To Stop Fraud Week, with the tax authority working to raise awareness of the tell-tale signs of fraud ahead of the Self Assessment deadline. Fraudsters alleging to be from HMRC send text messages to unsuspecting members of the public. In these messages they will make false claims, such as suggesting they are due a tax rebate. Messages will usually include links to websites that harvest personal information or spread malware. This can in turn lead to identity fraud and the theft of people’s personal savings.
HMRC will never contact customers who are due a tax refund by text message or by email. Reports of this type of fraud have quickly increased in volume over the last few years. People are 9 times more likely to fall for text message scams than other forms like email because they can appear more legitimate, with many texts displaying ‘HMRC’ as the sender, rather than a phone number. HMRC, working with public and private partners, began a pilot in April 2017 to combat these messages.
The new technology identifies fraud texts with ‘tags’ that suggest they are from HMRC and stops them from being delivered. Since the pilot began, there has been a 90% reduction in customer reports around the spoofing of these specific HMRC-related tags on SMS and a five-fold reduction in malicious SMS reports. The initiative has helped reduce reports of these scams from over 5,000 in March 2017, before the new programme was introduced, to fewer than 1,000 in December 2017. This progress comes after similar successes in tackling fraudulent emails and websites. In the last 12 months, HMRC has initiated the removal of 16,000 malicious websites, meaning even if the texts are delivered, the associated phishing website is likely to have been removed. We have made significant progress is cutting down these types of crime, but one of the most effective ways to tackle it is still to help the public spot the tell-tale signs of fraud. HMRC is working with the National Cyber Security Centre to further this work and extend the benefits beyond HMRC customers.
Tip of the week I: 30% discount on sale items at Urban Outfitters. https://www.moneysavingexpert.com/deals/urban-outfitters#deal39390
Tip of the week 2: National Express coach journeys for £5 or less. Details
http://www.nationalexpress.com/cheap-coach-tickets.aspx
Tip of the week 3: Four nights in Rome including flights from £79. Details
https://www.groupon.co.uk/deals/ga-kpx-travel-ltd-598
Keep training from me Steve and all the Team at EEVT, see you also on social media
https://www.linkedin.com/groups/7492941
https://www.facebook.com/EEVTLtd/?fref=ts
https://eevt.org/
https://twitter.com/EevtSteve
Patron of the BAME APPRENTICESHIPS ALLIANCE
http://bameaa.co.uk/
Newsletter & Bids 3 2018bids
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broadside ballads
Drive the cold Winter away: the meaning of a 17th century seasonal song
Ian Pittaway baroque, broadside ballads, Christmas, Come worldling see what paines I here do take, drive the cold Winter away, Playford John, When Phoebus did rest 8th October 2018 1st November 2018 baroque, broadside ballads, Christmas, Come worldling see what paines I here do take, drive the cold Winter away, Playford John, When Phoebus did rest 0 Comment
Drive the cold Winter away is a 17th century broadside ballad which appeals to its readers, singers and listeners to put aside differences, forget old wrongs, and to sing, dance, eat, drink and play together.
As this article outlines, there was good reason for this appeal for a Christmas truce in the 17th century, a time of bitterly cold winters, religious division and civil war. After describing what a 17th century Christmas feast consisted of, we explore the two distinct melodies the song was sung to and outline its long-lived popularity.
The song Shakespeare stole from: a discovery from the 16th century
Ian Pittaway broadside ballads, Romeo and Juliet, Shakespeare William 1st April 2017 9th June 2018 broadside ballads, Shakespeare William 2 Comments
A 16th century broadside ballad recently found in Glamorgan reveals that William Shakespeare stole some of his best-loved and most famous lines from a song he must have known in his youth. The broadside ballad sheet was found folded into the back leaf of a household book, circa 1574. The book itself includes no music. This article includes a video performance of the ballad and an account of the plays in which the Bard’s borrowed lines appear.
One song to the tune of another: early music common practice, 800 years before Humph
Ian Pittaway Bring us in good ale, broadside ballads, Bryng us in good ale, carolling, carols, Fortune my foe, goliards, Greensleeves, I’m sorry I haven’t a clue, Pepys Samuel, Perspice Christicola, salutacyon, Salutation, Sumer is icumen in 22nd November 2016 9th June 2018 Bring us in good ale, broadside ballads, Bryng us in good ale, carolling, carols, Fortune my foe, goliards, Greensleeves, I’m sorry I haven’t a clue, Pepys Samuel, Perspice Christicola, salutacyon, Salutation, Sumer is icumen in 2 Comments
A classic Clue line-up, left to right: Tim Brooke-Taylor, Humphrey Lyttelton, Barry Cryer, Willie Rushton, Graeme Garden.
Listeners to BBC Radio 4’s long-running antidote to panel games, I’m sorry I haven’t a clue, will be familiar with the round, one song to the tune of another. The joke is predicated on us being used to thinking ‘These are the words and this is the tune and they belong together’. The uniting of these separated elements is made funnier by an extreme contrast of styles: the words of Girlfriend In A Coma to the tune of Tiptoe Through The Tulips; the words of A Whiter Shade of Pale to the tune of The Muppet Show; the words of Ugly Duckling to the tune of Harry Nilsson’s Without You.
The stock-in-trade of the show is satire, the programme itself being a satire of panel games. Clue has been going since 1972, chaired for nearly all of that time by late jazz trumpeter, Humphrey Lyttelton, known to cast and listeners as Humph. What Humph and the rest of the panel may not have known is that the principle of one song to the tune of another, with sometimes wildly contrasting words fitted to the same tune, was widely used in early music, the earliest evidence for which stretches back 800 years before even Humph was on air. This article, with illustrative music videos, traces the history of the practice from 16th and 17th century broadside ballads back to medieval carols, to songs with both secular and religious sets of words, and to the iconoclastic musical comedy of the goliards.
The trees they do grow high: a ballad of medieval arranged marriage?
Ian Pittaway broadside ballads, Burns Robert, Carthy Martin, early music, Fletcher John, folk music, harp, Herd David, Johnson James, Lady Mary Ann, Lloyd A. L., Maidment James, mediaeval, medieval, medieval harp, myths, North Countrie Garland, Scots Musical Museum, Shakespeare William, traditional music, Trees they do grow high, Two Noble Kinsmen, Young Laird of Craigs Town 13th February 2016 23rd May 2019 broadside ballads, Burns Robert, Carthy Martin, early music, Fletcher John, harp, Herd David, Johnson James, Lady Mary Ann, Lloyd A. L., Long a-Growing, Maidment James, mediaeval, medieval, medieval harp, North Countrie Garland, Scots Musical Museum, Shakespeare William, Trees they do grow high, Two Noble Kinsmen, Young Laird of Craigs Town 4 Comments
The trees they do grow high is an originally Scottish ballad about an arranged child marriage, also known as The trees they grow so high, My bonny lad is young but he’s growing, Long a-Growing, Daily Growing, Still Growing, The Bonny Boy, and Lady Mary Ann. The song was very popular in the oral tradition in Scotland, England, Ireland, and the U.S.A. from the 18th to the 20th century. Questions about its true age (medieval?), the basis of its story (based on an actual marriage?) and its original author (Robert Burns?) have attracted conjectural claims. This article investigates the shifting narrative of the story over its lifetime and sifts the mere claims from the substantiated evidence.
Baroque music: a brief tour of the extravagant last period of early music
Ian Pittaway Bach Johann Sebastian, baroque, broadside ballads, catch clubs, dance, early instruments, early music, guitar, Lully Jean-Baptiste, lute, Monteverdi Claudio, Playford John 16th July 2015 2nd May 2019 Bach, baroque, broadside ballads, dance, early instruments, early music, Lully, Monteverdi, Playford John 2 Comments
Robert Tournières, Concert, France, 1690s, showing a baroque cello, virginal, singer, violin, and French baroque lute.
The baroque period was a time of ornate decoration, extravagance and the rise of ever larger ensembles, giving rise to opera and the early orchestra. Dance music was as popular as ever, with the renaissance galliard giving way to the baroque sarabande, chaconne, and bourée. Public dancing was briefly in trouble, banned by the Puritans, during which John Playford started a remarkable series of English dance instruction books which outlived Puritan censoriousness. Singing styles among the cultural elite were florid and declamatory, while broadside ballads for the masses continued to be sung and sold in the streets and at public hangings. And, in private, John Playford and his companions met to sing about farting.
Baroque is the final period of early music (medieval, renaissance, baroque) and this is the last of 3 articles charting them. This article includes 15 illustrative videos for the music of Robert Johnson, John Blow, Tobias Hume, Thomas Arne, John Playford, Claudio Monteverdi, Jean-Baptiste Lully, and Johann Sebastian Bach (click blue links).
Music of the renaissance: a whistle-stop tour
Ian Pittaway baroque, broadside ballads, dance, Dowland John, Dunstaple John, early instruments, early music, lute, mediaeval, medieval, renaissance, renaissance dance 15th July 2015 11th June 2018 baroque, broadside ballads, dance, Dowland John, Dunstaple John, early instruments, early music, lute, mediaeval, medieval, renaissance, renaissance dance 0 Comment
The renaissance marked a turning point for European culture. Beginning in Italy in the 14th century, its influence spread across Europe, affecting all aspects of culture, including music. But it was in England that the sound of the renaissance first developed, spreading out to Burgundy, Italy, and then back to England in new forms. The invention of the printing press and the spread of literacy profoundly affected music-making, with musicians in households now able to write down music, use the new printed songbooks of composers such as John Dowland, and sing from broadside ballad sheets sold in the street. The spread of printing and literacy also affects our own knowledge of the period, with surviving instructions for dances and a wealth of music. Includes 14 active links to videos of musical examples, illustrating the text.
Greensleeves: Mythology, History and Music. Part 3 of 3: Music
Ian Pittaway baroque, broadside ballads, early music, Greensleeves, lute, lute manuscripts and books, morris dance, passamezzo antico, Playford John, renaissance, romanesca 8th July 2015 11th June 2018 baroque, broadside ballads, early music, Greensleeves, lute, morris dance, passamezzo antico, Playford John, renaissance, romanesca 6 Comments
The remarkable longevity of a 16th century song and tune
Left to right: Adrien le Roy, French lutenist, one composer of a passamezzo antico; William Kimber, English morris dancer and concertina player, one player of Bacca Pipes; Ralph Vaughan Williams, composer of Fantasia on Greensleeves; John Coltrane, jazz saxophonist, and Nomansland, trance dance band, both performers of Greensleeves.
Greensleeves has captured the imagination of musicians for well over four centuries, testified by innumerous versions. This, the third of three articles about the mythology, history and music of Greensleeves, gives an audio flavour of the remarkable versatility and vitality of the melody and song, an à la carte menu to choose from. We begin with versions of the passamezzo antico and romanesca which are the foundation of Greensleeves; then advance to the song on period instruments; the Playford dance; two Greensleeves morris dances; the Christmas song; Ralph Vaughan Williams’ classical version; then a range of more modern interpretations: folk, blues, bluegrass, country, pop, rock, punk, black metal, jazz, flamenco, disco, trance, dubstep, Vietnamese ballet … and the ice cream van tune.
Greensleeves: Mythology, History and Music. Part 2 of 3: History
Ian Pittaway baroque, broadside ballads, early music, Greensleeves, lute, lute manuscripts and books, Merry Wives of Windsor, morris dance, passamezzo antico, Playford John, renaissance, romanesca, Shakespeare William, Sumer is icumen in 6th July 2015 11th June 2018 baroque, broadside ballads, early music, Greensleeves, lute, morris dance, renaissance, Shakespeare William, Sumer is icumen in 4 Comments
One of the first sources for the tune, in lute tablature as greene sleues in MS. 408/2, an anonymous amateur anthology dated c. 1592–1603. (All images, click for higher resolution.)
Greensleeves is well over four centuries old and is, even now, still going strong. This is a song first published in 1580, its tune used for a wide variety of other 16th and 17th century broadside ballads; used as the basis for virtuoso lute playing; that William Shakespeare used for a sophisticated joke; a tune that John Playford published for dancing to; that morris dancers still jig and kick bottoms to; that has become a Christmas favourite; and that pop singers continue to sing. This is the second of three articles, looking at the song’s mythology, its true history, and video examples of its musical transformations.
Greensleeves: Mythology, History and Music. Part 1 of 3: Mythology
Ian Pittaway Boleyn Anne, broadside ballads, Chappell William, Dowland John, early music, Flood William H. G., Greensleeves, Henry V (play), Henry VIII, lute, lute manuscripts and books, Merry Wives of Windsor, myths, Poulton Diana, renaissance, Shakespeare William, Tudors (TV series), Twelfth Night 3rd July 2015 22nd December 2018 Boleyn Anne, Chappell William, early music, Greensleeves, Henry VIII, lute, myths, Poulton Diana, renaissance, Tudors (TV series) 10 Comments
Greensleeves, composed anonymously in 1580, is a song which has been a magnet for fanciful claims. This article examines the claims that Henry VIII wrote it for Anne Boleyn; that Lady Greensleeves was a loose woman or a prostitute; and that the song has Irish origins. This is the first of three articles, looking at the song’s mythology; its true history; and video examples of its musical transformations.
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New Orleans braces for Tropical Storm Barry
A state of emergency was declared and the National Guard was activated in Louisiana amid the threat of Tropical Storm Barry. Improvements in flood protection were made after Katrina, and are about to be put to the test. Manuel Bojorquez reports from New Orleans.
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Eric Edwards Collected Works
Prolegomena
Category Archives: Chronicles
21/08/2015 · 11:40 am
Irish Chronicles
The Book of Leinster or Lebor Lainech or Leabhar Laighneach. A 12th century medieval Irish manuscript of circa 1160. Formery known as Lebor na Nuachongbala – the Book of Nuachongbail. It comprises early Leinster histories and poetry.
The second best source of Irish myth and legend after the Book of the Dun Cow. Its monastic site = Oughaval. Date and provenance – composite work – principal compiler and scribe = Aed Ua Crimthainn. Abbot of the monastery of Tir-Da-Glas on Shannon.
Manuscript – produced by Aed + pupils – long period of time between 1151 and 1224. Written between 1151 and 1201. Probably complete by 1160’s. The Dinsenchas = lore and history of places – some is 11th century.
Manuscript may have been commissioned by Diamait Mac Murchada – died qq71 – the king of Leinster. Stronghold or dun = Dun Masc, near Oughal = An Nuachongbail. History – whereabouts in 13th century unknown. In 14th century it came to light at Oughval. It may have been kept in the vicarage in between.
The Book of Leinster owes its present name to John O’Donavan, died 1861. Commonly accepted manuscript originally known as the Lebor na Nuachongbala = the Book of Noghoval. Now Oughaval in County Laois.
Manuscript = 187 leaves. As many as 45 leaves lost. Wide-ranging compilation = medieval Irish literature, sagas, and mythology. Therefore = Tain Bo Cuailnge – 8th century version of the Cattle Raid of Cooley. Also contains – Lebor Gabala Erenn – the Book of Invasions + Deirdre story + the grim tale of Boroama.
In addition – contains – metrical Dindshenshas + De excidio Troiae Historia. Plus the Martydom of Tallaght, the Exile of the sons of Usnech, Melodies of Buchet’s House, and the Destruction of Dinn Ris.
The Book of Ballymote = Leabhar Bhaile an Mhota. Named – parish of Ballymote, County Sligo. Compiled circa 1390 to 1391 in Sligo town.
Therefore = late 14th century manuscript of West of Ireland. Contains mainly historical materials produced by the scribes Aolam O Droma + Robertus Mac Sithigh + Tonnalttagh McDonah.
Manuscript purchased 1522 by Aed Og O’Donnell, prince of Tir Conaill. In 162 – given to Trinity College, Dublin. In 1875 – returned to Royal Irish Academy.
Contains one version of the Birth of Cormac + adventures of the Sons of Eochu Muigmedon. Contains motif of – loathly hag transformed to a beautiful woman by the kiss of the young Niall. Contains the key to the Ogham alphabet + Irish version of the Aenid.
Leabhar Gabhala – a narrative recounting the invasions of Ireland. The work – presented as historical fact = based on myth and legend. Material is a source of Irish mythology.
The Book of Fermoy = A mid-15th century manuscript housed in the Royal Irish Academy. Includes the text of Alcrom Tige Da Medar. Fermoy – small town in north-east County Cork, 16 miles east of Mallow.
The Book of Lecan = sometimes called the Great book of Lecan. Distinguished from earlier Yellow Book of Lecan – by the same family of scribes in the same location. This was thus – Leabhar Mor Mhic Fhir Bhisigh Leacain.
Compiled – circa 1400. Manuscript = 600 pages contain genealogical material. Also – a Book of Rights. Lecan is a ruined former castle in the west of County Sligo – 2 miles north of Inishcrone.
The Book of Ui Maine = in Irish the Leabhar Ui Maine or Book of Hy Many. The manuscript includes portions of the Lebor Gabala or Book of Invasions. Also – genealogies, poetry, and family pedigrees.
A small early 14th or 15th codex. Long possessed by descendants pf the Ui Maine sept that in medieval times much of County Galway + some of Roscommon.
Book of Armagh = the Liber Ardmachanus. Includes both Irish and Latin materials. Begun around 807 AD by Feardomnach in Armagh = the seat of the primate of Ireland.
Irish passages amongst earliest possessed. Many Latin passages deal with the life of St. Patrick. An 11th century insertion is about Brian Borama (Boru) describing him as the Emperor of the Irish. Manuscript in Trinity College, Dublin.
The Book of the Dun Cow = Lebor na hUidre. Irish vellum manuscript of 12th century AD. Oldest extant manuscript in Irish. Badly damaged. Held in Royal Irish Academy.
Book of the Dun Cow.
Only 67 leaves remain. Many texts incomplete. Made from the hide of a dun cow by Saint Ciaran of Clonmacnoise. Compiled before 1106 AD.
Contains the Mythological Cycle + the Ulster Cycle + the Voyage of Maelduin. Included is the Tain Bo Cualilnge or Cattle Raid of Cooley. = the oldest epic in ancient European sagas.
Disappeared at Cromwellian conquest and reappeared in 1837 – in a bookshop.
Filed under Chronicles
Welsh Mythology
The Cymry = tribal aristocracy – Brythonic origin. Holding down a serf class – a mixture of Goidels, Brythons, Bronze Age, New Stone Age peoples plus aboriginals. Cymry invaded Wales from north England in 5th century AD. [Graves: White Goddess].
Proinsas mac Cana (1970). Wales – also rich mythological tradition – poorly documented. Complications = end of 12th century.
Earliest surviving tales = Culhwch and Olwen. The Four Branches (11th). Mabinogion – mythology – “…they represent the mere debris of a tradition recast in a loose narrative framework by a talented author who was less interested in preserving sources than in producing an effective piece of literature.” (18).
Debris = anecdotes, allusions, motifs, characters = paradigms. Welsh evidence – linked – Arthurian Cycle.
Welsh – began to emerge from its common British Celtic parent, along with Cornish and Breton > 5th and 6th centuries AD.
In Welsh – early Brythonic myths and legends survived. Welsh material – not as extensive or as old as the Irish. Welsh literature – flourished by 8th century AD.
The oldest book wholly in Welsh = Llyfr Du Caerfyrddin > The Black book of Carmarthen – 13th century AD. Contains – few poems on Myrddin (Merlin) legends. The mythological texts – preserved in two sources = Llyfr Gwyn Rhydderch > White Book of Rhydderch (1300-1325); Llyfr Coch Hergest > Red Book of Hergest (1375-1425). Stories in these two books = the Mabinogi = in English, the Four Branches of the Mabinogion.
The Mabinogi = 11 tales and romances. At least 3 = period earlier than surviving written texts. Culhwch and Olwen = the Quest for Olwen = style of 200 years earlier.
Welsh > wealth of manuscript archival material. E.g. see – A. Breeze, Medieval Welsh Literature (1997). Thesis = several Mabinogi tales – written by a Welsh princess called Gwenllian (killed in battle with the Anglo-Normans, 1136-1137).
Welsh Creation Myth – found in Trioedd Ynys Prydain. Collection of Triads – serve as a mnemonic device. Speaks of Llyon-Llion – Lake of the Waves. Overflows due to Addunc (monster in the lake). Lured from lair by oxen of Hu Gadarn – disposed of. In some versions = killed by Peredur.
However – Addanc – creates overflow thence ‘ deluge.. Cognate with Griva – role in Hindu deluge myth. Nefyed Naf Nefion > builds a ship. In this Dwyvan and wife Dwyvach escape. Nefyed = cognate with Irish Nemed (arrived in Ireland after the deluge).
Addanc = hints of pre-Christian origin. Other sources compare more with ‘The Churning of the Ocean’. Comparative figures compare with Celtic Irish myth = Dhanu, Surabhi (the divine cow), the Tree of Knowledge. Dhanvantari = equivalent of Irish Dian Cecht (the physician of the gods).
The Battle of the Trees = Cad Goddeu. A battle in Brythonic mythology. Fought between Arawn and Amaethon. In myth became – white roebuck, the whelp, and the lapwing – all taken out of Annwn by Amaethon.
The Triads – describe it as one of three favourite battles in Britain. In the Book of Taliesin – a long, disorganised poem = Cad Goddeu. Names trees in order of battle. Also called the Battle of Achren – there was a woman of that name in the battle on the side of Amaethon.
Bran – fought on the side of Arawn. Gwydion sided with his brother Amaethon. Usual interpretation = Gwydion turned trees into warriors. Robert Graves – rearranged this poem + sequence which revealed its ancient meaning. Therefore = not a battle of warriors.
However = a battle of letters of the learned. Thus = symbolism of ancient Celtic Tree Alphabet + mysteries of the druids. Derwydd means oak-seer. Thus a complex magic that is centuries old and centuries hidden.
Druid = one of a class of priests, teachers, divinities, magicians and pre-Celtic religion. Possessed all supernatural and human wisdom. Rank = next to the king. Their decisions final in all matters. Learning never written down. Cult mysteries remained mysteries.
Druids functioned at all rituals of naming, burial, sacrifice. Mentioned in connection with human sacrifices associated with Beltane, Cromm Cruac, and at Tara.
Druids – could cause illness, sleep, death. They could raise storms and mists. Draw the druid’s hedge or airbe druad – a fence around an enemy or army by incantation. As healers – associated with mistletoe and its ritual gathering.
Annwn or Annwfn = the Brythonic mythological otherworld. Conceived as an abyss or as an (not) and dwfn (the world). Located – either on the face of or under the earth, or over, or under the sea. A group of fortified islands out at sea.
Also as a great revolving castle at sea. This land was known as – Land Over Sea, Land Under the Wave or – Caer Sidi = revolving castle. Annwn = land of delight and beauty. Without death or disease. Its lord or king was Arawn. Who made friends with Pwyll the king of Dyfed in the Mabinogion. Arawn owned a magic cauldron. The theft of the bitch, lapwing and roebuck led to the Battle of the Trees.
Shared a magic and inexhaustible mysterious cauldron with other Celtic Elysiums. Taliesin – located Annwn under the earth. Identified it with a magic castle visited by King Arthur.
Gwydion = the son of Don in Brythonic mythology. Brother of Amaethon and Govannon. Incestuous lover of Arianhod and by her father of Dylan and Llew Llaw Gyffes. Gwydion = Brythonic culture hero. Brought the gifts of gods to mankind.
Celtic magician – popularly credited with instituting the first April Fool. Conjured up a vision of armies to trick Arianhod who had cursed him.
Llew Llaw Gyffes = an early Welsh mythical hero. Son of Gwydion by his sister Arianhod. When born he had a triple curse laid on him The curse – deprived him of his name, arms and a wife. The curse was circumvented by Gwydion, Llew met his death at the hands of his wife and her lover. Was changed into an eagle. Gwydion found him and restored his shape.
Llyr = Welsh god of the Underworld. Equivalent of the Irish god Lir. Father of Bran the Blessed + Manawyddan.
Manawyddan = Celtic mythology. Son of Llyr by Penardun and brother of Bran and Branwen. Stepbrother of Evnissyen whose mother was Iweridd. He was the second husband of Rhiannon. Went to Prtderi’s aid and saved him from the spells of Lloyd. Corresponds – Irish Manannan, son of Ler.
Bran = a giant. Brother of Branwen + Manawyddan. Possessed – cauldron with power to bring dead back to life. But – not the power of speech. Wounded – Battle against Irish. Beheaded by other survivors. Legend = head buried in London. Eyes – turned towards France to ward off invaders. Sometimes called Bran the Blessed. Also = Bendigeid Vran.
Mabon = Welsh god of youth. God of hunters and fishermen. Son of earthly mother = Modron. Abducted at three days old. Known – north-western Britain. Cult = extends along Hadrian’s Wall. Known from many Romano-Celtic inscriptions. Syncretised with Romano-Greek god Apollo.
Uther Pendragon = Father of King Arthur – according to Geoffrey of Monmouth + later writers. Nothing in authentic Welsh tradition to link him with Arthur. Or with Merlin. Represented as brother of historic Ambrosius Aurelius. In declining years – defeated Saxons. One version – name means ‘leader of warriors’.
Madoc = Welsh prince. Alleged to have discovered America with a fleet of two ships. Landed – Mobile Bay, Alabama, in 1170. The Madon = extinct Native American tribe – said to be his descendants. Legend = 15th century Welsh poem.
Eric W. Edwards: 23rd April 1944 – 13th July 2017
The Legend of Saint George and the Dragon
The Miners’ Safety Lamp
Ststars on The Celtic Triple Goddess and…
Eden on Ptah-Sokar: Ancient Egyptian D…
MiamiMagus on The Folklore of the Hag and…
Cave Canem: Animals… on The Goddess Coventina of …
Badb – Trish… on Badb, the Irish goddess of…
Fictions and Fragments
Human Science
The Origin and Lore of Fairies and Fairy Land
Badb, the Irish goddess of war.
The Cult of the Mother Goddess
The Art and Influence of Caravaggio
Goddess Worship, Sacred Sexuality, and the Divine Feminine
The Celtic Triple Goddess and the Divine Hag
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Female Shamans and Medicine Women
Romanticism and 'The Raft of the Medusa'.
Shedding Light in Dark Places: the story of the miner’s lamp
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Eric Edwards Collected Works · Miscellaneous Writings & Articles
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Enemy of Troy
Some complacent god in the skies might have mistaken the Paeonians for a line of ants crawling toward their trivial ends. The stalking Achaean scouts knew better. The Paeonians were marching for almost a day at the fastest pace the caravan would sustain on rough terrain. Bags of precious wheat, barley and spelt tottered their way from the southern coast of Troad to the hungry army of king Alexander, son of Priam, of Troy.
Smell of pack animals and human sweat filled the nostrils of Teres and the two scores of Paeonian warriors he led as rearguard. Fine dust, stirred under hooves and dragging feet, stung their eyes and powdered their mouths and skins. Teres’ scalp itched under the bronze helmet. The scorching late summer sun had turned it into a boiling pot sending rivulets of sweat that washed paths on the dirty face down his square jaw. The skin under the stubble was irritated from the constant scratching, its color prominent against the white lumpy scar that ran along his left cheek. All his gear seemed to be specifically designed to obstruct his movement and to irritate him. His short bronze sword sheathed in a leather scabbard flapped annoyingly against his knee and his waterskin kept sliding down the long spear he carried on his shoulder. The splashing sound of the water distracted him and, he thought, gave him urges to piss.
“Dropion, do you hear it?” Teres raised his hand and turned to his cousin and best friend marching next to him.
“What?” Dropion’s thin sharp face tensed.
“My ass sizzling in my leggings.” The short burst of laughter startled a bony mule a few paces ahead.
“I miss the cold weather,” Teres said still smiling and lapsed back into silence. Images of the snow-covered mountains in his faraway home swam into his mind. He remembered how much he liked playing chicken over the frozen river and how he would show off for that girl, Meda, and keep walking long after the others had given up, with the ice crackling underneath.
Teres’ eyes were fixed on the rumps of the pack animals at the end of the caravan. He kept yelling at the caravan drivers to pick up pace. Every time he glanced around, some new grove, a crag, or an overgrown gully would have appeared as if out of nowhere. A sharp whistle from far ahead made him straighten and look over the line of men and animals.
“They’re stopping to wait for us. We must move faster,” he told Dropion and waved to his father.
At the head of the column, lord Pyraechmes watched his son pacing along the path urging the men on. The thick chest of the grey-bearded lord was protected by a hard leather corselet with polished bronze shoulder guards and a broad, ornamented copper belt. He carried a spear and a long sword with a bone handle and a horned crossguard. His half-brother Asteropaeus, leader of the Paeonian tribe of the Almopians, stood next to him. Asteropaeus’ long austere face did not reveal any discomfort under the weight of the heavy bronze-studded leather armor and the sheaf of thin-shafted javelins tucked under the round shield on his back.
The two seasoned warriors waited silently in the stifling heat. Finally Pyraechmes nodded and Asteropaeus turned to give orders to the avant-garde to resume marching. Some distance ahead the narrow track opened into a broad valley. A range of low hills was visible to the northwest and behind it were the Scamander and the trampled fields around Troy.
The convoy was climbing out of a shallow trough when a howling mob swarmed over the edge of the ridge to their right, spears and swords bristling. The salvo of arrows from behind them hammered on shields and armor. The time the Paeonians took to turn around while enduring the shower of arrows was enough for the attackers to cut them from the rest of the convoy. The Paeonian front line held the initial ferocious attack, but Pyraechmes’ men were pushed further down the path. In the midst of the press of men, a band of Achaeans were swinging long heavy swords, pounding and thrusting at the line of shields in front of them with fierce war cries. At one point a sword found a shoulder and slashed a chunk of muscle and fabric off and a heavy round shield dropped. A tall Achaean with a red-plumed helmet and an aura of confidence, wielding a heavy bronze axe, plunged into the front line of the Paeonians. The first vicious blow to the right smashed with a thud against a leather-capped head. A side swing broke the spine of a Paeonian warrior throwing forward the wriggling body and expanding the gap in the Paeonian front. Achaeans spilled through the opening, but soon found themselves surrounded by stinging copper spears and nasty sword slashes from three directions.
When Teres spotted the dark figures of the Achaeans and heard their vicious cries far ahead he yelled at his people to gather around him and prepared to run the length of the convoy. His last orders were drowned by the shrill sound of the Achaean bugle, salpinx, calling from behind them. They swung on their heels and crouched, but no enemy rushed down the path.
“Mydon, scout the path,” Teres shouted. His temples throbbed, waves of hot sweat washed over his body.
The young slender warrior darted toward the piercing demonic call of the salpinx, his figure dwarfed by the bulging rocks on both his sides. All Paeonians held their breaths as they watched Mydon sprinting away. He stopped at the point where the path veered behind the rock wall and carefully peered beyond. An arrow bounced off his helmet and a lightning moment later another one pierced and lodged into his oxhide shield. The warrior ducked and crawled back changing his vantage point. After a few moments, he turned and ran back.
30 thoughts on “Enemy of Troy”
Your knowledge of this part of history is impressive. I would add in more geographical information and chrolology. When did this take place? Exactly where? Why? What is the background of this event? Bags of precious wheat, barley and spelt tottered their way from the southern coast of Troad (where is this?) to the hungry army of king Alexander, son of Priam, of Troy. Wikipedia says, The Troad or Troas /ˈtroʊəs/ is the historical name of the Biga peninsula in the northwestern part of Anatolia, Turkey. I had to look this up. And didn’t know that Troy is in the Troas region of Turkey, which is on the wastern coast. Also, some of the long names, like Asteropaeus, Paeonian, Almopians, Pyraechmess, really slow down the reading. Can you shorten some of these names? And what is the Scamander? Why mention it? Just say behind it were the fields of Troy. A side swing broke the spine of a Paeonian warrior throwing forward the wriggling body and expanding the gap in the Paeonian front, think you can delete the second Paeonian. Again, the wording is so technical. I had to read Wikipedia to understand so much of this. In antiquity, Paeonia /piːˈoʊniə/ (Greek: Παιονία) was the land and kingdom of the Paeonians (Ancient Greek Παίονες). In the Illiad the Paeonians are said to have been allies of the Trojans. During the Persian invasion of Greece the conquered Paeonians as far as the Lake Prasias, including the Paeoplae and Siropaiones, were deported from Paeonia to Asia.[1] Paeonia roughly corresponds to the present-day Republic of Macedonia, as well as a narrow strip of Greek Macedonia on the borders with the Republic of Macedonia, and a small part of south-western Bulgaria. You need to let the reader know that Paeonia is north of Macedonia, which is north of Greece. And that the caravan was heading west toward the Turkish coast from inland. I was so confused by all the historical names and places that were not identified. Please clarify some of this so that someone with no knowledge of this era can read without constantly needing Wikipedia. I think a map of the area should definitely be added.
John G. Dawson says:
Thanks for the interesting historical detail Anonymous, it brings a whole new perspective to the piece. However, I don’t think its absence should be considered a flaw because to try to include it in this opening passage would have overloaded it with information at the expense of pace and drama to get readers hooked into the story. It would be a valid criticism if it remained unrevealed by the end of the first chapter.
Kathy Panzella says:
Your knowledge of this part of history is impressive. in my opinion, the story needs more geographical information and chronology. When did this take place? Exactly where? Why? What is the background of this event? Bags of precious wheat, barley and spelt tottered their way from the southern coast of Troad (where is this?) to the hungry army of king Alexander, son of Priam, of Troy. Wikipedia says, The Troad or Troas /ˈtroʊəs/ is the historical name of the Biga peninsula in the northwestern part of Anatolia, Turkey. I had to look this up. And didn’t know that Troy is in the Troas region of Turkey, which is on the wastern coast. Also, some of the long names, like Asteropaeus, Paeonian, Almopians, Pyraechmess, really slow down the reading. Can you shorten some of these names? And what is the Scamander? Why mention it? Just say behind it were the fields of Troy. A side swing broke the spine of a Paeonian warrior throwing forward the wriggling body and expanding the gap in the Paeonian front, think you can delete the second Paeonian. Again, the wording is so technical. I had to read Wikipedia to understand so much of this. In antiquity, Paeonia /piːˈoʊniə/ (Greek: Παιονία) was the land and kingdom of the Paeonians (Ancient Greek Παίονες). In the Illiad the Paeonians are said to have been allies of the Trojans. During the Persian invasion of Greece the conquered Paeonians as far as the Lake Prasias, including the Paeoplae and Siropaiones, were deported from Paeonia to Asia.[1] Paeonia roughly corresponds to the present-day Republic of Macedonia, as well as a narrow strip of Greek Macedonia on the borders with the Republic of Macedonia, and a small part of south-western Bulgaria. You need to let the reader know that Paeonia is north of Macedonia, which is north of Greece. And that the caravan was heading west toward the Turkish coast from inland. I was so confused by all the historical names and places that were not identified. Please clarify some of this so that someone with no knowledge of this era can read without constantly needing Wikipedia. I think a map of the area should definitely be added.
Alex Zaykov says:
Thanks a lot for the valuable input!
It gives me a few points to think about. Generally, I am trying not to dump too much information, only enough to make sure the reader places the story and the characters in the correct historical context. The fact that you and a couple of other fellow campers (from 2015 camp, too) could not quite figure the time and place is an indication that I need to work on it.
I mention king Alexander, son of Priam. This is the hero of legend that most people know as Paris from the Iliad, the one that eloped with Helen and caused the great Trojan War. His father, Priam is also sort of a famous name from the legend. Now, my problem is that I couldn’t bring myself to use the name Paris. King Paris just sounds so wrong on so many levels. First, it sounds a bit like a female name – Paris Hilton, etc, 🙂 Also, it links, at least in my mind, with the city of Paris, France. That is why I opted for the second name with which Paris was known in the legends – Alexander.
The Paeonians are a little known allied tribe during the Trojan War. Together with the Thracians, they were the only “continental” allies of Troy from across the Straits, and good candidates for a “barbarian” and “northerner” status that I was seeking. It also helps that I currently live in Bulgaria where both tribes used to reside. 🙂
I agree with you that names such as Asteropaeus and Pyraechmes are hard to read, but I do want to keep some of the characters from the legend of the Trojan War and Iliad even though my story departs seriously from the legend. I hope this adds a sort of believability and would make it more interesting for a historical fiction reader.
What I want to achieve in my writing of historical fiction is to have a story that represents the general catastrophe in the ancient world at that time, incl. the Trojan War, through the adventures of a Paeonian mercenary.
What I wonder is:
– Will a historical fiction reader, fan of the period (Trojan War, Bronze age) be able to figure out things better than the average reader?
– Is it correct to pursue the historical fiction readers of the period as a target group for my book? – Is this how a publishing house would view the historical fiction book- as proper or improper for a certain readership group?
Perhaps, these are questions for Ellen, too. 🙂
johnsonofdaw says:
If your story does depart “seriously from the legend” you are in good company – so do most of the retellings of the legend down through the centuries.
No doubt Ellen will answer your question but I can’t see why you shouldn’t target both the general reader and the history buff who would appreciate it on a different level.
Ditto above
gainford says:
I like it, well written, great descriptions and seems very well researched (but then I know little to nothing of Troy, if you made it all up I wouldn’t know but if so it’s well done). I’d like to read more.
Thanks Gainford,
Appreciate your time and feedback!
The story steps on the legend of the Trojan war and Homer’s Iliad. As I mention in another comment, my novel departs seriously in several important aspects: I have tried to represent what a prolonged war at the end of Bronze Age would look like, realistically, based on the sources we have. For example, it is very unlikely that the Greeks besieged Troy for 10 years. The wars were seasonal affairs, fought between spring and autumn and discontinued during winter. The other thing I have attempted is to show the general state of the world in this catastrophic period in history (the fall of the Hittite empire, the attacks of the Sea Peoples, etc.).
Bjorn Schievers says:
Alex, I love antiquity and several civilizations in particular. The Aegean coast of Turkey in the Bronze Age has long remained a mystery to historians. But you may find this site very interesting.
http://luwianstudies.org/
There is also an early medieval book about Troy that supposedly has great descriptions and much more info than any other source: Historia Destructionis Troiae.
By the way I assume the Trojan War lasted ten years, not the actual siege.
Hey Bjorn, a very interesting site, indeed! I was pretty surprised I hadn’t found it before. Then I saw the news that the English version of the site went live in May this year. It’s a pity, the information inside would have certainly influenced the details in my story. Still, I will definitely take time to dig into it and enjoy the information on this wonderful historical period!
Ooohhh, thanks for the link! My books are set few hundred years earlier in the Minoan civilization but I hope to have characters go to Troy in a future book.
Hi Bjorn,
Just remembered to share with you and Maureen the site I was using for information and visual inspiration on the late Bronze Age: http://www.salimbeti.com/micenei/index.htm
The English is at places messy, but the consolidated info is overall quite useful.
I like your style Alex, e.g. your descriptions of selected details – be careful not to overdo them.
To nitpick: Rethink “trivial”. “The Paeonians were”, or “had been”? Down to his square jaw “distracted him. and “gave him urges to piss” – no thought about it. Lord Pyraechmes. Change avant-garde to advance-guard – the french words in English usually denote the metaphorical rather than the literal meaning. A tall Achaean with a red-plumed helmet confidently wielding a heavy bronze axe. The syntax of some sentences seems a little off.
Best wishes with your ambitious project Alex. Do you have a link to your 2015 submission, I’m interested in comparing it?
thanks a lot for the good remarks! I’ve incorporated all of them except “were marching” vs. “had been marching”. Will do that doo, but need to double check something.
Appreciate your notes!
This is amazing! For the most part you write the way I want to be able to write. I taste the dust and I’m laughing along with these men. Your kind of writing is what I’m working towards.
I think for someone who has some notion of Antiquity it’s very clear your story takes place on the west coast of Turkey at the end of the Bronze Age. You even mention Troy by name, so it’s reasonable to expect this will be about the Trojan War or during the last 100 years previous to that. But when you mention Alexander, son of Priam, you totally lock it in. I have some notion of the Paeonians, the Achaeans are part of Greece and I know Troad too. But I think your kind of story best comes with a map before the opening of the novel. Your story is not for the general audience, they don’t care about Troy (or history). Your story is also not for historians (only). It’s for anyone who likes historical and mythological stories, people who watch shows like Spartacus and Rome, and people who like historical novels. They probably won’t know Paris was known by more than one name and they probably don’t know where Troad was. But you explain things well. However, I think your type of story inevitably comes with a map right before the opening.
I think you’re probably giving just enough description to picture everything, but not feel like you’re getting a history or geography lesson. When you mention the Scamander you could say it flows, making it clear for everyone that it’s a river. Other than that I really don’t want a lecture on page one. 😉
So don’t add background info. When you mentioned Alexander it could have confused some people, since that name is usually associated with Alexander The Great. But you do explain you are speaking of the son of Priam of Troy. People who like history will accept this.
I think you nicely set up that they were being ‘stalked’ by Aechean scouts and then later ambushed. I love the great attention for details. But there are so many personal names to keep track of so early on, this is probably your opening’s Achilles heel. No pun intended. I’d avoid names where possible. In paragraph one you can easily say ‘the hungry army of Troy’. Alexander (great choice by the way, I also dislike Paris) and Priam can be mentioned later, they’re not THAT important on page one. At the same time, PLEASE don’t shorten names, we want authenticity here! Instead of that girl Meda you could say he was showing off for THE GIRLS in general. Maybe you want to keep Meda, but they’re just simple ideas to reduce all the names to wrestle through.
I want to agree with Bjorn here–thought it was a great opening scene. I am a big fan (and writer) of ancient history, so I knew where the Scamander was and not too confused by all the names. Seriously, what confused me the most and brought me out of the story was calling Paris Alexander and my mind wandered to try and remember other sons of Priam besides Hector and Paris. Maybe, you can find a non-clunky way to throw in there: aka Paris and perhaps add River after Scamander. (Only if it isn’t info-dumping, otherwise, have someone call him Paris soon after and let him cringe or something so we know it’s him and he hates the name.) 🙂
I would absolutely keep reading and believe it sounds very polished. People with no interest in the time period, etc. are not your target audience because they are unlikely to pick it up over the 1000’s of other books available. People like me who eat up anything set in this time period will keep reading and referring to the accompanying map and character list until we get it all straight.
Cheers to your success!
Maureen, thanks so much for dropping by to offer your useful feedback. I think I will follow your advice on inserting the name Paris early on to make it clear for the reader, then drop it under a legitimate excuse. Thanks again!
Which one is your novel opening? I’d love to check it and comment.
Unfortunately, I didn’t get into the peer critiques, but I was following the boot camp posts for a completed novel I have out with some agents (and the sequel I am working on now). It is called Akrotiri and takes place sometime around 1600 BC on the Minoan island of Thera. One of my MC’s is from Thrace, and I pepper his comments with a few Bulgarian words. If you are looking for a writing pal, let me know and perhaps we can help each other out. Best luck!
Hi Maureen, iI’d love to help you out. There are numerous works on the Thracians, many of them in Bulgarian. Let me know when you need to check or reference something. Also, if you want me to review a draft, I’d be hapy to. My mail is aviolator@yahoo.com
I agree with everything Bjorn says here.
If you want to keep Meda in order to introduce a character of importance you might pick out a distinguishing feature: the girl with the dark angry eyes, with the long black hair, the slave girl, or whatever, then he/we find her name later.
Bjorn, John,
I totally take your point and I am kicking Meda out 😉
Last year, during the boot camp, I took out two more names from a dialogue that no longer exists. The feedback was the same – too many names.
I still have doubts about Alexander, son of Priam, as it fixes the period well. Problem is that the protagonist meets Hector sometime in the second chapter and Alexander is not organically mentioned. Probably I can devise a way for Hector to mention his royal brother.
BTW, Alexander and Asteropaeus are the antagonists of the first third of the book.
Thank you so much for the valuable feedback! I will critique John’s beginning.
Bjorn, if you have an excerpt loaded I can review it too.
Alex, I would love to hear your feedback since you write the way I’d love to write. I’m currently doing my best to edit my opening and would love it if you gave me a review after it’s up. I’ll let you know here when that’s happened. My opening is The Fall Of Arkanar, which is only the working title. Thanks and good luck!
By the way I still remembered the sentence about the crawling ants from last year! 😀
Hi Bjorn, I’ll be happy to critique your your novel beginning. We’ll try tomorrow evening or the day after, latest. I’ve read it and I like it, but I want to provide a meaningful feedback on both the details and the bigger picture.
One last vote re. names Alex. I do think Alexander is wrong for the reason mentioned, it has such a strong association with Alexander the Great that your readers will be confused for seconds or minutes depending on their historical knowledge, and you can do without that distraction. If you don’t like Paris, how about using a description of his rank or demeanor or defining physical feature?
I have to disagree, John. As long as the writer frames which Alexander we’re talking about I think it should be ok. There was more than one Cleopatra or Caesar too.
Hi John, Bjorn, I’ll continue to pound my head over the introduction of Alexander. I think that Maureen offers a good suggestion to allow the name Paris to appear early and then provide a plausible reason to drop it.
Hi Alex, I’m finally ready to get some feedback from you on the newer edit of The Fall Of Arkanar. It’s a struggle crawling my way up to your level of writing. 😉
My story is fantasy, but Arkanar could be loosely compared to Rome while Avarris could be loosely compared to Carthage. So I think it’s potentially a story that might interest you.
Bjorn, I have reviewed your opening. I will be most happy to continue as writing pals after the boot camp. Drop me a mail whenever you want: aviolator@yahoo.com
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Fat Grass Garden Designs
Affordable Gardens
About Fat Grass
Courtyard Gardens
Front gardens
Small suburban gardens
Large suburban gardens
Gardens before and after
Carolyn, Heaton Moor
“Dear Katherine
I just want to say thank you so much. I love the garden. I particularly love that you listened to everything I wanted in the design and the planting and then went away and created a stunning design and a planting scheme that I couldn’t have imagined!
Although the planting was only finished in April, the garden blossomed really quickly and looked fantastic over the summer. The colours are exactly what I wanted except that you suggested some yellow amongst the purples. Everyone who has seen the garden thinks the purple and yellow look stunning together.
You and Greg are a great team. If I was uncertain about anything, both of you were really happy to spend time explaining and talking concerns through with me.
Greg had a lot of ground work to do. Removing the old paving and walling and building the new layout but it all went ahead without any upheaval for me at all. The planting was the same. All done in a day.
I’d recommend you both to anyone and I can’t wait to see how the garden develops next year.
With best wishes”
Fiona & Andy, Old Trafford
“Our garden was an unloved, wild and un-useable area. We chose Katherine following an Internet search (not something we would normally do) to design a garden to suit our requirements. Having produced a design that we were happy with, we commissioned Katherine and her recommended builder, Greg, to carry out the work.
From start to finish we have been absolutely delighted with the approach of Katherine & Greg, and the resulting garden is a complete joy. Somehow from our very wooly brief, Katherine has managed to interpret what we actually wanted, despite us not being too sure ourselves! The result is a garden that far exceeds our expectations. The garden combines tranquility with interesting spaces to sit and relax. It has transformed the garden into an extra room for our home.
I would have absolutely no hesitation in recommending Katherine, and Greg for their professionalism, diligence and, most importantly, their creativity. The whole experience was a pleasure from start to finish.”
Helen, Chorlton
“I have been delighted with the garden that Katherine designed for me. At the back of a mid-terrace house, the former patch of grass had turned largely to moss, and flowering shrubs, manageable 20 years ago when first planted, had become hugely overgrown for the space. I wanted to make much better use of the area as I entered retirement, and after detailed consultation about what I was looking for, Katherine developed a design that was elegant, simple and practical, but has an undoubted “wow” factor! Two circular paved areas are linked together with brick islands and gravel, and several flower beds have been produced, for which Katherine also specified, acquired and planted the flowers and grasses. The end result is a feeling of space and tranquillity, which is easy to maintain, and will prove a powerful selling point whenever the time comes to move on. Katherine has also supplied a useful maintenance plan to keep everything in good order over the years. Special mention should also be made of the contractor Greg who cleared the original space and put in all the stone and brickwork. He and his colleague were always very punctual, considerate and hard-working, and did everything with care and meticulous attention to detail. I really can’t recommend Fatgrass highly enough!”
Helen & Michael, Chorlton
“Dear Katherine, I’ve just got home from Canada and am sitting outside in the evening, absolutely thrilled with the garden, which has come on so much in the last 6 weeks!!! Thanks so much for your inspiring design and planting, we both love it.”
Mike & Sameena, Old Trafford
“We are delighted with our new garden. Katherine did a fabulous job of the design taking into account all are needs and wants. Following this, work was completed to an absolutely excellent standard, everyone we met was very friendly and clearly cared about what they are doing.
In short my wife and I cannot recommend Katherine and the team at Fatgrass highly enough. If you are thinking of having a new garden then you can’t go wrong with the service provided by Fatgrass.”
Catherine, Wilmslow
“I called on Katherine to do a design for my new house in Wilmslow because of the fantastic job she had done in our previous garden in Didsbury. The garden absolutely sold the house and the new owners were delighted with both the design and the planting.”
Maureen, Hyde
“Katherine did a great job on our front garden. She had lots of great ideas but encouraged us to do what we wanted. A neighbour has described the end result as ‘wonderfully graceful’. The service was reliable, fairly priced and there were some good laughs too.”
Nick, Chorlton
“With Fatgrass/Katherine Watson, the garden was the first ‘room’ I had renovated when I moved to Chorlton. It was the best money I’ve ever spent on the house. The garden was designed to meet my expectations exactly; I was consulted at every stage, even down to the shape of the raised beds, the laying of the paving stones and, obviously, the planting scheme. The standard of work was outstanding but most of all I got precisely what I wanted.
I cannot recommend Katherine highly enough – come and have a look at my garden if you like!”
Jane & Dave, Stretford
“We are delighted with the front and back garden that Katherine (Fat Grass) designed and built for us. After an initial visit and chat about what we were hoping to achieve, Katherine came back to us with some design ideas. After some consideration we refined the design between us and then set the date for work to begin!
Now, after one (very hard) winter, we are beginning to see signs of springand there’s no doubt the green shoots are going to surprise us as the year progresses.
We can thoroughly recommend Fat Grass to anyone who wants to improve their outdoor space.”
Adele, Salford
“Katherine and her team came highly recommended to us, from a friend. She listened carefully to our brief, and produced plans that were practical, contemporary and really impressed us. Greg and Bret, the landscapers were a pleasure to have, they worked so hard and produced stunning results.
Our back garden has now been totally transformed from a flat, hotch potch planting mess, to a garden that looks twice the size!
We now have a space that has different areas. Raised engineered brick planters that look amazing, and will make gardening much easier, plus the decking and sandstone paving are a great contrast.
Our Corten steel fire pit has been in constant use, as has the water feature. It is now a perfect space for social gatherings!
Katherine has far exceeded our expectations, and we are absolutely thrilled with every aspect of her service.”
Mary & Helen, Glossop
“Katherine produced our garden plans from the barest of information, she came, sat, saw and listened to our ideas, and amended the plans in line with our feedback. She gave careful thought to the choice of plants that suited our gardening ability-me nil, as well as the growing conditions. The hard landscaping has worked very well and was done to a high standard by Greg. The end result was a joyous thing, and we have really enjoyed seeing how the garden has taken shape. Especially looking forward to seeing how it has grown in in its second full year.”
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L-O-V-E
The Capitol Collectors Series
The World Of Nat King Cole
(Get Your Kicks On) Route 66
After Midnight: The Complete Session
International Nat King Cole
Fly Me to the Moon (24 Bit Remastered)
Golden Masters
Ultimate Nat King Cole
Español And More Vol. 1 (HD Remastered)
The Christmas Song (Expanded Edition)
Early Morning Blues
Nat Sings and George Swings
Cole Espanol (Remastered)
The Beautiful Ballads
Xmas Classics
Songs About Summer
Straighten Up
Tributo a Nat King Cole
Banda Karisma Total
About Nat King Cole
Nat King Cole's great piano work with his jazz trio got overshadowed by his massive vocal success in the 1950s yet each phase of his career offers up so many riches that it proves that the lines between jazz and popular music just don't matter. Cole's easygoing vocals during the '40s matched his piano style charm for charm and his "lock-handed" approach and supple arrangements influenced everyone from Oscar Peterson to Diana Krall. But by the early 1950s, Cole weaned himself from the trio when his orchestrated and Big Band records sold in the millions. Thankfully, Cole's dreamy vocals just kept getting better and better when he didn't have the keyboard to preoccupy him and his concept albums for Capitol rank up there with Frank Sinatra's and Peggy Lee's in complete perfection. "Perfection" may just be the only word that can describe the true King's music. Bebop Digital
Billy Eckstine, Ella Fitzgerald, Erroll Garner, Frank Sinatra, Mel Tormè, Peggy Lee
Nat King Cole's great piano work with his jazz trio got overshadowed by his massive vocal success in the 1950s yet each phase of his career offers up so many riches that it proves that the lines between jazz and popular music just don't matter. Cole's easygoing vocals during the '40s matched his piano style charm for charm and his "lock-handed" approach and supple arrangements influenced everyone from Oscar Peterson to Diana Krall. But by the early 1950s, Cole weaned himself from the trio when his orchestrated and Big Band records sold in the millions. Thankfully, Cole's dreamy vocals just kept getting better and better when he didn't have the keyboard to preoccupy him and his concept albums for Capitol rank up there with Frank Sinatra's and Peggy Lee's in complete perfection. "Perfection" may just be the only word that can describe the true King's music.
Classic Swing
Traditional Jazz/Dixieland
Alt/Punk
Summer Throwback Selection
BigBand Kepler-Gymnasium Freudenstadt
Summer Garden Party Pop
The Summit: Live on Soundstage
Manhattan Transfer
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FIFPro competition: Valdrit’s dream come true
He thought that somebody was having a joke with him. When Valdrit Pllana (from Turku, Finland) was informed by FIFPro that he was the winner of the Predict the FIFA FIFPro World XI competition, he couldn't believe it was true. This Monday in Zurich, standing next to his favorite player, he knew it was all true.
Valdrit won FIFPro's prediction competition, in which 77,000 people worldwide participated. Apparently it was far from easy to predict all players that were chosen in the World XI by their peers, all professional footballers worldwide. Only two participants guessed the eleven names correctly. Valdrit was the lucky one as the draw indicated him to be the prize winner of this year's competition.
That meant, he would meet and greet all players in the 2014 FIFA FIFPro World XI in Zurich. He could bring a friend or a relative too. And as a bonus, Valdrit would make an appearance in the FIFA Ballon d'Or show, asking a question to one of the World XI players on stage.
"My friends at school did not believe me when I informed them", Valdrit remembered. The 17-year old scholar also had a tough time convincing his best friend Ahmed Rahim Nohair Al-Shafei, whom he had invited to be his companion on the trip to Switzerland. "He wanted to see the ticket first, then he would believe me."
That all changed instantly when FIFPro published Valdrit's name on Facebook and confirmed he was the winner of the contest. "Finally they all believed me."
Click on the pictures for a full photo report on FIFPro Flickr
Valdrit will always remember Monday January 12 2015. The World XI Meet and Greet kicked off with a blast as the first player stepping in the room was Lionel Messi, Valdrit's favorite player. "I thought I was dreaming, but I realized it was real when I felt Messi's arm wrapped around my back for the photo. It was great!", Valdrit said. Then smiling: "I will never wash this suit again, because Messi touched it."
Messi was one of eight players putting their arm around Valdrit's waist: Andrés Iniesta, Toni Kroos, Philipp Lahm, Arjen Robben, Ángel Di Maria, Sergio Ramos and Cristiano Ronaldo all stood shoulder to shoulder with Valdrit and his friend.
Unfortunately Manuel Neuer could not make it due to a flight delay, while Brazil's Thiago Silva and David Luiz were not allowed to attend the ceremony by their club Paris Saint-Germain.
To cap off the memorable day, Valdrit appeared during the Ballon d'Or show. With hundreds of millions of football fans in 180 countries worldwide watching, he asked the three World XI strikers (Arjen Robben, Lionel Messi and Cristiano Ronaldo) about their most satisfying goal. "I was a bit nervous, because I knew how many people were watching. But luckily it went well."
His performance did not go unnoticed. When Valdrit switched on his mobile phone after the gala, he received countless friend invitations on his social media account, while the number of followers on his Instagram account exploded. And of course, press were calling. From Finland and Albania, the country where his parents were born.
"I had a fantastic day, the World XI Meet and Greet was great", Valdrit said. "I hope I can win the competition again next year, because I definitely want to come back ... "
FIFPro Africa, CAF sign 5-year agreement...
De Gea, Kante and Mbappe in World 11
World 11: the reserve teams for 2017-18
Rankings: how all 55 players finished
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Home Tags Musketeers (2014)
Tag: Musketeers (2014)
Doctor Who Series 10 and Musketeers Series 3 Confirmed
Colin Davies - Jul 15th, 2015 @ 8:12 pm EDT
The Musketeers 110 “Musketeers Don’t Die Easily” – Season Finale
British Broadcasting Corporation - Aug 22nd, 2014 @ 5:41 pm EDT
The Musketeers 109 “Knight Takes Queen” – Vicious fighting
British Broadcasting Corporation - Aug 12th, 2014 @ 12:27 pm EDT
The Musketeers 108 “The Challenge” – Vicious fighting
British Broadcasting Corporation - Aug 5th, 2014 @ 5:44 pm EDT
The Musketeers 107 “A Rebellious Woman” – Under the skin
The Musketeers 106 “The Exiles” – Loyalty to the throne
British Broadcasting Corporation - Jul 20th, 2014 @ 5:50 am EDT
The Musketeers 105 “The Homecoming” – Proving innocence
The Musketeers 104 “The Good Soldier” – Or deserter?
The Musketeers 103 “Commodities” – Confronting the past
British Broadcasting Corporation - Jul 4th, 2014 @ 4:34 pm EDT
The Musketeers 102 “Sleight of Hand” – Notorious criminal trouble
British Broadcasting Corporation - Jan 19th, 2014 @ 6:55 am EDT
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Mauritius: The Mauritian sega selected by UNESCO to be part of the World heritage of mankind
After the Reunionese Maloya, four years ago, it is the turn of the Mauritian sega to follow along institutional way to try to be engraved in the history of mankind, with the inscription made in Mauritius Sega heritage World immemorial.
Mookhesswur Choonee, Minister of Arts and Culture of Mauritius announced on both cases presented (Sega and Bhojpuri folk songs), during the month of March, the Mauritian sega was selected by UNESCO and the final verdict will be known only in 2014.
The submission package of Sega had been in the hands of a trio of anthropologists who have worked with many sega dancers of Mauritius including Serge Lebrasse and Michel Legris, living memories of Mauritian Sega, as indicated the newspaper L'Express of Mauritius.
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Deutsche Welle with funding from the Federal Foreign Office
Goethe-Institut, financially supported by the Federal Foreign Office within the framework of the German-Arab Transformation Partnership
Key objectives of the measure:
Demand-oriented strengthening of media diversity and freedom of expression in newly emerging democracies with a focus on youth and women
Scope of the measure:
Nature of the measure:
Main feature of the measure:
1 Shababtalk: Arab-language interactive youth talk show, since 2011 2 Women’s radio in Tunisia, since 2013
Results expected through the implementation of the measure:
1 Shababtalk - Giving Arab youth a voice through which they can speak about and discuss socially critical topics in the Arab world such as interreligious tensions, corruption in politics, women’s rights and homosexuality 2 Women’s radio: - Fostering women’s greater participation in social and cultural life through access to a variety of information about their everyday lives and current issues such as women’s rights, elections and political education and awareness-raising work through the one-hour programme “9altelhom osktou”, which is run by Tunisian women in Tunis - Goal of independently continuing the programme after the end of the support period being pursued through the establishment of necessary structures and long-term sponsors
Main conclusions of the evaluation of the measure:
1 Shababtalk - Millions of listeners in Arab countries, especially in Egypt - Programme is produced weekly in Berlin and once per month in a city in the Arab world. It is broadcast via satellite through Arab partner broadcasters in the Arab world and on the Arabic-language website of Deutsche Welle. Since December 2015, the programme has also been broadcast to listeners in Europe. - Shababtalk recognised by the Arab State Broadcasting Union in 2015 as the best Arabic talk show. Moderator Jaafar Abdul Karim honoured as the “Newcomer of the Year” by Medium magazine in 2012. Arabic-language website of Shababtalk: http://sho.rtlink.de/5E4u23cF 2 Women’s radio: Broadcast three times per week since February 2014 through community radio in Tunis. Programmes are made available free of charge to small partner broadcasters in the country’s interior.
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Goal(s) of UNESCO's 2005 Convention
Area(s) of Monitoring
Culture in sustainable development frameworks
International cooperation for sustainable development
Human rights and fundamental freedoms
Artistic freedom
Cultural Domain(s)
Cultural Value Chain
Other measures from this goal
Guatemala | To promote cultural expressions
Andorra | Services pour la diversité culturelle de la Bibliothèque Publique Nationale
Burkina Faso | Soutien à l’élaboration de politiques culturelles par les collectivités territoriales
Armenia | UNESCO Operational Strategy for Youth
Spain | IBERESCENA
Other measures from the same country
Germany | Cultural governance in Germany
Germany | Citizen initiatives for cultural participation in urban society
Germany | Promoting partnerships in the cultural and creative industries in Europe
Germany | Fine arts, performing arts, literature, music and film
Germany | Mobilisation of German civil society for global sustainable development
Other measures from the same region
Canada | AMC - Programme Éducation pour l'emploi CARICOM
Armenia | Cultural cooperation with UNESCO
Andorra | Accord partiel sur les itinéraires culturels du Conseil de l’Europe
Switzerland | Cadre d'action fédéral pour l'intégration de la culture dans les politiques de développement durable
Poland | The "Gaude Polonia" Programme run out by the National Centre for Culture
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Uploading Photo
Glenn Basham
Singer / Songwriter in Lumberton, New Jersey
Drag Me Up & Down
Then click "Save Changes"
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Glenn Basham - Vocals, Playing All Instruments
Love (John Lennon cover) - Glenn Basham Here is my demo of John Lennon's song called "Love". This is another song that I performed at my son's wedding on the beach last month. Hope you enjoy it. Thanks for listening.
How long have you been playing?
I started playing guitar when I was sixteen. A lot of my friends knew how to play, so it was only natural for me to want to learn as well. A friend of mine taught me how to play the chords I needed to know to play House Of The Rising Sun. That was the first song I learned how to play. After that, I learned more on my own.
What was the first concert you ever went to?
The first concert I ever went to was in the Summer of 1976. My friends and I saw Peter Frampton, Gary Wright and Yes.
What gear do you use?
I have a Breedlove 12 string acoustic guitar with a built in pickup, a Yamaha 12 string acoustic guitar and a Gibson 6 string acoustic guitar. I like my Breedlove 12 string the best.
Who was your biggest musical influence growing up?
The Beatles were my biggest influence growing up.When they came out, no one else was like them. They created great melodies and I really liked their harmonies and overall sound. They had a lot of variety as well.
Are you in a band? Have you been in bands?
I've been in bands over the years, but I'm not in one right now. I've been in rock bands, folk groups and oldies bands. Right now, I either play solo or team up with other musicians and friends at places that have open mike nights. I also enjoy writing and performing my own songs.
If you could jam with anyone, who would it be?
I think it would be great to jam with Paul McCartney.
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Love Me Do (Beatles cover) - Glenn Basham and Mark Taylor Mark and I are back with another rendition of a classic Beatles' tune. This time we chose to cover "Love Me Do" which was The Beatles' first single back in 1962. Mark plays guitar and harmonica in our rendition and I do the vocals, bass guitar and drums. Thanks for listening and have a great weekend!
Glenn Basham - Vocals/ bass guitar and drums/collaboration
Lumberton, New Jersey
Sunset Road - Glenn Basham Here is a brand new original song by me called "Sunset Road". The inspiration for this song came to me when I saw a photo of the sun setting over a highway. On the surface, the song seems to be about a vacation of driving down Sunset Road, but it is much more than that. It is really about trying to finally live out one's dreams in the last years of one's life. What do you do with yourself and your life in the so-called golden years? What are one's plans when one retires and one is finally, hopefully free? Come take a journey down "Sunset Road". Thanks for travelling with me.
Glenn Basham - Songwriter/vocals and all instruments
You Can't Do That (Beatles cover) - Glenn Basham and Mark Taylor Glenn and Mark are back with their rendition of another Beatles' tune. This time they are covering a song from The Beatles' "A Hard Day's Night" album. The song is called "You Can't Do That". Mark plays all the instruments on this track. Glenn does all the vocals. Thanks for listening!
Glenn Basham - Vocals/collaboration
It's Only Love (Beatles cover) - Glenn Basham and Mark Taylor Mark and I are back with our rendition of a Beatles classic called "It's Only Love" which was from the American version of The Beatles' Rubber Soul" album. Mark plays all the instruments and I do all the vocals. We hope you enjoy our rendition. Thanks for listening.
Searching - Glenn Basham Here is another song that I pulled from my archives to create a music video for. This tune is an original song of mine called "Searching" that I composed back in 1989 and was part of my collection of songs years ago called "In Search Of The Tree Of Life". All of the songs in this collection fit together as part of a spiritual concept. In 2007, a year after I got my multi track recorder, I finally made decent recordings of all the songs. Thanks for listening and watching.
Glenn Basham - Songwriter/vocals and playing all instruments
Two Trees In A Field - Glenn Basham I was digging through my archives again and I pulled out this original song of mine that I composed back in 1995 called "Two Trees In A Field". This song ended up being a part of my collection of songs called "In Search Of The Tree Of Life" that I put together years ago. I decided that it was time to make a video for this tune. Thanks for watching and listening.
Yeshua - Glenn Basham Here is another original song from my archives called "Yeshua", which is a Hebrew name for Jesus. This song is a "bluesy" spiritual song about Jesus that I composed back in 1988. It was a part of my collection of originals called "In Search Of The Tree Of Life" I created years ago. I decided that now was a good time to make a video for it, considering that Easter is coming soon. I included bits of film footage from "Jesus de Nazareth"_teaser official by Beverly Hills Entertainment and "bbc - miracles of Jesus", both courtesy of Vimeo.com. Happy Spring to everyone and Happy Easter to all those who celebrate it! Thanks for watching and listening.
Seasons Swirling - Glenn Basham Here is another original song from my archives that I recorded back in 2010. I decided that it was time to create a video for it. Here it is. Hope you enjoy it. Thanks for your support!
Dear Prudence (Beatles cover) - Glenn Basham and Mark Taylor Mark and I are back with another rendition of a classic Beatles tune. This time, we did our acoustic rendition of "Dear Prudence" from The Beatles White Album. Mark did all the guitar work and I did all the vocals. Thanks for stopping by! :)
Falling From The Sky - Glenn Basham Here is a song from my archives that I composed back in 1989. It is called "Falling From The Sky" and it is probably one of the strangest songs I ever wrote. The song is about the third of the angels in Heaven and how they rebelled and were cast out of Heaven. This is rather unusual subject matter for me and is a different and dark direction for me as well. Obviously, the tune that I created had to reflect this strangeness as well. Time went on before I created a decent recording of it. In 2007, I finally did this recording of it, which was a year after I received my multi track recorder. I was able to experiment with sound and I tried to create sounds that would express the idea of "falling". Recently, I decided to create this strange video for it. Here is how it turned out.
Another Slice Of Pie - Zapple Pie (Yvalain Debodinance, Mark Taylor and Glenn Basham) Zapple Pie is back with another slice of music. This song was composed by Yvalain with Glenn on vocals, Mark on lead guitar and Yvalain on bass, acoustic guitar, electric guitar and arrangements. The audio was produced by Yvalain and the video was produced by Glenn. From our album "Destination Peace" that is available online on every known digital store and free streaming services such as Spotify or Deezer. Thank you for your support.
Hiking In The Woods - Zapple Pie (Yvalain Debodinance, Mark Taylor and Glenn Basham) Zapple Pie is back with a new song written by Mark Taylor (music) and Yvalain Debodinance (words). Glenn does the vocals, Mark is on lead guitar and Yvalain is on bass, acoustic guitar, percussion and production. Glenn put the video together using photos and photo collages both created by Glenn and Yvalain and also added some hiking film footage of Switzerland, courtesy of Vimeo.com All Zapple Pie original works are available on digital stores and free streaming services. Search "Zapple Pie" on Spotify, Deezer, Amazon Music, Google Play, Apple Music/iTunes, Tidal and more. Thanks for your support.
Don't Wanna Grow Old - Glenn Basham I am back with another song from my archives. I composed and recorded this one back in 2009. I finally decided to make this video for it. The tune has an old fashioned 50s rock and roll vibe. The words are about someone not wanting to grow older and the things that one goes through as they get older and their attempts to stay young. Maybe some of you, like me, can relate to it.
Misty Moon - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with their first song for 2019! "Misty Moon" was composed by Glenn Basham and the song was recorded by Zapple Pie. Mark Taylor plays lead guitar, Glenn does the vocals and Yvalain plays the bass and all other instruments. Yvalain produced the final audio mix and Glenn created the video. We hope you enjoy it. Thanks for stopping by.
Glenn Basham - Songwriter/vocals/collaboration
Tie Dyed Dreams - Glenn Basham Hi everyone! Here is another original from my archives. It's called "Tie-Dyed Dreams" and it is a tribute to Woodstock and the Woodstock generation. It was composed and recorded back in 2011. The 50th anniversary of Woodstock is happening this summer in August, so I was inspired to create this slide show music video for my song. I hope this year's festival is successful filled with peace, love and music.
Nobody Wants To Hear Love Songs Anymore - Glenn Basham Welcome to 2019! I decided to start the year off by diving into my archives and pulling out another original song from my past. Here is a song that I composed and recorded back in 2011. I decided to make a quick video for it so that I could post it. The song is called "Nobody Wants To Hear Love Songs Anymore". I got the idea for the song when I was performing at an "open mike nite" at a local bar. I played a love ballad and someone told me to only play fast songs, because "nobody wants to hear love songs anymore". So I played rockers for the rest of the night. Later, when I got home, I composed this song! I hope that some of you still like love songs! Ha ha! Thanks for listening.
2018 Retrospective - Zapple Pie Glenn, Mark and Yvalain look back on all the music created by Zapple Pie in 2018. The music you hear in this video is an unreleased instrumental version of Glenn's "Making Sparrows Out Of Clay" which features Juha Hintikka as a special guest playing saxophone with the band on all other instruments. Happy New Year to everyone from Zapple Pie!
Glenn Basham - Songwriter/collaboration
Zapple Pie's Christmas Message for 2018 - Zapple Pie It's that time of year again. Time for Zapple Pie's Christmas message for 2018. Mark, Yvalain and Glenn want to thank everyone for listening and supporting Zapple Pie! Merry Christmas and Happy New Year from the three of us! We are looking forward to creating more music in the year ahead! Wishing everyone all the best in 2019!
Glenn Basham - Songwriter/vocals and guitar/collaboration
Childlike Wonder - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with another original Christmas song. This song was composed by Glenn Basham. Mark plays lead guitar, Glenn does the vocals and Yvalain plays guitar, bass, zither, organ synth and percussions. The final audio mix and video were produced by Yvalain. Zapple Pie wishes everyone a Merry Christmas!
Helter Skelter (Beatles cover) - Mark Taylor and Glenn Basham It is the 50th anniversary of The Beatles white album, so to celebrate, Mark and I decided to do our rendition of a song from the white album, Here is our rendition of "Helter Skelter". Mark played all the instruments on this one and I sang all the vocals and created the video. Thanks for listening! Long live the music of The Beatles! :)
In My Life - (Beatles cover) Glenn Basham, Mark Taylor and Kristen Rider Mark and I are back with our rendition of another Beatles song. Kristen joins us with her piano on this one! Have a great day, everyone and thanks for listening!
Glenn Basham - Vocals/bass and drums
Scarecrows - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) We are back with a slice of Halloween pie! This song was composed by Glenn. Glenn does the vocals on this one, Mark plays lead guitar and Yvalain plays bass, acoustic guitars and drums programming. The audio and video were produced by Yvalain. Happy Halloween to everyone from Zapple Pie!
It Happened - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with their latest piece of "cosmic" pie! This song is an original composed by Yvalain! We hope you enjoy our song and "out of this world" video! Thanks for watching!
Do Lidee Do Lida - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with another original song. This one was composed by Yvalain. Glenn did the vocals, Mark played lead guitar and Yvalain did all the rest on this recording. We hope you enjoy it. Thanks for listening! If you have trouble seeing our video, you can use this link : http://dev213.fandalism.com/...
Our Magical Mystery Life - Zapple Pie (Mark Taylor, Yvalain Debodinance and Glenn Basham) Zapple Pie is back with a new original song co-written by all three of us. Mark and Yvalain composed the music and Glenn created the lyrics. We hope you enjoy our latest slice of music all about the gypsy life. Thanks for listening!
Glenn Basham - Lyrics/vocals/collaboration
Girl - (Beatles cover) by Glenn Basham and Mark Taylor Hi everyone! Mark and I are back with another rendition of another Beatles song. Thanks for listening! We hope we passed the audition!
Glenn Basham - Vocals/bass guitar and drums/collaboration
Misty Moon - Glenn Basham and friends Here is an original song that I wrote in 1983 and recorded on a cassette that year. (Remember cassettes? Ha ha!) I thought that the recording was decent, so I decided to make a video for it and post it.. I played guitar and did the vocals on this one. I am joined on this recording with my brother Mark Basham who plays drums and his friend Dennis Brennan who plays vibes. Hope you enjoy this blast from the past!
Glenn Basham - Songwriter/vocals and guitar
Scarecrows - Glenn Basham Here is a rather strange original song that I created back in 2001. I made this recording of it in 2011. This song is a "dark fairy tale" about a flock of crows and an army of scarecrows and the farmer battling over the farmer's cornfield. The song is obviously written from the crows' point of view. Maybe Zapple Pie will do their version of it for Halloween. Have a great summer and stay out of the cornfield, everyone! Ha ha! :)
Something - (Beatles cover) by Glenn Basham and Mark Taylor Mark and I are back with our rendition of "Something" by The Beatles, which was composed by George Harrison. Mark plays both lead and rhythm guitar. Glenn does the vocals and plays bass and drums. Thanks for listening!
One Is Too Many (2018 version) - Zapple Pie (Yvalain Debodinance and Glenn Basham) Here is a repost of a song that Yvalain composed called "One Is Too Many" that is from Zapple Pie's second album called "A Lot of Zapple Pie'. This is a new video that Yvalain produced for our tune. Because of all the things happening in the world right now, we felt that it was an appropriate time for posting our song. I hope that the day will come when everyone has a home in this world where they feel free, safe and at peace. I can only dream. We thank you for listening. Have a happy, peaceful summer,
Jenny Wren - (Paul McCartney cover) by Glenn Basham and Mark Taylor Mark and I are back with our rendition of a Paul McCartney song called "Jenny Wren". Mark plays all the instruments and Glenn does all the vocals. I can picture Mark and I playing and singing this one around a campfire. Too bad that we live so far away from each other. We hope that you enjoy our rendition. Thanks for listening. Have a great day, everyone!
Destination Peace - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with another original song. This one was written by Glenn Basham. Mark plays lead guitar, Yvalain plays acoustic guitar and bass and Glenn does all the vocals on this recording. Production, strings and drums arrangements are by Yvalain. The concept for this song came to Glenn in a dream. Hopefully someday, world peace will become a reality. Thanks for listening to our song of peace.
Soul Colors - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with another original tune. This song was composed by Yvalain with Mark on lead guitar, Glenn on all vocals and Yvalain on bass, guitars, keyboards and drums arrangement. The final mix and video was produced by Yvalain! We hope you enjoy this colorful production! Thanks for listening!
And I Love Her - (Beatles cover) by Glenn Basham and Mark Taylor I asked Mark if he would like to collaborate with me and do our rendition of this Beatles tune and he agreed. This is our cover of "And I Love Her". Mark plays lead and rhythm guitar and Glenn does the vocals, plays bass guitar and percussion. Mark and I are big Beatles fans! We hope you enjoy our rendition of this classic tune!
Glenn Basham - Vocals/bass guitar and percussion/collaboration
Little Red Bird - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with another original song. This one was composed by Glenn Basham with Glenn on all vocals, Mark on lead guitar and Yvalain on bass, guitar and orchestration. The audio and video production is by Yvalain. We hope you enjoy it! Have a zappley fantastic day!
Destination Peace - Glenn Basham "Destination Peace" is a new song that I have composed that was inspired by a dream that I recently had. In the dream, me and my two friends (Yvalain Debodinance and Mark Taylor) were hiking on foot for many miles, trying to find a special place that we had heard about where everyone is free and where everyone takes care of each other and the environment. It is basically "heaven on earth". As the dream continues, the sun is starting to go down and we finally see this beautiful city on the horizon, where the only flag flown is the flag of peace. At that point I woke up and realized that it was a great concept for a song! The verses describe the dream. The chorus is a request to everyone to do their part to bring about peace in this troubled world. Hopefully, someday peace can exist everywhere on the earth. I know it's a dream, but I am a dreamer. The video contains photos, photo collages that I have made and also some film footage from two films, courtesy of Vimeo.com. The films are : "Helvetia:The Great Switzerland" by Peter R. and "Zu nachtschlafender Zyt / Bern Hyperlapsed" by stadium-punctum. I dedicate this song and video to my two bandmates from our group "Zapple Pie", Mark Taylor and Yvalain Debodinance. I hope that you enjoy my song of peace.
Mr Regular - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with an original rocker. This song was composed by Yvalain. Mark plays lead guitar, Glenn is on vocals and Yvalain plays guitar, bass guitar and drums arrangement. Yvalain also did the audio and video production. We hope you enjoy our latest slice of music! Thanks for listening!
Centerfield (John Fogerty cover) - Glenn Basham and Mark Taylor Mark and I decided to do our rendition of John Fogerty's tune called "Centerfield". Mark plays lead guitar and bass guitar. Glenn plays drums, bass guitar and does the vocals. The video contains photo collages, photos and cartoon images. The video also contains various film clips courtesy of vimeo.com including : "Baseball Sounds" by Scott Duffy, "SSF Baseball" by Featherwax, "Major League Baseball - Stadiums" by Pete Harvey, "Los Angeles Dodgers : It's Time for Dodger Baseball" by Aaron James and "Major League Baseball 2017-Intro" by Onesal. We hope you enjoy our tribute to baseball! :)
Glenn Basham - Vocals/ drums and bass guitar/collaboration
Peace Canoe (2018 version) - Glenn Basham I went back into my archives and pulled out this original song of mine that I composed in 2003. I decided to rewrite some of the lyrics and make it more of a romantic song. Next, I made a new recording of the song. So here it is, my new 2018 version. Take a step into my "Peace Canoe"!
Every Color of the Rainbow - Glenn Basham I was going into my archives again and recently pulled out this original of mine from 1996. Recently, I rewrote some of the lyrics to this song. I pulled out a 2009 recording of it and recorded the vocal lyrical changes, keeping the instrumental background the same, instead of recording everything all over again from scratch. So here is my 2018 updated version of my original song called "Every Color of the Rainbow". Thanks for listening. Have a great weekend, everyone!
My Country Girl - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Howdy, everyone! Zapple Pie is back with a love song for Valentine's Day! The music was composed by Yvalain and the words were written by Glenn. Mark plays harmonica and lead guitar, Glenn does all the vocals and Yvalain plays acoustic guitars, bass and production. Thanks for listening! Happy Valentine's Day! :)
Glenn Basham - Vocals/lyrics
Dreams (Can Take You There) - Glenn Basham Here is another song from my archives. I wrote and recorded this original of mine back in 2014. I enjoy making videos of songs of my past and posting them! Each individual song is like a piece of me! Thanks for listening. Have a great day, everyone! :)
Wooden Nickel - Glenn Basham I decided to go back into my archives. Here is a song that I wrote back in 1982 called "Wooden Nickel". The inspiration for this song came from simply obtaining a wooden nickel. I thought it was kind of cool, even though I knew it wasn't worth anything. The next thing I knew I was composing this song! It's funny where inspiration comes from sometimes! This particular recording of the song was done in 2009. Recently, I decided to make a slide show music video for it, so I could post it. As far as the melody and music go, I was inspired by The Beatles. The inspiration for the loud and overly emphasized drums came from listening to songs like "I Dig Love" by George Harrison, which was on his "All Things Must Pass" album. While making the video, I also included some photos of myself from the early and mid eighties. It was a fun trip down memory lane!
Star of Wonder - Glenn Basham I know that Christmas is over, but I wanted to play a song by my tree, before it came down. That's right, my tree was still up! I have a strange tradition of playing a song by the Christmas tree every year before it comes down! I could not sing during the holidays, because I developed a bad cold and lost my voice at Christmas. I am finally getting my voice back, even though it's not 100 percent yet. I knew I needed to film this quickly, because the tree is coming down! Back in 1987 at Christmas time, I was playing around with some chords that I like and for some strange reason, I started to sing the words of "We Three Kings of Orient Are" to my own melody. I called my version "Star of Wonder". I revisited that song recently. I kept the first verse and chorus of "We Three Kings", but wrote words of my own for the last two verses. The original "We Three Kings" was written in 1857 by John Henry Hopkins Jr.. My version called "Star of Wonder" was filmed live. The only thing I did was add some visual effects to the film, just for fun. Hope you enjoy my version. Maybe someday I will record a studio version. Okay folks, now it is time to move on to Valentine's Day! Ha ha!
Glenn Basham - Guitar/vocals/songwriter
Keep Holding On - Glenn Basham Here is my first post for 2018. "Keep Holding On" is an original of mine that I wrote and recorded back in 2014. I recently decided to make a slide show music video for it. Happy 2018, everyone! Thanks for listening!
Zapple Pie's 2017 Christmas Message - Zapple Pie It's time for Zapple Pie's annual Christmas message! This is our audio video Christmas card for everyone! This is our last post for 2017. We are looking forward to creating more music in 2018. We are grateful for everyone's support during 2017. Have a Merry Christmas and a Happy New Year! :)
Glenn Basham - Vocals/guitar
If I Were Santa - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with a new original Christmas song. Yvalain composed the music and Glenn wrote the lyrics. Mark added some great lead guitar work and harmonica, while Glenn provided the vocals and Yvalain supplied all the other instruments. We hope that you enjoy our slice of Christmas pie. Merry Christmas to all from Zapple Pie!
Glenn Basham - Vocals/lyrics/collaboration
The Answer Is Love - Glenn Basham I went back into my archives, which I do every now and then, to post an original from my past. Here is a short little song about love that I wrote in 2014. Love is certainly something that we could use more of in this world today. So, I quickly put this slide show music video together for this tune the other day. Hope you enjoy it. Happy listening.
Pieces - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with a promo video for our new album called "Pieces of Zapple Pie". The video contains samples of the 15 songs that are on the album with some rare film footage of the group. It is like a visual musical scrapbook of Zapple Pie of all that we have done during the year. We hope that you enjoy it!
That Look of Love - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with another original tune. This song was composed by Glenn with Mark on lead guitar, Glenn on vocals and Yvalain on guitar, bass and programing of electric piano and production. The drums were created using Band in a Box's real drum samples. This song is from our new album "Pieces of Zapple Pie" available in all known online music stores. We hope you enjoy it. Thanks for listening.
My Moon Shadow - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back with an original Halloween song composed by Glenn Basham. Mark Taylor plays lead guitar, Glenn does all the vocals and Yvalain plays bass, guitar, strings and drums. Zapple Pie wishes everyone a Happy Halloween! We hope you enjoy this slice of Halloween pie!
Hello, My Love - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with a new original song with music composed by Yvalain and words written by Glenn. Mark plays lead guitar, Glenn does the vocals and Yvalain plays guitar, bass and did the audio and video production. Come to the studio and listen to us perform! Have a great day everyone!
Glenn Basham - Vocals and lyrics/collaboration
Whistling In The Wind - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with another original. Yvalain composed the music and Glenn created the lyrics for this song. Mark plays lead guitar, Glenn sings all the vocals and Yvalain plays bass, and acoustic guitar. Yvalain is also the mystery whistler! The drums were created with Band In A Box. The background video was borrowed from vimeo.com called "Muse of the Wind".by Fiev. An overall production by Yvalain. Thanks for tuning in!
Home - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with another original song. This particular song was composed by Yvalain and has an important message about the need for all of us to have a place we call "home". This music video is our first experience with using a "green screen" which allows us many creative possibilities! We hope you enjoy our newest song and video. Thanks for watching.
Silent Raindrops - Zapple Pie (Mark Taylor, Glenn Basham and Yvalain Debodinance) Zapple Pie is back with another original tune. Mark had composed an instrumental. Yvalain added his magical touch to it, adding strings and glockenspiel. Then, Glenn wrote lyrics for it and added a vocal melody. Yvalain created a final audio mix and produced the video. We hope you enjoy our creation! Thanks for listening! :)
Glenn Basham - Songwriter/vocals and lyrics/collaboration
Branches on the Vine - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is back! Here is our new original composed and sung by Glenn Basham with Mark Taylor on lead guitar and Yvalain Debodinance on bass, guitars and drums and synths programming. The final audio mix and video production was done by Yvalain. We hope you enjoy it. Thanks for listening.
For All Seasons - Glenn Basham Here is an original song that I wrote back in 1997 called "For All Seasons". It is the last song on my CD called "Seasons of the Heart" that I recorded in 2010. I recently decided to make a video for this song. Hope you enjoy it and I hope you are enjoying whatever season of your life you are in right now. Thanks for listening.
There's A Magic All Around You - Glenn Basham Here is an original song that I wrote and recorded in 2014. I decided to make a music video for it using home movies of 4th of July fireworks at Atlantic City, New Jersey back in 2011. Hope you enjoy the fireworks and the song! Have a great weekend!
Summer Sun - Glenn Basham Here is an original song of mine that I created back in 1993.This particular recording of it is from 2010 and I finally made a video for it two days ago, using home videos from recent years at the beach. This song is from my collection of my original songs called "Seasons of the Heart". Hope you enjoy it. Thanks for listening. Have a happy summer, everyone! :)
Susanne - Glenn Basham "Susanne" is one of my earliest originals going way back! I was influenced by early Beatle tunes like "love Me Do". So, I purposely wrote very basic lyrics with lots of oo-woos and oh-wohs. It is definitely not real deep and may sound a little dated now, but I still like it. I like the melody and groove, so I decided to post it. The video consists of kaleidoscope images created by Xxzzxcut and Raluca Buta, courtesy of Vimeo, com, Hope you enjoy it. Thanks for watching.
Carefree Sparrow (Studio Version) - Glenn Basham Here is a song that I created back in 1992. I recently did a multi track recording of it and made a video for it last weekend. The idea for the song came to me one day as I was watching a bird through a window as I was sitting in my parked car during my lunch break. Thanks for listening. May you have a carefree day!
We Were Going To Change The World - Glenn Basham This is an original song that I created and recorded back in 2014. I finally got around to making a music video for it. If you are from the "baby boomer generation" like me, you might be able to relate to the words! Ha ha! Thanks for listening.
Glenn Basham - Songwriter/playing everything
Life Swings To A Pendulum Beat / Grandfather Clock - Glenn Basham Here are a couple of songs that I created back in 1978 and recorded in 2009. I made the video and posted "Grandfather Clock" in the past, but I made the video for "Life Swings To A Pendulum Beat" last weekend. I thought that the two songs went well together, so here they are! Thanks for listening!
Snow In The Desert - Glenn Basham I have been having fun making music videos for original songs I have written in my past. Here is a song I wrote back in 1996 called "Snow In The Desert". Have a great day, everyone! :)
Boardwalk Blues - Glenn Basham Here is an old original tune that I wrote back in 1976. It is one of my earliest songs. It is called "Boardwalk Blues". This particular recording of it was done in 2009. I felt like posting something, so I gathered together some home movie footage I had and quickly made this music video for Blues Thursday! Thanks for listening!
Like A Movie - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with a new tune. This song was composed by Yvalain and the words were written by Glenn. On this recording, Mark plays lead guitar, Glenn does the vocals and Yvalain plays acoustic and electric guitars, bass and drums programming. Thanks for listening!
Spirit's Guitar - Zapple Pie (Mark Taylor, Glenn Basham and Yvalain Debodinance) Zapple Pie is back with their newest tune. The instrumental music was written by Mark Taylor. The vocal melody and words were created by Glenn Basham. On this recording, Mark plays guitar, Glenn is on vocals and Yvalain is on guitar and arrangements. Thanks for listening!
Glenn Basham - Vocals/songwriter/collaboration
Hand in Hand - Zapple Pie ( Yvalain Debodinance, Glenn Basham and Mark Taylor ) Here is a new romantic vaudeville tune by Zapple Pie, just in time for Valentine's Day! The music was composed by Yvalain and the words were written by Glenn. Mark plays lead guitar, Yvalain is on ukulele, guitar, bass and strings arrangement and Glenn sings all the vocals. We hope you enjoy it. Happy Hearts Day, everyone! :)
Making Sparrows Out Of Clay - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Here is a song I wrote back in 2009. My friends, Yvalain and Mark, heard it and liked it, so we decided to record Zapple Pie's version of it. Mark Taylor plays lead guitar on this version. Yvalain plays bass, guitar, arrangement (drums and mellotron) and production. I sang the lead vocal and all the harmony vocals. We hope you enjoy it. Thanks for listening!
Speaking Words of Wisdom - Glenn Basham Here is a song that I composed last year in January of 2016. I was busy trying out a new guitar pedal that I received from that Christmas in 2015, when I created the tune. The lyrics contain many famous quotes by John Lennon. This song is my tribute to John. The title of the song, "Speaking Words Of Wisdom", happens to be a phrase contained in a line of a famous song written by Paul McCartney called "Let It Be". Happy New Year, everyone! Thanks for listening.
Zapple Pie's Second Christmas Message (2016) - Zapple Pie Here is Zapple Pie's video Christmas card for 2016. Glenn, Yvalain and Mark wish everyone a very Merry Christmas and a Happy New Year! Thanks for supporting us throughout all of 2016!
Winter Holiday - Zapple Pie ( Glenn Basham, Yvalain Debodinance and Mark Taylor ) Here is a new Zapple Pie song written and composed by Glenn with Glenn on all vocals, Mark on lead guitar and Yvalain on guitar, bass, drums and synth programming. Zapple Pie wishes everyone a Merry Christmas, a wonderful winter holiday and a Happy New Year! Thanks for listening!
Glenn Basham - Songwriter/vocals
Hey Noah - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Here is a new song by Zapple Pie. Yvalain composed the music and Glenn wrote the lyrics. Glenn sang all the vocals, Mark played lead guitar and Yvalain played guitar, bass guitar and arrangements. We hope you enjoy our new slice of music!
One With Nature - Zapple Pie (Glenn Basham, Mark Taylor and Yvalain Debodinance) Here is a new original by the three of us. Glenn took an original instrumental composed by Mark and created a vocal melody for it and lyrics. Glenn added vocals to it. Next, it was presented to Yvalain, who added more guitar, bass guitar and synth to it. Yvalain made the final mix, resulting in this new song by Zapple Pie. We hope you enjoy it. Thanks for listening!
Desiree (Halloween 2016 Remix) - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Happy Halloween from Zapple Pie!
God Only Knows (Brian Wilson and Tony Asher cover) - Glenn Basham I have always wanted to sing "God Only Knows" which is a brilliant song written and composed by Brian Wilson and Tony Asher. It is my favorite song by The Beach Boys. Just for fun, I decided to sing it A Cappella. To make up for the missing instruments and orchestration in the background, I substituted vocals instead, which made it a rather strange recording, but a fun challenge! I hope you have fun listening as well!
Glenn Basham - Vocals ( a cappella)
Travel With Me - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Here is a new slice of original music by Zapple Pie with music and words created by Glenn. On this recording, Mark plays lead guitar, Yvalain plays bass guitar, rhythm guitar and production and Glenn does the vocals and plays acoustic guitar. Thanks for listening!
You Know I Need You - Zapple Pie (Yvalain Debodinance, Glenn Basham and Mark Taylor) Zapple Pie is back with a new original with music composed by Yvalain and words created by Glenn. Mark Taylor plays lead guitar, Glenn is on vocals and Yvalain is on bass, rhythm and lead guitar. Final audio mix and video is produced by Yvalain. Thanks for listening.
Oh, My Love (John Lennon cover) - Glenn Basham I felt like posting something live today, nothing fancy, just me and my guitar. This is me around the campfire, less than two weeks ago, performing a John Lennon song. The crickets and insects were very loud that evening! Maybe they were trying to sing with me! Ha ha! Thanks for listening.
Glenn Basham - Guitar/vocals
Travel With Me - Glenn Basham Here is a demo of a new original song I created last month. Hope you enjoy it. Thanks for listening!
A Touch Of Rainbow With The Sun - Glenn Basham I created this song for my son Adam and his wife Juli. It was my gift for them for their wedding. I decided to create it, when they asked me to perform at their wedding, which took place on the beach two weeks ago. I got the idea for the song, when I opened the door one day and saw a partial rainbow around the sun. It inspired me! I played the song at the wedding, which turned out to be a beautiful event! May Adam and Juli have a wonderful life together !
Glenn Basham - Songwriter/vocals/playing all instruments
Ovation Highway (Zapple Pie album promo) - Zapple Pie The group prepared this special compilation of the songs that compose their new album. We hope that our listeners will visit the links here below to enjoy the whole set of songs. there are 2 links: - https://www.jamendo.com/album/158961/ovation-highway for free listen and download, you can also leave comments there, - https://yvalain.bandcamp.com/album/ovation-highway to enjoy this album in High Definition. Thank you for all your great support.
Glenn Basham - Singer songwriter/collaboration
Our Love - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Here is an original love s... read moreong by Zapple Pie, written and composed by Yvalain Debodinance with Glenn Basham on all vocals, Mark Taylor on solo lead guitar and Yvalain on acoustic and electric guitars, bass and orchestration. We dedicate this song to our wives. Hope you enjoy this love song. Thanks for listening! This is the last extract of our 3rd album "Ovation Highway" available for free on: https://www.jamendo.com/album/158961/ovation-highway and on high definition on: https://yvalain.bandcamp.com/album/ovation-highway
Playing With Spirits - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) "Playing With Spirits" is an original by Zapple Pie, written and composed by Glenn Basham with Glenn Basham on vocals and acoustic guitar, Mark Taylor on lead guitar and Yvalain on bass and orchestration. An audio and video production by Yvalain. Contains some video footage from vimeo.com. Many thanks to the authors. Hope you enjoy our "haunted" tune! Thanks for stopping by!
Peace Flowers / Remember The Flower Children - Glenn Basham I wrote "Remember The Flower Children" back in 1982, but was not satisfied with it. Finally, in 2011, I decided to change the chorus in the song and was much happier with the song. Next, I wrote a short song called "Peace Flowers", which I decided to use as an intro for "Remember The Flower Children". I recorded these two songs in 2011. I also recorded a CD in 2011, which I titled "Peace Flowers". Hope you like my tribute to the flower children of the sixties! Thanks for listening!
Ovation Highway - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Here is Zapple Pie's newest tune called "Ovation Highway" which was composed by all three members of the group. Mark provided the main theme, Yvalain added the bridge and the ending and Glenn created the vocal melody and wrote the lyrics. On this recording, Mark plays lead guitar, Glenn does all the vocals and Yvalain plays acoustic guitar, bass, drums and synths programming. This song is from our third Zapple Pie album called "Ovation Highway". Thanks for cruising down the road with us!
Delighted At Work - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Zapple Pie is delighted to share with everyone their new original called "Delighted At Work" which was written and composed by Yvalain. Glenn sings all the delightful vocals, Mark plays all the delightful guitar solos and Yvalain plays the delightful bass, guitars and synths. We hope you enjoy watching this zany side of Zapple Pie!
Harlequin - Zapple Pie (Glenn Basham, Yvalain Debodinance and Mark Taylor) Welcome to Zapple Pie's Harlequin Masquerade Ball! The music for "Harlequin" was composed by Yvalain. The words were written by Glenn Basham. This recording includes Mark Taylor on guitar solo and riffs, Glenn Basham on all vocals and Yvalain on acoustic and electric guitars, bass, ukulele and arrangements (mellotron, drums and other SFX). The video was produced by Yvalain, which contains film footage of all the members of Zapple Pie plus some pictures borrowed from vimeo.com (many thanks to the authors). Thanks for attending! We hope that everyone has a splendid time! :)
Sighs and Hope - Zapple Pie ( Glenn Basham, Yvalain Debodinance and Mark Taylor) Here is a new original by Zapple Pie, composed by Yvalain with Glenn Basham on vocals, Mark Taylor on lead guitar and Yvalain on guitars, bass and arrangements (drums and mellotron). We hope you enjoy it. Thanks for listening!
Making Sparrows Out Of Clay - Glenn Basham Here is a song that I created and recorded back in March of 2009. Yesterday, I finally got around to making a music video for it. I thought it would be a good song to post for the beginning of spring.. I hope you like it. Thanks for listening!
Glenn Basham - Songwriter/all instruments and vocals
Views 2,380,740
Props 196,451
Location Lumberton, New Jersey
Instruments Songwriter, Vocals, Guitar
Genres Pop, Rock, Folk, Classic Rock, Oldies
Influences John Lennon, The Who , Simon and Garfunkle , Creedence Clearwater Revival , The Doors , The Beatles, British Invasion groups , The Rolling Stones , The Moody Blues, The Beach Boys, The Privileged Few Band, Paul McCartney
Private message to Glenn Basham
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Ghana among top places to visit in 2019 – CNN
By Thomas Moore January 4, 2019 No Comments
Ghana has been listed fourth among 19 places to visit in 2019, according CNN Travel.
The West African nation made the list because of its economic success and political stability.
Ghana is hoping to trade up its tourism status for 2019 as it marks 400 years since the first enslaved Africans arrived in North America with a campaign dubbed “Year of Return” targeting the African diaspora whose ancestors were victims of the brutal slave trade of centuries gone by, the report by CNN Travel said.
The report lists the Cape Coast Castle as one of the many historic coastal forts which is evident of the slave trade in Ghana.
“For all the sobriety of this anniversary, what also awaits visitors to Ghana is the warm, intoxicating embrace of a country completely at ease with its identity rushing headlong towards a bright future.
“The capital, Accra, crackles with the dynamism of a city on the upswing, with a nightlife scene to match.
For those wanting to escape its relentless excitement, Ghana’s 335-mile coastline boasts empty surfing spots like Cape Three Points, while its many protected wildlife zones, including Mole National Park, are home to wild elephants, Nolan warthogs and spotted hyenas,” it added.
Among the places to visit in 2019, according to CNN Travel are Christchurch, New Zealand; Egypt and Fukuoka, Japan.
Other places are Grand Canyon, United States; Hawaii Island, United States; The Hebrides, Scotland, UK; Jaffa, Israel; Kerala, India and Liechtenstein.
The rest are Lima, Peru; New York City; Normandy, France; Oaxaca, Mexico; Oman; Plovdiv, Bulgaria; St. Barts, French West Indies; Space Coast, Florida, United States and Weimar, Germany.
CNN Travel Ghana Places to visit
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VisaFreeAfrica Initiative Taps Continent’s Youth to Highlight Challenges in Intra-Continental Travel
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Equal Rights Issue
LiberalMedia
Maga First News
whinylgbt
Is there a Political Double Standard on What Gets You Fired if you Offend a Gay or Trans-person? Just Ask Mika & Joy
Written by Peter Boykin on December 17, 2018
Is there a Political Double Standard on What Gets You Fired if you Offend a Gay or Trans-person?
Just Ask Mika & Joy
Recently I was asked to Comment on this:
“Morning Joe” co-host Mika Brzezinski apologized last week for calling Secretary of State Mike Pompeo, a “butt-boy.” Meanwhile, the network’s Joy Reid, blamed homophobic rhetoric on her pre-fame blog on hackers before eventually admitting it was indeed her own act. Neither Brzezinski, nor Reid, were disciplined in any capacity.
Here is my FULL answer –
First of all, the biggest issue we see is, it’s okay for the left to do EVERYTHING they preach against.
The left claim everyone on the right is racist, yet use racism on a daily basis. Example; look at the way some white people are treated by some black people, simply because the narrative is, “all white people are racist.” Some may call this is reverse racism, but it IS merely racism, period.
In addition, rap artists have been using gay and homophobic slurs in their songs for decades. Not to mention, a vast majority of mainstream rap, hip-hop, and other modern music forms, objectify women on a regular basis. YET, the left are the primary ones who put out these types of media. Another example is Snoop Dog, Eminem, and other artists calling out Trump and his supporters saying he wants to grab women by the junk and other derogatory statements. Yet their music, time and time again, is downright everything they claim to be against.
Recently, comedian Kevin Hart, who made gay jokes in the past was removed from a major event as the Master of Ceremonies. Keep in mind, making fun of stereotypes has been the basis for comedy for as long as comedy has been around, at least in the modern world. Which is what makes comedy funny, it’s humor, and we need to be able to laugh at ourselves. But, to see a few tweets from 10 years ago shut down a comedian from hosting an awards show because the “gays” might be offended, is a bit absurd.
What’s next? Will Martin Lawrence get persecuted for his many years of doing Sheneneh Jenkins? Sheneneh Jenkins on the show Martin was a character played by Mr. Lawrence and was pretty much a big transsexual woman infatuated with the main character. Additionally, comedians in roles as Transgender or gay characters helped launch the careers of actors of such as, Tom Hanks in Bosom Buddies, Dustin Hoffman in Tootsie, and Wesley Snipes, Patrick Swayze, John Leguizamo, in To Wong Foo Thanks for Everything, Julie Newmar. Staring in these rolls may have helped kicked off their careers or move them into another category, such as comedy, but by today’s standards would they be trans-phobic, homophobic or prejudical? Let us not forget, Ladybugs, Birdcage, Mrs. Doubtfire, Big Momma’s House, Madea (in everything), White Chicks, etc. are some of the most iconic portrayals and could now be under attack. Movies and TV shows like these have been going on forever and were some of the best comedy characters in history.
In the minds of the far-left LGBTQ community, comedy in any form is now off limits. According to those siding with the far-left, which should really be deemed the gay mafia, if a comedian were to think or say anything remotely considered trans-phobic or homophobic, they would be subjected to ridicule and persecution to the highest level. Particularly if you are a Republican or not aligned with the left. This is not limited to Gay, or transgender, it’s Black vs White, Left vs Right. It’s an overall attack on comedy and the First Amendment. We are not talking slap on the wrist here, we are talking, end of your career type persecution. Remember Roseanne?
Morning Joe co-host Mika Brzezinski, asked her husband of less than a year and long-time co-host, Joe Scarborough, if Secretary of State Mike Pompeo was a patriot or if he cared or was he just a “wannabe dictator’s butt boy?” Brzezinski’s made this comment during a segment stating her opinion on Pompeo’s response to the murder of Saudi journalist during an interview on the Fox News program Fox & Friends. Brzezinski later apologized and recanted stating she meant to say water-boy. But the evidence is clear. When a liberal is caught in the wrong, “by accident” and apologizes – all is well. Remember Samantha Bee calling Ivanka Trump a “feckless cunt” on her television show. She also apologized. So all is well. Rosanne Barr also apologized for her off comment. Fired, killed off her own show, and career destroyed.
So it’s NO surprise, the woman who turned Joe into a liberal and down a path of degeneracy would feel free and clear to make such an outlandishly Gay Slur. It’s extremely dumbfounding to see those on the left thinking it’s perfectly okay to make statements like someone is someone’s “butt boy.” Brzezinski might as well had said someone’s “bottom bitch” or “fa**ot slave.”
Although she apologized with an OOOPS I’m sorry, (not really) “I meant to say “water boy” ” there should be no forgiveness as she said what she wanted to say when it first came out. There are NO take-backs. Ask Roseanne Barr, Kevin Hart, or a number of others who’ve been persecuted in social media and careers derailed again about take-backs.
.@morningmika just asked if Mike Pompeo is a “wannabe dictator’s butt boy,” as homophobic a term as I’ve heard on national morning television. @MSNBC tried and failed to censor it, and did not transcribe her remark in the closed captioning. #journalism pic.twitter.com/3zK7H8evjh
— G.E. Anderson (@g_e_anderson) December 12, 2018
Totally agree with you -SUPER BAD choice of words .. I should have said “water boy”… like for football teams or something like that.. apologize to @SenatorDurbin too! SO SORRY! https://t.co/zIqsGdK3Tk
— Mika Brzezinski (@morningmika) December 12, 2018
So where is the outrage from those on the left about Mika making racial or homophobic slurs? Where are all the Gay Supporting Groups demanding the removal of Mika or at least something? or the HRC for that matter? Oh that’s right, maybe it’s because the Human Rights Campaign is too busy with their own problems?! Such as their Head of Human Rights Campaign Foundation resigns after using racial slur.
If this was Laura Ingram or Tucker Carlson who said this, they would be YELLING for Blood! Resignations or firings would have already taken place. Sadly in this day and age, the group who yells the loudest is the one who gets their way.
After all, we are living in a upside down world, where the Proud Boys, a controversial yet effective group standing up for all rights are completely shut down and vilified. Meanwhile, Antifa continues to claim they are all about the right for free speech yet they are a extremely violent and a known hate group that continues to break, burn, and destroy everything they come in contact with all in the name of anti-fascism. Although, as Antifa demonstrates they practice the opposite of our Constitutional right to PEACEFUL free speech, and then they are championed by the left. Meanwhile they are allowed to remain on social media, attend rallies, and cause complete chaos, while the Proud Boys have been ultra banned from everything! In many places, such as Portland, OR, the police stand down to these thugs. It is the Proud Boys who are comprised of all races, LGBTQ, and women, who stood up against the violence of Antifa to protect peaceful free speech.
Trump was correct about Charlottesville. There were bad actors on both sides. Yet Antifa, which is again “anti fascist” is the most fascist group there is. They are full of hate, and will attack anyone if you disagree, in fact they will NOT even debate you. I was attacked by two of them in Durham last year so I would know. I tried to talk to them, rationalize with them. They were straight hateful.
As for Joy Reid, her excuse is about as bad as Hillary’s excuse that Benghazi was because of a YouTube video (that no one watched) it’s all cover up BS. I suppose they expect the brainwashed to just believe what they are told rather than seek the truth. After all this is the same left that believed Elizabeth Warren is a Indian and that this Ocasio-Cortez is of Jewish heritage. Joy Reid wrote homophobic items on her blogs, she tried to cover it up, but they forget, the internet is forever and she had to admit it was indeed her own acts.
Why are these people not disciplined? Same reason why Deadspin can write an article demanding conservative gays “shut the fuck up.” Which is NOT going to happen: you just asked a bunch of misplaced gays kicked out of their own community for voting for Trump and getting off the reservation to SHUT UP. (now remember this is the same community that preaches for diversity) LOL – that is not going to happen! See article. https://theconcourse.deadspin.com/conservative-gays-need-to-shut-the-fuck-up-1831029271
The left Lies to the Gays, in fact, I was told by an LGBTQ in their 20’s the person who killed all those people in Pulse nightclub was really a Hispanic and they hid it because it didn’t fit the “conservative media agenda.” Now remember, this is the same left who embraced Hillary Clinton in the last presidential election. Clinton is the same woman who hated same-sex marriage – see the evidence. https://www.politifact.com/truth-o-meter/statements/2015/jun/17/hillary-clinton/hillary-clinton-change-position-same-sex-marriage/
Additionally and how easily forgotten was how Clinton pushed the Keep Your DAMN mouth Shut About Being Gay in the Military or you will LOSE your JOB legislation. Otherwise called “Don’t Ask, Don’t Tell. Which we fell for. She is also the same woman who took the father of the Islamic terrorist who killed all those Gays in the Pulse Nightclub Terrorist attack and sat him behind her at a presidential campaign rally only a few weeks after the tragedy. See video. http://www.fox26houston.com/you-decide/father-of-pulse-shooter-attends-clinton-rally
The answer is the left – especially those who are LGBTQI..etc are brainwashed (just like Black people) that Democrats are looking out for them. But, unfortunately they are being- used, and the Democrats use them for their spokes people against the right.
On the contrary, as a recovering-liberal, the right has whole-heartedly accepted me. Just like Trump embraced all Gay people who are Republican or right leaning during and after the election. Gay people who want a Greater America are encouraged by those on the right. I have felt so much love from the right. and they are not using me, they are happy for me to be a part of the GOP… they encourage me to join NOT because I am gay… not because my husband is biracial… but because we match in our beliefs for a better and greater America. Gays For Trump and those on that are a part of the Gay Right are not about the identity politics of the left. These leftist identity politics are seen on LGBTQ nation and other Gay oriented media… where everything is about “muhhhh rights” and everything Trump does is anti gay while ignoring their own parties homophobia and slurs. Ignoring people on the left that EVERY single day just like Mika and Joy Reid who say nasty things about the “gays” who are extremely against gays (just look at a majority of black churches) but somehow they all get a pass… because those “evil Christians at chick-fla (which have you seen the workers (half of them a gay)) hate gays and Mike Pence wants us all to be shocked.
The problem with the left is that they generalize the extreme of the right… and think that 1% of the right which are bad eggs, ie white supremacists and homophobic and racist bigots somehow make up the rest of the 99% of the people on the right…. and for that we all get punished, we all get suspended from Twitter and other social media because the leftist lynch mobs are constantly out to get us… yet in their own minds, everyone on the left is WONDERFUL… everyone on the left is PRO GAY… everyone on the left is peaceful and loving and non hateful… the truth is so far from it…
So yes, Mika and Joy.. are just as guilty as those the left accuse of being homophobic, but the problem is perceptions and denial.. the Left has gone so far extreme they refuse to see that they are standing in a landfill but in their minds they are in a rose garden.
Tagged as double standard lgbt Twitter
demandfreespeech
Peter Boykin was Out to #DemandFreeSpeech in Washington DC along with Milo, Gavin, and Laura Loomer. Here is his speech.
Trump saluted America in A #MAGA July 4 event, despite critics, What Do you Think About His Speech?
.@AOC ain’t nothing but A Hounddog just crying/lying all the time.. do you think the news covers her way too much?
July 6 Freedom Plaza many will face the hate of Domestic Terror Group Antifa & #DemandFreeSpeech
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Cisco UK & Ireland Blog > Start-up Hub
Start-up Hub
Mi-IDEA recruits Manchester’s top tech start-ups
Safe to say, we like a get-together here in Manchester and as good an opportunity as any presented itself as we played host to the city’s great and good to show off our Mi-IDEA post-accelerator programme.
The programme will launch later this year with a cohort of the region’s finest tech start-ups, and this final recruitment event in the run up to the ribbon being cut was a chance for entrepreneurs to come along and find out more about what’s on offer.
Tom Kneen kicked off the evening, introducing the teams and partners in attendance and walking them through the IDEALondon and Mi-IDEA programmes.
He then brought up William Bainborough from Doordeck. One of nine start-ups accepted to the Starupbootcamp accelerator, Doordeck then enrolled into the post-accelerator programme at IDEALondon.
William walked the audience through Doordeck’s product development, successes and failures, and entire start-up journey as a timeline from conception to today where his door entry technology is being used in the new Mi-IDEA space along with many other big companies around the country.
“Cisco is in-tune. It understands that without us- all the start-ups in the room- you don’t continue to grow. And it’s us who ultimately bring the innovation ideas, but we need companies like Cisco to help us realise them and allow us to grow. Cisco, from my experience, is certainly willing to do that.”
After an insightful presentation, William then handed over the microphone to Kerry Wright and Tom Young from Purple, who talked about their experience of growing from a small start-up in Manchester through to a successful 120-employee, 125-country business, including their involvement, and alliance, with Cisco along the way.
“Cisco has been a really big part of our journey. It helped us navigate our way through its business, get on all the right programmes and get introduced to the right people, gave us opportunities to speak at events, and really hand-held us through the journey,” said Kerry.
“We’ve been introduced to other entrepreneurs at IDEALondon, like Will from Doordeck, who we’re already talking with to see how our products can potentially fit together.”
Purple is also working on a developer ecosystem, utilising its amazing technology to help thousands of venues across the world, which they want to open up via their APIs to start-ups, corporates, single developers, scale-ups.
Outside of offering APIs, Purple’s goal is to give back by providing mentorship and partnership opportunities to help the local Manchester community and beyond, giving all involved the opportunity to grow and perform faster.
“It helps to have peers who can tell you what they think of your business and any ideas they have,” Kerry added. “That has really helped inform the direction we’ve taken.”
After Purple’s presentation, Tom and William came back on stage, joined by myself for a Q&A panel discussion.
The panel answered some great questions around finding your minimum viable product (MVP), how to hire the right people as a start-up and more.
Once the session was over, it was on to everybody’s favourite part: canapés and networking! Anybody with an orange or purple lanyard was fair game, and the pitches started to fly faster than the pizza did.
From urban farming and food delivery, to mental health tech-related ideas, the attendees came to play. And by the sounds of it Mi-IDEA will have some great companies through its doors very soon.
For more updates on everything Mi-IDEA, you can find us over on Twitter.
Mi-IDEA
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The Expanse gets saved by Amazon
The Expanse will have a fourth season after all
by Cian Murray May 29, 2018, 1:38 pm
Rumor has it that The Expanse never really fancied Syfy anyway… The show, which is based on the bestselling book series by Daniel Abraham and Ty Franck (under the pen name James S. A. Corey), is being dumped by the channel after its current third season comes to a close. Fortunately for all involved with The Expanse, its rebound is pretty darn hot – Amazon has closed a deal to pick up the space drama after its third season finishes.
Amazon boss, Jeff Bezos, appropriately made the announcement at the National Space Society’s International Space Development Conference in Los Angeles.
The Expanse panel was at the same event and the likes of showrunner Naren Shankar and some of the cast there to join in with the celebrations.
Cas Anvar even filmed the joyful announcement.
I'll just let him say it…#TheExpanse#RocinanteIsSafe#BreakingNews
Thank you @JeffBezos pic.twitter.com/wxHN31zgJs
— Cas Anvar (@Casanvar) May 26, 2018
The last episode of this season will air in July.
Explaining why Syfy dropped the show, Chris McCumber, the President of Entertainment Networks for NBC Universal Cable Entertainment, gave The Expanse the old “it’s not you, it’s me” line.
He said: “Everyone at Syfy is a massive fan of the series, and this was an incredibly difficult decision.”
The space drama series will join Amazon, after they were targeted by fans of the show with the hashtag #SaveTheExpanse. There was also a GoFundMePage which collected money for a “Save the Expanse” banner to be flown over the Amazon HQ and a petition, with 138,000 signatures.
The Buffy reboot isn't going to be a reboot after all
When you combine that with the shows high Rotten Tomatoes reviews (its third season currently has a 100 percent review, while season 2 has 95 percent and season 1 has a rating of 76 percent), it does seem like a fairly stable bet for the producers.
However, the talks could have gone slightly smoother. It is thought that the SVOD rights delayed the deal, as Amazon owns North American SVOD rights to The Expanse, while Netflix carries the series globally outside of North America and New Zealand.
However, the show which was co-created and written by Oscar-nominated screenwriting duo Mark Fergus and Hawk Ostby (Children of Men), did eventually come to a deal.
Thus, all of you folks who brought the #SaveTheExpanse hashtag to life can consider your job done!
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dePresno
Produced by Rykkinnfella & The 23rd
Album The Last of the Romantics - EP
Mr. Big Lyrics
They call me Mr. Big
But it's not like that
It's only 'cause I want you girl
And I know that you want me back
But it don't mean jack
You could win an Oscar girl
Walking in to the club like that
And we're not stable
Oh Rachel, don't lead no friends like that
This ain't no movie, it's who we
Rolling those credits back
I'm not the one you're thinking of
Take it off, we fucked up
Don't call me Mr. Big
'Cause I'm not like that
Don't call me Mr
You call me Mr. Big
I could get enough off you girl
And you hook on me hm like crack
But I need more cash
I think I spendt too much on you girl
'Cause I'm deep in my overdraft
And you got dollar signs in your eyes
Diamonds when you cry
I'm not the one that you're thinking of
About “Mr. Big”
The 3rd and last single from DePresno’s 2nd EP The Last of the Romantics, which was released in 2017.
"Mr. Big" Track Info
Written By Jonny Wright, Henry Flint, George Flint & 2 more
The Last of the Romantics - EP dePresno
1. Breathing
2. Give Me Your Number
3. Mr. Big
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Like A Motherless Child
Produced by Moby
Album Everything Was Beautiful, and Nothing Hurt
Like A Motherless Child Lyrics
[Hook: Raquel Rodriguez]
Sometimes I feel like a motherless child
So far from home
[Verse 1: Moby]
This was life and this was safer
All was strange and always stranger
A latent hate but so much later
I'm never safe from all this danger
The demon's eyes and demon satyr
I was bait but what would bait her?
Don't know my needs, don't know my ways, sir
I hide my face, no way to face her
This was loss, this was name
This was my truth, this was no game
This was not hope, this was not sane
And from these broken places made
That was loss and this was later
I wanted less but nothing greater
I couldn't leave, I couldn't stay, sir
This was loss and this was later
Always hate but never hate her
I laid in wait but so much later
And never safe from all this danger
The demon's eyes, the demon satyr
I was bait, but what would bait her
About “Like A Motherless Child”
“Like A Motherless Child” was the first single released from Moby’s fifteenth album, Everything Was Beautiful and Nothing Hurt. After two albums of electronic punk-rock with his Void Pacific Choir project, “Motherless Child” was an indication that the musician was heading back to a more familiar sound: over a trip-hop drum loop and melancholic synth strings, Moby delivers two verses of spoken word while Los Angeles-based singer Raquel Rodriguez’s performs the hook. The song’s title (and hook) is paraphrased from the African-American spiritual “Sometimes I Feel Like a Motherless Child”.
The track’s sonic palette was inspired by the music of Burial, Sly & Robbie, and Marianne Faithfull.
i heard these lyrics played on a gramaphone on the netflix series "damnation" ?
The main hook/chorus of the song is based on an African-American spiritual called “Sometimes I Feel Like a Motherless Child”– perhaps the most famous version is by the iconic folk singer Odetta. It’s her version which was featured on Damnation.
"Like A Motherless Child" Track Info
Written By Moby
Vocals Raquel Rodriguez & Moby
Interpolates
Sometimes I Feel Like a Motherless Child by Odetta
Everything Was Beautiful, and Nothing Hurt Moby
1. Mere Anarchy
2. The Waste of Suns
3. Like A Motherless Child
4. The Last of Goodbyes
5. The Ceremony of Innocence
6. The Tired and the Hurt
7. Welcome to Hard Times
8. The Sorrow Tree
9. Falling Rain and Light
10. The Middle Is Gone
11. This Wild Darkness
12. A Dark Cloud Is Coming
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Sarah Hyland Shows Off Her Gorgeous Engagement Ring – See Her Huge Diamond
Hepatitis A: 5 Things To Know ABout Virus Scarily Spreading Around Southern California
September 21, 2017 2:05PM EDT
Two Door Cinema Club Updates Us On 4th Album & Reminisces About Breaking The Door Off A Taco Shop
Gabriella Ginsberg
Two Door Cinema Club is already working on their next album — sort of. The Irish indie rock trio tends to get distracted by touring, soccer and The Royal Family. We’ll let them explain.
I caught up with Alex Trimble, Sam Halliday and Kevin Baird of Two Door Cinema Club at The Meadows in NYC on Sept. 15; this interview has been edited and condensed for clarity. You can click through the gallery to see more photos of the band at the festival!
How is the tour going so far?
Alex: Good! We’re just easing into it. We started out in Portland, Maine, then last night was Ithaca, both of which we’ve never played before. We’re hitting a lot of spots on this run where we’ve never been. It’s nice to branch out.
I love that you guys picked Circa Waves for your opener.
Alex: We lucked out with Circa Waves. They’re a bunch of great people, and it’s really nice to want to watch your opening band every night. We’re friends and they’re a great band as well.
Where are you looking forward to playing?
Alex: Atlanta. And Vegas [for Life Is Beautiful] is always fun.
Sam: I’m excited to go back to New Orleans. Good food.
What’s the weirdest or most unique venue you’ve ever played?
Alex: We played in Cape Town, South Africa a few years ago. It was a disused cement factory or something, and it was half-falling down! The walls were crumbling.
Kevin: Wasn’t very high-quality cement…no matter they went out of business.
Alex: That was a surreal place to play. A lot of fun.
How far along are you on the next album?
Alex: It’s starting! It’s in the embryonic stages. It’s been tough to get anything solid for the last little while. The touring schedule has been busy and we all have priorities at home. We kind of leave the job at the door when we step off the bus. We’re winding up next month. Towards the end of the year, we’re going to get some studio time and work it out!
Are you guys working on anything else?
Kevin: I’m working on my soccer skills! I’m trying to get prepared for when we’re not touring next year.
Alex: We’ve even got a challenge set up with Circa Waves on this tour, where we’re going to play games against each other.
Okay, I meant more like music–
Kevin: –We’ve got jerseys and everything.
Alex: Oh, yeah, our keyboard player made them.
I see where the priorities lie.
Kevin: Yep!
Have you met a celebrity who was a fan of your band?
Kevin: We met Prince Charles once.
Alex: I can’t say that he’s a fan.
Kevin: But he was nice.
I bet he’s a fan.
Kevin: Yeah, the whole family is season ticket holders to Two Door Cinema Club gigs. Only in British Commonwealth countries, though.
Alex: Circa Waves are huge fans!
What’s something you’ve been passionate lately outside of your work?
Alex: I like taking pictures. We’re afforded a great opportunity when traveling to see so many places and meet people, so I always have a camera.
Sam: I like eating food.
What’s your advice to humanity?
Alex: Chill.
Sam: Calm down.
Kevin: No one cares what you think!
Do you have a favorite New York memory?
Sam: Ha! Breaking that door in the taco shop.
Alex: We were playing Central Park and went out and finished the night in a taco shop and we did it–
Kevin: –We were drunk.
Alex: Someone took the door off the taco shop. The whole front door.
Kevin: A Mom-and-pop taco shop. We felt so bad.
Sam: There was a young girl working the night shift, hating that we were there. She wanted to go home.
Alex: She was so sweet. The door came off, and she was like, “Just go.”
Kevin: “Just leave.” [Laughs]
Sam: It wasn’t like a violent act. It just came off its hinges.
Kevin: In our defense, it was an old door.
So Two Door Cinema Club…broke one door.
Kevin: Lock up your doors.
Alex: The tacos were really good, though.
Finally, who is the parent in the band?
Sam: Kevin, because he always has the medicine.
Kevin: Sam is the baby.
Alex: He always needs the medicine.
Kevin: He has the worst hay fever and never brings his hay fever tablets. He has the worst migraines and hangovers and zero remedies. He just looks at you, like, “Wah.”
Catch Two Door Cinema Club on tour.
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The Meadows -- Pics
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Miley Cyrus Gets Sweet & Soulful On New Breakup Song 'Week Without You'
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