Patent ID: 6432922
Filing Date: 2002-08-13
Classification: A61K,A61P,C07K

Abstract:
A compound of the formula: wherein:(a) X is selected from the group consisting of â€”S(O)2â€”, â€”N(Râ€²)â€”S(O)2â€”, â€”(C&boxH;O)â€”, â€”OC(&boxH;O)â€”, â€”NHâ€”C(&boxH;O)â€”, â€”P(O)(Râ€²)â€”, and a direct link, wherein Râ€² is independently hydrogen, alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 7 to about 16 carbon atoms, with the proviso that when X is â€”P(O)(Râ€²)â€”, then Râ€² is not hydrogen; (b) R1 is selected from the group consisting of: (1) alkyl of, 1 to about 12 carbon atoms which is optionally substituted with Y1, (2) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 5 to about 8 carbon atoms which is optionally mono-, di- or tri-substituted on the ring with Y1, Y2, and/or Y3, (3) cycloalkyl of 3 to about 15 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1, or 2 including, â€ƒwherein â€ƒis a 5 to 7 member heterocycle having 3 to 6 ring carbon atoms, where V is â€”CH2â€”, â€”Oâ€”, â€”S(&boxH;O)â€”, â€”S(O)2â€” or â€”Sâ€”, which is optionally mono-, di-, or tri-substituted on the ring carbons with Y1, Y2, and/or Y3, (6) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cycloalkyl of about 5 to about 8 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3, (8) heteroaryl of about 5 to about 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or , tri-substituted with Y1, Y2, and/or Y3, (9) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, (10) heteroaralkyl of about 5 to about 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y1, Y2, and/or Y3, (11) aralkenyl of about 8 to about 16 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, (12) heteroaralkenyl of about 5 to about 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3, (17) fused carbocyclic alkyl of about 9 to about 15 carbon atoms; (18) difluoromethyl or perfluoroalkyl of 1 to about 12 carbon atoms, (19) perfluoroaryl of about 6 to about 14 carbon atoms, (20) perfluoroaralkyl of about 7 to about 15 carbon atoms, and (21) hydrogen when X is a direct link; wherein each Y1, Y2, and Y3 is independently selected and is (i) selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, â€”CF3, â€”CF2CF3, â€”CH(CF3)2, â€”C(OH)(CF3)2, â€”OCF3, â€”OCF2H, â€”OCF2CF3, â€”OC(O)NH2, â€”OC(O)NHZ1, â€”OC(O)NZ1Z2, â€”NHC(O)Z1, â€”NHC(O)NH2, â€”NHC(O)NZ1, â€”NHC(O)NZ1Z2, â€”C(O)OH, â€”C(O)OZ1, â€”C(O)NH2, â€”C(O)NHZ1, â€”C(O)NZ1Z2, â€”P(O)3H2, â€”P(O)3(Z1)2, â€”S(O)3H, â€”S(O)mZ1, â€”Z1, â€”OZ1, â€”OH, â€”NH2, â€”NHZ1, â€”NZ1Z2, â€”N-morpholino, â€”S(CF2)qCF3, and â€”S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5, and Z1 and Z2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atom, heteroaryl of about 5 to about 14 ring atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 5 to about 14 ring atoms, or (ii) Y1 and Y2 are selected together to be â€”O[C(Z3)(Z4)]rOâ€”, wherein r is an integer from 1 to 4 and Z3 and Z4 are independently selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 ring atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 5 to about 14 ring atoms; (c) R2 is selected from the group consisting of H, â€”(CH2)2OA2, â€”CH(R6)OH, â€”CH(R6)OA2 and â€”CH2NHâ€”Xâ€²â€”R6 wherein A2 is â€”C(&boxH;O)OR9 or â€”C(&boxH;O)OR9; Xâ€² is selected from the group consisting of â€”(C&boxH;O)â€”, and â€”C(&boxH;O)â€”Oâ€”; R6 is selected from the group consisting of hydrogen; â€”CH3, 2-phenylethyl and benzyl; and â€ƒR9 is selected from the group consisting of: (1) alkyl of 1 to about 12 carbon atoms, optionally substituted with Y1, (2) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 5 to about 8 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (3) cycloalkyl of 3 to about 15 carbon atoms, which is optionally mono-, di-, or trisubstituted on the ring with Y1, Y2; and/or Y3, (4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1, or 2 including â€ƒwherein â€ƒis a 5 to 7 member heterocycle having 3 to 6 ring carbon atoms, where V is â€”CH2â€”, â€”Oâ€”, â€”S(&boxH;O)â€”, â€”S(O)2â€” or â€”Sâ€”, which is optionally mono-, di-, or tri-substituted on the ring carbons with Y1, Y2, and/or Y3, (6) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3, (7) heteroaryl of about 5 to about 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3, (8) aralkyl of about 7 to about 15 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, (9) heteroaralkyl of, about 5 to about 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y1, Y2, and/or Y3, and (10) hydrogen, with the proviso that R9 is not hydrogen when A2 is â€”C(&boxH;O)OR9; (d) R3 is selected from H or methyl, or R3 and R4 are selected together as set forth in (f); (e) the carbon bearing R4 is of the S configuration and R4 is selected from the group consisting of H, â€”CH2â€”Sâ€”CH3, â€”CH2OH, â€”CH2CN, lower alkyl of 1 to about 3 carbon atoms, â€”CH2C&boxH;CH, â€”CH2CH&boxH;CH2 and â€”CH&boxH;CH2 or R3 and R4 are-selected together as set forth in (f); (f) alternatively, R3 and R4 are selected together to be in the S configuration to give a group at P2 selected from the group consisting of prolyl, pipecolyl, azetidine-2-carbonyl, 4-hydroxyprolyl, 3-hydroxyprolyl, and 3,4-dehydroprolyl; (g) R5 is selected from the group consisting of wherein R7 is selected from wherein d is an integer from 1 to 3 and W is â€”Nâ€” or â€”CHâ€”; and(h) A1 is â€”NHR8, wherein R8 is alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 6 to about 15 carbon atoms, all optionally mono-, di or tri-substituted with Y1, Y2 and/or Y3 or is hydrogen; and pharmaceutically acceptable salts thereof with the proviso that when R5 is and R7 is â€”(CH2)2NHC(&boxH;NH)NH2), then R1 is not hydrogen.