KRAS G12C inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-10988485-B2
Application number	US-201916407889-A
Country	US
Kind code	B2
Filing date	May 9, 2019
Priority date	May 10, 2018
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

Provided herein are KRAS G12C inhibitors, composition of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

First claim

What is claimed is:

1. A compound having a structure of formula (I)

wherein
E 1 and E 2 are each independently N or CR 1 ;
is a single or double bond as necessary to give every atom its normal valence;
R 1 is independently H, hydroxy, —C 1-6 haloalkyl, —C 1-6 alkoxy, —NH—C 1-6 alkyl, —N(C 1-4 alkyl) 2 , cyano, or halo;
R 2 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —N(R 2a ) 2 , —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl, and each R 2a is independently H, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-14 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl, or two R 2a substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;

R 3 is halo, —C 1-6 alkyl, C 3-6 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl;
R 4 is

ring A is a saturated monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spirocyclic 6-11 membered ring, wherein the ring is a carbon ring system comprising 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S;
L is a bond, —C 1-6 alkylene, —O—C 0-6 alkylene, —S—C 0-6 alkylene, or —NH—C 0-6 alkylene, and for —C 2-6 alkylene, —O—C 2-6 alkylene, —S—C 2-6 alkylene, and —NH—C 2-6 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4a is H, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, C 0-3 alkylene-C 6-14 aryl, or selected from

R 5 and R 6 are each independently H, halo, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1-6 alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C 0-3 alkylene-C(O)OH, —C 0-3 alkylene-C(O)OC 1-4 alkyl, —C 1-6 alkylene-O-aryl, —C 0-3 alkylene-C(O)C 1-4 alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, —C 0-3 alkylene-C 2-14 heteroaryl, or cyano, or R 5 and R 6 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 7 is H or C 1-6 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 8 is H, —C 0-3 alkylene-C 6-14 aryl, —C 0-3 alkylene-C 3-14 heteroaryl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, —C 1-6 alkoxy, —O—C 0-3 alkylene-C 6-14 aryl, —O—C 0-3 alkylene-C 3-14 heteroaryl, —O—C 0-3 alkylene-C 3-14 cycloalkyl, —O—C 0-3 alkylene-C 2-14 heterocycloalkyl, —NH—C 1-8 alkyl, —N(C 1-8 alkyl) 2 , —NH—C 0-3 alkylene-C 6-14 aryl, —NH—C 0-3 alkylene-C 2-14 heteroaryl, —NH—C 0-3 alkylene-C 3-14 cycloalkyl, —NH—C 0-3 alkylene-C 2-14 heterocycloalkyl, halo, cyano, or C 1-6 alkylene-amine;
wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , and R 8 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 SO 2 ;
wherein the —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, and the —OC 1-6 alkyl of any of the R 2 , R 2a , R 3 , R 4 , R 4a , L, R 5 , R 6 , R 7 , and R 8 substituents is unsubstituted or substituted by 1, 2, or 3 R 9 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —NR a R b R c , —OSO 2 R a , —SO 2 R a , —CH 2 CH 2 OCH 3 , —(═O), —C(═O), —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —SiR a R b R c , —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 SO 2 ;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group of any of the R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , and R 8 , and R 9 substituents can be unsubstituted or substituted with 1, 2, 3, or 4 R 10 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , 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 R 10 have 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R 10 or the heterocycloalkyl group of R 10 may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein each R a , R b , R c , and R d is independently hydrogen, OH, —C 1-6 alkyl, —CH 2 CH 2 OCH 3 , phenyl, —C 1-6 alkylC(═O)OH, —C 1-6 alkylC(═O)—O—C 1-6 alkyl, —C 1-6 alkyl-3- to 12-membered cycloalkyl, —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, —C 1-6 alkyl-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 R a , R b , R c , and R d or the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group of R a , R b , R c , and R d has from 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S, wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may include a double bond, and further wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may contain a C═O group; and
the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of R a , R b , R c , and R d or the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d can be unsubstituted or substituted with from 1, 2, 3, or 4 R 12 substituents, wherein each R 12 is independently selected from H, OH, halo, —C 1-6 alkyl, N(CH 3 ) 2 , —C 1-6 haloalkyl, C(═O)CH 3 , —C(═O)OCH 3 , or —C 1-6 alkyl-O—C 1-6 alkyl; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acce

Assignees

• Amgen Inc

Inventors

• Minatti Ana Elena
• Low Jonathan Dante
• Wurz Ryan Paul
• Lanman Brian Alan
• Cee Victor J
• Bartberger Michael D
• Chu-Moyer Margaret

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K16/2818

  against CD28 or CD152 · CPC title

• C07K16/2896

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• A61P35/00

  Antineoplastic agents · CPC title