Benzimidazole compounds as c-kit inhibitors

Abstract

The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other serine-threonine kinase mediated diseases, having the Formula: (I) where A, L, R1, R2, R3, and n are described herein.

1 .- 29 . (canceled) 
     
     
         30 . A compound having one of the following formulae (Ii) or (Ij): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is H; 
         R 2  is —(C(R 6a ) 2 ) p -heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R 9 ; 
         R 3  is (C 1 -C 6 ) alkyl or halogen; 
         R 4  is (C 1 -C 5 ) haloalkyl; 
         R 5  is H; 
         each R 9  is independently at each occurrence (C 1 -C 6 ) alkyl or 5- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C 1 -C 6 ) alkyl or —C(Q)H, and wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C 1 -C 5 ) alkoxy, —OH, or (C 1 -C 6 ) dialkylamino; 
         p is 0; and 
         n is 0, 1 or 2. 
       
     
     
         31 - 32 . (canceled) 
     
     
         33 . The compound of  claim 30 , wherein R 4  is CF 3 . 
     
     
         34 . The compound of  claim 30  wherein n is 1, R 3  is methyl, R 1  is H, and R 2  is triazolyl substituted with methyl; or imidazolyl substituted with methyl or N-methyl piperidinyl. 
     
     
         35 . The compound of  claim 30 , wherein n is 1 and R 3  is methyl, R 2  is pyrazolyl optionally substituted with methyl; —(CH 2 ) 2 OH; —(CH 2 ) 2 OCH 3 ; —(CH 2 ) 2 N(CH 3 ) 2 ; —(CH 2 ) 2 N(CH 2 CH 3 ) 2 ; tetrahydropyranyl; or piperidinyl optionally substituted with methyl or —C(O)H. 
     
     
         36 .- 38 . (canceled) 
     
     
         39 . A pharmaceutical composition comprising a compound of  claim 30 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient or carrier. 
     
     
         40 . A method of treating a c-Kit-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 30 , or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 40 , wherein the cKit-mediated disease or disorder is selected from cell proliferative disorder, a fibrotic disorder, and a metabolic disorder. 
     
     
         42 . The method of  claim 41 , wherein said cell proliferative disorder is cancer. 
     
     
         43 . The method of  claim 42 , wherein said cancer is selected from the group consisting of leukemia, mast cell tumor, small cell lung cancer, testicular cancer, cancer of the gastrointestinal tract, cancer of the central nervous system, cancer of the female genital tract, sarcoma of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis; or
 said cancer is selected from the group consisting of small cell lung carcinoma, acute myeloid leukemia (AML), neuroblastoma, malignant melanomas, colorectal cancer, systemic mastocytosis (SM), and gastrointestinal stromal tumors (GISTs).   
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 40 , wherein said cKit-mediated disease or disorder is multiple sclerosis, asthma, an allergic reaction, inflammatory arthritis, or mastocytosis. 
     
     
         46 .- 49 . (canceled) 
     
     
         50 . A method of modulating or inhibiting c-Kit comprising administering to a subject a compound of  claim 30 . 
     
     
         51 . (canceled) 
     
     
         52 . A method of treating or preventing a disease in which c-Kit plays a role, comprising administering to a subject in need thereof an effective amount of a compound of  claim 30 . 
     
     
         53 . The compound of  claim 30 , having the following structure, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         54 . The compound of  claim 30 , having the following structure, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.