Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof

Patent metadata

Field	Value
Publication number	US-11739077-B2
Application number	US-202318106339-A
Country	US
Kind code	B2
Filing date	Feb 6, 2023
Priority date	Nov 12, 2021
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The disclosure provides for small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. The disclosure further provides methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.

First claim

What is claimed is:

1. A compound having the structure of Formula (IVa-2), or a pharmaceutically acceptable salt thereof,

wherein
Y 1 is N or CR Y1 ;
Y 2 is N or CR Y2 ;
Y 3 is CR Y3 ;
Y 4 is CR Y4 ;
each of R Y1 , R Y2 , R Y3 , and R Y4 is independently hydrogen or C 1 -C 6 alkyl;
R 1 is hydrogen or C 1 -C 6 alkyl;

and each R A is independently OH, C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3 -C 6 cycloalkyl; and
R B1 is 5 membered heteroaryl optionally substituted with one or more substituents selected from C 1-3 haloalkyl and C 1-3 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is CH, Y 2 is CH, Y 3 is CH, and Y 4 is CH;
Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH; or
Y 1 is N, Y 2 is CH, Y 3 is CH, and Y 4 is CH.

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

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B1 is

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is

or a pharmaceutically acceptable salt thereof.

15. A method of treating a disease or disorder associated with ubiquitin specific protease 1 (USP1) comprising administering to a subject a compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the subject has a disease or disorder associated with USP1.

16. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a BRCA1 mutant cancer, a BRCA2 mutant cancer, or a BRCA1 and BRCA2 mutant cancer.

17. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a DNA damage repair pathway deficient cancer.

18. The method of claim 15 , wherein the disease or disorder is a cancer, and wherein the cancer is a homologous recombination deficient (HRD) cancer.

19. A pharmaceutical composition comprising (i) a compound having the structure of Formula (IVa-2), or a pharmaceutically acceptable salt thereof,

wherein
Y 1 is N or CR Y1 ;
Y 2 is N or CR Y2 ;
Y 3 is CR Y3 ;
Y 4 is CR Y4 ;
each of R Y1 , R Y2 , R Y3 , and R Y4 is independently hydrogen or C 1 -C 6 alkyl;
R 1 is hydrogen or C 1 -C 6 alkyl;

and each R A is independently OH, C 1-6 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 3 -C 6 cycloalkyl; and
R B1 is 5 membered heteroaryl optionally substituted with one or more substituents selected from C 1-3 haloalkyl and C 1-3 alkyl; and
(ii) a pharmaceutically acceptable excipient.

20. The pharmaceutical composition of claim 19 , wherein:
Y 1 is CH, Y 2 is CH, Y 3 is CH, and Y 4 is CH;
Y 1 is CH, Y 2 is N, Y 3 is CH, and Y 4 is CH; or
Y 1 is N, Y 2 is CH, Y 3 is CH, and Y 4 is CH.

21. The pharmaceutical composition of claim 19 , wherein R 1 is —CH 3 ;

and R B1 is

22. The pharmaceutical composition of claim 19 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The pharmaceuti

Assignees

• Insilico Medicine Ip Ltd

Inventors

• Wu Jianping
• Qin Luoheng
• Liu Jinxin

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title