IP Library › Granted Patent US 10,730,864
Granted Patent B2
US 10,730,864 · App. 16/545,065 · Granted Aug 4, 2020

RAD51 inhibitors and uses thereof

Inventors: Jiewen Zhu (Irvine, CA); Wen-Hwa Lee (Newport Coast, CA); Hongyuan Chen (Irvine, CA); Xuning Guo (Irvine, CA); Xiao-Long Qiu (Haimen, CN)
Assignee: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
C07D417/04C07D209/44C07D223/16C07D277/56C07D401/04C07D403/04C07D471/04
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Quick Facts
Patent No.
US 10,730,864
App. No.
16/545,065
Granted
Aug 4, 2020
Kind
B2
Abstract

The present invention includes novel RAD51 inhibitors. The compounds of the invention may be useful in preventing or treating cancer in a subject in need thereof. The present invention also includes methods of preventing or treating cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the invention.

Claims (79)

1. A compound selected from the group consisting of formula (I), formula (II), and formula (III), a salt or solvate, and any combinations thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 29 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, F, Cl, Br, I, CN, NO 2 , OR 30 , SR 30 , S(═O)R 30 , S(═O) 2 R 30 , NHS(═O) 2 R 30 , C(═O)R 30 , OC(═O)R 30 , CO 2 R 30 , OCO 2 R 30 , CH(R 30 ) 2 , N(R 30 ) 2 , C(═O)N(R 30 ) 2 , OC(═O)N(R 30 ) 2 , NHC(═O)NH(R 30 ), NHC(═O)R 30 , NHC(═O)OR 30 , C(OH)(R 30 ) 2 , and C(NH 2 )(R 30 ) 2 ;

each occurrence of R 30 is independently selected from the group consisting of H and C 1 -C 6 alkyl;

Het is a 5- to 14-membered substituted or unsubstituted heteroaryl ring;

the bond between carbon 1 and carbon 2 may be a single bond or a double bond;

the bond between carbon 3 and carbon 4 may be a single bond or a double bond;

p is an integer from 0-3;

q is an integer from 0-3; and

r is an integer from 0-3,

with the proviso that in a compound of formula (II), if R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are all H, the bond between carbon 1 and carbon 2 is a double bond, and q is 1, then Het cannot be 3-indolyl.

2. The compound of claim 1 , wherein the compound is a compound of formula (I).

3. The compound of claim 1 , wherein the compound is a compound of formula (II).

4. The compound of claim 1 , wherein the compound is a compound of formula (III).

5. The compound of claim 2 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each H.

6. The compound of claim 3 , wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are each H.

7. The compound of claim 3 , wherein R 15 is selected from the group consisting of H, F, and CF 3 .

8. The compound of claim 3 , wherein R 16 is selected from the group consisting of H, F, and CF 3 .

9. The compound of claim 3 , wherein R 17 is selected from the group consisting of H, F, and CF 3 .

10. The compound of claim 4 , wherein R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 29 are each H.

11. The compound of claim 1 , wherein Het is selected from the group consisting of indolyl, azaindolyl, and thiazolyl, wherein the indolyl, azaindolyl, or thiazolyl group may be optionally substituted.

12. The compound of claim 1 , wherein Het is selected from the group consisting of:

wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , X 8 , and X 9 are each independently selected from the group consisting of N and CR 41 ;

X 6 and X 10 are each independently selected from the group consisting of S, O, C(R 42 ) 2 , and NR 43 ;

each occurrence of R 40 , R 41 , R 42 , and R 43 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, F, Cl, Br, I, CN, NO 2 , OR 44 , SR 44 , S(═O)R 44 , S(═O) 2 R 44 , NHS(═O) 2 R 44 , C(═O)R 44 , OC(═O)R 44 , CO 2 R 44 , OCO 2 R 44 , CH(R 44 ) 2 , N(R 44 ) 2 , C(═O)N(R 44 ) 2 , OC(═O)N(R 44 ) 2 , NHC(═O)NH(R 44 ), NHC(═O)R 44 , NHC(═O)OR 44 , C(OH)(R 44 ) 2 , and C(NH 2 )(R 44 ) 2 ; and

each occurrence of R 44 is independently selected from the group consisting of H and C 1 -C 6 alkyl.

13. The compound of claim 12 , wherein X 6 is S.

14. The compound of claim 12 , wherein X 8 is NR 41 .

15. The compound of claim 12 , wherein X 1 is NR 41 .

16. The compound of claim 12 , wherein X 2 is NR 41 .

17. The compound of claim 12 , wherein X 3 is NR 41 .

18. The compound of claim 1 , wherein Het is selected from the group consisting of:

19. The compound of claim 2 , wherein p is 1.

20. The compound of claim 3 , wherein q is 1.

21. The compound of claim 4 , wherein r is 1.

22. The compound of claim 1 , wherein the compound is selected from the group consisting of:

a salt or solvate, and any combinations thereof.

23. The compound of claim 1 , wherein the compound is:

a salt or solvate, and any combinations thereof.

24. A pharmaceutical composition comprising at least one compound of claim 1 .

25. A method of preventing or treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound selected from the group consisting of formula (I), formula (II), and formula (III), a salt or solvate, and any combinations thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 29 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, F, Cl, Br, I, CN, NO 2 , OR 30 , SR 30 , S(═O)R 30 , S(═O) 2 R 30 , NHS(═O) 2 R 30 , C(═O)R 30 , OC(═O)R 30 , CO 2 R 30 , OCO 2 R 30 , CH(R 30 ) 2 , N(R 30 ) 2 , C(═O)N(R 30 ) 2 , OC(═O)N(R 30 ) 2 , NHC(═O)NH(R 30 ), NHC(═O)R 30 , NHC(═O)OR 30 , C(OH)(R 30 ) 2 , and C(NH 2 )(R 30 ) 2 ;

each occurrence of R 30 is independently selected from the group consisting of H and C 1 -C 6 alkyl;

Het is a 5- to 14-membered substituted or unsubstituted heteroaryl ring;

the bond between carbon 1 and carbon 2 may be a single bond or a double bond;

the bond between carbon 3 and carbon 4 may be a single bond or a double bond;

p is an integer from 0-3;

q is an integer from 0-3; and

r is an integer from 0-3,

with the proviso that in a compound of formula (II), if R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are all H, the bond between carbon 1 and carbon 2 is a double bond, and q is 1, then Het cannot be 3-indolyl.

26. The method of claim 25 , wherein the compound is a compound of formula (I).

27. The method of claim 25 , wherein the compound is a compound of formula (II).

28. The method of claim 25 , wherein the compound is a compound of formula (III).

29. The method of claim 26 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each H.

30. The method of claim 27 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19 are each H.

31. The method of claim 27 , wherein R 15 is selected from the group consisting of H, F, and CF 3 .

32. The method of claim 27 , wherein R 16 is selected from the group consisting of H, F, and CF 3 .

33. The method of claim 27 , wherein R 17 is selected from the group consisting of H, F, and CF 3 .

34. The compound of claim 28 , wherein R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , and R 29 are each H.

35. The method of claim 25 , wherein Het is selected from the group consisting of indolyl, azaindolyl, and thiazolyl, wherein the indolyl, azaindolyl, or thiazolyl group may be optionally substituted.

36. The method of claim 25 , wherein Het is selected from the group consisting of:

wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , X 8 , and X 9 are each independently selected from the group consisting of N and CR 41 ;

X 6 and X 10 are each independently selected from the group consisting of S, O, C(R 42 ) 2 , and NR 43 ;

each occurrence of R 40 , R 41 , R 42 , and R 43 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, F, Cl, Br, I, CN, NO 2 , OR 44 , SR 44 , S(═O)R 44 , S(═O) 2 R 44 , NHS(═O) 2 R 44 , C(═O)R 44 , OC(═O)R 44 , CO 2 R 44 , OCO 2 R 44 , CH(R 44 ) 2 , N(R 44 ) 2 , C(═O)N(R 44 ) 2 , OC(═O)N(R 44 ) 2 , NHC(═O)NH(R 44 ), NHC(═O)R 44 , NHC(═O)OR 44 , C(OH)(R 44 ) 2 , and C(NH 2 )(R 44 ) 2 ; and

each occurrence of R 44 is independently selected from the group consisting of H and C 1 -C 6 alkyl.

37. The method of claim 26 , wherein X 6 is S.

38. The method of claim 26 , wherein X 8 is NR 41 .

39. The method of claim 26 , wherein X 1 is NR 41 .

40. The method of claim 26 , wherein X 2 is NR 41 .

41. The method of claim 26 , wherein X 3 is NR 41 .

42. The method of claim 25 , wherein Het is selected from the group consisting of:

43. The method of claim 26 , wherein p is 1.

44. The method of claim 27 , wherein q is 1.

45. The method of claim 28 , wherein r is 1.

46. The method of claim 25 , wherein the compound is selected from the group consisting of:

a salt or solvate, and any combinations thereof.

47. The method of claim 25 , wherein the compound is:

a salt or solvate, and any combinations thereof.

Continuity (3)
Continuation 15554829
Provisional Application 62126887 · Mar 2, 2015
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