Prodrugs of compounds that inhibit trpv1 receptor

Abstract

Compounds of formula (I) wherein A, R 1 , R 2 , and R 3 are defined in the specification, and which are useful as therapeutic compounds particularly for treating disorders or conditions associated with inflammation, pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by TRPV1.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein
 A is 
 
       
         
           
           
               
               
           
         
         R 1  is alkyl, cycloalkyl, alkenyl; halogen or haloalkyl; 
         R 2  is hydrogen or heterocyclealkyl wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-OR B , and -alkyl-N(R B ) 2 ; 
         R 3  is 
       
       
         
           
           
               
               
           
         
         wherein
 R 4  is —C(O)—O—(CH 2 ) m R 5 , —C(O)(CH 2 ) n —R 6 , —(CH 2 ) r —R 7 , —C(O)R 8 , or —CH 2 C(H)(OH)R 9  when R 2  is hydrogen; or 
 R 4  is hydrogen when R 2  is heterocyclealkyl; wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-OR B , and -alkyl-N(R B ) 2 ; 
 
         m is 1, 2, or 3; 
         n is 1, 2 or 3; 
         r is 1, 2 or 3; 
         t is 0, 1, 2, 3 or 4; 
         u is 0, 1, 2 or 3; 
         R 5  is alkyl, —O—P(O)(OR A )(OR A ), —P(O)(OR A )(OR A ), —OR A , —OC(O)(R A ), heterocycle, —C(O)OR A , —C(O)N(R B ) 2 , —C(O)(R A ), —NR A R B , or —N(R B )C(O)OR A , 
         R 6  is alkyl, —OC(O)(R A ), —OR A , —C(O)OR A , —NR A R B , —OP(O)(OR A )(OR A ), or —P(O)(OR A )(OR A ); 
         R 7  is alkoxy, heterocycle, —OC(O)(R A ), —OC(O)(hydroxyalkyl), —OP(O)(OR A )(OR A ), or —P(O)(OR A )(OR A ), 
         R 8  is heterocycle or N(R 8a )(R 8b ) wherein R 8a  and R 8b  are independently hydrogen or alkyl; 
         R 9  is alkoxyalkyl, —C(O)OR A , -alkyl-N(R B )C(O)OR A , or heterocyclealkyl; 
         R 10  is alkyl; 
         each occurence of R 11  are independently hydrogen, alkyl or aryl, or two R 11  groups that are attached to a single carbon atom together form a cycloalkyl ring; 
         R A  is hydrogen, alkyl, alkoxyalkyl, aryl or arylalkyl; 
         R B  is hydrogen or alkyl; 
         the heterocycle and the heterocycle moiety of the heterocyclealkyl, represented by R 5 , R 7 , R 8 , and R 9 , are each independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, —C(O)OH, -alkyl-C(O)OH, and —N(Z A )(Z B ); 
         Z A  and Z B  are each independently hydrogen, alkyl, —C(O)alkyl, formyl, aryl, or arylalkyl; and 
         the aryl and the aryl moiety of the arylalkyl, represented by R A , Z A  and Z B  are each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of alkyl, haloalkyl, alkoxy and haloalkoxy. 
       
     
     
         2 . The compound of  claim 1 , wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, alkenyl; halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —(CH 2 ) r —R 7 . 
 
     
     
         4 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is  - C(O)(CH 2 ) n   - R 6 . 
 
     
     
         5 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —CH 2 C(H)(OH)R 9 . 
 
     
     
         6 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)R 8.    
 
     
     
         7 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is heterocyclealkyl;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is hydrogen. 
 
     
     
         8 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)—O—(CH 2 ) m R 5.    
 
     
     
         9 . The compound of  claim 8  wherein
 R 5  is —O—P(O)(OR A )(OR A ). 
 
     
     
         10 . The compound of  claim 8  wherein
 R 5  is —P(O)(OR A )(OR A ). 
 
     
     
         11 . The compound of  claim 8  wherein
 R 5  is —OR A . 
 
     
     
         12 . The compound of  claim 8  wherein
 R 5  is —OC(O)(R A ). 
 
     
     
         13 . The compound of  claim 8  wherein
 R 5  is heterocycle. 
 
     
     
         14 . The compound of  claim 8  wherein
 R 5  is —C(O)OR A . 
 
     
     
         15 . The compound of  claim 8  wherein
 R 5  is selected from the group consisting of —C(O)R A , —N(R B )C(O)OR A , —NR A R B , and —C(O)N(R B ) 2 . 
 
     
     
         16 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)R 8.    
 
     
     
         17 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is —CH 2 C(H)(OH)R 9 . 
 
     
     
         18 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is selected from the group consisting of —C(O)—O—(CH 2 ) m R 5 , —C(O)(CH 2 ) n —R 6 , and —(CH 2 ) r —R 7 . 
 
     
     
         19 . The compound of  claim 2 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  is heterocyclealkyl;   R 3  is   
       
         
           
           
               
               
           
         
       
       and
 R 4  is hydrogen. 
 
     
     
         20 . The compound of  claim 1 , wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl;   R 2  1S hydrogen;   R 3  is   
       
         
           
           
               
               
           
         
       
       and 
       R 4  is —(CH 2 ) r —R 7 . 
     
     
         22 . The compound of  claim 20  wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)(CH 2 ) n —R 6 . 
 
     
     
         23 . The compound of  claim 20  wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4  is —CH 2 C(H)(OH)R 9 . 
 
     
     
         24 . The compound of  claim 20  wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)R 8 . 
 
     
     
         25 . The compound of  claim 20  wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is heterocyclealkyl; 
 R 3  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4  is hydrogen. 
 
     
     
         26 . The compound of  claim 20  wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4  is —C(O)—O—(CH 2 ) m R 5.    
 
     
     
         27 . The compound of  claim 26  wherein
 R 5  is —O—P(O)(OR A )(OR A ). 
 
     
     
         28 . The compound of  claim 26  wherein
 R 5  is —P(O)(OR A )(OR A ). 
 
     
     
         29 . The compound of  claim 26  wherein
 R 5  is —OR A . 
 
     
     
         30 . The compound of  claim 26  wherein
 R 5  is —OC(O)(R A ). 
 
     
     
         31 . The compound of  claim 26  wherein
 R 5  is heterocycle. 
 
     
     
         32 . The compound of  claim 26  wherein
 R 5  is —C(O)OR A , 
 
     
     
         33 . The compound of  claim 26  wherein
 R 5  is selected from the group consisting of —C(O)R A , —N(R B )C(O)OR A , —NR A R B , and —C(O)N(R B ) 2 . 
 
     
     
         34 . The compound of  claim 1 , wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 1 , wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 1 , wherein
 A is   
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound selected from the group consisting of
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-morphol in-4-ylethyl)-1H-indazol-4-yl]urea;   2-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-oxoethyl acetate;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-yl-N-(2-morpholin-4-ylethyl)urea;   N-{1-[(benzyloxy)acetyl]-1H-indazol-4-yl}-N′-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(methoxyacetyl)-1H-indazol-4-yl]urea;   4-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl1-4-oxobutanoic acid;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′t1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea trifluoroacetic acid salt;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-(1-glycoloyl-1H-indazol-4-yl)urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-yl-N-(2-piperidin-1-ylethyl)urea;   5-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-5-oxopentanoic acid;   2-(phosphonooxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(benzyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-hydroxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-[(di-tert-butoxyphosphoryl)oxy]ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   3-(benzyloxy)propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   3-hydroxypropyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   3-[(di-tert-butoxyphosphoryl)oxy]propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   3-(phosphonooxy)propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-/V[1-(hydroxymethyl)-1H-indazol-4-yl)urea;   {4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}methyl acetate;   {4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)am ino]-1H-indazol-1-yl}methyl 3-hydroxypropanoate;   {[bis(benzyloxy)phosphoryl]oxy}methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   (phosphonooxy)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   dibenzyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-3-oxopropyl phosphate;   3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-3-oxopropyl dihydrogen phosphate;   [bis(benzyloxy)phosphoryl]methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonie acid triethylamine salt;   2-methoxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   (2-oxo-1,3-dioxolan-4-yl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(benzyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-hydroxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(benzyloxy)-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-{[(benzyloxy)carbonyl]amino}ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]acetic acid;   2-aminoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate hydrochloride;   2-ethoxy-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   (diethoxyphosphoryl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(diethylamino)-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-oxopropyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(acetyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   2-(dimethoxyphosphoryl)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   [bis(benzyloxy)phosphoryl]methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonate, triethylamine salt;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, diethylaminoethanol salt;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, triethanolamine salt;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, piperazine salt;   [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, N-methyl-D-glucamine salt;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-hydroxy-3-methoxypropyl)-1H-indazol-4-yl]urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[2-(2-hydroxy-3-methoxypropyl)-2H-indazol-4-yl]urea;   methyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropanoate;   methyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-2H-indazol-2-yl}-2-hydroxypropanoate;   tert-butyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropylcarbamate;   3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropanoic acid;   3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-2H-indazol-2-yl}-2-hydroxypropanoic acid;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′t2-(2-hydroxy-3-morpholin-4-ylpropyl)-2H-indazol-4-yl]urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-hydroxy-3-morpholin-4-ylpropyl)-1H-indazol-4-yl]urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-{1-[(4-methylpiperazin-1-yl)carbonyl]-1H-indazol-4-yl}urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-{2-[(4-methylpiperazin-1-yl)carbonyl]-2H-indazol-4-yl}urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea;   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea, hydrochloride salt;   ((R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(2-methoxyethoxy)acetyl)-1H-indazol-4-yl)urea;   1-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(3,5,5-trimethylhexanoyl)-1H-indazol-4-yl)urea;   2-ethylhexyl 4-(3-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-carboxylate;   (R)-1-(1-(2-(2-butoxyethoxy)acetyl)-1H-indazol-4-yl)-3-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)urea;   methyl 4-(3-(7-fluoro-2,2-dimethylchroman-4-yl)ureido)-1H-indazole-1-carboxylate;   1-(7-fluoro-2,2-dimethylchroman-4-yl)-3-(1-(2-methoxyethyl)-1H-indazol-4-yl)urea;   3-(dimethylamino)propyl 4-(3-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-carboxylate;   1-(4-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea trifluoroacetate;   1-(5-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride;   1-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)-3-(4-(3,3-dimethylbutyl)-5-fluoro-2,3-dihydro-1H-inden-1-yl)urea;   (R)-1-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea;   (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride;   4-[3-(7-trifluoromethyl-chroman-4-yl)-ureido]-indazole-1-carboxylic acid methyl ester;   1-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)-3-(7-(trifluoromethyl)chroman-4-yl)urea;   methyl 4-({[(8-tert-butyl-3,4-dihydro-2H-chromen-4-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate; and   1-(8-tert-butylchroman-4-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride.   
     
     
         38 . A pharmaceutical composition comprising a therapeutically effective amount of one or more compound of formula (I) as described in  claim 1 , or a therapeutically acceptable salt, solvate, or combination thereof, and a pharmaceutically acceptable carrier. 
     
     
         39 . A method of treating or preventing disorders that may be ameliorated by inhibiting TRPV1 activity in a mammal comprising administering a therapeutically effective amount of one or more compounds of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A compound of formula (I) according according to  claim 1  for use in the manufacture of a medicament for the treatment or prevention of a disease or condition that may be ameliorated by inhibiting TRPV1 activity. 
     
     
         41 . A compound according to  claim 36  wherein the disease or disorder is associated with pain, inflammation, urinary incontinence and bladder dysfunction. 
     
     
         42 . A method of treating or preventing a disease or disorders associated with neuropathic pain, inflammatory pain, or both, which method comprises administering a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A method of treating or preventing a disease or disorder associated with bladder overactivity or urinary incontinence, or both, which method comprises administering a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The compound of  claim 2  of formula (II), 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 2  of formula (III), 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 20  of formula (IV), 
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound of  claim 20  of formula (V),