Compounds and methods for the treatment of cystic fibrosis

1. A compound of Formula IV or IVA, or a pharmaceutically acceptable salt thereof;

wherein

each independently represents a single bond or a double bond;

Cy 4 is selected from optionally substituted aryl, heteroaryl or carbocyclyl wherein the aryl, heteroaryl or carbocyclyl is optionally fused to an optionally substituted carbocyclyl, heterocyclyl or aryl;

n and p are independently 0, 1, 2, 3, 4, 5, or 6;

each R 1 and R 3 is independently selected from hydrogen, deuterium, halogen, —OR 12 , —SR 12 , —NR 10 R 13 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —S(O)R 12 , —S(O)NR 12 , —S(O) 2 R 12 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; alternatively, two R 1 groups, or two R 3 groups together with the atoms to which they are attached form an oxo (═O) or a vinyl group (═C); alternatively, two R 1 groups, or two R 3 groups or two R 4 groups together with the atoms to which they are attached form a 3, 4, 5, 6 or 7 membered, optionally substituted carbocyclic, heterocyclic or aryl group;

R 10 is hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteoaryl, or substituted heteroaryl; and

each R 12 and R 13 is independently selected from absent, hydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl; alternatively two R 12 groups, or two R 13 groups, or one R 12 group and one R 13 group, together with the atoms to which they are attached form a 3, 4, 5, 6 or 7 membered, optionally substituted carbocyclic, heterocyclic or aryl group; and

R 9 is selected from hydrogen, deuterium, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl.

2. The compound of claim 1 , selected from Table A, or a pharmaceutically acceptable salt thereof:

TABLE A

3. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier or excipient.

4. A method of treating a disease or disorder mediated by cystic fibrosis transmembrane conductance regulator (CFTR) in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the composition of claim 2 .

5. The compound of claim 1 represented by Formula V, or a pharmaceutically acceptable salt thereof;

6. The compound according to claim 1 , wherein Cy4 is selected from:

wherein r is selected from 0, 1, 2, and 3; and

R 8 is selected from hydrogen, deuterium, halogen, —OR 12 , —SR 12 , —NR 10 R 13 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —S(O)R 12 , —S(O)NR 12 , —S(O) 2 R 12 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; alternatively, two R 8 groups together with the atoms to which they are attached form a 3, 4, 5, 6 or 7 membered, optionally substituted carbocyclic, heterocyclic or aryl group.

7. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof;

wherein

R 14 and R 15 are each independently selected from the group consisting of hydrogen, deuterium, halogen, —OR 12 , —SR 12 , —NR 10 R 13 , —CF 3 , —CN, —NO 2 , —N 3 , —C(O)OR 12 , —C(O)R 12 , —C(O)NR 12 R 13 , —S(O)R 12 , —S(O)NR 12 , —S(O) 2 R 12 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; alternatively, R 14 and R 15 together with the atoms to which they are attached form a 3, 4, 5, 6 or 7 membered, optionally substituted carbocyclic, heterocyclic or aryl group; and;

X is N or CR 10 .

9. The compound according to claim 8 , wherein R 14 is —Cl, —Br, —F, —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 C(CH 3 ) 3 , —C(O)OCH 3 , —CH 3 , —CH 2 CH 3 , or —C(O)NH 2 .

10. The compound according to claim 8 , wherein R 15 is —Cl, —Br, —F, —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 C(CH 3 ) 3 , —C(O)OCH 3 , —CH 3 , —CH 2 CH 3 , or —C(O)NH 2 .

11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

12. The compound according to claim 1 , wherein Cy4 is:

13. The compound according to claim 1 , wherein Cy4 is:

14. The compound according to claim 8 , wherein R 14 is —Cl.

15. The compound according to claim 8 , wherein R 15 is —Cl.

16. The compound according to claim 8 , wherein R 14 and R 15 are —Cl.

17. A method of treating a disease or disorder mediated by cystic fibrosis transmembrane conductance regulator (CFTR) in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound of claim 1 .

18. A method of treating cystic fibrosis or a symptom thereof in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound of claim 1 .

19. A method of treating cystic fibrosis or a symptom thereof in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the compound of claim 2 .