Imidazolo-, oxazolo-, and thiazolopyrimidine modulators of trpv1

Abstract

Certain TRPV1-modulating imidazolo-, oxazolo-, and thiazolopyrimdine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.

1 - 20 . (canceled) 
     
     
         21 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by TRPV1 activity, comprising administering to the subject an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of said compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —H; —NR a R b ; a —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, or —SO 2 —C 1-6 alkyl group unsubstituted or substituted with an —OH, —OC 1-4 alkyl, or —NR c R d  substituent;
 where R a  and R b  are each independently —H; —C 1-6 alkyl; a —C 2 -4alkyl group substituted with a —OH, —OC 1-4 alkyl, or —NR e R f  substituent; or a saturated monocyclic cycloalkyl, —C 1 alkyl-(saturated monocyclic cycloalkyl), —C 1 alkyl-(carbon-linked, saturated monocyclic heterocycloalkyl), benzyl, or —C 1 alkyl-(monocyclic heteroaryl) group, each unsubstituted or substituted with a —C 1-6 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , or fluoro substituent; 
 or, R a  and R b  taken together with the nitrogen of attachment in —NR a R b  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-2 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 14 alkyl, —NR p R q , fluoro, —CO 2 H, and monocyclic cycloalkyl substituents;
 where R c  and R d  are each independently —H or —C 1-6 alkyl;
 or R c  and R d  taken together with the nitrogen of attachment in —NR c R d  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 R e  and R f  are each independently —H or —C 1-6 alkyl;
 or R e  and R f  taken together with their nitrogen of attachment in —NR e R f  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; and 
 
 R p  and R q  are each independently —H or —C 1-6 alkyl;
 or R p  and R q  taken together with the nitrogen of attachment in —NR P R q  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 
 
         R 2  is:
 1) a phenyl group unsubstituted or substituted with one, two, or three R g  substituents; 
 where each R g  substituent is —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —N(R h )R i , —C(O)N(R h )R i , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R h )R i , —SCF 3 ,
 halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C(R i ) 2 —CN, —C(R j ) 2 —CO 2 C 1-4 alkyl, —C(R j ) 2 —CO 2 H, —C(R j ) 2 —CON(R h )R i , —C(R j ) 2 —CH 2 N(R h )R i , or —C(R j ) 2 —OH; 
 or two adjacent R g  substituents taken together form —OC 1-2 alkylO-, —C 2-6 alkylO-, or —C 2-6 alkylN(R h )—; 
 where R h  and R i  are each independently —H or —C 1-6 alkyl;
 or R h  and R i  taken together with their nitrogen of attachment in —NR h R i  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 where each R j  is independently —H, —C 1-6 alkyl, or —CF 3 ;
 or both R j  substituents taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring; or 
 
 
 2) a thiadiazolyl or six-membered monocyclic heteroaryl ring, each substituted with —CF 3  or tert-butyl; 
 
         R 3  is —H, —CH 3 , —CF 3 ,
 halo, —CN, —COC 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R k )R l , —CH 2 N(R k )R l , —S(O) 0-2 —C 1-6 alkyl, —S—Si(C 1-6 alkyl) 3 , —SO 2 CF 3 , or —SO 2 N(R k )R l ; or a phenyl or 6-membered heteroaryl ring, each unsubstituted or substituted with —OH, —CH 2 N(R k )R l , —C(O)N(R k )R l , —SO 2 N(R k )R l , or —CO 2 H; 
 where R k  and R l  are each independently —H or —C 1-6 alkyl; or R k  and R l  taken together with their nitrogen of attachment in —NR k R l  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
         R 4  is —H, —CF 3 , halo, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R n )R o , —C 1-4 alkyl-OH, —C 1-4 alkyl-N(R n )R o , —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , or —SO 2 N(R n )R o ;
 where R n  and R o  are each independently —H or —C 1-6 alkyl; 
 
         X is S, O, or NH; 
         R 5  is —H, —CH 3 , halo, or —CF 3 ; and 
         R 6  and R 7  are each independently —H or methyl; or R 6  and R 7  taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring. 
       
     
     
         22 . A method according to  claim 21 , wherein said agent is selected from the group consisting of:
 [2-(2,6-Dichloro-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   (4-tert-Butyl-phenyl)-[2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2-Iodo-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;   (3-Chloro-4-trifluoromethyl-phenyl)-[2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-amine;   2-{4-[2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-ylamino]-phenyl}-2-methyl-propionitrile;   [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(3-fluoro-4-methanesulfonyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-methanesulfonyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine;   2-(2-Methylbenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2-Methylbenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2-Methylbenzyl)-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2-Chlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2-Chlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2-Chlorobenzyl)-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[2-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[3-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-tert-Butylphenyl)-2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   Methyl 2-(4-{[2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}phenyl)-2-methylpropanoate;   2-(2,4-Dichlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[4-(piperazin-1-ylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,4-Dichlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-[2-(Trifluoromethyl)benzyl]-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-[2-(Trifluoromethyl)benzyl]-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-Benzyl-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-Benzyl-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-Benzyl-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(4-Chlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(4-Chlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-(4-methoxyphenyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[6-(methylsulfanyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-(4-fluorophenyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-Chlorophenyl)-2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-Bromophenyl)-2-(2,6-dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(4-{[2-(2,6-Dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}phenyl)-2-methylpropanenitrile;   2-(2,6-Dichlorobenzyl)-N-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[4-(trifluoromethoxy)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-[3-fluoro-4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dichlorobenzyl)-N-(4-methylphenyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(4-{[2-(2,6-Dichlorobenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}phenyl)-2-methylpropanamide;   N-Phenyl-2-[2-(trifluoromethyl)benzyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-Bromophenyl)-2-[2-(trifluoromethyl)benzyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-tert-Butylphenyl)-2-[2-(trifluoromethyl)benzyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-[4-(Methylsulfonyl)phenyl]-2-[2-(trifluoromethyl)benzyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-[4-(Morpholin-4-ylsulfonyl)phenyl]-2-[2-(trifluoromethyl)benzyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(3-Chlorobenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(3-Chlorobenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dimethylbenzyl)-N-phenyl[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-Bromophenyl)-2-(2,6-dimethylbenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(4-tert-Butylphenyl)-2-(2,6-dimethylbenzyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dimethylbenzyl)-N-[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dimethylbenzyl)-N-[6-(trifluoromethyl)pyridin-3-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dimethylbenzyl)-N-[4-(morpholin-4-ylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   2-(2,6-Dimethylbenzyl)-N-[4-(methylsulfonyl)phenyl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   [2-(2,6-Dichloro-benzyl)-5-methanesulfonyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-(2-methyl-pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   2-(2,6-Dichloro-benzyl)-N 5 -(2-morpholin-4-yl-ethyl)-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   N 5 —Cyclopropylmethyl-2-(2,6-dichloro-benzyl)-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   [2-(2,6-Dichloro-benzyl)-5-pyrrolidin-1-yl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-(2-isopropyl-pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   2-(2,6-Dichloro-benzyl)-N 5 -isobutyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-[2-(2,6-Dichloro-benzyl)-7-(4-trifluoromethyl-phenylamino)-thiazolo[5,4-d]pyrimidin-5-ylamino]-propan-1-ol;   (S)-[2-(2,6-Dichloro-benzyl)-5-(2-methoxymethyl-pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   2-(2,6-Dichloro-benzyl)-N 5 -isopropyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   [5-Azetidin-1-yl-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-piperazin-1-yl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-(4-isopropyl-piperazin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [5-(4-Cyclopentyl-piperazin-1-yl)-2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-(4-pyrrolidin-1-yl-piperidin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   N 5 -Cyclopropyl-2-(2,6-dichloro-benzyl)-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   N 5 -Cyclobutyl-2-(2,6-dichloro-benzyl)-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichloro-benzyl)-N 5 ,N 5 -diisobutyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   [2-(2,6-Dichloro-benzyl)-5-piperidin-1-yl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   2-(2,6-Dichloro-benzyl)-N 5 -(2-pyrrolidin-1-yl-ethyl)-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   [2-(2,6-Dichloro-benzyl)-5-(4-isobutyl-piperazin-1-yl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   2-(2,6-Dichloro-benzyl)-N 5 -pyridin-2-ylmethyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichloro-benzyl)-N 5 -pyridin-3-ylmethyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichloro-benzyl)-N 5 -pyridin-4-ylmethyl-N 7 -(4-trifluoromethyl-phenyl)-thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -(1-pyridin-2-ylethyl)-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -[(1-ethylpyrrolidin-2-yl)methyl]-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -[(3R)-pyrrolidin-3-ylmethyl]-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -(piperidin-2-ylmethyl)-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -(piperidin-3-ylmethyl)-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   2-(2,6-Dichlorobenzyl)-N 5 -(piperidin-4-ylmethyl)-N 7 -[4-(trifluoromethyl)phenyl][1,3]thiazolo[5,4-d]pyrimidine-5,7-diamine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;   [2-(2,6-Dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;   2-[2-(Trifluoromethyl)benzyl]-N-[5-(trifluoromethyl)pyridin-2-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   [2-(2-Chloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;   2-(2,6-Dichlorobenzyl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine;   N-(5-tert-Butyl-1,3,4-thiadiazol-2-yl)-2-(2,6-dichlorobenzyl)[1, 3]thiazolo[5,4-d]pyrimidin-7-amine;   2-[7-(4-Trifluoromethyl-phenylamino)-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-benzonitrile;   [2-(2,6-Dichloro-benzyl)-5-methoxy-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-isopropoxy-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-isobutoxy-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   (4-Trifluoromethyl-phenyl)-[2-(2-triisopropylsilanylsulfanyl-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-amine;   (2-Biphenyl-2-ylmethylthiazolo[5,4-d]pyrimidin-7-yl)-(4-trifluoromethylphenyl)-amine;   2′-[7-(4-Trifluoromethylphenylamino)-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-biphenyl-2-o;   2′-[7-(4-Trifluoromethylphenylamino)-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-biphenyl-4-carboxylic acid amide;   1-{2-[7-(4-Trifluoromethylphenylamino)-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-phenyl}-ethanone;   [8-(2,6-Dichloro-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   (4-tert-Butyl-phenyl)-[8-(2,6-dichloro-benzyl)-9H-purin-6-yl]-amine;   [2-(2,6-Dimethyl-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2-Methyl-benzyl)-oxazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [2-(2,6-Dichloro-benzyl)-5-methyl-oxazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dimethyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2-Methyl-benzyl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dimethyl-benzyl)-2-methyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-methylsulfanyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-methanesulfonyl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-methoxy-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-(4-methyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-(4-isobutyl-piperazin-1-yl)-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-morpholin-4-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   [8-(2,6-Dichloro-benzyl)-2-piperidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   8-(2,6-Dichloro-benzyl)-N 2 -isobutyl-N 6 -(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine;   8-(2,6-Dichloro-benzyl)-N 2 -isopropyl-N 6 -(4-trifluoromethyl-phenyl)-9H-purine-2,6-diamine;   [8-(2,6-Dichloro-benzyl)-2-pyrrolidin-1-yl-9H-purin-6-yl]-(4-trifluoromethyl-phenyl)-amine;   {3,5-Dichloro-4-[7-(4-trifluoromethyl-phenylamino)-thiazolo[5,4-d]pyrimidin-2-ylmethyl]-phenyl}-methanol;   {2-[2-(1-Dimethylamino-ethyl)-benzyl]-thiazolo[5,4-d]pyrimidin-7-yl}-(4-trifluoromethyl-phenyl)-amine; and   {2-[2-(1-Morpholin-4-yl-ethyl)-benzyl]-thiazolo[5,4-d]pyrimidin-7-yl}-(4-trifluoromethyl-phenyl)-amine;   and pharmaceutically acceptable salts thereof.   
     
     
         23 . A method according to  claim 21 , wherein the disease, disorder, or condition is pain; itch or an inflammatory disorder; an inner ear disorder; fever or another condition or disorder of thermoregulation; tracheobronchial or diaphragmatic dysfunction; a gastrointestinal or urinary tract disorder; or a disorder associated with reduced blood flow to the central nervous system or CNS hypoxia. 
     
     
         24 . A method according to  claim 21 , wherein the disease, disorder, or condition is pain, arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder. 
     
     
         25 . A process for the preparation of a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula (XVI): 
       
       
         
           
           
               
               
           
         
         with thiourea, to give a compound of Formula (I); 
         wherein: 
         R 1  is —H; —NR a R b ; a —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, or —SO 2 —C 1-6 alkyl group unsubstituted or substituted with an —OH, —OC 1-4 alkyl, or —NR c R d  substituent;
 where R a  and R b  are each independently —H; —C 1-6 alkyl; a —C 2-4 alkyl group substituted with a —OH, —OC 1-4 alkyl, or —NR e R f  substituent; or a saturated monocyclic cycloalkyl, —C 1 alkyl-(saturated monocyclic cycloalkyl), —C 1 alkyl-(carbon-linked, saturated monocyclic heterocycloalkyl), benzyl, or —C 1 alkyl-(monocyclic heteroaryl) group, each unsubstituted or substituted with a —C 1-6 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , or fluoro substituent; 
 or, R a  and R b  taken together with the nitrogen of attachment in —NR a R b  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-2 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , fluoro, —CO 2 H, and monocyclic cycloalkyl substituents;
 where R c  and R d  are each independently —H or —C 1-6 alkyl;
 or R c  and R d  taken together with the nitrogen of attachment in —NR c R d  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 R e  and R f  are each independently —H or —C 1-6 alkyl;
 or R e  and R f  taken together with their nitrogen of attachment in —NR e R f  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; and 
 
 R p  and R q  are each independently —H or —C 1-6 alkyl;
 or R p  and R q  taken together with the nitrogen of attachment in —NR p R q  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 
 
         R 2  is:
 1) a phenyl group unsubstituted or substituted with one, two, or three R g  substituents; 
 where each R g  substituent is —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —N(R h )R i , —C(O)N(R h )R i , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R h )R i , —SCF 3 ,
 halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C(R i ) 2 —CN, —C(R i ) 2 —CO 2 C 1-4 alkyl, —C(R j ) 2 —CO 2 H, —C(R j ) 2 —CON(R h )R i , —C(R j ) 2 —CH 2 N(R h )R i , or —C(R j ) 2- OH; 
 or two adjacent R g  substituents taken together form —OC 1-2 alkylO-, —C 2-6 alkylO-, or —C 2-6 alkylN(R h )—; 
 where R h  and R i  are each independently —H or —C 1-6 alkyl;
 or R h  and R i  taken together with their nitrogen of attachment in —NR h R i  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 where each R j  is independently —H, —C 1-6 alkyl, or —CF 3 ;
 or both R j  substituents taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring; or 
 
 
 2) a thiadiazolyl or six-membered monocyclic heteroaryl ring, each substituted with —CF 3  or tert-butyl; 
 
         R 3  is —H, —CH 3 , —CF 3 ,
 halo, —CN, —COC 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R k )R l , —CH 2 N(R k )R l , —S(O) 0-2 —C 1-6 alkyl, —S—Si(C 1-6 alkyl) 3 , —SO 2 CF 3 , or —SO 2 N(R k )R k ; or a phenyl or 6-membered heteroaryl ring, each unsubstituted or substituted with —OH, —CH 2 N(R k )R l , —C(O)N(R k )R l , —SO 2 N(R k )R l , or —CO 2 H; 
 where R k  and R l  are each independently —H or —C 1-6 alkyl; or R k  and R l  taken together with their nitrogen of attachment in —NR k R l  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
         R 4  is —H, —CF 3 , halo, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R n )R o , —C 1-4 alkyl-OH, —C 1-4 alkyl-N(R n )R o , —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , or —SO 2 N(R n )R o ;
 where R n  and R o  are each independently —H or —C 1-6 alkyl; 
 
         X is S; 
         R 5  is —H, —CH 3 , halo, or —CF 3 ; and 
         R 6  and R 7  are each independently —H or methyl; or R 6  and R 7  taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring. 
       
     
     
         26 . A process according to  claim 25 , further comprising reacting a compound of formula (XV): 
       
         
           
           
               
               
           
         
         with a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         to generate a compound of formula (XVI); 
         wherein R is an amide coupling group. 
       
     
     
         27 . A compound of formula (XVI): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —H; —NR a R b ; a —C 1-6 alkyl, —OC 1-6 alkyl, —S—C 1-6 alkyl, or —SO 2 —C 1-6 alkyl group unsubstituted or substituted with an —OH, —OC 1-4 alkyl, or —NR c R d  substituent;
 where R a  and R b  are each independently —H; —C 1-6 alkyl; a —C 2-4 alkyl group substituted with a —OH, —OC 1-4 alkyl, or —NR e R f  substituent; or a saturated monocyclic cycloalkyl, —C 1 alkyl-(saturated monocyclic cycloalkyl), —C 1 alkyl-(carbon-linked, saturated monocyclic heterocycloalkyl), benzyl, or —C 1 alkyl-(monocyclic heteroaryl) group, each unsubstituted or substituted with a —C 1-6 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , or fluoro substituent; 
 or, R a  and R b  taken together with the nitrogen of attachment in —NR a R b  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-2 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , fluoro, —CO 2 H, and monocyclic cycloalkyl substituents;
 where R c  and R d  are each independently —H or —C 1-6 alkyl;
 or R c  and R d  taken together with the nitrogen of attachment in —NR c R d  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 R e  and R f  are each independently —H or —C 1-6 alkyl;
 or R e  and R f  taken together with their nitrogen of attachment in —NR e R f  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; and 
 
 R p  and R q  are each independently —H or —C 1-6 alkyl;
 or R p  and R q  taken together with the nitrogen of attachment in —NR P R q  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 
 
         R 2  is:
 1) a phenyl group unsubstituted or substituted with one, two, or three R g  substituents; 
 where each R g  substituent is —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —N(R h )R i , —C(O)N(R h )R i , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R h )R i , —SCF 3 ,
 halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C(R i ) 2 —CN, —C(R i ) 2 —CO 2 C 1-4 alkyl, —C(R i ) 2 —CO 2 H, —C(R j ) 2 —CON(R h )R i , —C(R j ) 2 —CH 2 N(R h )R i , or —C(R j ) 2 —OH; 
 or two adjacent R g  substituents taken together form —OC 1-2  alkylO-, —C 2-6 alkylO-, or —C 2-6 alkylN(R h )—; 
 where R h  and R i  are each independently —H or —C 1-6 alkyl;
 or R h  and R i  taken together with their nitrogen of attachment in —NR h R i  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
 where each R j  is independently —H, —C 1-6 alkyl, or —CF 3 ;
 or both R j  substituents taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring; or 
 
 
 2) a thiadiazolyl or six-membered monocyclic heteroaryl ring, each substituted with —CF 3  or tert-butyl; 
 
         R 3  is —H, —CH 3 , —CF 3 ,
 halo, —CN, —COC 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(R k )R l , —CH 2 N(R k )R l , —S(O) 0-2 —C 1-6 alkyl, —S—Si(C 1-6 alkyl) 3 , —SO 2 CF 3 , or —SO 2 N(R k )R l ; or a phenyl or 6-membered heteroaryl ring, each unsubstituted or substituted with —OH, —CH 2 N(R k )R l , —C(O)N(R k )R l , —SO 2 N(R k )R l , or —CO 2 H; 
 where R k  and R l  are each independently —H or —C 1-6 alkyl; or R k  and R l  taken together with their nitrogen of attachment in —NR k R l  form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with methyl; 
 
         R 4  is —H, —CF 3 , halo, —CN, —CO 2 H, —CO 2 Cl 1-6 alkyl, —C(O)N(R n )R o , —C 1-4 alkyl-OH, —C 1-4 alkyl-N(R n )R o , —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , or —SO 2 N(R n )R o ;
 where R n  and R o  are each independently —H or —C 1-6 alkyl; 
 
         R 5  is —H, —CH 3 , halo, or —CF 3 ; and 
         R 6  and R 7  are each independently —H or methyl; or R 6  and R 7  taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring.