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United States Patent (10) Patent No.: US 8,859,550 B2 Chen Et Al US00885955OB2 (12) United States Patent (10) Patent No.: US 8,859,550 B2 Chen et al. (45) Date of Patent: *Oct. 14, 2014 (54) HETEROCYCLIC INHIBITORS OF FOREIGN PATENT DOCUMENTS HISTAMINE RECEPTORS FOR THE TREATMENT OF DISEASE Wo 2004:36 A 358 (75) Inventors: Pingyun Chen, Chapel Hill, NC (US); W. SS: A. 33. Stephen A. R. Carino, Del Mar, CA WO 2009098320 A2 8, 2009 (US); Ricky Wayne Couch, Durham, WO 2010030785 A2 3, 2010 NC (US); Daniel S. Kinder, Del Mar, W. 38H 73 A. 338 sS); Beth A. Norton, Del Mar, CA WO 20110894.00 A1 7, 2011 (73) Assignee: Kalypsys, Inc., Del Mar, CA (US) OTHER PUBLICATIONS c Khankari et al. Thermochimica Acta 1995, 248, 61-79. (*) Notice: Subject to any disclaimer, the term of this Conalty, M.L. et akl., “Anticancer agents—XII. Pyridazine and patent is extended or adjusted under 35 Benzodiazine derivatives.” Proceedings of the Royal Irish Academy, U.S.C. 154(b) by O days. Section B: Biological, Geological and Chemical Science (1976), 76(10), 151-63. This patent is Subject to a terminal dis- Kim, HS et al., “Synthesis of tetrazolo 1.5-aquinoxalines with anti Ca10. microbial activity,” Journal of the Korean Chemical Society (2001), 45(4), 325-333. (21) Appl. No.: 13/606.947 Smits R. A. et al., “Major advances in the developments of histamine H4 receptor ligands.” Drug Discovery Today, vol. 14, No. 15/16, Aug. (22) Filed: Sep. 7, 2012 2009. Beres M. et al., “Ring Opening of 1.2.3Triazolo 1.5- (65) Prior Publication Data alpha pyrazinium Salts: Synthesis and Some Transformations of a US 2013/0245001A1 Sep. 19, 2013 Novel9393-94.00. Type of 2-Aza-1,3-butadienes.” Tetrahedron 53 (1997) 27. Makata S. et al., “Reduction of 4, 7-Diphenyl-1,2,5- O O thia(oxa)diazolo 3,4-cpyridines Affording 2,5-Diphenyl-3,4- Related U.S. Application Data diaminopyridines and Ring Closure of the Diamines to Fluorescent (60) Provisional application No. 61/533,455, filed on Sep. AZaheterocycles,” Journal of Heterocyclic Chemistry vol. 19, Issue 12, 2011. 6, pp. 1481-1488, 1982. s Paparin JL et al., “Synthesis of 2,5-bis-Arylpyridines by 4 + 2 (51) Int. Cl Cycloaddition of 1,4-bisAryl-2-aza-1,3-butadienes with Electron cond is 7/04 2006.O1 Poor Dienophiles,” J. Heterocyclic Chem. 37, 411 (2000). ( .01) Tetrazolopyrazines Registry Records Not Indexed in CAS subset A6 IK9/00 (2006.01) from STN (accessed approx. Jul. 20, 2009). A6 IK3I/4985 (2006.01) WO2010030785A2 Int'l Search Report, May 10, 2010. A6IP37/08 (2006.01) WO2010030785A2 Written Opinion of the Int'l Searching Author C07C309/04 (2006.01) ity, May 10, 2010. CD7C 53/26 (2006.01) WO2010030785A2 Int’l Preliminary Report on Patentability, Mar. C07C 55/10 (2006.01) 24, 2011. C07C 59/245 (2006.01) EP2324029 Extended European Search Report, Aug. 17, 2011. (52) U.S. Cl. Sarges R. et al., “4-Amino 1.2.4 triazolo 4.3-a Iquinoxalines. A CPC ............ C07D 487/04 (2013.01); C07C309/04 Novel Class of Potent Adenosine Receptor Antagonists and Potential (2013.01); A619/00 (2013.01); CD7C 53/26 Rapid-Onset Antidepressants.” Journal of Medicinal Chemistry (2013.01);s C07C 55/10 (2013.01);s C07C ( 1990), 33(8), 2240-54. 59/245 (2013.01); C70C59/255 (2013.01); (Continued) C07B 2.200/13 (2013.01) USPC ........... 514/249; 544/350:544/359: 548/953; 549/59 Primary Examiner — Sreeni Padmanabhan (58) Field of Classification Search Assistant Examiner — Irina Neagu CPC ..... C07D 487/04; A61K9/00; C07B 2200/13 (74) Attorney, Agent, or Firm — Dennis A. Bennett; Cynthia USPC ................... 514/249; 544/350, 359: 548/953; Hathaway 549/59 See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention relates to salts, hydrates, and polymor U.S. PATENT DOCUMENTS phs of bicyclic heteroaryl compounds, and pharmaceutical compositions thereof, which may be useful as inhibitors of 8,569,300 B2 * 10/2013 Borchardt et al. ............ 514,249 2008/O139572 A1 6/2008 Wang et al. HR for the treatment or prevention of diseases including 2010, 0120741 A1 5, 2010 Borchardt allergic rhinitis. 2010/0249142 A1 9/2010 Deleuze-Masquefa et al. 2011/0237565 A1 9, 2011 Borchardt et al. ....... 514,210.21 2011/0237599 A1 9, 2011 Borchardt 59 Claims, 32 Drawing Sheets US 8,859,550 B2 Page 2 (56) References Cited ture-Activity Relationships, and Biological Studies,” J. Med. Chem. 1999, 42,4362-4379. OTHER PUBLICATIONS EP11754043 Extended European Search Report, Jun. 20, 2013. WO2011 112687 International Search Report and Written Opinion of Nagarajan K et al., “Displacement reactions of 2,3-dichloro-6- the Int'l Searching Authority, Nov. 25, 2011. nitroquinoxaline: Synthesis of s-Triazolo 3,4-aquinoxaline.” Indian WO2011 112766 International Search Report and Written Opinion of Journal of Chemistry, Section B: Organic Chemistry Including the Int'l Searching Authority, Nov. 25, 2011. Medicinal Chemistry (1986), 25B(7), 739-40. Badran MM et al., “Part I: Novel quinoxaline derivatives of biologi Non-final rejection dated Jan. 2, 2013 in U.S. Appl. No. 13/044,661. cal interest.” Bulletin of Pharmaceutical Sciences, Assiut University filed Mar. 10, 2011 (publ. No. US2011/0237565A1, now patent No. (2001), 24(2), 135-144. 8,569,300). Campiani G. et al., “Pyrroloquinoxaline Derivatives as High-Affinity and Selective 5-HT3 Receptor Agonists: Synthesis, Further Struc * cited by examiner U.S. Patent Oct. 14, 2014 Sheet 1 of 32 US 8,859,550 B2 o c re V w g m N an t 5 () E xxx o cN O A. Od va D O C o O o o va va U.S. Patent Oct. 14, 2014 Sheet 2 of 32 US 8,859,550 B2 009000},009?.000Z009Z000€0099000?7 U.S. Patent Oct. 14, 2014 Sheet 3 of 32 US 8,859,550 B2 00909200Z09!,00?,090 os‘aunqeuadual U.S. Patent Oct. 14, 2014 Sheet 4 of 32 US 8,859,550 B2 8 on via ge is D S. U on v d : > O A.O. 9, SSewu effueuo U.S. Patent Oct. 14, 2014 Sheet 5 of 32 US 8,859,550 B2 | |009 000?. 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