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US8513234.Pdf USOO851.3234B2 (12) United States Patent (10) Patent No.: US 8,513,234 B2 Isaacs et al. (45) Date of Patent: Aug. 20, 2013 (54) HIV INTEGRASE INHIBITORS 7,217,713 B2 5/2007 Crescenzi et al. 7,232,819 B2 6/2007 Di Francesco et al. 7,273,859 B2 9, 2007 Naidu (75) Inventors: Richt C. E. AARA 7,279.487 B2 10/2007 Egbertson et al. (US), Wayne J. Thompson, Lansdale, 7,414,045 B2 8/2008 Crescenzi et al. PA (US); Peter D. Williams, 7,419,969 B2 9/2008 Naidu et al. Harleysville, PA (US); Dai-Shi Su, 7,435,734 B2 10/2008 Crescenzi et al. Dresher, PA (US); Shankar 7,494.984 B2 2/2009 Banville et al. s s 7,504.405 B2 3/2009 Wang et al. Venkatraman, Lansdale, PA (US); 2004/0229909 A1 1 1/2004 Kiyama et al. Mark W. Embrey, Harleysville, PA 2007/0083045 A1 4/2007 Di Francesco et al. (US); Thorsten E. Fisher, Hatfield, PA 2007/011 1984 A1 5, 2007 Naidu et al. (US); John S. Wai, Harleysville, PA 2007/011 1985 A1 5, 2007 Naidu et al. (US); David C. Dubost, Collegeville, PA (Continued) (US); Richard G. Ball, Edison, NJ (US); Eric J. Choi, Westfield, NJ (US); Tao FOREIGN PATENT DOCUMENTS Pei, Morganville, NJ (US); Sarah L. EP 1698.628 A1 9, 2006 Trice, Glenside, PA (US); Neil WO 2005/061501 A2 7/2005 Campbell, Cherry Hill, NJ (US); (Continued) Matthew Maddess, Boston, MA (US); Peter E. Maligres, Fanwood, NJ (US); OTHER PUBLICATIONS Michael Shevlin, Plainfield, NJ (US); Ferrara et al. “Synthesis of a hexahydropyrimido 1.2-Olazepine-2- Zhiguo Jake Song. Edison, NJ (US); carboxamide derivative useful as an HIV integrase inhibitor'. Tetra Dietrich P. Steinhuebel, Boston, MA hedron Letters, 2007, vol. 48, pp. 8379-8382. (US); Neil A. Strotman, Monmouth Junction, NJ (US); Jingjun Yin, Green (Continued) Brook, NJ (US) Primary Examiner — Brenda Coleman (73) Assignee: Merck Sharp & Dohme Corp., 74) Attorney,ey, AgAgent, or Firm — Sheldon O. Herber, Jeffrey Rahway, NJ (US) P. Bergman (*) Notice: Subject to any disclaimer, the term of this (57) ABSTRACT patent is extended or adjusted under 35 - - - - - U.S.C. 154(b) by 482 days. Compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (21) Appl. No.: 12/572,341 (22) Filed: Oct. 2, 2009 (I) H3C-N 4 CH (65) Prior Publication Data N O US 201O/OO87419 A1 Apr. 8, 2010 O Y N RIA Related U.S. Application Data Ri? B (60) Provisional application No. 61/195.271, filed on Oct. X 2 RIP, 6, 2008. Clu H N. N. N. (51) Int. Cl. X2 N S1s CO7D 487/2 (2006.01) (52) U.S. Cl. O OH USPC ...................................... 514/214.02:540/579 (58) Field of Classification Search wherein X', X,Y, R'', R', RandR are defined herein. The USPC . 514/214.02: 540/579 compounds are useful for the prophylaxis or treatment of See application file for complete search history. infection by HIV and the prophylaxis, treatment, or delay in the onset or progression of AIDS. The compounds are (56) References Cited employed against HIV infection and AIDS as compounds per se (or as hydrates or solvates thereof) or in the form of phar U.S. PATENT DOCUMENTS maceutically acceptable salts. The compounds and their salts 7,037,908 B2 5, 2006 Naidu et al. 7,115,601 B2 10/2006 Naidu et al. can be employed as ingredients in pharmaceutical composi 7,135,467 B2 11/2006 Walker et al. tions, optionally in combination with other antivirals, immu 7,157.447 B2 1/2007 Naidu et al. nomodulators, antibiotics or vaccines. Processes for making 7,169,780 B2 1/2007 Crescenzi et al. 7,173,022 B2 2/2007 Naidu et al. compounds of Formula I and intermediates thereof are also 7,176, 196 B2 2/2007 Naidu et al. described. 7,192,948 B2 3/2007 Banville et al. 7,211,572 B2 5/2007 Miyazaki et al. 21 Claims, 5 Drawing Sheets US 8,513,234 B2 Page 2 (56) References Cited OTHER PUBLICATIONS U.S. PATENT DOCUMENTS Kinzeletal. “The synthesis of tetrahydropyridopyrimidones as a new scaffold for HIV-1 integrase inhibitors'. Tetrahedron Letters, 2007. 2007, 0112190 A1 5/2007 Naidu 2007. O142635 A1 6, 2007 Askin et al. vol. 48, pp. 6552-6555. 2007/O149556 A1 6, 2007 Mikamiyama et al. Muraglia et al. “Design and Synthesis of Bicyclic Pyrimidinones as 2007/0281917 A1 12, 2007 Naidu et al. Potent and Orally Bioavailable HIV-1 Integrase Inhibitors'. Journal 2008.0004265 A1 1, 2008 Walker et al. of Medicinal Chemistry, 2008, vol. 51, pp. 861-874. 2008. O176869 A1 T/2008 Crescenzi et al. Pearl et al. "A structural model for the retroviral proteases”. Nature, 2008/024.9112 A1 10, 2008 Wang et al. 1987 vol. 329, pp. 351-354. 2008/0275004 A1 11, 2008 Crescenzi et al. Power et al. "Nucleotide Sequence of SRV-1, a Type D Simian 2009.0171082 A1 T/2009 Wang et al. Acquired Immune Deficiency Syndrome Retrovirus', Science, 1986, vol. 231, pp. 1567-1572. Ratner et al. “Complete nucleotide sequence of the AIDS virus, FOREIGN PATENT DOCUMENTS HTLV-III', Nature, 1985, vol. 313, pp. 277-284. WO 2006/060225 A2 6, 2006 Toh et al. “Close structural resemblance between putative WO 2006,103399 A1 10, 2006 polymerase of a Drosophila transposable genetic element 17.6 and WO 2007/058646 A1 5/2007 pol gene product of Moloney murine leukaemia virus'. The EMBO WO 2007/06431.6 A1 6, 2007 Journal, 1985, vol. 4, pp. 1267-1272. U.S. Patent Aug. 20, 2013 Sheet 1 of 5 US 8,513,234 B2 22500 10000 2500 5 10 15 20 25 30 35 20 (degrees) F.G. 1 U.S. Patent Aug. 20, 2013 Sheet 2 of 5 US 8.513,234 B2 6400 1 3600 1 6 OO 400 5 10 15 20 25 30 35 20 (degrees) FG.2 U.S. Patent Aug. 20, 2013 Sheet 3 of 5 US 8,513,234 B2 6400 3600 3. 1600 5 : T 400 twk. O rt it 10 20 30 40 20 (degrees) FIG.3 U.S. Patent Aug. 20, 2013 Sheet 4 of 5 US 8,513,234 B2 2 1600 3.s e 400 |W O -t-t-t-t-t-t-t- 10 20 30 20 (degrees) FIG.4 U.S. Patent Aug. 20, 2013 Sheet 5 of 5 US 8,513,234 B2 5 10 15 20 25 30 35 20 (degrees) FIG.5 US 8,513,234 B2 1. 2 HIV INTEGRASE INHIBITORS The following references are of interest as background: Kinzel et al., Tet. Letters 2007, 48(37): pp. 6552-6555 CROSS-REFERENCE TO RELATED discloses the synthesis of tetrahydropyridopyrimidones as a APPLICATIONS scaffold for HIV-1 integrase inhibitors. Ferrara et al., Tet. Letters 2007, 48(37), pp. 8379-8382 discloses the synthesis of a hexahydropyrimido 1,2-a This application claims the benefit of U.S. Provisional azepine-2-carboxamide derivative useful as an HIV integrase Application No. 61/195.271 (filed Oct. 6, 2008), the disclo inhibitor. sure of which is hereby incorporated by reference in its Muraglia et al., J. Med. Chem. 2008, 51:861-874 discloses entirety. 10 the design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors. FIELD OF THE INVENTION US2004/229909 discloses certain compounds having inte grase inhibitory activity. The present invention is directed to certain 2-(substituted U.S. Pat. No. 7,232,819 and US 2007/0083045 disclose benzyl)aminocarbonyl)-3-hydroxy-4-oxo-4,6,7,8,9,10 15 certain 5,6-dihydroxypyrimidine-4-carboxamides as HIV hexahydropyrimido 1,2-aazepin-10-yl)-N,N',N'-trialkyle integrase inhibitors. U.S. Pat. No. 7,169,780, U.S. Pat. No. 7,217,713, and US thanediamide compounds, certain 2-(substituted benzyl) 2007/0123524 disclose certain N-substituted 5-hydroxy-6- aminocarbonyl)-3-hydroxy-4-oxo-6,7,9,10-tetrahydro-4H oxo-1,6-dihydropyrimidine-4-carboxamides as HIV inte pyrimido 1,2-d1.4 oxazepin-10-yl)-N N grase inhibitors. N'-trialkylethanediamide compounds, and pharmaceutically U.S. Pat. No. 7,279.487 discloses certain hydroxynaphthy acceptable salts thereof, their synthesis, and their use as ridinone carboxamides that are useful as HIV integrase inhibitors of the HIV integrase enzyme. The compounds and inhibitors. pharmaceutically acceptable salts thereof of the present U.S. Pat. No. 7,135,467 and U.S. Pat. No. 7,037,908 dis invention are useful in the prophylaxis or treatment of infec 25 close certain pyrimidine carboxamides that are useful as HIV tion by HIV and in the prophylaxis, delay in the onset or integrase inhibitors. progression, or treatment of AIDS. U.S. Pat. No. 7,211,572 discloses certain nitrogenous con densed ring compounds that are HIV integrase inhibitors. BACKGROUND OF THE INVENTION U.S. Pat. No. 7,414,045 discloses certain tetrahydro-4H 30 pyrido 1,2-alpyrimidine carboxamides, hexahydropyrimido A retrovirus designated human immunodeficiency virus 1.2-aaZepine carboxamides, and related compounds that are (HIV), particularly the strains known as HIV type-1 (HIV-1) useful as HIV integrase inhibitors. virus and type-2 (HIV-2) virus, is the etiological agent of the WO 2006/103399 discloses certain tetrahydro-4H-pyrimi complex disease that includes progressive destruction of the dooxazepine carboaxmides, tetrahydropyrazinopyrimidine immune system (acquired immune deficiency syndrome; 35 carboxamides, hexahydropyrimidodiazepine carboxamides, AIDS) and degeneration of the central and peripheral nervous and related compounds that are useful as HIV integrase system.
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