IP Library › Granted Patent US 50,319

Granted Patent E1

US 50,319 · App. 17/984,910 · Granted Mar 4, 2025

Compounds and methods for treating cancer

Inventors: Alan D'Andrea (Winchester, MA); Raphael Ceccaldi (Paris, FR); Jia Zhou (Natick, MA)

Assignee: Dana-Farber Cancer Institute, Inc.

A61K31/7048 A61K31/357 A61K31/704 A61K31/706 A61K33/243 A61K45/06 A61P35/00 C07H15/20 C07H17/02 C07H17/07 C07H17/075

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Quick Facts

Patent No.: US 50,319
App. No.: 17/984,910
Granted: Mar 4, 2025
Kind: E1

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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.

Claims (134)

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 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 ;

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 R 7 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 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 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

33. The method of claim 1 , further comprising, before administering the compound to the patient, determining that the HR-deficient cancer contains a mutation or an alteration in a gene regulating homologous recombination.

34. The method of claim 33 , wherein the gene regulating homologous recombination is BRCA1/2.

35. The method of claim 1 , wherein the cancer is selected from prostate cancer, colon cancer, lung cancer, liver cancer, sarcoma, melanoma, breast cancer, ovarian cancer, and pancreatic cancer.

36. A method of treating a cancer selected from ovarian cancer and pancreatic cancer, wherein the ovarian cancer or pancreatic cancer is an HR-deficient cancer, a POLQ overexpressing cancer, or an HR-deficient, POLQ overexpressing 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 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 ;

37. The method of claim 1 , further comprising administering to the subject a therapeutically effective amount of an additional anti-cancer agent.

38. The method of claim 37 , wherein the additional anti-cancer agent is a platinum-based anti-cancer agent.

39. The method of claim 38 , wherein the platinum-based anti-cancer agent is selected from carboplatin and cisplatin.

40. The method of claim 37 , wherein the additional anti-cancer agent is a PARP inhibitor.

41. The method of claim 40 , wherein the PARP inhibitor is selected from olaparib, veliparib, BGB-290, talazoparib, BMN 673, and niraparib.

42. A method of inhibiting DNA polymerase θ (Polθ) in a homologous recombination (HR)-deficient cancer cell, the method comprising contacting the HR-deficient cancer cell with an 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 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 ;

43. The method of claim 42 , wherein the cancer cell is contacted in vitro.

44. The method of claim 42 , wherein the cancer cell is contacted in vivo.

45. The method of claim 42 , wherein the cancer cell is contacted ex vivo.

46. The method of claim 32 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

47. The method of claim 32 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

48. The method of claim 46 , further comprising, before administering the compound to the patient, determining that the HR-deficient cancer contains a mutation or an alteration in a gene regulating homologous recombination.

49. The method of claim 48 , wherein the gene regulating homologous recombination is BRCA1/2.

50. The method of claim 46 , wherein the cancer is selected from prostate cancer, colon cancer, lung cancer, liver cancer, sarcoma, melanoma, breast cancer, ovarian cancer, and pancreatic cancer.

51. A method of treating ovarian cancer or pancreatic cancer, wherein the ovarian cancer or pancreatic cancer is an HR-deficient cancer, a POLQ overexpressing cancer, or an HR-deficient, POLQ overexpressing cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

52. The method of claim 51 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

53. The method of claim 51 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

54. The method of claim 52 , further comprising administering to the subject a therapeutically effective amount of an additional anti-cancer agent.

55. The method of claim 54 , wherein the additional anti-cancer agent is a platinum-based anti-cancer agent.

56. The method of claim 55 , wherein the platinum-based anti-cancer agent is selected from carboplatin and cisplatin.

57. The method of claim 54 , wherein the additional anti-cancer agent is a PARP inhibitor.

58. The method of claim 57 , wherein the PARP inhibitor is selected from olaparib, veliparib, BGB-290, talazoparib, BMN 673, and niraparib.

59. A method of inhibiting DNA polymerase θ (Polθ) in a homologous recombination (HR)-deficient cancer cell, the method comprising contacting the HR-deficient cancer cell with an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

60. The method of claim 59 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

61. The method of claim 60 , wherein the cancer cell is contacted in vivo.

62. The method of claim 59 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

63. The method of claim 62 , wherein the cancer cell is contacted in vivo.

64. The method of claim 32 , further comprising administering to the subject a therapeutically effective amount of an additional anti-cancer agent.

65. The method of claim 64 , wherein the additional anti-cancer agent is a platinum-based anti-cancer agent.

66. The method of claim 65 , wherein the platinum-based anti-cancer agent is selected from carboplatin and cisplatin.

67. The method of claim 64 , wherein the additional anti-cancer agent is a PARP inhibitor.

68. The method of claim 67 , wherein the PARP inhibitor is selected from olaparib, veliparib, BGB-290, talazoparib, BMN 673, and niraparib.

69. The method of claim 36 , wherein the ovarian cancer or pancreatic cancer is an HR-deficient cancer.

70. The method of claim 51 , wherein the ovarian cancer or pancreatic cancer is an HR-deficient cancer.

Continuity (2)

Provisional Application 62572977 · Oct 16, 2017

Reissue 16643689 · Oct 16, 2018

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