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US 2011/0034441 A1Published application
Indazoles as wnt/b-catenin signaling pathway inhibitors and therapeutic uses thereof
AssigneeEpitherix, LLC
InventorsJohn Hood, Sunil Kumar KC
Life of this patent
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Abstract
Described herein are methods of treating a disorder or disease in which aberrant Wnt signaling is implicated, with a variety of compounds, including Wnt inhibitor compounds. More particularly, it 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.
Claims78
A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound having a structure of Formula I, or a pharmaceutically acceptable salt or pro-drug thereof:
- wherein R1, R2, R4, R5, R6, R7 and R8 are independently selected from the group consisting of H, C1-9 alkyl, halide, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)S(═O)R10, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- R3 is selected from the group consisting of —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)S(═O)R10, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- alternatively, one of each R1 and R2, R2 and R3, R3 and R4, R5 and R6, R6 and R7 or R7 and R8 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 R9 is independently selected from the group consisting of H, —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R10 is independently selected from the group consisting of —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R11 is independently selected from the group consisting of CN, —OR9 and R9;
- each R12 is 1-5 substituents each selected from the group consisting of H, —C1-9 alkyl, -alkylaminoalkyl, halide, —CF3, carbocyclylR12, heterocyclylR12, arylR12, heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- R13 and R14 are independently selected from the group consisting of H, C1-9 alkyl, halide, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- alternatively, R13 and R14 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 NR11;
- and
- each n is 0 or 1.
10 more elements
A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound having a structure of Formula II, or a pharmaceutically acceptable salt or pro-drug thereof:
- wherein R1, R2, R4, R5, R6, R7 and R8 are independently selected from the group consisting of H, C1-9 alkyl, halide, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)S(═O)R10, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- alternatively, one of each R1 and R2, R2 and R15, R15 and R4, R5 and R6, R6 and R7 or R7 and R8 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 R9 is independently selected from the group consisting of H, —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R10 is independently selected from the group consisting of —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R11 is independently selected from the group consisting of CN, —OR9 and R9;
- each R12 is 1-5 substituents each selected from the group consisting of H, C1-9 alkyl, -alkylaminoalkyl, halide, —CF3, carbocyclylR12, heterocyclylR12, arylR12, heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- R13 and R14 are independently selected from the group consisting of H, C1-9 alkyl, halide, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- alternatively, R13 and R14 are taken together to form a ring which is selected from the group consisting of benzene and pyridine;
- each R15 is selected from the group consisting of -carbocyclylR16, —(C1-9 alkyl)carbocyclylR12, -heterocyclylR16, —(C1-9 alkyl)heterocyclylR12, -arylR16, —(C1-9 alkyl)arylR12, -heteroarylR16, —(C1-9 alkyl)heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)N(R9)S(═O)R10, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- each R16 is 1-5 substituents each selected from the group consisting of H, C1-9 alkyl, halide, —CF3, carbocyclylR12, heterocyclylR12, arylR12, heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)N(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —N(R17)2, —(C1-9 alkyl)N(R9)2, —NR9C(═O)N(R17)2, —(C1-9 alkyl)N(R9)C(=A)N(R9)2, —C(═O)NR9R18, —(C1-9 alkyl)C(=A)N(R9)2, —(C1-9 alkyl)NR9C(═O)OR9, —(C1-9 alkyl)N(R9)C(=A)R9, —(C1-9 alkyl)OC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)C(=A)R9;
- each R17 is H, —(C1-9 alkyl)ncarbocyclyl, —(C1-9 alkyl)nheterocyclyl, —(C1-9 alkyl)naryl and —(C1-9 alkyl)nheteroaryl;
- each R18 is independently selected from the group consisting of H, —C1-9 alkyl, —CF3, -carbocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each A is independently selected from O, S and NR11;
- Y1, Y2, Y3 and Y4 are independently selected from the group consisting of carbon and nitrogen with the proviso that at least one of Y1, Y2, Y3 and Y4 are nitrogen;
- wherein
- if Y1 is nitrogen then R5 is absent;
- if Y2 is nitrogen then R6 is absent;
- if Y3 is nitrogen then R7 is absent;
- if Y4 is nitrogen then R8 is absent;
- and
- each n is 0 or 1.
19 more elements
A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound having a structure of Formula III, or a pharmaceutically acceptable salt or pro-drug thereof:
- wherein R1, R2, R4, R5 and R6 are independently selected from the group consisting of H, C1-9 alkyl, halide, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12, —(C1-9 alkyl)nheteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9 alkyl)nSR9, —(C1-9 alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)S(═O)R10, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- each R9 is independently selected from the group consisting of H, —C1-9 alkyl, —(C1-9 alkyl)OR9, —(C1-9 alkyl)N(R9)2, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R10 is independently selected from the group consisting of —C1-9 alkyl, —(C1-9 alkyl)OR9, —(C1-9 alkyl)N(R9)2, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- alternatively, R9 and R10 are taken together to form a 3-10 membered heterocyclyl ring;
- each R11 is independently selected from the group consisting of CN, —OR9 and R9;
- each R12 is 1-5 substituents each selected from the group consisting of H, C1-9alkyl, -alkylaminoalkyl, halide, —CF3, carbocyclylR12, heterocyclylR12, arylR12, heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9alkyl)nSR9, —(C1-9alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- each A is independently selected from O, S and NR11;
- and
- each n is 0 or 1.
6 more elements
A method of treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound having a structure of Formula IV, or a pharmaceutically acceptable salt or pro-drug thereof:
- wherein each R9 is independently selected from the group consisting of H, —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R10 is independently selected from the group consisting of —C1-9 alkyl, —CF3, —(C1-9 alkyl)ncarbocyclylR12, —(C1-9 alkyl)nheterocyclylR12, —(C1-9 alkyl)narylR12 and —(C1-9 alkyl)nheteroarylR12;
- each R11 is independently selected from the group consisting of CN, —OR9 and R9;
- each R12 is 1-5 substituents each selected from the group consisting of H, C1-9alkyl, -alkylaminoalkyl, halide, —CF3, carbocyclylR12, heterocyclylR12, arylR12, heteroarylR12, —(C1-9 alkyl)nOR9, —(C1-9alkyl)nSR9, —(C1-9alkyl)nS(═O)R10, —(C1-9 alkyl)nSO2R9, —(C1-9 alkyl)nN(R9)SO2R9, —(C1-9 alkyl)nSO2N(R9)2, —(C1-9 alkyl)nN(R9)2, —(C1-9 alkyl)nN(R9)C(=A)N(R9)2, —(C1-9 alkyl)nC(=A)N(R9)2, —(C1-9 alkyl)nNR9C(═O)OR9, —(C1-9 alkyl)nN(R9)C(=A)R9, —(C1-9 alkyl)nOC(═O)N(R9)2, —NO2, —CN, —(C1-9 alkyl)nCO2R9 and —(C1-9 alkyl)nC(=A)R9;
- R19 is independently selected from the group consisting of C1-9alkyl, —OR9, amino, —S(═O)R10, —SO2R9, —N(R9)S(═O)R10, —N(R9)SO2R9, —SO2N(R9)2, —N(R9)2, —N(R9)C(═O)N(R9)2, —NR9C(═O)OR9, —C(═O)N(R9)2, —N(R9)C(═O)R9, —OC(═O)N(R9)2, —CO2R9 and —C(═O)R9;
- R20 is independently selected from the group consisting of arylR12 and heteroarylR12;
- each A is independently selected from O, S and NR11;
- and
- each n is 0 or 1.
6 more elements
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of the formulas I, II, III, or IV, as set forth herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient:
Dependencies are inferred from the claim text.