Patent ID: 6576613
Filing Date: 2003-06-10
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 4 carbon atoms, aryl of 6 to 14 carbon atoms or aralkyl of 7 to 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 12 carbon atoms which is optionally substituted with Y1, (2) alkyl of 1 to 3 carbon atoms substituted with cycloalkyl of 5 to 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 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 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 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 carbons with Y1, Y2, and/or Y3, (6) alkenyl of 2 to 6 carbon atoms which is optionally substituted with cycloalkyl of 5 to 8 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3, (7) aryl of 6 to 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3, (8) heteroaryl of 5 to 14 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 7 to 15 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, (10) heteroaralkyl of 6 to 11 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 8 to 15 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, (12) heteroaralkenyl of 7 to 12 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 9 to 15 carbon atoms; (18) difluoromethyl or perfluoroalkyl of 1 to 12 carbon atoms, (19) perfluoroaryl of 6 to 14 carbon atoms, (20) perfluoroaralkyl of 7 to 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 12 carbon atoms, aryl of 6 to 14 carbon atoms, heteroaryl of 5 to 14 atoms having 1 to 9 carbon atoms, aralkyl of 7 to 15 carbon atoms, and heteroaralkyl of 6 to 11 atoms having 3 to 9 carbon 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 12 carbon atoms, aryl of 6 to 14 carbon atoms, heteroaryl of 5 to 14 atoms having 1 to 9 carbon atoms, aralkyl of 7 to 15 carbon atoms, and heteroaralkyl of 5 to 14 atoms having 3 to 9 carbon atoms; (c) R2 is selected from the group consisting of H, â€”CH(R6)OH, and â€”CH2NHâ€”Xâ€²â€”R6 wherein Xâ€² is selected from the group consisting of â€”(C&boxH;O)â€”, and â€”C(&boxH;O)â€”Oâ€”, and wherein R6 is selected from the group consisting of hydrogen, methyl, 2-phenylethyl and benzyl; (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 3 carbon atoms, â€”CH2Câ‰¡CH, â€”CH2CH&boxH;CH2 and â€”CH&boxH;CH2 or R3 and R4 are selected together as set forth in (f); (f) the carbon bearing R4 is of the S configuration and R3 and R4 are selected together 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 â€ƒwherein R7 is selected from â€ƒwherein 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 12 carbon atoms, aryl of 6 to 14 carbon atoms or aralkyl of 6 to 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 â€ƒwhere R7 is â€”(CH2)2NHC(&boxH;NH)NH2, then R1 is not hydrogen.