Granted Patent B2

US 12,735,425 · App. 18/038,367 · Granted Sep 15, 2026

Inventors: Yongxin Han (Needham, MA); Elisabeth Hennessy (Weston, MA); Andrew J. Hoover (Framingham, MA); Jesus Moreno (Dorchester Center, MA); Uma Swaminathan (Auburndale, MA)

Assignee: Merck Sharp & Dohme LLC

C07D491/052A61P35/00

Abstract

Claims (47)

1 . A compound of the Formula (I)

wherein:

ring C A is

(i) naphthyl;

(ii) phenyl;

(iii) a bicyclic 9- or 10-membered heteroaryl containing 1 to 3 ring atoms selected from N, O, or S; or

(iv) a tricyclic 13- or 14-membered heteroaryl containing 1 to 3 ring atoms selected from N, O, or S;

wherein ring C A is unsubstituted or substituted by 1 to 4 R CA substituents which are halo, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, hydroxy or cyano;

R 1 is H or C 1 -C 3 alkyl;

R 2a and R 2b are independently H, F, C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;

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 , CH 2 NH 2 , CH 2 N(H) CH 3 , CH 2 N(CH 3 ) 2 , CH 2 —NH-cyclopropyl,

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

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

 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; or

(b) —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 an aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl ring,

or a pharmaceutically acceptable 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 ring C A is unsubstituted or substituted naphthyl, phenyl, indazolyl, or benzo[e]indazolyl.

4 . The compound of claim 3 or the pharmaceutically acceptable salt thereof, wherein ring C A is

and the subscript p is 0, 1, or 2.

5 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein Y is —OC(R y ) 2 —.

6 . The compound of claim 5 or the pharmaceutically acceptable salt thereof, wherein Z is

7 . The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein the subscript n is 2.

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

9 . The compound of claim 8 or the pharmaceutically acceptable salt thereof, wherein Z is —N(R z3 ) 2 .

10 . The compound of claim 9 or the pharmaceutically acceptable salt thereof, wherein —Y—Z is

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

12 . The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently H, F, or methyl.

13 . The compound of claim 1 which is:

or the pharmaceutically acceptable salt thereof.

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

15 . 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.

16 . 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, wherein the cancer comprises a KRAS G12C mutation.

17 . The method of claim 16 , further comprising administering an additional active agent to the subject, wherein the additional active agent is an anti-cancer agent.

18 . The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition further comprises an additional active agent, wherein the additional active agent is an anti-cancer agent.

Assignments (1)

Continuity (2)

References Cited (258)