Bicycloheteroaryl compounds as P2X7 modulators and uses thereof

Abstract

Bicycloheteroaryl compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

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       3 . A bicycloheteroaryl compound capable of modulating P2X 7  receptor activity, in vivo, having a formula: 
     
       
         
         
             
             
         
       
       wherein 
       A is selected from CO; 
       B and Y are independently selected from CR 2a  and CR 2a R 2b ; 
       W, W′ and Z are independently selected from CR 4  and N, provided that all three of W, W′ and Z can not be N at the same time; 
       L 1  is a bond or a C 1 -C 5  alkylene group which can be optionally substituted by a substituent selected from alkyl, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halogen, carbamoyl, and C 1 -C 6  alkoxy; 
       n is 0, 1, 2 or 3; 
       R 1  is selected from a 3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl ring system, which can be optionally substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamido; 
       each of R 2a , R 2b , R 2′  and R 2″  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6  alkyl; or any of R 2′  and R 2″  can join together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms; 
       R 3  is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl, and substituted or unsubstituted bicycloheteroaryl; provided when L 1  is a bond, R 3  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
       R 4  is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; 
       and the dotted bond is a single or a double bond; 
       or a pharmaceutically acceptable salt, solvate or prodrug thereof; 
       and stereoisomers and tautomers thereof. 
     
   
   
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       29 . A compound according to  claim 3  wherein R 3  is 
     
       
         
         
             
             
         
       
       and wherein n′ is selected from 1-5 and each of R 4′  is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio. 
     
   
   
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       42 . A compound according to  claim 3  wherein the compound is selected from 
     2-Adamantan-1-yl-N-(2-benzyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide; 
     2-(1-adamantyl)-N-(2-benzyl-1-oxo-3,4-dihydroisoquinolin-5-yl)acetamide; 
     2-(1-adamantyl)-N-[2-[(4-fluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(4-fluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2,4-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2-fluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(7,10-dioxabicyclo[4.4.0]deca-2,4,11-trien-4-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2-chlorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(tetrahydrofuran-2-ylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methylpyrazin-2-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(1-phenylethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-furylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(3-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(4-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(tetrahydropyran-4-ylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[(1,3,5-trimethylpyrazol-4-yl)methyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1,5-dimethylpyrazol-3-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[(1S)-1-phenylethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[(1R)-1-phenylethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2-chloro-6-fluoro-phenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(o-tolylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(1,4-dioxan-2-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2,4-difluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(tetrahydrofuran-2-ylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(3-pyridylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[(1,3,5-trimethylpyrazol-4-yl)methyl]-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-furylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(1-phenylethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methylpyrazin-2-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2,6-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-3-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(3,4-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-dimethylaminoethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methylisoxazol-3-yl)methyl]-1 oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methyl-2-phenyl-triazol-4-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[(2S)-tetrahydrofuran-2-yl]methyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(1-phenylethyl)-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(2-fluorophenyl)methyl]-1 oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(2-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(1,5-dimethylpyrazol-3-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(1-methyl-4-piperidyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(4-dimethylaminophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     tert-butyl 4-[[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]methyl]piperidine-1-carboxylate; 
     2-(1-adamantyl)-N-[1-oxo-2-(4-piperidylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1-ethylpyrrolidin-2-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     N-(2-benzyl-1-oxo-5-isoquinolyl)-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-[2-(2-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-[[4-(trifluoromethyl)phenyl]methyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(4-fluorophenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(4-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(3-pyridylmethyl)-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(5-methylpyrazin-2-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     N-[2-(1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-ylmethyl)-1-oxo-5-isoquinolyl]-2-(3,5-dimethyl-1-adamantyl)acetamide; and 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(4-methylsulfonylphenyl)methyl]-1-oxo-5-isoquinolyl]acetamide. 
   
   
       43 . A compound according to  claim 3  wherein the compound is selected from 
     2-(3,5-dimethyl-1-adamantyl)-N-[2 (2-furylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(5-methylisoxazol-3-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(1,4-dioxan-2-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(2-dimethylaminoethyl)-1-oxo-5-isoquinolyl]acetamide; 
     N-[2-[(2,4-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     N-[2-[(2,4-difluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-3-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1-methyl-4-piperidyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(4-methylsulfonylphenyl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(7,10-dioxabicyclo[4.4.0]deca-1,3,5-trien-5-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(1-ethylpyrrolidin-2-yl)methyl]-1-oxo-5-isoquinolyl]acetamide; 
     tert-butyl 2-[[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]methyl]pyrrolidine-1-carboxylate; 
     tert-butyl (2R)-2-[[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]methyl]pyrrolidine-1-carboxylate; 
     tert-butyl (2S)-2-[[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]methyl]pyrrolidine-1-carboxylate; 
     (2S)-2-[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]-3-phenyl-propanamide; 
     N-(2-benzyl-1-oxo-3,4-dihydroisoquinolin-5-yl)-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(5-methylpyrazin-2-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-morpholinoethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(3-morpholinopropyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[2-(3-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[2-(4-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[2-(2-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-thiomorpholinoethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[3-(4-methylpiperazin-1-yl)propyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(1-methylpyrrolidin-2-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(3-pyrrolidin-1-ylpropyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2-fluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-9-ylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(o-tolylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2-chlorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1-methyl-4-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-pyridylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(1,4-dioxan-2-ylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1,5-dimethylpyrazol-3-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(2,6-difluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(3,4-difluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-dimethylaminoethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methylisoxazol-3-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(7,10-dioxabicyclo[4.4.0]deca-2,4,11-trien-4-ylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-(1-oxo-2H-isoquinolin-5-yl)acetamide; 
     2-(1-adamantyl)-N-(2-methyl-1-oxo-5-isoquinolyl)acetamide; 
     2-(1-adamantyl)-N-[2-[(5-methylpiperazin-2-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(2-pyridylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(pyrrolidin-2-ylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[(2S)-pyrrolidin-2-yl]methyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[[(2R)-pyrrolidin-2-yl]methyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-[(1S)-1-phenylethyl]-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(tetrahydropyran-4-ylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     N-[2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(2-morpholinoethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     N-(2-benzyl-1-oxo-5-isoquinolyl)-3-fluoro-adamantane-1-carboxamide; 
     2-(1-adamantyl)-N-[2-(2-morpholinoethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-[(1S)-1-phenylethyl]-5-isoquinolyl]acetamide; 
     N-[2-[(3,4-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(tetrahydropyran-4-ylmethyl)-5-isoquinolyl]acetamide; 
     N-[2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-5-isoquinolyl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(3-morpholinopropyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(7,10-dioxabicyclo[4.4.0]deca-1,3,5-trien-3-ylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(3-imidazol-1-ylpropyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[(3-methyl-2-pyridyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-hydroxy-1-(hydroxymethyl)ethyl]-1 oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(carbamoylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     3-[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]propanamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-piperazin-1-ylethyl)-5-isoquinolyl]acetamide; 
     tert-butyl 4-[2-[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]ethyl]piperazine-1-carboxylate; 
     N-(2-benzyl-1-oxo-3,4-dihydroisoquinolin-5-yl)-3-fluoro-adamantane-1-carboxamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(tetrahydropyran-4-ylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[(1-ethylpyrrolidin-2-yl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     N-[2-[(2,6-difluorophenyl)methyl]-1-oxo-5-isoquinolyl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(1-adamantyl)-N-[2-(3-imidazol-1-ylpropyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[1-(3-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(1-phenylethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(2-fluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     N-[2-[(2,6-difluorophenyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]-2-(3,5-dimethyl-1-adamantyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-(1-oxo-2H-isoquinolin-5-yl)acetamide; 
     2-(1-adamantyl)-N-[2-[2-(4-methylpiperazin-1-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(1,1-dimethyl-2-morpholino-ethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-hydroxyethyl)-1-oxo-5-isoquinolyl]acetamide; 
     tert-butyl 2-[[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-3,4-dihydroisoquinolin-2-yl]methyl]pyrrolidine-1-carboxylate; 
     2-(1-adamantyl)-N-[1-oxo-2-[1-(2-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-[1-(4-pyridyl)ethyl]-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(2,6-dimethylmorpholin-4-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-diethylaminoethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-(2-isobutyl-1-oxo-5-isoquinolyl)acetamide; 
     2-(1-adamantyl)-N-[2-(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-3-ylmethyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(3-furylmethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-(1-oxo-3,4-dihydro-2H-isoquinolin-5-yl)acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(4-piperidylmethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-(3-morpholinopropyl)-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-pyrrolidin-1-ylethyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[3-(4-methylpiperazin-1-yl)propyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(1-methylpyrrolidin-2-yl)ethyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(3-pyrrolidin-1-ylpropyl)-3,4-dihydroisoquinolin-5-yl]acetamide; 
     (2R)-2-[5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]-3-cyclohexyl-propanamide; 
     (2S)-2-[(2R)-5-[[2-(1-adamantyl)acetyl]amino]-1-oxo-2-isoquinolyl]-3-(1H-imidazol-4-yl)propanamide; 
     2-(1-adamantyl)-N-[(2S)-2-[(1R)-1-(hydroxymethyl)-2-(1H-imidazol-4-yl)ethyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(2-pyridylamino)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[1-oxo-2-(thiazol-2-ylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-[2-(4-methylpiperazin-1-yl)ethyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; 
     2-(1-adamantyl)-N-[2-[1-(hydroxymethyl)-2-methyl-propyl]-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-[2-(2-hydroxy-1-methyl-ethyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[1-oxo-2-(4-piperidylmethyl)-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-methyl-N-(1-oxo-2-vinyl-5-isoquinolyl)acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-(3-morpholinopropyl)-1-oxo-5-isoquinolyl]acetamide; 
     2-(1-adamantyl)-N-(2-isobutyl-1-oxo-5-isoquinolyl)-N-methyl-acetamide; 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[(1-methyl-4-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-5-yl]acetamide; and 
     2-(3,5-dimethyl-1-adamantyl)-N-[2-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-oxo-5-isoquinolyl]acetamide; and 
     2-Adamantan-1-yl-N-[2-((S)-2-hydroxy-1-methyl-ethyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-acetamide. 
   
   
       44 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of  claim 3 . 
   
   
       45 . (canceled) 
   
   
       46 . (canceled) 
   
   
       47 . (canceled) 
   
   
       48 . (canceled) 
   
   
       49 . A method for preventing, treating or ameliorating in a mammal a disease or condition that is causally related to the aberrant activity of the P2X 7  receptor in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition according to  claim 44 . 
   
   
       50 . (canceled) 
   
   
       51 . (canceled) 
   
   
       52 . (canceled) 
   
   
       53 . (canceled) 
   
   
       54 . A method for preventing, treating or ameliorating in a mammal a disease or condition selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache, Parkinson's disease, multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation, traumatic brain injury and encephalitis; centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itch/pruritus, psoriasis; obesity; lipid disorders; cancer; blood pressure; spinal cord injury; and renal disorders which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition of  claim 44 . 
   
   
       55 . (canceled) 
   
   
       56 . (canceled) 
   
   
       57 . (canceled) 
   
   
       58 . (canceled) 
   
   
       59 . (canceled) 
   
   
       60 . (canceled) 
   
   
       61 . A method of treating a mammal suffering from at least one symptom selected from the group consisting of symptoms of exposure to capsaicin, symptoms of burns or irritation due to exposure to heat, symptoms of burns or irritation due to exposure to light, symptoms of burns, bronchoconstriction or irritation due to exposure to tear gas, and symptoms of burns or irritation due to exposure to acid, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition of  claim 44 . 
   
   
       62 . The method of  claim 61 , wherein the pain is associated with a condition selected from the group consisting of postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, Charcot's pain, toothache, venomous snake bite, spider bite, insect sting, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, sciatic neuritis, peripheral neuritis, polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, cancer, and trauma. 
   
   
       63 . (canceled) 
   
   
       64 . (canceled) 
   
   
       65 . (canceled)