Compounds and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-11224608-B2
Application number	US-201816643689-A
Country	US
Kind code	B2
Filing date	Oct 16, 2018
Priority date	Oct 16, 2017
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present application provides, in some aspects, methods of treating cancers, such as homologous recombination (HR)-deficient cancers. In some embodiments, the disclosure provides a method for treating cancer by administering to a subject a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A method of treating a homologous recombination (HR)-deficient cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
the bond between X and Y is a single bond or a double bond;
X and Y are independently selected from the group consisting of: O, N, CH, and C(═O);
R 1 is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 6-12 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 groups independently selected from the group consisting of: Cy 1 and R g ;
R 2 and R 3 are independently selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
R 4 is selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 6-12 aryl, and C 6-12 aryl-C 1-3 alkylene;
R 5A and R 5B are independently selected from the group consisting of: H and C 1-3 alkyl;
R 6A , R 6B and R 6C are independently selected from the group consisting of: OH, C 1-6 alkoxy, C 1-6 haloalkoxy, C(═O)NR a1 R a2 , and C(O)OR a1 ;
R a1 and R a2 are independently selected from the group consisting of: H and C 1-3 alkyl;
R 7 is selected from the group consisting of: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-4 haloalkyl, each of which is optionally substituted by 1 or 2 Cy 1 ;
each Cy 1 is independently selected from the group consisting of: C 6-12 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R g groups; and
each R g is independently selected from the group consisting of: OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino.

2. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein R 1 is selected from the group consisting of: C 1-6 alkyl, C 6-12 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by 1 or 2 groups independently selected from the group consisting of: Cy 1 and R g .

4. The method of claim 3 , wherein R 1 is C 1-6 alkyl.

5. The method of claim 3 , wherein R 1 is 5-10 membered heteroaryl.

6. The method of claim 3 , wherein R 1 is C 6-12 aryl, optionally substituted by 1 or 2 groups independently selected from the group consisting of: Cy 1 and R g .

7. The method of claim 3 , wherein R 1 is selected from the group consisting of: methyl, 3-(3-methylbut-2-en-1-yl)-4-hydroxyphenyl, 3′,6-dimethoxy-[1,1′-biphenyl-3-yl], and indol-2-yl.

8. The method of claim 1 , wherein R 2 and R 3 are independently selected from the group consisting of: H and C 1-6 alkoxy.

9. The method of claim 8 , wherein R 2 and R 3 are each H.

10. The method of claim 8 , wherein R 2 is H and R 3 is C 1-6 alkoxy.

11. The method of claim 8 , wherein R 2 is C 1-6 alkoxy and R 3 is H.

12. The method of claim 8 , wherein R 2 and R 3 are independently selected from the group consisting of: H, methoxy, propoxy, and isopropoxy.

13. The method of claim 1 , wherein R 4 is selected from the group consisting of: H, C 1-6 alkyl, C 6-12 aryl, and C 6-12 aryl-C 1-3 alkylene.

14. The method of claim 13 , wherein R 4 is selected from the group consisting of: H, methyl, ethyl, phenyl, and benzyl.

15. The method of claim 1 , wherein R 5A and R 5B are each C 1-3 alkyl.

16. The method of claim 1 , wherein R 5A and R 5B are each methyl.

17. The method of claim 1 , wherein R 6A , R 6B and R 6C are independently selected from the group consisting of: OH, C 1-6 alkoxy, and C(═O)NR a1 R a2 .

18. The method of claim 17 , wherein R 6A is C 1-6 alkoxy.

19. The method of claim 17 , wherein R 6B is selected from the group selected from: OH and C(═O)NR a1 R a2 .

20. The method of claim 19 , wherein R 6B is selected from the group selected from: OH and C(═O)NH 2 .

21. The method of claim 17 , wherein R 6C is OH.

22. The method of claim 1 , wherein R 7 is selected from the group consisting of: H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with Cy 1 .

23. The method of claim 22 , wherein R 7 is selected from the group consisting of: H and 4-methoxybenzyl.

24. The method of claim 22 , wherein R 7 is H.

25. The method of any claim 1 , wherein Cy 1 is C 6-12 aryl, optionally substituted by 1 or 2 independently selected R g groups.

26. The method of claim 25 , wherein Cy 1 is phenyl, optionally substituted with R g .

27. The method of claim 25 , wherein Cy 1 is selected from the group consisting of: 3-methoxyphenyl and 4-methoxyphenyl.

28. The method of claim 1 , wherein R g is selected from the group consisting of: OH, C 2-6 alkenyl, and C 1-6 alkoxy.

29. The method of claim 28 , wherein R g is selected from the group consisting of: OH, 3-methylbut-2-en-1-yl, and methoxy.

30. The method of claim 1 , wherein:
R 1 is selected from the group consisting of: C 1-6 alkyl, C 6-12 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by 1 or 2 groups independently selected from the group consisting of: Cy 1 and R g ;
R 2 and R 3 are independently selected from the group consisting of: H and C 1-6 alkoxy;
R 4 is selected from the group consisting of: H, C 1-6 alkyl, C 6-12 aryl, and C 6-12 aryl-C 1-3 alkylene;
R 5A and R 5B are each C 1-3 alkyl;
R 6A , R 6B and R 6C are independently selected from the group consisting of: OH, C 1-6 alkoxy, and C(═O)NR a1 R a2 ;
R 1 is selected from the group consisting of: H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with Cy 1 ;
Cy 1 is C 6-12 aryl, optionally substituted by 1 or 2 independently selected R g groups; and
R g is selected from the group consisting of: OH, C 2-6 alkenyl, and C 1-6 alkoxy.

31. The method of claim 1 , wherein:
R 1 is selected from the group consisting of: methyl, indol-2-yl, and phenyl, wherein the phenyl is optionally substituted by 1 or 2 groups independently selected from the group consisting of: Cy 1 and R g ;
R 2 and R 3 are independently selected from the group consisting of: H, methoxy, propoxy, and isopropoxy;
R 4 is selected from the group consisting of: H, methyl, ethyl, phenyl, and benzyl;
R 5A and R 5B are each methyl;
R 6A is C 1-6 alkoxy;
R 6B is selected from the group selected from: OH and C(═O)NH 2 ;
R 6C is OH;
R 1 is selected from the group consisting of: H and C 1-6 alkyl substituted with Cy 1 ;
Cy 1 is phenyl, optionally substituted with R g ; and
R g is selected from the group consisting of: OH, 3-methylbut-2-en-1-yl, and methoxy.

32. The method of claim 1 , wherein the compound of Formula (I) is selected

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• D'Andrea Alan
• Ceccaldi Raphael
• Zhou Jia

Classifications

• A61K31/545

  Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-A61K-0953.gif] , e.g. cephalosporins, {cefaclor, or cephalexine} · CPC title

• A61K31/502

  ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D311/02

  ortho- or peri-condensed with carbocyclic rings or ring systems · CPC title

• A61K31/282

  Platinum compounds · CPC title