KRAS G12C inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-11045484-B2
Application number	US-201916402589-A
Country	US
Kind code	B2
Filing date	May 3, 2019
Priority date	May 4, 2018
Publication date	Jun 29, 2021
Grant date	Jun 29, 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 p is independently H, hydroxy, —C 1-6 alkyl, halo, —C 1-4 haloalkyl, —C 1-4 alkoxy, —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , cyano, —C 2-3 alkenyl, —C 2-3 alkynyl, —C 3-14 cycloalkyl, —C 2-14 heterocycloalkyl, aryl, or heteroaryl;
R 1 is independently H, hydroxy, —C 1-6 alkyl, —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, —OR 2a , —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 1-6 haloalkyl, —C 1-6 alkoxy, C 3-6 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl;

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring;
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 —C 1-6 alkyl, —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 p , 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 p , R 1 , 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 ) n , —OSO 2 R a , —SO 2 R a , —(CH 2 CH 2 O) n CH 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 p , R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , 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 O) n CH 3 , —NR 11 R 11 , —C 1-6 alkyl-NR 11 R 11 , phenyl, —C 1-6 alkyl-C(═O)OH, —C 1-6 alkyl-C(═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

Assignees

• Amgen Inc

Inventors

• Wurz Ryan Paul
• Cee Victor J
• Amegadzie Albert
• Chen Ning
• Lanman Brian Alan
• Bartberger Michael D

Classifications

• A61K45/06 Primary

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

• C07K16/30

  from tumour cells · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title