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 compound of formula (I):
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 hydrogen, halogen, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 1 -C 8 )alkoxy,
wherein the alkyl, alkenyl, alkynyl, and alkoxy are each optionally substituted with one or more halogen;
n is 2, 3, or 4; and
each occurrence of R is independently (C 1 -C 6 )alkyl.
2. The compound of claim 1 , wherein X is NH, and Y is S(O) 2 .
3. The compound of claim 1 , wherein X is S(O) 2 , and Y is NH.
4. The compound of claim 1 , wherein R′ is hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy, wherein the alkyl and alkoxyl are each optionally substituted with one or more halogen.
5. The compound of claim 1 , wherein R′ is hydrogen, halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more halogen.
6. The compound of claim 1 , wherein R′ is hydrogen, F, Cl, Br, (C 1 -C 4 )alkyl, CF 3 , or OCF 3 .
7. The compound of claim 1 , wherein R′ is hydrogen, Cl, Br, or (C 1 -C 4 )alkyl.
8. The compound of claim 1 , wherein R′ is hydrogen, chloro, bromo, or methyl.
9. The compound of claim 1 , wherein R′ is hydrogen.
10. The compound of claim 1 , wherein R′ is methyl.
11. The compound of claim 1 , wherein R′ is chloro.
12. The compound of claim 1 , wherein R′ is bromo.
13. A compound of formula (II):
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:
R 1 is independently (C 1 -C 6 )alkyl;
R 2 is independently hydrogen or (C 1 -C 6 )alkyl optionally substituted with one or more halogen;
R 3 is independently (C 1 -C 6 )alkyl optionally substituted with one or more halogen;
X is NH, and Y is S(O) 2 ; or X is S(O) 2 , and Y is NH; and
R′ is hydrogen, halogen, cyano, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 1 -C 8 )alkoxy, wherein the alkyl, alkenyl, alkynyl, and alkoxy, are each optionally substituted with one or more halogen.
14. The compound of claim 13 , wherein R 1 , R 2 , and R 3 are independently (C 1 -C 6 )alkyl.
15. The compound of claim 13 , wherein R 1 is methyl, ethyl, or isopropyl.
16. The compound of claim 13 , wherein R 2 is (C 1 -C 4 )alkyl.
17. The compound of claim 13 , wherein R 2 is methyl, isopropyl, or tert-butyl.
18. The compound of claim 13 , wherein R 3 is (C 1 -C 4 )alkyl.
19. The compound of claim 13 , wherein R 3 is methyl, ethyl, or isopropyl.
20. The compound of claim 13 , having formula (II-A):
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.
21. The compound of claim 20 , having 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.
22. The compound of claim 21 , wherein X is S(O) 2 , Y is NH, R′ is hydrogen, and R 1 , R 2 , and R 3 are isopropyl.
23. The compound of claim 21 , having 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.
24. A compound of:
25. A pharmaceutical composition comprising a compound of claim 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, and at least one pharmaceutically acceptable excipient or carrier.
26. The pharmaceutical composition of claim 25 , further comprising one or more additional active agents.
27. The pharmaceutical composition of claim 25 , further comprising paclitaxel or docetaxel.
28. The pharmaceutical composition of claim 25 , wherein the composition is formulated for single dose administration.
29. The pharmaceutical composition of claim 25 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
30. The pharmaceutical composition of claim 28 , wherein the oral dosage form is a tablet or capsule.