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WO 2010/000073 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 7 January 2010 (07.01.2010) WO 2010/000073 Al (51) International Patent Classification: mond Street W , Apt. 903, Toronto, Ontario M5V 1Y5 C07D 417/12 (2006.01) A61P 25/02 (2006.01) (CA). DOVE, Peter [CA/CA]; 568 Palmerston Avenue, A61K 31/538 (2006.01) C07D 413/12 (2006.01) Toronto, Ontario M6G 2P7 (CA). MADDAFORD, A61K 31/5415 (2006.01) C07D 413/14 (2006.01) Shawn [CA/CA]; 3 179 Folkway Drive, Mississauga, On A61P 25/00 (2006.01) C07D 417/14 (2006.01) tario L5L 1Y3 (CA). RAKHIT, Suman [CA/CA]; 856 Hidden Grove Lane, Mississauga, Ontario L5H 4L2 (CA). (21) International Application Number: PCT/CA2009/000923 (74) Agents: CHATTERJEE, Alakananda et al; Gowling Lafleur Henderson LLP, P.O. Box 30, Suite 2300, 550 (22) International Filing Date: Burrard Street, Vancouver, British Columbia V6C 2B5 3 July 2009 (03.07.2009) (CA). English (25) Filing Language: (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (30) Priority Data: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 61/133,887 3 July 2008 (03.07.2008) U S DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (71) Applicant (for all designated States except US): NEU- HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, RAXON, INC. [CA/CA]; 480 University Avenue, Suite KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 900, Toronto, Ontario M5G 1V2 (CA). ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (72) Inventors; and SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, (75) Inventors/Applicants (for US only): RAMNAUTH, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Jailall [CA/CA]; 12 Mendoza Drive, Brampton, Ontario L7A 3M3 (CA). ANNEDI, Subhash, C . [IN/CA]; 5 108 (84) Designated States (unless otherwise indicated, for every Oscar Peterson Boulevard, Mississauga, Ontario L5M kind of regional protection available): ARIPO (BW, GH, 7W4 (CA). SILVERMAN, Sarah [CA/CA]; 525 Rich GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, [Continued on next page] (54) Title: BENZOXAZINES, BENZOTHIAZINES, AND RELATED COMPOUNDS HAVING NOS INHIBITORY ACTIVI TY (57) Abstract: Disclosed are benzoxazines and benzothiazines of formula (I) wherein Q is O-(CHR 6)i_3 or S-(CHR 6)i_3; R 1 and 6 each R is H, optionally substituted [Ci. alkyl, Ci-4alkaryl, C alkheterocyclyl, C2-9 heterocyclyl, C3.s cycloalkyl, C alkcy- 1A 1B lc 1D 1A 1B lc 1D cloalkyl] or - (CR R )nNR R wherein R , R , R , R are independently hydrogen, optionally substituted [C L6 alkyl, Ci-4alkaryl, C1.4 alkheterocyclyl, C2-9 heterocyclyl, C3.8 cycloalkyl, etc.] or wherein R 1A and R 1B combine to form =O, or wherein R lc and R 1D combine to form an optionally substituted C2-9 heterocyclyl, and n is an integer between 1-6; each of R 2 and R3 is H, hal, optionally substituted [C 1-6 alkyl, C -ioaryl, d^alkaiyl, C2-9 heterocyclyl, Ci. alkoxy, Ci. thioalkoxy, (CH 2)^NHC(NH)R 2A, 2A C1-4 2A CH2)r2NHC(S)NHR , alkheterocyclyl] or hydroxy, wherein r2 is an integer from 0 to 2, R is optionally substituted [CL Λ alkyl, C .ioaryl, C alkaryl, C 2. heterocyclyl, alkheterocyclyl,Ci_6 thioalkoxy, C1.4 thioalkaryl, aryloyl, Ci. 4thioalkheterocylyl, 4 5 2A 2A 1 2 1 2 or amino]; each R and R is H, hal, (CH 2)r2NHC(NH)R or CH2)r2NHC(S)NH R ; Y and Y are together =O or Y and Y are independently H, optionally substituted [Ci. alkyl, C -ioaryl, Ci.ealkaryl, C2. heterocyclyl, Ci. alkoxy, Ci. thioalkoxy, 2 3 4 5 2A 2A Ci-4alkheterocyclyl] or hydroxy; wherein only one of R , R , R and R is (CH 2)r2NHC(NH)R or CH2)r2NHC(S)NH R ; or a pharmaceutically acceptable salt or prodrug thereof. Said benzoxazines and benzothiazines of formula (I) inhibit [Continued on next page] TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Published: ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, . , , ,, -, , MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, ~ m t national search report (Art./ 21(3))/ TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). nitric oxide synthase (NOS), particularly selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS iso- forms. The NOS inhibitors of formula (I), alone or in combinatioon with other pharmaceutically active agents, can be used for treating or preventing various medical conditions. BENZOXAZINES, BENZOTHIAZINES, AND RELATED COMPOUNDS HAVING NOS INHIBITORY ACTIVITY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No. 61/133,887, filed July 3, 2008, which is hereby incorporated by reference. BACKGROUND OF THE INVENTION The present invention relates to the fields of benzoxazines, benzothiazines, and related compounds and to their medical use. Nitric oxide (NO) has diverse roles both in normal and pathological processes, including the regulation of blood pressure, in neurotransmission, and in the macrophage defense systems (Snyder, S. H. and Bredt, D. S., Scientific American, May; 266(5) 1992:68). NO is synthesized by three isoforms of nitric oxide synthase, a constitutive form in endothelial cells (eNOS), a constitutive form in neuronal cells (nNOS), and an inducible form found in macrophage cells (iNOS). These enzymes are homodimeric proteins that catalyze a five-electron oxidation of L-arginine, yielding NO and citrulline. The role of NO produced by each of the NOS isoforms is quite unique. Overstimulation or overproduction of individual NOS isoforms, especially nNOS and iNOS, plays a role in several disorders, including septic shock, arthritis (Boughton-Smith et al., IDrugs 1:321-334, 1998 and Cochrane et al., Med Res. Rev. 16: 547-563, 1996), diabetes, ischemia-reperfusion injury, pain (Larson et al., Pain 86:103-1 11, 2000), and various neurodegenerative diseases (Kerwin et al., J. Med. Chem. 38:4343, 1995), while eNOS inhibition leads to unwanted effects such as enhanced white cell and platelet activation, hypertension, and increased atherogenesis (Valance et al., Nature Rev. Drug Disc. 1:939, 2002). NOS inhibitors have the potential to be used as therapeutic agents in many disorders. However, the preservation of physiologically important nitric oxide synthase function suggests the desirability of the development of isoform-selective inhibitors that preferentially inhibit nNOS, or nNOS and iNOS, over eNOS. Specifically, selective NOS inhibitors, particularly for nNOS or iNOS, are candidates for use in the treatment of chronic pain states such as neuropathic pain, chronic tension type headache or transformed migraine wherein the pain state results from the persistence of peripheral and/or central sensitization. SUMMARY O F THE INVENTION The invention features a compound having the formula: wherein, 6 6 Q is -O-(CHR ),-3 or -S-(CHR ) 1-3- ; R 1 and each R6 is, independently, H, optionally substituted Ci.βalkyl, optionally substituted C alkaryl, optionally substituted C alkheterocyclyl, optionally substituted C2-9 heterocyclyl, optionally substituted C3.gcycloalkyl, 1A 1B IC 1D optionally substituted C M alkcycloalkyl or -(CR R )nNR R ; R1A and R 1B are, independently, H, hydroxy, halo (e.g., fluoro), optionally substituted C 1 alkyl, optionally substituted Ci-e alkoxy, optionally substituted Q 4 alkcycloalkyl, optionally substituted C alkaryl, optionally substituted C alkheterocyclyl, optionally substituted C alkheteroaryl, optionally substituted C - 1Λ 1B cycloalkyl, or optionally substituted C2-9 heterocyclyl, or R and R combine to form =0; R 1C and R 1D are, independently, H, hydroxy, optionally substituted Ci_ alkyl, optionally substituted -6 alkoxy, optionally substituted C M alkcycloalkyl, optionally substituted C - alkaryl, optionally substituted Ci- alkheterocyclyl, optionally substituted C M alkheteroaryl, optionally substituted C3. cycloalkyl, optionally substituted C2-9 heterocyclyl, or an N-protecting group, or R 1C and R lD combine to π fo n an optionally substituted C2-9 heterocyclyl or an N-protecting group; n is an integer between 1-6; each of R and R is, independently, H, hal, optionally substituted C 1 alkyl, optionally substituted C6-io aryl, optionally substituted Ci_6 alkaryl, optionally substituted C2-9 heterocyclyl, hydroxy, optionally substituted C1.6 alkoxy, optionally 2A 2A substituted C 1-6 thioalkoxy, (CH 2)r2NHC(NH)R , or (CH 2)r2NHC(S)NHR , or optionally substituted C alkheterocyclyl, 2A wherein r2 is an integer from 0 to 2, R is optionally substituted Ci- alkyl, optionally substituted Q-io aryl, optionally substituted C alkaryl, optionally substituted C2-9 heterocyclyl, optionally substituted C alkheterocyclyl, optionally substituted C i-6 thioalkoxy, optionally substituted C thioalkaryl, optionally substituted aryloyl, optionally substituted C 1.4 thioalkheterocyclyl, or optionally substituted amino; 4 5 2A each of R and R is independently H, hal, (CH 2) NHC(NH)R , or 2A (CH 2)r2NHC(S)NHR ; wherein Y 1 and Y2 are each H, or Y 1 and Y2 together are =0, or Y 1 and Y2 are independently H, optionally substituted Q.6 alkyl, optionally substituted C -io aryl, optionally substituted Q .6 alkaryl, optionally substituted C2-9 heterocyclyl, hydroxy, optionally substituted C 1.6 alkoxy, optionally substituted C]_6 thioalkoxy, or optionally substituted C alkheterocyclyl; 2 3 4 5 2A wherein one and only one of R , R , R , and R is (CH 2)r2NHC(NH)R or A (CH 2)r2NHC(S)NHR ; or a pharmaceutically acceptable salt or prodrug thereof.
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