MXPA05013599A

MXPA05013599A - Thiazoline derivatives as selective androgen receptor modulators (sarms)

Info

Publication number: MXPA05013599A
Application number: MXPA/A/2005/013599A
Authority: MX
Inventors: Zhihua Sui; Raymond A Ng
Original assignee: Janssen Pharmaceutica Nv; Raymond A Ng; Zhihua Sui
Priority date: 2003-06-13
Filing date: 2005-12-13
Publication date: 2006-10-17

Abstract

The present invention is directed to novel thiazoline derivatives of the general fomula (I);wherein all variables are as herein defined, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

Description

TIAZOLINE DERIVATIVES AS SELECTIVE MODULATORS OF ANDROGEN RECEPTOR FIELD OF THE INVENTION The present invention relates to novel thiazoline derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor. More particularly, the compounds of the present invention are useful in the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as well as male and female contraceptives. as a male performance enhancer.

BACKGROUND OF THE INVENTION Androgens are anabolic spheroidal hormones of animals, which control muscle and skeletal mass, the maturation of the reproductive system, the development of secondary sexual characteristics and the maintenance of fertility in man. In women, testosterone is converted to estrogen in most of the target tissues, but androgens themselves may play a role in normal female physiology, for example in the brain. The main androgen found in Serum is testosterone and this is the effective compound in tissues such as the testicles and the pituitary gland. In prostate skin, testosterone is converted to dihydrotestosterone (DHT) by the action of 5V-reductase. DHT is a more potent androgen than testosterone because it binds more strongly to the androgen receptor. Like all steroid hormones, androgens bind to a specific receptor within the cells of target tissues, in this case the androgen receptor. This is a member of the nuclear receptor transcription factor family. The binding of androgen to the receptor activates it and causes it to bind to the DNA binding sites adjacent to the target genes. From there, it interacts with coactivating proteins and basic transcription factors to regulate gene expression. Thus, via its receptor, androgens cause changes in the expression of the gene in the cells. These changes eventually have consequences on the metabolic expenditure, cell differentiation or proliferation that are visible in the physiology of the target tissue. Although modulators of androgen receptor function have been used clinically for some time, the steroid compounds (Basaría, S., Wahlstrom, JT, Dobs, AS, J. Clin Endocrinol Metab (2001), 86, pp5108-5117; Shahidi, NT., Clin Therapeutics, (2001), 23, pp1355-1390) and non-steroids (Newling, DW, Br. J. Urol., 1996, 77 (6), pp 776-784) have significant sensitivities in relation to its pharmacological parameters that include gynecomastia, excessive pain in the breasts and hepatoxicity In addition, medication-drug interactions have been observed in patients receiving anticoagulation therapy using coumarins. Finally, patients with aniline sensitivities may be compromised by the metabolites of non-steroidal antiandrogens. The non-steroidal agonists and antagonists of the androgen receptor are useful in the treatment of a variety of disorders and diseases. More particularly, androgen receptor agonists can be used in the treatment of prostate cancer, benign prosthetic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne. Antagonists of the androgen receptor can be used in male contraception, improving male performance as well as in the treatment of cancer, AIDS, cachexia and other disorders. However, there is a need for a small molecule of non-steroidal antagonists of the androgen receptor. We now describe a novel series of thiazoline derivatives as modulators of the androgen receptor.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula wherein R1 is selected from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is attached through a carbon atom; wherein the aryl or heteroaryl group is optionally substituted with one to four substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (O) -, lower alkyl-C (O ) -NRA-, lower alkyl-S (0) o-2-, phenyl-S (O) 0-2, alkyl nferor-S (O) 0-2-NRA-, phenyl-S (O) 0-2-NRA- and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; RA is independently selected from hydrogen or lower alkyl; R2 and R2a are each independently selected from the group consisting of hydrogen, lower alkyl and lower alkyl substituted with halogen; R3 is selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is attached through a carbon atom; wherein the aryl or heteroaryl group is optionally substituted with one to four substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (0) -, lower alkyl-C (O ) -NRA-, lower alkyl-S (0) o-2-, phenyl-S (O) 0-2_ lower alkyl-S (O) 0-2-NRA-, phenyl-S (O) 0-2- NRA- and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; R5 is selected from the group consisting of hydrogen, lower alkyl and lower alkyl substituted with halogen; or a pharmaceutically acceptable salt thereof. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described in the foregoing. An illustration of the invention is a Pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrative of the invention is a process for producing a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier. Exemplary of the invention are methods for treating disorders and conditions modulated by the androgen receptor in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the foregoing. An example of the invention is a method for treating an androgen receptor modulated disorder that is selected from the group consisting of prostate carcinoma, benign prosthetic hyperplasia, hirsutism or male contraception, in a subject in need thereof, which comprises administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described in the above. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) prostate carcinoma, (b) benign prosthetic hyperplasia, (c) hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, for (j) male contraception or for (k) improvement of male performance in a subject in need thereof .

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula wherein R1, R2, R2a, R3, R4 and R are as defined above, useful as selective androgen receptor modulators for treatment of prostate carcinoma, benign prosthetic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive and as a male performance enhancer. In one embodiment of the present invention, R1 is aryl, wherein the aryl group is optionally substituted with one to two substituents that are independently selected from halogen, lower alkyl, lower alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (O) -, lower alkyl-C (0) -NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2, lower alkyl-S (O) 0-2- NRA-, phenyl-S (O) 0-2-NRA- and trifluoromethylsulfonyl; and wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower.

In another embodiment of the present invention, R1 is heteroaryl, wherein the heteroaryl group is optionally substituted with one to two substituents that are independently selected from halogen, lower alkyl, lower alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (0) -, lower alkyl-C (O) -NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2_ lower alkyl-S (O) 0-2-NRA -, phenyl-S (O) 0-2-NRA- and trifluoromethylsulfonyl; and wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower. In another embodiment of the present invention, R1 is aryl, wherein the aryl group is optionally substituted with a halogen. Preferably, R1 is selected from the group consisting of 4-fluorophenyl, 3-fluorophenyl, 4-chlorophenyl and 3-chlorophenyl. More preferably, R is selected from the group consisting of 4-fluorophenyl, 3-chlorophenyl and 4-chlorophenyl. Even more preferably, R1 is selected from the group consisting of 4-fluorophenyl and 4-chlorophenyl. In one embodiment of the present invention, RA is hydrogen or methyl. In one embodiment of the present invention, R 2 is selected from the group consisting of hydrogen, lower alkyl and trifluoromethyl. Preferably, R2 is selected from the group consisting of hydrogen, methyl and trifluoromethyl. More preferably, R2 is hydrogen or methyl. Even more preferably, R2 is hydrogen. In one embodiment of the present invention, R2a is selected from the group consisting of hydrogen, lower alkyl and trifluoromethyl. Preferably, R2a is selected from the group consisting of hydrogen, methyl and trifluoromethyl. More preferably, R2a is hydrogen or methyl.

Even more preferably, R2a is hydrogen. In one embodiment of the present invention, R3 is selected from the group consisting of hydrogen and lower alkyl, preferably, R3 is selected from the group consisting of hydrogen and methyl; more preferably, R3 is hydrogen. In one embodiment of the present invention, R 4 is aryl, wherein the aryl group is optionally substituted with one to three substituents that are independently selected from halogen, lower alkyl, lower alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (O) -, lower alkyl-C (0) -NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2. lower alkyl-S (0) o-2-NRA-, phenyl-S (O) 0.2-NRA- and trifluoromethylsulfonyl; and wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkyl or dialkylamino lower. In another embodiment of the present invention, R 4 is heteroaryl, wherein the heteroaryl group is optionally substituted with one to two substituents that are independently selected from halogen, lower alkyl, lower alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (0) -, lower alkyl-C (0) -NRA-, lower alkyl-S (0) o-2-phenyl-S (O) 0-2, lower alkyl-S (O) 0-2-NRA-, phenyl-S (O) 0-2-NRA- and trifluoromethylsulfonyl; and wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower. In another embodiment of the present invention, R 4 is aryl, wherein the aryl group is substituted with one to three substituents that are independently selected from halogen, cyano, nitro, lower alkyl, lower alkyl substituted with halogen and trifluoromethylsulfonyl. Preferably, R 4 is selected from the group consisting of 4-chlorophenyl, 4-cyanophenyl, 3-trifluoromethyl-4-cyanophenyl, 3-trifluoromethyl-4-nitrophenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethyl-4-chlorophenyl, 2,5-difluoro-4-cyanophenyl, 2-fluoro-3-trifluoromethylphenyl and 4-trifluoromethylsulfonylphenyl. More preferably, R 4 is selected from the group consisting of 3-trifluoromethyl-4-cyanophenyl, 3-trifluoromethyl-4-nitrophenyl, 3-trifluoromethyl-4-chlorophenyl and 4-trifluoromethylsulfonylphenyl. Even more preferably, R 4 is selected from the group consisting of 3-trifluoromethyl-4-nitrophenyl and 3-trifluoromethyl-4-chlorophenyl. In. one embodiment of the present invention, R5 is selected from the group consisting of hydrogen, lower alkyl and trifluoromethyl.

Preferably, R5 is selected from the group consisting of hydrogen, methyl and trifluoromethyl. More preferably, R5 is hydrogen or methyl, still much more preferably R5 is selected from the group consisting of hydrogen and methyl. Representative compounds of the present invention are prepared from L-amino acids according to the process described herein and are included in Table 1 below. The stereoscopic configuration of the final product is not determined.

TABLE 1 As used herein, the term "halogen" means chlorine, bromine, fluorine and iodine. As used herein, the term "alkyl" when used alone or as part of a substituent group, includes linear and branched For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like. Unless otherwise indicated, the term "lower" when used with alkyl means a carbon chain composition of 1-4 carbon atoms. As used herein, unless otherwise indicated, the term "lower alkyl substituted with halogen" shall mean a lower alkyl group as defined above wherein one or more hydrogen atoms are substituted with halogen atoms . Suitable examples include, but are not limited to, trifluoromethyl, 1,1,1-trifluoroethy, chloromethyl, fluoromethyl, and the like. As used herein, unless otherwise indicated, the term "alkoxy" will denote an oxygen ether radical of the straight or branched chain alkyl groups described above. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, terbutoxy, n-hexyloxy and the like. As used herein, unless otherwise indicated, the term "aryl" will refer to unsubstituted carbocyclic aromatic groups such as phenyl, naphthyl and the like. As used herein, unless otherwise indicated, the term "heteroaryl" will denote any five or six member monocyclic aromatic ring structure containing at least one heteroatom that is selected from the group consisting of O, N and S, which optionally contains one to three additional heteroatoms that are select independently of the group consisting of O, N and S; or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom which is selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms which are independently selected from the group consisting of O, N and S. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl. , indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzyl idozolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl and the like. As used herein, the notation "*" will indicate the presence of a stereogenic center. When a particular group is "substituted" (e.g., Phe, aryl, heteroalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents and much more preferably one or two substituents, which are independently selected from the list of substituents. With reference to substituents, the term "independently" means that when more than one or such substituents are possible, such substituents may be the same or different from each other.

Under the standard nomenclature used in this description, the terminal portion of the designated side chain is described first, followed by functionality adjacent to the point of attachment. Thus, for example, a substituent "phenylalkyl (1 to 6 carbon atoms) aminocarbonylalkyl of 1 to 6 carbon atoms" refers to a group of the formula u ^ alkyl of 1 to 6 carbone-alkyl atoms of 1 to 6 carbon atoms - - H Under the standard nomenclature used in this description the substituents in the thiazoline group of the group will be designated as joined in the following bonding positions: The abbreviations used in the specification, particularly the Schemes and Examples, are the following: The term "subject", as used herein, refers to an animal, preferably a mammal and more preferably a human who has been the object of treatment, observation or experiment. The term "therapeutically effective amount", as used herein, means an amount of active compound or pharmaceutical agent that induces the biological or medicinal response in a tissue, animal or human system that is being investigated by the investigator, veterinarian, doctor or other clinician, which includes relief of the symptoms of the disease or disorder being treated. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. When the compounds according to this invention have at least one chiral center, they can therefore exist as enantiomers. When the compounds possess two or more chiral centers, they may additionally exist as diastereoisomers. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. In addition, some of the crystalline forms for the compounds may exist as polymorphs and as such are designed to be included in the present invention. In addition, some of the compounds can form solvates with water (it is say, hydrates), or common organic solvents, and such solvates are also designed to be encompassed within the scope of the invention. When the process for the preparation of the compounds according to the invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form or individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. For example, the compounds can be separated into their constituent enantiomers by standard techniques such as the formation of diastereomeric pairs by salt formation with an optically active acid such as (-) - di-p-toluoyl-D-tartaric acid or acid ( +) - di-p-toluoyl-L-tartaric followed by fractional crystallization and regeneration of the free base. The compounds can also be separated by diastereoisomeric ester or amide formulation followed by chromatographic separation and separation of the auxiliary. Alternatively, the compounds can be separated using chiral HPLC on column. During any of the methods for preparing the compounds of the present invention, it may be necessary or desirable to protect sensitive or reactive groups in any of the molecules involved. This can be obtained by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The Protective groups can be separated in a convenient subsequent step using methods known in the art. The present invention includes within its scope precursors of the compounds of this invention. In general, such precursors will be functional derivatives of the compounds which are easily convertible in vivo to the required compound. Thus, in the methods of treatment of the present invention, the term "administer" will encompass the treatment of the various disorders described with the compound that are specifically described or with a compound which may not be specifically described but which is converted to the compound specified in vivo after its administration to the patient. Conventional procedures for the selection and propagation of suitable precursor derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. The compounds of formula (I) wherein R5 is hydrogen can be prepared according to the procedure indicated in Scheme 1.

SCHEME 1 (VI) (Vil) (the) Accordingly, a suitably substituted compound of formula (II), a known compound or a compound prepared by known methods is reacted with a compound of formula (III), wherein A1 is lower alkyl, a known compound or a compound prepared by known methods, in the presence of an acid such as hydrochloric acid, sulfuric acid and the like, optionally in an organic solvent such as diethylether and the like, to promote solubility, to provide the corresponding compound of formula (IV). The compound of formula (IV) is reacted with a suitably substituted compound of formula (V), wherein A2 is a lower alkyl, a known compound or a compound prepared by known methods, in the presence of a base such as TEA, DI PEA, pyridine and the like, in an organic solvent such as DCE, methylene chloride, THF and the like, to provide the corresponding compound of formula (VI). The compound of formula (VI) is reacted with a base such as KOH, NaOH, LiOH and the like, in an organic solvent such as THF, dioxane, water and the like in the presence of water, to provide the corresponding compound of formula (VII) ). The compound of formula (VII) is reacted with a suitably substituted compound of formula (VIII), a known compound or a compound prepared by known methods, in the presence of a catalyst or a catalyst stop such as PyBrOP and DMAP, DCC and DMAP, DCC and DMAP, EDCI and HOBT and the like, in the presence of a base such as DIPEA, TEA, pyridine and the like, in an aprotic solvent such as DMF, DCE, DCM and the like, preferably in an anhydrous aprotic solvent, to provide the corresponding compound of formula (la). The compounds of formula (I) wherein R5 is different from hydrogen can be prepared according to the procedure indicated in Scheme 2.

SCHEME 2 (VID (XD (Ib) Accordingly, a compound of formula (IX), wherein a known compound or a compound prepared by known methods (for example, according to the procedure described by Pattende, G., et al., Tetrahedron, (1993), 49 (10), pp2131-2138) is reacted with thionyl chloride, wherein A3 is a lower alkyl, in an alcohol solvent, to provide the corresponding compound of formula (X). The compound of formula (X) is reacted with a suitably substituted compound of formula (VIII), wherein A1 is a lower alkyl, a known compound or a compound prepared by known methods, in the presence of a base such as TEA, DIPEA , pyridine and the like, in an organic solvent such as DCE, methylene chloride, THF and the like to provide the corresponding compound of formula (XI). The compound of formula (XI) is reacted with a suitably substituted compound of formula (HIV), a compound known or a compound prepared by known methods, in the presence of a catalyst or a pair of catalysts such as PyBRoP and DMAP, DCC and DMAP, EDCI and HOBT and the like, in the presence of a base such as DIPEA, TEA, pyridine and the like, in an aprotic solvent such as DMF, DCE, DCM, and the like, preferably in an anhydrous aprotic solvent, to provide the corresponding compound of formula (la). A person skilled in the art will recognize that the compound of formula (I), wherein R2 or R2a are different from hydrogen, can be prepared in a similar manner according to the procedure indicated in Scheme 2 above with substitution of a suitably substituted compound of formula (XII) (XII) a known compound or compound prepared by known methods, for the compound of formula (IX). The following examples are set forth to aid in the understanding of the invention and are not intended or should be construed as limiting in any way the invention set forth in the claims, which are presented below.

EXAMPLE 1 (Compound # 9) 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethylphenyl) -amide Step A: 4-chlorobenzimidic acid ethyl ester hydrochloride To a solution of 4-chlorobenzonitrile (11.36 g, 85.6 mmol) in 60 ml of ethanol is bubbled into dry HCl (200 ml of 36% HCl which is added dropwise in 500 ml of concentrated H2SO4) at 5 ° C. The reaction mixture is stirred for an additional 0.5 hours at 0 ° C and then diluted with 500 ml of anhydrous diethyl ether. The mixture is then stirred at 5 ° C for 2 hours, filtered, washed with diethyl ether, dried under vacuum to provide the hydrochloride of 4-chlorobenzimidic acid ethyl ester. The product is taken to the next reaction step without further purification. Step B: 2 - (, 4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Triethylamine (2.44 g, 24.16 mmol) is added dropwise to a solution of ethyl ester hydrochloride of 4-chloro-4-carboxylic acid. -chlorobenzimide (5 g, 22.71 mmol) and L-cysteine methyl ester hydrochloride (4.29 g, 24.98 mmol) in 85 ml of dichloromethane at 0 ° C. The resulting mixture is stirred at temperature environment for 3 days. Water and dichloromethane are added and the aqueous layer is extracted with dichloromethane, dried over Na2SO and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 15% EtOAc / hexane) gives 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Step C: 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester (5.23 g, 0.02 mole) in 200 ml of THF and 200 ml of H2O is added KOH (11.4 g, 0.2 mole). The reaction mixture is stirred vigorously at room temperature for 17 hours, then diluted with water, extracted with diethyl ether and the diethyl ether layer washed with water. The combined aqueous layers are acidified with 1 N HCl to pH 1, extracted with diethyl ether and dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (400 MHz, d6-DMSO): d 13.03 (broad 1H), 7.81 (d, 2H, J = 8.5 Hz), 7.57 (d, 2H, J = 8.5 Hz), 5.31 (dd, 1H; = 8.3, 9.4 Hz), 3.62 -3.77 (m, 2H). Step D: 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethylphenyl) -amide To a solution of 2- (4-chlorophenyl) -4,5- dihydrothiazole-4-carboxylic acid (176 mg, 0.770 mmol) and 5-amino-2-cyanobenzotrifluoride (158 mg, 0.847 mmol) in 10 ml of DMF are added DMAP (94 mg, 770 mmoles)), 0.25 ml of / 'Pr2NEt and PyBroP (1.08 g, 2.311 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added. The EtOAc layer is washed with 1N HCl and brine, then dried over anhydrous Na2SO. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-cyano-3-trifluoromethylphenyl) amide. -carboxylic 1 H NMR (400 MHz, CDCl 3): d 9.06 (broad s, 1H), 8.04 (d, 1H, J = 1.9 Hz), 7.98 (dd, 1H, J = 2.0, 8.5 Hz), 7.84 (d, 2H, J = 8.5 Hz), 7.45 - 7.85 (m, 1H), 7.46 (d, 2H, J = 8.5 Hz), 5.34 (t, 1H, J = 10 Hz), 3.73 - 3.88 (m, 2H) MS m / z (MH) = 408.

EXAMPLE 2 2- (3-Fluorophenyl) - 4,5-dihydrothiazole-4-carboxylic acid compound # 3 (4-cyano-3-trifluoromethylphenyl) -amide Stage A: 3-fluorobenzimidic acid ethyl ester hydrochloride To a solution of 3-fluorobenzonitrile (10 g, 82.6 mmol) in 20 ml of ethanol is bubbled into dry HCl (200 ml of 36% HCl which is added dropwise in 500 ml of concentrated H2SO4) at 5 ° C. The reaction mixture is stirred for an additional 0.5 h at 0 ° C and then diluted with 500 ml of anhydrous ether. The reaction mixture is then stirred at 5 ° C for 2 hours, filtered, washed with diethyl ether and dried under vacuum to provide 3-fluorobenzimidic acid ethyl ester hydrochloride. The product is carried out to the next step without further purification. Step B: 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester 1.1 ml of triethylamine in a solution of 3-fluorobenzimidic acid ethyl ester hydrochloride (1.5 g, 7.366) are added dropwise. mmoles) and L-cysteine methyl ester hydrochloride (1.39 g, 8.102 mmol) in 25 ml of dichloromethane at 0 ° C. The resulting mixture is stirred at room temperature for 2 days. Water and dichloromethane are added and the aqueous layer is extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo to provide the crude product. The crude product is purified by column chromatography (silica gel, 15% EtOAc / hexane) to give 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Step C: 2-C3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethylphenyl) -amide To a solution of 2- (3-fluorophenyl) -methyl ester - 4,5- Dihydrothiazole-4-carboxylic acid (274 mg, 1145 moles) in 5-amino-2-cyanobenzonitrile (426 mg, 2287 mmol) in 5 ml of THF at 0 ° C is added 2M isopropylmagnesium chloride (1.14 ml in THF). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the c product. The c product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (3-fluorophenyl) -4,5-dihydrothiazole (4-cyano-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H NMR (400 MHz, CDCl 3): d 9.05 (broad s, 1H), 8.07 (d, 1H, J = 2.0 Hz), 7.98 (dd, 1H, J = 2.0, 8.5 Hz), 7.81 (d, 1 H) , J = 8.5 Hz), 7.62 - 7.67 (m, 2H), 7.43 - 7.50 (m, 1H), 7.23 - 7.30 (m, 1H), 5.35 (t, 1H, J = 10 Hz), 3.73 - 3.90 ( m, 2H) MS m / z (MH) = 391 EXAMPLE 3 (Compound # 17) 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide To a solution of 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (178 mg, 0.79 mmol) and 5-amino-2-chlorobenzonitrile (155 mg, 0. 79 mmol) in 10 ml of DMF is added DMAP (97 mg, 0.79 mmol), 0. 28 ml of / Pr2NEt and PyBroP (553 mg, 1185 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a c product. The c product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-chloro-3-trifluoromethylphenyl) amide. -carboxylic 1 H NMR (300 MHz, CDCl 3): d 8.83 (broad s, 1H), 7.93 (d, 1H, J = 2.6 Hz), 7.80 (dd, 1H, J = 2.6, 8.9 Hz), 7.62-7.67 (m, 2H), 7.41-7.49 (m, 3H), 7.25 - 7.28 (m, 1 H), 5.33 (t, 1 H, J = 9.9 Hz), 3.73 - 3.89 (m, 2H).

EXAMPLE 4 (Compound # 18) 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-fluoro-3-trifluoromethylphenyl) amide To a solution of 2- (3-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (187 mg, 0.83 mmol) and 5-amino-2-fluorobenzonitrile (149 mg, 0. 83 mmol) in 10 ml of DMF is added DMAP (104 mg, 0.83 mmol), 0. 29 ml of / Pr2NEt and PyBroP (581 mg, 1.24 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the c product. The c product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (3-fluorophenyl) -4,5-dihydrothiazole- (4-fluoro-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3): d 8.77 (broad s, 1 H), 7.15 - 8.01 (m, 7 H), 5.33 (t, 1 H, J = 10 Hz), 3.73 - 3.89 (m, 2 H).

EXAMPLE 5 (Compound # 9) 2- (4-chloropheniD-4,5-dihydrothiazole-4-carboxylic acid 4-cyano-3-trifluoromethylphenidi-amide Step A: 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester (5.23) g, 0.02 mole) in 200 ml of THF and 200 ml of H20 is added KOH (11.4 g, 0.2 mole). The reaction mixture is stirred vigorously at room temperature for 17 hours, the reaction mixture is then diluted with water, extracted with diethyl ether and the diethyl ether layer washed with water. The combined water layers are acidified with 1 N HCl to pH 1, then extracted with diethyl ether and dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (400 MHz, d 6 -DMSO): d 13.03 (broad 1 H), 7.81 (d, 2H, J = 8.5 Hz), 7.57 (d, 2H, J = 8.5 Hz), 5.31 (dd, 1 H, J = 8.3, 9.4 Hz), 3.62 -3.77 (m, 2H).

Step B: 2- (4-cyano-3-trifluoromethylphenyl) -amide of 2-C4-chlorophen-yl) -4,5-dihydro-rotiazole-4-carboxylic acid To a solution of 2- (4-chlorophenyl) -4.5 -dihydrothiazole-4-carboxylic acid (186 mg, 0.770 mmol) and 5-amino-2-cyanobenzotrifluoride (158 mg, 0.847 mmol) in 10 ml of DMF are added DMAP (94 mg, 0.770 mmol), 0.25 ml of / Pr2NEt and PyBroP (1.08 g, 2311 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added. The EtOAc layer is washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-cyano-3-trifluoromethylphenyl) amide. -carboxylic 1 H NMR (400 MHz, CDCl 3): d 9.06 (broad s, 1H), 8.04 (d, 1H, J = 1.9 Hz), 7.98 (dd, 1H, J = 2.0, 8.5 Hz), 7.84 (d, 2H, J = 8.5 Hz), 7.45 - 7.85 (m, 1H), 7.46 (d, 2H, J = 8.5 Hz), 5.34 (t, 1H, J = 10 Hz), 3.73 - 3.88 (m, 2H) MS m / z (MH) = 408.

EXAMPLE 6 (Compound # 11) (2- (4-chloropheni-4, 5-dihydrothiazole-4-carboxylic acid) 4-chloro-3-trifluoromethylphenidi-amide To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (214 mg, 0.8854 mmol) and 5-amino-2-chlorobenzotrifluoride (191 mg, 0.9740 mmol) in 10 ml of DMF were added. add DMAP (108 mg, 0.8854 mmoles)), 0.25 ml of / Pr2NEt and PyBroP (1.24 g, 2.6562 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) amide. H-NMR (300 MHz): d 8.79 (broad s, 1H), 7.89-7.96 (m, 3H), 7.42-7.49 (m, 4H), 5.31 (t, 1 H, J = 10 Hz), 3.71 - 3.89 (m, 2H) MS m / z (MH) = 418.

EXAMPLE 7 (Compound # 10) 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-nitro-3-trifluoromethylphenyl) -amide.

To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (188 mg, 0.7795 mmol) and 5-amino-2-nitrobenzotrifluoride (206 mg, 0.8575 mmol) in 10 ml of DMF was added. add DMAP (95 mg, 0.7795 mmoles)), 0.25 ml of / Pr2NEt and PyBroP (1.09 g, 2.3385 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with HCl 1 and brine, then dried over anhydrous Na 2 SO. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-nitrophenyl) -4,5-dihydroxy-4-carboxylic acid (4-nitro-3-trifluoromethylphenyl) amide. 1 H NMR (400 MHz, CDCl 3): d 9.09 (broad s, 1H), 7.98 - 8.07 (m, 3H), 7.85 (d, 2H, J = 8.6 Hz), 7.46 (d, 2H, J = 8.6 Hz) , 5.34 (t, 1H, J = 10 Hz), 3.73 - 3.89 (m, 2H).

MS m / z (M-H) = 428.

EXAMPLE 8 (Compound # 14) 2- (4-chloropheni-4,5-dihydrothiazole-4-carboxylic acid (4-fluoro-3-trifluoromethylene) -amide.

To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (131 mg, 0.5420 mmol) and 5-amino-2-fluorobenzotrifluoride (107 mg, 0.5962 mmol) in 10 mL of DMF were added. add DMAP (66 mg, 0.5420 mmole), 0.25 ml of / 'Pr2NEt and PyBroP (1.76 g, 1626 mmole) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, they are dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4 (4-fluoro-3-trifluoromethylene) -amide, 5-dihydrothiazole-4-carboxylic acid. MS m / z (M-H) 401.

EXAMPLE 9 (Compound # 16) 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-chlorophenol) -amide.

To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (151 mg, 0.6260 mmol) and 4-chloroaniline (76.5 mg, 0.6886 mmol) in 10 ml of DMF is added DMAP (76.5 mg, 0.626 mmole), 0.25 ml of / 'Pr2NEt and PyBroP (1.18 g, 2.521 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1 N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-chlorophenyl) -amide. 1 H-NMR (400 MHz, CDCl 3): d 8.63 (broad s, 1H), 7.84 (d, 2H, J = 8.5 Hz), 7.53-7.57 (m, 2H), 7.44 (d, 2H, J = 8.5 Hz), 7.01 - 7.07 (m, 1 H), 5.31 (t, 1H, J = 9.9 Hz), 3.74 - 3.87 (m, 2H). MS m / z (M-H) = 333.

EXAMPLE 10 (Compound # 24) 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl) -amide.

To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (112 mg, 0.463 mmol) and 3-amino-2-fluorobenzotrifiuoride (91 mg, 0. 509 mmol) in 10 ml of DMF are added DMAP (56.5 mg, 0.463 mmol), 0. 25 ml of / Pr2NEt and PyBroP (863 mg, 1.86 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-chlorophenyl) -4,5-dihydrothiazole- (2-fluoro-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H-NMR (300 MHz, CDCl 3): d 9.15 (broad s, 1 H), 8.64 (dt, 1 H, J = 1.3, 7.0 Hz), 7.84 (d, 2 H, J = 8.6 Hz), 7.79-7.89 ( m, 1 H), 7.45 (d, 2H, J = 8.6 Hz), 7.28 - 7.45 (m, 2H), 5.38 (t, 1H, 9.7 Hz), 3.73 - 3.89 (m, 2H) MS m / z (M + H) = 403.

EXAMPLE 11 (Compound # 14) 2- (4-chlorophenopyr-4,5-dihydrothiazole-4-carboxylic acid (4-fluoro-3-trifluoromethylphenyl) -amide) To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (112 mg, 0.4634 mmol) and 5-amino-2-fluorobenzotrifluoride (91.5 mg, 0.5107 mmol) in 10 mL of DMF were added. add DMAP (56.7 mg, 0.4642 mmol), 0.25 ml of / Pr2NEt and PyBroP (866 mg, 1.86 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The organic extracts are washed with 1N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4,5- (2-fluoro-3-trifluoromethy! Phenyl) -amide. dihydrothiazole-4-carboxylic acid. 1 H-NMR (300 MHz, CDCl 3): d 8.76 (broad s, 1 H), 7.84 (d, 2 H, J = 8.6 Hz), 7.78-7.83 (m, 2 H), 7.45 (d, 2 H, J = 8.6 Hz ), 7.18 (t, 1H, 9.5 Hz), 5.32 (t, 1H, J = 9.9 Hz), 3.71 - 3.88 (m, 2H). MS m / z (M-H) = 401.

EXAMPLE 12 (Compound # 25) 2- (4-chloropheni-4, 5-dihydrothiazole-4-carboxylic acid 2-fluoro-3-trifluoromethylphenidi-amide Step A: Fluorobenzimidic acid ethyl ester hydrochloride To a solution of 4-fluorobenzonitrile (7.89 g, 65.2 mmol) in ml of ethanol is bubbled in dry HCl (generated by adding 200 ml of 36% HCl dropwise in 500 ml of concentrated H2SO4) at 5 ° C. The reaction mixture is stirred for an additional 0.5 h at 0 ° C and then diluted with 500 ml of anhydrous diethyl ether. After the mixture is stirred at 5 ° C for 2 hours, the solids are filtered, washed with diethyl ether and dried under vacuum to provide the ethyl ester hydrochloride of fluorobenzimidic acid. The product is transported to the next stage without further purification.

Step B: 2 - (, 4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Triethylamine (2.86 g, 28.21 mmol) is added dropwise to a solution of fluorobenzimidic acid ethyl ester hydrochloride (5.42 g, 26.62 mmoles) and L-cysteine methyl ester hydrochloride (5.03 g, 29.28 mmoles) in 100 ml of dichloromethane at 0 ° C. The resulting mixture is stirred at room temperature for 3 days. Water and dichloromethane are added, the layers are separated, the aqueous layer is extracted with dichloromethane, dried over anhydrous Na 2 SO 4 and concentrated under vacuum to provide the crude product which is purified by column chromatography (silica gel, 15% strength). EtOAc / hexane) to give the 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. 1 H NMR (300 MHz, Step C: 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid To a solution of 2- (4-fluorophenyl) -4,5-methyl ester -dihydrothiazole-4-carboxylic acid (5.82 g, 0.024 mol) in 200 ml of THF and 200 ml of H2O is added KOH (13.65 g, 0.24 mol) .The reaction mixture is stirred vigorously at room temperature for 17 hours, The mixture The reaction mixture is diluted with water, extracted with diethyl ether and the diethyl ether layer is washed with water, the combined aqueous layers are acidified with 1 N HCl to pH 1, extracted with diethyl ether and dried over anhydrous Na2SO4. the desiccant and the filtrate is concentrated under vacuum to provide 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (300 MHz, d6-DMSO): d 12.92 (broad 1 H), 7.83-7.88 (m, 2 H), 731-7.37 (m, 2 H), 5.30 (dd, 1 H, J = = 1.0, 8.4 Hz ), 3.60-3.77 (m, 2H). Step D: 2- (4-fluorophenyl) -4,5-dichlorothiazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl) -amide To a solution of 2- (4-fluorophenyl) - 4,5-dihydrothiazole-4-carboxylic acid (151 mg, 0.671 mmol) and 3-amino-2-fluorobenzotrifluoride (132 mg, 0.738 mmol) in 10 ml of DMF were added DMAP (82 mg, 0.671 mmol), 0.25 ml of Pr2NEt and PyBroP (940 mg, 2.01 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -4,5-dihydrothiazole-2-fluoro-3-trifluoromethylphenyl) amide. -carboxylic 1 H-NMR (300 MHz, CDCl 3): d 9.17 (broad s, 1 H), 8.64 (dt, 1 H, J = 1.4, 6.9 Hz), 7.87-7.94 (m, 3H), 7.07-7.36 (m, 4H). ), 5.37 (t, 1H, J = 9.6 Hz), 3.74 - 3.88 (m, 2H). MS m / z (M-H) = 385.

EXAMPLE 13 (Compound # 1) 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (3-trifluoromethyl-4-cyanophenyl) -amide.

To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester (201 mg, 0.840 mmol) and 5-amino-2-cyanobenzotrifluoride (313 mg, 1.68 mmol) in 8 ml of THF at 0 ° C is added 2M isopropylmagnesium chloride (0.84 ml in THF). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-fluorophenyl) -4,5-dihydrothiazole- (4-cyano-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H NMR (400 MHz, CDCl 3): d 9.06 (broad s, 1H), 7.78 - 8.13 (m, 5H), 7.25 - 7.28 (m, 2H), 5.32 (t, 1H, J = 9.6 Hz), 3.71 - 3.88 (m, 2H). MS m / z (M-H) = 392.

EXAMPLE 14 (Compound # 7) (2- (4-fluoropheni-4,5-dihydrothiazole-4-carboxylic acid) 4-fluoro-3-trifluoromethylphenide-amide To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (201 mg, 0.892 mmol) and 5-amino-2-fluorobenzotrifluoride (160 mg, 0.892 mmol) in 10 ml of DMF were added. add DMAP (109 mg, 0.892 mmol), 0.25 ml of / Pr2NEt and PyBroP (832 mg, 1785 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-fluoro-3-trifluoromethylphenyl) amide. -carboxylic MS m / z (M-H) = 385.

EXAMPLE 15 (Compound # 6) 2- (4-Fluoro-phenoxy) -4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (200 mg, 0.887 mmol) and 5-amino-2-chlorobenzotrifluoride (173 mg, 0.887 mmol) in 10 ml of DMF were added. add DMAP (108 mg, 0.887 mmol)), 0.25 ml of / Pr2NEt and PyBroP (827 g, 1773 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-chloro-3-trifluoromethylphenyl) amide. -carboxylic H-NMR (300 MHz, CDCl 3): d 8.78 (broad s, 1 H), 7.79-8.03 (m, 4H), 7.13-2.21 (m, 3H), 5.31 (t, 1 H, J = 9.8 Hz), 3.71 - 3.88 (m, 2H). MS m / z (M-H) = 401.

EXAMPLE 16 (Compound # 4) (4- (N-Nitro-3-trifluoromethylphenyl) -amide of 2- (4-fluoropheniD-4,5-d ih id rotiazole-4-carboxylic acid To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazoi-4-carboxylic acid (202 mg, 0.897 mmol) and 5-amino-2-nitrobenzotrifluoride (185 mg, 0. 897 mmol) in 10 ml of DMF are added DMAP (110 mg, 0.897 mmol)), 0. 25 ml of / Pr2NEt and PyBroP (836 mg, 1794 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1N HCl and brine, then dried over anhydrous Na2S? 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-nitro-3-trifluoromethylphenyl) amide. 1 H NMR (400 MHz, CDCl 3): d 9.12 (broad s, 1H), 7.79 - 8.08 (m, 5H), 7.15 - 7.20 (m, 2H), 5.34 (t, 1H, J = 10 Hz), 3.71 - 3.90 (m, 2H). MS m / z (M-H) = 412.

EXAMPLE 17 (Compound # 2) (2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid 4-cyanopheniD-amide To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester (250 mg, 1045 mmol) and 4-aminobenzonitrile (247 mg, 2089 mmol) in 10 mL of THF at 0 ° C is added 2M isopropylmagnesium chloride (1.04 ml in THF). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-cyanophenyl) -amide. 1 H NMR (400 MHz, CDCl 3): d 9.21 (broad s, 1H), 7.63-7.52 (m, 4H), 7.08 - 7.19 (m, 4H), 5.32 (t, 1H, J = 9.6 Hz), 3.75 - 3.87 (m, 2H). MS m / z (M-H) = 324.

EXAMPLE 18 (Compound # 26) 2- (3-Chloropheni-4, 4-dihydrothiazole-4-carboxylic acid 4- (chloro-3-trifluoromethyl-phenyl) -amide Step A: 3-chlorobenzimidic acid ethyl ester hydrochloride To a solution of 3-chlorobenzonitrile (11.36 g, 85.6 mmol) in ml of ethanol is bubbled in dry HCl (generated by adding 200 ml of 36% HCl in drops, in 500 ml of concentrated H2SO4) at 5 ° C. The reaction mixture is stirred for an additional 0.5 hours at 5 ° C and then diluted with 500 ml of anhydrous diethyl ether. The mixture is then allowed to stand at 5 ° C for 12 hours, the solids are filtered, washed with diethyl ether and dried under vacuum to provide 3-chlorobenzimidic acid ethyl ester hydrochloride. The product is carried out on the next step without further purification. Step B: 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Triethylamine (2.44 g, 24.16 mmol) is added dropwise to a solution of 3-chlorobenzimidic acid ethyl ester hydrochloride ( 5 g, 22.71 mmoles) and L-cysteine methyl ester hydrochloride (4.29 g, 24.98 mmol) in 85 ml of dichloromethane at 0 ° C. The resulting mixture is stirred room temperature for 3 days. Water and dichloromethane are added and the aqueous layer is extracted with dichloromethane, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to provide a crude product which is purified by column chromatography (silica gel, 15% EtOAc / hexane ) to provide the 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester. Step C: 2- (3-chlorophenyl) -4,5-dihydrothioazole-4-carboxylic acid To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid methyl ester (5) g, 0.0196 moles) in 200 ml of THF and 200 ml of H2O is added KOH (10.97 g, 0.196 moles). The reaction mixture is stirred vigorously at room temperature for 17 hours. The reaction mixture is diluted with water, washed with diethyl ether and the organic layer is extracted with water. The combined aqueous layers are acidified with 1 N HCl until pH 1, extracted with diethyl ether and dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (300 MHz, d6-DMSO): d 13.07 (broad s, 1H), 7.80 (t, 1H, J = 1.7 Hz), 7.73 (d, 1H, J = 7.7 Hz), 7.65 (t, 1H, J = 1.0 Hz), 7.55 (t, 1H, J = 7.8 Hz), 5.33 (dd, 1 H, J = 8.3, 9.3 Hz), 3.64 - 3.78 (m, 2H). Step D: 2- (3-chloropheniD-4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) amide To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole- 4-carboxylic acid (147 mg, 0.606 mmol) and 5-amino-2-chlorobenzotrifluoride (130 mg, 0.667 mmol) in 10 ml of DMF was added DMAP (74 mg, 0.606 mmol), 0.25 ml of Pr2NEt and PyBrop (848 mg, 1.82 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na2SO4. The desiccant is removed by filtration and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (3-chlorophenyl) -4,5-dihydrothiazole- (4-chloro-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3) d 8.82 (broad s, 1 H), 7.90-7.95 (m, 2H), 7.72-7.80 (m, 2H), 7.37-7.52 (m, 3H), 5.32 (t, 1H) , J = 10 Hz), 3.71 - 3.88 (m, 2H) MS m / z (MH) = 418.

EXAMPLE 19 (Compound # 27) 2- (3-Chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethylphenyl) amide To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (162 mg, 0.6703 mmol) and 5-amino-2-cyanobenzotrifluoride (137 mg, 0.7373 mmol) in 10 ml of DMF were added. add DMAP (82 mg, 0.6703 mmoles)), 0.25 ml of iPr2NEt and PyBroP (938 mg, 2.01 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine. The organic extracts are dried over anhydrous a2SO4., it is filtered and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (3-chlorophenyl) -4,5-dihydrothiazole- (4-cyano-3-trifluoromethylphenyl) -amide. 4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3) d 9.05 (s broad, 1 H), 8.08 (d, 1 H, J = 1.9 Hz), 7.98 (dd, 1 H, J = 2.1, 8.5 Hz), 7.92 - 7.93 (m, 1H), 7.82 (d, 1 H, J = 8.5 Hz), 7.75 (dt, 1 H, J = 1.3, 7.8 Hz), 7.52 (dd, 1H, J = 1.1, 2.0 Hz), 7.43 (t, 1 H, J = 7.9 Hz), 5.35 (t, 1H , J = 10 Hz), 3.72 - 3.90 (m, 2H) MS m / z (MH) = 408.

EXAMPLE 20 (Compound # 28) 2- (4-FluorophenyD-4,5-dihydrothiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide) To a solution of 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (153 mg, 0.677 mmol) and 4-aminophenyltrifluoromethylsulfone (168 mg, 0.745 mmol) in 10 ml of DMF is added DMAP (83 mg, 0.6775 mmole), 0.25 ml of iPr2NEt and PyBroP (948 mg, 2.033 mmole) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine. The organic extracts are dried over anhydrous Na2SO4, filtered and the filtrate concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide. 1 H NMR (300 MHz, CDCl 3) d 9.13 (broad s, 1H), 7.88-8.01 (m, 6H), 7.12-7.20 (m, 2H), 5.35 (t, 1H, J = 10 Hz), 3.73 - 3.89 (m, 2H) MS m / z (MH) = 431.

EXAMPLE 21 (Compound # 29) 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide.

To a solution of 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (172 mg, 0.711 mmol) and 4-aminophenyltrifluoromethylsulfone (176 mg, 0.7819 mmol) in 10 ml of DMF is added DMAP (87 mg, 0.7108 mmoles), 0.25 ml of iPr2NEt and PyBroP (994 mg, 2.1324 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine. The organic extracts are dried over anhydrous Na2SO4, filtered and the filtrate concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide. 1 H NMR (300 MHz, CDCl 3) d 9.08 (broad s, 1 H), 7.62 - 8.02 (m, 4 H), 7.16 - 7.52 (m, 3 H), 5.35 (t, 1 H, J = 10 Hz), 3.74 - 3.86 (m, 2H).

EXAMPLE 22 (Compound # 31) 2- (3-Chlorophenyl) -4,5-dihydro-rotiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (170 mg, 0.701 mmol) and 4-aminophenyltrifluoromethylsulfone (174 mg, 0.771 mmol) in 10 ml of DMF is added DMAP (86 mg, 0.701 mmol), 0.25 ml of iPr2NEt and PyBroP (981 mg, 2104 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine. The organic extracts are dried over anhydrous a2SO4, filtered and the filtrate concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-trifluoromethanesulfonylphenyl) -amide. 1 H NMR (300 MHz, CDCl 3) d 9.09 (broad s, 1 H), 7.30-8.20 (m, 7H), 5.36 (t, 1 H, J = 9.9 Hz), 3.63-3.86 (m, 2H) EM m / z (MH) = 447.

EXAMPLE 23 (Compound # 30) 2- (3-Chlorophenyl) -4,5-d ih-idrothiazole-4-carboxylic acid (4-nitro-3-trifluoromethylphenyl) -amide.

To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (169 mg, 0.701 mmol) and 5-amino-2-nitrobenzotrifluoride (159 mg, 0.771 mmol) in 10 mL of DMF were added. add DMAP (86 mg, 0.701 mmol), 0.25 ml of iPr2NEt and PyBroP (980 mg, 2.102 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1 N HCl and brine. The organic extracts are dried over anhydrous Na2SO4, filtered and the filtrate concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (gel silica, 20% EtOAc / hexane) to give 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (4-nitro-3-trifluoromethylpheni) -amide. MS m / z (M-H) = 428.

EXAMPLE 24 (Compound # 32) 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl) -amide.

To a solution of 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (167 mg, 0.691 mmol) and 3-amino-2-fluorobenzotrifluoride (136 mg, 0.760 mmol) in 10 ml of DMF were added. add DMAP (84 mg, 0.691 mmol), 0.25 ml of iPr2NEt and PyBroP (966 mg, 2073 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine. The organic extracts are dried over anhydrous Na2SO4, filtered and the filtrate concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to 2- (3-chlorophenyl) -4,5-dihydrothiazole-4-carboxylic acid (2-fluoro-3-trifluoromethylphenyl) -amide. 1 H NMR (300 MHz) D d 9.13 (broad s, 1H), 8.61 (dt, 1 H, J = 1.3, 6.9), 7.77-7.88 (m, 2H), 7.27-7.53 (m, 4H), 5.39 (t , 1H, J = 9.7 Hz), 3.75 -3.89 (m, 2H).

EXAMPLE 25 (Compound # 33) 2- (4-Fluoro-phenyl-4-methyl-4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl) -amide) Step A: 2-tert-butyl-3-formyl-4-methylthiazolidin-4-carboxylic acid ethyl ester. N-butyllithium (2.5M in hexane, 18 ml, 0.0450 moles) is added dropwise to diisopropylamine (6.49 g, 0.064). moles) in 225 ml of THF at -78 ° C, then 32 ml of 1,3-dimethyltetrahydropyrimidin-2-one are added to the reaction mixture, in one portion. The reaction mixture is stirred at -78 ° C for 1 h. A solution of 2-tert-butyl-3,4-methylthiazolidin-4-carboxylic acid ethyl ester (10.5 g, 0.0428 mol) in 20 ml of THF is added dropwise at -90 ° C. The The solution is stirred at -90 ° C for 45 min and then iodomethane (7.29 g, 0.0514 mol) is added. The resulting mixture is stirred at -90 ° C for 2 hours and then warmed to room temperature. The volatile fractions are removed under vacuum and the oily residue is divided between brine and diethyl ether. The aqueous layer is extracted with diethyl ether 3 times. The combined ether layer is dried over anhydrous Na 2 S 4. The desiccant is filtered and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2-tert-butyl-3-formyl-4-methylthiazolidin-4-carboxylic acid ethyl ester. MS m / z (M + H) 282 Step B: 2-amino-3-mercapto-2-methylpropionic acid hydrochloride The ethyl ester of 2-terbutyl-3-formyl-4 is heated at 100 ° C for 15 hours. -methythiazolidin-4-carboxylic acid (1.34 g, 5.17 mmol) and HCl 5N. The mixture is then washed with EtOAc 3 times. The aqueous layer is evaporated to dryness to give 2-amino-3-mercapto-2-methylpropionic acid hydrochloride. MS m / z (M + H) 136; (MH) 134. Step C: 2-amino-3-mercapto-2-methylpropionic acid methyl ester hydrochloride Thionyl chloride (1.58 g, 13.27 mmol) is added in a solution of 2-amino-3-hydrochloride mercapto-2-methylpropionic (759 mg, 4,422 mmoles) in 16 mL of CH3OH. The resulting mixture is heated at 65 ° C overnight. The volatile fractions are removed under vacuum to provide a foamy residue which is dissolved in a small amount of CH 3 OH and triturated with diethyl ether. A gummy compound is precipitated and dried under vacuum to give the 2-amino-3-mercapto-2-methylpropionic acid methyl ester hydrochloride. The crude compound is transported to the next step without further purification. Stage D: 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid methyl ester To a mixture of 4-fluorobenzimidic acid ethyl ester hydrochloride (5.42 g), 0.794 g, 0.0039 mole) and 2-amino-3-mercapto-2-methylpropionic acid methyl ester hydrochloride (0.788 g, 0.004 mole) in 15 ml of dichloromethane at 0 ° C is added triethylamine (0.42 g, 0.004 mole). ) and then stirred at room temperature for 2 days. Water and dichloromethane are added to the reaction mixture. The aqueous layer is extracted with dichloromethane. The organic layer is washed with brine and dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give the 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid methyl ester as an oil.

Step E: 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid To a solution of 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole methyl ester -4-carboxylic acid (5.82 g, 0.024 mol) in 200 ml of THF and 200 ml of water at room temperature add KOH (13.65 g, 0.243 mol). The reaction is stirred at room temperature for 17 hours. The reaction mixture is diluted with water and extracted with diethyl ether. The aqueous layer is acidified with 50% HCl (aqueous) to pH 1, then extracted with diethyl ether. The diethyl ether layer is washed with brine and dried over anhydrous Na 2 SO 4. The mixture is stirred and the filtrate is concentrated under vacuum to provide a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid as an oil. Step F: 2- (4-fluorophenyl) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethylphenyl) -amide To a solution of 2- (4-fluorophenyl) acid ) -4-methyl-4,5-dihydrothiazole-4-carboxylic acid (11 mg, 0.046 mmol) and 5-amino-2-cyanobenzotrifluoride (9.4 mg, 0.051 mmol) in 1 ml of DMF is added DMAP (5.6 mg, 0.046) mmoles), 0.25 ml of iPr2NEt and PyBroP (64 mg, 0.138 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. Water and EtOAc are added to the reaction mixture. The organic layer is washed with 1N HCl and brine, then dried over Na 2 S 4. anhydrous. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to provide 2- (4-fluorophenyl) -4-methyl-4 (4-cyano-3-trifluoromethylphenyl) -amide, 5-dihydrothiazole-4-carboxylic acid. MS m / z (M-H) 406. Compound # 12 is prepared in a similar manner according to the procedure described in Example 25 above, substituting 5-amino-2-cyanobenzotrifluoride for 4-chloro-3-trifluoromethylphenylamine. Compound # 13 is prepared in a similar manner according to the procedure described in example 25 above, by substituting 5-amino-2-cyanobenzotrifluoride for 4-nitro-3-trifluoromethylphenylamin.

EXAMPLE 26 (Compound # 21) 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide.

Step A: 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid methyl ester. Triethylamine (0.95 ml, 6.836 mmol) in a solution of ethyl ester hydrochloride is added dropwise. of 4-fluorobenzimidic acid (1.33 g, 6.511 mmol) and penicillamine methyl ester hydrochloride (1.43 g, 7.163 mmol) in 20 ml of dichloromethane at 0 ° C. The resulting mixture is stirred at room temperature for 3 days. Water and dichloromethane are added and the aqueous layer is extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give the 2- (4-fluoro-5,5-dimethylphenyl) -4,5-dihydrothiazole-4-methyl ester. carboxylic Step B: 2- (4-fluoropheniD-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid To a solution of 2- (4-fluorophenyl) -5,5-dimethyl-4,5- methyl ester dihydrothiazole-4-carboxylic acid (610 mg, 2282 mmol) in 15 ml of THF and 5 ml of H20 is added KOH (640 mg, 11409 mmol) The mixture is stirred vigorously at room temperature overnight. dilute with water, wash with diethyl ether and the diethyl ether layer is extracted with water.The combined aqueous layers are acidified with 1 N HCl to pH 1, then extracted with diethyl ether and dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid.1H NMR (400 MHz, d6-DMSO): d 12.89 (broad s , 1H), 7.78 -7.83 (m, 2H), 7.28-7.34 (m, 2H), 4.85 (s, 1 H), 1.71 (s, 3H), 1.43 (s, 3H). Step C: 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide To a solution of 2- (4-fluorophenyl) acid -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (162 mg, 0.638 mmol) and 5-amino-2-chlorobenzotrifluoride (137 mg, 0.701 mmol) in 10 ml of DMF is added DMAP (78 mg, 0.638 mmoles) 0.25 ml of iPr2NEt and PyBroP (892 mg, 1.913 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1N HCl and brine, then dried on Na2S04 anhydrous. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -5,5-dimethyl- (4-chloro-3-trifluoromethylphenyl) -amide of 2- (4-fluorophenyl) -amide. 4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (400 MHz, CDCl 3): d 9.30 (broad s, 1H), 7.95 (d, 1H, J = 2.5 Hz), 7.87-7.91 (m, 2H), 7.83 (dd, 1H, J = 2.5, 8.7 Hz), 7.45 (d, 1 H, J = 8.7 Hz), 7.13 - 7.17 (m, 2H), 4.73 (s, 1 H), 1.96 (s, 3H), 1.47 (s, 3H). MS m / z (M-H) = 429.

EXAMPLE 27 (Compound # 19) 2- (4-Fluoro-phenoxy-5-methyl-4,5-dihydrothiazole-4-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl) -amide).

To a solution of 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (180 mg, 0.709 mmol) and 5-amino-2-cyanobenzotrifluoride (145 mg, 0.779 mmol) in 10 ml of DMF is added DMAP (87 mg, 0.709 mmol) 0.25 ml of iPr2NEt and PyBroP (991 mg, 2.126 mmol) sequentially. The reaction mixture is stirred at temperature Atmosphere during the night. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -5,5-dimethyl- (4-cyano-3-trifluoromethylphenyl) -amide of 2- (4-fluorophenyl) -amide. 4,5-dihydrothiazole-4-carboxylic acid. 1 H-NMR (300 MHz, CDCl 3): d 9.57 (broad s, 1H), 8.09 (d, 1H, J = 2.0 Hz), 8.01 (dd, 1H, J = 2.1, 8.5 Hz), 7.87-7.92 (m, 2H), 7.81 (d, 1 H, J = 8.5 Hz), 7.13-7.20 (m, 2H), 4.75 (s, 1H), 1.96 (s, 3H), 1.47 (s, 3H). MS m / z (M-H) = 420.

EXAMPLE 28 (Compound # 20) 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (4-nitro-3-trifluoromethylphenyl) -amide.

To a solution of 2- (4-fluorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (181 mg, 0.714 mmol) and 5-amino-2-nitrobenzotrifluoride (162 mg, 0.785 mmol) in 10 ml of DMF is added DMAP (87 mg, 0.709 mmol) 0.25 ml of iPr2NEt and PyBroP (998 mg, 2141 mmol) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -5,5-dimethyl- (4-nitro-3-trifluoromethylphenyl) -amide of 2- (4-fluorophenyl) -5,5-dimethyl- 4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3): d 9.60 (broad s, 1H), 8.06 - 8.10 (m, 2H), 7.98 - 8.01 (m, 1H), 7.88 - 7.92 (m, 2H), 7.14 - 7.20 (m, 2H), 4.77 (s, 1 H), 1.97 (s, 3H), 1.47 (s, 3H) ). MS m / z (M-H) = 440.

EXAMPLE 29 (Compound # 22) 2- (4-chlorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide.

Step A: 2- (4-chlorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid methyl ester. Triethylamine (2 ml, 14.31 mmol) is added dropwise in a hydrochloride solution of ethyl ester of 4-chlorobenzimidic acid (3.0 g, 13,630 mmol) and penicillamine methyl ester hydrochloride (3.0 g, 14,990 mmol) in 50 ml of dichloromethane at 0 ° C. The resulting mixture is stirred at room temperature for 3 days. Water and dichloromethane are added and the aqueous layer is extracted with dichloromethane, dried over Na2SO and concentrated in vacuo to provide the crude product. The crude product is purified by column chromatography (silica gel, 15% EtOAc / hexane) to give the 2- (4-c! Oro-5,5-dimethylphenyl) -4,5-dihydrothiazole- methyl ester. 4-carboxylic acid.

Step B: 2- (4-chlorophenyl) -5,5-dimethyl-4,5-d-hydrothazole-4-carboxylic acid To a solution of 2- (4-chlorophenyl) -5-methyl ester, 5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (1.4 g, 4930 mmol) in 30 ml of THF and 10 ml of H2O is added KOH (1.38 g, 24,660 mmol). The mixture is stirred vigorously at room temperature overnight. The reaction mixture is diluted with water, washed with diethyl ether and the diethyl ether layer is extracted with water. The combined aqueous layers are acidified with 1 N HCl to pH 1, then extracted with diethyl ether and dried over anhydrous Na2SO4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide 2- (4-chlorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (400 MHz, d6-DMSO) d 12.85 (broad s, 1H), 7.76 (d, 2H, J = 8.6 Hz), 7.56 (d, 2H, J = 8.6 Hz), 4.87 (s, 1H), 1.71 (s, 3H), 1.43 (s, 3H). Step C: 2- (4-chloropheniD-5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (4-chloro-3-trifluoromethylphenyl) -amide To a solution of 2- (4-chlorophenyl) acid) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (162 mg, 0.601 mmol) and 5-amino-2-chlorobenzotrifluoride (129 mg, 0.661 mmol) in 10 ml of DMF is added DMAP (73 mg, 0.601 mmoles) 0.25 ml of iPr2NEt and PyBroP (841 mg, 1.803 mmol) sequentially The reaction mixture is stirred at room temperature overnight The reaction mixture is diluted with water and EtOAc The organic layer is washed with 1N HCl and brine, then dry on anhydrous Na2S? 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 20% EtOAc / hexane) to give 2- (4-fluorophenyl) -5,5-dimethyl- (4-chloro-3-trifluoromethylphenyl) -amide of 2- (4-fluorophenyl) -amide. 4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3): d 9.28 (broad s, 1H), 7.95 (d, 1H, J = 2.5 Hz), 7.80-7.85 (m, 3H), 7.42-7.49 (m, 3H), 4.73 ( s, 1H), 1.96 (s, 3H), 1.47 (s, 3H).

EXAMPLE 30 (Compound # 23) 2- (4-chlorophenyl) -5,5-dihydrothiazole-4-carboxylic acid (4-cyano-2,5-difluorophenyl) -amide.

To a solution of 2- (4-chlorophenyl) -5,5-dimethyl-4,5-dihydrothiazole-4-carboxylic acid (162 mg, 0.601 mmol) and and 4-amino-2,5-difluorobenzonitrile (131 mg, 0.662) mmoles) in 10 ml of DMF is added DMAP (74 mg, 0.602 mmoles) 0.25 ml of Pr2NEt and PyBroP (842 mg, 1,806 mmoles) sequentially. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and EtOAc. The organic layer is washed with 1 N HCl and brine, then dried over anhydrous Na 2 SO 4. The desiccant is filtered off and the filtrate is concentrated under vacuum to provide the crude product. The crude product is purified by column chromatography (silica gel, 17% EtOAc / hexane) to give 2- (4-chlorophenyl) -5,5- (4-cyano-2,5-difluorophenyl) -amide. dimethyl-4,5-dihydrothiazole-4-carboxylic acid. 1 H NMR (300 MHz, CDCl 3): d 9.28 (broad s, 1 H), 7.95 (d, 1 H, J = 2.5 Hz), 7.80-7.85 (m, 3 H), 7.42 - 7.49 (m, 3 H), 4.73 (s, 1 H), 1.96 (s, 3H), 1.47 (s, 3H).

EXAMPLE 31 In Vitro Test - Androgen Receptor Filtration Binding Assay The assay is carried out in a 96-well plate with each well filled with a total reaction volume of 150 μl of a solution containing 5 pmol of the receptor. androgen LBD (Panvera) or 30 μl of freshly prepared rat cytosol, tracer [3H] R1881 0.5 nM (NEN), 1.5 μl (10 μM) of test compound or vehicle (diluted in 30% DMSO, final concentration of DMSO, 0.75%) and 150 μl of TED buffer (the TED buffer contains 10 mM Tris, HCl, pH 7.4, 1 mM sodium molybdate (60 mg / 250 ml), 1.5 mM EDTA and 1 mM DTT and 10% glycerol (v / v)). On day one, the solution containing receptor, tracer and TED buffer is distributed over a 96-well plate. Later add to the individual wells a diluted test or control vehicle and incubate the plate at 4 ° C overnight. On day two, 20 μl of human y-globulin (ICN 823102), prepared at 25 mg / ml in TE pH 8.0 and 55 μl polyethylene glycol 8000 40% (JT Baker U222-08), are added to each well. prepared in TE pH 8.0. The plate is incubated at 4 ° C for 60 minutes. During the incubation the harvester is rinsed with PEG 8000 10%, the TE pH 8.0 is prepared and GF / C Unifilter-96 is pre-humidified with PEG 10%. The binding reaction is filtered, the retentate is washed three times with 10% PEG and dried under vacuum for about four minutes, then dried at 50 ° C for 5 min and then sealed at its bottom. They are added to the filter wells 25 μ! of Microscint-20 (Packard) and the top is sealed. The plate wells are then counted in a TopCount (Packard) device. The selected compounds of the present invention are tested for their binding to androgen receptor, according to the procedure described in the foregoing and the results are included in Table 2. One or more negative numbers indicate that there is no antagonistic activity for the test compound However, the compound may have agonist activity, which has not been tested.

TABLE 2 Results of Androgen Receptor Binding f The results for compound # 4 are based on two separate synthesis batches. A third confirmation batch is not found at the time of submission. * Negative values indicate that there is no antagonistic activity. Compounds without measured antagonist activity may possess agonist activity. Although the above specification describes the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications that are within the scope of the invention. following claims and their equivalents.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) wherein R is selected from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is attached through a carbon atom; wherein the aryl or heteroaryl group is optionally substituted with one to four substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (0) -, lower alkyl-C (0) ) -NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2, lower alkyl-S (O) 0-2-NRA-, phenyl-S (O) or-2 -NRA- and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; RA is independently selected from hydrogen or lower alkyl; R2 and R2a are each independently selected from the group consisting of hydrogen, lower alkyl and lower alkyl substituted with halogen; R3 is selected from the group consisting of hydrogen and lower alkyl; R4 is selects from the group consisting of aryl and heteroaryl; wherein the heteroaryl group is attached through a carbon atom; wherein the aryl or heteroaryl group is optionally substituted with one to four substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (O) -, lower alkyl-C (0) ) -NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0.2, lower alkyl-S (O) 0-2-NRA-, phenyl-S (O) 0-2-NRA - and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; R5 is selected from the group consisting of hydrogen, lower alkyl and lower alkyl substituted with halogen; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that: R1 is selected from the group consisting of aryl; wherein the heteroaryl group is optionally substituted with one to two substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (O) -, lower alkyl-C (O) - NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2) lower alkyl-S (O) 0-2-NRA-, phenyl-S (O) 0-2- NRA- and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; R2 selects from the group consisting of hydrogen, lower alkyl and trifluoromethyl; R2a is selected from the group consisting of hydrogen, lower alkyl and trifluoromethyl; R3 is selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of aryl; wherein the aryl group is optionally substituted with one to two substituents that are independently selected from halogen, alkyl, alkyl substituted with halogen, lower alkyl ester, cyano, N (RA) 2C (0) -, lower alkyl-C (O) - NRA-, lower alkyl-S (O) 0-2-, phenyl-S (O) 0-2, lower alkyl-S (O) 0-2-NRA-, fenii-S (O) 0-2-NRA - and trifluoromethylsulfonyl; wherein the phenyl is optionally substituted with one or more substituents that are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, cyano, nitro, amino, lower alkylamino or dialkylamino lower; R5 is selected from the group consisting of hydrogen, lower alkyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, further characterized in that R1 is selected from the group consisting of aryl; wherein the aryl group is optionally substituted with a halogen; R2 selected from the group consisting of hydrogen and lower alkyl; R2a is selected from the group consisting of hydrogen and lower alkyl; R3 is hydrogen; R 4 is selected from the group consisting of aryl; wherein the aryl group is substituted with one to three substituents that are independently selected from halogen, cyano, nitro, lower alkyl, lower alkyl substituted with halogen and trifluoromethylsulfonyl; R5 is selected from the group which consists of hydrogen and lower alkyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, further characterized in that: R1 is selected from the group consisting of 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl and 4-chlorophenyl; R2 is selected from the group consisting of hydrogen and methyl; R2a is selected from the group consisting of hydrogen and methyl; R3 is hydrogen; R 4 is selected from the group consisting of 4-chlorophenyl, 4-cyanophenyl, 3-trifluoromethyl-4-cyanophenyl, 3-trifluoromethyl-4-nitrophenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethyl-4-fluorophenyl, 2, 5-difluoro-4-cyanophenyl, 2-fluoro-3-trifluoromethylphenyl and 4-trifluoromethylsulfonylphenyl; R5 is selected from the group consisting of hydrogen and methyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, further characterized in that: R1 is selected from the group consisting of 4-fluorophenyl, 3-chlorophenyl and 4-chlorophenyl; R2 is selected from the group consisting of hydrogen and methyl; R2a is selected from the group consisting of hydrogen and methyl; R3 is hydrogen; R 4 is selected from the group consisting of 3-trifluoromethyl-4-cyanophenyl, 3-trifluoromethyl-4-nitrophenyl, 3-trifluoromethyl-4-chlorophenyl and 4-trifluoromethylsulfonylphenyl; R5 is selected from the group consisting of hydrogen and methyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, further characterized in that: R1 is selected from the group consisting of 4- fluorophenyl and 4-chlorophenyl; R2 is hydrogen; R2a is hydrogen; R3 is hydrogen; R 4 is selected from the group consisting of 3-trifluoromethyl-4-nitrophenyl and 3-trifluoromethyl-4-chlorophenyl; R5 is selected from the group consisting of hydrogen and methyl; or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as defined in claim 1.

8. The use of the compound defined in claim 1 for preparing a medicament for treating a mediated disorder. an androgen receptor in a subject.

9. The use of a compound as defined in claim 1, for the preparation of a medicament for treating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (e) alopecia , (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, (j) For male contraception or (k) for improvement of male performance, in a subject in need of the same.