KRAS G12C inhibitors and methods of using the same

Patent metadata

Field	Value
Publication number	US-11285135-B2
Application number	US-201916675121-A
Country	US
Kind code	B2
Filing date	Nov 5, 2019
Priority date	Dec 22, 2016
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

Provided herein are methods of treating cancer with KRAS G12C inhibitors of Formula I and compositions of 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 ;
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 1-6 alkyl) 2 , cyano, or halo;
R 2 is halo, C 1-6 alkyl, C 1-6 haloalkyl, OR′, N(R′) 2 , C 2-3 alkenyl, C 2-3 alkynyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, and each R′ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 2-14 heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl, or two R′ substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
R 3 is halo, C 1-3 alkyl, C 1-2 haloalkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl;
R 4 is

ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring, wherein ring A is optionally substituted with one to three substituents selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxylic acid or ester, haloalkyl, alkylamine, C(O)NH 2 , oxo, halo, cyano and isocyano;
L is a bond, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
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 1-6 haloalkyl, cycloalklyl, heterocycloalkyl, C 0-3 alkylene-C 3-4 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; and
R 7 is H or C 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
wherein an alkyl, alkylene, alkenyl, alkynyl, alkoxy moiety is optionally substituted with one or more substituents independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —NC, amino, —CO 2 H, —CO 2 C 1 -C 8 alkyl, —OCOC 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 5 -C 10 aryl, and C 5 -C 10 heteroaryl;
an aryl moiety is optionally substituted with one or more substituents independently selected from halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —CF 3 , —OCF 3 , —NO 2 , —CN, —NC, —OH, alkoxy, amino, —CO 2 H, —CO 2 C 1 -C 8 alkyl, —OCOC 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 5 -C 10 aryl, and C 5 -C 10 heteroaryl;
a heteroaryl, cycloalkyl, or heterocycloalkyl moiety is optionally substituted with one or more substituents independently selected from halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, —OCF 3 , —NO 2 , —CN, —NC, —OH, alkoxy, amino, —CO 2 H, —CO 2 C 1 -C 8 alkyl, —OCOC 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, C 5 -C 10 aryl, and C 5 -C 10 heteroaryl,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E 1 and E 2 is CR 1 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E 1 is CR 1 and E 2 is N.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E 1 is N and E 2 is CR 1 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E 1 is N and E 2 is N.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, F, CH 3 , Cl, or CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is bromine,

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is halo.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 4 is

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein ring A is

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is H or F;
R 2 is bromine

R 3 is halo;
R 4 is

ring A is

R 5 and R 6 are H.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
1-(4-(6-(2-bromo-5-hydroxyphenyl)-5-chloro-7-fluorobenzo[c]isothiazol-3-yl)piperazin-1-yl)prop-2-en-1-one,
1-(4-(5-chloro-6-(2-fluoro-6-hydroxyphenyl)-2,1-benzothiazol-3-yl)-1-piperazinyl)-2-propen-1-one,
1-((3R)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(hydroxymethyl)-1-piperazinyl)-2-propen-1-one,
1-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-ethyl-1-piperazinyl)-2-propen-1-one,
1-((3S)-4-(5-chloro-7-fluoro-6-(5-methyl-1H-indazol-4-yl)-2,1-benzothiazol-3-yl)-3-methyl-1-piperazinyl)-2-propen-1-one,
1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(2-hydroxyethyl)-1-piperazinyl)-2-propen-1-one,
1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(hydroxymethyl)-1-piperazinyl)-2-propen-1-one,
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-2-(hydroxymethyl)-1-piperazinyl)-2-propen-1-one,
1-(4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-(hydroxymethyl)-1-piperazinyl)-2-propen-1-one,
1-((3S)-4-(5-chloro-7-fluoro-6-(3-hydroxy-1-naphthalenyl)-2,1-benzothiazol-3-yl)-3-methyl-1-piperazinyl)-2-propen-1-one,
1-(3-((5

Assignees

• Amgen Inc

Inventors

• Lanman Brian Alan
• Cee Victor J
• Pickrell Alexander J
• Reed Anthony B
• Yang Kevin C
• Kopecky David John
• Wang Hui-Ling
• Lopez Patricia
• Ashton Kate
• Booker Shon
• Tegley Christopher M

Classifications

• G06Q30/0207

  Discounts or incentives, e.g. coupons or rebates · CPC title

• G06Q10/109

  Time management, e.g. calendars, reminders, meetings or time accounting · CPC title

• G01C21/34

  Route searching; Route guidance · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title