Substituted biaryl sulfonamides and the use thereof
Provided herein are substituted biaryl sulfonamide compounds, pharmaceutical compositions comprising the compounds, methods of their preparation, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or amelioration of various disorders, including cancer and proliferative disorders. In one embodiment, the compounds provided herein modulate initiation of protein translation. In one embodiment, the compounds provided herein are used in combination with surgery, radiation therapy, immuno therapy and/or one or more additional anticancer drugs for the treatment, prevention, and/or amelioration of cancer and proliferative disorders.
1. A method of treating or ameliorating a cardiovascular disease in a subject, comprising administering to the subject a compound of formula (II-A-1):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
X is NH, and Y is S(O) 2 ; or X is S(O) 2 , and Y is NH;
R′ is (i) hydrogen, halogen, or cyano; or (ii) (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 2 -C 8 )alkenyloxy, (C 2 -C 8 )alkynyloxy, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyloxy, each of which is optionally substituted with one or more halogen;
R 1 is independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen;
R 2 is independently hydrogen; or (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen; and
R 3 is independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen;
wherein the cardiovascular disease is acute heart failure or congestive heart failure.
2. The method of claim 1 , wherein X is NH, and Y is S(O) 2 .
3. The method of claim 1 , wherein X is S(O) 2 , and Y is NH.
4. The method of claim 1 , wherein the compound has formula (III-A-1):
or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
5. The method of claim 1 , wherein R′ is hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy, wherein the alkyl and alkoxy are each optionally substituted with one or more halogen.
6. The method of claim 5 , wherein R′ is hydrogen, halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more halogen.
7. The method of claim 1 , wherein R′ is hydrogen, F, Cl, Br, (C 1 -C 4 )alkyl, CF 3 , or OCF 3 .
8. The method of claim 1 , wherein R′ is hydrogen, Cl, Br, or (C 1 -C 4 )alkyl.
9. The method of claim 1 , wherein R′ is hydrogen, chloro, bromo, or methyl.
10. The method of claim 1 , wherein R′ is hydrogen.
11. The method of claim 1 , wherein R′ is methyl.
12. The method of claim 1 , wherein R′ is chloro.
13. The method of claim 1 , wherein R′ is bromo.
14. The method of claim 1 , wherein R 1 , R 2 , and R 3 are independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl.
15. The method of claim 1 , wherein R 1 is (C 1 -C 4 )alkyl.
16. The method of claim 1 , wherein R 1 is methyl, ethyl, or isopropyl.
17. The method of claim 1 , wherein R 2 is hydrogen, or (C 1 -C 4 )alkyl.
18. The method of claim 1 , wherein R 2 is methyl, isopropyl, or tert-butyl.
19. The method of claim 1 , wherein R 3 is (C 1 -C 4 )alkyl.
20. The method of claim 1 , wherein R 3 is methyl, ethyl, or isopropyl.
21. The method of claim 4 , wherein the compound is:
22. The method of claim 1 , wherein X is S(O) 2 , Y is NH, R′ is hydrogen, and R 1 , R 2 , and R 3 are isopropyl.
23. The method of claim 1 , wherein the cardiovascular disease is acute heart failure.