Compounds having TRPV1 antagonistic activity and uses thereof

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X is O, S, N—CN, or N—OR 7 ;

W is N;

the dashed line denotes the absence of a bond, and

R 4 is absent;

R 1 is —H, -halo, —NO 2 , —CN, —OR 7 , —N(R 7 ) 2 , (C 1 -C 4 )alkyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);

each R 2 is independently -halo, —OR 7 , —CN, —NO 2 , —N(R 7 ) 2 , —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, or -phenyl,

each R 3 is independently:

(a) —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OR 13 , —C(O)R 13 , —C(O)OR 13 , —N(R 13 )C(O)R 13 , or —C(O)N(R 13 ) 2 ;

R 5 is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkyl-OC(O)R 7 , —C(O)R 7 , or —C(O)N(R 8 ) 2 ;

Z 1 and Z 2 are each independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, —OR 12 , —N(R 12 ) 2 , -halo, —(C 3 -C 8 )cycloalkyl, —C(O)OR 13 , —C(O)R 13 , or —CH═N—OR 13 , or Z 1 and Z 2 groups together form ═O or ═N—OR 13 ;

Z 3 and Z 4 are each independently —OR 12 or —N(R 12 ) 2 ;

Z 5 is —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, or -phenyl;

Ar 2 is

each R 9 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 1 -C 6 )hydroxyalkyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkynyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkynyl, —CN, -halo, —N 3 , —NO 2 , —CH═NR 13 , —N(R 13 ) 2 , —NR 13 OR 13 , —OR 13 , —SR 13 , —O(CH 2 ) b OR 13 , —O(CH 2 ) b SR 13 , —O(CH 2 ) b N(R 13 ) 2 , —N(R 13 )(CH 2 ) b OR 13 ,—N(R 13 )(CH 2 ) b SR 13 , —N(R 13 )(CH 2 ) b N(R 13 ) 2 , —N(R 13 )C(O)R 13 , —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —S(O)R 13 , —S(O) 2 R 13 , —S(O) 2 N(R 13 ) 2 , —S(O) 2 -(3- to 7-membered)heterocycle, —C(O)N(R 13 ) 2 , —(C 1 -C 6 )alkyl-C═N—OR 13 , —(C 1 -C 6 )alkyl-C(O)N(R 13 ) 2 , —(C 1 -C 6 )alkyl-NHS(O) 2 N(R 13 ) 2 , or —(C 1 -C 6 )alkyl-C(═NH)—N(R 13 ) 2 , each of which -phenyl, -(3- to 7-membered)heterocycle, or —(C 3 -C 8 )cycloalkyl is unsubstituted or substituted with 1, 2 or 3 independently selected R 13 groups;

each R 10 is independently:

(a) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, or -phenyl, each of which is unsubstituted or substituted with 1 or 2-OH groups;

(b) —CH 2 CH 2 (halo), —CH 2 CH(halo) 2 , —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, -halo, —N 3 , —NO 2 , —CH═NR 13 , —N(R 13 ) 2 , —NR 13 OR 13 , —OR 13 , —C(O)R 13 ,—C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —SR 13 , —S(O)R 13 , or —S(O) 2 R 13 ; or

(c) two R 10 groups on adjacent carbon atoms together form a (C 1 -C 2 )alkylenedioxy bridge, which is unsubstituted or substituted 1, 2 or 3 independently selected R 13 groups;

Y 1 , Y 2 , Y 3 are each independently C, N, or O;

wherein no more than one of Y 1 , Y 2 , or Y 3 can be O, no more than two of Y 1 , Y 2 , or Y 3 can be N and for each Y 1 , Y 2 , and Y 3 that is N, the N is bonded to one R 14 group, and for each Y 1 , Y 2 , and Y 3 that is C, the C is bonded to two R 5 groups, provided that there are no more than a total of two (C 1 -C 6 )alkyl groups substituted on all of Y 1 , Y 2 , and Y 3 ;

Y a and Y b are each independently —H, -halo, or —(C 1 -C 6 )alkyl, or Y a and Y b , together with the carbon to which they are attached, form a 3-8 member carbocyclic ring;

E is ═O, ═S, ═C(R 7 ) 2 , ═CH(C 2 -C 6 )alkenyl, —N(R 7 ) 2 , or ═N—OR 5 ;

each R 7 is independently —H or —(C 1 -C 6 )alkyl;

each R 8 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, or phenyl;

each R 12 is independently —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —C(O)R 15 , —C(O)OR 13 , or —C(O)N(R 13 ) 2 ;

each R 13 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cyclo alkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, —(C 1 -C 6 )halo alkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 8 ) 2 , or —C(O)N(R 8 ) 2 ;

each R 14 is independently —H, —(C 1 -C 6 )alkyl, —C(O)R 13 , —S(O)R 13 , —S(O) 2 R 13 ,

R 15 is H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )halo alkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 8 ) 2 , —(C 3 -C 8 )cyclo alkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, or -(3- to 7-membered)heterocycle;

each halo is independently —F, —Cl, —Br, or —I;

n is the integer 0, 1, or 2;

m is the integer 0, 1, or 2;

k is the integer 1 or 2;

q is the integer 0, 1, 2, 3, or 4;

s is the integer 0, 1, 2, 3, 4, or 5;

t is the integer 0, 1, 2, or 3;

u is the integer 0, 1, 2 or 3;

each b is independently 1 or 2; and

c is the integer 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

and Z 1a and Z 2a are each independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, -halo or —(C 3 -C 8 )cycloalkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

and Z 1a and Z 2a are each independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -phenyl, -halo or —(C 3 -C 8 )cycloalkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 is —H, —OR 12 , or -halo, Z 2 , Z 1a and Z 2a are each independently —H or -halo, Z 3 and Z 4 are each independently —OR 12 , and Z 5 is —H or —(C 1 -C 4 )alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 is —H, —OH, or -halo, Z 2 , Z 1a and Z 2a are each independently —H or -halo, Z 3 and Z 4 are —OH, and Z 5 is —H or —CH 3 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 , -halo or —C(halo) 3 .

12. The compound according to claim 1 for a pharmaceutically acceptable salt thereof, wherein X is O.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein s, q or u is 1 or 2.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from -halo, —C(halo) 3 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy, —OC(halo) 3 , and —S(O) 2 C (halo) 3 .

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from —CH 3 , -halo, —C(halo) 3 , —OCH 3 , and —OC(halo) 3 .

20. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein u is the integer 0, 1 or 2 and each R 10 is independently selected from -halo, —(C 1 -C 6 )alkyl, —C(halo) 3 , —SC(halo) 3 and —S(O) 2 C(halo) 3 , or two R 10 groups on adjacent carbon atoms together form a —O—C(halo) 2 -O-bridge.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is

R 9a is —C(halo) 3 or —OC(halo) 3 , R 9b is —H, -halo, —CH 3 , or —OCH 3 and R 10a and R 10b are independently selected from —H, -halo, and —CH 3 .

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n=0.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m=0, 1 or 2 and R 3 is —(C 1 -C 6 )alkyl.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein k is 1.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein s or q is 1 or 2.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein u is 1.

30. A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is -halo, (C 1 -C 4 )alkyl, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 3 is independently —(C 1 -C 6 )alkyl, —CH 2 OR 13 , —C(O)OR 13 , or —C(O)N(R 13 ) 2 ;

Z 1 is —H, —OH, or -halo;

Z 2 is —H or -halo;

or Z 1 and Z 2 groups together form ═O or ═N—OR 13 ;

Z 5 is —H, —CH 3 , or —CH 2 CH 3 ;

Ar 2 is

each R 8 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, or phenyl;

R 9a is —(C 1 -C 6 )haloalkyl, or —(C 1 -C 6 )haloalkoxy;

R 9b is —H, -halo, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkoxy;

R 10a and R 10b are independently selected from —H, -halo, —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkoxy;

each R 13 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 8 ) 2 , or —C(O)N(R 8 ) 2 ;

each halo is independently —F, —Cl, —Br, or —I; and

m is the integer 0, 1, or 2.

31. A compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is -halo, (C 1 -C 4 )alkyl, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 3 is independently —(C 1 -C 6 )alkyl, —CH 2 OR 13 , —C(O)OR 13 , or —C(O)N(R 13 ) 2 ;

Z 1 is —H, —OH, or -halo;

Z 2 , Z 1a and Z 2a are each independently —H or -halo;

or Z 1 and Z 2 groups together form ═O or ═N—OR 13 ;

Z 5 is —H, —CH 3 , or —CH 2 CH 3 ;

Ar 2 is

each R 8 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, or phenyl;

R 9a is —(C 1 -C 6 )haloalkyl, or —(C 1 -C 6 )haloalkoxy;

R 9b is —H, -halo, —(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkoxy;

R 10a and R 10b are independently selected from —H, -halo, —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )alkoxy;

each R 13 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cyclo alkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, —(C 1 -C 6 )halo alkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 8 ) 2 , or —C(O)N(R 8 ) 2 ;

each halo is independently —F, —Cl, —Br, or —I; and

m is the integer 0, 1, or 2.

32. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.