Pyrazole compounds useful as protein kinase inhibitors
This invention describes novel pyrazole compounds of formula III: wherein Z 1 , Z 2 , and Z 3 are as described in the specification; Q is —S—, —O—, —N(R 4 )—, or —CH(R 6 )—; R 1 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 R 2 and R 2 ′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.
1. A compound of formula III:
or a pharmaceutically acceptable salt thereof; wherein:
Z 1 is CH;
Z 2 is CH or N;
Z 3 is N;
Q is NH, O, —CH(R 6 )—, or S;
R 1 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 1-4ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V—Z—R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by —R 4 ;
T is a valence bond or a C 1-4 alkylidene chain;
Z is a C 1-4 alkylidene chain;
R 2 and R 2 ′ are independently selected from C 1-4 alkyl, a 3-6 membered cycloalkyl, or R 2 and R 2 ′ are taken together with their intervening atoms to form a fused phenyl ring, wherein each substitutable ring carbon of said fused ring formed by R 2 and R 2 ′ is independently substituted by halo, oxo, —CN, —NO 2 , —R 7 , or —V—R 6 ;
each R is independently selected from hydrogen or an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R 4 is independently selected from —R 7 , —COR 7 , —CO 2 (optionally substituted C 1-6 aliphatic), —CON(R 7 ) 2 , or —SO 2 R 7 ;
each R 5 is independently selected from —R, halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —NO 2 , —CN, —S(O)R, —SO 2 R, —SR, —N(R 4 ) 2 , —CON(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —OC(═O)R, —N(R 4 )COR, —N(R 4 )CO 2 (optionally substituted C 1-6 aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 4 )CON(R 4 ) 2 , —N(R 4 )SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 4 ) 2 ;
V is —O—, —S—, —SO—, —SO 2 —, —N(R 6 )SO 2 —, —SO 2 N(R 6 )—, —N(R 6 )—, —CO—, —CO 2 —, —N(R 6 )CO—, —N(R 6 )C(O)O—, —N(R 6 )CON(R 6 )—, —N(R 6 )SO 2 N(R 6 )—, —N(R 6 )N(R 6 )—, —C(O)N(R 6 )—, —OC(O)N(R 6 )—, —C(R 6 ) 2 O—, —C(R 6 ) 2 S—, —C(R 6 ) 2 SO—, —C(R 6 ) 2 SO 2 —, —C(R 6 ) 2 SO 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )—, —C(R 6 ) 2 N(R 6 )C(O)—, —C(R 6 ) 2 N(R 6 )C(O)O—, —C(R 6 )═NN(R 6 )—, —C(R 6 )═N—O—, —C(R 6 ) 2 N(R 6 )N(R 6 )—, —C(R 6 ) 2 N(R 6 )SO 2 N(R 6 )—, or —C(R 6 ) 2 N(R 6 )CON(R 6 )—;
each R 6 is independently selected from hydrogen or an optionally substituted C 1-4 aliphatic group, or two R 6 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 R 7 is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8membered heterocyclyl or heteroaryl ring.
2. The compound of claim 1 , wherein Q is S.
3. The compound of claim 1 , wherein Q is NH.
4. The compound of any one of claims 1 - 3 , wherein Z 2 is CH.
5. The compound of any one of claims 1 - 3 , wherein Z 2 is N.
6. The compound of claim 5 , wherein R 1 is phenyl, pyridyl, indazolyl, benzothiazolyl, or thiophene.
7. The compound of claim 6 , wherein R 1 is phenyl.
8. The compound of claim 5 , wherein R 1 is thiophene or phenyl.
9. The compound of claim 1 , selected from:
10. A composition comprising a compound according to any of claims 1 or 9 , and a pharmaceutically acceptable carrier.