USOO9376418B2 (12) United States Patent (10) Patent No.: US 9,376.418 B2 Haidle et al. (45) Date of Patent: Jun. 28, 2016 (54) SUBSTITUTED PYRIDINE SPLEEN 31/5377 (2013.01); A61K3I/5383 (2013.01); TYROSINE KINASE (SYK) INHIBITORS A61 K3I/551 (2013.01); A61K 45/06 (2013.01); C07D401/14 (2013.01); C07D (71) Applicants: Merck Sharp & Dohme Corp., 405/14 (2013.01); C07D 409/14 (2013.01); Rahway, NJ (US); Merck Canada Inc., C07D 413/14 (2013.01); C07D 417/14 Kirkland, Quebec (CA) (2013.01); C07D 471/04 (2013.01); (Continued) Inventors: (72) Andrew M. Haidle, Cambridge, MA (58) Field of Classification Search (US); Sandra Lee Knowles, Princeton, CPC ............... CO7D 401/12: CO7D 401/14: A61 K NJ (US); Solomon D. Kattar, Arlington, 31/5377; A61K31/506 MA (US); Denis Deschenes, Lachine USPC ........................ 544/122, 331; 514/235.8, 275 (CA); Jason Burch, Redwood City, CA See application file for complete search history. (US); Joel Robichaud, Dollard-des-Ormeaux (CA); Matthew (56) References Cited Christopher, Brookline, MA (US); Michael D. Altman, Needham, MA U.S. PATENT DOCUMENTS (US); James P. Jewell, Newtown, MA 5,710,129 A 1/1998 Lynch et al. (US); Alan B. Northrup, Reading, VA 6/2001 Uckun et al. (US); Marc Blouin, Saint-Lazare (CA); 6,248,790 B1 John Michael Ellis, Needham, MA (Continued) (US); Hua Zhou, Acton, MA (US); Christian Fischer, Natick, MA (US); FOREIGN PATENT DOCUMENTS Adam J. Schell, Decatur, GA (US); EP 877O2O A1 11, 1998 Michael H. Reutershan, Brookline, MA EP 2441755 A1 4/2012 (US); Brandon M. Taoka, Hoboken, NJ (US); Anthony Donofrio, Cambridge, (Continued) MA (US) OTHER PUBLICATIONS Assignees: Pearce et al., Failure modes in anticancer drug discovery and devel (73) Merck Sharp & Dohme Corp., opment, Cancer Drug Design and Discovery Edited by Stephen Rahway, NJ (US); Merck Canada Inc., Neidle, Chapter 18, pp. 424-435 (2008).* Kirkland, Quebec (CA) Johnson et al., Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials, British Journal of (*) Notice: Subject to any disclaimer, the term of this Cancer (2001) 64(10): 1424-1431.* patent is extended or adjusted under 35 Simone. Oncology: Introduction, Cecil Textbook of Medicine, 20th U.S.C. 154(b) by 13 days. Edition, vol. 1, pp. 1004-1010, 1996.* (Continued) (21) Appl. No.: 14/409,151 Primary Examiner — Deepak Rao (22) PCT Fled: Jun. 17, 2013 (74) Attorney, Agent, or Firm — Eric A. Meade: Anna L. (86) PCT NO.: PCT/US2O13/046151 CocuZZO S371 (c)(1), (57) ABSTRACT (2) Date: Dec. 18, 2014 The invention provides certain substituted pyridines of the Formula (I) or pharmaceutically acceptable salts thereof, (87) PCT Pub. No.: WO2O13/192098 wherein R. R. R. R. R. C., and t are as defined herein. PCT Pub. Date: Dec. 27, 2013 The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the com (65) Prior Publication Data pounds for treating diseases or conditions mediated by Spleen US 2015/O 1483.27 A1 May 28, 2015 Tyrosine Kinase (Syk) kinase. Related U.S. Application Data (I) (RC), (60) Provisional application No. 61/663,290, filed on Jun. 22, 2012. (O R2 R3 (51) Int. C. 21 NN CO7D 40/12 (2006.01) CO7D 40/4 (2006.01) NN 1. N (Continued) H (52) U.S. C. CPC ............ C07D401/12 (2013.01); A61K3I/505 (2013.01); A61 K3I/506 (2013.01); A61 K 18 Claims, No Drawings US 9,376.418 B2 Page 2 (51) Int. Cl. 2011/0301 175 A1 12/2011 Molteni et al. A6 IK3I/506 (2006.01) 2014/0148474 A1 5/2014 Altman et al. A 6LX3L/505 2006.O1 2014/0243336 A1 8/2014 Altman et al. (2006.01) 2014/0249 130 A1 9, 2014 Deschenes et al. A6 IK 45/06 (2006.01) 2015, 0166486 Al 6, 2015 Haidle et al. A 6LX3/5377 (2006.01) 2015,0175575 A1 6, 2015 Lim et al. A6 IK3I/5383 (2006.01) 33.85: A 58 NE A6 IK3I/55 (2006.01) CO7D 405/4 (2006.01) FOREIGN PATENT DOCUMENTS CO7D 413/4 (2006.01) CO7D 417/4 (2006.01) JP 20042O3748 12/2002 CO7D 47L/04 (2006.01) WO WOO3078.404 A1 9, 2003 CO7D 47L/TO (2006.01) WO WO2004080463 A1 9, 2004 CO7D 487/04 (2006.015 WO WO2005O13996 A2 2, 2005 WO WO2O06093247 A1 2, 2005 C07D 491/107 (2006.01) WO WO2005O26158 A1 3, 2005 CO7D 49 I/II3 (2006.01) WO WO2005033103 A1 4, 2005 CO7D 49.8/04 (2006.01) W: Woo: A 39. C E. 3:08: WO WO2006050480WO2006O28833 A2A1 3f20065, 2006 CO7D 487/10 (2006.01) WO WO200606877O A1 6, 2006 (52) U.S. Cl WO WO2006078846 A1 T 2006 AV e. we WO WO2006129 100 A1 12/2006 CPC ........... C07D 471/10 (2013.01); C07D487/04 WO WO2006133426 A2 12/2006 (2013.01); C07D 487/10 (2013.01); C07D WO WO2006135915 A2 12/2006 491/08 (2013.01); C07D491/107 (2013.01); WO WO2007OO9681 A1 1, 2007 C07D491/113 (2013.01); C07D498/04 WO WO2007OO9773 A1 1, 2007 (2013.01) WO WO2007028445 A1 3, 2007 WO WO2007042298 A1 4/2007 WO WO2007042299 A1 4/2007 (56) References Cited WO WO2007070872 A1 6, 2007 WO WO2007085540 A1 8, 2007 U.S. PATENT DOCUMENTS WO WO2007 120980 A2 10/2007 WO WO2009084695 A1 12/2007 6.432,963 B1 8/2002 Hisamichi et al. WO WO2009031011 A2 3, 2009 6,552,029 B1 4/2003 Davis et al. WO WO2009097287 A1 8, 2009 6,589,950 B1 7/2003 Hayler et al. WO WO2009102468 A1 8, 2009 6,770,643 B2 8, 2004 Cox et al. WO WO2009 131687 A2 10/2009 6,797,706 B1 9, 2004. Hisamichi et al. WO WO2009 136995 A2 11/2009 6,897,207 B2 5, 2005 Cox et al. WO WO2O0914585.6 A1 12/2009 6,897,208 B2 5, 2005 Edwards et al. WO WO2O10068257 A1 6, 2010 6,911,443 B2 6, 2005 Yura et al. WO WO2O10068258 A1 6, 2010 7,060,827 B2 6/2006 Singh et al. WO 2011 O75515 A1 6, 2011 7,122,542 B2 10/2006 Singh et al. WO WO2O14031438 A2 2, 2014 7,259,154 B2 8, 2007 Cox et al. OTHER PUBLICATIONS 7.276,502 B2 10/2007 Brenchley et al. Gura, Systems for identifying New Drugs Are Often Faulty, Cancer 7,803,801 B2 9/2010 Kodama et al. Models, Science, vol. 278, No. 5340, pp. 1041-1042, Nov. 1997.* 5. g R: 1933 AA et Pamuk et al., Spleen tyrosine kinase inhibition in the treatment of 8,759,366- - B2 6, 2014 Childerstman et et al. al. autoimmune, allergic and autoinflammatoryck diseases, Arthritis 8,796.310 B2 8, 2014 R. tal Research & Therapy, (2010), 12:222, pp. 1-11. - w OO a International Search Report and Written Opinion for PCT/US 13/ 8.987,456 B2 3/2015 Altman et al. 46151 illed on Nov. 1, 2013 9,006,444 B2 4/2015 Altman et al. is mailed on Nov. 1, . 9,120,785 B2 9, 2015 Altman et al. Villasenor et al., Structural Insights for Design of Potent Spleen 2004.00299.02 A1 2/2004 Singh et al. Tyrosine Kinase Inhibitors from Crystallographic Analysis of Three 2004.0054179 A1 3, 2004 Yura et al. Inhibitor Complexes,& 8 Chem Biol Drug Des. 2009, 466-470, 73. 2006, O135543 A1 6/2006 Singh et al. Yamamoto et al, The Orally Available Spleen Tyrosine Kinase 2006/01784.07 A1 8/2006 Argade et al. inhibitor (2-7-(3,4-Dimethoxyphenyl)imidazo[12-elpyrimidin-5- 2006/0211657 A1 9/2006 Singh et al. ylaminol-nicotinamide Dihydrochloride (BAY 6 1.3606) Blocks 2006/0234483 A1 10, 2006 Arak et al. Antigen-Induced Airway. Inflammation in Rodents , The Journal of 2006/0247262 A1 11/2006 Baenteli et al. Pharmacology and Experimental Therapeutics, 2003, pp. 1174-1181. 2007/0004626 A1 1/2007 Masuda et al. vol. 306(3). 2007/0129362 A1 6/2007 Bhamidipati et al. European Search Report for PCT/US2013/046151 mailed Nov. 18, 2007/O197782 A1 8/2007 Clough et al. 2015. 2008, 0221171 A1* 9, 2008 Eberle et al. .................. 514,352 2011/0245205 A1 10, 2011 Altman et al. * cited by examiner US 9,376,418 B2 1. 2 SUBSTITUTED PYRIDINE SPLEEN mediators and spasmogens (Wong et al. 2004, Expert Opin. TYROSINE KINASE (SYK) INHIBITORS Investig. Drugs (2004) 13 (7) 743-762). Recently, it has been shown that the Syk kinase inhibitor CROSS REFERENCE TO RELATED R112 (Rigel), dosed intranasally in a phase I/II study for the APPLICATIONS treatment of allergic rhinitis, gave a statistically significant decrease in PGD, a key immune mediator that is highly This application is a U.S. National Phase application under correlated with improvements in allergic rhinorrhea, as well 35 U.S.C. S371 of PCT Application No. PCT/US2013/ as being safe across a range of indicators, thus providing the 046151, filed Jun. 17, 2013, which claims priority under 35 first evidence for the clinical safety and efficacy of a topical U.S.C. S 119(e) from U.S. Provisional Application No. 10 Syk kinase inhibitor. (Meltzer, Eli O.; Berkowitz, Robert B.: 61/663,290, filed Jun. 22, 2012. Grossbard, Elliott B. Journal of Allergy and Clinical Immu nology (2005), 115(4), 791-796). In a more recent phase II FIELD OF THE INVENTION clinical trial for allergic rhinitis (Clinical Trials.gov Identifier NCT0015089). R112 was shown as having a lack of efficacy The present invention relates to certain substituted pyridine 15 Versus placebo. Rheumatoid Arthritis (RA) is an auto-immune disease compounds of the Formula (I) (also referred to herein as the affecting approximately 1% of the population.