Bicyclo[3.2.1]Octyl Amide Derivatives and Uses of Same

Abstract

The present invention provides bicyclo[3.2.1]octyl amide derivatives of formula (I): wherein L, R 1 and R 2 are as defined herein, or a pharmaceutically acceptable salt thereof; and pharmaceutical compositions and methods using the same.

What is claimed is: 
     
         1 . A compound having the formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         L is —NHCO— or —CONH—; and 
         R 1  and R 2  are both heteroaryl, wherein at least one of R 1  and R 2  is unsubstituted and one of R 1  and R 2  is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-R 3 , —N(alkyl)R 3 , —C(O)NHR 3 , —C(O)N(alkyl)R 3 , —NHC(O)R 3 , —N(alkyl)C(O)R 3 , —OH or —OR 3 , wherein: 
         R 3  is C 1 -C 6 alkyl or C 1 -C 6 cycloalkyl, which is optionally substituted with halogen, —CN, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , C 1 -C 3 alkylheterocyclyl, C 1 -C 3 alkylcarbamate, —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —NHC(O)—C 1 -C 3 alkyl, —N(C 1 -C 3 alkyl)-C(O)—C 1 -C 3 alkyl, OH, or —O—C 1 -C 6 alkyl. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt thereof of  claim 1  wherein one of R 1  and R 2  is optionally mono-, di-, or tri-substituted independently with alkyl, alkoxy, halogen, cyano, nitro, trifluoroalkyl, amino, alkylamino, dialkylamino, acyl, —OH or —OR 3 ; and wherein R 3  is C 1 -C 6 alkyl. 
     
     
         3 . The compound or pharmaceutically acceptable salt thereof of  claim 1  wherein R 1  and R 2  are each independently selected from the group consisting of pyridinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 2-quinolinyl, 2-quinazolinyl and 3-phenyl-2-quinolinyl. 
     
     
         4 . The compound or pharmaceutically acceptable salt thereof of  claim 3 , wherein R 1  and R 2  are both pyridinyl. 
     
     
         5 . The compound or pharmaceutically acceptable salt thereof of  claim 1  wherein L is —NHCO—. 
     
     
         6 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is selected from the group consisting of:
 1: N,N′-(bicyclo[3.2.1]octane-1,5-diyl)dipicolinamide;   4: 6-methyl-pyrazine-2-carboxylic acid {5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   56: N-(5-{[(5-methylpyrazin-2-yl)carbonyl]amino}bicyclo[3.2.1]oct-1-yl)pyrimidine-4-carboxamide;   57: N-(5-(5-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   68: 6-methyl-N-(5-(nicotinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   71: N-(5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   72: N-(5-(6-methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   78: 6-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   79: N-(5-(6-methyl-N-(6-(methylpyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide;   83: N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   84: N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide;   85: N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   86: N-(5-(6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   94: N-(5-(3-fluoro-6-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   97: pyrazine-2-carboxylic acid {5-[(3-fluoro-pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;   100: 2-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   101: 4-methyl-N-(5-(pyrazine-2-carboxamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   102: N-(5-(5-fluoropicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   103: N-(5-(4-methylpicolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   104: 2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-4-carboxamide;   105: 6-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   106: 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide;   107: 4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)pyrimidine-2-carboxamide;   108: 4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)thiazole-2-carboxamide;   109: 2-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl(thiazole-5-carboxamide;   110: 5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   111: 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   112: 4-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   113: N-(5-(5-methylnicotinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   119: 6-methyl-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;   121: pyrimidine-4-carboxylic acid {(1S,5R)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide;   126: 6-methyl-pyridine-2-carboxylic acid {(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   127: pyrimidine-4-carboxylic acid {(1R,5S)-5-[(6-methyl-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   129: 6-methyl-pyridine-2-carboxylic acid {(1S,5R)-5-[(thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   143: pyridine-2-carboxylic acid {(1S,5R)-5-[(4-methyl-thiazole-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   144: 2-methyl-pyrimidine-4-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;   145: 5-fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide;   146: 6-fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide;   147: 3-fluoro-6-methyl-pyridine-2-carboxylic acid {(1R,5S)-5-[pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide;   158: 6-methyl-pyrazine-2-carboxylic acid {(1R,5S)-5-pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide;   and   159: 6-methyl-pyrazine-2-carboxylic acid {(1S,5R)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}-amide.   
     
     
         7 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is:
 110: 5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide.   
     
     
         8 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is:
 111: 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide.   
     
     
         9 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is:
 119: 6-methyl-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide.   
     
     
         10 . The compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said compound is:
 146: 6-fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide.   
     
     
         11 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of  claim 6  and a pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of  claim 12 , wherein said compound is:
 110: 5-fluoro-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   111: 5-methyl-N-(5-(picolinamido)bicyclo[3.2.1]octan-1-yl)picolinamide;   119: 6-methyl-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]bicyclo[3.2.1]oct-1-yl}-amide, or   146: 6-fluoro-pyridine-2-carboxylic acid {(1R,5S)-5-[(pyridine-2-carbonyl)-amino]-bicyclo[3.2.1]oct-1-yl}amide.   
     
     
         14 . A method of treating a central nervous system disease or disorder, which comprises administering a therapeutically effective amount of the pharmaceutical composition of  claim 11  to a subject in need thereof. 
     
     
         15 . A method of treating a central nervous system disease or disorder, which comprises administering a therapeutically effective amount of the pharmaceutical composition of  claim 12  to a subject in need thereof. 
     
     
         16 . A method of treating a central nervous system disease or disorder, which comprises administering a therapeutically effective amount of the pharmaceutical composition of  claim 13  to a subject in need thereof. 
     
     
         17 . The method of  claim 14 , wherein the central nervous system disease or disorder is a cognitive, neurodegenerative, psychiatric or neurological disease or disorder. 
     
     
         18 . The method of  claim 14 , wherein the central nervous system disease or disorder is one or more of the anxiety diseases or disorders selected from the group consisting of: generalized anxiety disorder, panic anxiety, obsessive compulsive disorder, social phobia, performance anxiety, post-traumatic stress disorder, acute stress reaction, an adjustment disorder, a hypochondriacal disorder, separation anxiety disorder, agoraphobia, a specific phobia, anxiety disorder due to general medical condition, substance-induced anxiety disorder, and alcohol withdrawal-induced anxiety. 
     
     
         19 . The method of  claim 14 , wherein the central nervous system disease or disorder is one or more of the depressive disorders selected from the group consisting of: atypical depression, bipolar depression, unipolar depression, major depression, endogenous depression, involutional depression, reactive depression, postpartum depression, primary depression, psychotic depression and secondary depression. 
     
     
         20 . The method of  claim 14 , wherein the central nervous system disease or disorder is one or more of the pain diseases or disorders selected from the group consisting of: inflammatory pain, neuropathic pain, migraine pain and a migraine pain disease or disorder selected from the group consisting of allodynia, hyperalgesic pain, phantom pain, neuropathic pain related to diabetic neuropathy, and neuropathic pain related to migraine.