Ras inhibitors

Patent metadata

Field	Value
Publication number	US-2025195662-A1
Application number	US-202519070930-A
Country	US
Kind code	A1
Filing date	Mar 5, 2025
Priority date	Sep 15, 2020
Publication date	Jun 19, 2025
Grant date	—

Abstract

The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.

First claim

1 . A compound having the structure of Formula Ib:

or a pharmaceutically acceptable salt thereof,
wherein
A is optionally substituted thiazole;
Y is

 wherein the carbonyl carbon is bonded to W;
W is

X 1 is CH (CH 3 );
X 4 is NH;
R 1 is optionally substituted pyridine;
R 2 is —CH 2 CH 3 ;
R 10 is hydrogen; and
R 12 and R 13 are —CH 3 .

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

wherein ** indicates a bond to —CH(R 10 )—,
and R 1 is

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is

and R 1 is

4 . A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5 . A method of treating cancer in a subject in need thereof, wherein the cancer comprises a Ras mutation, comprising administering to the subject a therapeutically effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.

6 . The method of claim 5 , wherein the Ras mutation is at position 12.

7 . The method of claim 6 , wherein the Ras mutation is K-Ras G12D or K-Ras G12V.

8 . The method of claim 5 , wherein the Ras mutation is at a position selected from the group consisting of G12C, G12D, G12V, G12R, G13C, G13D, and Q61K, or a combination thereof.

9 . The method of claim 5 , wherein the cancer is pancreatic cancer.

10 . The method of claim 5 , wherein the method further comprises administering an additional anticancer therapy.

11 . The method of claim 10 , wherein the additional anticancer therapy is a K-Ras (OFF) inhibitor.

12 . The method of claim 10 , wherein the additional anticancer therapy is a PD-L1 inhibitor or a PD-1 inhibitor.

13 . The method of claim 10 , wherein the additional anticancer therapy is chemotherapy.

14 . The method of claim 13 , wherein the chemotherapy comprises docetaxel.

15 . A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 3 , or a pharmaceutically acceptable salt thereof.

16 . The method of claim 15 , wherein more than one Ras protein is inhibited in the cell.

17 . The method of claim 15 , wherein the cell is a cancer cell.

18 . The method of claim 17 , wherein the cancer cell is a pancreatic cancer cell.

19 . The method of claim 15 , wherein the method further comprises administering an additional anticancer therapy.

20 . The method of claim 19 , wherein the additional anticancer therapy is a K-Ras (OFF) inhibitor.

21 . The method of claim 19 , wherein the additional anticancer therapy is a PD-L1 inhibitor or a PD-1 inhibitor.

22 . The method of claim 19 , wherein the additional anticancer therapy is chemotherapy.

23 . The method of claim 22 , wherein the chemotherapy comprises docetaxel.

Assignees

• Revolution Medicines Inc

Inventors

• Koltun Elena S
• Cregg James
• Liu Yang
• Gill Adrian L

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/22

  in which the condensed systems contains four or more hetero rings · CPC title

• C07D498/22

  in which the condensed system contains four or more hetero rings · CPC title