Pyrazole compounds useful as protein kinase inhibitors
AssigneeVertex Pharmaceuticals Incorporated
InventorsDavid Bebbington, Jean-Damien Charrier, Julian Golec, Francoise Pierard
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Abstract
This invention describes novel pyrazole compounds of formula III: wherein Z1, Z2, and Z3 are as described in the specification; Q is —S—, —O—, —N(R4)—, or —CH(R6)—; R1 is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; and R2 and R2′ are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.
Claims11
1-26. (canceled)
A compound of formula III:
- or a pharmaceutically acceptable salt thereof;
- wherein:
- Z1 is CH;
- Z2 and Z3 are CH or N;
- Q is NH, O, or S;
- R1 is T-(Ring D);
- Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R5, or V—Z—R5, and each substitutable ring nitrogen of Ring D is independently substituted by —R4;
- T is a valence bond or a C1-4 alkylidene chain;
- Z is a C1-4 alkylidene chain;
- L is —O—, —S—, —SO—, —SO2—, —N(R6)SO2—, —SO2N(R6)—, —N(R6)—, —CO—, —CO2—, —N(R6)CO—, —N(R6)C(O)O—, —N(R6)CON(R6)—, —N(R6)SO2N(R6)—, —N(R6)N(R6)—, —C(O)N(R6)—, —OC(O)N(R6)—, —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —C(R6)2N(R6)C(O)—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, or —C(R6)2N2N(R6)CON(R6)—;
- R2 and R2′ are independently selected from —R, -T-W—R6, or R2 and R2′ are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2′ is independently substituted by halo, oxo, —CN, —NO2, —R6, or —V—R6, and each substitutable ring nitrogen of said ring funned by R2 and R2′ is independently substituted by R4;
- R3 is selected from —R, -halo, —OR, —C(═O)R, —CO2R, —COCOR, —COCH2COR, —NO2, —CN, —S(O)R, —S(O)2R, —SR, —N(R4)2, —CON(R7)2, —SO2N(R7)2, —OC(═O)R, —N(R7)COR, —N(R7)CO2(C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR, —N(R7)CON(R7)2, —N(R7)SO2N(R7)2, —N(R4)SO2R, or —OC(═O)N(R7)2;
- each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
- each R4 is independently selected from —R7, —COR7, —CO2 (optionally substituted C1-6 aliphatic), —CON(R7)2, or —SO2R7;
- each R5 is independently selected from —R, halo, —OR, —C(═O)R, —CO2R, —COCOR, —NO2, —CN, —S(O)R, —SO2R, —SR, —N(R4)2, —CON(R4)2, —SO2N(R4)2, —OC(═O)R, —N(R4)COR, —N(R4)CO2 (optionally substituted C1-6 aliphatic), —N(R4)N(R4)2, —C═NN(R4)2, —C═N—OR, —N(R4)CON(R4)2, —N(R4)SO2N(R4)2, —N(R4)SO2R, or —OC(═O)N(R4)2;
- V is —O—, —S—, —SO—, —SO2—, —N(R6)SO2—, —SO2N(R6)—, —N(R6)—, —CO—, —CO2—, —N(R6)CO—, —N(R6)C(O)O—, —N(R6)CON(R6)—, —N(R6)SO2N(R6)—, —N(R6)N(R6)—, —C(O)N(R6)—, —OC(O)N(R6)—, —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —C(R6)2N(R6)C(O)—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, or —C(R6)2N(R6)CON(R6)—;
- W is —C(R6)2O—, —C(R6)2S—, —C(R6)2SO—, —C(R6)2SO2—, —C(R6)2SO2N(R6)—, —C(R6)2N(R6)—, —CO—, —CO2—, —C(R6)OC(O)—, —C(R6)OC(O)N(R6)—, —C(R6)2N(R6)CO—, —C(R6)2N(R6)C(O)O—, —C(R6)═NN(R6)—, —C(R6)═N—O—, —C(R6)2N(R6)N(R6)—, —C(R6)2N(R6)SO2N(R6)—, —C(R6)2N(R6)CON(R6)—, or —CON(R6)—;
- each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
- and
- each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
The compound of claim 1, selected from:
Dependencies are inferred from the claim text.