Bicarbocyclic and tricarbocyclic ethynyl derivatives and uses of same

Abstract

The present invention provides compounds of formula (I): where R 1 , R 2 , X, Y and n are as described herein, and pharmaceutical compositions, uses and methods comprising same.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently aryl, heteroaryl, heterocyclyl which is optionally mono-, di-, or tri-substituted independently with alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, ketocycloalkyl, alkoxy, hydroxylalkyl, trifluoromethyl; and 
         When n=0 and 1, X and Y are H; and 
         When n=1, both X and Y are bonds that are linked to —CH 2 — to form a tricyclic adamantyl core. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are both heteroaryl. 
     
     
         3 . The compound of  claim 1 , wherein either R 1  or R 2  is heteroaryl 
     
     
         4 . The compound of  claim 1 , wherein either R 1  or R 2  is substituted aryl or heteroaryl. 
     
     
         5 . The compound of  claim 1 , wherein R 1  and R 2  is alkyl substituted heteroaryl. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is halogen substituted aryl. 
     
     
         7 . The compound of  claim 6 , wherein the halogen, is fluorine or chlorine. 
     
     
         8 . The compound of  claim 1 , wherein R 2  is alkyl substituted heteroaryl. 
     
     
         9 . The compound of  claim 8  wherein the alkyl, is methyl. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is aryl and R 2  is heteroaryl. 
     
     
         11 . The compound of  claim 1 , wherein at least one aryl is phenyl. 
     
     
         12 . The compound of  claim 1 , wherein the mono-, di-, or tri-substituents are independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, ketocycloalkyl, alkoxy, hydroxylalkyl, trifluoromethyl. 
     
     
         13 . The compound of  claim 1 , wherein the compound is:
 (A) (1) Pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (2) Pyrazine-2-carboxylic acid [5-(6-fluoro-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (3) Pyrazine-2-carboxylic acid [5-(3-fluoro-phenylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (4) Pyrazine-2-carboxylic acid [5-(3-chloro-phenylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (5) Pyrazine-2-carboxylic acid [5-(3-fluoro-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (6) 6-Methyl-pyrazine-2-carboxylic acid [5-(3-fluoro-phenylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (7) 6-Methyl-pyrazine-2-carboxylic acid (5-pyridin-2-ylethynyl-bicyclo[3.2.1]oct-1-yl)-amide;   (8) 6-Methyl-pyrazine-2-carboxylic acid [5-(2-methyl-pyrimidin-4-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (9) Pyridine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (10) Pyridine-2-carboxylic acid [5-(6-methyl-pyrazin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (11) 6-Methyl-pyridine-2-carboxylic acid (5-pyridin-2-ylethynyl-bicyclo[3.2.1]oct-1-yl)-amide;   (12) 6-Methyl-pyridine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide;   (13) 3-Chloro-N-(5-pyrazin-2-ylethynyl-bicyclo[3.2.1]oct-1-yl)-benzamide;   (14) 6-Methyl-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (15) 6-Methyl-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (16) N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (17) N-((1R,5S)-5-pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (18) 2-Methyl-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   (19) N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   (20) 5-Fluoro-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (21) 5-Methyl-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (22) 1-Methyl-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)-1H-pyrazole-3-carboxamide;   (23) 3-Fluoro-N-((1R,5S)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (24) 6-Methyl-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (25) 6-Methyl-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (26) N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (27) N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (28) 2-Methyl-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   (29) N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   (30) 5-Fluoro-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (31) 5-Methyl-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (32) 1-Methyl-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)-1H-pyrazole-3-carboxamide;   (33) 3-Fluoro-N-((1S,5R)-5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (34) N-((1R,5S)-5-((6-methylpyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (35) N-((1R,5S)-5-((6-methylpyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (36) N-((1S,5R)-5-((6-methylpyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (37) N-((1S,5R)-5-((6-methylpyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (38) N-((1R,5S)-5-((6-fluoropyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (39) N-((1S,5R)-5-((6-fluoropyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (40) N-((1R,5S)-5-((3-fluoropyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (41) N-((1S,5R)-5-((3-fluoropyridin-2-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (42) N-((1R,5S)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (43) 6-Methyl-N-((1R,5S)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (44) 1-Methyl-N-((1R,5S)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)-1H-pyrazole-3-carboxamide;   (45) 4-Methyl-N-((1R,5S)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   (46) 2-Methyl-N-((1R,5S)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)thiazole-4-carboxamide;   (47) N-((1S,5R)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (48) 6-Methyl-N-((1S,5R)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)picolinamide;   (49) 1-Methyl-N-((1S,5R)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)-1H-pyrazole-3-carboxamide;   (50) 4-Methyl-N-((1S,5R)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   (51) 2-Methyl-N-((1S,5R)-5-(pyrazin-2-ylethynyl)bicyclo[3.2.1]octan-1-yl)thiazole-4-carboxamide;   (52) N-((1R,5S)-5-((2-methylthiazol-4-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (53) N-((1S,5R)-5-((2-methylthiazol-4-yl)ethynyl)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   (54) 3-Chloro-N-[3-(6-methylpyrazin-2-ylethynyl)-1-adamantyl]benzamide;   (55) 3-Chloro-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]benzamide;   (56) 3-Fluoro-N-[3-(6-methylpyrazin-2-ylethynyl)-1-adamantyl]benzamide;   (57) 3-Fluoro-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]benzamide;   (58) 6-Methyl-N-[3-(pyridin-3-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (59) 6-Methyl-N-[3-(pyridin-4-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (60) 6-Methyl-N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (61) N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (62) 5-Fluoro-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]nicotinamide;   (63) 2-Methyl-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]pyrimidine-4-carboxamide;   (64) 6-Methyl-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (65) 5-Fluoro-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (66) 1-Methyl-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]-1H-pyrazole-3-carboxamide;   (67) 3-Cyano-N-[3-(pyrazin-2-ylethynyl)-1-adamantyl]benzamide;   (68) 2-Methyl-N-[3-(6-methylpyrazin-2-ylethynyl)-1-adamantyl]pyrimidine-4-carboxamide;   (69) N-[3-(6-methylpyrazin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (70) 5-Fluoro-N-[3-(6-methylpyrazin-2-ylethynyl)-1-adamantyl]nicotinamide;   (71) N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (72) N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (73) 6-Methyl-N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyridine-2-carboxamide;   (74) 2-Methyl-N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyrimidine-4-carboxamide;   (75) N-[3-(pyridin-2-ylethynyl)-1-adamantyl]pyrimidine-4-carboxamide;   (76) 1-Methyl-N-[3-(pyridin-2-ylethynyl)-1-adamantyl]-1H-pyrazole-3-carboxamide;   (77) N-[3-(pyridin-2-ylethynyl)-1-adamantyl]isoxazole-5-carboxamide;   (78) N-[3-(6-methylpyridin-2-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (79) N-[3-(2-methylpyridin-4-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide;   (80) N-[3-(6-methylpyridin-3-ylethynyl)-1-adamantyl]pyrazine-2-carboxamide; or   (81) 1-Methyl-N-[3-(4-methylthiazol-2-ylethynyl)-1-adamantyl]-1H-pyrazole-3-carboxamide; or   (B) pharmaceutically acceptable salt thereof.   
     
     
         14 . A pharmaceutical composition comprising the compound of  claim 1  and at least one pharmaceutical excipient. 
     
     
         15 . A method for treating an mGlu5 receptor mediated disease or disorder comprising administering a therapeutically effective amount of the compound of  claim 1  to a subject in need thereof sufficient to treat said disease or disorder.