Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

What is claimed is: 
     
         1 . A compound of formula (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         each R 1  is independently selected from optionally substituted lower alkyl or optionally substituted heteroaryl; 
         R 2  is hydrogen or halogen; 
         R 3  is optionally substituted aryl; 
         R 4  is hydrogen; 
         the subscript m is 2; and 
         Ar is optionally substituted heteroaryl, with the proviso that Ar is other than 
       
       
         
           
           
               
               
           
         
       
       wherein   indicates the point of the attachment to the phenyl moiety in formula (Ic). 
     
     
         2 . The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is halogen. 
     
     
         4 . The compound of  claim 2 , wherein R 3  is optionally substituted phenyl. 
     
     
         5 . The compound of  claim 2 , wherein R 3  is phenyl optionally substituted with one or more halogen substituents. 
     
     
         6 . The compound of  claim 1 , wherein R 3  is phenyl optionally substituted with one or more fluoro substituents. 
     
     
         7 . The compound of  claim 6 , wherein R 3  is phenyl substituted with two fluoro substituents. 
     
     
         8 . The compound of  claim 1 , wherein each R 1  is independently optionally substituted lower alkyl or optionally substituted heteroaryl. 
     
     
         9 . The compound of  claim 8 , wherein one R 1  is lower alkyl and the other R 1  is heteroaryl substituted with one or more NH 2  groups. 
     
     
         10 . The compound of  claim 8 , wherein one R 1  is lower alkyl and the other R 1  is pyrimidinyl substituted with one or more NH 2  groups. 
     
     
         11 . The compound of  claim 10 , wherein one R 1  is t-butyl and the other R 1  is pyrimidinyl substituted with NH 2 . 
     
     
         12 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
       wherein each X is independently N or CH; and Y is S. 
     
     
         13 . The compound of  claim 12 , wherein Ar is thiazolyl. 
     
     
         14 . The compound of  claim 12 , wherein Ar is 4-thiazolyl. 
     
     
         15 . A compound of formula (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 each R 1  is independently selected from t-butyl or pyrimidinyl substituted with NH 2 ; 
 R 2  is H; 
 R 3  is phenyl substituted with two fluoro groups; 
 R 4  is hydrogen; 
 the subscript m is 2; and 
 Ar is 4-thiazolyl. 
 
       
     
     
         16 . A pharmaceutical composition comprising: a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         17 . A pharmaceutical composition comprising: a compound of  claim 15  and a pharmaceutically acceptable carrier or excipient. 
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 1  and another therapeutic agent. 
     
     
         19 . A method for treating a subject suffering from melanoma, thyroid cancer or colorectal cancer, said method comprising: administering to the subject an effective amount of a compound of  claim 15 . 
     
     
         20 . The method of  claim 19 , wherein the melanoma is melanoma having a mutation encoding a V600E amino acid substitution.