Compounds for treatment of cystic fibrosis

1. A compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, deuteride, N-oxide, stereoisomer, or isomer thereof:

Y 1 -L 1 -B 1 -A 1 -X-A 2 -B 2 -L 2 -Y 2    Formula (I);

wherein:

A 1 and A 2 are independently selected from:

B 1 and B 2 are independently selected from:

L 1 and L 2 are independently selected from:

Y 1 and Y 2 are independently selected from:

X is —C(O)—, —C(O)C(O)—

Z is O or CR 2 R 2 ;

aa is

each R 1 is independently selected from H, alkyl, haloalkyl, arylalkyl, and heteroarylalkyl;

each R 2 is independently selected from H, halo, —CN, —SR 1 , alkyl, cycloalkyl, haloalkyl, —OR 1 , —CO 2 R 1 , and -(alkylene)CO 2 R 1 );

each R 3 is independently selected from halo, alkyl, —CN, haloalkyl, —OR 1 , and —NR 1 R 1 ;

each R 4 is independently selected from —CO 2 R 1 , -(alkylene)-(CO 2 R 1 ), hydroxyalkyl, -(alkylene)(S(O) t )(alkyl), -(alkylene)(NR 5 R 5 ), and

each R 5 is independently selected from H, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, aryl, and heteroaryl;

each R 21 , R 22 , R 23 , and R 24 are independently selected from H, halo, —CN, —SR 1 , alkyl, cycloalkyl, haloalkyl, —NR 1 R 1 , and —OR 1 ;

R 31 , R 32 , and R 33 are independently selected from halo, alkyl, —CN, haloalkyl, —OR 1 , and —NR 1 R 1 ;

each k is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

each m is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

each p is independently selected from 0, 1, 2, 3, and 4;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

r is 3, 4, 5, 6, or 7;

each s is independently selected from 0, 1, 2, 3, and 4;

each t is independently selected from 0, 1, and 2; and

each u is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

2. The compound of claim 1 wherein Y 1 and Y 2 are both

3. The compound of claim 2 wherein B 1 and B 2 are both

4. The compound of claim 3 wherein n is 1, 2, 3, 4, or 5.

5. The compound of claim 4 wherein n is 3 or 4.

6. The compound of claim 5 wherein p is 0.

7. The compound of claim 6 wherein A 1 and A 2 are both

8. The compound of claim 7 wherein Z is O.

9. The compound of claim 8 wherein k is 1.

10. The compound of claim 9 wherein each m is independently 0, 1, 2, or 3.

11. The compound of claim 10 wherein L 1 and L 2 are both

12. The compound of claim 11 wherein L 1 and L 2 are both

13. The compound of claim 12 wherein X is

14. The compound of claim 13 wherein X is

15. The compound of claim 14 wherein q is 3.

16. The compound of claim 1 wherein the compound is selected from:

17. The compound of claim 1 wherein the compound is selected from:

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, deuteride, N-oxide, stereoisomer, or isomer thereof, and a pharmaceutically acceptable excipient.

19. A method to treat cystic fibrosis in a subject in need thereof, the method comprising administering a composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, deuteride, N-oxide, stereoisomer, or isomer thereof.

20. A method to treat chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering a composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, deuteride, N-oxide, stereoisomer, or isomer thereof.