N-linked carbamates and ureas of heterocyclic thioesters

Abstract

This invention relates to neurotrophic low molecular weight, small molecule N-linked ureas and carbamates 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 3 ;  
 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, 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;  
 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, alkylamino, 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;  
 W is oxygen or sulfur;  
 U is either O or N, wherein when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of:  
 Ar as defined above, C 3 -C 8  cycloalkyl, C l -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 and when U is N, R 1  and R 2  are selected independently from the group consisting of:  
 hydrogen, Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 or R 1  and R 2  may be taken together to form a heterocyclic ring.  
 
     
     
         2 . The compound of  claim 1 , wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         3 . The compound of  claim 1 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         4 . The compound of  claim 3 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         5 . The compound of  claim 1 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         6 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
 3-Phenylpropyl (2S)-1-(-cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (17);    Phenethyl (2S)-N-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (18);    3-(2,3,5-Trimethylphenyl)propyl 1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (19);    3-(2,3,5-Trimethylphenyl)propyl 1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (20);    3-(3-Fluorophenyl)propyl (2S)-1-(Cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (21);    3-(2-Fluorophenyl)propyl (2S)-1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (22);    3-(2-Fluorophenyl)propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (23);    3-(4-Methylphenyl)propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (24);    3-(4-Methylphenyl)propyl (2S)-1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (25);    3-(4-Methylphenyl)propyl (2S)-1-(tert-butylcarbamoyl)-2-pyrrolidinecarbothioate (26);    3-(2-Chlorophenyl)propyl (2S)-1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (27);    3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S)-1-(1-naphthyl)ethyl]-carbamoyl}-2-pyrrolidinecarbothioate (28);    3,3-Diphenylpropyl (2S)-1-[(1,1,3,3-tetramethylbutyl)carbamoyl]-2-pyrrolidinecarbothioate (29);    3-Cyclohexylpropyl (2S)-1-[(2,6-diisopropylphenyl)carbamoyl]-2-pyrrolidinecarbothioate (31);    3-Cyclohexylpropyl (2S)-1-(hexylcarbamoyl)-2-pyrrolidinecarbothioate (32);    3,3-Diphenylpropyl (2S)-1-[(2,4-dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (33);    3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S,2R)-2-phenyl-cyclopropyl]carbamoyl]-2-pyrrolidinecarbothioate (34);    3-Phenylpropyl (2S)-1-[(2,4-Dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (35);    3-Phenylpropyl (2S)-1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (36);    3-Phenylpropyl (2S)-1-(1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (37);    3-Phenylpropyl (2S)-1-[1-adamantylamino) (thioxo)-methyl]-2-pyrrolidinecarbothioate (38);    3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(hexylcarbamoyl)-2-pyrrolidinecarbothioate (39);    3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(benzylcarbamoyl)-2-pyrrolidinecarbothioate (40);    3-Phenylpropyl (2S)-1-(dimethylcarbamoyl)-2-pyrrolidinecarbothioate (41);    3-Phenylpropyl (2S)-1-(1-pyrrolidinylcarbonyl)-2-pyrrolidinecarbothioate (42);    3-Phenylpropyl (2S)-1-(morphilinocarbonyl)-2-pyrrolidinecarbothioate (43);    3-Phenylpropyl (2S)-1-(diisopropylcarbamoyl)-2-pyrrolidinecarbothioate (44);    3-Phenylpropyl (2S)-1-[methyl(phenyl)carbamoyl]-2-pyrrolidinecarbothioate (45); and    3-Phenylpropyl (2S)-1-(diphenylcarbamoyl)-2-pyrrolidinecarbothioate (46).    
     
     
         7 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . 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 .    
     
     
         9 . The method of  claim 8 , 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.  
     
     
         10 . The method of  claim 9 , 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.  
     
     
         11 . The method of  claim 10 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         12 . 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 3  wherein at least two of E, F, G, and H are CH 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 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, 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;  
 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, alkylamino, 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;  
 W is oxygen or sulfur;  
 U is either O or N, wherein when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of:  
 Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 and when U is N, R 1  and R 2  are selected independently from the group consisting of:  
 hydrogen, Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 or R 1  and R 2  may be taken together to form a heterocyclic ring.  
 
     
     
         13 . The compound of  claim 12 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         14 . The compound of  claim 12 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         15 . The compound of  claim 14 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         16 . The compound of  claim 12 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         17 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 12  and a pharmaceutically acceptable carrier.  
     
     
         18 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 12 .    
     
     
         19 . The method of  claim 18 , 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.  
     
     
         20 . The method of  claim 19 , 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.  
     
     
         21 . The method of  claim 20 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         22 . 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 3 wherein at least 2 of E, F, and G are CH 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 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, 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;  
 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, alkylamino, 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;  
 W is oxygen or sulfur;  
 U is either O or N, wherein when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of:  
 Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 and when U is N, R 1  and R 2  are selected independently from the group consisting of:  
 hydrogen, Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 or R 1  and R 2  may be taken together to form a heterocyclic ring.  
 
     
     
         23 . The compound of  claim 22 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         24 . The compound of  claim 22 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         25 . The compound of  claim 24 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         26 . The compound of  claim 22 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         27 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 22  and a pharmaceutically acceptable carrier.  
     
     
         28 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 22 .    
     
     
         29 . The method of  claim 28 , 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.  
     
     
         30 . The method of  claim 29 , 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.  
     
     
         31 . The method of  claim 30 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.  
     
     
         32 . 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, 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;  
 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, alkylamino, 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;  
 W is oxygen or sulfur;  
 U is either O or N, wherein when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of:  
 Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 and when U is N, R 1  and R 2  are selected independently from the group consisting of:  
 hydrogen, Ar as defined above, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl or alkenyl, or C 1 -C 6  straight or branched chain alkyl or alkenyl 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;  
 or R 1  and R 2  may be taken together to form a heterocyclic ring.  
 
     
     
         33 . The compound of  claim 32 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         34 . The compound of  claim 32 , wherein the compound has an affinity for FKBP-type immunophilins.  
     
     
         35 . The compound of  claim 34 , wherein the FKBP-type immunophilins are FKBP12.  
     
     
         36 . The compound of  claim 32 , wherein the compound inhibits rotamase enzyme activity.  
     
     
         37 . A pharmaceutical composition comprising a neurotrophically effective amount of the compound of  claim 32  and a pharmaceutically acceptable carrier.  
     
     
         38 . A method of effecting a neuronal activity in an animal, comprising: 
 administering to the animal a neurotrophically effective amount of the compound of  claim 32 .    
     
     
         39 . The method of  claim 38 , 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.  
     
     
         40 . The method of  claim 39 , 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.  
     
     
         41 . The method of claim  40 , wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.