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 compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3 is independently halogen, —CN, —NO 2 , —N 3 , optionally substituted C 1-6 alkyl, —OR 3A , N(R 3B ) 2 , or optionally substituted C 1-6 acyl;
n is 0, 1, 2, 3, 4, or 5;
R 4 is hydrogen or optionally substituted C 1-6 alkyl;
R 5 is halogen;
R 2 is hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3A is independently hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3B is independently hydrogen or optionally substituted C 1-6 alkyl; and
R 6 is hydrogen, halogen, or optionally substituted C 1-6 alkyl;
wherein each optional substituent is selected from the group consisting of halogen, C 1-6 alkyl, —CN, —NO 2 , —N 3 , —OH, —OR aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , and —NR bb C(═O)N(R bb ) 2 , or two geminal hydrogens on a carbon atom are replaced with the group ═O;
each instance of R aa is independently C 1-6 alkyl; and
each instance of R bb is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
2. The compound of claim 1 , wherein the compound is of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3 is independently halogen, —CN, —NO 2 , —N 3 , optionally substituted C 1-6 alkyl, —OR 3A , —N(R 3B ) 2 , or optionally substituted C 1-6 acyl;
n is 0, 1, 2, 3, 4, or 5;
R 4 is hydrogen or optionally substituted C 1-6 alkyl;
R 5 is halogen;
R 2 is hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3A is independently hydrogen or optionally substituted C 1-6 alkyl;
each instance of R 3B is independently hydrogen or optionally substituted C 1-6 alkyl;
wherein each optional substituent is selected from the group consisting of halogen, C 1-6 alkyl, —CN, —NO 2 , —N 3 , —OH, —R aa , —N(R bb ) 2 , —SH, —SR aa , —C(═O)R aa , —CO 2 H, —CHO, —CO 2 R aa , —OC(═O)R aa , —OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , and —NR bb C(═O)N(R bb ) 2 , or two geminal hydrogens on a carbon atom are replaced with the group ═O;
each instance of R aa is independently C 1-6 alkyl; and
each instance of R bb is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
3. The compound of claim 1 , wherein the compound is of Formula (I-a):
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound is of Formula (I-b):
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted C 1-6 alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 1-6 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1; and R 3 is —OR 3A .
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3A is optionally substituted C 1-6 alkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —Br.
11. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is unsubstituted C 1-6 alkyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is ethyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1; R 3 is —OR 3A ; and R 3A is unsubstituted C 1-6 alkyl.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1; and R 3 is —OMe.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is unsubstituted C 1-6 alkyl;
R 2 is unsubstituted C 1-6 alkyl;
n is 1;
R 3 is —OR 3A ;
R 3A is unsubstituted C 1-6 alkyl;
R 4 is hydrogen; and
R 6 is hydrogen.
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —Br.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is optionally substituted C 1-6 alkyl;
R 2 is optionally substituted C 1-6 alkyl;
R 4 is hydrogen; and
R 6 is hydrogen.
20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein n is 1; R 3 is —OR 3A ; and R 3A is optionally substituted C 1-6 alkyl.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —Br.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or unsubstituted C 1-6 alkyl;
R 2 is hydrogen or unsubstituted C 1-6 alkyl;
R 4 is hydrogen or unsubstituted C 1-6 alkyl; and
R 6 is hydrogen or unsubstituted C 1-6 alkyl.
23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein n is 1; R 3 is —OR 3A ; and R 3A is hydrogen or unsubstituted C 1-6 alkyl.
24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —Br.
25. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.