Inhibitors of kras g12c

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R 1 , R 2a , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

1 - 95 . (canceled) 
     
     
         96 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or a pharmaceutically acceptable salt thereof comprising a 6,6-bicyclic heteroaryl ring system substituted with at least one substituent group and optionally substituted with one or more additional substituent groups, wherein:
 the two rings of the 6,6-bicyclic heteroaryl ring system share two carbon atoms;   each heteroatom in the 6,6-bicyclic heteroaryl ring system is a nitrogen;   the at least one substituent group is   
       
         
           
           
               
               
           
         
         the 6,6-bicyclic heteroaryl ring system is also covalently bonded to a structure of the formula: 
       
       
         
           
           
               
               
           
         
         wherein L 1  is a bond to the 6,6-bicyclic heteroaryl ring system; 
         R 3a  and R 3b  are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; 
         R 4a  and R 4b  are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; 
         L 2  is a bond; and 
       
       
         
           
           
               
               
           
         
       
       and
 the optional additional substituent groups are selected from the group consisting of: —Cl, —Br, —F, —CN, —OH, oxo, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaminyl group, a substituted or unsubstituted alkoxy group, an unsubstituted heterocyclyloxy, a substituted or unsubstituted heterocyclylaminyl, an unsubstituted heterocyclylalkyl, an unsubstituted phenoxy group, a substituted pyrazolyloxy group, a substituted pyrazolylaminyl, an unsubstituted morpholinyl, an unsubstituted piperidinyl, an unsubstituted cyclopropyl group, —NH 2 , —CH 3 , —CH 2 CH 3 , —CF 3 , —C(═O)NH 2 , —CCH, and —CH 2 N(CH 3 ) 2 . 
 
     
     
         97 . The pharmaceutical composition of  claim 96 , wherein R 3a , R 3b , R 4a , and R 4b  are, at each occurrence, independently H, —CN, —CH 3 , —CCH, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 CN, —CH 2 C(═O)NH 2 , or —C(═O)NH 2 . 
     
     
         98 . The pharmaceutical composition of  claim 96 , wherein one of R 3a , R 3b , R 4a , and R 4b  is selected from —CN, —CH 3 , —CCH, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 CN, —CH 2 C(═O)NH 2 , or —C(═O)NH 2 , and the remaining R 3a , R 3b , R 4a , and R 4b  are each hydrogen. 
     
     
         99 . The pharmaceutical composition of  claim 98 , wherein one of R 3a , R 3b , R 4a , and R 4b  is —CH 3 , and the remaining R 3a , R 3b , R 4a , and R 4b  are each hydrogen. 
     
     
         100 . The pharmaceutical composition of  claim 96 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a halogen. 
     
     
         101 . The pharmaceutical composition of  claim 96 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from —F. 
     
     
         102 . The pharmaceutical composition of  claim 101 , wherein one of R 3a , R 3b , R 4a , and R 4b  is —CH 3 , and the remaining R 3a , R 3b , R 4a , and R 4b  are hydrogen. 
     
     
         103 . The pharmaceutical composition of  claim 102 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from an oxo (═O). 
     
     
         104 . The pharmaceutical composition of  claim 103 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a heteroaryl. 
     
     
         105 . The pharmaceutical composition of  claim 103 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted heteroaryl. 
     
     
         106 . The pharmaceutical composition of  claim 103 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted pyridyl. 
     
     
         107 . The pharmaceutical composition of  claim 96 , wherein the additional substituent groups on the 6,6-bicyclic heteroaryl ring system are a fluoro, an oxo (═O), and a substituted pyridyl group. 
     
     
         108 . The pharmaceutical composition of  claim 107 , wherein one of R 3a , R 3b , R 4a , and R 4b  is —CH 3 , and the remaining R 3a , R 3b , R 4a , and R 4b  are hydrogen.