WO2007085202A1

WO2007085202A1 - Oxamic acid derivatives,preparation methods and medical uses thereof

Info

Publication number: WO2007085202A1
Application number: PCT/CN2007/000318
Authority: WO
Inventors: Song Li; Jianlei Kang; Zhibing Zheng; Lili Wang; Dan Qin; Junhai Xiao; Wu Zhong; Hao Cui
Original assignee: Beijing Molecule Science And Technology Co., Ltd ,
Priority date: 2006-01-27
Filing date: 2007-01-29
Publication date: 2007-08-02
Also published as: CN101007790B; CN101007790A

Abstract

Compounds represented by the general formula I, their pharmaceutically acceptable salts, solvates are disclosed. The definitions of substituents of formula I are the same as description. The pharmaceutical compositions containing the compounds of general formula I, their preparation methods and their uses in manufactures of pharmaceutical medicaments for treatment or preventing various diseases and dangerous factors relating to human being’s peroxisome proliferator-activating receptor (hPPAR).

Description

Oxine derivative, preparation method thereof and medical use

The present invention relates to novel compounds, and more particularly to a oxalic acid derivative capable of activating a human peroxisome proliferator-activated receptor (hPPAR), and a method for preparing the same, including A pharmaceutical composition of the compound, and the use of the compound in the manufacture of a medicament for the treatment and/or prevention of a hPPAR mediated disease or condition. Background technique

The peroxisome proliferator-activated receptor (abbreviated as PPAR) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily equivalent to the glucocorticoid receptor, retinoic acid receptor, and thyroxine receptor. To date, three subtypes of PPARs have been found: ot, gamma and delta (also known as beta), which are encoded by different genes. Moreover, PPAR y is divided into two isoforms due to different promoters and splicing methods: _{V l} , _V 2 , which differ only in the N-terminal sequence (Vida l- Puig, J. Cl in. Inves t. , 97: 2553 -2561, 1996). When activated by a specific small molecule, PPARs interact with the PPARs response element (PPRE) of the target gene promoter region to regulate expression of the gene. PPARs are important transcriptional regulators of glucose, lipids, and cholesterol metabolism in the body.

PPAR alpha is expressed primarily in tissues with very high catabolic activity in lipids such as brown adipose tissue and liver, followed by kidney, heart, and skeletal muscle (Endocrinology, 1995, 137, 354). It can positively or negatively control genes involved in fatty acid metabolism and intracellular delivery (such as acyl-CoA synthetase, fatty acid-binding protein and lipoprotein lipase) and apolipoproteins (AI) involved in the metabolism of cholesterol and neutral lipids. , All, CI II) gene expression. PPAR γ is mainly present in adipose tissue and is also present in small amounts in skeletal muscle, liver, colon, retina, and immune system. Recent research results also mention It is highly expressed in macrophages, including atherosclerotic foam cells. among them, ? ? 11丫_{2 is} mainly expressed in adipose tissue, while PPAR _{Y l} is found in various tissues, with the highest expression in kidney, intestine and heart. PPARy primarily regulates expression of genes involved in adipocyte differentiation and insulin sensitivity (J. Lipid. Res., 1996, 37 907). PPAR5 is widely distributed and expressed in many tissues, with the highest expression in the intestine, kidney and heart. Activation of PPAR5 has been shown to cause an increase in HDL levels, a decrease in LDL and VLDL levels.

Thiazolidinediones, such as rosiglitazone, have been shown to enhance insulin action in patients with type 2 diabetes and reduce serum glucose. Thiazolidinediones have been reported to be potent and selective activators of PPARY and bind directly to PPARY (J. M. Lehmann et al, J. Biol. Chem. 12953-12956, 270 (1995)).

Fibrates have been widely used as therapeutic agents for hyperlipidemia, lowering serum triglycerides (20-50%) LDLc (10-15%) and increasing HDLc (10-15%). Experiments have shown that the effect of fibrates on serum lipids is mediated through activation of PPAR alpha. See, for example, B. Staels et al, Curr. Pharm. Des., 1-14, 3 (1), (1997) Activation of PPARa causes increased fatty acid catabolism and reduced re-synthesis of fatty acids in the liver (causing triglyceride synthesis and VLDL) Transcription of enzymes that produce/secretion is reduced. In addition, PPARa activation reduces the production of apoC-III. Reduction of apoC-111 (inhibitor of LPL activity) increases clearance of VLDL (J. Arx et al, Atherosclerosis, J59-S37, 124 (Suppl), (1996))

PPAR involves many biological processes and disease states, including hypercholesterolemia, dyslipidemia, and diabetes. However, current drugs are not ideal because of toxic side effects, etc. Therefore, a safe and effective PPAR agonist is needed. Optionally activate a subtype or activate multiple subtypes simultaneously. Summary of invention The object of the present invention is to find and develop small molecule compounds having hPPAR agonistic activity for the treatment of hPPAR mediated diseases, risk factors or conditions such as dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, Hyperglycemia, type 1 diabetes, type 2 diabetes, insulin resistance, diabetic complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, and for suffering from diseases such as obesity, anorexia, bulimia and nerves Regulation of appetite and food absorption in patients with anorexia nervosa.

The inventors have discovered that the compounds of formula I below can be used to treat or prevent a variety of diseases, risk factors or conditions mediated by hPPAR.

Thus, in one aspect, the invention provides a compound of formula I, as well as pharmaceutically acceptable salts and solvates thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. The pharmaceutical composition of the present invention comprises at least one compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

In another aspect, the invention provides a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

In a further aspect, the invention provides a method of treating or preventing a hPPAR mediated disease, risk factor or disorder comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of the invention.

hPPAR-mediated diseases, risk factors or conditions including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type 1 diabetes, type II diabetes, insulin resistance, diabetic complications, and glucose tolerance Incomplete, X syndrome, heart failure, cardiovascular disease, obesity, anorexia, bulimia and anorexia nervosa. Detailed description of the invention

In one aspect, the invention provides a compound of formula I, and pharmaceutically acceptable Salts and solvates,

among them:

a linear or branched alkyl group selected from H, (^-, and a benzyl group optionally substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl , trifluoromethyl, trifluoromethoxy, d-C ₆ straight and branched alkyl, C ₂ -C ₆ straight and branched alkenyl, oxy, (^ ₂ -( ₄ alkenyloxy, Phenoxy, benzyloxy, nitrile, carboxyl and amino;

R ₂ and R _{3 are} independently selected from H, (^ - alkyl, halogen, C ₂ -C ₆ straight and branched chain linear and branched ₍₆ alkenyl, and C ₃ -C ₆ cycloalkyl alkyl;

R _{4 is} selected from the group consisting of linear and branched alkyl groups of d-C ₄ , halogen, dC ₃ alkoxy, trifluoromethyl, trifluoromethoxy, and nitrile;

m is 0, 1, 2, 3 or 4;

X is selected from the group consisting of 0 and S atoms;

n is 1, 2, 3 or 4;

One of Y and Z is N and the other is S or 0;

Ar is selected from a monocyclic, bicyclic or tricyclic aromatic carbocyclic or heterocyclic group wherein each ring consists of 5 to 6 ring atoms, and the heterocyclic group includes 1 to 4 hetero atoms selected from the group consisting of : 0, S and Ν; the ring may be unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC ₆ straight and branched alkyl, C ₂ -C ₆ straight and branched alkenyl, d -C ₄ alkoxy, C ₂ -C ₄ alkenoxy, phenoxy, benzyloxy, Nitrile group, carboxyl group and amino group. The compounds of the invention activate hPPAR.

According to a preferred embodiment, the present invention relates to a compound represented by the formula II, and pharmaceutically acceptable salts and solvates thereof,

among them:

R _{3 is} selected from the group consisting of H, d-Cs straight and branched alkyl, halogen, C ₂ -C ₆ straight and branched alkenyl, and C ₃ -C ₆ cycloalkyl;

R _{4 is} selected from the group consisting of linear and branched alkyl groups of dC ₄ , halogen, (^-C ₃ alkoxy, trifluoromethyl, trifluoromethoxy, and nitrile groups;

m is 0, 1, 2, 3 or 4;

X is selected from the group consisting of 0 and S atoms;

n is 1, 2, 3 or 4;

One of Y and Z is N and the other is S or 0;

Ar is selected from a monocyclic, bicyclic or tricyclic aromatic carbocyclic or heterocyclic group wherein each ring consists of 5 to 6 ring atoms, and the heterocyclic group includes 1 to 4 hetero atoms selected from the group consisting of : 0, S and N; the ring may be unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, -(: ₆ straight-chain and branched alkyl groups, C ₂ -C ₆ straight-chain and branched alkenyl groups, d-(^ alkoxy, C ₂ -C ₄ alkenyloxy, phenoxy, benzyloxy Base, nitrile group, carboxyl group and amino group.

Preferred compounds of the invention include:

N- {4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)-methoxy]-phenyl}-oxalyl; N-(4-{[4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-indolyl-2-(4-bromophenyl)-1,3-thiazole-5-yl]-methoxy]-phenyl)-oxalyl;

N-(4- { [4-indolyl-2-(4-fluorophenyl)-1,3-thiazole-5-indole]-decyloxy}-phenyl)-oxalyl;

N-(4-{[4-mercapto-2-(4-methoxyphenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4- { [4-methyl-2-(3,5-dimethoxyphenyl)-1, 3-thiazole-5-yl]-methoxy}-phenyl)-oxaline ;

N-(4-{[4-methyl- ² - (2, 4-dichlorophenyl)-1,3-thiazol-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-methyl-2-(4-tert-butylphenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4- { [4-methyl-2-(thiophen-2-yl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-methyl-2-(thiophen-3-yl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4- { [ ⁴ -Indolyl- ² - (naphthalen-2-yl)-1, 3-thiazol-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4- { [4-methyl-2-(1,3-benzodioxole-5-yl)-1, 3-thiazole-5-yl]-methoxy} Phenyl)-oxalysine;

N- {4- [2-(5-Methyl-2-phenyl-1,3-oxazole-4-yl)-ethoxy]-phenyl}-oxalysine;

And a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention relates to the preparation of a compound of the above formula I or a medicament thereof A method of using a salt or a solvate, which comprises:

1) reacting a compound of the formula 111 with a substituted p-nitrophenol or a substituted p-nitrophenylthiophenol in the presence of a base (e.g., cesium carbonate, potassium carbonate, sodium hydroxide, etc.) to give a compound of the formula V;

Alternatively, a compound of formula IV is reacted with a substituted p-nitrophenol or a substituted p-nitrophenylthiophenol in the presence of DEAD and PPh _{3 to give} a compound of formula V,

Wherein W is halogen, and X, Y, Z, R ₃ , , m, n and Ar are as defined above for formula I;

2) The compound of the formula V is reduced with Raney Ni and hydrazine hydrate to give a compound of the formula VI,

Wherein X, Y, Z, R ₃ , R, m, n and Ar are as defined above for Formula I;

3) Compounds of formula VII

VI I

Wherein, the definition is the same as the definition of Formula I above, but not H.

Reaction with a compound of formula VI to give a compound of formula I wherein 11 ₂ is H, optionally wherein said compound of formula I wherein 11 ₂ is H and R ₂ W (wherein R _{2 is} as defined above for formula I except A substitution reaction occurs in which W is a halogen other than H, and a compound of the formula I wherein R _{2 is} not H is obtained,

Wherein, X, Y, Z, R ₂ , R ₃ , , m, n and Ar are as defined above for Formula I, and R! is as defined above for Formula I but not Η;

4) Optionally, the compound of the formula I obtained in the above 3), which is not H, is hydrolyzed to obtain a ^! ! A compound of formula I, which comprises hydrolyzing a compound of formula I wherein R ₂ is H with a base such as sodium hydroxide or potassium hydroxide or an acid such as dilute hydrochloric acid or trifluoroacetic acid to provide a compound of formula II,

II Wherein X, Y, Ζ, R ₃ , R, m, n and Ar are as defined above for Formula I.

According to a specific embodiment, the synthesis of the compound of formula I and formula II:

Reaction step one:

III V

The compound of the formula III is added dropwise to a solution of the substituted p-nitrophenol or substituted p-nitrothiophenol in dry acetonitrile, using, for example, cesium carbonate as a base, stirring at room temperature overnight or refluxing for 5 to 8 hours. The reaction mixture was filtered, and the filtrate was evaporated. The silica gel used herein may be silica gel for conventional column chromatography, and has a particle size of 10 - 40 μm.

or

IV V

Reaction of a compound of formula IV with a substituted p-nitrophenol or substituted p-nitrothiophenol in dry tetrahydrofuran in the presence of DEAD (diethyl azodicarboxylate) and PPh ₃ (triphenylphosphine) The mixture was stirred at room temperature for 24 h or recycled for 5-8 hours and separated by column (eluent: n-hexane / ethyl acetate system) to give compound of formula V.

Reaction step two:

V VI

To the hot ethanol reaction solution of the compound of the formula V and Raney Ni, hydrazine hydrate is added, and after refluxing for 0.5 to 1 hour, it is allowed to cool and filtered to obtain a compound of the formula VI.

Reaction step three:

VI VII Γ

The compound of the formula VII was added dropwise to the Ot reaction solution of the compound of the formula VI and triethylamine in dichloromethane, and the reaction was terminated after stirring for 4 hours. The reaction was concentrated column (eluent: n-hexane / ethyl acetate system), to give a compound of formula Gamma], i.e. a compound of formula wherein R ₂ is I H. Optionally,

Γ I (R _{2 is} not H) W (wherein R _{2 is} as defined above for formula I but except H, and W is a halogen) is added dropwise to the DMF solution of the compound of formula ,, 0. The reaction is concentrated at C to 50 ° C for 0.5 to 3 hours, and the reactant is concentrated and the column is separated (eluent: n-hexane / ethyl acetate system) to obtain a compound of formula I wherein R _{2 is} not H.

Reaction step four:

I I I

The compound of formula I is hydrolyzed in the presence of a base such as a metal hydroxide or an acid such as dilute hydrochloric acid, trifluoroacetic acid or the like for ₂ to 6 hours to give a compound of formula II.

Those skilled in the art will appreciate that the compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates. The pharmaceutically acceptable salts of the compound of formula I or formula II include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. Examples of suitable salts with acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid. , citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene a salt of sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid or the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. Examples of suitable salts with bases include sodium, lithium, potassium, rubidium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts. When reference is made hereinafter to a compound of the invention, it includes a compound of formula I or formula II, and pharmaceutically acceptable salts and solvates thereof.

The present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I. For example, the selection and preparation of suitable prodrug derivatives are described in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985. Regulation method.

The invention also includes active metabolites of the compounds of the invention.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient which is useful for in vivo treatment and is biocompatible. The pharmaceutical composition can be prepared in various forms depending on the route of administration.

The pharmaceutical compositions of the present invention comprise an effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt or solvate thereof, such as a hydrate, and one or more suitable pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutically acceptable carrier, diluent or excipient includes, but is not limited to: ion exchangers, alumina, aluminum stearate, ovolipids, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, Sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, trisilicon Magnesium, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.

The pharmaceutical composition of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, Intraventricular, intrasternal, and intracranial injections or inputs, or by means of an explant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.

When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the capsule preparation generally comprises lactose and dried corn starch. Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If necessary, some sweeteners and aromatics may be added to the above oral preparations. A fragrance or coloring agent.

When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as the eyes and skin, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs, and the specific description is as follows: :

When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide. For ophthalmic use, the compound can also be formulated into a bone form such as vaseline.

When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not Limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

It should also be noted that the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the patient, the activity of the compound used, the time of administration, the rate of metabolism, the severity of the condition. And the subjective judgment of the doctor. A preferred dosage is from 0.01 to 100 mg/kg body weight per day, and the most preferred dose is from 5 to 10 mg/kg body weight per day.

detailed description

The invention is further illustrated by the following intermediates and examples, these intermediates and The examples are not intended to limit the invention.

The melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected. The ^-NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic instrument. FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.

Intermediate preparation

General procedure for the preparation of 2-aryl-4-methyl-5-hydroxymercaptothiazole from substituted aromatic amides

(a) Add 211111101?^ to 100 ml of dry toluene. 20 mmol of NaHC0 ₃ , then the reaction mixture was heated to reflux for 30 min. 10 mmol of amide was added to the reaction mixture, and the reaction was complete after 1 h. The reaction mixture was filtered, and the filtrate was concentrated and evaporated to silica gel eluting

(b) 1 mmol of the substituted thioaromatic formamide, ll mmol of ethyl 2-chloro-3-oxobutanoate (available from ACR0S) were added to 100 ml of ethanol, and the reaction mixture was heated to reflux for 12-24 hours. The reaction mixture was concentrated, and then purified to silica gel eluted elution elution

(c) A solution of 10 mmol of (2-substituted aryl-4-methylthiazol-5-yl)carboxylate in 100 ml of dry tetrahydrofuran was added dropwise to ll mmol of lithium aluminum hydride at 30 ° C in 30 ml of dry tetrahydrofuran. In the reaction mixture, after the dropwise addition is completed, the reaction is carried out at room temperature for 2-4 hours, and then a little water, a 15% aqueous sodium hydroxide solution and water are added dropwise to the reaction mixture to terminate the reaction, dried over anhydrous magnesium sulfate, filtered, and evaporated to give the product 2 -Aryl- 4-methyl- 5-hydroxymethylthiazole.

Intermediate 1 2 -Phenyl-4-indolyl-5-hydroxymethylthiazole

The title compound was prepared from benzamide as a crude material.

MS [Ml = 206. 0 m/e; 'H-NMR (400 MHz, DMSO) δ 7. 89 - 7. 87 (m, 2H), 7. 50 - 7. 44 (m, 3H) , 5. 55 (t, 1H), 4. 64 (d, 2H), 2. 35 (s, 3H).

Intermediate 2 2-(p-Trifluoromethylphenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared using p-trifluoromethylbenzamide as a crude material. Rap: 120. 5 ~ 122 °C

MS [Ml = 274. 0 m/e; 'H-NMR (400 MHz, DMSO) δ 8. 10 (d, 2H) 7. 83 (d, 2H), 5. 66 (t, 1H), 4. 67 (d, 2H), 2. 37 (s, 3H).

Intermediate 3 2-(p-Bromophenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared using p-bromobenzamide as a crude material.

MS [Ml -285. 0 m/e; !H-NMR (400MHz, DMSO) δ 7. 82 (d, 2H) 7. 67 (d, 2H), 5. 58 (t, 1H), 4. 63 (d, 2H), 2. 34 (s, 3H).

Intermediate 4 2-(p-Fluorophenyl)-4-methyl-5-hydroxyindolethiazole

The title compound was prepared using p-fluorobenzamide as a crude material. MS [Ml = 224.0 m/e

Intermediate 5 2-(p-methoxyphenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared using p-methoxybenzamide as a crude material. MS[M+]-236.0 m/e

Intermediate 6 2- (3, 5-Dimethoxyphenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared from 3,5-dimethoxy phthalamide as a crude material. MS[M+]=266.0 m/e

Intermediate 7 2- (2,4-dichlorophenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was obtained as a crude material. MS[M+]=274.0 m/e

Intermediate 8 2-(p-T-Butylphenyl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared from p-tert-butyl benzamide as a general procedure A to give a pale yellow solid. MS [M+] = 262. 0 ra/e

Intermediate 9 2-(Thien-2-yl)-4-methyl-5-hydroxydecylthiazole

The title compound was prepared using 2-thiophenecarboxamide as a crude material. MS [Ml = 212. 0 m/e

Intermediate 10 2-(Thien-3-yl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared using 3-thiophenecarboxamide as a crude material. MS [M+] = 212. 0 m/e

Intermediate 11 2-(Naphthalene-2-yl)-4-methyl-5-hydroxymethylthiazole

The title compound was prepared from 2-naphthylcarboxamide as described in General procedure A to give a pale yellow solid. MS [M+] -256. 0 m/e

Intermediate 12 2-(3,4-Methylenedioxyphenyl)-4-methyl-5-hydroxymethyl thiophene

The title compound was prepared as a crude yd. MS [Ml =250.0 m/e

, 3-oxazole-4-yl)-ethanol

Methyl 4-bromo-3-oxo-pentanoate (23.2 g, 0.11 mol) and benzamide (20. lg, 0.17 mol) were dissolved in 160 mL of toluene and heated to reflux for 20 hours. Concentration, the obtained crude product was obtainedjjjjjjjjjjjjjjjjj 4-yl)-methyl acetate 5.6 g, yield 22%.

2-(5-Methyl-2-phenyl- 1,3-oxazol-4-yl)-acetic acid methyl ester (2.3 g, 10 mmol) was dissolved in 16 mL of THF and added dropwise to LiAlH _{4 at} 0 ° C ( 0.38 g, 10 mmol) in a suspension of 1⁄4 L THF. Stir at room temperature overnight. To the reaction liquid, 0.4 mL of water, 0.4 mL of a 15% aqueous NaHH solution, 1.2 mL of water, and a spoonful of anhydrous magnesium sulfate were added carefully. Filtration and concentration of the filtrate gave 1.6 g of 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethanol as a pale yellow solid. MS[M ⁺ 〗 = 204.0 m/e; 'H-NMR (400MHz, CDC 1 ₃ ) δ 7.99 ~ 7.78 (m, 2H) , 7.43 - 7.42 (m, 3H), 3.94 (t, 2H), 2.74 ( t, 2H), 2.34 (s, 3H).

Preparation of 4-[(2-aryl-4-methyl-1,3-thiazol-5-yl)-methoxy]-aniline from 2-aryl-4-methyl-5-hydroxymethylthiazole General operation B

(i) 2-aryl-4-methyl-5-hydroxymethylthiazole (5 legs ol) was dissolved in 20 ml of dry chloroform, and ⁵ ml of S0C1 _{2 was} added dropwise thereto, and the mixture was refluxed for 3 to 5 hours and then distilled under reduced pressure. To the dry, the product is ready for use.

(ii) To a 50 ml round bottom flask, p-nitrophenol (6 mmol), cesium carbonate (7.5 awake) and 20 ml of dry acetonitrile were added, and the reaction product of the step (i) was slowly added dropwise thereto with stirring, and allowed to react at room temperature overnight. After filtration, the concentrated crude product was purified by silica gel chromatography eluting

(iii) Dissolving the reaction product of step (ii) in 30 ml of hot absolute ethanol, adding a small spoon of Raney Ni, adding hydrazine hydrate (20 mmol) dropwise, heating and refluxing for 0.5-1 hour, cooling, filtering, and spinning the filtrate. Dry is 4-[(2-aryl-4-methyl-1,3-thiazol-5-yl)-methoxy]-phenylamine.

Intermediate 14 4- ^[(2 - phenyl - ⁴ - methyl - -1, ³ - thiazol-5 - yl) - methoxy] - phenylamine

The title compound was prepared using Intermediate 1 as a crude material. MS [M ⁺ ]=297.0 m/e Intermediate 15 4- [(2-(p-)-trifluoromethylphenyl)-4-methyl-1,3-thiazol-yl)-methoxy]-aniline

The title compound was prepared from Intermediate 1 using crude material as a crude brown solid. MS [M = 365.0.0 m/e

Intermediate 16 4- [(2 -(p-Bromophenyl)-4-indolyl-1,3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared from Intermediate 3 using crude material as a crude material. MS[M+]=376.0 m/e

Intermediate 17 4- [(2-(p-fluorophenyl)-4-methyl-1,3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared from Intermediate 4 using mp. MS[M+]=315.0 m/e

Intermediate 18 4- [ (2-(p-methoxyphenyl)-4-indolyl-1,3-thiazole-5-yl)-methoxy]-aniline The title compound was prepared using Intermediate 5 as a crude material. MS [M ⁺ ] -327. 0 ra/e

Intermediate 19 4- [ (2-(3, 5-Dimethoxyphenyl)-4-methyl-1, 3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared using Intermediate 6 as a crude material. MS [M ⁺ ] = 357. 0 m/e

Intermediate 20 4- [ (2-(2, 4 -Dichlorophenyl)-4-methyl- 1, 3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared using Intermediate 7 as a crude material. MS [M = 366. 0 m/e

Intermediate 21 4- [ (2-(p-tert-Butylphenyl)-4-methyl-1,3-thiazole-5-yl)-methoxy]-aniline

The title compound is prepared from Intermediate 8 as described in General Procedure B. Gray solid. MS[M+]=353.0 m/e

Intermediate 22 4-[(2-(Thien-2-yl)-4-methyl-1, 3-thiophene

Methoxy]-aniline

The title compound was prepared using Intermediate 9 as a crude material. MS[M+]=303.0 m/e

Intermediate 23 4- [(2-(Thien-3-yl)-4-methyl- 1, 3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared using Intermediate 10 as a crude material. MS[M+]=303.0 m/e

Intermediates 24 4- [ (2-(Cai-2-yl)-4-methyl-1, 3-thiazole-5-yl)-methoxy]-aniline

The title compound was prepared from Intermediate 11 using crude material as a crude material. MS[M+]=347.0 m/e

Intermediate 25 4- [ (2-(3, 4-Methylenedioxyphenyl)-4-methyl-1,3-thiazol-5-yl)-methoxy]-aniline The title compound was prepared using Intermediate 12 as a crude material. MS[M ⁺ ]=341.0 iii/e

Intermediate 26 4-[2-( ² -Phenyl-5-methyl-1,-3-oxazole-4-yl)-ethoxy]-aniline

Intermediate 13 (1.01 g, 5 leg ol), p-nitrophenol (0.97 g, 7 mmol), triphenylphosphine ( ^2. g, 10 mmol) were dissolved in dry tetrahydrofuran (20 mL) and DEAD (1.74) g, lOmmol) in tetrahydrofuran (20 ml). Stir at room temperature for 20 hours. The residue was purified by EtOAcjjjjj elut elut

The obtained yellow solid was dissolved in 30 ml of hot anhydrous ethanol, and a small spoon of Raney Ni was added thereto, and 1. ml of 85% hydrazine hydrate (20 mmol) was added dropwise, and the mixture was refluxed for 1 hour, cooled, and filtered to obtain a light gray solid. - [2-(2-Phenyl-5-methyl- 1, 3-oxazole-4-yl)-ethoxy]-phenylamine. MS [Ml = 295.0 m/e Example 1: N-{4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)-methoxy]-phenyl}-grass Amino acid

0. 3g (1. Olmmol) of intermediate 14 and 0.13g of triethylamine was dissolved in 10ml of dry dichloromethane, cooled to 0 ° C, then added 0.15g (l. lmmol) of oxalyl chloride monoethyl ester (purchased from ACR0S) A solution in 5 ml of dichloromethane. After the reaction was stirred for 5 hours, the reaction was quenched with water and extracted with ethyl acetate. The extract was concentrated and then purified on silica gel column (hexane/ethyl acetate (please give ratio)) to obtain N-{4-[(4- Methyl-2-phenyl-1, 3-thiazole-5-yl)-methoxy]-phenyl}-oxalyl ethyl ester 0.33 g, yield 82.5%.

The obtained -{4-[(4-methyl-2-phenyl- 1, 3-thiazol-5-yl)-methoxy]-phenyl}-oxalyl ethyl ester 0.33 g was dissolved in 10 ml of tetrahydrofuran In a mixed solvent of 5 ml of water, 0.85 ml (lraol/L) of NaOH aqueous solution was added, and the reaction was stirred for 0.5 hour, and then acidified with dilute hydrochloric acid to a neutral pH. Water was added and filtered to give a pale yellow solid N-{4- [ (4-methyl-2-phenyl-1,3-thiazole-5-yl)-methoxy]-phenyl}-oxalyl 0.29 g, yield 94.6%.

MS [M ⁺ ]= 369. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) δ 10.38 (s, 1H,), 7.90 ~ 7.88 (m, 2H), 7.74 (d, 2H), 7.47 ( m, 3H), 7.01 (d, 2H), 5.29 (s, 2H), 2.43 (s, 3H) Example 2: N-(4-{[4-methyl-2-(4-trifluoromethyl) Phenyl)- 1, 3-thiazole-5-yl]-methoxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 15 to give N-(4-{[4-methyl-2-(4-trifluoromethylphenyl)- 1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalysine.

MS [M ⁺ ] = 437.0 m/e; 'H-NMR (400 MHz, DMS0-d ₆ ) δ 10.31 (s, 1H), 8.09 (d, 2H), 7.82 (d, 2H), 7.76 (d, 2H) ), 7.01 (d, 2H), 5.31 (s, 2H), 2.45 (s, 3H) Example 3: N-(4-{[4-methyl-2-(4-bromophenyl)-1, 3-thiazole-5-yl]-methoxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 16 to give N-(4-{[4-methyl-2-(4-bromophenyl)-1 as a pale yellow solid. 3-thiazole-5-yl]-methoxy}-phenyl)-oxalysine. MS [M ⁺ ]= 448. Om/e; Ή-NMR (400MHz, DMSO-d ₆ ) δ 14.13 (s, 1H), 10.67 (s, 1H), 7.85 (d, 2H), 7.70 (m, 4H ), 7.03 (d, 2H), 5.31 (s, 2H), 2.44 (s, 3H) Example 4: N-(4- { [4-indolyl-2-(4-fluorophenyl)-1, 3-thiazole-5-yl]-decyloxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to an intermediate.

17, a pale yellow solid of N-(4-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-grass Amino acid.

MS[M ⁺ ]= 387. Om/e; 'H-NMR (400MHz, DMS0-d ₆ ) δ 10.97 (s, 1H), 10.32 (s, 1H), 7.94 (q, 2H), 7.74 (d, 2H), 7.31 (t, 2H), 7.01 (d, 2H), 5.28 (s, 2H), 2.42 (s, 3H) Example 5: N- (4- {[4-methyl- 2- (4 -methoxyphenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxaline

18, N-(4-{[4-methyl-2-(4-methoxyphenyl)-1,3-thiazolyl-5-yl]-methoxy}-phenyl) as a pale yellow solid - oxamate.

MS [Ml = 399. lm/e; 'H-NMR (400MHz, DMS0-d ₆ ) δ - 14.11 (brs, 1H), 10.63 (s, 1H) , 7.83 (d, 2H), 7.70 (d, 2H ), 7.03 (m, 4H), 5.27 (s, 2H), 3.82 (s, 3H), 2.41 (s, 3H) Example 6: N-(4-{[4-methyl- 2-(3, 5-dimethoxyphenyl)-1,3-thiazole-5-yloxy-methoxy}-phenyl)-oxalysine

19, a pale yellow solid of 1^(4-{[4-methyl-2-(3,5-dimethoxybenzene) Base)-1, 3-thiazole-5-yl]-methoxy}-phenyl)-oxalysine.

MS[M ⁺ ]= 429. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) δ - 14.08 (brs, 1H), 10.64 (s, 1H), 7.70 (d, 2H), 7.04 ~ 7.01 ( m, 4H), 6.61 (t, 1H), 5.30 (s, 2H), 3.81 (s, 6H), 2.44 (s, 3H) Example 7: N-(4 - {[4-methyl-2- (2,4-dichlorophenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 20 to give N-(4-{[4-methyl-2-(2,4-dichlorophenyl)- 1,3 -thiazole-5-yl]-methoxy}-phenyl)-oxalyl.

MS[M ⁺ ]= 437. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) δ - 14.06 (brs, 1H), 10.64 (s, 1H), 8.22 (d, 1H), 7.83 (d, 1H), 7.70 (d, 2H), 7.58 (dd, 1H), 7.05 (d, 2H), 5.35 (s, 2H), 2.47 (s, 3H) Example 8: N- (4- {[4 - Methyl-2-(4-tert-butylphenyl)-1,3-thiazol-5-yl]-methoxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 21 to give (4-{[4-methyl-2-(4-tert-butylphenyl)-1) as a pale yellow solid. 3-thiazole-5-yl]-methoxy}-phenyl)-oxalysine.

MS [M ⁺ ] = 425. Om/e; 'H-NMR (400MHz, DMS0-d ₆ ) δ 10.22 (brs, 1H), 7.81 (d, 2H), 7.74 (d, 2H), 7.49 (d, 2H), 6.99 (d, 2H), 5.26 (s, 2H), 2.41 (s, 3H), 1.30 (s, 9H) Example 9: N- (4- {[4-methyl-2- (thiophene) -2-yl)- 1,3-thiazol-5-yl]-methoxy}-phenyl)-oxalysine Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 22 to give (4-{[4-methyl-2-(thiophen-2-yl)-1, 3-thiazole as a pale yellow solid. -5-yl]-methoxy}-phenyl)-oxalysine.

MS [Ml = 375. Om/e; Ή-NMR (400MHz, DMSO-d ₆ ) δ - 14.10 (brs, 1H), 10.64 (s, 1H), 7.71 - 7.69 (m, 3H), 7.62 (dd, 1H), 7.15 (dd, 1H), 7.03 (d, 2H), 5.28 (s, 2H), 2.39 (s, 3H) Example 10: N- (4-{[4-methyl-2- (thiophene) -3-yl)- 1, 3 -thiazol-5-yl]-methoxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 23 to give N-(4-{[4-methyl-2-(thiophen-3-yl)-1,3 as a pale yellow solid. -thiazol-5-yl]-decyloxy}-phenyl)-oxalysine.

MS [Ml = 375. Om/e; 'H-NMR (400MHz, DMS0-d ₆ ) δ - 14.10 (brs, 1H), 10.64 (s, 1H), 8.10 (dd, 1H), 7.71 ~ 7.68 (m , 3H), 7.54 (dd, 1H), 7.02 (d, 2H), 5.28 (s, 2H), 2.41 (s, 3H) Example 11: N- (4- {[4-methyl-2- ( Cai-2-yl)-1,3-thiazol-5-yl]-methoxyphenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 24 to give N-(4-{[4-methyl-2-(Cai-2-yl)-1, 3 as a pale yellow solid. -thiazole-5-yl]-methoxy}-phenyl)-oxalysine.

S[M ⁺ ]= 419. Om/e; ^-NMR (400MHz, DMSO-d ₆ ) δ - 14.10 (s, 1H), 10.65 (s, 1H), 8.10 ~ 7.95 (m, 4H), 7.71 ( d, 2H), 7.59 (m, 4H), 7.06 (d, 2H), 5.34 (s, 2H), 2.48 (s, 3H) Example 12: N-(4-{[4-Mercapto-2-(1,3-benzodioxole-5-yl)-1,3-thiazole-5-yl]-A Oxy}-phenyl)-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 25 to obtain N-(4-{[4-mercapto-2-(1,3-benzo)dioxole as a pale yellow solid. Cyclopentene-5-yl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxaline.

MS[M ⁺ ]= 413. Om/e; NMR (400MHz, DMS0-d ₆ ) δ - 14.10 (s, 1H), 10.64 (s, 1H), 7.70 (d, 2H), 7.44 ~ 7.41 (m, 2H), 7.04 ~ 7.00 (m, 3H), 6.11 (s, 2H), 5.27 (s, 2H), 2.40 (s, 3H) Example 13: N- {4- [2- (5-methyl- 2-phenyl- 1, 3-oxazol-4-yl)-ethoxy]-phenyl}-oxaline

Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 26 to give N-{4-[2-(5-methyl-2-phenyl-1, 3-oxazole) as a pale yellow solid. 4-yl)-ethoxy]-phenyl}-oxalysine.

MS [Ml = 367. Om/e; 'H-NMR (400MHz, DMS0-d ₆ ) δ ~ 14.10 (brs, 1H), 10.66 (s, 1H), 7.92 - 7.90 (m, 2H), 7.74 (d , 2H), 7.51 ~ 7.48 (m, 3H), 7.00 (d, 2H), 4.14 (t, 2H), 2, 35 - 2.30 (m, 5H) Transfection assay:

The functional effects of transient transfection of compounds in 293-T cells were screened to determine their ability to activate PPAR subtypes. The effect of the receptor subtype on the transcriptional activity of the same target gene was compared using a pre-established chimeric receptor system, and Rluc was used as an internal standard to reduce endogenous effects. Human PPAR α, PPAR γ and PPAR δ ligand binding domains are each The yeast transcription factor GAL4 DNA binding domain is fused. Then, the mammalian expression vector pM was ligated, and three plasmids pM-hPPAR ot /GAL4, pM-PPAR γ /GAL4 and pM-PPAR 5 /GAL4 were constructed. The GAL4 DNA binding region was ligated to pB4-tk-luc to constitute PB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4 DNA binding site). Transfection efficiency and endogenous effects were corrected using pRL-CMV-R luc as an internal standard.

293-T cells were seeded into 48-well plates at a cell density of 2 - 4 χ 10 ⁴ /well, and the culture medium was 10% non-fat fetal bovine serum (FCS) in phenol red free antibiotic-free 1640 medium. After 48 hours, the culture medium was changed to 5% defatted FCS phenol red-free antibiotic-free 1640 medium, and then three subtypes of pM-hPPAR/GAL4, pB4-RES-tk-luc and pRL-CMV-, respectively. Three plasmids of Rluc were co-transfected into 293-T cells, and the test compound was added 24 hours later, and the intensity of luciferase was measured 24 hours after the addition of the compound. 0%. DMS0 was used as a blank control. The agonistic effect of some compounds on PPAR (Ι Ο μ Μ )

PPAR a PPAR γ PPAR 6

Compound photon number increase magnification photon number increase magnification photon number increase

( X 10 ⁵ ) Number ( X 10 ⁵ ) Number ( X 10 ⁴ ) Number comparison 1. 05 1. 49 3. 50

Example 1 ― ― ― ― 5. 22 1. 49 Example 3 2. 72 2. 59 ― . 6. 96 1. 99 Example 7 1. 19 1. 13 ― 6. 61 1. 89 Example 8 ― ― ― 一 5. 56 1. 59 Example 9 ― 一― ― 8. 89 2. 54 Example 10 ― ― ― ― 9. 29 2. 66 Example 11 ― ― ― ― 6. 94 1. 98 Example 13 3. 13 2. 98 4. 65 3. 12 9. 49 2. 71

Claims

Compounds of formula I:

And pharmaceutically acceptable salts and solvates thereof, wherein:

An alkyl group selected from H, straight or branched, and optionally substituted on the phenyl ring

- 5 benzyl groups substituted with a substituent selected from the group consisting of: -3⁄4, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d-C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, d-( ₄ alkoxy, C ₂ -(enyloxy, phenoxy, benzyloxy, nitrile, carboxy and amino;

R ₂ and R _{3 are} independently selected from H, -(^ straight and branched alkyl, halo, C ₂ -C ₆ straight and branched alkenyl, and C ₃ -C ₆ cycloalkyl ;

R _{4 is} selected from the group consisting of d-( ₄ linear and branched alkyl, halogen, d-C ₃ alkoxy, trifluoromethyl, trifluoromethoxy and nitrile;

m is 0, 1, 2, 3 or 4;

X is a 0 or S atom;

n is 1, 2, 3 or 4;

One of Y and Z is N and the other is S or 0;

Ar is selected from the group consisting of a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring and a heterocyclic group, wherein each ring consists of 5-6 ring atoms, and the heterocyclic group includes 1-4 selected from 0, S and a hetero atom of N; may be unsubstituted on the ring or may be substituted with from 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC ₆ straight and branched alkyl, C ₂ -C ₆ straight and branched alkenyl, d-(^ alkoxy, 0 ₂ -( ₄ alkenyloxy, phenoxy, benzyloxy, nitrile , carboxyl and amino groups.

2. A compound according to claim 1 which is a compound represented by the formula π, which comprises pharmaceutically acceptable salts and solvates thereof,

II

among them:

R _{3 is} selected from the group consisting of H, d-( ₆ straight and branched alkyl, halogen, C ₂ -C ₆ straight and branched alkenyl, and C ₃ -C ₆ cycloalkyl;

a linear and branched alkyl group selected from d-C ₄ , a halogen, a d-Cs alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, and a nitrile group;

m is 0, 1, 2, 3 or 4;

X is a 0 or S atom;

n is 1, 2, 3 or 4;

One of Y and Z is N and the other is S or 0;

Ar is selected from the group consisting of a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring and a heterocyclic group, wherein each ring consists of 5 to 6 ring atoms, and the heterocyclic group includes 1 to 4 selected from 0, S and Heteroatoms of the oxime; the ring may be unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC ₆ Linear and branched alkyl, C ₂ -C ₆ straight and branched alkenyl, d-c ₄ alkoxy, c ₂ -c ₄ alkenoxy, phenoxy, benzyloxy, nitrile, carboxy And amino groups.

3. A compound as claimed in claim 2, wherein R ₃ is methyl.

4. A compound according to any one of claims 1 to 3 which is selected from the group consisting of:

N- {4-[(4-methyl-2-phenyl- 1, 3-thiazol-5-yl)-methoxy]-phenyl}-oxalyl;

N-(4-{[4-indolyl-2-(4-trifluorodecylphenyl)-1, 3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-indolyl-2-(4-bromophenyl)-1,3-thiazole-5-yl]-methoxy]-phenyl)-oxalyl;

N-(4- { [4-methyl-2-(4-fluorophenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-methyl-2-(4-methoxyphenyl)-1,3-thiazole-5-yl]-methoxy)-phenyl)-oxalyl;

N-(4- { [4-methyl-2-(3, 5-dimethoxyphenyl)-1, 3-thiazole-5-yl]-decyloxy}-phenyl)-oxaline ;

N-(4-{[4-methyl-2-(2,4-dichlorophenyl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-indolyl-2-(thiophen-2-yl)-1, 3-thiazole-5-yl]-decyloxy}-phenyl)-oxalyl;

N-(4-{[4-methyl-2-(thiophen-3-yl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

N-(4-{[4-methyl-2-(naphthalen-2-yl)-1,3-thiazole-5-yl]-methoxy}-phenyl)-oxalyl;

11- (4- { [4-methyl-2-(1,3-benzodioxole-5-yl)-1,3-thiophene Azul-5-yl]-methoxy}-phenyl)-oxalysine;

N- {4- [2-(5-methyl-2-phenyl- 1, 3-oxazole-4-yl)-ethoxy]-phenyl } - oxa

And pharmaceutically acceptable salts and solvates thereof.

The compound according to any one of claims 1 to 4, wherein the compound activates hPPAR.

A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

7. A method of preparing a compound of any one of claims 1 to ⁵ , comprising:

1) reacting a compound of the formula 与 with a substituted p-nitrophenol or a substituted p-nitrophenylthiophenol in the presence of a base such as cesium carbonate, potassium carbonate or sodium hydroxide to obtain a compound of the formula V; a compound of formula IV is reacted with a substituted p-nitrophenol or a substituted p-nitrophenylthiophenol in the presence of DEAD and PPh _{3 to give} a compound of formula V,

Wherein W is halogen, and X, Y, Z, R ₃ , R ₄ , m, n and Ar are as defined in claim 1;

2) The compound of formula V is reduced with Raney Ni and hydrazine hydrate to give a compound of formula VI,

Wherein X, Y, Z, R ₃ , , m, n and Ar are as defined in claim 1;

3) reacting a compound of formula VI with a compound of formula VI I to give a compound of formula I wherein R ₂ is H, optionally wherein said compound of formula I wherein R ₂ is H and (wherein R _{2 is} as defined in claim 1 A substitution reaction is defined, except that H is a halogen, and a compound of formula I wherein R _{2 is} not H is obtained,

Wherein, the definition is the same as claim 1 but not H,

Wherein X, Y, Z, R ₂ , R ₃ , , m, n and Ar are as defined in claim 1 with the claim 1 but not H; 4) Optionally, the compound of formula I wherein R, which is not H, obtained in the above 3) is hydrolyzed to obtain wherein ^ is! ! A compound of formula I, which comprises hydrolyzing a compound of formula I wherein R ₂ is H with a base such as sodium hydroxide or potassium hydroxide, or an acid such as dilute hydrochloric acid or trifluoroacetic acid to provide a compound of formula II,

Wherein X, Y, Z, R ₃ , R ₄ , m, n and Ar are as defined in claim 1.

Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of a hPPAR mediated disease, risk factor or condition.

9. The use according to claim 8, wherein the disease, risk factor or condition is dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type I diabetes, type II diabetes, insulin resistance , Diabetes complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, obesity, anorexia, bulimia or bulimia nervosa.