Pyrazole compounds useful as protein kinase inhibitors

Abstract

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.

We claim:  
     
         1 . A compound of formula III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 
 Z 1  is nitrogen or CR 8 , Z 2  is nitrogen or CH, and Z 3  is nitrogen or CR x , provided that one of Z 1  and Z 3  is nitrogen;  
 R x  is T-R 3  or L-Z-R 3 ;  
 Q is selected from —N(R 4 )—, —O—, —S—, or —CH(R 6 )—;  
 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 1-4 ring 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, wherein when Q is —CH(R 6 )—, a methylene unit of said C 1-4  alkylidene chain is optionally replaced by —O—, —S—, —N(R 4 )—, —CO—, —OC(O)NH—, or —NHCO 2 —;  
 Z is a C 1-4  alkylidene chain;  
 L 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 )O 2 N(R 6 )—, or —C(R 6 ) 2 N(R 6 )CON(R 6 )—; 
 R 2  and R 2  are independently selected from —R, -T-W—R 6 , or R 2  and R 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 R 2  and R 2 ′ is independently substituted by halo, oxo, —CN, —NO 2 , —R 7 , or —V—R 6 , and each substitutable ring nitrogen of said ring formed by R 2  and R 2 ′ is independently substituted by R 4 ;  
 R 3  is selected from —R, -halo, —OR, —C(═O)R, —CO 2 R, —COCOR, —COCH 2 COR, —NO 2 , —CN, —S(O)R, —S(O) 2 R, —SR, —N(R 4 ) 2 , —CON(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —OC(═O)R, —N(R 7 )COR, —N(R 7 )CO 2 (C 1-6  aliphatic), —N(R 4 )N(R 4 ) 2 , —C═NN(R 4 ) 2 , —C═N—OR, —N(R 7 )CON(R 7 ) 2 , —N(R 7 )SO 2 N(R 7 ) 2 , —N(R 4 )SO 2 R, or —OC(═O)N(R 7 ) 2 ;  
 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)—, —C(R 6 ) 2 N(R 6 )SO 2 N(R 6 )—, or —C(R 6 ) 2 N(R 6 )CON(R 6 )—;  
 W is —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 )—, —CO—, —CO 2 —, —C(R 6 )OC(O)—, —C(R 6 )OC(O)N(R 6 )—, —C(R 6 ) 2 N(R 6 )CO—, —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 )—, —C(R 6 ) 2 N(R 6 )CON(R 6 )—, or —CON(R 6 )—; 
 each R 7  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;  
 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 5-8 membered heterocyclyl or heteroaryl ring; and  
 R 8  is 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 .  
 
 
     
     
         2 . The compound according to  claim 1 , wherein Q is —N(R 4 )—, —S—, or —CH(R 6 )—, and said compound is of formula IIIa, IIIb, IIIc, or IIId:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative or prodrug thereof.  
     
     
         3 . The compound according to  claim 2 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R x  is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4  aliphatic group;    (b) R 1  is T-(Ring D), wherein T is a valence bond or a methylene unit;    (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and    (d) R 2  is —R or -T-W—R and R 2  is hydrogen, or R 2  and R 2  are taken together to form an optionally substituted benzo ring.    
     
     
         4 . The compound according to  claim 3 , wherein: 
 (a) R x  is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1-4  aliphatic group;    (b) R 1  is T-(Ring D), wherein T is a valence bond or a methylene unit;    (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and    (d) R 2  is —R or -T-W—R 1  and R 2  is hydrogen, or R 2  and R 2  are taken together to form an optionally substituted benzo ring.    
     
     
         5 . The compound according to  claim 3 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 1  is T-(Ring D), wherein T is a valence bond, and Q is —S— or —NH—;    (b) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and    (c) R is —R and R 2  is hydrogen, wherein R is selected from hydrogen, C 1-6  aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.    
     
     
         6 . The compound according to  claim 5 , wherein: 
 (a) R 1  is T-(Ring D), wherein T is a valence bond, and Q is —S— or —NH—;    (b) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and    (c) R 2  is —R and R 2  is hydrogen, wherein R is selected from hydrogen, C 1-6  aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.    
     
     
         7 . The compound according to  claim 5 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R x  is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido;    (b) R 1  is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, —CN, —NO 2 , —N(R 4 ) 2 , optionally substituted C 1-6  aliphatic group, —OR, —CO 2 R, —CON(R 4 ) 2 , —OCO(R 4 ) 2-N(R 4 )COR, —N(R 4 )SO 2 R, —N(R 6 )COCH 2 CH 2 N(R 4 ) 2 , or —N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 ; and    (c) R 2  is hydrogen or a substituted or unsubstituted C 1-6  aliphatic.    
     
     
         8 . The compound according to  claim 7 , wherein: 
 (a) R x  is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido;    (b) R 1  is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, —CN, —NO 2 , —N(R 4 ) 2 , optionally substituted C 1-6  aliphatic group, —OR, —CO 2 R, —CON(R 4 ) 2 , —OCO(R 4 ? 2 , —N(R 4 )COR, —N(R 4 )SO 2 R, —N(R 6 )COCH 2 CH 2 N(R 4 ) 21  or —N(R 6 )COCH 2 CH 2 CH 2 N(R 4 ) 2 ; and    (c) R 2  is hydrogen or a substituted or unsubstituted C 1-6  aliphatic.    
     
     
         9 . A compound selected from the group consisting of: 
 N 5 -(1H-Indazol-6-yl)-N 3 -(5-methyl-1H-pyrazol-3-yl)-[1,2,4]triazine-3,5-diamine;    N-{4-[3-(5-Methyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-5-ylsulfanyl]-phenyl}-acetamide;    [5-(3-Methoxy-benzyl)-[1,2,4]triazin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;    N 3 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 5 -pyridin-3-ylmethyl-[1,2,4]triazine-3,5-diamine;    [5-(Benzothiazol-6-ylsulfanyl)-[1,2,4]triazin-3-yl]-(5-cyclopropyl-1H-pyrazol-3-yl)-amine;    {4-[3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-5-yloxy]-phenyl}-acetonitrile;    N-{4-[3-(1H-Indazol-3-ylamino)-[1,2,4]triazin-5-ylamino]-phenyl}-methanesulfonamide;    (1H-Indazol-3-yl)-[5-(thiophen-2-ylmethylsulfanyl)-[1,2,4]triazin-3-yl]-amine;    N 5 -(5-Methyl-1H-pyrazol-3-yl)-N 3 -pyridin-3-ylmethyl-[1,2,4]triazine-3,5-diamine;    [3-(Benzothiazol-6-ylsulfanyl)-[1,2,4]triazin-5-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;    {4-[5-(5-Methyl-H-pyrazol-3-ylamino)-[1,2,4]triazin-3-yloxy]-phenyl}-acetonitrile;    N 5 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 3 -(1H-indazol-6-yl)-[1,2,4]triazine-3,5-diamine;    N-{4-[5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-[1,2,4]triazin-3-ylsulfanyl]-phenyl}-acetamide;    N 5 -(1H-Indazol-3-yl)-N 3 -(1H-indazol-6-yl)-[1,2,4]triazine-3,5-diamine;    (1H-Indazol-3-yl)-[3-(3-methoxy-phenylsulfanyl)-[1,2,4]triazin-5-yl]-amine; N 5 (1H-Indazol-6-yl)-N 3 -(5-methyl-1H-pyrazol-3-yl)-pyridazine-3,5-diamine;    N-{4-[6-(5-Methyl-1H-pyrazol-3-ylamino)-pyridazin-4-ylsulfanyl]-phenyl}-acetamide;    [5-(3-Methoxy-benzyl)-pyridazin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;    N 3 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 5 -pyridin-3-ylmethyl-pyridazine-3,5-diamine;    [5-(Benzothiazol-6-ylsulfanyl)-pyridazin-3-yl]-(5-cyclopropyl-1H-pyrazol-3-yl)-amine;    {4-[6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyridazin-4-yloxy]-phenyl}-acetonitrile;    N-{4-[6-(1H-Indazol-3-ylamino)-pyridazin-4-ylamino]-phenyl}-methanesulfonamide;    (1H-Indazol-3-yl)-[5-(thiophen-2-ylmethylsulfanyl)-pyridazin-3-yl]-amine;    N 5 -(5-Methyl-1H-pyrazol-3-yl)-N 3 -pyridin-3-ylmethyl-pyridazine-3,5-diamine;    [6-(Benzothiazol-6-ylsulfanyl)-pyridazin-4-yl]-(5-methyl-1H-pyrazol-3-yl)-amine;    {4-[5-(5-Methyl-1H-pyrazol-3-ylamino)-pyridazin-3-yloxy]-phenyl}-acetonitrile;    N 5 -(5-Cyclopropyl-1H-pyrazol-3-yl)-N 3 -(1H-indazol-6-yl)-pyridazine-3,5-diamine;    N-{4-[5-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyridazin-3-ylsulfanyl]-phenyl}-acetamide;    N 5 -(1H-Indazol-3-yl)-N 3 -(1H-indazol-6-yl)-pyridazine-3,5-diamine; and    (1H-Indazol-3-yl)-[6-(3-methoxy-phenylsulfanyl)-pyridazin-4-yl]-amine.    
     
     
         10 . A composition comprising a compound according to any of claims  1 - 9 , and a pharmaceutically acceptable carrier.  
     
     
         11 . The composition according to  claim 10 , further comprising an additional therapeutic agent.  
     
     
         12 . A method of inhibiting Aurora-2 or GSK-3 activity in a biological sample comprising the step of contacting said biological sample with a compound according to any one of claims  1 - 9 .  
     
     
         13 . A method of inhibiting Aurora-2 activity in a patient comprising the step of administering to said patient a composition according to  claim 10 .  
     
     
         14 . A method of inhibiting Aurora-2 activity in a patient comprising the step of administering to said patient a composition according to  claim 11 .  
     
     
         15 . A method of treating an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to  claim 10 .  
     
     
         16 . The method according to  claim 15 , wherein said disease is selected from colon, breast, stomach, or ovarian cancer.  
     
     
         17 . The method according to  claim 16 , wherein said method further comprises administering an additional therapeutic agent.  
     
     
         18 . The method according to  claim 17 , wherein said additional therapeutic agent is a chemotherapeutic agent.  
     
     
         19 . A method of inhibiting GSK-3 activity in a patient comprising the step of administering to said patient a composition according to  claim 10 .  
     
     
         20 . A method of inhibiting GSK-3 activity in a patient comprising the step of administering to said patient a composition according to  claim 11 .  
     
     
         21 . A method of method of treating a GSK-3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to  claim 10 .  
     
     
         22 . The method according to  claim 21 , wherein said GSK-3-mediated disease is selected from diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, or baldness.  
     
     
         23 . The method according to  claim 22 , wherein said GSK-3-mediated disease is diabetes.  
     
     
         24 . A method of enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to said patient a therapeutically effective amount of a composition according to  claim 10 .  
     
     
         25 . A method of inhibiting the production of hyperphosphorylated Tau protein in a patient, which method comprises administering to a patient in need thereof a therapeutically effective amount of a composition according to  claim 10 .  
     
     
         26 . A method of inhibiting the phosphorylation of β-catenin, which method comprises administering to a patient in need thereof a therapeutically effective amount of a composition according to  claim 10.