3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
The present disclosure provides a compound of Formula (I′): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R 1 , R 2 , R x , X 1 , n, n1, and q are as defined herein, and methods of making and using same.
1. A compound of Formula (Ic):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
each R 1 is independently (C 1 -C 6 )alkyl;
R 2 is (C 1 -C 6 )alkyl substituted with one to three R 4 ;
each R 4 is independently selected from (C 6 -C 10 )aryl and (C 3 -C 8 )cycloalkyl, wherein the aryl and cycloalkyl groups are optionally substituted with one or more R 7 ;
each R 7 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 9 , (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —NH 2 , CN, (C 6 -C 10 )aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 7 )cycloalkyl, and 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, or
two R 7 , when on adjacent atoms, together with the atoms to which they are attached form a (C 6 -C 10 )aryl ring or a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one or more R 10 , or
two R 7 , when on adjacent atoms, together with the atoms to which they are attached form a (C 5 -C 7 )cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one or more R 10 ;
R 8 and R 9 are each independently H or (C 1 -C 6 )alkyl;
each R 10 is independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, halogen, —OH, —NH 2 , and CN; and
q is 0.
2. The compound according to claim 1 , wherein R 4 is phenyl or (C 3 -C 8 )cycloalkyl optionally substituted with one to three R 7 .
3. The compound according to claim 1 , wherein R 4 is phenyl optionally substituted with one to three R 7 .
4. The compound according to claim 1 , wherein R 4 is (C 3 -C 8 )cycloalkyl optionally substituted with one to three R 7 .
5. A compound selected from:
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
6. The compound of claim 5 , wherein the compound is compound (I-156):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
7. The compound of claim 5 , wherein the compound is compound (I-57):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
8. The compound of claim 5 , wherein the compound is compound (I-87):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
9. The compound of claim 5 , wherein the compound is compound (I-88):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
10. The compound of claim 5 , wherein the compound is compound (I-112):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
11. The compound of claim 5 , wherein the compound is compound (I-303):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
12. The compound of claim 5 , wherein the compound is compound (I-11):
and
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
14. The pharmaceutical composition of claim 13 further comprising at least one additional pharmaceutical agent.
15. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
16. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
17. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
18. The method of claim 17 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
19. The method of claim 17 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
20. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 5 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
22. The pharmaceutical composition of claim 21 further comprising at least one additional pharmaceutical agent.
23. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 6 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
24. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 6 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
25. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 6 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
26. The method of claim 25 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
27. The method of claim 25 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
28. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 6 , or a pharmaceutically acceptable salt.
29. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 7 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
30. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 7 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
31. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 7 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
32. The method of claim 31 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
33. The method of claim 31 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
34. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 7 , or a pharmaceutically acceptable salt.
35. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 8 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
36. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 8 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
37. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 8 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
38. The method of claim 37 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
39. The method of claim 37 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
40. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 8 , or a pharmaceutically acceptable salt.
41. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 9 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
42. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 9 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
43. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 9 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
44. The method of claim 43 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
45. The method of claim 43 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
46. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 9 , or a pharmaceutically acceptable salt.
47. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 10 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
48. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 10 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
49. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 10 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
50. The method of claim 49 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
51. The method of claim 49 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
52. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 10 , or a pharmaceutically acceptable salt.
53. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 11 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
54. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 11 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
55. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 11 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
56. The method of claim 55 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
57. The method of claim 55 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
58. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 11 , or a pharmaceutically acceptable salt.
59. A method of treating an IKZF2-dependent disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound according to claim 12 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
60. A method of reducing proliferation of a cell, wherein the method comprises: contacting the cell with a compound according to claim 12 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and reducing IKZF2 protein levels.
61. A method of treating an IKZF2-dependent cancer comprising administering to the patient in need thereof a compound according to claim 12 , or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
62. The method of claim 61 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST).
63. The method of claim 61 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.
64. A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 12 , or a pharmaceutically acceptable salt.