Prodrugs of compounds that inhibit TRPV1 receptor

1. A compound of formula (I)

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein

A is cyclopently

R 1 is alkyl, cycloalkyl, alkenyl, halogen or haloalkyl;

R 2 is hydrogen;

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 (H)(OH)R 9 ;

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 —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 —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 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 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

R 1 is alkyl, cycloalkyl, alkenyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —(CH 2 ) r —R 7 .

3. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —C(O)(CH 2 ) n —R 6 .

4. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —CH 2 C(H)(OH)R 9 .

5. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —C(O)R 8 .

6. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is heterocyclealkyl;

R 3 is

R 4 is —C(O)—O—(CH 2 ) m R 5 .

7. The compound of claim 6 , wherein

R 5 is —O—P(O)(OR A )(OR A ).

8. The compound of claim 6 wherein

R 5 is —P(O)(OR A )(OR A ).

9. The compound of claim 6 wherein

R 5 is —OR A .

10. The compound of claim 6 wherein

R 5 is —OC(O)(R A ).

11. The compound of claim 6 wherein

R 5 is heterocycle.

12. The compound of claim 6 wherein

R 5 is —C(O)OR A .

13. The compound of claim 6 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 .

14. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —C(O)R 8 .

15. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

R 4 is —CH 2 C(H)(OH)R 9 .

16. The compound of claim 1 , wherein

R 1 is alkyl, cycloalkyl, halogen or haloalkyl;

R 2 is hydrogen;

R 3 is

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 .

17. A compound selected from the group consisting of

N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-morpholin-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-{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-yl}-4-oxobutanoic acid;

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

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]-N′-[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)amino]-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]methylphosphonic 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;

[({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′-[2-(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;

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; and

(R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride;

18. 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 thereof, or combination thereof, and a pharmaceutically acceptable carrier.

19. A method of treating neuropathic pain, inflammatory pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

20. A method of treating thermal hyperalgesia, bladder overactivity or urinary incontinence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 of formula (II),

22. The compound of claim 1 of formula (III),