Heterocyclic compounds as kinase inhibitors

Abstract

The present invention is directed to certain amides and heterocyclic compounds. The present invention also relates to uses of these compounds to treat several diseases including autoimmune disorders, cardiovascular disorders, inflammation, central nervous system disorders, arterial thrombotic disorders, fibrotic disorders, glaucoma, and neoplastic disorders.

What is claimed is: 
     
         1 . A method of treating a neoplastic disease in a subject comprising: administering to the subject a therapeutically effective amount of a compound Formula (I): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; 
         wherein: 
         A pyrazol-4-yl; 
         Z is 
       
       
         
           
           
               
               
           
         
       
       wherein
 G 1 , G 2  and G 3  are independently CH or N; 
 Z′ is a bond; 
 R is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R 1  is —H; 
 Q is a bond or methyl; 
 J is a bond; 
 W is —H or —OH; and 
 Ar is a phenyl, naphthyl, or C5-10 heterocycle, each of which is substituted with halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, C 3-7  cycloalkyl, or 3- to 10-membered heterocycle, wherein the C 1-6  alkyl, aryl, C 3-7  cycloalkyl, or 3 to 10-membered heterocycle is unsubstituted or substituted with one or more of halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, or C 3-7  cycloalkyl; wherein each of R a  and R b  is independently —H or C 1-6  alkyl; and optionally R a  and R b  together attaching to N or O form a 4- to 8-membered heterocycle; 
 wherein the neoplastic disease is a disorder associated with inappropriate ROCK activity selected from the group consisting of a lymphoma, carcinoma, leukemia, sarcoma, and blastoma. 
 
     
     
         2 . The method of  claim 1 , wherein the neoplastic disease is acute myeloid leukemia (AML). 
     
     
         3 . The method of  claim 1 , wherein G 1  is N; and G 2  and G 3  are CH. 
     
     
         4 . The method of  claim 3 , wherein Q is methyl. 
     
     
         5 . The method of  claim 4 , wherein Ar is a substituted phenyl. 
     
     
         6 . The method of  claim 5 , wherein the phenyl is substituted with —OR a  and R a  is —H or C 1-6  alkyl. 
     
     
         7 . The method of  claim 5 , wherein R is —H. 
     
     
         8 . A method of treating a neoplastic disease in a subject comprising: administering to the subject a therapeutically effective amount of a compound Formula (I): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; 
         wherein: 
         A is pyrazol-4-yl or 
       
       
         
           
           
               
               
           
         
         
           wherein 
           (i) G is CR′; 
           (ii) X is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, —OR 2  or —NR 3 R 4 ; and 
           (iii) R′, R″, R 2 , R 3 , and R 4  are independently —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
         
         Z is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 5  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 (ii) R 7  and R 8  are independently —H, halo, C 1-6  alkyl, C 3-7  cycloalkyl, —O—(C 1-6  alkyl), —OH, —CN, —COOR′, —OC(O)R′, —NHR′, —N(R′) 2 , —NHC(O)R′ or —C(O)NHR′; and 
 (iii) G 1 , G 2 , and G 3  are independently CH or N; 
 Z′ is a bond or NR 6 , wherein R 6  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R 1  is —H or C 1-6  alkyl; 
 Q is a bond or C 1-6  alkyl; 
 J is a bond or C 1-6  alkyl; 
 W is —H, —OR 9  or —NR 10 R 11 , wherein R 9 , R 10  and R 11  are independently —H, C 1-6  alkyl, C 3-7  cycloalkyl, formyl, C 1-6  alkylcarbonyl, C 3-7  cycloalkylcarbonyl or C 1-6  alkylsulfonyl; and 
 Ar is a phenyl, optionally substituted with —F, —Br, —I, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, C 3-7  cycloalkyl or 3- to 10-membered heterocycle; Ar is a naphthyl, optionally substituted with halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, C 3-7  cycloalkyl or 3- to 10-membered heterocycle; or Ar is a C 5-10  heterocycle, optionally substituted with halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, C 3-7  cycloalkyl or 3- to 10-membered heterocycle; wherein the C 1-6  alkyl, aryl, C 3-7  cycloalkyl, or 3 to 10-membered heterocycle is unsubstituted or substituted with one or more of halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl or C 3-7  cycloalkyl; wherein each of R a  and R b  is independently —H or C 1-6  alkyl; and optionally R a  and R b  together attaching to N or O form a 4- to 8-membered heterocycle; 
 wherein the neoplastic disease is a disorder associated with inappropriate ROCK activity selected from the group consisting of a lymphoma, carcinoma, leukemia, sarcoma, and blastoma. 
 
     
     
         9 . The method of  claim 8 , wherein the neoplastic disease is acute myeloid leukemia (AML). 
     
     
         10 . The method of  claim 8 , wherein the compound has a structure of Formula II: 
       
         
           
           
               
               
           
         
         wherein
 (i) G is CR′; 
 (ii) X is hydrogen or C 1-6  alkyl; and 
 (iii) R′ and R″ are independently —H C 1-6  alkyl or C 3-7  cycloalkyl; and 
 
         Z is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein
 (i) R 5  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; and 
 (ii) R 7  and R 8  are independently —H, halo, C 1-6  alkyl, C 3-7  cycloalkyl, —O—(C 1-6  alkyl), —OH, —CN, —COOR′, —OC(O)R′, —NHR′, —N(R′) 2 , —NHC(O)R′, or —C(O)NHR′; 
 Z′ is a bond or NR 6 , wherein R 6  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R is —H, C 1-6  alkyl or C 3-7  cycloalkyl; 
 R 1  is —H or C 1-6  alkyl; 
 Q is a bond or C 1-6  alkyl; 
 J is a bond or C 1-6  alkyl; 
 W is —H, —OR 9  or —NR 10 R 11 , wherein R 9 , R 10  and R 11  are independently —H, C 1-6  alkyl, C 3-7  cycloalkyl, formyl, C 1-6  alkylcarbonyl, C 3-7  cycloalkylcarbonyl or C 1-6  alkylsulfonyl; and 
 Ar is a phenyl, optionally substituted with —F, —Br, —I, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, C 3-7  cycloalkyl or 3- to 10-membered heterocycle; Ar is a naphthyl, optionally substituted with halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, C 3-7  cycloalkyl, or 3- to 10-membered heterocycle; or Ar is a C 5-10  heterocycle, optionally substituted with halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, C 3-7  cycloalkyl, or 3- to 10-membered heterocycle; wherein the C 1-6  alkyl, aryl, C 3-7  cycloalkyl, or 3 to 10-membered heterocycle is unsubstituted or substituted with one or more of halo, —OH, —CN, —COOR a , —OR a , —SR a , —OC(O)R a , —NHR a , —NR a R b , —NHC(O)R a , —NHC(O)NR a R b , —C(O)NR a R b , —NS(O) 2 R a , —S(O) 2 NR a R b , —S(O) 2 R a , guanidino, nitro, nitroso, C 1-6  alkyl, aryl, or C 3-7  cycloalkyl; wherein each of R a  and R b  is independently —H or C 1-6  alkyl; and optionally R a  and R b  together attaching to N or O form a 4- to 8-membered heterocycle. 
 
     
     
         11 . The method of  claim 8 , wherein Z′ is a bond. 
     
     
         12 . The method of  claim 11 , wherein Ar is a substituted phenyl. 
     
     
         13 . The method of  claim 8 , wherein Z is 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; and 
         R 7  is —H, halo, C 1-6  alkyl, C 3-7  cycloalkyl, —O—(C 1-6  alkyl), —OH, —CN, —COOR′, —OC(O)R′, —NHR′, —N(R′) 2 , —NHC(O)R′ or —C(O)NHR′. 
       
     
     
         14 . The method of  claim 8  wherein W is —OH, —NH 2 , —NHCH 3  or —N(CH 3 ) 2 . 
     
     
         15 . A method of treating a neoplastic disease in a subject comprising: administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the neoplastic disease is a disorder associated with inappropriate ROCK activity selected from the group consisting of a lymphoma, carcinoma, leukemia, sarcoma, and blastoma. 
       
     
     
         16 . The method of  claim 15 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 8 , wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 10 , wherein Z is 
       
         
           
           
               
               
           
         
         wherein 
         R 5  is —H, C 1-6  alkyl or C 3-7  cycloalkyl; and 
         R 7  is —H, halo, C 1-6  alkyl, C 3-7  cycloalkyl, —O—(C 1-6  alkyl), —OH, —CN, —COOR′, —OC(O)R′, NHR′, N(R′) 2 , —NHC(O)R′. 
       
     
     
         19 . The method of  claim 10 , wherein Z′ is a bond. 
     
     
         20 . The method of  claim 18 , wherein Ar is an optionally substituted phenyl.