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(12) United States Patent )-X- NZ US008895596B2 (12) United States Patent (10) Patent No.: US 8,895,596 B2 Jiang et al. (45) Date of Patent: Nov. 25, 2014 (54) CYCLIC BENZMDAZOLE DERVATIVES (56) References Cited USEFUL AS ANT-DABETICAGENTS U.S. PATENT DOCUMENTS (75) Inventors: Jinlong Jiang, Scotch Plains, NJ (US); 5,596,025 A 1/1997 Oxman et al. Andrew J. Kassick, Scotch Plains, NJ 6,312,662 B1 11/2001 Erion et al. (US); Ahmet Kekec, Jersey City, NJ 6,489.476 B1 12/2002 Dang et al. (US); Iyassu K. Sebhat, Jersey City, NJ 7,098,220 B2 8, 2006 Rault et al. 7,268,145 B2 9, 2007 Matsumoto et al. (US) 2005, OO38068 A1 2/2005 Iyengar et al. 2005.0113283 A1 5/2005 Solow-Cordero et al. (73) Assignee: Merck Sharp & Dohme Corp, Rahway, 2005. O148643 A1 7/2005 Rui et al. NJ (US) 2005/O187277 A1 8/2005 Malti et al. 2005/0255415 A1 11/2005 Louwet et al. (*) Notice: Subject to any disclaimer, the term of this 2005/0272765 A1 12/2005 Feng et al. patent is extended or adjusted under 35 2006.0160872 A1 7/2006 Norman et al. 2006/0287356 Al 12/2006 Iyengaret al. U.S.C. 154(b) by 0 days. 2007, OO15665 A1 1/2007 Potluri et al. 2007/0O32529 A1 2/2007 Takagi et al. (21) Appl. No.: 13/578,302 2008. O1325O1 A1 6/2008 Sun et al. (22) PCT Fled: Feb. 21, 2011 FOREIGN PATENT DOCUMENTS (86) PCT NO.: PCT/US2011/025585 DE 33 16095 A1 11, 1983 EP O120403 A2 10, 1984 S371 (c)(1), EP O126030 A2 11, 1984 (2), (4) Date: Aug. 10, 2012 EP 0.128862 A2 12, 1984 EP O1295.06 A2 12, 1984 (87) PCT Pub. No.: WO2O11A106273 (Continued) PCT Pub. Date: Sep. 1, 2011 OTHER PUBLICATIONS (65) Prior Publication Data Janssens, et al. Document No. 110:212855, retrieved from CAPLUS, Jun. 10, 1989.* US 2012/0309736A1 Dec. 6, 2012 Janssens, et al. Document No. 108:21891, retrieved from CAPLUS, Jan. 23, 1988.* Related U.S. Application Data Cancer and Metastasis Reviews (1998), 17(1), 91-106.* Science (1999), vol. 286, 531-537.* (60) Provisional application No. 61/307,909, filed on Feb. Cancer online, retrieved on Jul. 6, 2007. Retrieved from the 25, 2010. internet, URL http://www.nlm.nih.gov/medlineplus/cancer.html>.* Cancer online, retrieved on Jul. 6, 2007. Retrieved from the (51) Int. C. internet, URL: http://en.wikipedia.orglwikilCancer.* CO7D 235/06 (2006.01) CO7D 235/26 (2006.01) (Continued) C07D 235/28 (2006.01) Primary Examiner — Shawquia Young C07D 235/30 (2006.01) (74) Attorney, Agent, or Firm — Baerbel R. Brown; A6 IK 45/06 (2006.01) Catherine D. Fitch A6 IK3I/366 (2006.01) A 6LX3/397 (2006.01) (57) ABSTRACT A6 IK3I/484 (2006.01) Novel compounds of the structural formula (I) are activators A6 IK3I/4985 (2006.01) of AMP-protein kinase and are useful in the treatment, pre CO7D 40/12 (2006.01) vention and suppression of diseases mediated by the AMPK A6 IK3I/442 (2006.01) activated protein kinase. The compounds of the present inven CO7D 403/2 (2006.01) tion are useful in the treatment of Type 2 diabetes, CO7D 405/2 (2006.01) hyperglycemia, metabolic syndrome, obesity, hypercholes (52) U.S. C. terolemia, and hypertension. CPC ............ C07D405/12 (2013.01); C07D 235/26 (2013.01); A61K 45/06 (2013.01); A61 K 31/366 (2013.01); A61 K3I/397 (2013.01); (I) A6 IK3I/4184 (2013.01); A61 K3I/4985 (2013.01); C07D 401/12 (2013.01); A61 K 3 1/44.12 (2013.01); C07D 403/12 (2013.01) N Y USPC ..................... 514/387: 548/304.4: 548/307.1; )-x- NZ 548/307.4 N (58) Field of Classification Search CPC. C07D 235/06; C07D 235/26: C07D 235/28; R4 R5 CO7D 235/30 USPC .................. 548/304.4, 307.1, 307.4: 514/387 See application file for complete search history. 23 Claims, No Drawings US 8,895,596 B2 Page 2 (56) References Cited WO 2009/O19504 A1 2/2009 WO 2009/100 130 A1 8, 2009 WO 2010/036613 A1 4/2010 FOREIGN PATENT DOCUMENTS WO 2010/047982 A1 4, 2010 WO 2010/051176 A1 5, 2010 EP O161219 A2 11, 1985 WO 2010/051206 A1 5, 2010 EP O161220 A2 11, 1985 WO 2011/106273 A1 9, 2011 EP O161222 A2 11, 1985 WO 2012,116145 A1 8, 2012 EP O560407 A1 9, 1993 EP O637585 A1 2/1995 OTHER PUBLICATIONS EP O655439 A2 5, 1995 Lan, “An efficient method to access 2-substituted GB 2099167 A 12/1982 benzimiclazoles...”. Tetrahedron Letters, 2008, vol. 49, pp. 1910 JP 6298731 A 10, 1994 1914. JP 9227854. A 9, 1997 Pangano, "Optimization of protein kinase CK2 inhibitors derived JP 2002141067 A 5, 2002 from . .”. J. Med. Chem, 2004, vol. 47, pp. 6239-6247. JP 200467629. 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