Isoindoline compounds and methods of their use
Provided herein are isoindoline compounds, pharmaceutical compositions comprising one or more of such compounds, and methods of their use for treating, preventing, or managing various diseases.
1. A compound of Formula II:
or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, wherein:
X is CH 2 ;
m is an integer of 0, 1, 2, or 3;
R 4 is C 3-10 cycloalkyl, 5 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl, or C 0-4 alkyl-NR 41 R 42 ; wherein the cycloalkyl, heterocyclyl, and heteroaryl are each optionally substituted with one or more halogen, C 1-6 alkyl, —CO—NR 43 R 44 , —COOR 45 , or C 0-4 alkyl-C 6-10 aryl, wherein the aryl itself may be optionally substituted with one or more halogen; and
R 41 , R 42 , R 43 , R 44 and R 45 are each independently hydrogen or C 1-6 alkyl.
2. The compound of claim 1 , wherein R 4 is 3-(N,N-diethylamino)propyl, 4-tert-butylcyclohexyl, cis-4-tert-butylcyclohexyl, trans-4-tert-butylcyclohexyl, 4-methylcyclohexyl, cis-4-methylcyclohexyl, trans-4-methylcyclohexyl, 1-benzylpiperidin-4-yl, 4-methyltetrahydro-2H-pyran-4-yl, piperidin-4-yl, 4-phenylcyclohexyl, cis-4-phenylcyclohexyl, or trans-4-phenylcyclohexyl.
3. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof.
4. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable excipients or carriers.
5. The pharmaceutical composition of claim 4 , further comprising a second therapeutic agent.
6. The pharmaceutical composition of claim 4 , wherein the composition is formulated for single dose administration.
7. The pharmaceutical composition of claim 4 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
8. The pharmaceutical composition of claim 7 , wherein the oral dosage form is a tablet or capsule.
9. A method of treating or managing cancer comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , wherein the cancer is Non-Hodgkin's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, or cutaneous T-cell lymphoma.
10. The method of claim 9 , which further comprises administration of one or more additional agents.
11. The method of claim 9 , wherein the compound is administered orally or parenterally.
12. A method of treating or managing cancer comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , wherein the cancer is prostate cancer, pancreatic cancer, breast cancer or colorectal cancer.
13. The method of claim 12 , which further comprises administration of one or more additional agents.
14. The method of claim 12 , wherein the compound is administered orally or parenterally.
15. The compound of claim 1 , wherein X is CH 2 .
16. The compound of claim 1 , wherein m is 1.
17. The compound of claim 1 , wherein R 4 is C 3-10 cycloalkyl, optionally substituted with one or more (C 1-6 ) alkyl or C 0-4 alkyl-C 6-10 aryl.
18. The compound of claim 1 , wherein R 4 is 5 to 6 membered heterocyclyl, optionally substituted with one or more (C 1-6 ) alkyl or C 0-4 alkyl-C 6-10 aryl.
19. The compound of claim 1 , wherein R 4 is C 0-4 alkyl-NR 41 R 42 , wherein R 41 and R 42 are each independently hydrogen or C 1-6 alkyl.