Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor

1. A compound of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

- - - is absent or a single bond;

X 1 is N or CR 1 ;

X 2 is N or CR 2 ;

X 3 is N, NR 3 , or CR 3 ;

X 4 is a bond, N, or CR 4 ;

X 5 is N;

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

Z 1 is O;

Z 2 is NH;

Ar 1 is dihydro-1H-indenyl, 1H-indenyl, tetrahydronaphthalenyl, or dihydronaphthalenyl, wherein the Ar 1 group is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, heterocycle, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF 3 ) 2 (HO)C—, —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 )carbonyl, (NZ A Z B )carbonylalkyl or (NZ A Z B )sulfonyl, wherein Z A and Z B are each independently hydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl;

R 1 , R 3 , R 5 , R 6 , and R 7 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF 3 ) 2 (HO)C—, —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 )carbonyl, (NZ A Z B )carbonylalkyl or (NZ A Z B )sulfonyl;

R 2 and R 4 are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF 3 ) 2 (HO)C—, —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, (NZ A Z B )sulfonyl, (NZ A Z B )C(═NH)—, (NZ A Z B )C(═NCN)NH—, or (NZ A Z B )C(═NH)NH—;

R A is hydrogen or alkyl;

R B is alkyl, aryl, or arylalkyl;

R 8a is hydrogen or alkyl; and

R 8b is absent.

2. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 is N; and

Ar 1 is dihydro-1H-indenyl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen.

3. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 and X 5 are is N;

Ar 1 is 2,3-dihydro-1H-inden-1-yl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen;

R 1 , R 4 , R 5 , R 6 , R 7 , and R 8a are hydrogen; and

R 2 is hydrogen or alkyl.

4. The compound according to claim 3 that is

N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;

N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;

(+) N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;

(−) N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;

(−) N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;

(+) N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea; or

N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea.

5. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 is N; and

Ar 1 is 2,3-dihydro-1H-inden-1-yl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen.

6. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 and X 5 are is N; and

Z 1 is O;

Z 2 is NH;

Ar 1 is tetrahydronaphthalenyl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen.

7. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 is N;

Ar 1 is tetrahydronaphthalenyl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen;

R 1 , R 4 , R 5 , R 6 , R 7 , and R 8a are hydrogen; and

R 2 is hydrogen or alkyl.

8. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 is N; and

Ar 1 is dihydronaphthalenyl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen.

9. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 4 is CR 4 ;

X 3 is N;

Ar 1 is dihydronaphthalenyl optionally substituted with 1 or 2 substituents independently selected from alkyl or halogen;

R 1 , R 4 , R 5 , R 6 , R 7 , and R 8a are hydrogen; and

R 2 is hydrogen or alkyl.

10. The compound according to claim 1 wherein

- - - is absent;

X 1 is CR 1 ;

X 2 is N;

X 3 is NR 3 ;

X 4 is a bond; and

Ar 1 is 2,3-dihydro-1H-inden-1-yl optionally substituted with 1 or 2 substituents independently selected from alkyl, haloalkyl, halogen, or heterocycle.

11. The compound according to claim 1 wherein

- - - is absent;

X 1 is CR 1 ;

X 2 is N;

X 3 is NR 3 ;

X 4 is a bond;

Ar 1 is 2,3-dihydro-1H-inden-1-yl optionally substituted with 1 or 2 substituents independently selected from alkyl, haloalkyl, halogen, or heterocycle, wherein the heterocycle is piperidinyl or hexahydro-1H-azepinyl; and

R 3 is hydrogen.

12. The compound according to claim 11 that is

N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea;

N-[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea;

N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea;

N-1H-indazol-4-yl-N′-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]urea;

N-1H-indazol-4-yl-N′-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea;

N-(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea;

N-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea; or

N-1H-indazol-4-yl-N′-[(1S)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea.

13. The compound according to claim 1 wherein

- - - is absent;

X 1 is CR 1 ;

X 2 is N;

X 3 is NR 3 ;

X 4 is a bond;

Ar 1 is 2,3-dihydro-1H-inden-1-yl optionally substituted with 1 or 2 substituents independently selected from alkyl, haloalkyl, halogen, or heterocycle, wherein the heterocycle is piperidinyl or hexahydro-1H-azepinyl; and

R 3 is alkoxycarbonyl.

14. The compound according to claim 13 that is

methyl 4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;

methyl 4-[({[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;

methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;

methyl 4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;

methyl 4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;

methyl 4-({[(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;

isopropyl 4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate; or

isobutyl 4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt or prodrug thereof.