CFTR regulators and methods of use thereof
Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders, and other diseases and disorders.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X is —O—;
R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines, substituted heteroalkyl, or unsubstituted heteroalkyl;
R 3 is hydrogen;
R 4 is substituted or unsubstituted alkyl;
R 5 is hydrogen; and
R 1 , R 6 , R 7 , R 8 and R 9 are each hydrogen.
2. The compound of claim 1 , wherein R 4 is —CH 3 or —CH 2 CH 3 .
3. The compound of claim 1 , wherein R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines.
4. The compound of claim 3 , wherein R 2 is —CH(CF 3 ) 2 or —CH 2 —CF 2 —CHF 2 .
5. The compound of claim 1 , wherein the compound of Formula I is:
6. A compound that is:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein the compound is:
8. The compound of claim 6 , wherein the compound is a pharmaceutically acceptable salt of:
9. A pharmaceutical composition, comprising a pharmaceutically acceptable excipient, and a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X is —O—;
R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines, substituted heteroalkyl; or unsubstituted heteroalkyl;
R 3 is hydrogen;
R 4 is substituted or unsubstituted alkyl;
R 5 is hydrogen; and
R 1 , R 6 , R 7 , R 8 and R 9 are hydrogen.
10. The pharmaceutical composition of claim 9 , wherein R 4 is —CH 3 or —CH 2 CH 3 .
11. The pharmaceutical composition of claim 9 , wherein R 2 is C 2 -C 4 haloalkyl substituted with at least four fluorines.
12. The pharmaceutical composition of claim 11 , wherein R 2 is —CH(CF 3 ) 2 or —CH 2 —CF 2 —CHF 2 .
13. The pharmaceutical composition of claim 9 , wherein the compound of Formula I is:
14. A pharmaceutical composition comprising a compound that is:
or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition of claim 14 , wherein the compound is:
16. The pharmaceutical composition of claim 14 , wherein the compound is a pharmaceutically acceptable salt of: