Methods and compositions for inhibition of ras

A compound having the following structure (I):

• or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
• A is CR1, CR2b, NR5 or S;
• B is a bond, CR1 or CR2c;
• G1 and G2 are each independently N or CH;
• W, X and Y are each independently N, NR5 or CR6;
• Z is a bond, N or CR6;
• L1 is a bond or NR7;
• L2 is a bond or alkylene;
• R1 is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;
• R2a, R2b and R2c are each independently H, halo, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or aryl;
• R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
• or R3a and R3b join to form oxo or a carbocyclic or heterocyclic ring;
• or R3a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl, and R3b joins with R4b to form a carbocyclic or heterocyclic ring;
• R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
• or R4a and R4b join to form oxo or a carbocyclic or heterocyclic ring;
• or R4a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl, and R4b joins with R3b to form a carbocyclic or heterocyclic ring;
• R5 and R7 are each independently H or C1-C6 alkyl;
• R6 is, at each occurrence, independently H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminocarbonyl, alkylaminyl, halo alkyl amino, hydroxylalkyamino, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C1-C6 alkoxy, aminylalkoxy, alkylcarbonylaminylalkoxy, C1-C6 alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, heteroarylalkylamino, aryl, aryloxy, arylamino, arylalkylamino, arylalkyloxy or a bond to L1;
• m1 and m2 are each independently 1, 2 or 3;
• indicates a single or double bond such that all valences are satisfied;
• and
• T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
• wherein at least one of W, X, Y or Z is CR6 where R6 is a bond to L1;
• and
• provided that when R1, R2a, R2b and R2a are all independently selected from H and halo, then X and Z are both N and at least one of R3a, R3b, R4a or R4b is not H, and provided that at least one of R2a, R2b or R2c is not H when R1 is pyridyl.