N-linked sulfonamides of heterocyclic thioesters

Abstract

This invention relates to neurotrophic low molecular weight, small molecule N-linked sulfonamides of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

What is claimed is:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH 2 , O, S, SO, SO 2 , NH or NR 2  in any chemically stable oxidation state;  
 X is either O or S;  
 Y is a direct bond to Z, a C 1 -C 6  straight or branched chain alkyl, or a C 1 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxgen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 Z is a direct bond, or a C 1 -C 6  straight or branched chain alkyl, or a C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, akylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 C and D are independently:  
 hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, or C 3 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C 1 -C 6  alkyl, C 2 -C 6  alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; and  
 R 1  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, or C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO 2 , O, or NR 2  wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C 3 -C 8  cycloalkyl.  
 
     
     
         2 . The compound of  claim 1 , wherein Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five position(s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-8 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of O, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.  
     
     
         3 . The compound of  claim 2 , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.  
     
     
         4 . The compound of  claim 1 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         5 . The compound of  claim 4  wherein the FKBP-type immunophilins are FKBP12.  
     
     
         6 . The compound of  claim 1 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         7 . A compound selected from the group consisting of: 
 3-(4-Methoxyphenyl)propyl (2S)-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate;    3-(4-Methoxyphenyl)propyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate;    3-(4-Methoxyphenyl)propyl (2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarbothioate;    (2,2-methylphenyl)ethyl (2S)-1-[(4-ethylphenyl) sulfonyl]-2-pyrrolidinecarbothioate;    3-Phenylpropyl (2S)-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate;    3-Phenylpropyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate;    3-(1-Naphthyl)propyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate;    3-Phenylpropyl (2S) -1-[(4-ethylphenyl)sulfonyl]-2-pyrrolidinecarbothioate;    3-(4-Methoxyphenyl)propyl 1-[(4-methylphenyl)sulfonyl]-2-piperidinecarbothioate;    3-(4-Methoxyphenyl)propyl 1-(benzylsulfonyl)-2-piperidinecarbothioate;    3-(4-Methoxyphenyl)propyl 1-(phenylsulfonyl)-2-piperidinecarbothioate;    3-[(4-Trifluoromethylphenyl]propyl 1-[(4-methylphenyl)sulfonyl]-2-piperidinecarbothioate;    and a pharmaceutically acceptable salt, ester, or solvate thereof.    
     
     
         8 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         9 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 1 .    
     
     
         10 . The method of  claim 9 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         11 . The method of  claim 10 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         12 . The method of  claim 11 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         13 . A compound of formula II:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 E, F, G, and H are independently CH 2 , O, S, SO, SO 2 , NH or NR 2 ;  
 X is either O or S;  
 Y is a direct bond to Z, a C 1 -C 6  straight or branched chain alkyl, or a C 1 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxgen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 Z is a direct bond, or a C 1 -C 6  straight or branched chain alkyl, or a C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, akylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 C and D are independently:  
 hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C 1 -C 6  alkyl, C 2 -C 6  alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; and  
 R 1  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, or C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO 2 , O, or NR 2  wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C 3 -C 8  cycloalkyl.  
 
     
     
         14 . The compound of  claim 13 , wherein Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted or substituted in one to five position(s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-8 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of O, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.  
     
     
         15 . The compound of  claim 14 , wherein Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.  
     
     
         16 . The compound of  claim 13 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         17 . The compound of  claim 16 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         18 . The compound of  claim 13 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         19 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 13  and a pharmaceutically acceptable carrier.  
     
     
         20 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 13 .    
     
     
         21 . The method of  claim 20 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         22 . The method of  claim 21 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         23 . The method of  claim 22 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         24 . A compound of formula III:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 E, F, and G are independently CH 2 , O, S, SO, SO 2 , NH or NR 2 ;  
 X is either O or S;  
 Y is a direct bond to Z, a C 1 -C 6  straight or branched chain alkyl, or a C 1 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxgen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 1 , S, SO, or SO 2 , wherein R 1  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 Z is a direct bond, or a C 1 -C 6  straight or branched chain alkyl, or a C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, akylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 1 , S, SO, or SO 2 , wherein R 1  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 C and D are independently:  
 hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C 1 -C 6  alkyl, C 2 -C 6  alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 1 , S, SO, or SO 1 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; and  
 R 1  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, or C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO 2 , O, or NR 1  wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C 3 -C 8  cycloalkyl.  
 
     
     
         25 . The compound of  claim 24 , wherein Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted or substituted in one to five position(s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-8 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of O, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.  
     
     
         26 . The compound of  claim 25 , wherein Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.  
     
     
         27 . The compound of  claim 24 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         28 . The compound of  claim 27 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         29 . The compound of  claim 24 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         30 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 24  and a pharmaceutically acceptable carrier.  
     
     
         31 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 24 .    
     
     
         32 . The method of  claim 31 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         33 . The method of  claim 32 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         34 . The method of  claim 33 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         35 . A compound of formula IV:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 n is 1, 2 or 3 forming a 5-7 member heterocyclic ring;  
 X is either O or S;  
 Y is a direct bond to Z, a C 1 -C 6  straight or branched chain alkyl, or a C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxgen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 Z is a direct bond, or a C 1 -C 6  straight or branched chain alkyl, or a C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, akylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 C and D are independently:  
 hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C 1 -C 6  alkyl, C 2 -C 6  alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR 2 , S, SO, or SO 2 , wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 6 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;  
 wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; and  
 R 1  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, or C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO 2 , O, or NR 2  wherein R 2  is selected from the group consisting of hydrogen, (C 1 -C 6 )-straight or branched chain alkyl, (C 3 -C 8 )-straight or branched chain alkenyl or alkynyl, and (C 1 -C 4 ) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR 1  and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C 3 -C 8  cycloalkyl.  
 
     
     
         36 . The compound of  claim 35 , wherein Ar is a cyclic or fused cyclic ring and includes a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted or substituted in one to five position(s) with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain alkenyl, C 1 -C 6  alkoxy, C 2 -C 6  alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, and sulfonyl; wherein the individual ring sizes are 5-8 members; wherein the heterocyclic ring contains 1-4 heteroatom(s) selected from the group consisting of O, N, or S; wherein aromatic or tertiary alkyl amines are optionally oxidized to a corresponding N-oxide.  
     
     
         37 . The compound of  claim 36 , wherein Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.  
     
     
         38 . The compound of  claim 35 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         39 . The compound of  claim 33 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         40 . The compound of  claim 35 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         41 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 35  and a pharmaceutically acceptable carrier.  
     
     
         42 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 35 .    
     
     
         43 . The method of  claim 42 , wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.  
     
     
         44 . The method of  claim 43 , wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.  
     
     
         45 . The method of  claim 44 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         46 . A process for preparing a compound of Formula I, II, III, or IV, which comprises: 
 contacting a compound of structure (a)                          with a compound of structure (b),   HS—R  (b)   wherein said contacting results in a compound of Formula I, II, III, or IV.    
     
     
         47 . A process for preparing a compound of Formula I, II, III, or IV, which comprises: 
 contacting a compound of structure (a)                          with a compound of structure (b),                          wherein said contacting results in a compound of Formula I, II, III, or IV.