IP Library Granted Patent US 12,466,840
Granted Patent B2
US 12,466,840 · App. 18/920,212 · Granted Nov 11, 2025

Small molecule inhibitors of KRAS proteins

Inventors: Shuhei Kawamura (Cambridge, MA); Yu Kobayakawa (Ibaraki, JP); Tsuyoshi Oshima (Ibaraki, JP); Takao Uno (Ibaraki, JP); Patrick Schöpf (London, GB)
Assignee: Merck Sharp & Dohme LLC
C07D498/22A61K31/553A61K45/06A61P35/00C07D519/00
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Quick Facts
Patent No.
US 12,466,840
App. No.
18/920,212
Filed
Oct 18, 2024
Granted
Nov 11, 2025
Kind
B2
Art Unit
1627
USPC
514/211.09
Abstract

Compounds of Formulae (I)-(VII) or their pharmaceutically acceptable salts can inhibit the G12C, G12D, G12V, and/or G13D mutants of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds of Formulae (I)-(VII) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.

Claims (32)

1 . A compound of:

or a pharmaceutically acceptable salt thereof.

2 . A compound of:

or a pharmaceutically acceptable salt thereof.

3 . A compound of:

or a pharmaceutically acceptable salt thereof.

4 . A compound of:

or a pharmaceutically acceptable salt thereof.

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

6 . A pharmaceutical composition comprising the compound of claim 2 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7 . A pharmaceutical composition comprising the compound of claim 3 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8 . A pharmaceutical composition comprising the compound of claim 4 or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9 . A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

10 . A pharmaceutical composition comprising the compound of claim 2 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

11 . A pharmaceutical composition comprising the compound of claim 3 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

12 . A pharmaceutical composition comprising the compound of claim 4 or the pharmaceutically acceptable salt thereof, an additional anti-cancer agent, and a pharmaceutically acceptable carrier.

13 . A method of treating cancer comprising inhibiting at least one of KRAS-G12D protein, KRAS-G12C protein, KRAS-G12V protein, and KRAS-G13D protein by 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.

14 . A method of treating cancer comprising inhibiting at least one of KRAS-G12D protein, KRAS-G12C protein, KRAS-G12V protein, and KRAS-G13D protein by administering a therapeutically effective amount of the compound of claim 2 , or the pharmaceutically acceptable salt thereof, to a subject in need of such.

15 . A method of treating cancer comprising inhibiting at least one of KRAS-G12D protein, KRAS-G12C protein, KRAS-G12V protein, and KRAS-G13D protein by administering a therapeutically effective amount of the compound of claim 3 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

16 . A method of treating cancer comprising inhibiting at least one of KRAS-G12D protein, KRAS-G12C protein, KRAS-G12V protein, and KRAS-G13D protein by administering a therapeutically effective amount of the compound of claim 4 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

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 . A method of treating cancer comprising administering a therapeutically effective amount of the compound of claim 2 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

19 . A method of treating cancer comprising administering a therapeutically effective amount of the compound of claim 3 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

20 . A method of treating cancer comprising administering a therapeutically effective amount of the compound of claim 4 , or the pharmaceutically acceptable salt thereof, to a subject in need of such treatment.

21 . The method of claim 17 , further comprising administering an additional active agent to the subject.

22 . The method of claim 18 , further comprising administering an additional active agent to the subject.

23 . The method of claim 19 , further comprising administering an additional active agent to the subject.

24 . The method of claim 20 , further comprising administering an additional active agent to the subject.

25 . The compound of claim 1 , wherein the compound is:

26 . The compound of claim 2 , wherein the compound is:

27 . The compound of claim 3 , wherein the compound is:

28 . The compound of claim 4 , wherein the compound is:

Assignments (7)
CORRECTIVE ASSIGNMENT TO CORRECT THE CONVEYING PARTY NAME PREVIOUSLY RECORDED AT REEL: 70706 FRAME: 874. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Oct 9, 2025
From: KOBAYAKAWA, YU; OSHIMA, TSUYOSHI; UNO, TAKAO
To: TAIHO PHARMACEUTICAL CO., LTD.
Reel/Frame 074217/0152 →
CORRECTIVE ASSIGNMENT TO CORRECT THE TYPOGRAPHICAL ERROR IN THE PREVIOUS COVER SHEET IN THE RECEIVING PARTY DATA COMPANY NAME FROM MERCK SHARP & DOHME CORP. TO MERCK SHARP & DOHME LLC PREVIOUSLY RECORDED ON REEL 70706 FRAME 923. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Sep 18, 2025
From: TAIHO PHARMACEUTICAL CO., LTD.
To: MERCK SHARP & DOHME LLC
Reel/Frame 072910/0700 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 17, 2025
From: ASTEX THERAPEUTICS LIMITED
To: MERCK SHARP & DOHME LLC
Reel/Frame 072284/0800 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 17, 2025
From: SCHÖPF, PATRICK
To: ASTEX THERAPEUTICS LIMITED
Reel/Frame 072916/0225 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 2, 2025
From: TAIHO PHARMACEUTICAL CO. LTD.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 070706/0923 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 2, 2025
From: KOBAYAKAWA, YU; OSHIMA, TSUYOSH; UNO, TAKAO
To: TAIHO PHARMACEUTICAL CO. LTD.
Reel/Frame 070706/0874 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 2, 2025
From: KAWAMURA, SHUHEI
To: MERCK SHARP & DOHME CORP.
Reel/Frame 070706/0870 →
Continuity (4)
Provisional Application 63680205 · Aug 7, 2024
Provisional Application 63638789 · Apr 25, 2024
Provisional Application 63591871 · Oct 20, 2023
Related Publication 20250136615A1 · May 1, 2025
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