Oxadiazole transient receptor potential channel inhibitors

1. A method for treating a disease or condition in a mammal in need thereof, the disease or condition selected from pain, migraine, asthma, chronic obstructive pulmonary disease, cough, and itch, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

A is: substituted or unsubstituted 6-6 fused bicyclic heteroaryl, which may be partially saturated; substituted or unsubstituted 5-6 fused bicyclic heteroaryl, which may be partially saturated; or substituted and unsubstituted 6-5 fused bicyclic heteroaryl, which may be partially saturated;

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

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.

2. The method of claim 1 , wherein A is:

wherein:

E is a 5-membered or a 6-membered heteroaryl ring wherein one ring carbon atom is optionally substituted with oxo;

G is a 6-membered heteroaryl ring, wherein one ring carbon atom is substituted with oxo;

wherein 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, wherein 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;

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

p is 0, 1 or 2;

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

q is 0 or 1;

R 14 and R′ 5 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 —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′ 7 are each independently H or —C 1-4 alkyl.

3. The method of claim 1 , wherein A is selected from:

wherein:

each R 2 is independently: H; D; —C 1-4 alkyl; —C 1-4 haloalkyl; —C 1-4 alkoxy; halo; —C 1-4 haloalkoxy; —OH; —SO 2 —C 1-4 alkyl; —C 1-4 alkyl-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;

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 —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.

4. The method of claim 3 , wherein A is:

5. The method of claim 3 , wherein A is:

6. The method of claim 3 , 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.

7. The method of claim 1 , wherein A is:

8. The method of claim 1 , wherein A is:

9. The method of claim 1 , wherein A is:

10. The method of claim 1 , wherein A is:

11. The method of claim 1 , wherein X is methylene.

12. The method of claim 1 , wherein R 4 is:

wherein:

each R 18 is independently selected from H, —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 alkyl-CN, C 1-4 aldehyde, —SF 5 , C 1-4 ketone, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted phenyl, and unsubstituted or substituted 5- to 6-membered heteroaryl; and

k is 0, 1, 2, or 3.

13. The method of claim 12 , wherein each R 18 is independently: H; F; Cl; —OCHF 2 ; —OCF 3 ; —OCH 3 ; or —CN.

14. The method of claim 12 , wherein each R 18 is independently fluoro or chloro.

15. The method of claim 1 , wherein R 4 is:

wherein:

each R 10 is independently: H; halo; —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; —SF 5 ; —SO 2 —C 1-4 alkyl; C 1-4 alkyl-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 heterocycloalkyl; or substituted or unsubstituted C 5-6 aryl; and

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

16. The method of claim 1 , wherein R 4 is:

17. The method of claim 1 , wherein the compound of formula (I) is a compound of formula (II):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

18. The method of claim 2 , wherein the compound of formula (I) is a compound of formula (IIIa) or formula (IIIb):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

19. The method of claim 2 , wherein the compound of formula (I) is a compound of formula (IVa) or formula (IVb):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

20. The method of claim 3 , wherein the compound of formula (I) is a compound of formula (Va):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

21. The method of claim 20 , wherein the compound of formula (I) is a compound of formula (VIc) or formula (VId):

or a pharmaceutically acceptable salt or tautomer thereof.

22. The method of claim 20 , wherein the compound of formula (I) is a compound of formula (VIIc) or formula (VIId):

or a pharmaceutically acceptable salt or tautomer thereof.

23. The method of claim 1 , wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt or tautomer thereof.

24. The method of claim 1 , wherein the disease or condition is asthma.

25. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

26. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

27. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

28. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

29. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

30. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

31. A method for treating asthma in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

32. The method of claim 1 , wherein the disease or condition is cough.

33. The method of claim 32 , wherein the cough is chronic cough.

34. The method of claim 1 , wherein the disease or condition is chronic obstructive pulmonary disease.

35. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

36. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

37. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

38. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

39. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

40. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

41. A method for treating cough in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

42. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

43. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

44. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

45. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

46. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

47. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.

48. A method for treating chronic obstructive pulmonary disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt or tautomer thereof.