KRAS G12C inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-11053226-B2
Application number	US-201916687546-A
Country	US
Kind code	B2
Filing date	Nov 18, 2019
Priority date	Nov 19, 2018
Publication date	Jul 6, 2021
Grant date	Jul 6, 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
R 1 , R 1A and R 1B are independently H, —C 1-6 alkyl, —C 1-6 alkylene-OH, —C 1-6 alkylene-O—C 1-6 alkyl, or C 1-6 alkylene-NR 10 R 11 ;
R 2 is independently H, or —C 1-6 alkyl;
R 3 is independently H, —C 1-6 alkyl, or —C 1-6 alkyl-OH;
R 4 is independently H, or —C 1-6 alkyl;
R 4A is independently H, or —C 1-6 alkyl; or
R 4 and R 4A , together with the atoms to which they are attached, form a 6- to 12-membered aryl or heteroaryl, a 3- to 8-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 8-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl 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 group may include a S═O or SO 2 ;
R 4B is independently H, or —C 1-6 alkyl;
R 5 is independently H, halo, —C 1-6 alkyl, or —C 1-6 alkyl-CN;
R 6 is independently H, halo or —C 1-6 alkyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 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, spiroheterocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl group may include a S═O or SO 2 ;
R 7 is independently H, halo or —C 1-6 alkyl, —O—C 1-6 alkyl, —S—C 1-6 alkyl, —NO 2 , —CN, —CF 3 , a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, 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 ;
R 8 is independently H, halo or —C 1-6 alkyl;
R 9 is independently selected from H, OH, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —C 1-6 alkyl-C(═O)—NR a R b , —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)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 12-membered cycloakyl), —O-(3- to 12-membered heterocycloakyl), —C(═O)-6- to 12-membered aryl, —C(═O)-5- to 12-membered heteroaryl, —C(═O)-3- to 12-membered cycloalkenyl, —C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, —C(═O)-5- to 12-membered spirocycloalkyl, —C(═O)-5- to 12-membered spiroheterocycloalkyl, —C 1-6 alkyl-C(═O)-6- to 12-membered aryl, —C 1-6 alkyl-C(═O)-5- to 12-membered heteroaryl, a —C 1-6 alkyl-C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, a —C 1-6 alkyl-C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, —C 1-6 alkyl-C(═O)-5- to 12-membered monocyclic or bicyclic spirocycloalkyl, —C 1-6 alkyl-C(═O)-5- to 12-membered spiroheterocycloalkyl group, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 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, a 5- to 12-membered monocyclic or bicyclic spirocycloalkyl, or a 5- to 12-membered monocyclic or bicyclic spiroheterocycloalkyl group, wherein the heteroaryl, heterocycloalkyl and spiroheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl 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 ; and still further wherein two adjacent carbon atoms or an adjacent carbon atom and adjacent N atom on a R 9 group that includes a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocycloalkyl, or a spiroheterocycloalkyl group may join together to form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, heteroaryl spirocycloalkyl, or a spiroheterocycloalkyl ring that is unsubstituted or is substituted with 1, 2, or 3 R 11 groups;
R 10 is independently H, halo, —OH, —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 -14heteroaryl, —NH—C 0-3 alkylene-C 3-14 cycloalkyl, —NH—C 0-3 alkylene-C 2-14 heterocycloalkyl, cyano, or C 1-6 alkylene-amine, —C 1-6 alkyl, —C(═O)NR a R b , —C(═O)OR a , —C(═O), —C 0-3 alkylene-C 3-14 cycloalkyl, —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, —C(═O)-(3- to 10-membered heterocycloakyl), —C(═O)-6- to 12-membered aryl, —C(═O)-5- to 12-membered heteroaryl, —C(═O)-3- to 12-membered cycloalkenyl, —C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, a —C(═O)-5- to 12-membered bicyclic spirocycloalkyl, a —C(═O)-5- to 12-membered spiroheterocycloalkyl, a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 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, a 5- to 12-membered monocyclic or bicyclic spirocycloalkyl, or a 5- to 12-membered monocyclic or bicyclic spiroheterocycloalkyl group, wherein the heteroaryl, heterocycloalkyl and spiroheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl 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 ;
or R 9 and R 10 , together with the atoms to which they are attached, form a ring selected from a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 3-8 membered cycloalkyl, or a 3- to 8-membered heterocycloalkyl group, wherein the heteroaryl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein when R 9 and R 10 form the ring, the ring is unsubstituted or substituted with 1, 2, or 3 R 11 groups; further wherein when the ring is a cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group, the ring may further include a C═O group;
R 11 is independently selected from H, —OH, halo, cyano, —C 1-8 alkyl, —C 1-6 haloalkyl, —C 1-6 alkyl-OH, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —(CH 2 CH 2 O) n R a , —CSR a , —CS(═O)R a , —SR a , —SOR a , —OSO 2 R a , —SO 2 R a , —(CH 2 CH 2 O) n CH 3 , —(═O), —C(═O), —O—R a , —C(═O)R a , —(CH 2 ) n —NR a R b , NR a R b ; —C(═O)NR a R b , —C(═O)OR a , —CH(═O), —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 3-14 heteroaryl, —C 1-6 -alkylene-amine, —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 alk

Assignees

• Amgen Inc

Inventors

• Shin Youngsook
• Cee Victor J
• Tegley Christopher M
• Lanman Brian Alan
• Wurz Ryan Paul
• Yang Kevin C
• Ma Vu Van
• Erlanson Daniel
• Jeong Joon Won
• Fucini Raymond V
• Iwig Jeffrey

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title