Kras g12c inhibitors and methods of using the same

A compound having a structure of formula (I)

• wherein
• E1 and E2 are each independently N or CR1;
• is a single or double bond as necessary to give every atom its normal valence;
• Rp is independently H, hydroxy, —C1-6alkyl, halo, —C1-4haloalkyl, —C1-4alkoxy, —NH—C1-4alkyl, —N(C1-4alkyl)2, cyano, —C2-3alkenyl, —C2-3alkynyl, —C3-14cycloalkyl, —C2-14heterocycloalkyl, aryl, or heteroaryl;
• R1 is independently H, hydroxy, —C1-6alkyl, —C1-6haloalkyl, —C1-6alkoxy, —NH—C1-6alkyl, —N(C1-4alkyl)2, cyano, or halo;
• R2 is halo, —C1-6alkyl, —C1-6haloalkyl, —OR2a, —N(R2a)2, —C2-6alkenyl, —C2-6alkynyl, —C0-3alkylene-C3-14cycloalkyl, —C0-3alkylene-C2-14heterocycloalkyl, aryl, heteroaryl, —C0-3alkylene-C6-14aryl, or —C0-3alkylene-C2-14heteroaryl, and each R2a is independently H, —C1-6alkyl, —C1-6haloalkyl, —C3-14cycloalkyl, —C2-14heterocycloalkyl, —C2-6alkenyl, —C2-6alkynyl, aryl, or heteroaryl, or two R2a substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
• R3 is halo, —C1-6alkyl, —C1-6haloalkyl, —C1-6alkoxy, C3-6cycloalkyl, —C2-14heterocycloalkyl, —C2-6alkenyl, —C2-6alkynyl, aryl, or heteroaryl;
• R4 is
• ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring;
• L is a bond, —C1-6alkylene, —O—C0-6alkylene, —S—C0-6alkylene, or —NH—C0-6alkylene, and for —C2-6alkylene, —O—C2-6alkylene, —S—C2-6alkylene and NH—C2-6 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
• R4a is H, C1-6alkyl, C2-6alkynyl, C1-6alkylene-O—C1-4alkyl, C1-6alkylene-OH, C1-6 haloalkyl, cycloalkyl, heterocycloalkyl, C0-3alkylene-C3-14cycloalkyl, C0-3alkylene-C2-14 heterocycloalkyl, aryl, heteroaryl, C0-3alkylene-C6-14aryl, or selected from
• R5 and R6 are each independently H, halo, —C1-6alkyl, —C2-6alkynyl, —C1-6 alkylene-O—C1-4alkyl, —C1-6alkylene-OH, —C1-6haloalkyl, —C1-6alkyleneamine, —C0-6 alkylene-amide, —C0-3alkylene-C(O)OH, —C0-3alkylene-C(O)OC1-4alkyl, —C1-6 alkylene-O-aryl, —C0-3alkylene-C(O)C1-4alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C0-3alkylene-C3-14cycloalkyl, —C0-3alkylene-C2-14heterocycloalkyl, —C0-3alkylene-C6-14aryl, —C0-3alkylene-C2-14heteroaryl, or cyano, or R5 and R6, together with the atoms to which they are attached, form a 4-6 membered ring;
• R7 is H or C1-6alkyl, or R7 and R5, together with the atoms to which they are attached, form a 4-6 membered ring;
• R8 is —C1-6alkyl, —C0-3alkylene-C6-14aryl, —C0-3alkylene-C3-14heteroaryl, —C0-3 alkylene-C3-14cycloalkyl, —C0-3alkylene-C2-14heterocycloalkyl, —C1-6alkoxy, —O—C0-3 alkylene-C6-14aryl, —O—C0-3alkylene-C3-14heteroaryl, —O—C0-3 alkylene-C3-14cycloalkyl, —O—C0-3 alkylene-C2-14heterocycloalkyl, —NH—C1-8alkyl, —N(C1-8alkyl)2, —NH—C0-3alkylene-C6-14aryl, —NH—C0-3alkylene-C2-14heteroaryl, —NH—C0-3alkylene-C3-14cycloalkyl, —NH—C0-3 alkylene-C2-14heterocycloalkyl, halo, cyano, or C1-6alkylene-amine;
• wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the Rp, R2, R2a, R3, R4, R4a, R5, R6, R7, and R8 substituents have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO2;
• wherein the —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl and the —OC1-6alkyl of any of the Rp, R1, R2, R2a, R3, R4, R4a, L, R5, R6, R7, and R8 substituents is unsubstituted or substituted by 1, 2 or 3 R9 substituents independently selected from OH, —OC1-6alkyl, —C1-6alkyl-O—C1-6 alkyl, halo, —O-haloC1-6alkyl, —CN, —NRaRb, —(NRaRbRc)n, —OSO2Ra, —SO2Ra, —(CH2CH2O)nCH3, —(═O), —C(═O), —C(═O)Ra, —OC(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —O—SiRaRbRc, —SiRaRbRc, —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO2;
• wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group of any of the Rp, R1, R2, R2a, R3, R4, R4a, R5, R6, R7, R8 and R9 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R10 substituents independently selected from OH, halo, —NRcRd, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-O—C1-6alkyl, C1-6haloalkyl, —O-haloC1-6alkyl, —SO2Rc, —CN, —C(═O)NRcRd, —C(═O)Rc, —OC(═O)Ra, —C(═O)ORc, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R10 have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R10 or the heterocycloalkyl group of R10 may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S—O or SO2;
• wherein each Ra, Rb, Rc and Rd is independently hydrogen, OH, —C1-6alkyl, —(CH2CH2O)nCH3, —NR11R11, —C1-6alkyl-NR11R11, phenyl, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)—O—C1-6alkyl, —C1-6alkyl-3- to 12-membered cycloalkyl, —C1-6alkyl-3- to 12-membered heterocycloalkyl, —C1-6alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl group, heterocycloalkyl group of Ra, Rb, Rc, and Rd or the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl group of Ra, Rb, Rc, and Rd has from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl and heterocycloalkyl groups of Ra, Rb, Rc, and Rd and the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd may include a double bond, and further wherein the cycloalkyl and heterocycloalkyl groups of Ra, Rb, Rc, and Rd and the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd may contain a C═O group;
• and
• the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of Ra, Rb, Rc, and Rd or the heterocycloalkyl groups of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd can be unsubstituted or substituted with from 1, 2, 3, or 4 R12 substituents, wherein each R12 is independently selected from H, OH, halo, —C1-6alkyl, N(CH3)2, —C1-6haloalkyl, C(═O)CH3, —C(═O)OCH3, or —C1alkyl-O—C1-6alkyl;
• or
• a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.