AU8252898A - N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses - Google Patents

Description

WO99/62485 PCTIUS98/11244 N-LINKED UREA OR CARBAMATE OF HETEROCYCLIC THIOESTER HAIR GROWTH COMPOSITIONS AND USES This application is a continuation-in-part of 5 U.S. Patent Application No. 08/869,426, filed on June 4, 1997, the entire contents of which are herein incorporated by reference. BACKGROUND OF THE INVENTION 10 1. Field of Invention This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using low molecular weight, 15 small molecule N-linked ureas or carbamates of heterocyclic thioesters. 2. Description of Related Art Hair loss occurs in a variety of situations. 20 These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing 25 hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.

WO99/62485 PCT/US98/11244 2 The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been 5 reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth 10 in a dose-dependent manner. One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss. The 15 hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic 20 compounds, known for their immunosuppressive effects, as hair revitalizing agents. The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.S. patents (Goulet et al., U.S. Patent No. 5,258,389; 25 Luly et al., U.S. Patent No. 5,457,111; Goulet et al., U.S. Patent No. 5,532,248; Goulet et al., U.S. Patent No. 5,189,042; and Ok et al., U.S. Patent No. 5,208,241; Rupprecht et al., U.S. Patent No.

WO 99/62485 PCT/US98/11244 3 5,284,840; Organ et al., U.S. Patent No. 5,284,877). These patents claim FK506 related compounds. Although they do not claim methods of hair revitalization, they disclose the known use of FK506 for effecting hair 5 growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's 10 efficacy is well known. Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Patent No. 5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt 15 et al., U.S. Patent No. 4,996,193). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth. 20 However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds which are useful as hair revitalizing 25 compounds. Hamilton and Steiner disclose in U.S. Patent No. 5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate WO 99/62485 PCT/US98/11244 4 nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their 5 novel small molecule structure and non immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art. 10 SUMMARY OF THE INVENTION The present invention relates to 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 15 of a heterocyclic thioester. The present invention further relates to a pharmaceutical composition which comprises: (i) an effective amount of an N-linked urea or carbamate of a heterocyclic thioester for treating 20 alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. The N-linked ureas or carbamates of heterocyclic thioesters used in the inventive methods and pharmaceutical compositions have an affinity for FKBP 25 type immunophilins, such as FKBP12, and do not exert any significant immunosuppressive activity.

WO 99/62485 PCTIUS98/11244 5 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photograph of C57 Black 6 mice before being shaved for the hair regeneration experiment. FIG. 2 is a photograph of mice treated with a 5 vehicle after six weeks. FIG. 2 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered. FIG. 3 is a photograph of mice treated with GPI 1046, a related non-immunosuppressive neuro 10 immunophilin FKBP ligand, after six weeks. FIG. 3 shows the remarkable effects of non-immunosuppressive neuroimmunophilin FKBP ligands, wherein 90% of the shaved area is covered with new hair growth. FIG. 4 is a photograph of mice treated with 30 pM 15 of GPI 1046, a related non-immunosuppressive neuro immunophilin FKBP ligand, after six weeks. FIG. 4 shows the remarkable ability of non-immunosuppressive neuroimmunophilin FKBP ligands to achieve, essentially, complete hair regrowth in the shaved 20 area. FIG. 5 is a bar graph depicting the relative hair growth indices for C57 Black 6 mice treated with a vehicle, FK506, and various non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI 1605, 14 25 days after treatment with each identified compound. Figure 5 demonstrates the remarkable early hair growth promoted by a wide variety of non-immuno-suppressive neuroimmunophilin FKBP ligands.

WO 99/62485 PCT/US98/11244 6 DETAILED DESCRIPTION OF THE INVENTION Definitions "Alopecia" refers to deficient hair growth and partial or complete loss of hair, including without 5 limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania. Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the 10 hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs 15 fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs. "GPI 1605" refers to a compound of formula 20 S 2OO HN 0O 2 GPI 1605 25 "GPI 1046" refers to 3-(3-pyridyl)-1-propyl (2s) 1- (3, 3-dimethyl-l,2-dioxopentyl)-2 pyrrolidinecarboxylate, a compound of formula WO 99/62485 PCT/US98/11244 7 N 0 N o 0 0 o GPI1046 5 "GPI 1312" refers to a compound of formula S O=2 O 10 GPI 1312 "GPI 1572" refers to a compound of formula N 15 .- 5 o OO N ( o 0 0 GPI 1572 "GPI 1389" refers to a compound of formula 20 N 2OO 0 0 0 OGPI 1389 25 "GPI 1511" refers to a compound of formula WO 99/62485 PCT/US98/11244 8 (N~y S o " GPI 1511 5 "GPI 1234" refers to a compound of formula N 10 0 GPI 1234 "Isomers" refer to different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are 15 arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing 20 equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers. "Pharmaceutically acceptable salt, ester, or solvate" refers to a salt, ester, or solvate of a 25 subject compound which possess the desired pharmacological activity and which is neither biologically nor otherwise undesirable. A salt, ester, or solvate can be formed with inorganic acids WO 99/62485 PCTIUS98/11244 9 such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, 5 ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, 10 nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of base salts, esters, or solvates include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; 15 salts with organic bases, such as dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quarternized with such agents as lower alkyl halides, 20 such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl 25 halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.

WO99/62485 PCT/US98/11244 10 "Pilar cycle" refers to the life cycle of hair follicles, and includes three phases: (1) the anagen phase, the period of active hair growth which, insofar as scalp hair is 5 concerned, lasts about three to five years; (2) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and 10 (3) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months. Normally 80 to 90 percent of the follicles are in the 15 anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase. In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By contrast, in the anagen phase, hair has a large colored bulb at its 20 root. "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair. "Treating alopecia" refers to: 25 (i) preventing alopecia in an animal which may be predisposed to alopecia; and/or (ii) inhibiting, retarding or reducing alopecia; and/or WO99/62485 PCT/US98/11244 11 (iii) promoting hair growth; and/or (iv) prolonging the anagen phase of the hair cycle; and/or (v) converting vellus hair to growth as terminal 5 hair. Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis. Vellus hair, on the other hand, is fine, thin, non-pigmented short hair in which the hair bulb is located superficially in the dermis. As 10 alopecia progresses, the hairs change from the terminal to the vellus type. Methods of the Present Invention The present invention relates to a method for 15 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. The inventive method is particularly useful for 20 treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional 25 disorders and internal secretion disorders.

WO99/62485 PCT/US98/11244 12 Pharmaceutical Compositions of the Present Invention The present invention also relates to a pharma ceutical composition comprising: (i) an effective amount of an N-linked urea or 5 carbamate of a heterocyclic thioester for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier. 10 N-LINKED UREAS AND CARBAMATES OF HETEROCYCLIC THIOESTERS The N-linked ureas and carbamates of heterocyclic thioesters used in the methods and pharmaceutical compositions of the present invention are low 15 molecular weight, small molecule compounds having an affinity for an FKBP-type immunophilin, such as FKBPl2. When an N-linked urea or carbamate of a heterocyclic thioester binds to an FKBP-type immunophilin, it has been found to inhibit the prolyl 20 peptidyl cis-trans isomerase, or rotamase, activity of the binding protein. Unexpectedly, these compounds have also been found to stimulate hair growth. These compounds are devoid of any significant immunosuppressive activity. 25 FORMULA I The N-linked urea or carbamate of a heterocyclic thioester may be a compound of formula I WO99/62485 PCT/US98/11244 13 B 1 N D I Rz or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 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, S02, N, 15 NH, or NR 3 heteroatom(s); X is either 0 or S; Y is a direct bond, C,-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 20 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 25 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 WO99/62485 PCT/US98/11244 14 straight or branched chain alkenyl or alkynyl, and Cj

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 5 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 10 or more substituent(s) independently selected from the group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, CI-C 9 straight or branched chain alkyl, CI-C 9 alkoxy, C 2

-C

9 alkenyloxy, C 2

-C

9 straight or branched chain alkenyl, 15 C 3 -C cycloalkyl, C 5

-C

7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, 20 thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from 25 the group consisting of O, N, and S; and wherein said aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; WO99/62485 PCTIUS98/11244 15 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 5 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 10 replaced with O, NH, NR 3 , S, SO, or SO 2 ; C and D are independently hydrogen, Ar, Cl-C 6 straight or branched chain alkyl, or C 2 -C, straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more 15 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 Cl-C 6 alkyl, C 2

-C

6 alkenyl, hydroxy, 20 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 25 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 0 or S; and WO 99/62485 PCT/US98/11244 16 U is either 0 or N, provided that: when U is O, then R i is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3 -C, cycloalkyl, CI-C. straight 5 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; 10 and when U is N, then R, and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3

-C

8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2

-C

6 straight or branched chain 15 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, and R 2 are taken together to form a heterocyclic 5 or 6 membered 20 ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, 25 azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, WO99/62485 PCT/US98/11244 17 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, 5 triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, 10 pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In a preferred embodiment of formula I, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, 15 pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. In a more preferred embodiment of the compounds 20 of formula I, the N-linked urea or carbamate of a heterocyclic thioester is the compound GPI 1605, of the formula S 25 0GPI 1605 oGPI 1605 WO99/62485 PCT/US98/11244 18 FORMULA II The N-linked urea or carbamate of a heterocyclic thioester may also be a compound of formula II 5 F/GH E N y S---Y--Z R, X D R2U W X I R, 10 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, G and J are independently CH 2 , O, S, SO, SO2, NH, or NR 3 ; 15 X is either 0 or S; Y is a direct bond, Cl-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 20 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 25 replaced with O, NH, NR 3 , S, SO, or SO 2 ;

R

3 is selected from the group consisting of hydrogen, Cl-C 4 straight or branched chain alkyl, C 3

-C

4 straight or branched chain alkenyl or alkynyl, and Ci- WO99/62485 PCT/US98/11244 19

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 5 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) independently selected from the 10 group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, CI-C 9 straight or branched chain alkyl, Cl-C 9 alkoxy, C 2

-C

9 alkenyloxy, C 2

-C

9 straight or branched chain alkenyl,

C

3

-C

8 cycloalkyl, C,-C 7 cycloalkenyl, carbonyl, carboxy, 15 cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and 20 heterocyclic moieties, including alicyclic and aromatic structures; 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 25 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 WO99/62485 PCT/US98/11244 20 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, 5 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 S02; C and D are independently hydrogen, Ar, CI-C 6 10 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, cycloalkenyl, 15 hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C,-C 6 alkyl, C 2

-C

6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, 20 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 25 replaced with O, NH, NR 3 , S, SO, or SO 2 ; W is 0 or S; and U is either 0 or N, provided that: when U is O, then R i is a lone pair of WO99/62485 PCT/US98/11244 21 electrons and R 2 is selected from the group consisting of Ar, C 3 -C, cycloalkyl, C 1

-C

6 straight or branched chain alkyl, and C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or 5 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, and R 2 are independently 10 selected from the group consisting of hydrogen, Ar, C 3

-C

8 cycloalkyl, Cl-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 15 substituent(s) independently selected from the group consisting of Ar and C 3

-C

8 cycloalkyl; or R I and R 2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, 20 pyrazolidine, piperidine, and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, 25 benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, WO99/62485 PCTIUS98/11244 22 furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, 5 pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. 10 In a preferred embodiment of formula II, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, 15 pyrazolyl, and thienyl. FORMULA III Additionally, the N-linked urea or carbamate of a heterocyclic thioester may be a compound of formula 20 III F-G / /C 25 R U w

R,

WO99/62485 PCT/US98/11244 23 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , O, S, SO, SO 2 , NH, and NR 3 ; 5 X is either 0 or S; Y is a direct bond, C,-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 10 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 15 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 20 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 25 tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group including, but not limited to, alkylamino, WO99/62485 PCT/US98/11244 24 amido, amino, aminoalkyl, azo, benzyloxy, C 1

-C

9 straight or branched chain alkyl, C,-C 9 alkoxy, C 2

-C

9 alkenyloxy, C 2

-C

9 straight or branched chain alkenyl,

C

3

-C

8 cycloalkyl, C.-C 7 cycloalkenyl, carbonyl, carboxy, 5 cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and 10 heterocyclic moieties, including alicyclic and aromatic structures; 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 15 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 20 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 25 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, Cl-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or WO99/62485 PCTIUS98/11244 25 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, Cs-C 7 cycloalkenyl, 5 hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cl-C 6 alkyl, C 2 -C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, 10 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 15 replaced with O, NH, NR 3 , S, SO, or SO 2 ; W is 0 or S; and U is either 0 or N, provided that: when U is O, then R i is a lone pair of electrons and R 2 is selected from the group 20 consisting of Ar, C 3

-C

8 cycloalkyl, CI-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 25 the group consisting of Ar and C 3

-C

8 cycloalkyl; and when U is N, then R, and R 2 are independently selected from the group consisting of hydrogen, WO99/62485 PCTIUS98/11244 26 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 5 substituent(s) independently selected from the group consisting of Ar and C 3

-C

8 cycloalkyl; or RI and R 2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, 10 pyrazolidine, piperidine, and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, 15 benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, 20 thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, 25 quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. In a preferred embodiment of formula III, Ar is WO99/62485 PCT/US98/11244 27 selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, 5 pyrazolyl, and thienyl. In a more preferred embodiment of the compounds of formula III, the N-linked urea or carbamate of a heterocyclic thioester is the compound GPI 1605, of the formula 10 S N HN 1'O 1 GPI 1605 15 FORMULA IV The N-linked urea or carbamate of a heterocyclic thioester may further be a compound of formula IV 20

(CH

2 ) n C ~~S-Y-Z IV R2w X R 2 1 U W 25 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: WO99/62485 PCT/US98/11244 28 n is 1, 2 or 3; X is either 0 or S; Y is a direct bond, CI-C 6 straight or branched chain alkyl, or C 2

-C

6 straight or branched chain 5 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, 10 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, Cl-C, straight or branched chain alkyl, C 3

-C

4 15 straight or branched chain alkenyl or alkynyl, and C,

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 20 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) independently selected from the 25 group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C 1

-C

9 straight or branched chain alkyl, Cl-C 9 alkoxy, C 2

-C

9 alkenyloxy, C 2

-C

9 straight or branched chain alkenyl, WO99/62485 PCT/US98/11244 29

C

3

-C

8 cycloalkyl, C 5

-C

7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, 5 thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring 10 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, Ci-C 6 straight or branched 15 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, 20 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, Cl-C 6 25 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 WO99/62485 PCTIUS98/11244 30 consisting of C 3

-C

8 cycloalkyl, C.-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with CI-C6 alkyl, C 2

-C

6 alkenyl, hydroxy, 5 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 10 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 0 or S; and U is either 0 or N, provided that: 15 when U is O, then R, is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3

-C

8 cycloalkyl, CI-C 6 straight or branched chain alkyl, and C 2

-C

6 straight or branched chain or alkenyl, wherein said alkyl or 20 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 RI and R 2 are independently 25 selected from the group consisting of hydrogen, Ar, C 3

-C

8 cycloalkyl, C-C 6 straight or branched chain alkyl, and C 2

-C

6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is WO99/62485 PCT/US98/11244 31 optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C 3

-C

8 cycloalkyl; or R, and R 2 are taken together to form a heterocyclic 5 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine. Useful carbo- and heterocyclic rings include without limitation phenyl, benzyl, naphthyl, indenyl, 10 azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, 15 isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, 20 pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. 25 In a preferred embodiment of formula IV, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, WO 99/62485 PCT/US98/11244 32 furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. Exemplary compounds of formula IV are presented in TABLE I. 5 TABLE I

(CH

2 ) nC N D 10 R 2 U - X U W I Rz 15 No. n W Y Z C D R, R 2 1 1 O (CH 2

)

2 CH 3-Pyridyl H H 2-Methylbutyl 20 2 1 O (CH 2

)

2 CH 3-Pyridyl H H 1,1-dimethylpropyl 3 1 O (CH 2

)

2 CH 4-Methoxy H H 1,1-dimethylpropyl phenyl 25 4 1 O CH 2 CH Phenyl H H 1,1-dimethylpropyl 5 1 S (CH 2

)

2 CH 4-Methoxy H H Cyclohexyl phenyl 30 6 1 O (CH 2

)

2 CH 3-Pyridyl H H Cyclohexyl 7 1 S (CH 2

)

2 CH 3-Pyridyl H H Cyclohexyl 8 1 S (CH 2

)

2 CH 3-Pyridyl H H 1-Adamantyl 35 9 1 S (CH 2

)

2 CH 3-Pyridyl H H 1,1-dimethylpropyl WO 99/62485 PCT/US98/11244 33 TABLE I (continued) No. n W Y Z C D R 1

R

2 5 10 1 O (CH 2

)

2 CH Phenyl Phenyl H 1,1-dimethylpropyl 11 2 O (CH 2

)

2 CH Phenyl H H 1,1-dimethylpropyl 10 12 2 O (CH 2

)

2 CH Phenyl H H Phenyl 13 2 O Direct CH 2-Phenyl 2-Phenyl H Phenyl bond ethyl ethyl 15 14 2 O Direct CH 2-Phenyl 2-Phenyl H Cyclohexyl bond ethyl ethyl 15 2 S Direct CH 2-Phenyl 2-Phenyl H Cyclohexyl 2 0 bond ethyl ethyl 16 2 O (CH2) 2 CH 4-Methoxy H H Cyclohexyl phenyl 25 The most preferred compounds of formula IV are selected from the group consisting of: 3-(3-Pyridyl) -1l-propyl-2S-1 -[(2-methylbutyl) carbamoyll]pyrrolidine-2-carboxylate; 3-(3-Pyridyl)-l-propyl-2S-l-[(1',1' 30 Dimethylpropyl) carbamoyl] pyrrolidine-2 -carboxylate; 3-(3-Pyridyl)-l-propyl-2S-l-[(cyclohexyl) thiocarbamoyl] pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof. 35 FORMULA V The N-linked urea or carbamate of a heterocyclic thioester may be a compound of formula V WO99/62485 PCT/US98/11244 34 B A 1 S-Y-Z R2A S-- Z D v 5 U RI or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 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 15 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 20 replaced with O, NH, NR 3 , S, SO, or SO 2 ;

R

3 is selected from the group consisting of hydrogen, Cl-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 25 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; WO99/62485 PCT/US98/11244 35 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 5 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; 10 Z is a direct bond, C,-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, 15 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 ; 20 C and D are independently hydrogen, Ar, C1i-C6 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 25 consisting of C 3

-C

8 cycloalkyl, C,-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, WO99/62485 PCT/US98/11244 36 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 5 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 10 defined in formula I above. All the compounds of Formulas I-V possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S stereoisomers. The individual stereoisomers may be 15 obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-V. It is understood that the compounds of 20 Formulas I-V encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention. 25 Synthesis of N-linked Ureas and Carbamates of Heterocyclic Thioesters The compounds of formulas I to V may be readily WO 99/62485 PCTIUS98/11244 37 prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme I, cyclic amino acids 1 protected by suitable blocking groups P on the amino 5 acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively. 10 SCHEME I

(CH

2 ) n (CH 2 ) n OH R-SH S-R Deprotect N 1 N Coupling Method P 0 P 0 15 1 2 (CH2 ) n R'-N=C=W (CH 2 ) n S-R 4 S-R N - N

CH

2 C1 2 H O O HN 20 3 5 Isocyanates (R'NCO) or isothiocyanates (R'NCS) 4 may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or 25 thiophosgene, as depicted in Scheme II.

WO99/62485 PCT/US98/11244 38 SCHEME II W R ',NH 2 + R' -NCW Cl Cl 5 Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halide by sulfur, as described in Scheme III. Halides may be reacted with 10 thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods. 15 SCHEME III S 1) PBr 3 H 2 N ) NH 2 or 20 R-OH R-Br R-SH

CBI

4 /Ph 3 P 2) OH Affinity for FKBP12 The compounds used in the inventive methods and 25 pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase WO99/62485 PCTIUS98/11244 39 activity of FKBP may be measured as an indicator of this affinity. Ki Test Procedure 5 Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Nature, 1989, 341:758-760; 10 Holt et al. J. Am. Chem. Soc., 115:9923-9938). These values are obtained as apparent Ki's and are presented for representative compounds in TABLE II. The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe 15 p-nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is 20 determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent Ki values. In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL 25 of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml in 1 mM HC1) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is WO99/62485 PCT/US98/11244 40 initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35 mM LiCI in trifluoroethanol). The absorbance at 390 nm versus time is monitored 5 for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files. TABLE II 10 In Vitro Test Results - Formulas I to V Compound Ki (nM) 1 +++ 2 ++ 3 ++ 15 4 ++ 5 ++ 6 + 7 ++ 8 +++ 20 9 +++ 10 +++ 11 ++ 12 +++ 13 +++ 25 14 +++ 15 +++ 16 ++ WO99/62485 PCT/US98/11244 41 Relative potencies of compounds are ranked according to the following scale: ++++ denotes K i or ED50 < 1 nM; +++ denotes K i or ED50 of 1-50 nM; ++ denotes K i or ED 50 of 51-200 nM; + denotes K i or ED of 201-500 5 nM. Route of Administration To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods 10 and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin. For topical application to the skin, the 15 compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene 20 polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more 25 of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

WO99/62485 PCT/US98/11244 42 Other routes of administration known in the pharmaceutical art are also contemplated by this invention. 5 Dosage Dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 10 mg. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of 15 administration; the rate of excretion; drug combination; the severity of the particular disease being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient 20 administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art. The compounds can be administered with other hair revitalizing agents. Specific dose levels for 25 the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination.

WO99/62485 PCTIUS98/11244 43 EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, 5 all percentages are based upon 100% by weight of the final composition. Example 1 Synthesis of 3-(3-Pyridyl)-1-propylmercaptyl 2S-1 10 [(2-methylbutyl)carbamoyl]lpyrrolidine-2-carboxylate (1) 3-(3-Pyridvyl)-1-propylchloride To a solution of 3-(3-pyridyl)-1-propanol (10 g; 72.4 mmol) in chloroform (100 mL) was added dropwise 15 a solution of thionyl chloride (12.9 g; 108.6 mmol) in chloroform (50 mL). The resulting mixture was refluxed for 1 hour, then poured into ice-cold 50% aqueous potassium hydroxide (150 mL). The layers were separated, and the organic phase was dried, 20 concentrated, and purified on a silica gel column, eluting with 40% ethylacetate in hexane, to obtain 10 g (65%) of the chloride as a clear oil. 1H NMR (300 MHz, CDC1, 3 ): 6 2.02-2.11 (m, 2H); 2.77 (m, 2H); 3.51 (m, 2H); 7.20 (m, 1H); 7.49 (m, 1H); 8.45 (m, 2H). 25 3-(3-Pyridyl)-1-propylmercaptan A mixture of 3-(3-pyridyl)-l-propylchloride (3 g; 19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium WO99/62485 PCT/US98/11244 44 hydroxide, 15 mL of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the 5 crude thiol on a silica gel column eluting with 50% ethyl acetate in hexane delivered 1.2 g of 3-(3 Pyridyl)-l-propylmercaptan as a clear liquid. 'H NMR (300 MHz, CDC1 3 ): 6 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H); 10 8.42 (m, 2H). 3-(3-Pyridyvl)-l-propylmercaptyl N-(tert butyloxycarbonyl)pyrrolidine-2-carboxylate A mixture of N-(tert-butyloxycarbonyl)-(S) proline (3.0 g; 13.9 mmol); 3-(3-Pyridyl)-l 15 propylmercaptan (3.20 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4 dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight. 20 The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the crude residue was purified on a 25 silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the thioester as a thick oil. 'H NMR (300 MHz, CDC1 3 ): 6 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H) ; 2.71 (t, 2H) ; 2.85 (m, 2H) ; 3.50 (m, WO 99/62485 PCT/US98/11244 45 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H). 3-(3-Pyridyl)-1-propylmercaptyvl pyrrolidine-2 carboxylate 5 A solution of 3-(3-Pyridyl)-l-mercaptyl N-(tert butyloxycarbonyl)pyrrolidine-2-carboxylate (4.60 g; 13.1 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium 10 carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 2.36 g (75%) of the free amine as a thick oil. 'H NMR (300 MHz, CDC1 3 ): 6 1.87-2.20 15 (m, 6H); 2.79 (m, 2H); 3.03-3.15 (m, 4H total); 3.84 (m, 1H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57 (m, 2H). 3-(3-Pyridyl)-l-propylmercaptvyl 2S-1- [(2 methylbutyl)carbamoyl]pyrrolidine-2-carboxylate (1) A solution of 2-methylbutylamine (113 mg; 1.3 mmol) 20 and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL). The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3-(3-Pyridyl)-l 25 propylmercaptyl pyrrolidine-2-carboxylate (300 mg; 1.3 mmol) in 5 mL of methylene chloride was added and the resulting mixture was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl WO 99/62485 PCT/US98/11244 46 acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 250 mg (55%) of the compound of Example 1 (Compound 1, Table II) as an 5 oil. 'H NMR (300 MHz, CDC1 3 ): d 'H NMR (CDC1 3 , 300 MHz): 6 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H); 2.92-3.54 (m, 6H); 4.45 4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 10 8.46-8.48 (s, 2H). Example 2 Synthesis of 3-(3-Pyridyl)-l-propyl 2S-1-[(l',1' Dimethylpropyl) carbamoyl] pyrrolidine-2 -carboxylate 15 (2) Reaction of 3-(3-pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate with the isocyanate generated from tert-amylamine and triphosgene, as described for Example 1, provided the compound of 20 Example 2 (Compound 2, Table II) in 62% yield. iH NMR (CDC1 3 , 300 MHz): 6 0.83 (t, 3H); 1.27 (s, 6H); 1.64 1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H); 2.85 (m, 2H); 3.29-3.42 (m, 2H); 4.11 (br, 1H); 4.37 4.41 (m, 1H). 25 WO 99/62485 PCT/US98/11244 47 Example 3 Synthesis of 3-(3-pyridyl)-1-propylmercaptvl 2S-1 [(cyclohexyl)thiocarbamoyl] -pyrrolidine-2 carboxylate (7) 5 A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol), 3-(3-pyridyl) -1-propylmercaptyl pyrrolidine-2 carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water 10 and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 7, Table II). 'H NMR (CDC1 3 , 300 MHz): 5 15 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.03 (m, 2H); 3.40-3.60 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H). 20 Example 4 In Vivo Hair Generation Tests With C57 Black 6 Mice Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of a low molecular weight, small molecule, non-immuno 25 suppressive neuroimmunophilin FKBP ligand, GPI 1046, which is related to N-linked ureas and carbamates of heterocyclic thioesters. Referring now to FIGS. 1 and 2 of the drawings, C57 black 6 mice, approximately 7 WO99/62485 PCT/US98/11244 48 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in 5 anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 2, 3 and 4, four animals per group were treated by topical administration with 20% propylene glycol vehicle (FIG. 2), 10 AM GPI 1046 (FIG. 3) or 30 AM GPI 1046 (FIG. 4) 10 dissolved in the vehicle. The animals were treated with vehicle or GPI 1046 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area 15 covered by new hair growth during this time period. FIG. 2 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIG. 3 shows 20 that animals treated with 10

A

M GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals. Further, FIG. 4 shows that mice treated with 30 AM GPI 1046 exhibited essentially complete hair regrowth and their shaved 25 areas were indistinguishable from unshaven C57 black 6 mice. Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of a WO99/62485 PCT/US98/11244 49 variety of low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI 1605. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on 5 their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, 10 FK506, or one of the low molecular weight, small molecule, non-immunosuppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046, 1312, 1572, 1389, 1511, and 1234) at a concentration of one micromole per milliliter to the shaved area. The animals were 15 treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to five 20 (complete hair regrowth in shaved area). Figure 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of growth in small tufts. In contrast, animals treated with one of the low molecular weight, small molecule, 25 non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI 1605, exhibited dramatic hair growth.

WO99/62485 PCT/US98/11244 50 Example 5 A lotion comprising the following composition may be prepared. 5 (%) 95% Ethanol 80.0 an N-linked urea or carbamate of a 10.0 heterocyclic thioester as defined above 10 a-Tocopherol acetate 0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil purified water 9.0 perfume and dye q.s. 15 Into 95% ethanol are added an N-linked urea or carbamate of a heterocyclic thioester, a-tocopherol acetate, ethylene oxide (40 mole) adducts of hardened 20 castor oil, perfume and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion. 5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia. 25 WO99/62485 PCT/US98/11244 51 Example 6 A lotion comprising the following composition shown may be prepared. 5 (%) 95% Ethanol 80.0 an N-linked urea or carbamate of a 0.005 heterocyclic thioester as defined above Hinokitol 0.01 10 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oil Purified water 19.0 Perfume and dye q.s. 15 Into 95% ethanol are added an N-linked urea or carbamate of a heterocyclic thioester, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye. The resulting mixture is stirred, and purified water is added to the mixture to 20 obtain a transparent liquid lotion. The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia. 25 WO99/62485 PCT/US98/11244 52 Example 7 An emulsion may be prepared from A phase and B phase having the following compositions. 5 (A phase) (%) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane 10.0 10 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monooleate 1.0 an N-linked urea or carbamate of a 0.01 heterocyclic thioester as defined above (B phase) (%) 15 Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative q.s. 20 The A phase and the B phase are respectively heated and melted and maintained at 80 0 c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion. The emulsion may be applied by spraying once to 25 four times per day to a site having marked baldness or alopecia.

WO99/62485 PCT/US98/11244 53 Example 8 A cream may be prepared from A phase and B phase having the following compositions. 5 (A Phase) (%) Fluid paraffin 5.0 Cetostearyl alcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0 10 Polyoxyethylene (20 mole) 2-octyldodecyl 3.0 ether Propylparaben 0.3 (B Phase) (%) an N-linked urea or carbamate of a 0.8 15 heterocyclic thioester as defined above Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005 20 Purified water 44.895 The A phase is heated and melted, and maintained at 70 0 c. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The 25 emulsion is then cooled to obtain a cream. The cream may be applied once to 4 times per day to a site having marked baldness or alopecia.

WO 99/62485 PCTIUS98/11244 54 Example 9 A liquid comprising the following composition may be prepared. 5 (%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 an N-linked urea or carbamate of a 0.001 heterocyclic thioester as defined above 10 Propylene glycol 5.0 Polyoxyethylene hardened castor oil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q.s. Purified water q.s. 15 Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, an N-linked urea or carbamate of a heterocyclic thioester, and perfume. The resulting 20 mixture is stirred, and purified water is added to the mixture to obtain a liquid. The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia. 25 WO99/62485 PCT/US98/11244 55 Example 10 A shampoo comprising the following composition may be prepared. 5 (%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0 10 Polyethylene glycol 5.0 an N-linked urea or carbamate of a 5.0 heterocyclic thioester as defined above Ethanol 2.0 Perfume 0.3 15 Purified water 69.7 Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethyl 20 aminoacetate. Then a mixture obtained by adding 5.0 g of an N-linked urea or carbamate of a heterocyclic thioester, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume are 25 successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo. The shampoo may be used on the scalp once or twice per day.

WO 99/62485 PCT/US98/11244 56 Example 11 A patient is suffering from alopecia senilis. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a pharmaceutical composition 5 comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. Example 12 10 A patient is suffering from male pattern alopecia. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is 15 expected to occur following treatment. Example 13 A patient is suffering from alopecia areata. An N-linked urea or carbamate of a heterocyclic thioester 20 as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. 25 Example 14 A patient is suffering from hair loss caused by skin lesions. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a WO99/62485 PCT/US98/11244 57 pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. 5 Example 15 A patient is suffering from hair loss caused by tumors. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be 10 administered to the patient. Increased hair growth is expected to occur following treatment. Example 16 A patient is suffering from hair loss caused by 15 a systematic disorder, such as a nutritional disorder or an internal secretion disorder. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased 20 hair growth is expected to occur following treatment. Example 17 A patient is suffering from hair loss caused by chemotherapy. An N-linked urea or carbamate of a 25 heterocyclic thioester as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

WO99/62485 PCT/US98/11244 58 Example 18 A patient is suffering from hair loss caused by radiation. An N-linked urea or carbamate of a heterocyclic thioester as identified above, or a 5 pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment. The invention being thus described, it will be 10 obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims (30)

1. A method for treating alopecia or promoting hair growth in an animal, which comprises 5 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 10 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 15 affinity for an FKBP-type immunophilin.

4. The method of claim 3, wherein the FKBP-type immunophilin is FKBP-12. 20

5. The method of claim 1, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula I B 25 A NS-Y-Z 25 D R N X R2, U W I R, WO 99/62485 PCTIUS98/11244 60 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, 5 form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more additional 0, S, SO, So 2 , N, NH, or NR 3 heteroatom(s); X is either 0 or S; 10 Y is a direct bond, CI-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, 15 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 ; 20 R 3 is selected from the group consisting of hydrogen, CI-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 25 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 WO99/62485 PCT/US98/11244 61 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 5 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, Ci-C 6 straight or branched 10 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, 15 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, Cl-C 6 20 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, Cs-C 7 cycloalkenyl, 25 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, WO99/62485 PCT/US98/11244 62 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 5 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 0 or S; and U is either 0 or N, provided that: 10 when U is O, then R, 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 15 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 RI and R 2 are 20 independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-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 25 substituent(s) independently selected from the group consisting of Ar and C 3 -C 8 cycloalkyl; or R, and R 2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group WO99/62485 PCT/US98/11244 63 consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

6. The method of claim 5, wherein Ar is 5 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 10 urea or carbamate of a heterocyclic thioester is a compound of formula II FGH F H E N/)y S-Y-Z 15 N D II R 2 U/, U'W X R, or a pharmaceutically acceptable salt, ester, or 20 solvate thereof, wherein: E, F, G and J are independently selected from the group consisting of CH 2 , O, S, SO, SO2, NH and NR3; X is either O or S; Y is a direct bond, C 1 -C 6 straight or branched 25 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 WO99/62485 PCT/US98/11244 64 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, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 5 straight or branched chain alkenyl or alkynyl, and Cj 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 10 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 15 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; 20 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 25 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, Ci-C6 straight or branched chain alkyl, or C 2 -C 6 straight or WO99/62485 PCTIUS98/11244 65 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, Cs-C 7 cycloalkenyl, 5 hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cl-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 10 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 0 or S; and U is either 0 or N, provided that: 15 when U is O, then R, 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 -C6 straight or branched chain alkenyl, wherein said alkyl or 20 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 and R 2 are 25 independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or WO99/62485 PCT/US98/11244 66 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, and R 2 are taken together to form a 5 heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine. 10

8. The method of claim 7, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. 15

9. The method of claim 1, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula III F-G / 7 C 20 E S-Y-Z\ 'N D / III R2-U X UW I R, 25 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 ; WO99/62485 PCT/US98/11244 67 X is either 0 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 5 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 10 hydrogen, C,-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 15 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 20 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 25 oxidized to a corresponding N-oxide; Z is a direct bond, Cz-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 WO 99/62485 PCT/US98/11244 68 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 ; 5 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 10 consisting of C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C,-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 15 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 0 or S; and 20 U is either 0 or N, provided that: when U is O, then R, is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or 25 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; WO99/62485 PCT/US98/11244 69 and when U is N, then R, and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C, cycloalkyl, Ci-C 6 straight 5 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; 10 or R i 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. 15

10. The method of claim 9, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. 20

11. The method of claim 1, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula IV 25 (CH 2 )n C- S-Y-Z\ N D IV R2~U X UW I R, WO99/62485 PCT/US98/11244 70 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: n is 1, 2 or 3; X is either 0 or S; 5 Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 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 10 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, Cl-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and Cj 15 C, 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; 20 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 25 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; WO99/62485 PCTIUS98/11244 71 Z is a direct bond, Cl-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 5 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, Cz-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or 10 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, 15 alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with Ci-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 20 of said alkyl or alkenyl is optionally replaced with O, NH, NR 3 , S, SO, or SO 2 ; W is 0 or S; and U is either 0 or N, provided that: when U is O, then Ri is a lone pair of 25 electrons and R 2 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or branched chain or alkenyl, wherein said alkyl or WO99/62485 PCT/US98/11244 72 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 5 when U is N, then R, and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or branched chain alkenyl, wherein said alkyl or 10 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 I and R 2 are taken together to form a heterocyclic 5 or 6 membered ring selected from 15 the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

12. The method of claim 11, wherein Ar is 20 selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

13. The method of claim 11, wherein: 25 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- WO99/62485 PCTIUS98/11244 73 phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1-dimethylpropyl, 5 cyclohexyl, 1-adamantyl, or phenyl.

14. The method of claim 13, wherein the compound is selected from the group consisting of: 3-(3-Pyridyl)-l-propyl-2S-l-[(2-methylbutyl) 10 carbamoyl]pyrrolidine-2-carboxylate; 3-(3-Pyridyl)-l-propyl-2S-1-[(1',1 ' Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate; 3-(3-Pyridyl)-l-propyl-2S-l- [(cyclohexyl) thiocarbamoyl]pyrrolidine-2-carboxylate; and 15 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 20 compound of formula V B A ~S--Z V R2 D v 25 U RI WO 99/62485 PCTIUS98/11244 74 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; Y is a direct bond, CI-C 6 straight or branched 5 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, 10 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 15 hydrogen, CI-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 20 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 25 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 WO99/62485 PCTIUS98/11244 75 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 5 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, 10 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, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or 15 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, cycloalkyl, C 5 -C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, 20 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 25 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 WO99/62485 PCTIUS98/11244 76 replaced with O, NH, NR 3 , S, SO, or SO2; and A, B, RI, R2, U, W, and X are as otherwise defined in claim 5 above. 5

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 10 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 15 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 20 type immunophilin.

19. The pharmaceutical composition of claim 18, wherein the FKBP-type immunophilin is FKBP-12. 25

20. The pharmaceutical composition of claim 16, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula I WO 99/62485 PCTIUS98/11244 77 B 1 R25 X I Rz or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A and B, taken together with the nitrogen and 10 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 0, S, SO, So 2 , N, NH, or NR 3 heteroatom(s); 15 X is either 0 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 20 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 25 replaced with O, NH, NR 3 , S, SO, or SO 2 ; R 3 is selected from the group consisting of hydrogen, CI-C 6 straight or branched chain alkyl, C 3 -C 6 straight or branched chain alkenyl or alkynyl, and C,- WO99/62485 PCT/US98/11244 78 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 5 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 10 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; 15 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, 20 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 ; 25 C and D are independently hydrogen, Ar, Cz-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 WO99/62485 PCTIUS98/11244 79 substituent(s) independently selected from the group consisting of C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally 5 substituted with CI-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 10 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 S02; W is 0 or S; and 15 U is either 0 or N, provided that: when U is O, then R i is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or 20 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 25 when U is N, then Ri and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or WO 99/62485 PCT/US98/11244 80 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, 5 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

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. 15

22. The pharmaceutical composition of claim 16, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula II /G F GH 20 I/ E ly S-Y-Z N D ITI R2-U W X R, 25 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 ; WO99/62485 PCT/US98/11244 81 X is either 0 or S; Y is a direct bond, Cl-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or 5 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 S02; R 3 is selected from the group consisting of 10 hydrogen, Cl-C 4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C, 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 15 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 20 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 25 oxidized to a corresponding N-oxide; Z is a direct bond, Cl-C6 straight or branched chain alkyl, or C1-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or WO99/62485 PCTIUS98/11244 82 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 ; 5 C and D are independently hydrogen, Ar, Ci-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 10 consisting of C 3 -C, cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cl-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 15 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 SO2; W is O or S; and 20 U is either 0 or N, provided that: when U is O, then R i is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, Cz-C 6 straight or branched chain alkyl, and C 2 -C 6 straight or 25 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; WO99/62485 PCT/US98/11244 83 and when U is N, then R, and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight 5 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; 10 or R, 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. 15

23. The pharmaceutical composition of claim 22, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. 20

24. The pharmaceutical composition of claim 16, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula III 25 F-G C 2s/ /c N D E I NI I I R2U X URW RI WO99/62485 PCT/US98/11244 84 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH 2 , O, S, SO, SO 2 , 5 NH or NR 3 ; X is either 0 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 10 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 S02; R 3 is selected from the group consisting of 15 hydrogen, Cl-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Cj 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 20 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 25 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 WO99/62485 PCT/US98/11244 85 aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain 5 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 ; 10 C and D are independently hydrogen, Ar, Cl-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 15 consisting of C 3 -C 8 cycloalkyl, Cs-C 7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C,-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 20 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 S02; W is 0 or S; and 25 U is either 0 or N, provided that: when U is O, then R, is a lone pair of electrons and R 2 is selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight WO 99/62485 PCT/US98/11244 86 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 5 the group consisting of Ar and C 3 -C 8 cycloalkyl; and when U is N, then R i and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, Cl-C 6 straight 10 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, cycloalkyl; 15 or R, 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. 20

25. The pharmaceutical composition of claim 24, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. 25

26. The pharmaceutical composition of claim 16, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula IV WO 99/62485 PCTIUS98/11244 87 (CH 2 )n C N D U W I Rz or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: 10 n is 1, 2 or 3; X is either 0 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 15 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 0, NH, NR 3 , S, SO, or SO 2 ; R 3 is selected from the group consisting of 20 hydrogen, C,-C 4 straight or branched chain alkyl, C 3 -C 4 straight or branched chain alkenyl or alkynyl, and Cj 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 25 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 WO99/62485 PCT/US98/11244 88 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 5 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, Cl-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain 10 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 S02; 15 C and D are independently hydrogen, Ar, Ci-C6 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 20 consisting of C 3 -C 8 cycloalkyl, Cs-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is optionally substituted with Cl-C 4 alkyl, C 2 -C 4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is 25 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 ; WO99/62485 PCTIUS98/11244 89 W is 0 or S; and U is either 0 or N, provided that: when U is O, then R, is a lone pair of electrons and R 2 is selected from the group 5 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 10 the group consisting of Ar and C 3 -C 8 cycloalkyl; and when U is N, then R i and R 2 are independently selected from the group consisting of hydrogen, Ar, C 3 -C 8 cycloalkyl, CI-C 6 straight 15 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; 20 or R, 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

27. The pharmaceutical composition of claim 26, wherein Ar is selected from the group consisting of WO99/62485 PCT/US98/11244 90 naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

28. The pharmaceutical composition of claim 26, 5 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 10 phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1l-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl. 15

29. The pharmaceutical composition of claim 28, wherein the compound is selected from the group consisting of: 3- (3-Pyridyl)-l-propyl-2S-l-[(2-methylbutyl) 20 carbamoyl]pyrrolidine-2-carboxylate; 3-(3-Pyridyl)-1l-propyl-2S-1- [(1', 1 Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate; 3-(3-Pyridyl)-l-propyl-2S-l- [(cyclohexyl) thiocarbamoyl]pyrrolidine-2-carboxylate; and 25 pharmaceutically acceptable salts, esters, and solvates thereof. WO 99/62485 PCTIUS98/11244 91

30. The pharmaceutical composition of claim 16, wherein the N-linked urea or carbamate of a heterocyclic thioester is a compound of formula V 5 B A S-Y-z D VW \ R2 X D I U 2 X V RI 10 or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: V is C, N, or S; 15 Y is a direct bond, Cl-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, 20 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 ; 25 Z is a direct bond, Cl-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 WO 99/62485 PCT/US98/11244 92 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 5 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,-C 6 straight or branched chain alkyl, or C 2 -C 6 straight or branched chain alkenyl; wherein said alkyl or alkenyl 10 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 15 substituted with Cz-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 20 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 25 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 WO99/62485 PCT/US98/11244 93 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 5 A, B, R1, R2, U, W, and X are as otherwise defined in claim 20 above.