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(12) United States Patent (10) Patent No.: US 9,206,198 B2 Ding Et Al

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(12) United States Patent (10) Patent No.: US 9,206,198 B2 Ding Et Al USOO9206198B2 (12) United States Patent (10) Patent No.: US 9,206,198 B2 Ding et al. (45) Date of Patent: Dec. 8, 2015 (54) INHIBITORS OF THE RENAL OUTER (56) References Cited MEDULLARY POTASSIUM CHANNEL U.S. PATENT DOCUMENTS Applicant: Merck Sharp & Dohme Corp., (71) 2.988,551 A 6, 1961 Morren Rahway, NJ (US) 3.435,002 A 3, 1969 Holub 3,632,608 A 1, 1972 Holub (72) Inventors: Fa-Xiang Ding, Staten Island, NY (US); 3,749,722 A 7, 1973 Holub Shuzhi Dong, Plainsboro, NJ (US); 4,579,863. A 4, 1986 Horwell et al. Jessica Frie, Harleysville, PA (US); Xin 4,806,536 A 2f1989 Cross et al. 4,992,547 A 2f1991 Berner et al. Gu, Scotch Plains, NJ (US); Jinlong 5,145,885 A 9, 1992 Berner et al. Jiang, Scotch Plains, NJ (US); 5,215,989 A 6/1993 Baldwin et al. Alexander Pasternak, Princeton, NJ 5,614,526 A 3, 1997 Godel et al. (US); Haifeng Tang, Metuchen, NJ 5,736,546 A 4, 1998 Kawashima et al. (US); Zhicai Wu, Montvale, NJ (US); (Continued) Yang Yu, Edison, NJ (US); Takao Suzuki, Pudong Shanghai (CN) FOREIGN PATENT DOCUMENTS (73) Assignee: Merck Sharp & Dohme Corp., EP O099.148 B1 2/1988 Rahway, NJ (US) EP O175376 B1 4f1991 (Continued) (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Felix; Assay and Drug Development Technologies, 2012, 10, 417 431.* Doggrell; Cardiovascular Research, 1998, 39, 89-105.* (21) Appl. No.: 14/569,858 ACCF/AHA Practice Guideline, 2009 Focused update incorporated into the ACC/AHA 2005 guidelines . Circulation, 2009, e391 (22) Filed: Dec. 15, 2014 e436, 119. Baltzly, R., The preparation of N-mono-substituted and unsym (65) Prior Publication Data metrically disubstituted piperazines, J. Am. Chemoc., 1944, 263 266, 66. US 2015/OO99729 A1 Apr. 9, 2015 Bhave, G., Small-molecule modulators of inward rectifier K-- chan nels: recent advances and future possibilities, Future Med Chem, 2010, 757-774, 205). Related U.S. Application Data Bhave.G. Development of a selective Small-molecule inhibitor Kirl. (62) Division of application No. 13/951,096, filed on Jul. 1, the renal outer medullary potassium channel, Mol. Pharmacol., 25, 2013, now Pat. No. 8,952,166. 2011, 42-50, 79. (Continued) (60) Provisional application No. 61/759,040, filed on Jan. 31, 2013, provisional application No. 61/691,390, Primary Examiner — Janet L. Andres filed on Aug. 21, 2012. Assistant Examiner — Daniel Carcanague (74) Attorney, Agent, or Firm — Nicole M. Beeler; (51) Int. C. Catherine D. Fitch C07D 47L/20 (2006.01) A6 IK3I/435 (2006.01) (57) ABSTRACT A6 IK3 L/46 (2006.01) The present invention provides compounds of Formula I A6 IK3I/5386 (2006.01) CO7D 47L/TO (2006.01) A6 IK 45/06 (2006.01) CO7D 49.8/20 (2006.01) A 6LX3L/21995 (2006.01) CO7D 45L/00 (2006.01) C07D 519/00 (2006.01) (52) U.S. C. CPC ............ C07D 498/20 (2013.01); A61K3I/435 (2013.01); A61 K3I/46 (2013.01); A61 K 3 1/4995 (2013.01); A61 K3I/5386 (2013.01); A61K 45/06 (2013.01); C07D 451/00 (2013.01); C07D 471/10 (2013.01); C07D 471/20 (2013.01); C07D 519/00 (2013.01) and the pharmaceutically acceptable salts thereof, which are (58) Field of Classification Search inhibitors of the ROMK (Kir1.1) channel. The compounds CPC. C07D 519/00; C07D 451/00; C07D 471/10; may be used as diuretic and/or natriuretic agents and for the CO7D 498/20: A61K 45/06; A61K 31/435: therapy and prophylaxis of medical conditions including car A61K 31/46; A61K 31/4995; A61K 31/5386 diovascular diseases such as hypertension, heart failure and USPC ........................................... 514/278; 546/200 conditions associated with excessive salt and water retention. See application file for complete search history. 12 Claims, No Drawings US 9,206,198 B2 Page 2 (56) References Cited WO 2013,062892 A1 5, 2013 WO 2013062900 A1 5, 2013 U.S. PATENT DOCUMENTS WO 2013066714 A1 5, 2013 WO 2013066717 A1 5, 2013 6,258,813 B1 7/2001 Arlt et al. WO 2013066718 A2 5, 2013 6,787,543 B2 9/2004 Take et al. WO 2013.09.0271 A1 6, 2013 2004/0204404 A1 10, 2004 Zelle et al. 2005/0215526 A1 9, 2005 Hulme et al. OTHER PUBLICATIONS 2005/0267121 A1 12, 2005 Li et al. Brater et al., Diuretic Therapy, Drug Therapy, 1998,387-395,339, 2006/0183739 A1 8/2006 Tsaklakidis et al. Brewster et al. Antihypertensive 14-bis (2-indol-3- 2006, O183742 A1 8, 2006 Mederski et al. ylethyl)piperazines, Chimie Ther. 1973, 169-172 (English trans.), 2. 2006/0211692 A1 9, 2006 Mederski et al. Cerkvenik-Flajs V. Determination of residues of azaperone in the 2007,0004750 A1 1/2007 LOrsbach et al. ity, lighgatography with fluorescence, Anal. Chim. SSA A. 158. Mcterial ChemicalCia., AbstractsJ tJ OZ, (2004),you. Abstract No. 697771-49-6, 1,3- 2010/0286123 A1 11/2010 Pasternak eral Isobenzofurandione 5-4-(5-chloro-2-methoxyphenyl) sulfonyl 1- . Cheymol et al., Increase in the effects of epinephrine and acetylcho FOREIGN PATENT DOCUMENTS line . Comptes Rendus des Seances de la Societe de Biologie, 1951, 496-499 (English trans.), 145. E. 19: A. 1399, Dorwald, Side reactions in Organic Synthesis: A Guide to Successful FR 2673 182 8, 1992 Synthesis Design, 2005, Chapter 1. FR 2673182 A1 8, 1992 Fallen, K., The Kirchannel immunoglobuling domain is essential for GB 949088 A 2, 1964 Kirl. 1 (ROMK) thermodynamic stability, trafficing and gating, GB 1575310 A 9, 1980 Channels, 2009, 57-66, 3. GB 2116967 T 1986 Felker et al. Diuretic strategies in patients with acute decompensated JP 10203986 8, 1998 heart failure, New Eng. J. Med., 2011, 797-805, 364. WO 9744329 11, 1997 Frank, Managing hypertension using combination therapy, Am. Fam. WO 0051611 A1 9, 2000 Physician, 2008, 1279-1286, 77. W. 85. A. g: International Search Report for PCT/US2013/052079 mailed on WO 2004020422 A1 3f2004 Ri 15, 2013, 8 pages. WO O232874 4/2004 ulkarni, YD, Possible antifertility agents, part III. Synthesis of WO 2004037817 A1 5, 2004 4-(substituted aminomethyl)-5,6,7-trimethoxy phthalid WO 2004O46110 6, 2004 (abstract)), Biol. Mem., 1987, 141-144, 13. WO 2005037843 4, 2005 Lanyi et al., Piperazine-Derivatives II, Res. Lab, of Chinoin-Fabrik WO 2005044797 5, 2005 Chemisch-Pharma. Prod., 1968, 1431-1435 (English trans.), 18. WO 2006.034341 A2 3, 2006 Lewis, L. M., High-throughput screening reveals a small-molecule WO 2006.034769 A1 4/2006 inhibitor of the Renal Outer Medullary Potassium Channel and Kir7. WO 2006098342 A1 9, 2006 1, Mol. Pharncol., 2009, 1094-1 103,76. WO 20061291.99 A1 12/2006 Lutz, R. E., Antimalarials. Some Piperazine Derivatives, J. Org. WO 2007075629 A2 7/2007 Chem., 1947, 771-775, 12, BO. W 39. A2 33. Miyake et al., Synthesis of 1-Substituted isochroman.... Takeda Res. WO 2009 1495.08 11, 2009 Lab., 1982, 24-40 (English trans.), 41. WO 2010.129379 A1 11, 2010 Sica, D. A., Diuretic use in renal disease, Nature, 2012, 100-109, 8. WO 20120581 16 A1 5, 2012 Zejc et al., Piperazine derivative of dimethylxanthines, Polish J. WO 2012058134 A1 5, 2012 Pharmacol. & Pharm., 1975, 311-316 (English trans.), 27. WO 20130284.74 A1 2, 2013 WO 2013 0398O2 A1 3f2013 * cited by examiner US 9,206,198 B2 1. 2 INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL VU590 BACKGROUND OF THE INVENTION ON y The Renal Outer Medullary Potassium (ROMK) channel (Kir1.1) (see e.g., Ho, K., et al., Cloning and expression of an - O inwardly rectifying ATP-regulated potassium channel. O u?, Nature, 1993, 362(6415): p. 31-8.1, 2; and Shuck, M. E., et al., Cloning and characterization of multiple forms of the 10 ( NONO human kidney ROM-K potassium channel, J Biol Chem, 1994, 269(39): p. 24261-70) is a member of the inward rec VU591 tifier family of potassium channels expressed in two regions of the kidney: thick ascending loop of Henle (TALH) and 15 cortical collecting duct (CCD) (see Hebert, S. C., et al., Molecular diversity and regulation of renal potassium chan nels, Physiol Rev. 2005, 85(1): p. 319-713). At the TALH, ROMK participates in potassium recycling across the luminal -Sirr membrane which is critical for the function of the Na/K/ 2Cl co-transporter, the rate-determining step for salt reuptake in this part of the nephron. At the CCD, ROMK Patent application publication number WO2010/129379, provides a pathway for potassium secretion that is tightly published Nov. 11, 2010 having common representative coupled to Sodium uptake through the amiloride-sensitive Merck Sharp & Dohme Corp., (also published as US2010/ Sodium channel (see Reinalter, S.C., et al., Pharmacotyping 25 0286123 on same date), describes ROMK inhibitors having of hypokalaemic salt-losing tubular disorders, Acta Physiol the generic formula: Scand, 2004, 181 (4): p. 513-21; and Wang, W., Renal potas sium channels: recent developments, Curr Opin Nephrol Hypertens, 2004, 13(5): p. 549-55). Selective inhibitors of the ROMK channel (also referred to herein as inhibitors of 30 ROMK or ROMK inhibitors) are expected to represent novel diuretics for the treatment of hypertension and other condi tions where treatment with a diuretic would be beneficial with potentially reduced liabilities (i.e., hypo- or hyperkalemia, new onset of diabetes, dyslipidemia) over the currently used 35 clinical agents (see Lifton, R. P. A. G. Gharavi, and D.
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