Granted Patent B2

US 12,630,559 · App. 18/038,364 · Granted May 19, 2026

Inventors: Yongxin Han (Needham, MA); Elisabeth Hennessy (Weston, MA); Andrew J. Hoover (Framingham, MA); Jesus Moreno (Dorchester Center, MA); David L. Sloman (Newton, MA); Uma Swaminathan (Auburndale, MA); Yingchun Ye (Belmont, MA)

Assignee: Merck Sharp & Dohme LLC

C07D491/107A61K45/06C07D491/20

Abstract

Claims (56)

1 . A compound of the Formula (I)

wherein:

the substructure

X is C(H) or N;

R A1 is fluoro, C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;

R A2 is halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, hydroxy or cyano;

the subscript j is 0 or 1;

the subscript k is 0, 1 or 2;

the subscript r is 0, 1, 2, or 3;

the subscript p is 0, 1, 2, 3, or 4;

R 2 is H, C 1 -C 3 alkyl, or fluoro;

each R 3 is independently:

(a) C 1 -C 4 alkyl, C 1 -C 4 cyanoalkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkylphenyl, oxo, or carboxy;

(b) or, alternatively, two R 3 substituents, together with the carbon atoms to which they are attached, can form a 3- to 6-membered bicyclo- or spirocyclic ring system with the illustrated piperazine ring;

the subscript q is 0, 1, 2, or 3;

W 1 is —C(O)— or —S(O) 2 —;

W 2 is a group of the formula:

wherein

W 2a is H, CH 3 , F, cyano, CH 2 OH, CH 2 CH 2 OH, or CH 2 Br;

W 2b is CH 3 ;

Y is —O(C(R y ) 2 ) m —, —C(O)—N(H)—(C(R y ) 2 ) m —, or absent;

each R y is independently H or C 1 -C 3 alkyl, or alternatively two R y together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring;

the subscript m is 1, 2, or 3;

Z is

(a)

wherein

R z1 is C 1 -C 3 alkyl;

each R z2 is independently fluoro or C 1 -C 3 alkyl;

the subscript n is 1, 2, or 3;

the subscript o is 0, 1, or 2;

(b) —N(R z3 ) 2 ; or

(c) —C(O)N(R z3 ) 2 , wherein

each R z3 is independently H or C 1 -C 3 alkyl; or

alternatively, two R z3 , together with the nitrogen atom to which they are attached, form a ring C z , wherein ring C z is an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl ring;

wherein ring C z is unsubstituted or substituted by 1 to 3 fluoro, C 1 -C 3 alkyl, amino, —N(H)(C 1 -C 3 alkyl), or —N(C 1 -C 3 alkyl) 2 ;

or a pharmaceutically salt thereof.

2 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the group —W 1 —W 2 is —C(O)—C(H)═CH 2 .

3 . The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein the subscript q is 0 or 1 and R 3 is methyl or —CH 2 CN.

4 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the substructure

5 . The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein the subscript j is 0 and the subscript k is 2.

6 . The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein the subscript j is 0 and the subscript k is 1.

7 . The compound of claim 4 or the pharmaceutically acceptable salt thereof, wherein X is C(H).

8 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the substructure

9 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 2 is H.

10 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is —O(C(R y ) 2 ) m — and the subscript m is 1 or 2.

11 . The compound of claim 10 or the pharmaceutically acceptable salt thereof,

wherein Z is

12 . The compound of claim 11 or the pharmaceutically acceptable salt thereof, wherein the subscript n is 2.

13 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the group —Y—Z is

14 . A compound selected from the group consisting of:

or the pharmaceutically acceptable salt thereof.

15 . A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16 . A method of inhibiting KRAS G12C protein comprising contacting KRAS G12C protein with the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS G12C protein.

17 . A method of treating cancer comprising administering a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

18 . The method of claim 17 , further comprising administering an additional active agent to the subject, wherein the additional active agent is an anti-cancer agent.

19 . The pharmaceutical composition of claim 15 , further comprising an additional active agent, wherein the additional active agent is an anti-cancer agent.

Assignments (1)

Continuity (2)

References Cited (374)