Substituted pyridine and pyrimidines and their use as glun2b receptor modulators

Abstract

Substituted pyrimidine and pyridines as NR2B receptor ligands. Such compounds may be used in NR2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by NR2B receptor activity.

1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a Pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
 wherein 
 R 1  is selected from: H, OH, C 1-4 alkyl, CH 2 OH, CH 2 F, CHF 2 , OC 1-4 alkyl, OCHF 2 , CN, and cyclopropyl; 
 X is N; 
 R 3  is:
 (a) 
 
 
       
         
           
           
               
               
           
         
         
           wherein 
           R a  is selected from: OH, (C═O)NH 2 , (C═O)NHCH 3 , (C═O)NHCH 2 CH 2 OH, CH 2 (C═O)NH 2 , CH 2 C(═O)CH 3 , (C═O)CH 3 , CH 2 NH(C═O)CH 3 , NH(C═O)C 1-4 alkyl, NCH 3 (C═O)C 1-4 alkyl, NH(C═O)CH 2 CH 2 NH 2 , NH(C═O)CH 2 CH 2 OH, NH(C═O)haloC 1-4 alkyl, NH(C═O)cyclopropyl, NHSO 2 CH 3 , 
         
       
       
         
           
           
               
               
           
         
         
           each R b  is independently selected from: H, F, CH 3  and OH; and 
           n is 0, 1 or 2; 
           (b) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein 
             R c  is selected from: NH(C═O)CH 3 , CH 2 NH(C═O)CH 3 , (C═O)CH 3 , and (C═O)NHCH 3 ; and 
             Z 1  is NHCH 2 ; 
           
           (c) 
         
       
       
         
           
           
               
               
           
         
         
           wherein 
           Z 2  is NH or CH 2 NH; or 
           (d) Z 3 —C 1-6 alkyl-NH(C═O)CH 3  or Z 3 —C 4-6 cycloalkyl-NH(C═O)CH 3 ; 
           wherein 
           Z 3  is NH, NCH 3 , or O; 
         
         R 4  is H or CH 3 ; and 
         A is selected from the group consisting of:
 (a) 
 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R d  is selected from: halo, C 1-4 alkyl, CH 2 OH, C 1-4 haloalkyl, OC 1-4 alkyl, and OC 1-4 haloalkyl; and 
           R e  is selected from: halo, C 1-4 alkyl, CH 2 OH, OC 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, and (C═O)CH 3 ; 
           (b) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein 
             R f  is H or F; and 
             R e1  is selected from: C 1-4 alkyl, C 1-4 haloalkyl, and OC 1-4 haloalkyl; and 
           
           (c) 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein 
             R d1  and R e2  are halo; and 
             R g  is OC 1-4 haloalkyl. 
           
         
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R 1  is H, OH, CH 3 , CH 2 CH 3 , CH 2 OH, OCH 3 , CH 2 F, CHF 2 , OCHF 2 , CN, or cyclopropyl. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R 3  is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R 4  is H. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein A is 
       
         
           
           
               
               
           
         
       
       wherein R d  is Cl, F, C 1-4 alkyl, CH 2 OH, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl; and R e  is halo, C 1-4  alkyl, CH 2 OH, OC 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, or (C═O)CH 3 . 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , having the structure of Formula (IC): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
 wherein 
 R 1  is selected from: H, CH 3 , CH 2 CH 3 , CH 2 OH, OCH 3 , and cyclopropyl; 
 R a  is selected from: OH, (C═O)NH 2 , (C═O)NHCH 3 , (C═O)NHCH 2 CH 2 OH, CH 2 (C═O)NH 2 , CH 2 C(═O)CH 3 , (C═O)CH 3 , CH 2 NH(C═O)CH 3 , NH(C═O)C 1-4 alkyl, NCH 3 (C═O)C 1-4 alkyl, NH(C═O)CH 2 CH 2 NH 2 , NH(C═O)CH 2 CH 2 OH, NH(C═O)CHF 2 , NH(C═O)cyclopropyl, NHSO 2 CH 3 , 
 
       
         
           
           
               
               
           
         
         each R b  is independently selected from: H, F, and CH 3 ; 
         n is 0, 1 or 2; 
         R 4  is H or CH 3 ; and 
         A is 4-(trifluoromethoxy)phenyl, 4-(trifluoromethyl)phenyl, 4-(1,1-difluoroethyl)phenyl, 4-(difluoromethoxy)phenyl, 4-(difluoromethyl)phenyl, 3-fluoro-4-(trifluoromethoxy)phenyl, 3-methyl-4-(trifluoromethoxy)phenyl, 3-methoxy-4-(trifluoromethoxy)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-(hydroxymethyl)-4-(trifluoromethoxy)phenyl, 4-(trifluoromethoxy)-3-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-fluoro-4-methyl-phenyl, 3-fluoro-4-methoxy-phenyl, 3-chloro-4-methyl-phenyl, 4-chloro-3-methyl-phenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-(hydroxymethyl)phenyl, 3-chloro-4-methoxy-phenyl, 3,4-dichlorophenyl, 3-(difluoromethoxy)-4-fluoro-phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-3-fluoro-phenyl, or 3,5-difluoro-4-(trifluoromethoxy)phenyl. 
       
     
     
         12 . The compound of  claim 1 , having the structure of Formula (ID): 
       
         
           
           
               
               
           
         
       
       or a Pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
 wherein R 3  is 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . (canceled) 
     
     
         14 . A compound selected from the group consisting of:
 1-[6-[4-(Trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]acetamide;   (trans)-N-[3-Fluoro-1-[2-methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-(hydroxymethyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   (racemic)-N-Methyl-1-[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]pyrrolidine-3-carboxamide;   (Trans)-N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]cyclopropanecarboxamide;   3-Amino-N-[1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]propanamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]azetidin-3-yl]acetamide;   1-[6-[4-(Trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-3-carboxamide;   1-[6-[4-(Difluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[2-Methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[4-(Trifluoromethyl)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[5-Methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Fluoro-4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[2-Cyclopropyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[2,5-Dimethyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[6-[3-Methoxy-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[2-Ethyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   1-[2-Methoxy-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   N-[1-[6-[4-(Difluoromethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Methyl-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-N-(2-hydroxyethyl)piperidine-4-carboxamide;   1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-N-(2-hydroxyethyl)piperidine-4-carboxamide;   1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-N-(2-hydroxyethyl)piperidine-4-carboxamide;   N-[1-[2-Methyl-6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-methyl-N-[1-[6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-(2-Hydroxyethyl)-1-[2-methyl-6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   N-(2-Hydroxyethyl)-1-[6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   N-[1-[6-[4-(1,1-Difluoroethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(3-Fluoro-4-methoxy-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(3-Chloro-4-methoxy-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(4-Chloro-3-fluoro-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(3-Chloro-4-methyl-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(4-Chloro-3-methyl-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Chloro-4-(hydroxymethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-(3-Fluoro-4-methyl-phenyl)pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[4-(Difluoromethoxy)-3-fluoro-phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-(Hydroxymethyl)-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3,5-Difluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[2-Methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (trans)-N-[3-Fluoro-1-[2-methyl-6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[4-(Trifluoromethoxy)-3-(trifluoromethyl)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-Methyl-1-[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   N-(2-Hydroxyethyl)-1-[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   4-[4-(1H-Imidazol-4-yl)-1-piperidyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine;   N-(2-Hydroxyethyl)-1-[2-methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]piperidine-4-carboxamide;   4-[4-(1H-Imidazol-4-yl)-1-piperidyl]-2-methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidine;   1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-N-(2-hydroxyethyl)piperidine-4-carboxamide;   4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-6-[4-(1H-imidazol-4-yl)-1-piperidyl]pyrimidine;   2-[1-[6-[4-(Trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[4-(Trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   4-[4-(1H-Imidazol-2-yl)-1-piperidyl]-6-[4-(trifluoromethoxy)phenyl]pyrimidine;   N-[[1-[6-[4-(Trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]methyl]acetamide;   8-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4,8-diazaspiro[4;5]decan-3-one;   1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]piperidin-4-ol;   N-Methyl-1-[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]azetidine-3-carboxamide;   (*R/*R)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]acetamide;   (*S/*S)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]acetamide;   (trans)-N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*S/*S)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*R/*R)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (trans)-N-[3-Fluoro-1-[6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*S/*S)—N-[3-Fluoro-1-[6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*R/*R)—N-[3-Fluoro-1-[6-[3-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (trans)-N-[1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-3-fluoro-4-piperidyl]acetamide;   (*S/*S)—N-[1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-3-fluoro-4-piperidyl]acetamide;   (*R/*R)—N-[1-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-3-fluoro-4-piperidyl]acetamide;   (cis)-N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*R/*S)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (*S/*R)—N-[3-Fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-methyl-4-piperidyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-pyrimidin-4-yl]-4-piperidyl]methanesulfonamide;   4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methyl-6-[4-(1H-pyrazol-5-yl)-1-piperidyl]pyrimidine;   1-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]ethanone;   1-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]propan-2-one;   N-[[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]azetidin-3-yl]methyl]acetamide;   (racemic)-N-[[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]pyrrolidin-3-yl]methyl]acetamide;   (racemic)-N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]pyrrolidin-3-yl]acetamide;   (racemic)-N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-3-piperidyl]acetamide;   (racemic)-N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]azepan-4-yl]acetamide;   (trans)-N-[3-Fluoro-1-[6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   (racemic)-N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-3-methyl-4-piperidyl]acetamide;   (racemic)-N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-2-methyl-4-piperidyl]acetamide;   2,2-Difluoro-N-[1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   1-[2-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-2,6-diazaspiro[3;3]heptan-6-yl]ethanone;   N-[4-[[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]amino]cyclohexyl]acetamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]propanamide;   N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]-3-hydroxy-propanamide;   (trans)-3-Amino-N-[3-fluoro-1-[6-[3-fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]propanamide;   N-[3-[[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]amino]propyl]acetamide;   (racemic)-N-[3-[[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]amino]-2-methyl-propyl]acetamide;   (*R)—N-[3-[[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]amino]-2-methyl-propyl]acetamide;   (*S)—N-[3-[[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]amino]-2-methyl-propyl]acetamide;   
       and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof. 
     
     
         15 . A compound is selected from the group consisting of:
 N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   N-[1-[6-[3-Methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide;   
       and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof. 
     
     
         16 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, and a pharmaceutically acceptable excipient. 
     
     
         18 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by NR2B receptor activity, comprising administering to the subject an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. 
     
     
         19 . The method of  claim 18 , wherein the disease, disorder, or medical condition mediated by the NR2B receptor is selected from the group consisting of: bipolar disorder, major depressive disorder, treatment-resistant depression, post-partum depression, seasonal affective disorder, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, cognitive impairment, head injury, spinal cord injury, stroke, epilepsy, dyskinesias, amyotrophic lateral sclerosis, neurodegeneration associated with bacterial or chronic infections, pain, diabetic neuropathy, migraine, cerebral ischemia, schizophrenia, encephalitis, autism and autism spectrum disorders, memory and learning disorders, obsessive compulsive disorder, attention deficit hyperactivity disorder (ADHD), and addictive illnesses. 
     
     
         20 . The method of  claim 18 , wherein the disease, disorder, or medical condition is selected from the group consisting of treatment-resistant depression, major depressive disorder and bipolar disorder. 
     
     
         21 . The method of  claim 20 , wherein the disease, disorder, or medical condition is treatment-resistant depression. 
     
     
         22 . The method of  claim 20 , wherein the disease, disorder, or medical condition is major depressive disorder.