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 a substituted or unsubstituted naphthyl group;   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
                     
 is a substituted or unsubstituted acryloyl group; 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
                       .   
     
     
         98 . The pharmaceutical composition of  claim 97 , wherein the naphthyl group is substituted with a substituent selected from: a halogen, a hydroxyl, a methoxy, —NH 2 , and —CF 2 H. 
     
     
         99 . The pharmaceutical composition of  claim 97 , wherein the naphthyl group is substituted with a halogen. 
     
     
         100 . The pharmaceutical composition of  claim 98 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted or unsubstituted alkoxy group. 
     
     
         101 . The pharmaceutical composition of  claim 99 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted or unsubstituted alkoxy group. 
     
     
         102 . The pharmaceutical composition of  claim 97 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted or unsubstituted alkoxy group. 
     
     
         103 . The pharmaceutical composition of  claim 97 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted alkoxy group. 
     
     
         104 . The pharmaceutical composition of  claim 99 , wherein the 6,6-bicyclic heteroaryl ring system is substituted with an additional substituent group selected from a substituted alkoxy group. 
     
     
         105 . The pharmaceutical composition of  claim 103 , wherein the substituted alkoxy group is a heterocyclylalkyloxy group. 
     
     
         106 . The pharmaceutical composition of  claim 104 , wherein the substituted alkoxy group is a heterocyclylalkyloxy group. 
     
     
         107 . The pharmaceutical composition of  claim 103 , wherein the substituted alkoxy group is a pyrrolidinylalkyloxy group. 
     
     
         108 . The pharmaceutical composition of  claim 104 , wherein the substituted alkoxy group is a pyrrolidinylalkyloxy group. 
     
     
         109 . The pharmaceutical composition of  claim 98 , wherein R 9  is cyano. 
     
     
         110 . The pharmaceutical composition of  claim 100 , wherein R 9  is cyano. 
     
     
         111 . The pharmaceutical composition of  claim 101 , wherein R 9  is cyano. 
     
     
         112 . The pharmaceutical composition of  claim 102 , wherein R 9  is cyano. 
     
     
         113 . The pharmaceutical composition of  claim 104 , wherein R 9  is cyano. 
     
     
         114 . The pharmaceutical composition of  claim 105 , wherein R 9  is cyano. 
     
     
         115 . The pharmaceutical composition of  claim 106 , wherein R 9  is cyano. 
     
     
         116 . The pharmaceutical composition of  claim 97 , wherein R 9  is methyl. 
     
     
         117 . The pharmaceutical composition of  claim 98 , wherein R 9  is methyl. 
     
     
         118 . The pharmaceutical composition of  claim 99 , wherein R 9  is methyl. 
     
     
         119 . The pharmaceutical composition of  claim 100 , wherein R 9  is methyl. 
     
     
         120 . The pharmaceutical composition of  claim 101 , wherein R 9  is methyl. 
     
     
         121 . The pharmaceutical composition of  claim 102 , wherein R 9  is methyl. 
     
     
         122 . The pharmaceutical composition of  claim 103 , wherein R 9  is methyl. 
     
     
         123 . The pharmaceutical composition of  claim 104 , wherein R 9  is methyl. 
     
     
         124 . The pharmaceutical composition of  claim 105 , wherein R 9  is methyl. 
     
     
         125 . The pharmaceutical composition of  claim 106 , wherein R 9  is methyl.