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. A 3, 2004 Bortolato, “In slico binding free energy predictability by using . JP 20073.9406 A 2, 2007 J. Chem. Inf. Model, 2007, vol. 47, pp. 572-582. WO 92.20642 A1 11, 1992 Narayan, “Heterocyclic systems containing bridgehead WO 93,07124 A1 4f1993 nitrogen . .”. Indian J. Chem., 1986, pp. 267-270. WO 94,08982 A1 4, 1994 Czarnocka-Janowicz. “Derivatives of 4(7)-methyl-and 5,6- WO 95/29897 A1 11, 1995 dimethyl . .”. Pol. J. Pharmacol. Pharm, 1977, vol. 29, pp. 69-73. WO 98.08818 A1 3, 1998 Bindal, “Heterocyclic systems containing bridgehead nitrogen . WO 98.39342 A1 9, 1998 Indian J. of Chemistry, 1986, vol. 25B, pp. 807-811. WO 98.39343 A1 9, 1998 Tunnicliff, “The action of structural analogues of gamma WO 98.39344 A1 9, 1998 aminobutyric acid...”. Drug Develop. Res, 1984, vol. 4, pp. 51-59. WO 98.56761 A2 12, 1998 Lee, “Obesity: The role of hypothalamic AMP-activated WO 99.01454 A1 1, 1999 protein...”. The Int'l J. of Biochem & Cell Biol. 2005, vol. 37, pp. WO 99.43672 A1 9, 1999 2254-2259. WO 99.45O16 A2 9, 1999 Hardie, AMP-activated protein kinase as a drug target'. Annu. Rev. WO OO?O3997 A1 1/2000 Pharmacol. Toxicol. 2007, vol. 47, pp. 185-210 WO OO 14095 A1 3, 2000 vol. 47, pp. - . s WO OO,52015 A1 9, 2000 Musi, "AMP-activated protein kinase and type 2 diabetes'. Current WO 01.25238 A2 4, 2001 Med. Chem, 2006, vol. 13, pp. 583-589. WO O1, 53272 A1 T 2001 Kim, "Metformin inhibits hepatic gluconeogenesis . .”. Diabetes, WO O1,53291 A1 T 2001 2008, vol. 57, pp. 306–314. WO O2/40019 A1 5, 2002 Towler, AMP-activated protein kinase in metabolic control . Cir WO O2/O76454 A1 10, 2002 culation Res., 2007, vol. 100, pp. 328-341. WO O2/O92575 A1 11, 2002 Ofir, Increased glycogen stores due to gamma-AMPK overexpres WO 02/100833 A1 12/2002 sion . Biochem. Pharmacol., 2008, vol. 75, pp. 1482-1491. WO O3, 18061 A1 3, 2003 Hardie, “Role of Amp-activated protein kinase ... ', FEBS Letters, WO O3,O24937 A1 3f2003 2008, vol. 582, pp. 81-89. WO O3,062392 A2 T 2003 Labanauskas, “Synthesis and antiphlogistic activity of novel . WO 2004/035740 A2 4/2004 Khimiko-Farmatsevticheskii Zhurnal, 1998, Vo. 32, pp. 15-16. WO 2004/0439 13 A2 5, 2004 Viollet, “Targeting AMP-activated protein kinase as a novel . .”. WO 2004/071447 A2 8, 2004 Diabets & Metabolism, 2007, vol. 33, pp. 395-402. WO 2004/085425 A1 10, 2004 Winder, "AMP-activated protein kinase, a metabolic master . .”. WO 2005/OO2520 A2 1, 2005 Am. J. Physiol, 1999, vol. 277, pp. El-E10. WO 2005/OO9389 A2 2, 2005 Rebstock, "The synthesis of several acid analogs ... ', Ph.D. thesis, WO 2005.009997 A1 2/2005 Michigan State University, 1956, pp. 5831-5832. WO 2005/O18672 A1 3, 2005 Rebstock, “Effect of chemical structure on the growth WO 2005/02O892 A2 3, 2005 inhibition . .”. Ph.D. theis, Michigan State University, 1956, pp. WO 2005/028624 A2 3, 2005 19-22. W. 38885 A: 3.399 Bergeron, R. et al., “Effect of 5-Aminoimidazole-4-Carboxamide-1- WO 2005/047266 A1 5, 2005 B-n-Ribofuranoside Infusion on InVivo Glucose and Lipid Metabo WO 2005/051298 A2 6, 2005 lism in Lean and Obese Zucker Rats', Diabetes, 2001, pp. 1076-, vol. WO 2005/051298 A3 6/2005 50. WO 2005,121132 A1 12/2005 Blazquez, C, et al., “The AMP-Activated Protein Kinase Is Involved WO 2006/018850 A2 2, 2006 in the Regulation of Ketone Body Production by Astrocytes”,Journal WO 2006/018850 A3 2, 2006 of Neurochemistry, 1999, pp. 1674-, vol. 73. WO 2006/030.031 A1 3, 2006 Buhl, E. S. et al., “Long-Term AICAR Administration Reduces meta W. 29: : A. 2.3. bolic Disturbances and Lowers Blood Pressure in Rats Displaying WO 2006/053342 A2 9, 2006 in the Insulin Resistance Syndrome', Diabetes, 2002, pp. W. 3:39: A: 23: Butler, A.E., et al., “B-Cell Deficit and Increased B-Cell Apoptosis in WO 2006/116412 A2 11/2006 Hijmans With Type 2 Diabetes', Diabetes, 2003, pp. 102-, vol. 52. WO 2006/126171 A2 11/2006 Carling, D. et al., “A common Bicyclic protein kinase cascade inac WO 2006/126171 A3 11 2006 tivates the regulatory enzymes of fatty acid and cholesterol WO 2007/OO7463 A1 1, 2007 biosynthesis”, FEB, 1987, pp. 217-222, vol. 223, No. 2. WO 2007/007464 A1 1, 2007 Chen, Z-P, et al., “AMP-activated protein kinase phosphorylation of WO 2007/063993 A1 6, 2007 endothelial NO synthase”, FEB Letters, 1999, pp.