Azabicyclic compounds are central nervous system active agents

Abstract

Compounds of formula (I) are novel CNS active agents that are useful for treating pain and for treating other disorders associated with the cholinergic system.

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof, wherein 
    represents a single bond or a double bond;  
 A is selected from the group consisting of a covalent bond and CH 2 ;  
 D is selected from the group consisting of CH 2 , CH 2 CH 2  and CH 2 CH 2 CH 2 , provided that when D is CH 2 CH 2 CH 2 , then A is a covalent bond;  
 Y is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH 2 ;  
 Z is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH 2 , provided that when Z is CH 2 CH 2 , then Y is a covalent bond, and further provided that when Y is CH 2 CH 2 , then Z is a covalent bond;  
 R 1  is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, benzyloxycarbonyl, cyanoalkyl, dihydro-3-pyridinylcarbonyl, hydroxy, hydroxyalkyl, phenoxycarbonyl, —NR 10 R 11 , (NR 10 R 11 )alkyl and (NR 10 R 11 )carbonylalkyl wherein R 10  and R 11  are independently selected from the group consisting of hydrogen, alkyl and alkylcarbonyl;  
 R 2  and R 4  are independently selected from the group consisting of hydrogen, aryl and heterocycle, provided that one of R 2  or R 4  is hydrogen; and  
 R 3  and R 5  are both absent or are independently selected from the group consisting of hydrogen, alkoxy and hydroxy;  
 provided that when A is a covalent bond, D is CH 2  and Y is a covalent bond, then Z is other than a covalent bond; and  
 further provided that when A is a covalent bond, D is CH 2  and Z is a covalent bond, then Y is other than a covalent bond.  
 
   
   
       2 . The compound according to  claim 1  of formula (II)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof.  
   
   
       3 . The compound according to  claim 2  wherein Y is a covalent bond and Z is CH 2 .  
   
   
       4 . The compound according to  claim 2  wherein Y is CH 2  and Z is a covalent bond.  
   
   
       5 . A compound according to  claim 2  wherein Y is a covalent bond and Z is CH 2 CH 2 .  
   
   
       6 . The compound according to  claim 2  wherein Y is CH 2  and Z is CH 2 .  
   
   
       7 . The compound according to  claim 2  wherein Y is CH 2 CH 2  and Z is a covalent bond.  
   
   
       8 . The compound according to  claim 1  of formula (III)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof.  
   
   
       9 . The compound according to  claim 8  wherein Y is a covalent bond and Z is a covalent bond.  
   
   
       10 . The compound according to  claim 8  wherein Y is a covalent bond and Z is CH 2 .  
   
   
       11 . The compound according to  claim 8  wherein 
    represents a double bond;    Y is a covalent bond;    Z is CH 2 ;    R 2  is hydrogen;    R 3  and R 5  are absent; and    R 4  is heterocycle.    
   
   
       12 . The compound according to  claim 11  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       13 . The compound according to  claim 11  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       14 . The compound according to  claim 11  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       15 . The compound according to  claim 14  that is (cis)-5-(3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole.  
   
   
       16 . The compound according to  claim 8  wherein Y is CH 2  and Z is a covalent bond.  
   
   
       17 . The compound according to  claim 8  wherein 
    represents a double bond;    Y is CH 2 ;    Z is a covalent bond;    R 2  is heterocycle;    R 3  and R 5  are absent; and    R 4  is hydrogen.    
   
   
       18 . The compound according to  claim 17  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       19 . The compound according to  claim 17  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       20 . The compound according to  claim 17  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       21 . The compound according to  claim 20  that is (cis)-5-(3-pyridinyl)-1,2,3,3a,6,6a-hexahydrocyclopenta[b]pyrrole.  
   
   
       22 . The compound according to  claim 8  wherein Y is a covalent bond and Z is CH 2 CH 2 .  
   
   
       23 . The compound according to  claim 8  wherein Y is CH 2  and Z is CH 2 .  
   
   
       24 . The compound according to  claim 8  wherein Y is CH 2 CH 2  and Z is a covalent bond.  
   
   
       25 . The compound according to  claim 1  of formula (IV)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof.  
   
   
       26 . The compound according to  claim 25  wherein Y is a covalent bond and Z is a covalent bond.  
   
   
       27 . The compound according to  claim 25  wherein 
    represents a double bond;    Y is a covalent bond;    Z is a covalent bond;    R 2  is hydrogen;    R 3  and R 5  are absent; and    R 4  is heterocycle.    
   
   
       28 . The compound according to  claim 27  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       29 . The compound according to  claim 27  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       30 . The compound according to  claim 27  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       31 . The compound according to  claim 30  selected from the group consisting of 
 (cis)-6-(6-methyl-3-pyridinyl)-3-azabicyclo[3.2.0]hept-6-ene; and    cis)-6-(5,6-dichloro-3-pyridinyl)-3-azabicyclo[3.2.0]hept-6-ene.    
   
   
       32 . The compound according to  claim 25  wherein 
    represents a single bond;    Y is a covalent bond;    Z is a covalent bond;    R 2 , R 3  and R 5  are hydrogen; and    R 4  is heterocycle.    
   
   
       33 . The compound according to  claim 32  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(H)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 23 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       34 . The compound according to  claim 32  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       35 . The compound according to  claim 32  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       36 . The compound according to  claim 35  selected from the group consisting of 
 (exo)-6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.2.0]heptane;    (exo)-6-(6-chloro-3-pyridinyl)-3-azabicyclo[3.2.0]heptane; and    (endo)-6-(5,6-dichloro-3-pyridinyl)-3-azabicyclo[3.2.0]heptane.    
   
   
       37 . The compound according to  claim 25  wherein Y is a covalent bond and Z is CH 2 .  
   
   
       38 . The compound according to  claim 25  wherein 
    represents a double bond;    Y is a covalent bond;    Z is CH 2 ;    R 2  is hydrogen;    R 3  and R 5  are absent; and    R 4  is heterocycle.    
   
   
       39 . The compound according to  claim 38  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, phenyl, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       40 . The compound according to  claim 38  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, phenyl, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       41 . The compound according to  claim 40  selected from the group consisting of 
 (cis)-5-(3-methyl-5-isoxazolyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-2-methyl-5-(3-methyl-5-isoxazolyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(3-bromo-1,2,4-thiadiazol-5-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1,3-thiazol-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1H-imidazol-4-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1,3-thiazol-5-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(imidazo[1,2-a]pyridin-3-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(imidazo[1,2-a]pyridin-6-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(thieno[3,2-b]pyridin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1-trityl-1H-imidazol-4-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-(aminosulfonyl)-2-thienyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-(amino(imino)methyl)-2-thienyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(2-methyl-2H-tetrazol-5-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(thieno[2,3-b]pyridin-5-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(imidazo[1,2-a]pyridin-7-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-nitro-1,3-thiazol-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1,3,4-thiadiazol-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-phenylpyridazin-3-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole; and    (cis)-2-methyl-5-(6-phenylpyridazin-3-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole.    
   
   
       42 . The compound according to  claim 38  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       43 . The compound according to  claim 42  selected from the group consisting of 
 (cis)-5-(6-chloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-methoxy-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-chloro-5-methyl-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5,6-dichloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-chloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-methyl-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(2-methyl-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-chloro-5-fluoro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-chloro-3-pyridinyl)-2-cyanomethyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-fluoro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(2-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(4-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(6-methyl-2-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-bromo-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(5-vinyl-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    (cis)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)nicotinonitrile;    (3aS,6aR)-5-(6-chloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole;    and    (3aR,6aS)-5-(6-chloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole.    
   
   
       44 . The compound according to  claim 25  wherein 
    represents a single bond;    Y is a covalent bond;    Z is CH 2 ;    R 2  and R 3  are hydrogen;    R 5  is selected from the group consisting of hydrogen and hydroxy; and    R 4  is heterocycle.    
   
   
       45 . The compound according to  claim 44  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C( 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       46 . The compound according to  claim 44  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       47 . The compound according to  claim 44  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       48 . The compound according to  claim 47  selected from the group consisting of 
 (cis)-5-(3-pyridinyl)octahydrocyclopenta[c]pyrrole;    (endo)-5-(6-chloro-3-pyridinyl)octahydrocyclopenta[c]pyrrole;    (exo)-5-(6-chloro-3-pyridinyl)octahydrocyclopenta[c]pyrrole; and    (cis)-5-(6-chloro-3-pyridinyl)octahydrocyclopenta[c]pyrrol-5-ol.    
   
   
       49 . The compound according to  claim 25  wherein 
    represents a double bond;    Y is a covalent bond;    Z is CH 2 ;    R 2  is heterocycle;    R 3  and R 5  are absent; and    R 4  is hydrogen.    
   
   
       50 . The compound according to  claim 49  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3-c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       51 . The compound according to  claim 49  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       52 . The compound according to  claim 49  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       53 . The compound according to  claim 52  that is (cis)-6-chloro-3-pyridinyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole.  
   
   
       54 . The compound according to  claim 25  wherein 
    represents a single bond;    Y is a covalent bond;    Z is CH 2 ;    R 2  is heterocycle;    R 3  is selected from the group consisting of hydrogen and hydroxy; and    R 4  and R 5  are hydrogen.    
   
   
       55 . The compound according to  claim 54  wherein the heterocycle is selected from the group consisting of furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, furo[2,3-c]pyridine, furo[3,2-c]pyridine, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, thieno[2,3c]pyridine, thieno[3,2-c]pyridine, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, triphenylmethyl(trityl), —C(NH)NR 10 R 11 , —NR 10 R 11 , (NR 10 R 11 )alkyl, (NR 10 R 11 )carbonyl, (NR 10 R 11 )carbonylalkyl, (NR 10 R 11 )sulfonyl, —NR 12 S(O) 2 R 13 , —C(NR 12 )NR 13 R 14 , —CH 2 C(NR 12 )NR 13 R 14 , —C(NOR 12 )R 13 , —C(NCN)R 12 , —C(NNR 12 R 13 )R 14 , —S(O) 2 OR 12 , and —S(O) 2 R 12 .  
   
   
       56 . The compound according to  claim 54  wherein the heterocycle is selected from the group consisting of imidazolyl, isoxazolyl, pyridinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, imidazo[1,2-a]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[2,3-b]pyridinyl wherein the heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, nitro, (NR 10 R 11 )sulfonyl, and —C(NH)NR 10 R 11 .  
   
   
       57 . The compound according to  claim 54  wherein the heterocycle is pyridinyl substituted with 0, 1, or 2 substituents independently selected from the group consisting of alkenyl, alkenyloxy, alkoxy, alkyl, alkynyl, cyano, halogen, and nitro.  
   
   
       58 . The compound according to  claim 57  selected from the group consisting of 
 (cis)-4-(3-pyridinyl)octahydrocyclopenta[c]pyrrol-4-ol; and    (endo)-4-(6-chloro-3-pyridinyl)octahydrocyclopenta[c]pyrrole.    
   
   
       59 . The compound according to  claim 25  wherein Y is a covalent bond and Z is CH 2 CH 2 .  
   
   
       60 . The compound according to  claim 25  wherein Y is CH 2  and Z is CH 2 .  
   
   
       61 . The compound according to  claim 1  of formula (V)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof thereof.  
   
   
       62 . The compound according to  claim 61  wherein Y is a covalent bond and Z is a covalent bond.  
   
   
       63 . The compound according to  claim 61  wherein Y is a covalent bond and Z is CH 2 .  
   
   
       64 . The compound according to  claim 61  wherein Y is CH 2  and Z is a covalent bond.  
   
   
       65 . The compound according to  claim 61  wherein Y is a covalent bond and Z is CH 2 CH 2 .  
   
   
       66 . The compound according to  claim 61  wherein Y is CH 2  and Z is CH 2 .  
   
   
       67 . The compound according to  claim 61  wherein Y is CH 2 CH 2  and Z is a covalent bond.  
   
   
       68 . The compound according to  claim 1  of formula (VI)  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, amide, ester or prodrug thereof thereof.  
   
   
       69 . The compound according to  claim 68  wherein Y is a covalent bond and Z is a covalent bond.  
   
   
       70 . The compound according to  claim 68  wherein Y is a covalent bond and Z is CH 2 .  
   
   
       71 . The compound according to  claim 68 ,wherein Y is CH 2  and Z is a covalent bond.  
   
   
       72 . The compound according to  claim 68  wherein Y is a covalent bond and Z is CH 2 CH 2 .  
   
   
       73 . The compound according to  claim 68  wherein Y is CH 2  and Z is CH 2 .  
   
   
       74 . The compound according to  claim 68  wherein Y is CH 2 CH 2  and Z is a covalent bond.  
   
   
       75 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof in combination with a pharmaceutically acceptable carrier.  
   
   
       76 . A method of treating a disorder wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, nicotinic withdrawal syndrome, Tourette's syndrome and schizophrenia in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof.  
   
   
       77 . A method of treating pain in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof.  
   
   
       78 . A method of treating pain in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof in combination with a non-steroid anti-inflammatory agent.  
   
   
       79 . A method of treating pain in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof in combination with an opioid.  
   
   
       80 . A method of treating pain in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof in combination with a tricyclic antidepressant.  
   
   
       81 . A method of treating pain in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amide, ester or prodrug thereof in combination with an anticonvulsant.