Substituted n-heterocycle derivatives and methods of their use

Abstract

The present invention is directed to substituted N-heterocycle derivatives, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         A is phenyl, naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, or benzothiophenyl, where 1 to 3 carbon atoms of said A is optionally replaced with a nitrogen atom; 
         U is N or O; 
         W is H or OR 8 ; 
         R 1  and R 2  are, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R 1 ), phenyloxy (optionally substituted with one or more R 1 ), naphthyloxy (optionally substituted with one or more R 1 ), phenylethoxy (optionally substituted with one or more R 1 ), phenoxyethoxy (optionally substituted with one or more R 1 ), naphthylmethoxy (optionally substituted with one or more R 1 ), phenylcarbonylamino (optionally substituted with one or more R 1 ), phenylaminocarbonyl (optionally substituted with one or more R 1 ), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R 1 ), heteroaryl (optionally substituted with one or more R 1 ), heteroaryloxy (optionally substituted with one or more R 1 ), or heteroarylmethyloxy (optionally substituted with one or more R 1 ); 
         R 3  and R 4  are, independently, H, (C 1 -C 6 )alkyl, benzyl (optionally substituted with one or more R 1 ), naphthylmethyl (optionally substituted with one or more R 1 ), phenyl(C 2 -C 6 )alkyl, heteroarylmethyl, cycloalkyl, cycloalkenyl, or cycloalkylmethyl (where any carbon atom of said cycloalkylmethyl may be optionally replaced with N, S, or O), provided that, when U is O, one of R 3  and R 4  is absent; 
         or when U is N, R 3  and R 4 , together with U, form a ring with 3 to 7 ring carbon atoms, and any ring carbon atom can be optionally replaced with N, S, or O; 
         R 5  is H, (C 1 -C 6 )alkyl, halo, or trifluoromethyl; 
         or R 3  and R 5 , together with U, form a ring with 3 to 7 ring carbon atoms, and any ring carbon atom can be optionally replaced with N, S, or O; 
         R 6  and R 7  are, independently, (C 1 -C 6 )alkyl or (C 3 -C 6 )cycloalkyl; 
         or R 6  and R 7  can together form a ring of 4 to 8 carbon atoms; 
         where any carbon atom of said R 6  and R 7  may be optionally replaced with N, S, or O; 
         where R 6  and R 7  may be optionally substituted with R 5  or OH; or 
         where R 6  and R 7  can form a ring with 4 to 8 carbons fused onto a cycloalkyl ring of 4 to 6 carbon atoms; 
         R 8  is H, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkyl-C(═O); 
         t is 1, 2, or 3; 
         x is 0, 1, or 2; 
         y is 0, 1, or 2; and 
         z is 0, 1, or 2. 
       
     
     
         2 . A compound according to  claim 1 ,
 wherein A is phenyl, naphthyl or benzothienyl.   
     
     
         3 . A compound according to  claim 1 ,
 wherein R 1  and R 2  each are the same or different selected from hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl, trifluoromethoxy, phenoxy-, phenylethoxy optionally substituted by an R 1  substitutent, benzyloxy and naphthylmethoxy.   
     
     
         4 . A compound according to  claim 1 ,
 wherein W is OH.   
     
     
         5 . A compound according to  claim 1 ,
 wherein R 5  and R 7  form a ring of 4, 5, or 6 carbon atoms, optionally fused to a ring of 6 carbon atoms; said ring or rings being optionally substituted by up to four C 1 -C 6  alkyl groups.   
     
     
         6 . A compound according to  claim 5 ,
 wherein R 6  and R 7  form a cyclohexanol ring.   
     
     
         7 . A compound according to  claim 1 ,
 wherein R 6  and R 7  are each a C 1 -C 6  alkyl groups, the same or different.   
     
     
         8 . A compound according to  claim 1 ,
 wherein t is 1.   
     
     
         9 . A compound according to  claim 1 ,
 wherein y is 1.   
     
     
         10 . A compound according to  claim 1 ,
 wherein x is 0 or 1.   
     
     
         11 . A compound according to  claim 1 ,
 wherein z is 0 or 1.   
     
     
         12 . A compound according to  claim 1 ,
 wherein U is N.   
     
     
         13 . A compound according to  claim 1 ,
 wherein R 3  and R 4  are independently H or (C 1 -C 6 )alkyl or together with the nitrogen form a pyrrolidine or piperidine ring.   
     
     
         14 . A compound according to  claim 1 ,
 wherein U is O and one of R 3  and R 4  is absent, the other is (C 1 -C 6 )alkyl.   
     
     
         15 . A compound according to  claim 1 ,
 wherein:   A is phenyl, naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, or benzothiophenyl, where 1 to 3 carbon atoms of said A is optionally replaced with a nitrogen atom;   U is N or O;   W is H or OR 8 ;   R 1  and R 2  are, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R 1 ), phenyloxy (optionally substituted with one or more R 1 ), naphthyloxy (optionally substituted with one or more R 1 ), phenylethoxy (optionally substituted with one or more R 1 ), phenoxyethoxy (optionally substituted with one or more R 1 ), naphthylmethoxy (optionally substituted with one or more R 1 ), phenylcarbonylamino (optionally substituted with one or more R 1 ), phenylaminocarbonyl (optionally substituted with one or more R 1 ), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R 1 ), heteroaryl (optionally substituted with one or more R 1 ), heteroaryloxy (optionally substituted with one or more R 1 ), or heteroarylmethyloxy (optionally substituted with one or more R 1 );
 R 3  and R 4  are, independently, H, or (C 1 -C 6 )alkyl; 
   or R 3  and R 4 , together with U, form a ring with 3 to 7 ring carbon atoms, and any ring carbon atom can be optionally replaced with N, S, or O;
 R 5  is H, (C 1 -C 6 )alkyl, halo, or trifluoromethyl; 
 or R 3  and R 5 , together with U, form a ring with 3 to 7 ring carbon atoms, and any ring carbon atom can be optionally replaced with N, S, or O; 
 R 6  and R 7  together form a ring of 4 to 8 carbon atoms; 
 R 5  is H; 
 t is 1 or 2; 
 x is 0, 1, or 2; 
 y is 0, 1, or 2; and 
 z is 0. 
   
     
     
         16 . A compound of formula I,
 wherein:   A is phenyl, naphthyl, thiophenyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl, xanthenyl, pyrrolyl, indolizinyl, isoindolyl, indolyl, or benzothiophenyl, where 1 to 3 carbon atoms of said A is optionally replaced with a nitrogen atom;
 U is N; 
 W is OR 8  
 R 1  and R 2  are, independently, H, OH, alkyl, alkoxy, halo, trifluoromethyl, alkanoyloxy, methylenedioxy, benzyloxy (optionally substituted with one or more R 1 ), phenyloxy (optionally substituted with one or more R 1 ), naphthyloxy (optionally substituted with one or more R 1 ), phenylethoxy (optionally substituted with one or more R 1 ), phenoxyethoxy (optionally substituted with one or more R 1 ), naphthylmethoxy (optionally substituted with one or more R 1 ), phenylcarbonylamino (optionally substituted with one or more R 1 ), phenylaminocarbonyl (optionally substituted with one or more R 1 ), nitro, trifluoromethoxy, nitrile, alkenyl, alkynyl, sulfoxide, sulfonyl, sulfonamido, phenyl (optionally substituted with one or more R 1 ), heteroaryl (optionally substituted with one or more R 1 ), heteroaryloxy (optionally substituted with one or more R 1 ), or heteroarylmethyloxy (optionally substituted with one or more R 1 ); 
 R 3  and R 4  are, independently, H, or (C 1 -C 6 )alkyl; 
 or R 3  and R 4 , together with U, form a ring with 3 to 7 ring carbon atoms, 
 R 5  is H, (C 1 -C 6 )alkyl, halo, or trifluoromethyl; 
 R 6  and R 7  together form a ring of 4 to 8 carbon atoms; 
 R 8  is H 
 t is 1 
 x is 1, or 2; 
 y is 1, or 2; and 
 z is 0. 
 
   
     
     
         17 . A compound according to  claim 1 , 
       wherein said compound is: 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[1-(3-chlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(3-bromophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[1-(3-bromophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[1-(3-bromo-4-methoxyphenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-[1-(3,4-dichlorophenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3,4-dichlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(3,4-dichlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-aminopyrrolidin-1-yl]-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(3-bromophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3-bromophenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-(1,4′-bipiperidin-1′-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{2-(4-pyrrolidin-1-ylpiperidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3-bromo-4-methoxyphenyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[4-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-[1-(2-naphthyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-(4-aminopiperidin-1-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(1-naphthyl)ethyl]cyclobutanol dihydrochloride; 
       1-[2-[4-(methylamino)piperidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(1-naphthyl)ethyl]cyclohexane; 
       1-{2-[(3R)-3-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-aminopiperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-(dimethylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopiperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(dimethylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-aminopiperidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3S)-3-(methylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopiperidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3S)-3-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[(3R)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-[(3R)-3-aminopyrrolidin-1-yl]-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3-chlorophenyl)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-aminopyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-aminopyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)phenyl]-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-[4-(benzyloxy)phenyl]-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cyclopentylethyl]-N-methylpiperidin-4-amine dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cyclopentylethyl]-N,N-dimethylpiperidin-4-amine dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cyclohexylethyl]-N-methylpiperidin-4-amine dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cyclohexylethyl]-N,N-dimethylpiperidin-4-amine dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cycloheptylethyl]-N-methylpiperidin-4-amine dihydrochloride; 
       1-[2-(3-chlorophenyl)-2-cycloheptylethyl]-N,N-dimethylpiperidin-4-amine dihydrochloride; 
       2-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{2-(1-hydroxycyclohexyl)-2-[3-(trifluoromethoxy)phenyl]ethyl}piperidin-4-ol hydrochloride; 
       1-[2-[4-(benzyloxy)-3-chlorophenyl]-2-(1-hydroxycyclohexyl)ethyl]piperidin-4-ol hydrochloride; 
       1-[1-[4-(benzyloxy)-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)ethyl]cyclohexanol hydrochloride; 
       4-(4-aminopiperidin-1-yl)-3-(3-chlorophenyl)-2-methylbutan-2-ol dihydrochloride; 
       3-(3-chlorophenyl)-4-[4-(dimethylamino)piperidin-1-yl]-2-methylbutan-2-ol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(5-methoxy-1-benzothien-3-yl)ethyl]cyclohexanol dihydrochloride; 
       4-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]heptan-4-ol dihydrochloride; 
       1-{2-(1,4′-bipiperidin-1′-yl)-1-[4-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-(4-aminopiperidin-1-yl)-1-[4-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-(4-aminopiperidin-1-yl)-1-[4-(trifluoromethoxy)phenyl]ethyl}cyclobutanol dihydrochloride; 
       1-{2-(4-aminopiperidin-1-yl)-1-(4-phenoxyphenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-[3-(phenoxyphenyl)ethyl]cyclohexanol dihydrochloride; 
       1-{2-(4-aminopiperidin-1-yl)-1-(3-phenoxyphenyl)ethyl]cyclohexanol dihydrochloride; 
       1-[1-(3-phenoxyphenyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol dihydrochloride; 
       1-[2-[4-(dimethylamino)piperidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol dihydrochloride; 
       1-{1-(3-bromo-4-methoxyphenyl)-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3-bromophenyl)-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{1-(3,4-dichlorophenyl)-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol dihydrochloride; 
       1-{2-[4-(dimethylamino)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride; 
       2-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]decahydro naphthalen-2-ol dihydrochloride; 
       1-[2-(4-aminopiperidin-1-yl)-1-(3-chlorophenyl)ethyl]-4-methylcyclo hexanol dihydrochloride; 
       1-[1-[4-(benzyloxy)-3-chlorophenyl]-2-(4-methoxypiperidin-1-yl)ethyl]cyclohexanol; 
       1-[2-(4-aminopiperidin-1-yl)-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol; 
       1-[2-[4-(dimethylamino)piperidin-1-yl]-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol; 
       1-{1-(6-methoxy-2-naphthyl)-2-[4-(methylamino)piperidin-1-yl]ethyl}cyclohexanol; 
       1-[1-(6-methoxy-2-naphthyl)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]cyclohexanol; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol; 
       1-[(1S)-2-(1,4′-bipiperidin-1′-yl)-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol; 
       1-[(1R)-2-(1,4′-bipiperidin-1′-yl)-1-(6-methoxy-2-naphthyl)ethyl]cyclohexanol; 
       1-[(2S)-2-(3-chlorophenyl)-2-cyclohexylethyl]-N-methylpiperidin-4-amine; 
       1-[(2R)-2-(3-chlorophenyl)-2-cyclohexylethyl]-N-methylpiperidin-4-amine; 
       1-{(1S)-2-[4-(methylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-{(1S)-2-[4-(dimethylamino)piperidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-{2-(4-morpholin-4-ylpiperidin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-{(1S)-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-{(1S)-2-(1,4′-bipiperidin-1′-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-[2-[(3R)-3-aminopyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol; 
       1-[2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol; 
       1-[2-[(3R)-3-(methylamino)pyrrolidin-1-yl]-1-(2-naphthyl)ethyl]cyclohexanol; 
       1-[2-[(3R)-3-aminopyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol 
       1-[2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol; 
       1-[2-[(3R)-3-(methylamino)pyrrolidin-1-yl]-1-(1-naphthyl)ethyl]cyclohexanol; 
       1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)phenyl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)phenyl]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)phenyl]-2-[(3R)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol; 
       1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(dimethylamino) pyrrolidin-1-yl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[(3R)-3-(methylamino)pyrrolidin-1-yl]ethyl}cyclohexanol; 
       1-{2-[(3R)-3-aminopyrrolidin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol; 
       1-[(1S)-2-[(3S)-3-aminopyrrolidin-1-yl]-1-(3-chlorophenyl)ethyl]cyclohexanol; 
       1-[(1R)-2-[(3S)-3-aminopyrrolidin-1-yl]-1-(3-chlorophenyl)ethyl]cyclohexanol; 
       (3R)-1-{2-(1,4′-bipiperidin-1′-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}-3-methylcyclopentanol; 
       1-{2-(4-aminopiperidin-1-yl)-1-[4-(benzyloxy)-3-chlorophenyl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)-3-chlorophenyl]-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol; 
       1-{2-(4-aminopiperidin-1-yl)-1-[3-chloro-4-(2-naphthylmethoxy)phenyl]ethyl}cyclohexanol; 
       1-{1-[3-chloro-4-(2-naphthylmethoxy)phenyl]-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol; 
       1-{2-(4-aminopiperidin-1-yl)-1-[4-(benzyloxy)-3-methoxyphenyl]ethyl}cyclohexanol; 
       1-{1-[4-(benzyloxy)-3-methoxyphenyl]-2-[4-(dimethylamino)piperidin-1-yl]ethyl}cyclohexanol; 
       1-[2-(1,4′-bipiperidin-1′-yl)-1-(3-chloro-4-methoxyphenyl)ethyl]cyclohexanol; 
       1-{2-(1,4′-bipiperidin-1′-yl)-1-[4-(2-phenylethoxy)phenyl]ethyl}cyclohexanol; 
       1-(2-(1,4′-bipiperidin-1′-yl)-1-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}ethyl)cyclohexanol; or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         18 . A composition, comprising:
 a. at least one compound according to  claim 1  or a pharmaceutically acceptable salt thereof; and   b. at least one pharmaceutically acceptable carrier.   
     
     
         19 . A method for treating or preventing a condition ameliorated by monoamine reuptake in a subject in need thereof, comprising the step of:
 administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof.   
     
     
         20 . A method according to  claim 19 ,
 wherein said condition ameliorated by monoamine reuptake is selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof.   
     
     
         21 . A method according to  claim 19 ,
 wherein said condition ameliorated by monoamine reuptake is selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.   
     
     
         22 . A method for treating or preventing at least one vasomotor symptom in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         23 . A method according to  claim 22 ,
 wherein said vasomotor symptom is hot flush.   
     
     
         24 . A method according to  claim 22 ,
 wherein said subject is human.   
     
     
         25 . A method according to  claim 24 ,
 wherein said human is a female.   
     
     
         26 . A method according to  claim 25 ,
 wherein said female is pre-menopausal.   
     
     
         27 . A method according to  claim 25 ,
 wherein said female is peri-menopausal.   
     
     
         28 . A method according to  claim 25 ,
 wherein said female is post-menopausal.   
     
     
         29 . A method according to  claim 24 ,
 wherein said human is a male.   
     
     
         30 . A method according to  claim 29 ,
 wherein said male is naturally, chemically or surgically andropausal.   
     
     
         31 . A method for treating or preventing at least one depression disorder in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         32 . A method according to  claim 31 ,
 wherein said depression disorder is major depressive disorder, anxiety, sleep disturbance, or social phobia.   
     
     
         33 . A method for treating or preventing at least one sexual dysfunction in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         34 . A method according to  claim 33 ,
 wherein said sexual dysfunction is desire-related or arousal-related.   
     
     
         35 . A method for treating or preventing pain in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         36 . A method for treating or preventing gastrointestinal or genitourinary disorder in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         37 . A method according to  claim 36 ,
 wherein said disorder is stress incontinence or urge urinary incontinence.   
     
     
         38 . A method for treating or preventing chronic fatigue syndrome in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         39 . A method for treating or preventing fibromylagia syndrome in a subject in need thereof, comprising the step of: administering to said subject an effective amount of a compound according to  claim 1  or pharmaceutically acceptable salt thereof. 
     
     
         40 . A method according to any one of  claims 31  to  39 ,
 wherein said subject is human.