5-Membered Heterocyclic Amides And Related Compounds

Abstract

5-Membered heterocyclic amides and related compounds are provided, of the Formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

1 - 27 . (canceled) 
     
     
         28 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or hydrate thereof, wherein:
 Z 1 , Z 2  and Z 3  are independently N, NH, CH, S or O; such that no more than one of Z 1 , Z 2  and Z 3  is chosen from O and S; 
 W is —C(═O)NR 4 —, —NR 4 C(═O)— or —NR 4 —NR 4 —C(═O)—: 
 V is C 1 -C 6 alkylene that is substituted with from 0 to 4 substituents independently chosen from: (i) C 1 -C 4 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl and phenylC 0 -C 2 alkyl; (ii) substituents that are taken together, with any intervening carbon atoms, to form a 3- to 7-membered cycloalkyl or a 4- to 7-memhered heterocycloalkyl ring; and (iii) substituents that are taken together with R 4  and any intervening atoms to form a 4- to 7-membered heterocycloalkyl; 
 Y is C 3 -C 16 cycloalkyl, 6- to 16-membered aryl or 5- to 16-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from hydroxy, halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, —COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, (C 3 -C 2 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 R 2  represents from 0 to 2 substituents independently chosen from halogen, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, —COON, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkanoyl, C 2 -C 6 alkyl ether, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 Each R 1  is independently hydrogen, C 1 -C 6 alkyl, (C 3 -C 3 cycloalkyl)C 0 -C 2 alkyl or taken together with a substituent of V to form a 4- to 7-membered heterocycloalkyl; 
 Either:
 (i) each R 5  is independently hydrogen, —COOH, C 1 -C 6 alkyl or (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, such that at least one R 5  is not hydrogen; or 
 (ii) both R 5  moieties are taken together, with the carbon atom to which they are bound, to form a C 3 -C 7 cycloalkyl; and 
 
 R A  is a group of the formula -L-A-M, wherein:
 L is absent or C 1 -C 6 alkylene that is optionally modified by the replacement of a carbon-carbon single bond with a double or triple carbon-carbon bond, which alkylene is optionally substituted with oxo, —COOH, —SO 3 H, —SO 2 NH 2 , —PO 3 H 2 , tetrazole or oxadiazolone; 
 A is absent or CO, O, NR 6 , S, SO, SO 2 , CONR 6 , (C 4 -C 7 cycloalkyl)C 0 -C 2 alkyl, or 4- to 7-membered heterocycloalkyl; wherein R 6  is hydrogen or C 1 -C 6 alkyl; and 
 M is a (5- to 10-membered heteroaryl)C 0 -C 4 alkyl that is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbony I, aminosulfonyl, —COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, and 4- to 7-membered heterocycle; 
 
 
       such that R A  is not pyrrole. 
     
     
         29 - 45 . (canceled) 
     
     
         46 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or hydrate thereof, wherein:
 W is —C(═O)NR 4 — or —NR 4 C(═O)—; 
 X is C 2 -C 6 alkylene that is substituted with from 0 to 4 substituents independently chosen from:
 (i) hydroxy and —COOH; 
 (ii) C 1 -C 8 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, C 1 -C 6 aminoalkyl, C 2 -C 8 alkyl ether, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and phenylC 0 -C 2 alkyl; 
 (iii) substituents that are taken together, with any intervening carbon atoms, to form a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; and 
 (iv) substituents that are taken together with R 4  and any intervening atoms to form a 4- to 7-membered heterocycloalkyl; 
 each of which (ii), (iii) and (iv) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, oxo, aminocarbonyl, aminosulfonyl, —COOH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and 4- to 7-membered heterocycloalkyl; 
 
 Y is C 3 -C 16 cycloalkyl, phenyl or 6- to 10-membered heterocycle, each of which is substituted with from 0 to 6 substituents independently chosen from hydroxy, halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, —COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, (C 3 -C 2 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 R 2 , represents from 0 to 2 ring substituents independently chosen from halogen, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, —COOH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkanoyl, C 2 -C 6 alkyl ether, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 Each R 4  is independently hydrogen, C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl or taken together with a substituent of X to form a 4- to 7-membered heterocycloalkyl; 
 R A  comprises a ring and has the formula -L-A-M, wherein:
 L is absent or C 1 -C 6 alkylene that is optionally modified by the replacement of a carbon-carbon single bond with a double or triple carbon-carbon bond, which alkylene is optionally substituted with oxo, —COOH, —SO 3 H, —SO 2 NH 2 , —PO 3 H 2 , tetrazole or oxadiazolone; 
 A is absent or CO, O, NR 6 , S, SO, SO 2 , CONR 6 , NR 6 CO, (C 4 -C 7 cycloalkyl)C 0 -C 2 alkyl, 4- to 7-membered heterocycloalkyl or 5- or 6-membered heteroaryl; wherein R 6  is hydrogen or C 1 -C 6 alkyl; and 
 M is:
 (i) hydroxy, cyano, amino, halogen, aminocarbonyl, aminosulfonyl or —COON; or 
 (ii) C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (4- to 10-membered carbocycle)C 0 -C 4 alkyl, (4- to 7-membered heterocycle)C 0 -C 4 alkyl, C 1 -C 6 alkanoyloxy, C 1 -C 6 alkanoylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, C 1 -C 6 alkylsulfonyloxy, mono- or di-C 1 -C 6 alkylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, or mono- or di-(C 1 -C 6 alkyl)aminocarbonyl; each of which is substituted with from 0 to 4 substituents independently chosen from:
 (a) oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl and —COOH; and 
 (b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl, mono- or di-(C 1 -C 6 alkyl)aminoC 0 -C 2 alkyl, phenylC 0 -C 2 alkyl and (4- to 7-membered heterocycle)C 0 -C 4 alkyl; each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 1 -C 4 haloalkyl; 
 
 
 
 such that R A  is not: (i) pyridazine that is substituted with C 1 -C 6 alkoxy, (ii) substituted or unsubstituted benzyl, (iii) unsubstituted phenyl or (iv) an O-linked moiety. 
 
     
     
         47 - 56 . (canceled) 
     
     
         57 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or hydrate thereof, wherein:
 W is —C(═O)NR 4 —, —NR 4 C(═O)— or —NR 4 —NR 4 —C(═O)—; 
 X is absent or C 1 -C 6 alkylene that is substituted with from 0 to 4 substituents independently chosen from:
 (i) hydroxy and —COOH; 
 (ii) C 1 -C 8 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl, C 1 -Cominoalkyl, C 2 -C 8 alkyl ether, mono- or di-(C 1 -C 8 alkyl)aminoC 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl and phenylC 0 -C 2 alkyl; 
 (iii) substituents that are taken together, with any intervening carbon atoms, to form a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; and 
 (iv) substituents that are taken together with R 4  and any intervening atoms to form a 4- to 7-membered heterocycloalkyl; 
 each of which (ii), (iii) and (iv) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, oxo, aminocarbonyl, aminosulfonyl, —COON, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and 4- to 7-membered heterocycloalkyl; 
 
 Y is C 3 -C 16 cycloalkyl, 6- to 16-membered aryl or 5- to 16-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from hydroxy, halogen, cyano, amino, nitro, oxo, aminocarbonyl, aminosulfonyl, —COOH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, C 1 -C 6 alkanoyl, C 1 -C 6 alkylsulfonyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl and (C 1 -C 6 alkyl)sulfonylamino; 
 R 3  is hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkyl ether or (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl; 
 Each R 4  is independently hydrogen, C 1 -C 6 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl or taken together with a substituent of X to form a 4- to 7-membered heterocycloalkyl; and 
 R A  is phenylC 0 -C 4 alkyl, (5- or 6-membered heterocycle)C 0 -C 4 alkyl, phenylC 0 -C 2 alkyl-T- or (5- or 6-membered heterocycle)C 0 -C 4 alkyl-T-, wherein T is S or O; each of which is substituted with from 0 to 4 substituents independently chosen from:
 (i) oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl and —COOH; and 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 0 alkylthio, C 2 -C 6 alkyl ether, C 1 -C 0 alkanoylamino, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylamino, mono- or di-(C 1 -C 6 alkyl)aminosulfonyl, mono- or di-(C 1 -C 6 alkylamino)carbonyl and (4- to 7-membered heterocycle)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, C 2 -C 4 alkenyl and C 1 -C 4 haloalkyl. 
 
 
     
     
         58 . The compound or salt or hydrate thereof according to  claim 57 , wherein R 3  is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. 
     
     
         59 . The compound or salt or hydrate thereof according to  claim 57 , wherein —W—X—Y is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein:
 J and K are independently CH or N; 
 R 1  represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and mono- or di-(C 1 -C 6 alkyl)amino; and 
 Each R 5  is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl. 4- to 7-membered heterocycloalkyl or phenyl; or taken together with another R 5  moiety and the carbon atom or carbon atoms to which they are bound to form a C 3 -C 8 cycloalkyl or 4- to 7-membered heterocycloalkyl. 
 
     
     
         60 . The compound or salt or hydrate thereof according to  claim 59 , wherein —W—X—Y is: 
       
         
           
           
               
               
           
         
       
     
     
         61 . The compound or salt or hydrate thereof according to  claim 60 , wherein at least one R 5  is not hydrogen. 
     
     
         62 . The compound or salt or hydrate thereof according to  claim 61 , wherein both R 5  are taken together, with the carbon atom to which they are bound, to form a C 3 -C 8 cycloalkyl or 4- to 7-membered heterocycloalkyl. 
     
     
         63 . The compound or salt or hydrate thereof according to  claim 57 , wherein R A  is phenyl or 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from:
 (i) oxo, amino, and halogen; and   (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)amino, and (4- to 7-membered heterocycle)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, C 2 -C 1 alkenyl and C 1 -C a haloalkyl.   
     
     
         64 . The compound or salt or hydrate thereof according to  claim 57 , wherein R A  is 5- to 7-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from:
 (i) oxo, amino, and halogen; and   (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)amino, and (4- to 7-membered heterocycle)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 1 -C 4 haloalkyl.   
     
     
         65 . The compound or salt or hydrate thereof according to  claim 57 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 m is 0 or 1; 
 Y is: 
 
       
         
           
           
               
               
           
         
         J and K are independently CH or N; 
         R 1  represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, and mono- or di-(C 1 -C 6 alkyl)amino; 
         R 3  is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; 
         Each R 5  is independently (i) hydrogen; (ii) C 1 -C 0 alkyl, C 3 -C 7 cycloalkyl, 4- to 7-membered heterocycloalkyl or phenyl; or (iii) taken together with another R 5  moiety and the carbon atom to which they are bound to form a C 3 -C 8 cycloalkyl or 4- to 7-membered heterocycloalkyl; each of which (ii) or (iii) is substituted with from 0 to 3 substituents independently chose from hydroxy, halogen, amino, aminocarbonyl, C 1 -C 6 alkyl C 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, mono- or di-(C 1 -C 6 alkyl)aminocarbonyl, and 4- to 7-membered heterocycloalkyl; and 
         R A  is 5- to 7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from:
 (i) oxo, amino, and halogen; and 
 (ii) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkyl ether, mono- or di-(C 1 -C 6 alkyl)amino, and (4- to 7-membered heterocycle)C 0 -C 2 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, C 2 -C 4 alkenyl and C 1 -C 4 haloalkyl. 
 
       
     
     
         66 - 99 . (canceled) 
     
     
         100 . A compound or pharmaceutically acceptable salt or hydrate thereof, wherein the compound is selected from the group consisting of compounds 1-321. 
     
     
         101 - 102 . (canceled) 
     
     
         103 . A pharmaceutical composition, comprising at least one compound or salt or hydrate thereof according to  claim 28  in combination with a physiologically acceptable carrier or excipient. 
     
     
         104 - 107 . (canceled) 
     
     
         108 . A method for treating a condition responsive to P2X 7  receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or salt or hydrate thereof according to  claim 28 , and thereby alleviating the condition in the patient. 
     
     
         109 . The method according to  claim 108 , wherein the condition is pain. 
     
     
         110 . The method according to  claim 109 , wherein the pain is neuropathic pain. 
     
     
         111 . The method according to  claim 109 , wherein the pain is arthritis-associated pain, a neuropathic pain syndrome, visceral pain, dental pain, headache, stump pain, meralgia paresthetica, burning-mouth syndrome, pain associated with nerve and root damage, causalgia, neuritis, neuronitis, neuralgia, surgery-related pain, musculoskeletal pain, central nervous system pain, spinal pain, Charcot's pains, ear pain, muscle pain, eye pain, orofacial pain, carpel tunnel syndrome, acute and chronic back pain, gout, scar pain, hemorrhoidal pain, dyspeptic pains, angina, nerve root pain, complex regional pain syndrome, cancer-associated pain, pain associated with venom exposure, trauma-associated pain, pain associated with autoimmune diseases or immunodeficiency disorders, or pain that results from hot flashes, burns, sunburn, or exposure to heat, cold or external chemical stimuli. 
     
     
         112 . The method according to  claim 108 , wherein the condition is inflammation, a neurological or neurodegenerative disorder, a centrally-mediated neuropsychiatric disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder. 
     
     
         113 . The method according to  claim 108 , wherein the condition is osteoarthritis, rheumatoid arthritis, arthrosclerosis, glaucoma, irritable bowel syndrome, inflammatory bowel disease, cirrhosis, lupus, scleroderma, Alzheimer's disease, traumatic brain injury, asthma, chronic obstructive pulmonary disease, or interstitial fibrosis. 
     
     
         114 - 115 . (canceled) 
     
     
         116 . The method according to  claim 108 , wherein the patient is a human. 
     
     
         117 . The compound or salt or hydrate thereof according to  claim 28 , wherein the compound is radiolabeled. 
     
     
         118 - 122 . (canceled) 
     
     
         123 . The method according to  claim 112 , wherein the centrally-mediated neuropsychiatric disorder is depression, depression mania, bipolar disease, anxiety, schizophrenia, an eating disorder, a sleep disorder or a cognition disorder. 
     
     
         124 . The method according to  claim 112 , wherein the neurological disorder is epilepsy.