Oxadiazole transient receptor potential channel inhibitors

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof,

wherein:

A is selected from:

X is; a bond; C 1-4 alkylene; —O—; —S—; —SO 2 —; or —N(R a )—;

n is: 0, 1, 2 or 3;

R a is H or C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

R 1 is: H; or C 1-6 alkyl; and

each R 2 is independently: H; D; —C 1-4 alkyl; —C 1-4 haloalkyl; C 1-4 alkoxy; —CN, halo; halo-C 1-4 alkoxy; —OH; —SO 2 —C 1-4 alkyl; —C 1-4 CN, C 1-4 aldehyde; C 1-4 ketone; benzylamino; or NR 14 R 15 —;

each R 3 is independently: H; D: —C 1-4 alkyl; —C 1-4 haloalkyl; —CN; NR 14 R 15 ; or halo;

R 4 is: substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl;

or R 1 and R 4 may together form an unsubstituted or substituted C 3-6 cylcoalkyl fused to a substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl,

p is 0, 1 or 2;

q is 0 or 1;

R 14 and R 15 are each independently: H; substituted or unsubstituted —C 1-4 alkyl; substituted or unsubstituted —C(O)—C 1-4 alkyl; substituted or unsubstituted C 3-6 cycloalkyl; substituted or unsubstituted 3- to 6-membered heterocycloalkyl; substituted or unsubstituted —C 1-4 heteroalkyl; —C(O)NR 16 R 17 ; substituted or unsubstituted alkyl-C(O)NR 16 R 17 ; substituted or unsubstituted phenyl; or substituted or unsubstituted benzyl;

or R 14 and R 15 together with the atoms to which they are attached may form a 4-, 5-, 6- or 7-membered ring that optionally includes one additional heteroatom selected from O, N and S; and

R 16 and R 17 each are independently H and C 1-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently; H; —CH 3 ; CN; -halo; —NH 2 ; —NHCH 3 ; NHCH 2 CH 3 ; —NHCH 2 CH 2 CH 2 OH; —NHCH 2 CH 2 OCH 3 ; —NHC(O)CH 3 ; —NHCH 2 C(O)N(CH 3 ) 2 ;

and p is 0 or 1.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is:

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is methylene.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein:

each R 18 is independently selected from H, halogen, —OH, —C 1-4 alkyl, —C 1-4 haloalkyl, —CN, halo, C 1-4 haloalkoxy, C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C 1-4 CN, C 1-4 aldehyde, —SF 5 , C 1-4 ketone, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, fused aryl, and fused heteroaryl; and

k is from 0 to 3.

11. The compound claim 10 or a pharmaceutically acceptable salt thereof, wherein each R 18 is independently: H; Cl; —OCHF 2 ; —OCF, —OCH 3 ; or —CN.

12. The compound claim 10 , or a pharmaceutically acceptable salt thereof, wherein each R 18 is independently fluoro or chloro.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

wherein:

each R 10 is independently: H; halogen; —CN; —OH; C 1-4 alkyl; substituted or unsubstituted C 3-6 cycloalkyl; C 1-4 haloalkyl; C 1-4 haloalkoxy; C 1-4 alkoxy; —SO 2 —C 1-4 alkyl; C 1-4 CN; C 1-4 aldehyde; C 1-4 ketone; —S—C 1-4 haloalkyl; substituted or unsubstituted 5- to 6-membered heteroaryl; substituted or unsubstituted 4- to 6-membered hetercycloalkyl; or substituted or unsubstituted C 5-6 aryl; and

each u is independently 0, 1, 2 or 3.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is:

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II)

16. A compound of formula (IVa) or formula (IVb), or a pharmaceutically acceptable salt thereof,

wherein:

E is a five membered or a six membered heteroaryl ring wherein one ring carbon atom is optionally substituted with oxo;

G is a six membered heteroaryl ring having one ring carbon atom substituted with oxo;

one to three of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are nitrogen, and the other of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are carbon, and one of Y 1 , Y 2 , Y 3 and Y 4 may be —C(O)— or —C(S)—;

one or two of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are nitrogen and the other of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are carbon;

R 1 is: H; or C 1-6 alkyl;

each R 2 is independently; H; D; —C 1-4 alkyl; —C 1-4 haloalkyl; —CN; halo; haloC 1-4 alkoxy; C 1-4 alkoxy; —OH; —SO 2 —C 1-4 alkyl; C 1-4 aldehyde; C 1-4 ketone; benzylamino; or NR 14 R 15 ;

each R 3 is independently: H; D; alkyl; —C 1-4 haloalkyl; —CN; halo; or NR 14 R 15 ;

R 4 is: substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl;

or R 1 and R 4 may together form an unsubstituted or substituted C 3-6 cycloalkyl fused to a substituted or unsubstituted phenyl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted naphthyl,

p is 0, 1 or 2;

q is 0 or 1;

R 14 and R 15 are each independently: H; substituted or unsubstituted —C 1-4 alkyl; substituted or unsubstituted —C(O)—C 1-4 alkyl; substituted or unsubstituted C 3-6 cycloalkyl; substituted or unsubstituted 3- to 6-membered heterocycloalkyl; substituted or unsubstituted —C 1-4 heteroalkyl; —C(O)N 16 R 17 ; substituted or unsubstituted —C 1-4 alkyl-C(O)NR 16 R 17 ; substituted or unsubstituted phenyl; or substituted or unsubstituted benzyl;

or R 14 and R 15 together with the atoms to which they are attached may form a 4-, 5-, 6- or 7-membered ring that optionally includes one additional heteroatom selected from O, N and S; and

R 16 and R 17 each are independently H and C 1-4 alkyl.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Va)

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (VIc) or formula (VId)

19. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (VIIc) or formula (VIId)

wherein:

each R 18 is independently selected from H, halogen, —OH, —C 1-4 alkyl, —C 1-4 haloalkyl, —CN, halo, C 1-4 haloalkoxy, C 1-4 alkoxy, —SO 2 —C 1-4 alkyl, —C 1-4 CN, C 1-4 aldehyde, —SF 5 , C 1-4 ketone, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, fused aryl, and fused heteroaryl; and

k is from 0 to 3.

20. A compound selected from:

or a pharmaceutical salt thereof.

21. A pharmaceutical composition, comprising a compound as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

22. The compound of claim 1 , or a pharmaceutical salt thereof, wherein A is:

23. The compound of claim 3 , or a pharmaceutical salt thereof, wherein A is:

24. The compound of claim 3 , or a pharmaceutical salt thereof, wherein A is:

25. The compound of claim 3 , or a pharmaceutical salt thereof, wherein A is:

26. The compound of claim 3 , or a pharmaceutical salt thereof, wherein A is:

27. The compound of claim 3 , or a pharmaceutical salt thereof, wherein A is:

28. The compound of claim 22 , or a pharmaceutical salt thereof, wherein A is:

29. The compound of claim 20 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 20 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 20 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

32. The compound

or a pharmaceutically acceptable salt thereof.

33. The compound

or a pharmaceutically acceptable salt thereof.

34. The compound

or a pharmaceutically acceptable salt thereof.

35. The compound

or a pharmaceutically acceptable salt thereof.

36. The compound

or a pharmaceutically acceptable salt thereof.

37. The compound

or a pharmaceutically acceptable salt thereof.

38. The compound

or a pharmaceutically acceptable salt thereof.