Heteroaryl Amide Analogues

Abstract

Compounds, pharmaceutical compositions, and methods of use are disclosed for heteroaryl amide analogues of formula Ia and/or Ib: In certain embodiments, the heteroaryl amide analogues are agonists and/or ligands of dopamine receptors and may be useful, inter alia, for the treatment of a condition responsive to P2X 7 receptor modulation, for example, pain, inflammation, a neurological or neurodegenerative disorder, a cardiovascular disorder, an ocular disorder or an immune system disorder.

1 . A compound or salt or hydrate thereof according to formula Ia or Ib: 
       
         
           
           
               
               
           
         
         wherein: 
         U is CR 1A ; 
         W is —C(═O)NR 4 —, —NR 4 C(═O)— or —NR 4 —NR 4 —C(═O)—; 
         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; 
         X is absent or C 1 -C 6 alkylene that is optionally substituted with 1 to 4 substituents selected from R B , R C , R D , and R E ; 
         R B , R C , R D , and R E  are each independently hydroxy, —COOH, 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; or any two of R B , R C , R D , and R E  taken together with the carbon atom or atoms through which they are connected form a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl; or any one of R B , R C , R D , and R E  taken together with R 4  and the atom or atoms through which they are connected form a 4- to 7-membered heterocycloalkyl; 
         Y is C 1 -C 8 alkyl, C 3 -C 16 cycloalkyl, 4- to 16-membered heterocycloalkyl, 6- to 16-membered aryl or 5- to 16-membered heteroaryl, each of which is optionally substituted with 1 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 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; 
         Z 1 , Z 2 , Z 3 , and Z 4  are independently CR 1  or N; 
         R 1A  is hydrogen, hydroxy, halogen, cyano, amino, 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 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 or (C 1 -C 6 alkyl)sulfonylamino; 
         each R 1  is independently hydrogen, hydroxy, halogen, cyano, amino, 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 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 or (C 1 -C 6 alkyl)sulfonylamino; 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 (i) the replacement of a carbon-carbon single bond with a double or triple carbon-carbon bond, or (ii) substitution 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, halogen, cyano, amino, aminocarbonyl, aminosulfonyl, carboxyalkyl, or —COOH; or 
         (ii) C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (4- to 10-membered carbocycle)C 0 -C 4 alkyl, (4- to 10-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 optionally substituted with 1 to 4 substituents independently chosen from oxo, amino, halogen, hydroxy, cyano, aminocarbonyl, aminosulfonyl, —COOH, alkoxycarbonyl, alkanoyloxy, C 1 -C 6 alkyl, 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; 
         provided that for a compound of Formula Ia; 
         (a) when U is CH, then W—X—Y is other than: 
       
       
         
           
           
               
               
           
         
         wherein Rx is H or C(═O)—O-alkyl; 
         (b) when one of Z 1 , Z 2 , Z 3 , and Z 4  is N, and the others of Z 1 , Z 2 , Z 3 , and Z 4  are each CH, R A  and Y are each independently alkyl, aryl aralkyl or heteroaryl, W is —C(═O)N(H)—, and U is CR 1A , wherein R 1A  is other than OH; 
         (c) when Z 1 , Z 2 , Z 3 , and Z 4  are each CH, R A  is unsubstituted phenyl, W is —C(═O)N(H)—, X is unsubstituted alkylene or alkylene substituted with one hydroxyl, Y is dialkylamino, unsubstituted heterocycloalkyl, or heterocycloalkyl substituted with one alkyl, and U is CR 1A , wherein R 1A  is other than halogen; and 
         (d) when Z 1 , Z 2 , Z 3 , and Z 4  are each CR 1 , at least two of R 1  are H and the remaining R 1  are each independently H, halogen, nitro, hydroxy, or alkoxy, R A  is cycloalkyl or substituted or unsubstituted phenyl, W is —C(═O)N(H)—, X is unsubstituted alkylene, Y is alkyl or cycloalkyl each optionally substituted with one COOH, dialkylamino, unsubstituted heteroaryl, unsubstituted heterocycloalkyl, or heterocycloalkyl substituted with nitrile or amino, and U is CR 1A , wherein R 1A  is other than alkyl. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound or salt or hydrate thereof according to  claim 2 , having formula Ia. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The compound or salt or hydrate thereof according to  claim 1 , wherein R B , R C , R D , and R E  are each independently C 1 -C 4 alkyl, (C 3 -C 8 cycloalkyl)C 0 -C 2 alkyl, or phenylC 0 -C 2 alkyl; or any two of R B , R C , R D , and R E  taken together with the carbon atom or atoms through which they are connected form a 3- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl. 
     
     
         8 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The compound or salt or hydrate thereof according to  claim 1 , wherein Y is C 1 -C 8 alkyl, C 3 -C 16 cycloalkyl, 6- to 16-membered aryl or 5- to 16-membered heteroaryl, each optionally substituted. 
     
     
         12 . (canceled) 
     
     
         13 . The compound or salt or hydrate thereof according to  claim 11 , wherein Y is optionally substituted with from 1 to 3 substituents. 
     
     
         14 . The compound or salt or hydrate thereof according to  claim 1 , wherein Z 1 , Z 2 , Z 3 , and Z 4  are CH. 
     
     
         15 . The compound or salt or hydrate thereof according to  claim 1 , wherein W is —NR 4 C(═O)—. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The compound or salt or hydrate thereof according to  claim 1 , wherein R A  is other than halophenyl, other than haloaryl, other than cycloalkyl, other than thienyl, and/or other than carbocyclic. 
     
     
         20 - 24 . (canceled) 
     
     
         25 . The compound or salt or hydrate thereof according to  claim 1 , wherein when R A  is optionally substituted heteroaryl, said heteroaryl contains at least one nitrogen ring atom. 
     
     
         26 . The compound or salt or hydrate thereof according to  claim 1 , wherein when R A  is optionally substituted heteroaryl, said heteroaryl contains at least two nitrogen ring atoms. 
     
     
         27 . (canceled) 
     
     
         28 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is other than unsubstituted —C(═O)N(H)aralkyl. 
     
     
         29 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is other than unsubstituted —C(═O)N(H)heteroaralkyl. 
     
     
         30 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is other than unsubstituted —C(═O)N(H)heterocyclic. 
     
     
         31 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is other than unsubstituted —C(═O)N(H)alkoxyalkyl. 
     
     
         32 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is other than unsubstituted —C(═O)N(H)R v , wherein R v  is aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl, alkyl, alkenyl, or alkynyl. 
     
     
         33 . The compound or salt or hydrate thereof according to  claim 1 , wherein U is CH and W—X—Y is optionally substituted —C(═O)N(H)R v , wherein R v  is arylC 1 -C 4 alkyl or heteroarylC 1 -C 4 alkyl. 
     
     
         34 . The compound or salt or hydrate thereof according to  claim 1 , wherein W is —C(═O)N(H)—. 
     
     
         35 . The compound or salt or hydrate thereof according to  claim 34 , wherein M is optionally substituted heteroaryl. 
     
     
         36 . The compound or salt or hydrate thereof according to  claim 35 , wherein said heteroaryl contains at least one nitrogen ring atom. 
     
     
         37 . The compound or salt or hydrate thereof according to  claim 35 , wherein said heteroaryl contains at least two nitrogen ring atoms. 
     
     
         38 . The compound or salt or hydrate thereof according to  claim 37 , wherein M is optionally substituted pyrimidinyl. 
     
     
         39 . The compound or salt or hydrate thereof according to  claim 38 , wherein M optionally substituted pyrimidin-2-yl. 
     
     
         40 . The compound or salt or hydrate thereof according to  claim 34 , wherein X is C 1 -C 2 alkylene, optionally substituted. 
     
     
         41 . The compound or salt or hydrate thereof according to  claim 40 , wherein X is C 1 -C 2 alkylene, substituted with C 1 -C 4 alkyl. 
     
     
         42 . (canceled) 
     
     
         43 . The compound or salt or hydrate thereof according to  claim 40 , wherein X is substituted with at least 2 substituents selected from R B , R C , R D , and R E , wherein:
 any two of R B , R C , R D , and R E  taken together with the carbon atom or atoms through which they are connected form a 5- to 6-membered cycloalkyl.   
     
     
         44 . The compound or salt or hydrate thereof according to  claim 34 , wherein Y is an optionally substituted carbocycle or an optionally substituted heterocycle. 
     
     
         45 . The compound or salt or hydrate thereof according to  claim 44 , wherein Y is adamantyl, phenyl, pyridyl, or morpholinyl, each of which are optionally substituted. 
     
     
         46 . A compound or salt or hydrate thereof according to  claim 1 , wherein the compound is:
 N-(adamantan-1-ylmethyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{4-methyl-2-[4-(trifluoromethyl)phenyl]pentyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)pentyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   1-pyrimidin-2-yl-N-({1-[4-(trifluoromethyl)phenyl]cyclohexyl}methyl)-1H-indole-3-carboxamide;   N-{[1-(4-chlorophenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-methoxyphenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[(1-morpholin-4-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   2-{3-[(adamantan-1-ylmethyl)carbamoyl]-1H-indol-1-yl}benzoic acid;   N-[4-methyl-2-(4-methylphenyl)pentyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-(4-methyl-2-pyridin-3-ylpentyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-(4-methyl-2-phenylpentyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(6-methylpyridin-3-yl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-fluorophenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   2-{3-[(adamantan-1-ylmethyl)carbamoyl]-1H-indol-1-yl}pentanoic acid;   1-(5-fluoropyrimidin-2-yl)-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1H-indole-3-carboxamide;   1-(3-ethylpyrazin-2-yl)-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1H-indole-3-carboxamide;   4-chloro-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-methoxyphenyl)cyclopentyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-methylphenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-chloro-3-fluorophenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   Methyl 2-(3-{[(1-pyridin-3-ylcyclohexyl)methyl]carbamoyl}-1H-indol-1-yl)nicotinate;   N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   4-bromo-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-cyano-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-methoxyphenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   N-{[1-(4-fluorophenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   N-{[1-(6-methylpyridin-3-yl)cyclohexyl]methyl}-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   7-chloro-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-(4-methyl-2-pyridin-3-ylpentyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-4-methylpentyl]-4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-[4-methyl-2-(4-methylphenyl)pentyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-{4-methyl-2-[4-(trifluoromethyl)phenyl]pentyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-chloro-3-fluorophenyl)cyclohexyl]methyl}-4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-{[1-(4-methylphenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-{[1-(4-methoxyphenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-{[1-(4-fluorophenyl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-chlorophenyl)cyclohexyl]methyl}-4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   1-Pyrimidin-2-yl-1H-indole-3,4-dicarboxylic acid 4-amide 3-[(1-pyridin-3-yl-cyclohexylmethyl)-amide];   1-[(1-methyl-1H-imidazol-2-yl)methyl]-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1H-indole-2-carboxamide;   4-methyl-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-methyl-N-(4-methyl-2-pyridin-3-ylpentyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-methoxyphenyl)cyclohexyl]methyl}-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-4-methylpentyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-{[1-(4-chlorophenyl)cyclohexyl]methyl}-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-4-(trifluoromethyl)-1H-indole-3-carboxamide;   N-(adamantan-1-ylmethyl)-4-chloro-1-[2-(dimethylamino)ethyl]-1H-indole-3-carboxamide;   N-(adamantan-1-ylmethyl)-4-chloro-1-[3-(dimethylamino)propyl]-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-4-methylpentyl]-1-[3-(dimethylamino)propyl]-1H-indole-3-carboxamide;   4-chloro-1-[3-(dimethylamino)propyl]-N-(4-methyl-2-pyridin-3-ylpentyl)-1H-indole-3-carboxamide;   4-chloro-1-[2-(dimethylamino)ethyl]-N-(4-methyl-2-pyridin-3-ylpentyl)-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-4-methylpentyl]-1-[2-(dimethylamino)ethyl]-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-4-fluoro-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-fluoro-N-[2-(6-methoxypyridin-3-yl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(6-methoxypyridin-3-yl)-2-piperidin-1-ylethyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-(adamantan-1-ylmethyl)-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-2-piperazin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-(2-morpholin-4-yl-2-phenylethyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-{2-piperidin-1-yl-2-[4-(trifluoromethyl)phenyl]ethyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chloro-3-fluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(6-methoxypyridin-3-yl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(3,4-difluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   3-chloro-1-[(1-methyl-1H-imidazol-2-yl)methyl]-N-(4-methyl-2-pyridin-3-ylpentyl)-1H-indole-2-carboxamide;   4-chloro-N-[(1-pyridin-3-ylcyclohexyl)methyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-(4-methyl-2-pyridin-3-ylpentyl)-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   2-adamantan-1-yl-N-(4-chloro-1-pyrimidin-2-yl-1H-indol-3-yl)acetamide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (adamantan-1-ylmethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-adamantan-1-yl-ethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid ((R)-6,6-dimethylbicyclo[3.1.1]hept-2-ylmethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-p-tolyl-pentyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2-(4-chloro-phenyl)-4-methyl-pentyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1-(4-chloro-phenyl)-cyclohexylmethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1-(4-trifluoromethyl-phenyl)-cyclohexylmethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1-(4-methoxy-phenyl)-cyclohexylmethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [4-methyl-2-(4-trifluoromethyl-phenyl)-pentyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2-(4-chloro-phenyl)-pentyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-pyridin-3-yl-pentyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [1-(4-chloro-phenyl)-cyclobutylmethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-adamantan-1-yl-2-hydroxy-ethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-methyl-butyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-phenyl-pentyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-methyl-2-phenyl-pentyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-cyclopentyl-2-phenyl-propyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2-cyclohexyl-2-phenyl-ethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (2,3-diphenyl-propyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3-phenyl-butyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-phenyl-butyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2-(4-bromo-phenyl)-ethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid adamantan-2-ylamide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid cycloheptylmethyl-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid [2-(2-bromo-phenyl)-ethyl]-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid ((1S,2R)-2-hydroxy-cyclohexylmethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (1-hydroxy-cyclopentylmethyl)-amide;   4-Chloro-1-pyrimidin-2-yl-1H-indole-3-carboxylic acid (4-hydroxy-tetrahydro-thiopyran-4-ylmethyl)-amide;   N-[2-(4-fluorophenyl)-2-piperidin-1-ylethyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(3,4-difluorophenyl)-2-piperidin-1-ylethyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-methyl-N-(2-morpholin-4-yl-2-phenylethyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   3-chloro-N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-indole-2-carboxamide;   N-{[4-(4-chlorophenyl)tetrahydro-2H-pyran-4-yl]methyl}-4-methyl-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   3-chloro-N-{[4-(4-chlorophenyl)tetrahydro-2H-pyran-4-yl]methyl}-1-[(1-methyl-1H-imidazol-2-yl)methyl]-1H-indole-2-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-4-methyl-1-pyrazin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-4-methyl-1-pyrazin-2-yl-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-(3-cyanopyridin-2-yl)-4-methyl-1H-indole-3-carboxamide;   1-(3-cyanopyridin-2-yl)-4-methyl-N-(2-morpholin-4-yl-2-phenylethyl)-1H-indole-3-carboxamide;   N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-1-(3-cyanopyridin-2-yl)-4-methyl-1H-indole-3-carboxamide;   4-methyl-N-(4-methyl-2-morpholin-4-ylpentyl)-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-{2-piperidin-1-yl-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-fluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[(1-hydroxycycloheptyl)methyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(3,4-difluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(2,4-difluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-indole-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-2-morpholin-4-ylethyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-[2-(4-chlorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-{[4-(4-chlorophenyl)tetrahydro-2H-pyran-4-yl]methyl}-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-[(1-hydroxycycloheptyl)methyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-[(1-hydroxycyclohexyl)methyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-[2-(3,4-difluorophenyl)-2-piperidin-1-ylethyl]-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide;   4-chloro-N-(2-morpholin-4-yl-2-phenylethyl)-1-pyrimidin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; or   4-chloro-N-{[1-(4-methylpiperazin-1-yl)cyclohexyl]methyl}-1-pyrimidin-2-yl-1H-indole-3-carboxamide.   
     
     
         47 - 48 . (canceled) 
     
     
         49 . The pharmaceutical composition, comprising at least one compound or salt or hydrate thereof according to  claim 1  in combination with a physiologically acceptable carrier or excipient. 
     
     
         50 - 53 . (canceled) 
     
     
         54 . 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 1 , and thereby alleviating the condition in the patient. 
     
     
         55 . The method according to  claim 54 , wherein the condition is pain. 
     
     
         56 . The method according to  claim 55 , wherein the pain is neuropathic pain. 
     
     
         57 . The method according to  claim 55 , 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. 
     
     
         58 . The method according to  claim 54 , 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. 
     
     
         59 . The method according to  claim 54 , 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. 
     
     
         60 . (canceled) 
     
     
         61 . The method according to  claim 54 , wherein the patient is a human. 
     
     
         62 . The compound or salt or hydrate thereof according to  claim 1 , wherein the compound is radiolabeled. 
     
     
         63 - 67 . (canceled) 
     
     
         68 . The method according to  claim 58 , wherein the centrally-mediated neuropsychiatric disorder is depression, depression mania, bipolar disease, anxiety, schizophrenia, an eating disorder, a sleep disorder or a cognition disorder. 
     
     
         69 . The method according to  claim 58 , wherein the neurological disorder is epilepsy.