USOO9062O29B2 (12) United States Patent (10) Patent No.: US 9,062,029 B2 Schadt et al. (45) Date of Patent: *Jun. 23, 2015 (54) PYRIMIDINYL PYRIDAZINONE 417/10 (2013.01); C07D 417/14 (2013.01); DERVATIVES C07D 451/06 (2013.01); C07D 453/02 (2013.01); A61 K3I/501 (2013.01); A61 K (71) Applicant: Merck Patent GmbH, Darmstadt (DE) 3 1/506 (2013.01); A61 K3I/5355 (2013.01): (72) Inventors: Oliver Schadt, Rodenbach (DE); Dieter A6IK3I/5377 (2013.01); A61K3I/55 Dorsch, Ober-Ramstadt (DE); Frank (2013.01); A61K 45/06 (2013.01) Stieber, Heidelberg (DE); Andree (58) Field of Classification Search Blaukat, Schriesheim (DE) CPC C07D 403/14: A61K31/506; A61K31/5377 USPC ................... 514/236.5, 252.02:544/123, 298 (73) Assignee: Merck Patent GmbH, Darmstadt (DE) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (56) References Cited U.S.C. 154(b) by 0 days. This patent is Subject to a terminal dis U.S. PATENT DOCUMENTS claimer. 6,242.461 Bl 6/2001 Goldstein 6,403,586 B1 6/2002 Ohkuchi et al. (21) Appl. No.: 14/149,110 8,071,593 B2 12/2011 Schadt et al. 8,173,653 B2 5, 2012 Dorsch et al. (22) Filed: Jan. 7, 2014 8,329,692 B2 12/2012 Schadt et al. 8,580,781 B2 * 1 1/2013 Dorsch et al. ............ 514,217.06 (65) Prior Publication Data 8,658,643 B2 * 2/2014 Schadt et al. .............. 514,236.5 2004/O152739 A1 8, 2004 Hanau US 2014/O128396 A1 May 8, 2014 2004/0259863 A1 12/2004 Eggenweiler et al. 2005/0107391 A1 5/2005 Cui et al. 2007, OO15771 A1 1/2007 Matteucci et al. Related U.S. Application Data 2007/0043057 A1 2/2007 Matteucci et al. 2007/0203136 A1 8, 2007 Lu et al. (62) Division of application No. 13/565,914, filed on Aug. 2007/0265272 A1 1 1/2007 Cheng et al. 3, 2012, now Pat. No. 8,658,643, which is a division of 2008.O293719 A1 11/2008 Dorsch et al. application No. 12/668,491, filed as application No. 2009/00981.81 A1 4/2009 Lu et al. PCT/EP2008/005508 on Jul. 4, 2008, now Pat. No. 2009, O124612 A1 5/2009 Albrecht et al. 8,329,692. 2010/O197690 A1 8, 2010 Schadt et al. 2010, O234354 A1 9/2010 Dorsch et al. (30) Foreign Application Priority Data (Continued) Jul. 12, 2007 (DE) ......................... 10 2007 032 507 FOREIGN PATENT DOCUMENTS Apr. 29, 2008 (WO)................. PCT/EP2008/OO3473 DE 196 04388 8, 1997 (51) Int. Cl. DE 10 2005 057 924 6, 2007 A6 IK3I/506 (2006.01) (Continued) A 6LX3/5377 (2006.01) CO7D 403/4 (2006.01) OTHER PUBLICATIONS CO7D 403/0 (2006.01) CO7D 40/0 (2006.01) “Cancer MedLine Plus (2009). Accessed Mar 17, 2009. http:// CO7D 40/4 (2006.01) www.nlm.nih.gov/medlineplus/cancer.html. CO7D 405/4 (2006.01) CO7D 409/4 (2006.01) (Continued) CO7D 43/10 (2006.01) CO7D 413/4 (2006.01) CO7D 4 7/10 (2006.01) Primary Examiner — James O Wilson CO7D 417/4 (2006.01) Assistant Examiner — Ebenezer O Sackey CO7D 45/06 (2006.01) (74) Attorney, Agent, or Firm — Millen, White, Zelano & CO7D 453/02 (2006.01) Branigan, P.C. A6 IK3I/50 (2006.01) A 6LX3/5355 (2006.01) A6 IK3I/55 (2006.01) (57) ABSTRACT A6 IK 45/06 (2006.01) (52) U.S. Cl. Compounds selected from the group according to Claim 1 are CPC ............ C07D 403/10 (2013.01); C07D401/10 inhibitors of tyrosine kinases, in particular of Metkinase, and (2013.01); C07D401/14 (2013.01); C07D can be employed, interalia, for the treatment of tumours. 403/14 (2013.01); C07D405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/10 (2013.01); C07D 413/14 (2013.01); C07D 4 Claims, No Drawings US 9,062,029 B2 Page 2 (56) References Cited Database CA (Online) Chemical Abstracts Service, Columbus, Ohio US; 1967. Nitta, yoshihiro et al: “Benzoxazolone derivatives.” U.S. PATENT DOCUMENTS XPOO24963.58. Databse Beilstein, Beilstein Institute for Organic Chemistry, Frank 2010/0273796 A1 10/2010 Dorsch et al. furt, DE, XPOO2506065, 2008. 2010/0280030 A1 11/2010 Schadt et al. Ettmayer et al. “Lessons Learned from Marketed and Investigational 2010/0286390 A1 11/2010 Shigeta et al. 2011/0034474 A1 2/2011 Dorsch et al. Prodrugs” J. Med. Chem. (2004), 47(10):2393-2404. 2011/0092498 A1 4/2011 Dorsch et al. Flouzat, Christine et al. “Synthesis and N-substitution of an uncom 2011/0098.269 A1 4/2011 Becknell et al. mon heterocyclic system: oxazolo5,4-bipyridin-2(1H)-one.” Tetra 2011 0112061 A1 5, 2011 Hu et al. hedron Letters, Bd. 33, Nr. 32, 1992 Seiten 4571-4574, XP00249354. 2011/0263596 A1 10/2011 Schadt et al. Fujisawa Pharmaceut Co Ltd., “Pyrazolopyridine compound and 2011/0269957 A1 11/2011 Fandricket al. pharmaceutical use thereof.” Patent Abstracts of Japan, Publication 2012/0028988 A1 2/2012 Sakamoto et al. Date: Jul. 17, 2001; English Abstract of JP-2001 192384. 2012/004O949 A1 2/2012 Berthelet al. Glen, H. et al., “E7080, a multi-targeted tyrosin kinase inhibitor Suppresses tumor cell migration and invasion.” BMC Cancer, 2011, FOREIGN PATENT DOCUMENTS vol. 11, No. 309. Golub et al. “Molecular Classification of Cancer: Class Discovery EP 1061 O77 12/2000 and Class Prediction by Gene Expression Monitoring” Science JP 1O 259176 9, 1998 (1999), 286:521-537. JP 2001 192384 T 2001 Gould et al., “Salt selection for basic drugs.” International Journal of WO WO-03 O37349 5, 2003 Pharmaceutics, 1986, vol. 33, p. 201. WO WO-2004 O58762 T 2004 WO WO-2005 0046O7 1, 2005 Guessous, Fadila et al. "An orally Bioavailable c-Met Kinase Inhibi WO WO-2006 O15263 2, 2006 tor Potently Inhibits Brain Tumor Malignancy and Growth'. Anti WO WO-2007 O44796 4/2007 Cancer in Medicinal Chemistry, 2010, 10(1):28-35. WO WO-2007 064797 6, 2007 H. Refaat et al., “Synthesis and Anti-Inflammatory Activity of Cer WO WO-2007 O65518 6, 2007 tain Piperazinylthienylpyridazine Derivatives.” Arch Pharm Res., WO WO-2007 O75567 7/2007 vol. 30, No. 7 (2007) pp. 803-811. WO WO-2007 130383 11, 2007 Hackh's Chem Dict. 3". Ed 1944, p. 18. WO WO-2007 1323O8 11, 2007 Hawley's Condensed Chem Dict. 14' Ed., 2002. WO WO-2008 O08539 1, 2008 Hill, K. S. et al., "Met Receptor Tyrosine Kinase Signaling Induces WO WO-2008 O75068 6, 2008 Secretion of the Angiogenic Chemokine Interleukin-8/CXCL8 in WO WO-2009 OO6959 1, 2009 Pancreatic Cancer. PLoS ONE, Jul. 1, 2012, vol. 7, No. 7, e40420. WO WO-2009 OOTO74 1, 2009 http://www.iupac.org/goldbook/A00123.pdf downloaded Oct. 29. WO WO-2009 05O197 4/2009 2010. WO WO-2009 O53737 4/2009 WO WO-2009 063061 5, 2009 http://www.uspto.gov/wb/offices/pac/dapp/lpecha.htm#7; last WO WO-2009 080314 T 2009 accessed on Nov. 22, 2011. WO WO-2009 080364 T 2009 International Search Report “International Application No. PCT/ WO WO-2009 080533 T 2009 EP2008/003696.” Date of Completion Sep. 18, 2008, Date of Mailing WO WO-2009 080534 T 2009 Oct. 1, 2008, 4 pages. WO WO-2009 080555 T 2009 International Search Report for PCT/EP2008/003473 dated Jul. 28, WO WO-2009 080721 T 2009 2008. WO WO-2009 080725 T 2009 International Search Report for PCT/EP2008/005928 dated Dec. 11, WO WO-2009 081197 T 2009 2008. WO WO-2009 083076 T 2009 International Search Report of PCT/EP2008/009970 dated Jan. 28, WO WO-2009 083105 T 2009 2009. WO WO-2009 O85659 T 2009 WO WO-2009 O86041 T 2009 International Search Report of PCT/EP2009/002137 (Jun. 4, 2009). WO WO-2009 O86264 T 2009 International Search Report of PCT/EP2009/003675 (Aug. 26, 2009). OTHER PUBLICATIONS International Search Report of PCT/EP2009/005172 dated Jan. 26, 2010. Berge et al., “Pharmaceutical salts.” Journal of Pharmaceutical Sci International Search Report of PCT/EP2009/008358 dated Feb. 5, ence, 1977, vol. 66, No. 1, pp. 1-19. 2010. Berthou, S. et al., “The Met kinase inhibitor SU 11274 exhibits a Japan Tobacco Inc., “New Amide derivative having vascularization selective inhibition pattern toward different receptor mutated vari inhibiting action and its use.” Patent Abstracts of Japan, Publication ants.” Oncogene, 2004, vol. 23, pp. 5387-5393. Date: Sep. 29, 1998; English Abstracts of JP-10 259176. Jin et al., Mol. Cancer Ther., Jul. 2006, vol. 5, pp. 1754-1763. Buchanan, Sean G. “SGX523 is an exquisitely selectively, ATP Jin, Hongkuiet al. “MetMAb, the One-Armed 5D5Anti-c-Met Anti competitive inhibitor of the MET receptor tyrosine kinase with anti body, Inhibits Orthotopic Pancreatic Tumor Growth and Improves tumor activity in vivo”. Molecular Cancer Therapeutics, Dec. Survival”, Cancer Res 2008:68(11):4360-4368; Jun. 1, 2008. www. 2009;8(12): 3181-3190. aacrjournals.org. Cancer Drug Design and Discovery, Neidle, Stephen, ed. (Elsevier/ Johnson et al. “Relationships between drug activity in NCI preclini Academic Press), pp. 427-431, 2008. cal in vitro and in vivo models and early clinical trials.” British Chen et al., Circulation, 2008, vol. 118, pp. 84-95. Journal of Cancer (2001) 84(10): 1424-1431. Database Beilstein, Beilstein Institute for Organic Chemistry, Frank Knowles, Lynn M. et al. “HGF and c-Met Participate in Paracrine furt, DE, XPOO2506064, 1991. Tumorigenic Pathways in Head and Neck Squamous Cell Cancer', Database CA (Online) Chemical Abstracts Service, Columbus, Ohio Clin Cancer Res, Jun.