Covalent inhibitors of KRAS G12C

A method for treating a cancer mediated by a K-Ras G12C, H-Ras G12C or N-Ras G12C mutation, the method comprising administering an effective amount of a compound having the following structure (VI):

• or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, isotopically-labeled derivative or prodrug thereof, to a subject in need thereof, wherein:
• A is CR37b, N or NR38a;
• B is CR37c, N, NR38b or S;
• C is CR37d, N, NR38c or S;
• G3 and G4 are each independently N or CR, wherein R is H, cyano, halo or C1-C6alkyl C1-C6alkyl;
• L1a is a bond, —NH—, alkylene or heteroalkylene;
• L2 is a bond or alkylene;
• R32a and R32b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl;
• or R32a and R32b join to form a carbocyclic or heterocyclic ring;
• or R32a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R32b joins with R33b to form a carbocyclic or heterocyclic ring;
• R33a and R33b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl;
• or R33a and R33b join to form a carbocyclic or heterocyclic ring;
• or R33a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R33b joins with R32b to form a carbocyclic or heterocyclic ring;
• R37a, R37b, R37c, R37d and R37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C1-C6alkyl, C1-C6alkylsulfonyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6hydroxylalkyl, C1-C6alkoxyalkyl, C1-C6aminoalkyl, heterocyclyl or aryl -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl;
• R38a, R38b and R38c are each independently H, C1-C6alkyl or aryl;
• n3 and n4 are each independently 1, 2 or 3;
• m is 0 or 1;
• is a single or double bond such that all valences are satisfied;
• and
• E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.