Epoxyamides as kras g12c and kras g12d inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-2024190862-A1
Application number	US-202017769631-A
Country	US
Kind code	A1
Filing date	Oct 22, 2020
Priority date	Oct 24, 2019
Publication date	Jun 13, 2024
Grant date	—

Abstract

Provided herein are KRAS G12C and KRAS G12D 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:

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

wherein
R 1 is H, halo, or —CH 3 ;
R 2 is H, halo, or —CH 3 ;
R 3 is

b is optionally a single or a double bond;
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring;
L is a bond or NR 4 ;
R 4 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- 6haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C(O)OH, —C(O)OC 1-4 alkyl, —C 1-6 alkylene-O-aryl, —N═N, —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, or —C 0-3 alkylene-C 2-14 heteroaryl;
R 5 is H, halo, an —C 1-6 alkyl, —C 2-6 alkynyl, —C 0-6 alkylene-O—C 1-6 alkyl, —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(O)OH, —C(O)OC 1-4 alkyl, —C 0-6 alkylene-O—C 6-14 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;
R 5a is selected from H, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1- 6alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C(O)OH, —C(O)OC 1- 4alkyl, , —C 0-6 alkylene-O—C 6-14 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 -14heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl;
R 5b is selected from H, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1- 6alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C(O)OH, —C(O)OC 1- 4alkyl, , —C 0-6 alkylene-O—C 6-14 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 -14heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl;
or R 5a and R 5b together, may represent an ═O or ═N═N;
R 6 is 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(O)OH, —C(O)OC 1-4 alkyl, , —C 0-6 alkylene-O—C 6-14 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 -14aryl, or —C 0-3 alkylene-C 2-14 heteroaryl;
R 5a and R 6a , together with the atoms to which they are attached, may form a 3-6 membered ring that optionally includes one or two heteroatoms selected from 0, S or N; or
R 5a and R 6a are absent when b is a double bond;
R 6A is H, or —C 1-6 alkyl;
R 6b 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, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C(O)OH, —C(O)OC 1-4 alkyl, —C 0-6 alkylene-O—C 6-14 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 -14aryl, —C 0-3 alkylene-C 2-14 heteroaryl, or cyano;

or R 6a and R 6b together, may represent an ═0;
R 7 is H or C 1-8 alkyl;
R 8 is H, OH, NR a R b ;

wherein R a and R b are each independently H, halo, —C 1-6 alkyl, —C 2-6 alkynyl;
wherein the ring A or the —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1- 6alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C(O)OC 1- 4alkyl, —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 -14heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl groups of any of the R 4 , R 5 , R 1a , R 51 , R 6 , R 6a , R 6b , R 7 and R 8 may be unsubstituted or substituted with 1, 2, 3, or 4 substituents, as allowed, independently selected from halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —OH, or —C 1-6 alkyl-CN;

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.

2 . The compound of claim 1 , having the structure:

3 . The compound of any one of claims 1-2 , wherein ring A is a monocyclic 4-7 membered ring.

4 . The compound of any one of claims 1-2 , wherein ring A is a or a bicyclic ring.

5 . The compound of any one of claims 1-2 , wherein ring A is a spiro 6-11 membered ring.

6 . The compound of any one of claims 1-5 , wherein R 1 is F.

7 . The compound of any one of claims 1-6 , wherein R 2 is Cl.

8 . The compound of any one of claims 1-7 , wherein R 5 is H, halo, —C 1-6 alkyl, or —C 0-6 alkylene-O—C 6-14 aryl.

9 . The compound of claim 8 , wherein R 5 is H.

10 . The compound of claim 8 , wherein R 5 is halo.

11 . The compound of claim 8 , wherein R 5 is C 1 or F.

12 . The compound of claim 8 , wherein R 5 is —C 1-6 alkyl.

13 . The compound of claim 8 , wherein R 5 is —C 0-3 alkylene-C 6-14 aryl.

14 . The compound of any one of claims 1-13 , wherein R 5a is selected from H, —C 1- 6alkyl, —C 1-6 alkylene-OH, —C(O)OH, —C(O)OC 1-4 alkyl, and —C 0-3 alkylene-C 2-14 heterocycloalkyl, unless b is a double bond.

15 . The compound of claim 14 , wherein R 5a is H.

16 . The compound of claim 14 , wherein R 5a is —C 1-6 alkyl.

17 . The compound of claim 14 , wherein R 5a is —C 1-6 alkylene-OH.

18 . The compound of claim 14 , wherein R 5a is —C(O)OH.

19 . The compound of claim 14 , wherein R 5a is —C(O)OC 1-4 alkyl.

20 . The compound of claim 14 , wherein R 5a is —C 0-3 alkylene-C 2-14 heterocycloalkyl.

21 . The compound of any one of claims 1-20 , wherein R 6 is H, halo, or —C 1-6 alkyl, unless R 3 has the following structure

22 . The compound of claim 21 , wherein R 6 is H.

23 . The compound of claim 21 , wherein R 6 is halo.

24 . The compound of claim 21 , wherein R 6 is —C 1-6 alkyl.

25 . The compound of any one of claims 1-24 , wherein R 6b is H, —C 1-6 alkyl, C 1- 6alkylene-OH, —C(O)OH, —C(O)OC 1-4 alkyl, or —C 0-3 alkylene-C 2-14 heterocycloalkyl, unless R 3 has the following structure

26 . The compound of claim 25 , wherein R 6b is H.

27 . The compound of claim 25 , wherein R 6b is —C 1-6 alkyl.

28 . The compound of claim 25 , wherein R 6b is C 1-6 alkylene-OH.

Assignees

• Amgen Inc

Inventors

• Wang Hui-Ling
• Cee Victor J

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title