Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor

1. A compound of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X 1 is CR 1 ;

X 2 is CR 2 ;

X 3 is N;

X 4 is N;

X 5 is N ;

Z 1 is O;

Z 2 is NH;

L is selected from the group consisting of alkenylenyl, alkylenyl, alkynylenyl, cycloalkylenyl,

—(CH 2 ) m O(CH 2 ) n —, and N(R Y ), wherein the left end of —(CH 2 ) m O(CH 2 ) n — is attached to Z 2 and the right end is attached to R 9 ;

m and n are each independently 1-6;

R Y is selected from the group consisting of hydrogen and alkyl;

R 1 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, —NR A S(O) 2 R B , —S(O) 2 R B , —NZ A Z B , (NZ A Z B )alkyl, (NZ A Z B )carbonylalkyl and (NZ A Z B )sulfonyl, wherein Z A and Z B are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, and arylalkyl;

R 2 is selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, allyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, —NR A S(O) 2 R B , —S(O) 2 OR A , —S(O) 2 R B , —NZ A Z B , (NZ A Z B )alkyl, (NZ A Z B )alkylcarbonyl, (NZ A Z B )carbonyl, (NZ A Z B )carbonylalkyl, and (NZ A Z B )sulfonyl;

R A is selected from the group consisting of hydrogen and alkyl;

R B is selected from the group consisting of alkyl, aryl, and arylalkyl;

R 8a , is selected from the group consisting of hydrogen and alkyl;

R 8b is absent; and

R 9 is selected from the group consisting of hydrogen, aryl, cycloalkyl, and heterocyclyl.

2. The compound or salt according to claim 1 , wherein

L is alkylenyl; and

R 9 is aryl.

3. The compound or salt according to claim 1 , wherein

R 1 , R 5 , R 6 and R 7 , are each hydrogen;

R 2 is selected from the group consisting of alkyl and halogen;

L is alkylenyl;

R 9 is aryl wherein said aryl is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ C Z D ; and

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

4. The compound or salt according to claim 3 , wherein the compound is N-(3,4-dichlorobenzyl)-N′-(3-methylcinnolin-5-yl)urea.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

6. A method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) receptor, wherein the disorder is selected from the group consisting of pain, urinary incontinence, bladder overactivity and inflammatory thermal hyperalgesia, in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6 , wherein the disorder is pain.

8. The method according to claim 6 , wherein the disorder is bladder overactivity.

9. The method according to claim 6 , wherein the disorder is urinary incontinence.

10. The method according to claim 6 , wherein the disorder is inflammatory thermal hyperalgesia.