Heterocyclic inhibitors of ERK2 and uses thereof

Abstract

Described herein are compounds that are useful as protein kinase inhibitors having the formula: wherein Z 1 and Z 2 are each independently nitrogen or CH and Ring A, T m R 1 , QR 2 , U n R 3 , and Sp are as described in the specification. The compounds are especially useful as inhibitors of ERK2 and for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, diabetes, and cardiovascular disease.

1 . A method of treating a cancer selected from melanoma, colon cancer, lung cancer, kidney carcinoma, ovarian cancer, pancreatic cancer, or prostate cancer, which method comprises administering to said patient a compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein: 
 Sp is a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2  are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6  substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;  
 Z 1  and Z 2  are each independently selected from N or CH;  
 T is a linker group selected from —NH—, —CH 2 —, —CO—;  
 Q is —CO 2 —, —C(O)NR 7 —, or —S(O) 2 NR 7 —;  
 U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, —CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;  
 m and n are each independently selected from zero or one;  
 R 1  is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;  
 R 2  is selected from —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , —N(R 4 ) 2 , or —NR 4 (CH 2 ) y N(R 4 ) 2 ;  
 y is 0-6;  
 R 3  is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;  
 each R is independently selected from 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 3-10 ring atoms;  
 each R 4  is independently selected from R, R 7 , —COR 7 , —CO 2 R, —CON(R 7 ) 2 , —SO 2 R 7 , —(CH 2 ) y R 5 , or —(CH 2 ) y CH(R 5 ) 2 ;  
 each R 5  is independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;  
 each R 6  is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;  
 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;  
 R 8  is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N(R 4 ) 2 , or (CH 2 ) w SR 7 ; and  
 each w is independently selected from 0-4.  
 
     
     
         2 . (canceled)  
     
     
         3 . The method according to  claim 1 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring;    (c) Q is —CO 2 —, —CONH—, or —SO 2 NH;    (d) R 2  is —NR 4 (CH 2 ) y N(R 4 ) 2 , —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;    (f) R 4  is R, R 7 , or —(CH 2 ) y CH(R 5 ) 2 ; and    (g) R 5  is an optionally substituted group selected from C 1-6  aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.    
     
     
         4 . The method according to  claim 3 , wherein: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring;    (c) Q is —CO 2 —, —CONH—, or —SO 2 NH;    (d) R 2  is —NR 4 (CH 2 ) y N(R 4 ) 2 , —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5  ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;    (f) R 4  is R, R 7 ; or —(CH 2 ) y CH(R 5 ) 2 ; and    (g) R 5  is an optionally substituted group selected from C 1-6  aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.    
     
     
         5 . The method according to  claim 3 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;    (b) T m R 1  is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ;    (c) Q is —CO—, —CONH—, or —SO 2 NH—;    (d) R 2  is —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , wherein R 8  is OH or CH 2 OH; and    (e) R is —CH 2 OH, —(CH 2 ) 2 OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.    
     
     
         6 . The method according to  claim 5 , wherein: 
 (a) R 3  is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;    (b) T m R 1  is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ;    (c) Q is —CONH— or —SO 2 NH—;    (d) R 2  is —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , wherein R 8  is OH or CH 2 OH; and    (e) R 5  is —CH 2 OH, —(CH 2 ) 2 OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyldiazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.    
     
     
         7 - 9 . (canceled)  
     
     
         10 . A method of inhibiting ERK-2 activity in a biological sample, which method comprises contacting said sample with a compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein: 
 Sp is a a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2  are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6  substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;  
 Z 1  and Z 2  are each independently selected from N or CH;  
 T is a linker group selected from —NH—, —CH 2 —, —CO—;  
 Q is —CO 2 —, —C(O)NR 7 —, or —S(O) 2 NR 7 —;  
 U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, ——CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;  
 m and n are each independently selected from zero or one;  
 R 1  is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;  
 R 2  is selected from —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , —N(R 4 ) 2 , or —NR 4 (CH 2 ) y N(R 4 ) 2 ;  
 y is 0-6;  
 R 3  is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;  
 each R is independently selected from 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 3-10 ring atoms;  
 each R 4  is independently selected from R, R 7 , —COR 7 , —CO 2 R, —CON(R 7 ) 2 , —SO 2 R 7 , —(CH 2 ) y R 5 , or —(CH 2 ) y CH(R 5 ) 2 ;  
 each R 5  is independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, SO 2 N(R 7 ) 2 ;  
 each R 6  is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;  
 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;  
 R 8  is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N(R 4 ) 2 , or (CH 2 ) w SR 7 ; and  
 each w is independently selected from 0-4.  
 
     
     
         11 - 19 . (canceled)  
     
     
         20 . A compound of formula I′:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof, wherein: 
 Sp is a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2  are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6  substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;  
 Z 1  and Z 2  are each independently selected from N or CH;  
 T is a linker group selected from —NH—, —CH 2 —, —CO—;  
 Q′ is selected from —CO 2 —, —C(O)NR 7 — or —SO 2 NR 7 —;  
 U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, —CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;  
 m and n are each independently selected from zero or one;  
 R 1  is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;  
 R 2′  is selected from —(CH 2 ) y CH(R 5 ) 2  or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;  
 y is 0-6;  
 R 3  is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;  
 each R is independently selected from 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 3-10 ring atoms;  
 each R 4  is independently selected from R, R 7 , —COR 7 , —CO 2 R, —CON(R 7 ) 2 , —SO 2 R 7 , —(CH 2 ) y R 5 , or —(CH 2 ) y CH(R 5 ) 2 ;  
 each R 5  is independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;  
 each R 6  is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;  
 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;  
 R 8  is selected from R, (CH 2 ) w OR 7 , (CH 2 ) w N(R 4 ) 2 , or (CH 2 ) w SR 7 ; and  
 each w is independently selected from 0-4.  
 
     
     
         21 . (canceled)  
     
     
         22 . The compound according to  claim 20 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is R or OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.    
     
     
         23 . The compound according to  claim 22 , wherein: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is R or OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.    
     
     
         24 . The compound according to  claim 22 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;    (b) T m R 1  is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ; and    (c) R 5  is OH, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q′ is —C(O)NH—.    
     
     
         25 . The compound according to  claim 24 , wherein: 
 (a) R 3  is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;    (b) T m R 1  is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ; and    (c) R 5  is OH, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q′ is —C(O)NH—.    
     
     
         26 . The compound according to  claim 20 , wherein said compound is of formula I″:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof.  
     
     
         27 . The compound according to  claim 26 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, N(R 4 ) 2 , OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.    
     
     
         28 . The compound according to  claim 27 , wherein: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, N(R 4 ) 2 , OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.    
     
     
         29 . The compound according to  claim 20 , wherein said compound is of formula I o :  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable derivative thereof.  
     
     
         30 . The compound according to  claim 29 , wherein said compound has one or more features selected from the group consisting of: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is R or OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.    
     
     
         31 . The compound according to  claim 30 , wherein: 
 (a) R 3  is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4  aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;    (b) T m R 1  is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring; and    (c) R 5  is R or OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.    
     
     
         32 - 40 . (canceled)  
     
     
         41 . A composition comprising a compound according to  claim 20  and a pharmaceutically acceptable carrier.  
     
     
         42 . The composition according to  claim 41 , further comprising an additional therapeutic agent selected from a chemotherapeutic agent or anti-proliferative agent.  
     
     
         43 . A method of treating a cancer selected from melanoma, colon cancer, lung cancer, kidney carcinoma, ovarian cancer, pancreatic cancer, or prostate cancer in a patient comprising the step of administering to said patient a therapeutically effective amount of the composition according to  claim 41 .  
     
     
         44 - 70 . (canceled)