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 III:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
X is C(═O) or CH 2 ;
m is an integer of 0, 1, 2, or 3;
R 5 and R 6 are each independently: hydrogen, halo, C 1-6 alkyl, oxo, —NO 2 , C 1-6 alkoxy, —Z—C 1-6 alkyl, C 0-6 alkyl-(5 to 10 membered heteroaryl), C 0-6 alkyl-(5 to 6 membered heterocyclyl), C 0-6 alkyl-OH, C 0-4 alkyl-NH 2 , —NHCO—C 1-6 alkyl, —OR 21 , or —(CH 2 —Y) 0-2 -(5 to 10 membered heteroaryl),
wherein Z is S or SO 2 ;
wherein R 21 is as defined above;
wherein each heteroaryl and heterocyclyl above is optionally substituted with one or more C 1-6 alkyl; and
wherein the alkyl or alkoxy above may be optionally substituted with one or more: halogen; cyano; nitro; amino; C 1-6 alkylidenedioxy; C 1-6 alkoxy, itself optionally substituted with one or more halogens; or C 1-6 alkylthio, itself optionally substituted with one or more halogens;
R 7 is —COR 71 or —PO(OR 72 )(OR 73 );
R 71 is C 1-10 alkyl, C 6-10 aryl, or 5 to 6 membered heterocyclyl; wherein the alkyl, aryl, heterocyclyl may be optionally substituted with one or more amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or —COOR 74 ; and
R 72 , R 73 , and R 74 are each independently hydrogen or C 1-10 alkyl.
2. The compound of claim 1 , wherein R 5 is fluoro or chloro.
3. The compound of claim 1 , wherein R 6 is fluoro or chloro.
4. The compound of claim 1 , which is:
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
5. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable excipients or carriers.
6. The pharmaceutical composition of claim 5 , further comprising a second therapeutic agent.
7. The pharmaceutical composition of claim 5 , wherein the composition is formulated for single dose administration.
8. The pharmaceutical composition of claim 5 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
9. The pharmaceutical composition of claim 8 , wherein the oral dosage form is a tablet or capsule.
10. A method of treating or managing a disease or disorder which comprises administering to a subject a therapeutically effective amount of a compound of any of claims 1 to 4 , wherein the disease is cancer.
11. The method of claim 10 , wherein the cancer is hematologic or solid cancer.
12. The method of claim 9 , which further comprises administration of one or more additional active agents.
13. The method of claim 9 , wherein the compound is administered orally or parenterally.