Patent ID: 6833378
Filing Date: 2004-12-21
Classification: A61K,A61P,C07D

Abstract:
A compound of the formula or a pharmaceutically acceptable salt thereof, whereinA is â€”CR7; B is â€”NR1R2, â€”CR1R2R11, â€”C(&boxH;CR2R12)R1, â€”NHCHR1R2, â€”OCHR1R2, â€”SCHR1R2, â€”CHR2OR1, â€”CHR1OR2, â€”CHR2SR1, â€”CHR2NR1R2, â€”CHR1NHR2, â€”CHR1N(CH3)R2, or â€”NR12NR1R2; Z is NH, O, S, â€”N(C1-C2 alkyl), â€”NC(O)CF3, or â€”C(R13R14), wherein R13 and R14 are each, independently, hydrogen, trifluoromethyl or methyl, or one of R13 and R14 is cyano and the other is hydrogen or methyl, or â€”C(R13R14) is a cyclopropyl group, or Z is nitrogen or CH and forms a five or six membered heterocyclic ring fused with R5, which ring optionally includes two or three further hetero members selected independently from oxygen, nitrogen, NR12, and S(O)m, and optionally includes from one to three double bonds, and is optionally substituted with halo, C1-C4 alkyl, â€”O(C1-C4 alkyl), NH2, NHCH3, N(CH3)2, CF3, or OCF3, with the proviso that said ring does not include any â€”Sâ€”Sâ€”, â€”Sâ€”Oâ€”, â€”Nâ€”Sâ€”, or â€”Oâ€”Oâ€” bonds, and does not include more than two oxygen or S(O)m heterologous members; R1 is C(O)H, C(O)(C1-C6 alkyl), C(O)(C1-C6 alkylene)(C3-C8 cycloalkyl), C(O)(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), C(O)(C1-C6 alkylene)(C4-C8 heterocycloalkyl), â€”C(O)(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), C3-C8 cycloalkyl, C4-C8 heterocycloalkyl, â€”(C1-C6 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), â€”(C1-C6 alkylene)(C4-C8 heterocycloalkyl), â€”(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), or â€”Oâ€”aryl, or â€”Oâ€”(C1-C6 alkylene)-aryl; wherein said aryl, C4-C8 heterocycloalkyl, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylene, and C1-C6 alkylene groups may each independently be optionally substituted with from one to six fluoro and may each independently be optionally substituted with one or two substituents R8 independently selected from the group consisting of C1-C4 alkyl, â€”C3-C8 cycloalkyl, hydroxy, chloro, bromo, iodo, CF3, â€”Oâ€”(C1-C6alkyl), â€”Oâ€”(C3-C5 cycloalkyl), â€”Oâ€”COâ€”(C1-C4 alkyl), â€”Oâ€”COâ€”NH(C1-C4 alkyl), â€”Oâ€”COâ€”N(R24)(R25), â€”N(R24)(R25), â€”S(C1-C4 alkyl), â€”S(C3-C5 cycloalkyl), â€”N(C1-C4alkyl)CO(C1-C4 alkyl), â€”NHCO(C1-C4 alkyl), â€”COO(C1-C4 alkyl), â€”CONH(C1-C4 alkyl), â€”CON(C1-C4 alkyl)(C1-C2 alkyl), CN, NO2, â€”OSO2(C1-C4 alkyl), S+(C1-C6 alkyl)(C1-C2 alkyl)lâˆ’, â€”SO(C1-C4 alkyl) and â€”SO2(C1-C4 alkyl); and wherein the C1-C6 alkyl, C1-C6 alkylene, C5-C8 cycloalkyl, C5-C8 cycloalkylene, and C5-C8 heterocycloalkyl moieties of R1 may optionally independently include from one to three double or triple bonds; and wherein the C1-C4 alkyl moieties and C1-C6 alkyl moieties of R8 can optionally independently be substituted with hydroxy, amino, C1-C4 alkyl, aryl, â€”CH2-aryl, C3-C5 cycloalkyl, or â€”Oâ€”(C1-C4 alkyl), and can optionally independently be substituted with from one to six fluoro, and can optionally include one or two double or triple bonds; and wherein each heterocycloalkyl group of R1 includes from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12; R2 is hydrogen, C1-C12 alkyl, C3-C8 cycloalkyl, C4-C8 heterocycloalkyl, â€”(C1-C6 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), â€”(C1-C6 alkylene)(C4-C8 heterocycloalkyl), â€”(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), aryl, â€”(C1-C6 alkylene)aryl, or â€”(C3-C8 cycloalkylene)(aryl); wherein each of the foregoing R2 groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, and C1-C6 alkyl, wherein one of said one to three substituents can further be selected from bromo, iodo, C1-C6 alkoxy, â€”OH, â€”Oâ€”COâ€”(C1-C6 alkyl), â€”Oâ€”COâ€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”S(C1-C6 alkyl), â€”S(O)(C1-*C6 alkyl), â€”S(O)2(C1-C6 alkyl), S+(C1-C6 alkyl)(C1-C2 alkyl)lâˆ’, CN, and NO2; and wherein the C1-C12 alkyl, â€”(C1-C6 alkylene), â€”(C5-C8 cycloalkyl), â€”(C5-C8 cycloalkylene), and â€”(C5-C8 heterocycloalkyl) moieties of R2 may optionally independently include from one to three double or triple bonds; and wherein each heterocycloalkyl group of R2 includes from one to three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR12; or when R1 and R2 are as in â€”NHCHR1R2, â€”OCHR1R2, â€”SCHR1R2, â€”CHR1R2 or â€”NR1R2, R1 and R2 of B may form a saturated 5-to 8-membered ring which may optionally include one or two double bonds and in which one or two of the ring carbons may optionally be replaced by an oxygen, S(O)m, nitrogen or NR12; and which carbocyclic ring can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, C1-C4 alkyl, fluoro, chloro, bromo, iodo, CF3, â€”Oâ€”(C1-C4 alkyl), â€”Oâ€”COâ€”(C1-C4 alkyl), â€”Oâ€”COâ€”NH(C1-C4 alkyl), â€”Oâ€”COâ€”N(C1-C4 alkyl)(C1-C2 alkyl), â€”NH(C1-C4 alkyl), â€”N(C1-C2 alkyl)(C1-C4 alkyl), â€”S(C1-C4 alkyl), â€”N(C1-C4 alkyl)CO(C1-C4 alkyl), â€”NHCO(C1-C4 alkyl),â€”COO(C1-C4 alkyl), â€”CONH(C1-C4 alkyl), â€”CON(C1-C4 alkyl)(C1-C2 alkyl), CN, NO2, â€”OSO2(C1-C4 alkyl), â€”SO(C1-C4 alkyl), and â€”SO2(C1-C4 alkyl), wherein one of said one to three substituents can further be selected from phenyl; R3 is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy, OCF3, NH2, NH(C1-C2 alkyl), N(CH3)2, â€”NHCOCF3, â€”NHCH2CF3, S(O)m(C1-C4 alkyl), CONH2, â€”CONHCH3, CON(CH3)2, â€”CF3, or CH2OCH3; R4 is hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, â€”(C1-C4 alkylene)(C3-C5 cycloalkyl), â€”(C3-C5 cycloalkylene)(C3-C5 cycloalkyl), cyano, fluoro, chloro, bromo, iodo, â€”OR24, C1-C6 alkoxy, â€”Oâ€”(C3-C5 cycloalkyl), â€”Oâ€”(C1-C4 alkylene)(C3-C5 cycloalkyl), â€”Oâ€”(C3-C5 cycloalkylene)(C3 -C5 cycloalkyl), â€”CH2SC(S)O(C1-C4 alkyl), â€”CH2OCF3, CF3, amino, nitro, â€”NR24R25, â€”(C1-C4 alkylene)â€”OR24, â€”(C1-C4 alkylene)Cl, â€”(C1-C4 alkylene)NR24R25, â€”NHCOR24, â€”NHCONR24R25, â€”C&boxH;NOR24, â€”NHNR24R25, â€”S(O)mR24, â€”C(O)R24, â€”OC(O)R24, â€”C(O)CN, â€”C(O)NR24R25, â€”C(O)NHNR24R25, and â€”COOR24, wherein the alkyl and alkylene groups of R4 may optionally independently include one or two double or triple bonds and may optionally independently be substituted with one or two substituents R10 independently selected from hydroxy, amino, â€”NHCOCH3, â€”NHCOCH2Cl, â€”NH(C1-C2 alkyl), â€”N(C1-C2 alkyl)(C1-C2 alkyl), â€”COO(C1-C4 alkyl), â€”COOH, â€”CO(C1-C4 alkyl), C1-C6 alkoxy, C1-C3 thioalkyl, cyano and nitro, and with one to four substituents independently selected from fluoro and chloro; R5 is aryl or heteroaryl and is substituted with from one to four substituents R27 independently selected from halo, C1-C10 alkyl, â€”(C1-C4 alkylene)(C3-C8 cycloalkyl), â€”(C1C4 alkylene)(C4-C8 heterocycloalkyl), â€”(C3-C8 cycloalkyl), â€”(C4-C8 heterocycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), C1-C4 haloalkyl, C1-C4 haloalkoxy, nitro, cyano, â€”NR24R25, â€”NR24COR25, â€”NR24CO2R26, â€”COR24, â€”OR25, â€”CONR24R25, â€”CO(NOR22)R23, â€”CO2R26, â€”C&boxH;N(OR22)R23, and â€”S(O)mR23; wherein said C1-C10 alkyl, C3-C8 cycloalkyl, (C1-C4 alkylene), (C3-C8 cycloalkyl), (C3-C8 cycloalkylene), and (C4-C8 heterocycloalkyl) groups can be optionally substituted with from one to three substituents independently selected form C1-C4 alkyl, C3-C8 cycloalkyl, (C1-C4 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), C1-C4 haloalkyl, hydroxy, C1-C6 alkoxy, nitro halo, cyano, â€”NR24R25, â€”NR24COR25, NR24CO2R26, â€”COR24, â€”OR25, â€”CONR24R25, CO2R26, â€”CO(NOR22)R25, and â€”S(O)mR23; and wherein two adjacent substituents of the R5 group can optionally form a 5-7 membered ring, saturated or unsaturated, fused to R5, which ring optionally can include one, two, or three heterologous members independently selected from O, S(O)m, and N, but not any â€”Sâ€”Sâ€”, â€”Oâ€”Oâ€”, â€”Sâ€”Oâ€”, or â€”Nâ€”Sâ€” bonds, and which ring is optionally substituted with C1-C4 alkyl, C3-C8 cycloalkyl, â€”(C1-C4 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cyloalkylene)(C3-C8 cycloalkyl), C1-C4 haloalkyl, nitro, halo, cyano â€”NR24R25, NR24COR25, NR24CO2R26, â€”COR24, â€”OR25, â€”CONR24R25, CO2R26, â€”CO(NOR26)R25, or â€”S(O)mR23; wherein one of said one to four optional substituents R27 can further be selected from â€”SO2NH(C1-C4 alkyl), â€”SO2NH(C1-C4 alkylene)(C3-C8 cycloalkyl), â€”SO2NH(C3-C8 cycloalkyl), â€”SO2NH(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), â€”SO2N(C1-C4 alkyl)(C1-C2 alkyl), â€”SO2NH2, â€”NHSO2(C1-C4 alkyl), â€”NHSO2(C3-C8 cycloalkyl), â€”NHSO2(C1-C4 alkylene)(C3-C8 cycloalkyl), and â€”NHSO2(C3-C8 cycloalkylene)(C3-C8 cycloalkyl); and wherein the alkyl, and alkylene groups of R5 may independently optionally include one double or triple bond; R7 is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, â€”O(C1-C2 alkyl), â€”O(cyclopropyl), â€”COO(C1-C2 alkyl), â€”COO(C3-C8 cycloalkyl), â€”OCF3, CF3, â€”CH2OH, or CH2OCH3; R11 is hydrogen, hydroxy, fluoro, ethoxy, or methoxy; R12 is hydrogen or C1-C4 alkyl; R22 is independently at each occurrence selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl; R23 is independently at each occurrence selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C8 cycloalkyl, aryl, â€”(C1-C4 alkylene)aryl, piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, and thiomorpholine; R24 and R25 are independently at each occurrence selected from hydrogen, â€”C1-C4 alkyl, C1-C4 haloalkyl, â€”(C1-C4 alkylene)OH, â€”(C1-C4 alkylene)â€”Oâ€”(C1-C4 alkyl), â€”(C1-C4 alkylene)â€”Oâ€”(C3-C5 cycloalkyl), C3-C8 cycloalkyl, â€”(C1-C4 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), â€”C4-C8 heterocycloalkyl, â€”(C1-C4 alkylene)(C4-C8 heterocycloalkyl), â€”(C3-C8 cycloalkylene)(C4-C8 heterocycloalkyl), aryl, and â€”(C1-C4 alkylene)(aryl), wherein the â€”C4-C8 heterocycloalkyl groups can each independently optionally be substituted with aryl, CH2-aryl, or C1-C4 alkyl, and can optionally include one or two double or triple bonds; or, when R24 and R25 are as NR24R25, â€”C(O)NR24R25, â€”(C1C4 alkylene)NR24R25, or â€”NHCONR24R25, then NR24R25 may further optionally form a 4 to 8 membered heterocyclic ring optionally including one or two further hetero members independently selected from S(O)m, oxygen, nitrogen, and NR12, and optionally including from one to three double bonds; R26 is independently at each occurrence selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, â€”(C1-C4 alkylene)(C3-C8 cycloalkyl), â€”(C3-C8 cycloalkylene)(C3-C8 cycloalkyl), aryl, and â€”(C1-C4 alkylene)(aryl); and wherein each m is independently zero, one, or two, with the proviso that heterocycloalkyl groups of the compound of formula I do not include any â€”Sâ€”Sâ€”, â€”Sâ€”Oâ€”, â€”Nâ€”Sâ€”, or â€”Oâ€”Oâ€” bonds, and do not include more than two oxygen or S(O)m heterologous members.