Furopyrimidinedione derivatives as trpai modulators

Abstract

The present invention is related to novel furopyrimidinedione derivatives as TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1). Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1.

1 .- 42 . (canceled) 
     
     
         43 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 R 1  and R 2 , which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R Y ) n OR x , C(O)R x , C(O)OR x , C(O)NR x R y , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , NR x (CR x R Y ) n CONR x R Y , (CH 2 ) n NR x R y  and (CH 2 ) n NHC(O)R x ; 
 R 3  is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl; 
 Z 1  and Z 2  are independently oxygen or CR a ; with a proviso that one of Z 1  or Z 2  is always oxygen and other is CR a ; 
 L is a linker selected from —(CR x R y ) n —, —O—(CR x R y ) n —, —C(O)—, —NR x —, —S(O) m NR x —, —NR x (CR x R y ) n — and —S(O) m NR x (CR x R y ) n ; 
 at each occurrence, R a  is selected from hydrogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, OR x , (CR x R y ) n OR x , C(O)R x , C(O)OR x , C(O)NR x R y , S(O) m NR x R y , NR x R y , NR x (CR x R y ) n OR x , (CH 2 ) n NR x R Y , (CH 2 ) n CHR x R y , NR x (CR x R Y ) n C(O)NR x R Y , (CH 2 ) n NHC(O)R x , (CH 2 ) n NH(CH 2 ) n SO 2 R x , (CH 2 ) n NHSO 2 R x , SR x  and OR x ; 
 U is selected from —(CR x R y ) n —, substituted or unsubstituted aryl, substituted or unsubstituted five membered heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole and 1,2,4-triazole, or substituted or unsubstituted six membered heterocycle selected from the group consisting of pyrimidine, pyridine and pyridazine; 
 V is selected from hydrogen, cyano, nitro, —NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR x , —OR x , —C(O)NR x R y , —C(O)R x  and —SO 2 NR x R y ; or 
 alternatively U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; 
 at each occurrence, R x  and R y  are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl and 
 at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, both inclusive. 
 
     
     
         44 . The compound according to  claim 43 , wherein Z 1  is oxygen and Z 2  is CR a . 
     
     
         45 . The compound according to  claim 43 , wherein Z 2  is oxygen and Z 1  is CR a . 
     
     
         46 . The compound according to  claim 43 , wherein R a  is hydrogen. 
     
     
         47 . The compound according to  claim 43 , wherein R a  is methyl. 
     
     
         48 . The compound according to  claim 43 , wherein L is CH 2 . 
     
     
         49 . The compound according to  claim 43 , wherein R 1  and R 2  are (C 1 -C 4 ) alkyl. 
     
     
         50 . The compound according to  claim 49 , wherein (C 1 -C 4 ) alkyl is methyl. 
     
     
         51 . The compound according to  claim 43 , wherein R 3  is hydrogen. 
     
     
         52 . The compound according to  claim 43 , wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine. 
     
     
         53 . The compound according to  claim 43 , wherein V is substituted or unsubstituted aryl. 
     
     
         54 . The compound according to  claim 53 , wherein aryl is phenyl. 
     
     
         55 . The compound of  claim 43  having the formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein R 1 , R 2 , R a , U and V are as defined for  claim 43 . 
     
     
         56 . The compound according to  claim 55 , wherein R 1  and R 2  are (C 1 -C 4 ) alkyl. 
     
     
         57 . The compound according to  claim 56 , wherein (C 1 -C 4 ) alkyl is methyl. 
     
     
         58 . The compound according to  claim 55 , wherein R a  is hydrogen or (C 1 -C 4 ) alkyl. 
     
     
         59 . The compound according to  claim 55 , wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine. 
     
     
         60 . The compound according to  claim 55 , wherein V is substituted or unsubstituted aryl. 
     
     
         61 . The compound according to  claim 60 , wherein aryl is phenyl. 
     
     
         62 . The compound according to  claim 43 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 R 1 , R 2  and R a , which may be the same or different, are each independently hydrogen or (C 1 -C 4 )alkyl; and 
 R 4 , R 5 , R 6 , R 7 , R 8  and R 9 , which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl. 
 
     
     
         63 . The compound according to  claim 62  wherein R a  is hydrogen 
     
     
         64 . The compound according to  claim 62  wherein R a  is (C 1 -C 4 ) alkyl. 
     
     
         65 . The compound according to  claim 62  wherein R 1  and R 2  are (C 1 -C 4 ) alkyl. 
     
     
         66 . The compound according to  claim 65 , wherein (C 1 -C 4 ) alkyl is methyl. 
     
     
         67 . The compound according to  claim 62 , wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl or trifluoromethoxy. 
     
     
         68 . The compound according to  claims 62 , wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl or trifluoromethoxy. 
     
     
         69 . The compound according to  claim 62 , wherein R 8  is hydrogen. 
     
     
         70 . The compound according to  claim 62 , wherein R 9  is hydrogen. 
     
     
         71 . The compound according to  claim 62 , wherein R 9  is methyl. 
     
     
         72 . The compound selected from:
 N1-[4-(4-Trifluoromethylphenoxy)phenyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[2-(2,4-Dichlorophenyl)ethyl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(Trifluoromethyl)-1,3-thiazol-2-yl]-2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N-(4,6-Difluoro-1,3-benzothiazol-2-yl)-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(4-Isobutylphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N-1-[4-(4-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Trifluorormethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Bromo-4-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Fluoro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Chloro-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide; and   N1-[4-(3-Bromo-4-difluoromethoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Bromo-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Bromo-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Bromo-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,4,5,-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,3,4-Trichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-5-fluoro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(3-methylbutoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide; and   N1-{4-[3,5-Difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-(Trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{ 4 -[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,3-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2-Fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide; and   N1-{4-[3-Chloro-5-(trifluoromethoxyphenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Fluoro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3-Chloro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-[2,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,4,5-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,3,4-Trifluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3-Chloro-2,4-difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(2,4-Dichloro-5-fluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,5-Difluoro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-[4-(3,5-Dichloro-4-isobutoxyphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Dichloro-4-(difluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Difluoro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[3,5-Dichloro-4-(2,2,2-trifluoro ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   N1-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-methyl-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide; and   N1-[5-(4-Bromophenyl)-1,3,4-thiadiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         73 . The compound having formula 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof. 
     
     
         74 . The compound having formula 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof. 
     
     
         75 . A pharmaceutical composition comprising one or more compound according to  claim 43 , and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof. 
     
     
         76 . A method for treating disease or condition associated with TRPA1 function in a subject in need thereof comprising administering to the subject an effective amount of a compound according to  claim 43 . 
     
     
         77 . The method according to  claim 76 , wherein the symptoms of a disease or condition associated with TRPA1 function is selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. 
     
     
         78 . The method according to  claim 77 , wherein the symptoms of a disease or condition is associated with chronic pain. 
     
     
         79 . The method according to  claim 77 , wherein the symptoms of a disease or condition is associated with neuropathic pain. 
     
     
         80 . The method according to  claim 77 , wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.