Benzimidazole modulators of vr1

Abstract

The invention is directed to compounds of Formula (I): to pharmaceutical compositions containing such compounds and to methods of treatment using them.

1 - 14 . (canceled) 
     
     
         15 . A method for treating a VR1 ion channel mediated disease in a subject in need thereof comprising administering to the subject an effective amount of the compound of claim Formula (I): 
       
         
           
           
               
               
           
         
       
       and a salt, stereoisomer, tautomer or ester thereof, wherein:
 the dashed lines between positions 1, 2 and 3 in Formula (I) indicate the positions of a tautomeric double bond, 
 wherein when a double bond is formed between positions 1 and 2, then R 3b  is present, and 
 wherein, when a double bond is formed between postions 2 and 3, then R 3a  is present; 
 p is 1 or 2; 
 q is 0 or 1; 
 r is 0, 1, 2 or 3; 
 L is C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl or cyclopropyl; 
 A 1  is selected from the group consisting of phenyl, biphenyl, naphthyl, pyridinyl, quinolinyl and indole; 
 R 1  is each selected from the group consisting of hydroxy, cyano, halogen, formyl, carboxy, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-8 cycloalkyl-C 1-4 alkoxy, C 3-8 cycloalkyl-oxy, amino, (C 1-6 alkyl) 1-2 -amino, (C 3-8 cycloalkyl) 1-2 -amino, (C 3-8 cycloalkyl-C 1-4 alkyl) 1-2 -amino, aminocarbonyl, (C 1-6 alkyl) 1-2 -aminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, aminocarbonylamino, (C 1-6 alkyl) 1-2 -aminocarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylsulfinylamino, aminosulfonyl, (C 1-4 alkyl) 1-2 -aminosulfonyl, aminosulfonylamino and (C 1-6 alkyl) 1-2 -aminosulfonylamino, 
 wherein alkyl is optionally substituted with C 1-8 alkoxy, amino, (C 1-4 alkyl) 1-2 -amino, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, aminocarbonylamino, (C 1-6 alkyl) 1-2 -aminocarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonylamino, (C 1-6 alkyl) 1-2 -aminosulfonylamino hydroxy and phenyl, 
 wherein phenyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylsulfonyl, and 
 wherein, each instance of alkyl and alkoxy is optionally perfluorinated; 
 R 2  is selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylsulfonyl, nitro, amino, (C 1-4 alkyl) 1-2 -amino and cyano, 
 wherein each instance of alkyl and alkoxy is optionally perfluorinated; 
 R 3a  and R 3b  are each selected from the group consisting of hydrogen and optionally perfluorinated C 1-4 alkyl; and 
 R 4  is each selected from the group consisting of halogen, nitro, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylthio, haloC 1-6 alkylthio, C 1-6 alkylsulfonyl, haloC 1-6 alkylsulfonyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, C 3-8 cycloalkyl-C 1-4 alkoxy, C 3-8 cycloalkyl-oxy, amino, (C 1-6 alkyl) 1-2 -amino, (C 3-8 cycloalkyl) 1-2 -amino, (C 3-8 cycloalkyl-C 1-4 alkyl) 1-2 -amino, aminocarbonyl, (C 1-6 alkyl) 1-2 -aminocarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, aminocarbonylamino, (C 1-6 alkyl) 1-2 -aminocarbonylamino, C 1-6 alkylsulfonylamino, haloC 1-6 alkylsulfonylamino, C 1-6 alkylsulfinylamino, aminosulfonyl and (C 1-4 alkyl) 1-2 -aminosulfonyl, 
 wherein each instance of alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C 1-8 alkoxy, amino, (C 1-4 alkyl) 1-2 -amino, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, aminocarbonylamino, (C 1-6 alkyl) 1-2 -aminocarbonylamino, C 1-6 alkylsulfonylamino, oxo and hydroxy, and 
 
       wherein, each instance of alkyl and alkoxy is optionally perfluorinated. 
     
     
         16 . The method of  claim 15 , wherein the VR1 ion channel mediated disease is chronic or acute pain due to disease that causes inflammatory pain, burning pain or post-operative pain. 
     
     
         17 . The method of  claim 15 , wherein the effective amount of the compound of claim  1  is in a range of from about 0.001 mg/kg/day to about 300 mg/kg/day. 
     
     
         18 - 20 . (canceled)