Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
This invention provides for substituted pyrazolo[3,4-d]pyrimidine compounds of the Formula (I): as Wee1 inhibitors. The substituted pyrazolo[3,4-d]pyrimidine compounds may find use as therapeutic agents for the treatment of diseases. The substituted pyrazolo[3,4-d]pyrimidine compounds may also find particular use in oncology.
1. A compound of Formula (I):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein:
Y is H or R 4 ;
each R 1 is independently F, Cl, or CH 3 ;
R 2 is (C 1 -C 3 alkylene)-CF 3 , C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
R 3 is:
wherein:
M 1 is N;
M 2 is absent, CH, CR 3b , or N;
M 3 is CH, CR 3b , N, O, or S;
M 4 is CH, CR 3b , N, O, or S;
R 3a is C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is substituted by one or more substituents independently selected from the group consisting of CN and C 1 -C 6 haloalkyl;
each R 3b is independently halogen or CN; and
is an aromatic ring;
each R 4 is independently halogen, CN, (C 1 -C 3 alkylene)-CN, (C 1 -C 3 alkylene)-CF 3 , (C 1 -C 3 alkylene)-C(O)R 17 , (C 1 -C 3 alkylene)-C(O)NR 17 R 18 , (C 1 -C 3 alkylene)-NR 17 R 18 , (C 1 -C 3 alkylene)-NR 17 C(O)R 18 , (C 1 -C 3 alkylene)-NR 17 S(O) 2 R 18 , (C 1 -C 3 alkylene)-OR 17 , (C 1 -C 3 alkylene)-S(O) 2 R 17 , (C 1 -C 3 alkylene)-S(O) 2 NR 17 R 18 , (C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 3 alkylene)-(3- to 6-membered heterocyclyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)R 17 , C(O)NR 17 R 18 , C(O)OR 17 , NR 17 R 18 , NR 17 C(O)R 18 , NR 17 S(O) 2 R 18 , OR 17 , OC(O)NR 17 R 18 , ═O, S(O) 2 R 17 , S(O) 2 NR 17 R 18 , Si(C 1 -C 6 alkyl) 3 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each R 4 is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, C(O)R 19 , NR 19 R 20 , OR 19 , and ═O; or
any two geminal R 4 , together with the carbon atom to which they are attached, independently form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each C 3 -C 6 cycloalkyl and 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more independently selected R 19 substituents;
each R 17 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, OH, and ═O;
each R 18 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, OH, and ═O; or
each R 17 and R 18 , together with the atom(s) to which they are attached, independently form a 3- to 6-membered heterocyclyl, wherein each 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, OH, and ═O;
each R 19 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, OH, and ═O;
each R 20 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and 3- to 6-membered heterocyclyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, OH, and ═O;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, 3, or 4;
with the provisos that:
(1) when M 2 is absent and M 4 is O or S, then M 3 is CH, CR 3b , or N; and
(2) when M 2 is absent and M 3 is O or S, then M 4 is CH, CR 3b , or N.
2. The compound of claim 1 , wherein the compound is of Formula (II):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
3. The compound of claim 1 , wherein the compound is of Formula (III):
or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
4. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is H.
5. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is (C 1 -C 3 alkylene)-CF 3 .
6. The compound of claim 5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH 2 CF 3 .
7. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 1 -C 6 alkyl.
8. The compound of claim 7 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH 2 CH 3 or CH(CH 3 ) 2 .
9. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C 3 -C 6 cycloalkyl.
10. The compound of claim 9 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is cyclopropyl.
11. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is:
12. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3a is C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is substituted by one or more independently selected C 1 -C 6 haloalkyl substituents.
13. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3a is C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is substituted by one or more CN substituents.
14. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3a is:
15. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 3b is independently halogen.
16. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 3b is independently CN.
17. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is:
18. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 4 is independently C 1 -C 6 alkyl; or
any two geminal R 4 , together with the carbon atom to which they are attached, independently form a C 3 -C 6 cycloalkyl.
19. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 0.
20. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1.
21. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.
22. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 1.
23. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 2.
24. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein
is:
25. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 25 , wherein the compound is:
27. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 27 , wherein the compound is:
29. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 29 , wherein the compound is:
31. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 31 , wherein the compound is:
33. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 33 , wherein the compound is:
35. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 35 , wherein the compound is:
37. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 37 , wherein the compound is:
39. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 39 , wherein the compound is:
41. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 41 , wherein the compound is:
43. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
44. The compound of claim 43 , wherein the compound is:
45. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
46. The compound of claim 45 , wherein the compound is:
47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
48. A kit comprising a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
49. A method for inducing premature mitosis in a cell, wherein the method comprises contacting the cell with a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
50. A method for inducing apoptosis in a cell, wherein the method comprises contacting the cell with a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
51. A method for suppressing a G 2 -M deoxyribonucleic acid damage checkpoint in a cell, wherein the method comprises contacting the cell with a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
52. A method for inhibiting Wee1 activity in a cell, wherein the method comprises contacting the cell with a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
53. A method for treating a cancer in an individual in need thereof, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
54. The method of claim 53 , wherein the cancer comprises a mutant tumor protein p53 gene.
55. The method of claim 53 , wherein the method further comprises:
(i) selecting the individual for treatment based on the presence of one or more mutations in the tumor protein p53 gene in the cancer; or
(ii) selecting the individual for treatment based on expression of the mutant tumor protein p53 gene in the cancer.
56. The method of claim 53 , wherein the method further comprises administering to the individual a therapeutically effective amount of an additional therapeutic agent.
57. The method of claim 56 , wherein the additional therapeutic agent is selected from the group consisting of a cancer immunotherapy agent and a chemotherapeutic agent.
58. The method of claim 56 , wherein the additional therapeutic agent is selected from the group consisting of a deoxyribonucleic acid alkylating agent, a deoxyribonucleic acid damage repair pathway inhibitor, a kinase inhibitor, and a platinum-based chemotherapeutic agent.
59. The method of claim 53 , wherein the method further comprises administering to the individual a therapeutically effective amount of a radiation therapy.
60. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.