US00877914.4B2 (12) United States Patent (10) Patent No.: US 8,779,144 B2 Kelly et al. (45) Date of Patent: *Jul. 15, 2014 (54) BICYCLOHETEROARYL COMPOUNDSAS (56) References Cited P2X7 MODULATORS AND USES THEREOF U.S. PATENT DOCUMENTS (75) Inventors: Michael G. Kelly, Thousand Oaks, CA (US); John Kincaid, San Mateo, CA 5,095,103 A 3, 1992 Hoechstetter (US); Yunfeng Fang, Foster City, CA 5,484.926 A 1/1996 Dressman et al. 5,670.517 A 9/1997 Choy et al. (US); Jianhua He, legal representative, 6,110,934. A * 8/2000 Harling et al. ................ 514,307 Foster City, CA (US); Yeyu Cao, Foster 7,402,596 B2 7/2008 Kelly et al. City, CA (US); Carl Kaub, San Mateo, CA (US); Sumithra Gowlugari, San FOREIGN PATENT DOCUMENTS Mateo, CA (US) DE 39 42 893 A1 6, 1991 (73) Assignee: Evotec (US) Inc., South San Francisco, JP 2006220522 8, 2006 CA (US) WO WO94/17066 8, 1994 WO WO94,27969 12/1994 (*) Notice: Subject to any disclaimer, the term of this WO WO95/09843 4f1995 patent is extended or adjusted under 35 WO WOO3,068743 8, 2003 U.S.C. 154(b) by 1644 days. WO WOO3,080579 10, 2003 WO WO 2004/106305 12, 2004 This patent is Subject to a terminal dis WO 2005.009968 2, 2005 claimer. WO WO 2005/087767 9, 2005 WO WO 2005/087768 9, 2005 Appl. No.: 11/722,514 WO WO 2005,105814 11, 2005 (21) WO WO 2005.115986 12/2005 WO WO 2006/005.941 1, 2006 (22) PCT Fled: Mar. 16, 2007 WO WO 2006/029210 3, 2006 WO 2006102,588 9, 2006 (86) PCT NO.: PCT/US2OOTFOO6685 WO WO 2006/0993.79 9, 2006 S371 (c)(1), WO WO 2006,102610 9, 2006 (2), (4) Date: Sep. 28, 2010 (Continued) OTHER PUBLICATIONS (87) PCT Pub. No.: WO2OOTA10916O Silva, A., Mini-Reviews in Medicinal Chemistry, 2005, vol. 5, pp. PCT Pub. Date: Sep. 27, 2007 893-014. Mathison, I et al J Med Chem 1973 vol. 16 pp. 332-338.* (65) Prior Publication Data Patani, G. et al., Chem. Rev. 1996, vol. 96, pp. 3147-3176.* Baskin, I.I. et al., “Quantitative relation between the mutagenic activ US 2011 FO118287 A1 May 19, 2011 ity of heterocyclic analogs of pyrene and phenanthrene and their structure.” Doklady Akademii Nauk, 1994, 339(1): 106-8. Related U.S. Application Data (60) Provisional application No. 60/782,782, filed on Mar. (Continued) 16, 2006, provisional application No. 60/783,121, Primary Examiner — Janet Andres filed on Mar. 16, 2006, provisional application No. Assistant Examiner — Heidi Reese 60/783,304, filed on Mar. 16, 2006, provisional application No. 60/782,923, filed on Mar. 16, 2006, (74) Attorney, Agent, or Firm — Klauber & Jackson LLC provisional application No. 60/782.973, filed on Mar. 16, 2006, provisional application No. 60/783,590, (57) ABSTRACT filed on Mar. 15, 2006, provisional application No. Bicycloheteroaryl compounds are disclosed that have a for 60/782,922, filed on Mar. 16, 2006, provisional mula represented by the following: application No. 60/782,776, filed on Mar. 16, 2006, provisional application No. 60/782,775, filed on Mar. 16, 2006, provisional application No. 60/783,748, filed on Mar. 16, 2006, provisional application No. R3s, In 1 B 60/782,781, filed on Mar. 16, 2006, provisional Y O R.' R" application No. 60/831,416, filed on Jul. 17, 2006, provisional application No. 60/918,086, filed on Mar. A 21 >{ R1 15, 2007, provisional application No. 60/846,993, filed on Sep. 25, 2006. Ws-w H (51) Int. C. C07D 217/00 (2006.01) The compounds may be prepared as pharmaceutical compo A6 IK3I/47 (2006.01) sitions, and may be used for the prevention and treatment of a (52) U.S. C. variety of conditions in mammals including humans, includ USPC ........................................... 54.6/139; 514/311 ing by way of non-limiting example, pain, inflammation, (58) Field of Classification Search traumatic injury, and others. None See application file for complete search history. 51 Claims, No Drawings US 8,779,144 B2 Page 2 (56) References Cited derivatives of phenanthridone and dioxotetrahydrodiazapyrene.” Khimiya Geterotsiklicheskikh Soedinenii, 1981, (3): 394-7. Migachev, G.I. et al. “Studies on phenanthridone and FOREIGN PATENT DOCUMENTS dioxotetrahydrodiazapyrene. 3. Study of the nitration of 5 H-phenanthridin-6-one and its derivatives.” Khimiya WO WO 2006,104141 10, 2006 Geterotsiklicheskikh Soedinenii, 1981, (3): 388-93. WO WO 2006/121831 11, 2006 Migachev, G.I. etal, “Cyclization reaction in a series of diphenic acid WO WO 2006/123061 11, 2006 derivatives. IV. Study of the nitration of 2,6-biphenyldicarboxylic WO WO 2007/0085O2 1, 2007 acid and the reduction of its nitro derivatives.” Zhurnal WO WO 2007/030761 3, 2007 Organicheskoi Khimi, 1979, 15(7): 1491-8. WO WO 2007/079162 7/2007 Migachev, G.I. et al. “Synthesis of 5,9-dioxo-4.5.9,10-tetrahydro WO 2008112205 9, 2008 4, 10-diazapyrene.” Zhurnal Vsesoyuznogo Khimicheskogo OTHER PUBLICATIONS Obshchestva im. D. I. Mendeleeva, 1978, 23(3): 351-2. Coffin, B. et al. “4, 10-Diazapyrenes,” Journal of the Chemical Soci Mitchell, G. et al., “1.3.4(2H)-Isoquinolinetrione herbicides: novel ety, 1965, 3379-82. redox mediators of photosystem I.” Pesticide Science, 1995, 44(1): Ding. Q. et al. “Synthesis and antitumor cytotoxicity evaluation of 49-58. Morii, N. etal, "Orientation of Dye Molecules in DNA-Based Films pyrido4,3,2-de]quinolines and isoquinolino6,5,4,3- with Chain Alignment and Judgment of Their DNA-Binding Modes.” cdelquinolines.” Anti-Cancer Drug Design, 2000, 15(2): 99-108. Journal of Physical Chemistry B, 2005, 109(32): 15636-15644. Ding, Q. etal, “Reactions of 1H-2,3-diketopyrido4,3,2-de]quinoline Reuveni, H. etal, “Toward a PKB Inhibitor: Modification of a Selec with acetone and acetophenone: a novel synthesis of the tive PKA Inhibitor by Rational Design.” Biochemistry, 2002, 41(32): isoquinolino 6.5.4.3-cdequinoline nucleus.” Heterocyclic Commu 10304-10314. nications, 1998, 4(6): 535-545. Sanchez-Martinez, C. et al., "Arylalpyrrolo5,4-ccarbazoles as Frey, H.M. etal, “The photolysis of 3-tert-butyldiazirine,” Journal of selective cyclin D1-CDK4 inhibitors.” Bioorganic & Medicinal the Chemical Society, 1965, 3101-8. Chemistry Letters, 2003, 13(21): 3835-3839. Kalish, V. J. et al. “Structure-based drug design of nonpeptidic P2 Zhang, Y. etal, “A Novel Lumazine Synthase Inhibitor Derived from Substituents for HIV-1 protease inhibitors.” Bioorganic & Medicinal Oxidation of 1,3,6,8-Tetrahydroxy-2,7-naphthyridine to a Chemistry Letters, 1995, 5(7): 727-32. Tetraazaperylenehexaone Derivative.” Journal of Organic Chemistry, Lyubimova, I.K. et al., “Computer-aided prediction of the mutagenic 2007, 72(8): 2769-2776. activity of Substituted polycyclic compounds. Biology Bulletin, Zhu, G. et al. “Synthesis of quinolinyl isoquinolinylalpyrrolo 2001, 28(2): 139-145. 3,4-c carbazoles as cyclin D1/CDK4 inhibitors.” Bioorganic & Migachev, G.I., et al. “Synthesis of trinitro- and triamino-Substituted Medicinal Chemistry Letters, 2003, 13(7): 1231-1235. tetrahydrodiazapyrene phenanthridones and their derivatives.” Baraldi, et al., Bioorganic & Medicinal Chemistry Letters, “Synthe Zhurnal Vsesoyuznogo Khimicheskogo Obshchestva im. D.I. sis of Conformationally Constrained Analogues of KN62, a Potent Mendeleeva, 1981, 26(4): 476-8. Antagonist of the P2X7-Receptor.” 2000; 10: 681-684. Migachev, G.I. et al. “Studies on phenathridone and dioxotetrahydrodiazapyrene. 4. Synthesis of amino-Substituted * cited by examiner US 8,779,144 B2 1. 2 BICYCLOHETEROARYL COMPOUNDSAS rP2X, is structurally related to other members of the P2X P2X7 MODULATORS AND USES THEREOF family but it has a longer cytoplasmic C-terminus domain (there is 35-40% amino acid identity in the corresponding CROSS REFERENCE TO RELATED region of homology, but the C-terminus is 239 amino acids APPLICATIONS long in the rP2X, receptor compared with 27-20 amino acids in the others). The rP2X, receptor functions both as a channel The present application is a National Stage Application permeable to Small cations and as a cytolytic pore. Brief claiming the priority of co-pending PCT Application No. applications of ATP (1-2s) transiently open the channel, as is PCT/US07/06685 filed Mar. 16, 2007, which in turn, claims the case of other P2X receptors. Repeated or prolonged appli priority from U.S. Provisional application Ser. Nos. 60/782, 10 cations of agonist cause cell permeabilization reducing the 782 filed Mar. 16, 2007; 60/783,121 filed Mar. 16, 2006; extracellular magnesium concentration potentiates this 60/783,304 filed Mar. 16, 2006; 60/782,923 filed Mar. 16, effect. The unique C-terminal domain of rP2X, is required for 2006; 60/782,973 filed Mar. 16, 2006; 60/783,590 filed Mar. cell permeabilization and the lytic actions of ATP (Suprenant 16, 2006; 60/782,922 filed Mar. 16, 2006; 60/782,776 filed etal, Science 272:735 (1996)). Mar. 16, 2006; 60/782,775 filed Mar. 16, 2006; 60/783,748 15 The P2Z/rP2X, receptor has been implicated in lysis of filed Mar. 16, 2006; 60/782,781 filed Mar. 16, 2006; 60/831, antigen-presenting cells by cytotoxic T lymphocytes, in the 416 filed Jul. 17, 2006; 60/846,993 filed Sep. 25, 2006 and mitogenic stimulation of human T lymphocytes, as well as in 60/918,086 filed Mar. 15, 2007. Applicants claim the benefits the formation of multinucleated giant cells (Blanchard et al. of 35 U.S.C. S 120 as to the PCT application and priority Blood 85:3173 (1995); Falzonietal, J. Clin. Invest. 95:1207 under 35 U.S.C. S 119 as to the said U.S.