N-linked urea or carbamate of heterocyclic thioester hair growth compositons and uses

Abstract

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using N-linked ureas or carbamates of heterocyclic thioesters.

We claim:  
     
         1 . A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of an N-linked urea or carbamate of a heterocyclic thioester.  
     
     
         2 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is non-immunosuppressive.  
     
     
         3 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester has an affinity for an FKBP-type immunophilin.  
     
     
         4 . The method of  claim 3 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         5 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional O, S, SO, SO 2 , N, NH, or NR 3  heteroatom(s);  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  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 a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is 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, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         6 . The method of  claim 5 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.  
     
     
         7 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 E, F, G and J are independently selected from the group consisting of CH 2 , O, S, SO, SO 2 , NH and NR 3 ;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkali or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide,  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 1 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 is when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         8 . The method of  claim 7 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         9 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 E, F, and G are independently selected from the group consisting of CH 2 , O, S, SO, SO 2 , NH and NR 3 ;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or S 2 ;  
 C and D are independently hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain or alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected From the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         10 . The method of  claim 9 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         11 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 n is 1, 2 or 3;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent (s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
     
     
         12 . The method of  claim 11 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         13 . The method of  claim 11 , wherein: 
 n is 1 or 2;    Y is (CH 2 ) 2  or a direct bond;    Z is CH;    C is 3-pyridyl, 4-methoxyphenyl, phenyl, or 2-phenylethyl;    D is hydrogen, phenyl or 2-phenylethyl;    R 1  is hydrogen; and    R 2  is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl.    
     
     
         14 . The method of  claim 13 , wherein the compound is selected from the group consisting of: 
 3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl) carbamoyl]pyrrolidine-2-carboxylate;    3-(3-Pyridyl)-1-propyl-2S-1-[(1′,1′- Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate;    3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl) thiocarbamoyl] pyrrolidine-2-carboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         15 . The method of  claim 1 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is C, N, or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, chioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  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 a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is 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, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ; and  
 A, B, R1, R2, U, W, and X are as otherwise defined in  claim 5  above.  
 
     
     
         16 . A pharmaceutical composition which comprises: 
 (i) an effective amount of an N-linked urea or carbamate of a heterocyclic thioester for treating alopecia or promoting hair growth in an animal; and    (ii) a pharmaceutically acceptable carrier.    
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester is non-immunosuppressive.  
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester has an affinity for an FKBP-type immunophilin.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the FKBP-type immunophilin is FKBP-12.  
     
     
         20 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional O, S, SO, SO 2 , N, NH, or NR 3  heteroatom(s);  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  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 a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is 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, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.  
     
     
         22 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 E, F, G and J are independently CH 2 , O, S, SO, SO 2 , NH or NR 3 ;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 1 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom or said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either C or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein the N-linked urea or carbamate of a heterocyclic thioester is 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 ;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -Cl straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 C and D are independently hydrogen, Ar, C 1 -C 6  straight or branched chain alkyl, C 2 -C 6  straight or branched chain or alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         26 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 n is 1, 2 or 3;  
 X is either O or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 R 3  is selected from the group consisting of hydrogen, C 1 -C 4  straight or branched chain alkyl, C 3 -C 4  straight or branched chain alkenyl or alkynyl, and C 1 -C 4  bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or a tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 W is O or S; and  
 U is either O or N, provided that: 
 when U is O, then R 1  is a lone pair of electrons and R 2  is selected from the group consisting of Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; and  
 when U is N, then R 1  and R 2  are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8  cycloalkyl, C 1 -C 6  straight or branched chain alkyl, and C 2 -C 6  straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3 -C 8  cycloalkyl; or R 1  and R 2  are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.  
 
 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.  
     
     
         28 . The pharmaceutical composition of  claim 26 , wherein: 
 n is 1 or 2;    Y is (CH 2 ) 2  or a direct bond;    Z is CH;    C is 3-pyridyl, 4-methoxyphenyl, phenyl, or 2-phenylethyl;    D is hydrogen, phenyl or 2-phenylethyl;    R is hydrogen; and    R 2  is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl.    
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the compound is selected from the group consisting of: 
 3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl) carbamoyl]pyrrolidine-2-carboxylate;    3-(3-Pyridyl)-1-propyl-2S-1-[(1′,1′-Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate;    3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl) thiocarbamoyl]pyrrolidine-2-carboxylate; and    pharmaceutically acceptable salts, esters, and solvates thereof.    
     
     
         30 . The pharmaceutical composition of  claim 16 , wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula V  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 
 V is C, N, or S;  
 Y is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 Z is a direct bond, C 1 -C 6  straight or branched chain alkyl, or C 2 -C 6  straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 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 said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C 3 -C 8  cycloalkyl, C 5 -C 7  cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is 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, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ;  
 Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; and  
 A, B, R1, R2, U, W, and X are as otherwise defined in  claim 20  above.