Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof

摘要

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases due to mutations in Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

主权项

1. A method of treating a bone or cartilage disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof: wherein: R1, R2, R4, R6, R7, R8 and R9 are independently selected from the group consisting of H, C1-9 alkyl, halide, —CF3, —(C1-9 alkyl)ncarbocyclylR13, —(C1-9 alkyl)nheterocyclylR13, —(C1-9 alkyl)narylR13, —(C1-9 alkyl)nheteroarylR13, —(C1-9 alkyl)nOR10, —(C1-9 alkyl)nSR10, —(C1-9 alkyl)nS(═O)R11, —(C1-9 alkyl)nSO2R10, —(C1-9 alkyl)nN(R10)SO2R10, —(C1-9 alkyl)nSO2N(R10)2, —(C1-9 alkyl)nN(R10)2, —(C1-9 alkyl)nN(R10)C(=A)N(R10)2, —(C1-9 alkyl)nC(=A)N(R10)2, —(C1-9 alkyl)nN(R10)C(=A)R10, —NO2, —CN, —(C1-9 alkyl)nCO2R10, and —(C1-9 alkyl)nC(=A)R10; R3 is selected from the group consisting of —NRS(═O)R14, —(C1-9 alkyl)R14, -carbocyclylR14R15, -heterocyclylR14R15, -arylR14R15, and -heteroarylR14R15; alternatively, one of each of R1 and R2, R2 and R3, R3 and R4, R6 and R7, R7 and R8 or R8 and R9 are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl, wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond; each R10 is independently selected from the group consisting of H, —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclyl, —(C1-9 alkyl)nheterocyclyl, —(C1-9 alkyl)naryl, and —(C1-9 alkyl)nheteroaryl; each R11 is independently selected from the group consisting of —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclyl, —(C1-9 alkyl)nheterocyclyl, —(C1-9 alkyl)naryl, and —(C1-9 alkyl)nheteroaryl; each R12 is independently selected from the group consisting of —OR10 and R10; each R13 is 1-5 substituents each selected from the group consisting of H, C1-9 alkyl, halide, —CF3, carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C1-9 alkyl)nOR10, —(C1-9 alkyl)nSR10, —(C1-9 alkyl)nS(═O)R11, —(C1-9 alkyl)nSO2R10, —(C1-9 alkyl)nN(R10)SO2R10, —(C1-9 alkyl)nSO2N(R10)2, —(C1-9 alkyl)nN(R10)2, —(C1-9 alkyl)nN(R10)C(=A)N(R10)2, —(C1-9 alkyl)nC(=A)N(R10)2, —(C1-9 alkyl)nN(R10)C(=A)R10, —NO2, —CN, —(C1-9 alkyl)nCO2R10, and —(C1-9 alkyl)nC(=A)R10; R14 is selected from the group consisting of —NR10C(=A)R10, —NR10S(═O)R11, —NR10SO2R10, —NR10C(═O)N(R16)2, —NR10C(═S)N(R10)2, —NR10C(═NR12)N(R10)2, —N(R16)2, —C(═O)NR10R17, —C(═S)N(R10)2, —C(═NR12)N(R10)2, —OC(=A)R10, —C(=A)R10, —NR10C(=A)OR10, and —OC(=A)NR10R10; R15 is 1-4 substituents each selected from the group consisting of H, C1-9 alkyl, halide, —CF3, carbocyclylR13, heterocyclylR13, arylR13, heteroarylR13, —(C1-9 alkyl)nOR10, —(C1-9 alkyl)nSR10, —(C1-9 alkyl)nS(═O)R11, —(C1-9 alkyl)nSO2R10, —(C1-9 alkyl)nN(R10)SO2R10, —(C1-9 alkyl)nSO2N(R10)2, —(C1-9 alkyl)nN(R10)2, —(C1-9 alkyl)nN(R10)C(=A)N(R10)2, —(C1-9 alkyl)nC(=A)N(R10)2, —(C1-9 alkyl)nN(R10)C(=A)R10, —NO2, —CN, —(C1-9 alkyl)nCO2R10, and —(C1-9 alkyl)nC(=A)R10; R16 is —C1-9 alkyl; each R17 is independently selected from the group consisting of -heterocyclylR13, —(C1-9 alkyl)heterocyclylR13, and —(C1-9 alkyl)carbocyclylR13; R18 and R19 are independently selected from the group consisting of H, C1-9 alkyl, halide, —(C1-9 alkyl)ncarbocyclylR13, —(C1-9 alkyl)nheterocyclylR13, —(C1-9 alkyl)narylR13, —(C1-9 alkyl)nheteroarylR13, —(C1-9 alkyl)nOR10, —(C1-9 alkyl)nSR10, —(C1-9 alkyl)nS(═O)R11, —(C1-9 alkyl)nSO2R10, —(C1-9 alkyl)nN(R10)SO2R10, —(C1-9 alkyl)nSO2N(R10)2, —(C1-9 alkyl)nN(R10)2, —(C1-9 alkyl)nN(R10)C(=A)N(R10)2, —(C1-9 alkyl)nC(=A)N(R10)2, —(C1-9 alkyl)nN(R10)C(=A)R10, —NO2, —CN, —(C1-9 alkyl)nCO2R10, and —(C1-9 alkyl)nC(=A)R10; alternatively, R18 and R19 are taken together to form a ring which is selected from the group consisting of benzene and pyridine; each A is independently selected from O, S, and NR12; Y1, Y2, and Y4 are C; Y3 is nitrogen and R8 is absent; and each n is 0 or 1.