| 主权项 |
1. A method of ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of formula I:wherein
each of ring A and ring B are independently selected from the group consisting of cycloalkyl, aryl and heteroaryl; each R1 and R2 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl-CN, C1-6 alkylhydroxy, —OR2a, —NR2bR2d, C1-6 alkyl-NR2bR2d, —C(O)R1a, —C(O)R2d, —C(O)OR2a, C1-6 alkyl-C(O)OR2b, —OC(O)R2b, —OC(O)OR2b, —C(O)NR2aR2b, —C(O)N(OH)R2b, —NR2bC(O)R2c, C1-6 alkyl-NR2bC(O)R2c, —NR2bC(O)OR2c, C1-6 alkyl-NR2bC(O)OR2c, —OC(O)NR2bR2c, —NR2bC(O)NR2bR2c, —NR2bC(NR2b)NR2bR2c, —C(O)NR2bC(O)R2b, C1-6 alkyl-NR2bC(O)NR2bR2c, —SR2a, —SO2R2b, —SO2OR2b, —SO2NR2bR2d, —NR2bSO2R2b, —P(O)(OR2b)2, —B(OR2b), —CN, —NO2, —N3, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-heterocycloalkyl, C1-6 alkyl-aryl, C1-6 alkyl-O-aryl, C1-6 alkyl-heteroaryl, and heteroaryl-aryl, and wherein the heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 to 2 R2a groups; R1a is selected from the group consisting of —OR1b and —NR1bR1c; R1b and R1c are each independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-aryl, and C1-6 alkyl-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with from 1 to 4 R1d groups; each R1d is independently selected from the group consisting of H, C1-6 alkyl, C1-6 alkoxy, and —NO2; each R2a is independently selected from the group consisting of H, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-cycloalkyl, C1-6 alkyl-heterocycloalkyl, C1-6 alkyl-aryl and C1-6 alkyl-heteroaryl, optionally substituted with 1 to 2 R2b groups; each R2b and R2c is independently selected from the group consisting of H, and C1-6 alkyl; each R2d is independently selected from the group consisting of H, C1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-cycloalkyl, C1-16 alkyl-heterocycloalkyl, C1-6 alkyl-aryl and C1-6 alkyl-heteroaryl, each optionally substituted with 1 to 2 R2b groups; each of L1 and L2 are independently selected from the group consisting of a bond, C1-6 alkylene, C2-6 alkenylene, C1-6 alkylene-O—, —O—C1-6 alkylene, C1-6 alkylene-NR3a—, —NR3a—C1-6 alkylene, —C(O)—, C1-6 alkylene-C(O)—, —C(O)—C1-6 alkylene-NH—, —NH—C1-6 alkylene-C(O)—, —C(O)NH—, —NHC(O)—, C1-6 alkylene-NHC(O)—, —SO2NH—, —NHSO2—, —NHC(O)NH—, cycloalkylene, —N═N—, and —C(R3a)═N(R3c)—, wherein the alkylene group is optionally substituted with from 1-4 R3b groups; R3a is selected from the group consisting of H, and C1-6 alkyl; each R3b is independently selected from the group consisting of H, C1-6 alkyl, halogen, —OR3a and —NR3aR3a; R3c is absent or —OH; alternatively, L2 is combined with R1, L1 is combined with L2, L1 is combined with R2, two R1 groups on adjacent ring atoms, or two R2 groups on adjacent ring atoms are combined to form a 5-6 membered heterocycloalkyl with from 1 to 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl with from 1 to 3 heteroatoms selected from N, O and S, and optionally substituted with from 1 to 3 groups selected from the group consisting of H, C1-6 alkyl and oxo; subscripts m and n are each an integer from 1 to 3; wherein:
(a) L1 is a bond, L2 is —C(O)NH—, ring B is phenyl, and at least one R2 is —CN or phenyl, or(b) at least one R1 is —C(O)OH, ring A is phenyl, L2 is —C(O)NH—, and L1 is a bond or C1-6 alkylene, or(c) each of ring A and ring B is phenyl, at least one R1 is —C(O)OH or combined with L2, and at least one R2 is selected from the group consisting of H, —CN and —C(O)OH; wherein when R1 is —CO2H, subscript n is 1, ring A is phenyl, L2 is —C(O)NH—, L1 is a bond, ring B is phenyl, subscript m is 1, and R2 is phenyl, then the phenyl of R2 is substituted with C1-6 alkyl, or salts and isomers thereof, thereby ameliorating arthritis or joint injury in the mammal. |
