Compounds and methods for treating cancer
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.
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 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, 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.
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 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.
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.