3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

1. A compound of Formula (Ib):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,

wherein:

each R 1 is independently (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )hydroxyalkyl, or halogen;

R 2 is (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or (C 3 -C 8 )cycloalkyl, wherein the alkyl is optionally substituted with one or more R 4 ; and the aryl, heteroaryl, and cycloalkyl are optionally substituted with one or more R 5 ;

each R 4 is independently selected from —C(O)OR 6 , —C(O)NR6R 6 , —NR 6 C(O)R 6′ , (C 6 -C 10 )aryl, 5-or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 3 -C 5 )cycloalkyl, and 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups are optionally substituted with one or more R 7 ;

each R 5 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 1 -C 6 )hydroxy alkyl, halogen, —OH, —NH 2 , CN, (C 3 -C 7 )cycloalkyl, 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, (C 6 -C 10 )aryl, and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or

two R 5 , 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 0, N, and S, optionally substituted with one or more R 10 , or

two R 5 , 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 6 and R 6′ are each independently H or (C 1 -C 6 )alkyl;

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;

n is 1 or 2; and

q is 0, 1, 2, 3, or 4.

2. The compound according to claim 1 , wherein n is 1.

3. The compound according to claim 1 , wherein n is 2.

4. The compound according to claim 1 , wherein q is 0, 1, or 2.

5. The compound according to claim 1 , wherein R 2 is (C 6 -C 10 )aryl or (C 3 -C 8 )cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with one to three R 5 .

6. The compound according to claim 1 , wherein R 2 is (C 6 -C 10 )aryl or (C 3 -C 8 )cycloalkyl.

7. The compound according to claim 1 , wherein R 2 is (C 1 -C 6 )alkyl optionally substituted with one to three R 4 .

8. The compound of claim 1 , having a Formula (Ic) or Formula (Id):

9. The compound according to claim 8 , wherein R 2 is (C 6 -C 10 )aryl or (C 3 -C 8 )cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with one to three R 5 .

10. The compound according to claim 8 , wherein R 2 is (C 6 -C 10 )aryl or (C 3 -C 8 )cycloalkyl.

11. The compound according to claim 8 , wherein R 2 is (C 1 -C 6 )alkyl optionally substituted with one to three R 4 .

12. 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.

13. The pharmaceutical composition according to claim 12 further comprising at least one additional pharmaceutical agent.

14. A method of degrading IKZF2 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.

15. A method of treating a 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 modulating 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.

17. A method of reducing the proliferation of a cell the method comprising, 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.

18. 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.

19. The method according to claim 18 , 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, acute myelogenous leukemia, and gastrointestinal stromal tumor (GIST).

20. The method according to claim 18 , wherein the cancer is a cancer for which the immune response is deficient or an immunogenic cancer.

21. 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.