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Eight. E. N. Spung Sapplication Is for Complete Arch R USO09556193B2 (12) United States Patent (10) Patent No.: US 9,556,193 B2 Apgar et al. (45) Date of Patent: Jan. 31, 2017 (54) BENZIMIDAZOLE (52) U.S. Cl. HEXAHYDROFURO3.2-BFURAN CPC ........... C07D 493/04 (2013.01); A61 K3I/366 DERVATIVES (2013.01); A61 K3I/397 (2013.01); A61 K 31/4184 (2013.01); A61K 31/4196 (2013.01); (71) Applicant: Merck Sharp & Dohme Corp., A6 IK3I/427 (2013.01); A61K 31/4245 Rahway, NJ (US) (2013.01); A61 K3I/454 (2013.01); A61 K s 3 1/4985 (2013.01); A61K 3 1/506 (2013.01); (72) Inventors: James M. Apgar, Highland, NJ (US); A61K3I/5377 (2013.01); tests Ashok Arasappan, Bridgewater, NJ (US);Eight. Tesfaye E. Biftu, N.Freehold, Spung NJ (US); (58) SapplicationField of Classification is for Searchcomplete arch R" Guidry, Cranford, NJ (US); Jacqueline (56) References Cited Hicks, Scotch Plains, NJ (US); Ahmet Kekec, Jersey City, NJ (US); Kenneth U.S. PATENT DOCUMENTS J. Leavitt, Mount Laurel, NJ (US); Bing Li, Towaco, NJ (US); Iyassu 6,312,662 B1 1 1/2001 Erion et al. s e.V. 6,489.476 B1 12/2002 Dang et al. Sebhat Jersey City, NJ (US), Xiaoxia 6,969,712 B2 * 1 1/2005 Okamoto ............. CO7D 235/28 Qian, New York, NY (US); Lan Wei, 514,218 Berkeley Heights, NJ (US); Robert R. 8,153,829 B2 4/2012 Lemaire et al. Wilkening, Maplewood, NJ (US); 9,290,517 B2 * 3/2016 Apgar .................. A61K 31,366 Zhicai Wu, Montvale, NJ (US) 2005, OO38068 A1 2/2005 Iyengar et al. (Continued) (73) Assignee: Merck Shapr & Dohme Corp., Rahway, NJ (US) FOREIGN PATENT DOCUMENTS (*)c Notice:- r Subject to any disclaimer, the term of this EPDE O12040333 16095 A2A1 10,5, 19831984 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 14/.420,011 OTHER PUBLICATIONS (22) PCT Filed: Aug. 16, 2013 Chemical Abstracts Registry No. 723241-28-9, indexed in the e - V.9 Registry file on STN CAS Online on Aug. 5, 2004.* Chemical Abstracts Registry No. 428869-59-4, indexed in the (86). PCT No.: PCT/US2O13/OSS246 Registry file on STN CAS Online Jun. 12, 2002.* S 371 (c)(1) Bergeron, R. et al., Effect of 5-Aminoimidazole-4-Caroboxamide (2) Date: s Feb 6, 2015 1-B-D-Ribofuranoside Infusion on In Vivo Glucose and Lipid a vs. Metabolism in Lean and Obese Zucker Rats, Diabetes, 2001, p. 1076-1082, vol. 50. (87) PCT Pub. No.: WO2014/031468 (Continued) PCT Pub. Date: Feb. 27, 2014 Primary Examiner — Laura L. Stockton (65) Prior Publication Data (74) Attorney, Agent, or Firm — Baerbel R. Brown; US 2015/0218183 A1 Aug. 6, 2015 Catherine D. Fitch (57) ABSTRACT O O The novel benzimidazole hexahydrofuro3.2-B furan Related U.S. Application Data derivatives of the present invention are activators of AMP (60) Provisional application No. 61/692,056, filed on Aug. protein kinase and may be useful in the treatment, preven 22, 2012. tion and suppression of diseases mediated by the AMPK activated protein kinase. The compounds of the present (51) Int. Cl. invention may be useful in the treatment of Type 2 diabetes, CO7D 49.3/04 (2006.01) hyperglycemia, metabolic syndrome, obesity, hypercholes A6 IK3I/366 (2006.01) terolemia, and hypertension. A 6LX 3L/397 (2006.01) A6 IK 3/4985 (2006.01) A6 IK 3/484 (2006.01) (I) A6 IK 3/496 (2006.01) 4. N / A6 IK 3/42.45 (2006.01) X-X A6 IK 3/427 (2006.01) VS Z A6 IK 3L/454 (2006.01) W A6 IK3I/506 (2006.01) A 6LX 3/5.377 (2006.01) A6 IK 45/06 (2006.01) 16 Claims, No Drawings US 9,556,193 B2 Page 2 (56) References Cited Buhl. E. 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E622-E629, vol. 279. in the Reulation of Ketone Body Production by Astrocytes, Journal of Neurochemistry, 1999, p. 1674-1682, vol. 73. * cited by examiner US 9,556,193 B2 1. 2 BENZMDAZOLE hypertriglyceridemia; (3) low high-density lipoprotein cho HEXAHYDROFURO3.2-BFURAN lesterol (HDL); (4) high blood pressure; and (5) elevated DERVATIVES fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these CROSS-REFERENCE TO RELATED symptoms is defined clinically in the Third Report of the APPLICATIONS National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cho This application is a U.S. National Phase application lesterol in Adults (Adult Treatment Panel III, or ATP III), under 35 U.S.C. S371 of PCT Application No. PCT/ National Institutes of Health, 2001, NIH Publication No. US2013/055246, filed on Aug. 16, 2013, which claims 10 01-3670. Patients with Metabolic Syndrome, whether or not priority from and the benefit of U.S. Provisional Application they have or develop overt diabetes mellitus, have an No. 61/692,056, filed Aug. 22, 2012. increased risk of developing the macrovascular and micro vascular complications that occur with Type 2 diabetes. Such BACKGROUND OF THE INVENTION as atherosclerosis and coronary heart disease. 15 There are several available treatments for Type 2 diabetes, Diabetes is characterized by elevated levels of plasma each of which has its own limitations and potential risks.
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