Substituted heteroaromatic pyrazolo-pyridines and their use as glun2b receptor modulators

Abstract

Substituted Pyrazolo-pyridines as GluN2B receptor ligands. Such compounds may be used in GluN2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by GluN2B receptor activity.

1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof,
 wherein: 
 
         R 1  is H, halo, or CH 3 ; 
         Ar 1  is selected from the group consisting of:
 (a) phenyl substituted with one member selected from the group consisting of: halo, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 perhaloalkyl, and OC 1-6 perhaloalkyl; 
 (b) phenyl substituted with two or three members each independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 perhaloalkyl, OC 1-6 perhaloalkyl, and CO 2 H; and 
 (c) thienyl substituted with a member selected from the group consisting of: halo, C 1-6 alkyl, and C 1-6 perhaloalkyl; and pyridine substituted with CF 3 ; and 
 
         R 2  is: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is H. 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is F. 
     
     
         4 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is CH 3 . 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar 1  is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar 1  is phenyl substituted with F, Cl, CH 3 , OCH 3 , CF 2 H, CF 3 , CF 2 CH 3 , or OCHF 2 . 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar 1  is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar 1  is phenyl substituted with two or three members independently selected from the group consisting of: F, Cl, Br, CH 3 , CF 2 H, CF 3 , CF 2 CH 3 , and OCHF 2 . 
     
     
         9 . The compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar 1  is 
       
         
           
           
               
               
           
         
       
     
     
         10 - 25 . (canceled) 
     
     
         26 . A compound selected from the group consisting of:
 1-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;   1-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;   3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;   1-[(4-Methoxyphenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;   6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridine;   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;   
       and pharmaceutically acceptable salts and stereoisomers thereof. 
     
     
         27 . (canceled) 
     
     
         28 . A pharmaceutical composition comprising:
 (A) at least one compound selected from compounds of Formula (I):   
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and stereoisomers of compounds of Formula (I), 
       wherein: 
       R 1  is H, halo, or CH 3 ; 
       Ar 1  is selected from the group consisting of:
 (a) phenyl substituted with one member selected from the group consisting of: halo, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 perhaloalkyl, and OC 1-6 perhaloalkyl; 
 (b) phenyl substituted with two or three members each independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 perhaloalkyl, OC 1-6 perhaloalkyl, and CO 2 H; and
 (c) thienyl substituted with a member selected from the group consisting of: halo, C 1-6 alkyl, and C 1-6 perhaloalkyl; and pyridine substituted with CF 3 ; and 
 
 
       R 2  is: 
       
         
           
           
               
               
           
         
          and 
         (B) at least one pharmaceutically acceptable excipient. 
       
     
     
         29 - 31 . (canceled) 
     
     
         32 . A pharmaceutical composition comprising the compound of  claim 26  or a pharmaceutically acceptable salt thereof or stereoisomer thereof and at least one pharmaceutically acceptable excipient. 
     
     
         33 . A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         34 . A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         35 . A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the compound of  claim 26  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         36 . A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the compound of  claim 26  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
         37 . A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 28 . 
     
     
         38 . A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 28 . 
     
     
         39 . A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 32 . 
     
     
         40 . A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 32 .