Covalent inhibitors of Kras G12C

摘要

Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.

主权项

1. A compound having the following structure (V): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein: R1 is aryl; R30a and R30b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R30a and R30b join to form a carbocyclic or heterocyclic ring; or R30a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R30b joins with R31b to form a carbocyclic or heterocyclic ring; R31a and R31b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R31a and R31b join to form a carbocyclic or heterocyclic ring; or R31a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R31b joins with R30 b to form a carbocyclic or heterocyclic ring; 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; L1 heteroalkylene, heterocycloalkylene, heteroarylene, heteroalkylenecarbonyl, heterocycloalkylenecarbonyl or heteroarylenecarbonyl; L2 is a bond or alkylene; G1, G2, G3 and G4 are each independently N or CR, where R is H, cyano, halo or C1-C6alkyl; n1, n2, n3 and n4 are each independently 1, 2 or 3; 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.