Phenylsulfonamido-benzofuran derivatives and uses thereof in the treatment of proliferative diseases
Described herein are phenylsulfonamido-benzofuran derivatives, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, methods, uses, and kits involving compounds of Formulae (I), (II), (III), (IV), (V), or (VI) for treating and/or preventing proliferative diseases (e.g. cancers, inflammatory diseases, and autoimmune diseases) in a subject. The compounds and pharmaceutical compositions as described herein inhibit at least one protein of the BCL-2 family in a biological sample or subject to treat and/or prevent a proliferative disease. In certain embodiments, compounds described herein are selective inhibitors of MCL-1, a BCL-2 family member protein.
1. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or alkyl, wherein the alkyl is optionally substituted with one instance of —O—C 1-6 alkyl;
each instance of R 3 is independently halogen, alkyl, —OR 3A , —N(R 3B ) 2 , or acyl;
each instance of R 3A is independently hydrogen or alkyl;
each instance of R 3B is independently hydrogen or alkyl;
n is 0, 1, 2, or 3;
R 4 is hydrogen, alkyl, or acyl;
R 7 is hydrogen or alkyl;
R 8 is hydrogen, halogen, or alkyl;
R 9 is alkyl or —OR 2 ;
R 2 is hydrogen or alkyl; and
wherein the cancer is lung cancer, colorectal cancer, multiple myeloma, or leukemia.
2. The method of claim 1 , wherein the cancer is associated the addiction of a cell to a BCL-2 family member protein.
3. The method of claim 1 wherein the BCL-2 family member is an anti-apoptotic BCL-2 family member protein.
4. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 9 is —OR 2 .
5. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
6. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 8 is halogen.
7. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
8. The method of claim 1 , wherein the compound of Formula (IV) is of Formula (III):
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl.
10. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
11. The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
12. The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
13. The method of claim 1 , wherein the compound of Formula (IV) is of Formula (III-a):
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound of Formula (IV) is of Formula (III-b):
or a pharmaceutically acceptable salt thereof.
15. The method of claim 4 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl.
16. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 3 is C 1-6 alkyl or —OR 3A .
17. The method of claim 16 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein at least one instance of R 3 is —OR 3A ; and R 3A is C 1-6 alkyl.
18. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein n is 1.
19. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-6 acyl.
20. The method of claim 1 comprising administering a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1-6 alkyl;
each instance of R 3 is independently C 1-6 alkyl or —OR 3A ;
each instance of R 3A is independently C 1-6 alkyl;
n is 1;
R 4 is hydrogen or —C(═O)C 1-6 alkyl;
R 7 is hydrogen;
R 8 is hydrogen or halogen;
R 9 is —OR 2 ; and
R 2 is C 1-6 alkyl.
21. The method of claim 1 , wherein the cancer is lung cancer.
22. The method of claim 1 , wherein the cancer is colorectal cancer.
23. The method of claim 1 , wherein the cancer is multiple myeloma.
24. The method of claim 1 , wherein the cancer is leukemia.
25. The method of claim 1 , wherein the cancer is associated with overexpression of a BCL-2 family member protein.