Novel 1-Aryl-3-Azabicyclo[3.1.0]Hexanes: Preparation And Use To Treat Neuropsychiatric Disorders

Abstract

The invention provides novel, multiply-substituted 1-aryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including depression and anxiety.

1 . A compound of the following formula I: 
     
       
         
         
             
             
         
       
     
     and enantiomers and pharmaceutically acceptable salts thereof, wherein:
 Ar is a phenyl group substituted with two substituents independently selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino; 
 R 1  and R 2  are independently selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy; and 
 R 3  is selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 2-6  alkanoyl, C 3-8  cycloalkyl, C 4-9  cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10  alkenyl, C 2-10  alkynyl, and substituted C 1-6  alkyl, C 2-10  alkenyl and C 2-10  alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 2-6  alkyloxycarbonyloxy, C 1-6  alkanoyl, C 1-6  alkanoyloxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 4-9  cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; 
 
     with the proviso that when the substituted phenyl group is 3,4-dichlorophenyl, R 3  cannot be hydrogen. 
   
   
       2 . The compound according to  claim 1  wherein the phenyl group is substituted with two substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, and trifluoromethoxy. 
   
   
       3 . The compound according to  claim 2  wherein R 1  and R 2  are hydrogen or methyl and R 3  is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or cyclopropyl. 
   
   
       4 . The compound according to  claim 3  selected from the group consisting of: 1-(2,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(2,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-difluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-fluorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-fluorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(2,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(4-fluoro-3-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(4-fluoro-3-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methylphenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-methoxyphenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; and 1-(3-chloro-4-nitrophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof. 
   
   
       5 . The compound according to  claim 4  which is (1R,5S)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       6 . The compound according to  claim 4  which is (1S,5R)-1-(3-fluoro-4-methylphenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       7 . The compound according to  claim 4  which is 3-ethyl-1-(3,4-difluorophenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       8 . The compound according to  claim 4  which is 1-(3-chloro-4-fluorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       9 . The compound according to  claim 4  which is 1-(3-chloro-4-fluorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       10 . The compound according to  claim 4  which is (1R,5S)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       11 . The compound according to  claim 3  selected from the group consisting of: Cis-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane; Cis-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-2-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-2,3-dimethyl-3-aza-bicyclo[3.1.0]hexane; Cis-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-4-methyl-3-aza-bicyclo[3.1.0]hexane; Trans-1-(3,4-dichlorophenyl)-3,4-dimethyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-propyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-isopropyl-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-cyclopropyl-3-aza-bicyclo[3.1.0]hexane; 3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; 1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(3,4-dichlorophenyl)-3-isobutyl-3-aza-bicyclo[3.1.0]hexane; 3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane; and (1S,5R)-3-tert-butyl-1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof. 
   
   
       12 . The compound according to  claim 11  which is (1R,5S)-1-(3,4-dichlorophenyl)-3-ethyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       13 . A compound according to  claim 1  characterized by the following formula II: 
     
       
         
         
             
             
         
       
     
     and enantiomers and pharmaceutically acceptable salts thereof, wherein:
 R 1  and R 2  are independently selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
 R 3  is selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 2-6  alkanoyl, C 3-8  cycloalkyl, C 4-9  cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10  alkenyl, C 2-10  alkynyl, and substituted C 1-6  alkyl, C 2-10  alkenyl and C 2-10  alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 2-6  alkyloxycarbonyloxy, C 1-6  alkanoyl, C 1-6  alkanoyloxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 4-9  cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and 
 R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino. 
 
   
   
       14 . The compound according to  claim 13  wherein R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy. 
   
   
       15 . The compound according to  claim 14  wherein R 1  and R 2  are hydrogen, R 3  is hydrogen, methyl, ethyl or isopropyl and R 4  and R 5  are independently selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy and ethoxy. 
   
   
       16 . The compound according to  claim 15  selected from the group consisting of: 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; and 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof. 
   
   
       17 . The compound according to  claim 16  which is 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       18 . The compound according to  claim 16  which is (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       19 . The compound according to  claim 16  which is (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       20 . The compound according to  claim 16  which is (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       21 . The compound according to  claim 16  which is (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts thereof. 
   
   
       22 . The compound according to  claim 16  which is 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       23 . The compound according to  claim 16  which is 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane and pharmaceutically acceptable salts and enantiomers thereof. 
   
   
       24 . A compound of the following formula III: 
     
       
         
         
             
             
         
       
     
     and enantiomers and pharmaceutically acceptable salts thereof, wherein:
 R 1  and R 2  are independently selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy; R 3  is selected from hydrogen, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 2-6  alkanoyl, C 3-8  cycloalkyl, C 4-9  cycloalkanoyl, aryl, heteroaryl, saturated heterocyclic, C 2-10  alkenyl, C 2-10  alkynyl, and substituted C 1-6  alkyl, C 2-10  alkenyl and C 2-10  alkynyl wherein the substituent is one or more of cyano, halogen, hydroxy, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, C 2-6  alkyloxycarbonyloxy, C 1-6  alkanoyl, C 1-6  alkanoyloxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 4-9  cycloalkanoyl, aryl, aryloxy, heteroaryl and saturated heterocyclic; and 
 R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from halogen, C 1-3  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halo(C 1-3 )alkyl, cyano, hydroxy, C 3-5  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxy, nitro, amino, C 1-3  alkylamino, and di(C 1-3 )alkylamino. 
 
   
   
       25 . The compound according to  claim 24  wherein R 4  and R 5  are independently hydrogen or 1-4 substituents independently selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, cyano, nitro, methoxy, ethoxy and trifluoromethoxy. 
   
   
       26 . The compound according to  claim 25  wherein R 1  and R 2  are hydrogen, R 3  is hydrogen, methyl, ethyl or isopropyl and R 4  and R 5  are independently selected from hydrogen, methyl, chloro, fluoro, propyl, methoxy and ethoxy. 
   
   
       27 . The compound according to  claim 26  selected from the group consisting of: 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; 3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(1-fluoronaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; and 3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane, and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates and prodrugs thereof. 
   
   
       28 - 34 . (canceled) 
   
   
       35 . An isolated (+) enantiomer of a compound of  claim 1 ,  13  or  24  substantially free of its corresponding (−) enantiomer. 
   
   
       36 . An isolated (−) enantiomer of a compound of  claim 1 ,  13  or  24  substantially free of its corresponding (+) enantiomer. 
   
   
       37 - 53 . (canceled) 
   
   
       54 . A neurobiologically active composition effective to inhibit cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject comprising an effective amount of a compound, or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, and prodrug thereof, selected from the group consisting of: 1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-methyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-ethyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-isopropyl-1-(naphthalen-2-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(2-methoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(2-ethoxynaphthalen-6-yl)-3-aza-bicyclo[3.1.0]hexane; and 1-(2-ethoxynaphthalen-6-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane, and a pharmaceutically acceptable carrier or excipient therefor. 
   
   
       55 . (canceled) 
   
   
       56 . A neurobiologically active composition effective to inhibit cellular uptake of one or more biogenic amine neurotransmitter(s) selected from norepinephrine, serotonin, and dopamine in a mammalian subject comprising an effective amount of a compound, or a pharmaceutically acceptable salt, enantiomer, polymorph, solvate, hydrate, and prodrug thereof, selected from the group consisting of: 1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; 3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1R,5S)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; (1S,5R)-3-methyl-1-(naphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(1-fluoronaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; 1-(1-fluoronaphthalen-4-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; 1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane; and 3-methyl-1-(1-methylnaphthalen-4-yl)-3-aza-bicyclo[3.1.0]hexane, and a pharmaceutically acceptable carrier or excipient therefor. 
   
   
       57 - 93 . (canceled)