Thienopyridyl compounds that inhibit vanilloid receptor subtype 1 (VR1) and uses thereof

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

- - - is absent or a covalent bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 3 is N;

X 4 is selected from CR 4 ;

X 5 is selected from N and CH 2 ;

provided that at least one of X 1 , X 2 , X 3 and X 4 is N;

X 6 is selected from O, NH and S;

Z 1 is selected from O, NH and S;

Z 2 is absent or selected from NH and O;

L is selected from aryl, alkenylene, alkylene, alkynylene, cycloalkylene, heterocycle, —(CH 2 ) m O(CH 2 ) n —, —N(H)O—, and —NHNH— wherein the left end of —(CH 2 ) m O(CH 2 ) n —and —N(H)O— is attached to Z 2 and the right end is attached to R 7 ;

provided that when Z 2 is NH or O then L is other than —N(H)O— or —NHNH—;

m and n are each independently 1-6;

R 1 , R 3 and R 5 are each independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, amines, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF 3 ) 2 (HO)C—, R B S(O) 2 R A N—, R A OS(O) 2 —, R B —S(O) 2 —, Z A Z B N—, (Z A Z B N)alkyl, (Z A Z B N)carbonyl, (Z A Z B N)alkylcarbonyl and (Z A Z B N)sulfonyl, wherein Z A and Z B are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl, and alkylalkyl;

R 2 and R 4 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, amines, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF 3 ) 2 (HO)C—, R B S(O) 2 R A N—, R A OS(O) 2 —, R B —S(O) 2 —, Z A Z B N—, (Z A Z B N)alkyl, (Z A Z B N)carbonyl, (Z A Z B N)alkylcarbonyl, (Z A Z B N)sulfonyl, (Z A Z B N)C(═NH)—, (Z A Z B N)C(═NCN)NH—, and (Z A Z B N)C(═NH)NH—;

R A is selected from hydrogen and alkyl;

R B is selected from alkyl, aryl and arylalkyl;

R 6 is absent or selected from hydrogen and alkyl;

provided that R 6 is absent when X 5 is CH 2 and R 4 is selected from hydrogen and alkyl when X 5 is N;

R 7 is selected from hydrogen, aryl and heterocycle; and

provided that R7 is aryl when L is alkylene.

2. The compound of formula (I) according to claim 1 wherein,

- - - is a covalent bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 3 is N;

X 4 is C R 4 ;

R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , X 5 , X 6 , Z 1 , Z 2 and L are as defined in claim 1 .

3. The compound according to claim 2 wherein,

X 5 is N;

X 6 is S;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined in formula (I).

4. The compound of claim 3 wherein,

R 5 is a halogen; and

R 1 , R 2 , R 4 , R 6 , and R 7 are as defined in formula (I).

5. The compound of claim 3 wherein,

R 5 is alkyl.

6. The compound of claim 5 wherein,

R 5 is methyl,

R 7 is aryl.

7. The compound of claim 6 wherein,

R 1 , R 2 , R 4 and R 6 are each hydrogen; and

R 7 is aryl wherein said aryl is phenyl substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, alkylsulfonyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, and Z A Z B N—.

8. The compound of claim 7 selected from the group consisting of:

1-Benzyl-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(4-Chloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2,4-Dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3,4-Dichloro-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Methyl-thieno[2,3-c]pyridin-3yl)-3-[1-methyl-1-(4-trifluoromethyl-phenyl)-ethyl]-urea,

1-(2,3-Difluoro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2,4-Bis-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Chloro-4-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(4-Bromo-3-methyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(4-Trifluoromethoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Trifluoromethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Trifluoromethoxybenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Mehtyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Mehtyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(4-Mehtyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Fluoro-5-trifluoromethyl-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(4-Methoxy-benzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Fluorobenzyl)-3-(2-methyl-thieno[2,3-e]pyridin-3-yl)-urea,

1-(4-Fluorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Chlorobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2-Bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(3-Bromobenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2,3-Dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea,

1-(2,5-Dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea, and

1-(3,4-Dimethylbenzyl)-3-(2-methyl-thieno[2,3-c]pyridin-3-yl)-urea.

9. The compound of claim 6 , wherein

R 7 is aryl wherein said aryl is naphthyl substituted with 0, 1, 2, or 3 substituents independently selected from alkoxy, alkyl, alkylsulfonyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy.

10. The compound of claim 9 that is

1-(2-Methyl-thieno[2,3-c]pyridin-3y1)-3-naphthalen-1ylmethylurea.

11. The compound of claim 2 wherein,

X 5 is N;

X 6 is S;

Z 1 is O;

Z 2 is NH;

L is aryl;

R 7 is heterocycle.

12. The compound of claim 11 wherein L is indanyl.

13. The compound of claim 12 that is 1-(2-Methyl-thieno[2,3-c]pyridin-3-yl)-3(5-piperidin-1-yl-indan-1-yl)-urea.

14. The compound of claim 2 wherein,

X 5 is N;

X 6 is S;

Z 1 is O;

Z 2 is NH;

L is heterocycle.

15. The compound of claim 2 , wherein

X 5 is N;

X 6 is S;

Z 1 is O;

Z 2 is O;

L is alkylene;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are as defined in formula (I).

16. The compound of claim 15 , wherein

R 7 is aryl.

17. The compound of claim 16 wherein

R 7 is aryl wherein said aryl is phenyl substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, alkylsulfonyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, and Z A Z B N—.

18. The compound of claim 17 selected from the group consisting of

(2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid 4-trifluoromethyl-benzyl ester,

(2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid 4-trifluoromethoxy-benzyl ester,

(2-Methyl-thieno[2,3-c]pyridin-3-yl)-carbamic acid 4-trifluoromethylsulfanyl-benzyl ester.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.