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WO 2009/140517 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 19 November 2009 (19.11.2009) WO 2009/140517 Al (51) International Patent Classification: (71) Applicant (for all designated States except US): HYDRA AOlN 43/58 (2006.01) A61K 31/495 (2006.01) BIOSCIENCES, INC. [US/US]; 790 Memorial Drive, A61K 31/50 (2006.01) Cambridge, MA 02139 (US). (21) International Application Number: (72) Inventor; and PCT/US2009/043985 (75) Inventor/Applicant (for US only): CHONG, Jayhong, A. [-/US]; 84 Fuller Street #3, Brookline, MA 02446 (22) International Filing Date: (US). 14 May 2009 (14.05.2009) (74) Agent: MCCARTY, Catherine, M.; Lowrie, Lando & (25) Filing Language: English Anastasi, LIp, One Main Street, Eleventh Floor, Cam (26) Publication Language: English bridge, MA 02142 (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 61/127,722 14 May 2008 (14.05.2008) US kind of national protection available): AE, AG, AL, AM, 61/082,809 22 July 2008 (22.07.2008) US AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, [Continued on nextpage] (54) Title: COMPOUNDS AND COMPOSITIONS FOR TREATING CHEMICAL WARFARE AGENT-INDUCED INJURIES (57) Abstract: Compounds and compositions for treating injuries caused by exposure to chemical warfare agents are described herein. 0 / N °j '° Ii FIGURE 1 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, UG, US, UZ, VC, VN, ZA, ZM, ZW. MR, NE, SN, TD, TG). (84) Designated States (unless otherwise indicated, for every Published: searcnreport (Art. 21(3)) Compounds and Compositions for Treating Chemical Warfare Agent-Induced Injuries Claim of priority This application claims priority from U.S.S.N. 61/127,722, filed May 14, 2008, and U.S.S.N. 61/082,809, filed July 22, 2008, both of which are incorporated herein by reference in their entirety. Background The invention relates to compounds and compositions useful for treating injuries caused by chemical warfare and similar agents. A variety of ion channel proteins exist to mediate ion flux across cellular membranes. The proper expression and function of ion channel proteins is essential for the maintenance of cell function and intracellular communication. Numerous diseases and disorders are the result of misregulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest, both as research tools and as therapeutic agents. Summary of the invention The present invention provides compounds and compositions for treating or preventing injuries resulting from chemical warfare agents by modulating the activity of the TRPAl channel. In one aspect, the invention features methods for treating injuries caused by exposure to a chemical warfare agent, or a similar agent, by administering a compound of formula (I) or a salt thereof, Attorney Docket No.: H2038-7008WO Formula (I) Wherein each of R and R is, independently, H , Ci-C alkyl, C -C alkenyl, or C -C alkynyl, each o f which is optionally substituted with 1-4 R 5; 6 6 6 6 6 6 6 6 L is N R SO 2 , SO 2N R , C(O)NR , N R C(O), OC(O)NR , N R C(O)O, N R C(O)NR , S , S(O), 6 S(O) 2, N R , C H 2, O , C(O)NS(O) 2 , S(O) 2NC(O), heteroaryl, or cyclyl; R 3 is C4-C14 cyclyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R 7; each R 5 is independently halo, hydroxyl, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl; 6 each R is independently H , Ci-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, aryl, arylalkyl, or acetyl; 7 each R is independently Ci-C 6 alkyl, C 2-C 6 alkenyl, C 2-C 6 alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, arylalkoxy, amino, akylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, hydroxyl alkoxyl, alkoxy alkoxyl, acyl, nitro, or cyano, each o f which is optionally substituted with 1-3 R 8; each R is independently Ci-C 6 alkyl, C 2-C 6 alkenyl, or C 2-C 6 alkynyl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, amino, akylamino, dialkylamino, thioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea acyl, nitro, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; 9 R is independently H , Ci-C 6 alkyl, C 2-C 6 alkenyl, or C 2-C 6 alkynyl, halo, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, akylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, and is optionally substituted with 1-3 R 8; n 14 each o f R -R is, independently, H , Ci-C 6 alkyl, C 2-C 6 alkenyl, or C 2-C 6 alkynyl, halo, hydroxyl, alkoxy, amino, akylamino, thiol, alkylthiol, nitro, or cyano, each o f which is optionally substituted with 1-2 R 8; each o f m and n is, independently, O, 1, 2 , 3 , 4 , 5 , or 6 . In some embodiments, R is aryl, such as phenyl. In some embodiments, R is a nitrogen N con ttain in g heterocyc 1ly1l suc vh, as . Iτn other embodiments, R is a nitrogen containing heteroaryl, for example, Attorney Docket No.: H2038-7008WO N . In some embodiments, the heteroaryl is substituted by R7 is in the 3 or 4 position of the 5 membered ring. In some embodiments, R is a 6 membered nitrogen-containing heteroaryl, for example, . In some embodiments, R is a heteroaryl or heterocycyl having two fused rings. In some embodiments, R is a heteroaryl or heterocycyl having three fused rings. In some embodiments, R is substituted by 1-3 R . In some embodiments, R is Me, OMe, or halo. In another aspect, the invention relates to a method for treating injuries caused by exposure to chemical warfare agents by administering an effective amount of a compound of Formula II, or a salt thereof: II wherein R3 is as defined above and n is 1-3. In another aspect, the invention relates to a method for treating injuries caused by exposure to chemical warfare agents by administering an effective amount of a compound of Formula III, or a salt thereof: Attorney Docket No.: H2038-7008WO III 2 1 22 Wherein each of R and R is, independently, H, Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, each of which is optionally substituted with 1-4 R25; 26 26 26 26 26 26 26 26 L is NR SO2, SO2NR , C(O)NR , NR C(O), OC(O)NR , NR C(O)O, NR C(O)NR , S, 26 S(O), S(O) 2, NR , CH2, O, C(O)NS(O) 2, S(O) 2NC(O), heteroaryl, or cyclyl; R23 is C4-C14 cyclyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1-4 R27; each R25 is independently halo, hydroxyl, alkoxy, thiol, alkylthio, amino, alkylamino, dialkylamino, cyano, nitro, amido, alkylamido, dialkylamido, thioyl, sulfonyl, cyclyl, heterocyclyl, aryl, or heteroaryl; 26 each R is independently H, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, arylalkyl, or acetyl; 27 each R is independently Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyclyl, heterocyclyl, aryl, heteroaryl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, arylalkoxy, amino, akylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, hydroxyl alkoxyl, alkoxy alkoxyl, acyl, nitro, or cyano, each of which is optionally substituted with 1-3 R28; each R is independently Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, halo, hydroxyl, alkoxy, thiol, alkylthio, aryloxy, amino, akylamino, dialkylamino, thioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea acyl, nitro, cyano, cyclyl, heterocyclyl, aryl, or heteroaryl; 29 R is independently H, Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, halo, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, akylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, and is optionally substituted with 1-3 R28; 3 1 34 each of R -R is, independently, H, Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, halo, hydroxyl, alkoxy, amino, akylamino, thiol, alkylthiol, nitro, or cyano, each of which is optionally substituted with 1-2 R28; each of m and n is, independently, O, 1, 2, 3, 4, 5, or 6. In another aspect, the present invention provides a method for treating injuries from chemical warfare agents by administering an effective amount of a compound of Formula IV, or a salt thereof: Attorney Docket No.: H2038-7008WO (IV) Wherein each of R4 1 and R42 is, independently, H or Ci-C alkyl; one of R43 and R44 is H and the 53 53 other is MmR ; R is substituted or unsubstituted aryl; M, independently for each occurrence, is 6 1 62 C(R XR ), NRi, O, S, C(O), S(O), or S(O2), preferably selected such that no two heteroatoms are adjacent to each other, where each of R6 1 and R62 is, independently, H, Ci-C alkyl, C -C alkenyl, or C -C6 alkynyl, halo, hydroxyl, alkoxy, amino, akylamino, thiol, alkylthiol, nitro, or 45 cyano; R is H, Ci-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, halo, hydroxyl, alkoxy, aryloxy, arylalkoxy, amino, akylamino, dialkylamino, thioyl, alkylthioyl, sulfonyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, or cyano; and m is an integer from 1-5.
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