WO2007085136A1 - 1,3-benzodioxolecyclopentene derivates, preparation process and medical uses thereof - Google Patents

Abstract

The present invention relates to compounds of the general formula (I), racemates, or optical isomers, pharmaceutically acceptable salts or solvates thereof, as well as pharmaceutical compositions containing them, in which, each substituent group of general formula (I) is as defined in claims, and also relates to process for their manufacture and to the use of the compounds in preparing medicines to treat and/or prevent various diseases and danger factors associated with human peroxisome proliferate activated receptors(hPPAR).

Description

 Benzodioxole derivatives and their

 Preparation method and medical use

 The present invention relates to a novel benzodioxole derivative capable of activating a human peroxisome proliferator-activated receptor (hPPAR), a process for preparing the same, a pharmaceutical composition comprising the above compound, and Use of the compounds for 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 PP AR) 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, PPARs have been found to have three subtypes: alpha, 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: _γι , γ ₂ , which differ only in the terminal sequence (Vida Bu 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.

PPARa is mainly expressed in tissues with very high catabolic activity in lipids such as brown adipose tissue and liver, followed by kidney, heart and skeletal muscle (Endocnnology, 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. , Al l , CI II) gene expression. ΡΡΑΙΙγ is mainly found in adipose tissue, and is also present in small amounts in skeletal muscle, liver, colon, retina, and immune system. Recent findings also suggest that it is highly expressed in macrophages, including atherosclerotic foam cells. Its Among them, PPAR is mainly expressed in adipose tissue, while PPAR _yi is found in various tissues and has the highest expression in kidney, intestine and heart. ΡΡΑΙΙγ major regulation involves adipocyte differentiation and expression of insulin-sensitive genes (L Lipid. Res., 1996, 37, 907). PPARS is widely distributed and expressed in many tissues, with the highest expression in the intestine, kidney and heart. Activation of PPARS has been shown to cause an increase in HDL levels, a decrease in LDL and VLDL levels.

 Thiazolidinediones such as troglitazone and rosiglitazone have been clinically 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 ΡΡΑΙγ and bind directly to ΡΡΑΙΙγ receptors (L M. Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)).

 Firbrates have been widely used as therapeutic agents for hyperlipidemia, which can lower serum triglycerides (20-50%), LDLc (10-15%), and increase HDLc (10-15%). ). Experiments have shown that the effect of f ibrates on serum lipids is mediated through the activation of PPARa, see for example B. Stael s et al, Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPARa causes transcription of enzymes that increase fatty acid catabolism and reduce the re-synthesis of fatty acids in the liver, causing triglyceride synthesis and reduced VLDL production/secretion. In addition, PPARo activation reduces the production of apoC-I I I. The reduction in apoC-I I I (inhibitor of LPL activity) increases the clearance of VLDL (J. Auwerx et al, Atheroscleros i s, J59-S37, 124 (Suppl), (1996)).

 PPAR involves many biological processes and disease states, including hypercholesterolemia, dyslipidemia and diabetes. However, current drugs are not ideal due to toxic side effects, etc. Therefore, a safe and effective PPAR agonist is needed. Optionally activate a subtype or activate multiple subtypes simultaneously. Summary of the invention

The object of the present invention is to find and develop a small molecule with PPAR agonistic activity Compound for the treatment of hPPAR-mediated diseases, risk factors or conditions such as dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type 1 diabetes, type II diabetes, insulin resistance , Diabetes complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, regulation of appetite and food absorption in patients with obesity, anorexia, bulimia and anorexia nervosa.

 The present inventors have discovered that compounds of formula I are useful in the treatment or prevention of a variety of diseases, risk factors or conditions mediated by hPPAR.

 Thus, in one aspect, the invention provides a compound of formula I, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

其中：

among them:

a linear or branched alkyl group selected from H, dC ₆ , optionally a benzyl group substituted by one or more on the phenyl ring, said substituent being selected from a linear or branched alkoxy group of (^) d - c a straight-chain or branched-chain alkyl group of _6, c ₂ - C ₆ alkenyl group, linear or branched, c ₃ - C ₆ cycloalkyl, halogen, nitrile, trifluoromethyl, trifluoromethoxy a Oxylate

R _{2 is} selected from H, halogen, linear or branched alkyl of dC ₆ , C ₂ - C ₆ straight or branched alkenyl, C ₃ -cycloalkyl, 5- to 6-membered aromatic carbocyclic or aromatic a ring, the aromatic heterocyclic ring containing 1 to 3 hetero atoms selected from 0, S, N, and the aromatic carbocyclic ring or aromatic heterocyclic ring may be optionally substituted by 1 to 5 substituents selected from the group consisting of: , nitro, hydroxy, hydroxydecyl, trifluoromethyl, trifluoromethoxy, dC ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, Ci-C alkoxy , C ₂ - (alkenyloxy, phenoxy, benzyloxy, carboxy or amino;

m and n are each independently selected from 0, 1, 2, 3, 4, 5 and 6; Xi, X ₂ and X ₃ are each independently absent or are 0, S, NR ₃ , NR ₄ C(=0), S0, S(0) ₂ , C0, C(=N-0R ₅ ), CH ( 0R ₆ ), (CH ₂ ) _Y , C=C, C≡C, wherein R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from a hydrogen atom or a linear or branched alkane of d-C ₆ Base, γ is selected from 1, 2 and 3;

A is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 selected from 0, N a hetero atom of S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoro Methoxy, d-C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, d-alkoxy, C ₂ -C ₄ alkenoxy, phenoxy, benzyloxy Base, carboxyl or amino group;

Ar _{2 is} selected from a H atom, an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 a hetero atom selected from 0, N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted with 1 to 5 substituents selected from the group consisting of: 3⁄4, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d-C ₆ straight or branched alkyl, -(^ straight or branched alkenyl, d-alkoxy Base, C ₂ -C ₄ alkenyloxy, phenoxy, benzyloxy, carboxy or amino.

 In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the invention, which comprises at least one compound of formula I, its racemate or optical isomer or a pharmaceutically acceptable salt or solvate thereof And one or more pharmaceutically acceptable carriers or excipients.

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

 In yet another aspect, the invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment and/or prevention of a hPPAR mediated disease or condition.

In a further aspect, the invention provides a method of treating and/or preventing a hPPAR mediated disease, risk factor or disorder comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention. The hPPAR-mediated diseases, risk factors or conditions described in the present invention include dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type I diabetes, type II diabetes, insulin resistance, Diabetes complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, regulation of appetite and food absorption in patients with obesity, anorexia, bulimia and anorexia nervosa.

 In one embodiment of the invention, the invention provides a compound of formula I, a racemate or an optical isomer thereof, a pharmaceutically acceptable salt or solvate thereof:

I

a straight or branched alkyl group selected from H, dC ₆ , optionally substituted or substituted with a benzyl group on the phenyl ring, said substituent being selected from a linear or branched alkoxy group, d-c a straight-chain or branched-chain _alkyl group, alkenyl group c ₂ C ₆ straight-chain or a branched chain, c ₃ - cycloalkyl, halogen, nitrile, trifluoromethyl, trifluoromethoxy Yue group;

R _{2 is} selected from H, halogen, d-C ₆ linear or branched alkyl, -(: ₆ straight or branched alkenyl, C ₃ -cycloalkyl, 5- to 6-membered aromatic carbocyclic or aromatic A heterocyclic ring, the aromatic heterocyclic ring comprising 1 to 3 hetero atoms selected from 0, S, N, and the aromatic carbocyclic ring or aromatic heterocyclic ring may be optionally substituted with 1 to 5 substituents 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 - C ₄ methoxy, 0 ₂ -(^-alkenyloxy, phenoxy, benzyloxy, carboxy or amino;

 m and n are each independently selected from 0, 1, 2, 3, 4, 5 and 6;

, X ₂ and X ₃ are each independently absent or are 0, S, NR ₃ , NR ₄ C (=0), S0, S(0) ₂ , C0, C(=N-0R ₅ ), CH(0R ₆ ), (CH ₂ ) _Y , C=C, C≡C, where R ₃ , R ₄ , R ₅ and R _{6 is} each independently selected from a hydrogen atom or a linear or branched alkyl group of d-C ₆ , and Y is selected from 1, 2 and 3;

Is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be monocyclic, bicyclic or tricyclic; each ring is composed of 5-6 atoms, and the aromatic heterocyclic ring includes 1-4 selected from 0, N, a hetero atom of S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted by from 1 to 5 substituents selected from the group consisting of: 素, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethyl Oxy, dC ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, oxy, 0! ₂ -( ₄ alkenyloxy, phenoxy, benzyloxy, carboxy or amino Ar _{2 is} selected from the group consisting of a halogen atom, an aromatic carbon ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 a hetero atom selected from 0, N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted with from 1 to 5 substituents selected from the group consisting of: ?3⁄4, nitro, hydroxy, hydroxy oxime , trifluoromethyl, trifluoromethoxy, straight or branched alkyl, C ₂ - straight or branched alkenyl, d-oxy, C ₂ -C ₄ alkenyl, phenoxy, Benzyloxy, carboxy or amino.

 According to the present invention, examples of the term "aromatic carbocyclic ring" include, but are not limited to, benzene, naphthalene, anthracene, phenanthrene, 1, 3-benzodioxole, hydrazine, hydrazine, hydrazine.

 According to the invention, examples of the term "aromatic heterocycle" include, but are not limited to, pyridine, pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, oxazole, isoxazole, hydrazine, benzofuran, benzimidazole, hydrazine Azole, oxime, pyrimidine, pyrocoat, quinoline, isoquinoline, indole, phenoxazine, phenoxazine.

In a preferred embodiment of the invention, the invention provides a compound represented by the formula ,, including the racemate or optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof:

 II

 among them:

 m, n are independently selected from 0, 1, 2, 3, 4, 5 and 6;

, X ₂ and X ₃ are each independently absent or are 0, S, NR ₃ , NR ₄ C(-0), S0, S(0) ₂ , C0, C(=N-0R ₅ ), CH(0R ₆ ), (CH ₂ ) _Y , C=C, C≡C, wherein R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from a hydrogen atom or a linear or branched alkyl group of d-C ₆ , Y is selected from 1, 2 and 3;

A is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a silent ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1-4 selected from 0, a hetero atom of N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, three Fluoromethoxy, dC ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, d-alkoxy, C ₂ - ( ₄ alkenyloxy, phenoxy, benzyloxy , carboxyl or amino;

Ar _{2 is} selected from a H atom, an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 a hetero atom selected from 0, N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted with from 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxydecyl, trifluoro Methyl, trifluoromethoxy, dC ₆ straight or branched alkyl, 0 ₂ -(: ₆ straight or branched alkenyl, oxy, C ₂ -C ₄ alkenoxy, phenoxy, benzyl Oxy, carboxyl or amino.

 Preferred compounds of the invention include:

2-{5-[(4-methyl-2-phenyl- 1, 3-thiazol-5-yl)-methylthio]-1,3-benzodioxole}-acetic acid;

2-(5- { [4-mercapto-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl]-methyl sulfide }}-1,3-benzodioxole)-acetic acid;

 2-(5- {[4-mercapto-2-(4-bromophenyl)-1,3-thiazol-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;

 2-(5-{[4-methyl-2-(4-fluorophenyl)-1,3-thiazole-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;

 2-(5- {[4-Methyl-2-(4-.methoxyphenyl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzodioxane Heterocyclopentene)-acetic acid;

 2-(5- { [4-methyl-2-(3,5-dimethoxyphenyl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzophenan Dioxol)-acetic acid;

 2-(5- {[4-Methyl-2-(2,4-dichlorophenyl)- 1, 3-thiazole-5-yl]-indolyl}- 1, 3-phenyl-dioxy Heterocyclopentene)-acetic acid;

 2-(5- { [4-methyl-2-(4-tert-butylphenyl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzodioxan Cyclopentene)-acetic acid;

 2-(5- {[4-mercapto-2-(thiophen-2-yl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzodioxole Alkene)-acetic acid;

 2-(5- {[4-Methyl-2-(thiophen-3-yl)-1,3-thiazol-5-yl]-methylthio}-1,3-benzodioxole Alkene)-acetic acid;

 2-(5-{[4-methyl-2-(naphthalen-2-yl)-1,3-thiazol-5-yl]-indolyl}-1,3-benzodioxole Alkene)-acetic acid;

 2-(5-{[4-Methyl-2-(1,3-benzodioxole-5-yl)-1,3-thiazol-5-yl]-indenyl}- 1, 3-benzodioxole)-acetic acid;

2-[5-(2- {4- [(4-ethyl)phenyl]phenoxy}ethylthio)-1,3-benzodioxancyclopentene]-acetic acid;

 2-{5-[2-(carbazol-9-yl)ethylthio]-1,3-benzodioxole}-acetic acid; 2-{5-[2-(phenothiazine) -10-yl)ethylthio]-1,3-benzodioxole}-acetic acid;

Or a pharmaceutically acceptable salt or solvate thereof. According to the present invention, the above compound of the formula I and / or formula II or a pharmaceutically acceptable salt or solvate thereof can be prepared by the following method, which comprises the steps of:

1) reacting catechol with sodium thiocyanate in the presence of bromine and sodium bromide to give a compound of formula III, reacting a compound of formula III with triethyl orthoformate to provide a compound of formula IV;

 III IV

其中， A , Ar₂, X₂， X₃， n的定义同通式 I所述， X为卤素， 得到式 VI的化合物， 2) reducing the compound of formula IV with sodium borohydride, followed by reaction with an intermediate of formula V in the presence of a base such as sodium hydroxide, cesium carbonate or potassium carbonate.

Wherein A, Ar ₂ , X ₂ , X ₃ , n have the same meanings as defined in Formula I, and X is a halogen, to give a compound of Formula VI,

 VI

X ₂ , X ₃ , n are as defined for formula I;

3) Deprotecting the compound of formula VI in the presence of p-toluenesulfonic acid to give a compound of formula VII wherein ₁ is 3. 06000373

4) reacting a compound of formula VII with a compound of formula VIII:

 VIII

Wherein 1^ and R _{2 are} as defined in formula I, but Ri is not H, obtaining a compound of formula I wherein m = 1, not H, and S:

其中， Ar , Ar₂， X₂， X₃， n的定义同通式 I。

Wherein, Ar, Ar ₂ , X ₂ , X ₃ , n have the same meanings as in Formula I.

 The synthesis of the compound of the formula VIII used in the above reaction scheme can be referred to: Tetrahedron Letters 1989, 30 (34), 4525-4526.

 The intermediate of formula V used in the reaction scheme can be prepared as follows:

a) When X ₂ is 0, S, NR ₃ , (0=)CNR ", the intermediate of formula V can be prepared as follows

X, _χ

~~ - 严) 其中， Ar^ Ar₂, X₃， n的定义同通式 I， X为卤素。 用二卤代烷烃 a2对原料 al中 X₂杂原子进行烃代反应即得式 V中间体。 b) 当 X₂为 S0,S0₂时， 利用方法 a)中得到的硫醚氧化即得式 V中 间体

~~ - 严) wherein, Ar^ Ar ₂ , X ₃ , n are as defined in the formula I, and X is a halogen. Hydrogenation of the X ₂ heteroatom in the starting material a1 with a dihaloalkane a2 affords the intermediate of formula V. b) When X ₂ is S0, S0 ₂ , the thioether obtained in the method a) is oxidized to obtain the intermediate of the formula V

Wherein, A , Ar ₂ , X ₃ , n are as defined in the formula I, and X is a halogen.

c) When X ₂ is C0, C(=N-0R ₅ ), CH(0R ₆ ) or - R ₄ NC(=0), it can be prepared as follows

 O

 X^义 X

(CH ₂ )r^

.An —— ^ Ar ₂

利用酰 ¾对芳香环 人！： 进行酰化反应， 接着对酮羰基进行相应的 官能团转换即可得 X₂为 C0、 C (=N-0R₅) , CH(0R₆)的式 V中间体； 或者 Χ3

Use acyl 3⁄4 for aromatic rings! : performing an acylation reaction, followed by corresponding functional group conversion of the ketone carbonyl group to obtain an intermediate of formula V wherein X ₂ is C0, C (=N-0R ₅ ) , CH(0R ₆ );

, ^ N

The acylation of an amine group on the aromatic ring Ar with an acyl group gives an intermediate of the formula V wherein X ₂ is - R ₄ NC (=0).

Wherein, A , Ar ₂ , X ₃ , n, R ₄ , R ₅ and R _{6 have} the same meanings as defined in the formula I, and X is a halogen.

d) When X ₂ is absent or is (CH ₂ ) _Y , C=C, C≡C, then the appropriate starting material can be used to synthesize the dl compound according to the actual situation, and then the hydroxyl group in the dl compound can be used for 3⁄4 generations. Formula V intermediate.

Among them, ^ people ^ ^! ! The definition is the same as the general formula ^ X is halogen. Further, the compound of the above formula I can be reacted with an alkali metal hydroxide or with an acid such as dilute hydrochloric acid or trifluoroacetic acid to obtain m = l and ^ as S, by hydrolysis. ^ Compound of formula I which is H:

 I

Wherein, Α _Γι , Ar ₂ , X ₂ , X ₃ , n and R _{2 have} the same meanings as defined in Formula I.

Among the above hydrolyzed products, when R ₂ is H, it is a compound of the formula II wherein m = 1 and 3

 II

Wherein, Α _Γι , Ar ₂ , X ₂ , X ₃ , n have the same meanings as defined in Formula II.

The above is a method for preparing a compound of the formula I and II wherein ₁ is 3, and when it is NR ₃ , NR, C (=0) (the definition of R ₃ and ^ is the same as the formula I), the formula can be prepared as described above. For the I and II compounds, the starting material in the first step is simply changed to the corresponding 4-substituted catechol; the thioether in the intermediate VI is oxidized to the sulfone or sulfoxide, and then the above method can be used. Preparation of compounds of the formulae I and 11 which are S (=0), S (=0) ₂ ; for YES, C(=N-0R ₅ ), CH(0R ₆ ), (CH ₂ ) _Y , C=C , C≡C's general formula The preparation of the compounds of I and II (R ₅ , R ₆ and Y are as defined for the general formula I) requires only the preparation of the compound of the formula VI I, after which the synthetic route is the same as above. Specifically, the synthesis scheme of the compound of the formula I is detailed in the following reaction scheme: Reaction step one:

 (I I I) (IV)

A solution of Br ₂ /NaBr in methanol was slowly added dropwise to 0 of catechol and sodium thiocyanate. (In the sterol reaction solution, after reacting at 0 ° C for 3-4 hours, the reaction was terminated with water, saturated NaHC0 ₃ water was adjusted to near neutral, ethyl acetate was extracted, dried. Filtration, concentration and column separation (eluent: Hexane/ethyl acetate/acetic acid system) gave the compound of formula III as a white solid. The compound of formula III, triethyl orthoformate, acidic ion exchange resin, 4 molecular sieves were refluxed in anhydrous benzene for 72-96 hours, filtered , Concentration, column separation (silica gel for conventional column chromatography with silica gel, particle size 10 - 40 μΐ; eluent: n-hexane / ethyl acetate system) to give the compound of formula IV as a pale yellow oil.

(VI)

Wherein, Α _Γι , Ar ₂ , Χ ₂ , Χ ₃ , η are defined as the same formula I, X is halogen, preferably Br, Cl.

 The compound of the formula IV and sodium borohydride are refluxed in ethanol for 10-15 minutes, then cooled, and the compound of the formula V is added dropwise after adding a base (barium carbonate, potassium carbonate or sodium hydroxide), and the reaction is carried out overnight at room temperature or back to 3- After 8 hours, filtration, concentration, and column chromatography (eluent: hexane/ethyl acetate system) gave compound of formula VI as a yellow oil. Reaction step three:

 (VI I)

 The compound of the formula VI is deprotected with p-toluenesulfonic acid in a methanol/water reaction system, reacted at room temperature for 12-24 hours, concentrated, and separated by column (eluent: chloroform/methanol system) to give a white to yellow formula. VI I compound.

Reaction Step 4:

 I

Using 4-(N,N-dimethylamino)pyridine (DMAP) as a catalyst to formulate VI I The compound is reacted with a compound of the formula VI II in anhydrous acetonitrile or acetone at room temperature for 2-5 hours, concentrated and separated by a column (eluent: n-hexane / ethyl acetate system) to give a pale yellow to yellow oily compound of formula I Wherein, 1, ^ is not 11, ^ is an S atom, Α _Γι , Ar ₂ , X ₂ , X ₃ , R ₂ and n are the same as Formula I.

 Further, the above compound of the formula I wherein m=l, ^ is not H, is an S atom, can be reacted with an alkali metal hydroxide or with an acid such as dilute hydrochloric acid or trifluoroacetic acid for 2-6 hours, and hydrolyzed. A compound of the formula I wherein ra = 1, ^ is S, 1 is H atom.

I

Wherein, Α _Γι , Ar ₂ , X ₂ , X ₃ , n and R _{3 have} the same meanings as in Formula I.

In the above hydrolyzed product, when R ₂ is H, it is a compound of the formula II having m=l and 3

 II

Wherein, Ar^Ar ₂ , X ₂ , X ₃ , n are as defined in the formula II.

Those skilled in the art will recognize that the compound of Formula I or Formula II is present in stereo Heart. When a compound of formula I or formula II is desired as a single enantiomer, it can be prepared using reactants in the form of a single enantiomer in all possible steps, or in the form of a single enantiomer. It is prepared by carrying out the reaction in the presence of a catalyst or by dissolving a mixture of stereoisomers by a conventional method. Some preferred methods include resolution using a microorganism, resolution of a diastereomeric salt formed with any usable acid such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, or the like, or splitting with a hand. Salts of diastereomers formed by alkaloids such as brac ine, cinchona alkaloids and derivatives thereof. A commonly used method is found in "Enant ioraers, Raceraates and Resolution" edited by Jaques et al. (Wiley Intersc ience, 1981).

 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 compounds of formula I include the conventional salts formed with pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and the acid addition salts of quaternary ammonium. Specific examples of suitable acid salts 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, a salt of benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, 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 or pharmaceutically acceptable salts thereof. Specific examples of suitable base salts include sodium, lithium, bell, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene Amine, N-decyl glucosamine and procaine salt. Hereinafter, when referring to the compounds of the present invention, the compounds of formula I, and pharmaceutically acceptable salts and solvates thereof, are included.

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 into the body in vivo. The desired compound of formula (I). Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985.

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

 The compounds of the invention activate the hPPAR receptor, and preferably, the compounds of the invention selectively activate the hPPARa receptor. The agonistic effect of the compound of the present invention on PPAR can be measured by the following method.

 The functional effects of transient transfection of compounds in 293-T cells were screened to determine their ability to activate PPAR isoforms. 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 R luc was used as an internal standard to reduce endogenous effects. The human PPARa, γ γ and PPARS ligand binding domains are each fused to the yeast transcription factor GAL4 DNA binding domain. Then, the mammalian expression vector pM was ligated to construct three plasmids: pM-hPPARa/GAL4, pM-PPAIly/GAL4 and pM-PPARS/GAL4. The GAL4 DNA binding region is 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-Rluc as an internal standard.

Specifically, the 293-T cells were seeded into 48-well plates at a cell density of 2-4xl 0 ⁴ / well, culture was 10% defatted fetal calf serum (FCS) in phenol red-free 1640 medium without antibiotics. 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/GAM, pB4-RES-tk-luc and pRL-CMV-, respectively. Three plasmids of Rluc were co-transfected into 293-T cells and administered 24 hours later. Then, the intensity of luciferase was measured 24 hours after administration. The results showed that the compounds of the present invention have strong agonistic effects on various subtypes of PPAR, and the agonistic effect on PPAR6 is particularly strong.

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 hydrate thereof, and one or more suitable pharmaceutically acceptable carriers. It can be used for body Internal treatment and biocompatibility. The pharmaceutical compositions can be prepared in a variety of dosage forms as desired for different routes of administration.

 The pharmaceutically acceptable carrier includes, but is not limited to, an ion exchanger, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, sorbic acid clock, Partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , Cellulose, Polyethylene Glycol, Sodium Carboxymethyl Cellulose, Polyacrylate, Beeswax, Lanolin.

 The pharmaceutical composition of the compound 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, sheath Intra, intraventricular, intrasternal, and intracranial injection or input, 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 or suspension. If desired, some sweetening, aroma or coloring agents may be added to the above oral formulation.

In the case of topical administration, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. The form is specifically described as follows: When the eye is topically applied, the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH of sterile saline, which may or may not be added. Preservatives such as benzyl chloride alkoxide. For ophthalmic use, the compound can also be formulated into a bone form such as vaseline. When the skin is applied topically, 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: minerals 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 compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor. A preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is from 5 mg/kg to 10 rag/kg body weight per day. detailed description

 The invention is further illustrated by the following examples, which 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. - NMR spectra were determined by a Bruker ARX 400 nuclear magnetic instrument. FAB mass spectra were determined by a Zabspec t high resolution magnetic mass spectrometer. Preparation of intermediates

General procedure A for the preparation of 2-aryl-4-methyl-5-hydroxymethylthiazole from aromatic amide

(a) Add 2mmol of P ₄ S ₁₀ , 20mraolNaHC0 _{3 to} 100ml of dry toluene, heat under reflux for 30 minutes, add 1 Q to let ol amide, l-2h after the reaction is complete, filter, and concentrate column separation (elution system: n-hexane / acetic acid Ethyl ester) gives a solid thioaromatic formamide.

 (b) Add 10 mmol of substituted thioaromatic formamide, l lmmo l 2-chloro-3-oxo-butyric acid ethyl ester (purchased from ACR0S) in 100 ml of ethanol, heat under reflux for 12-24 hours, concentrate, column Separation (elution system: n-hexane/ethyl acetate) gave (2-substituted aryl-4-methylthiazole-5-yl) ethyl formate.

 (c) A solution of 10 ol (2-substituted aryl-4-methylthiazole-5-yl)carboxylate in 100 ml of dry tetrahydrofuran was added dropwise to 30 ml of dry THF of 1 lmmol of lithium aluminum hydride at 0 °C. In the reaction solution, after the dropwise addition is completed, the reaction is carried out at room temperature for 2-4 hours, the reaction is stopped by adding a little water, 15% aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, filtered, and evaporated to give the product 2-aryl- 4-methyl-5-hydroxymercaptothiazole.

 Intermediate 1

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

 MS [M] += 205. 2 ra/e; ^-NMR (400MHz, 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

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

 MS [M] +=273. 1 m/e; 'H-NMR (400MHz, DMSO) δ 8. 10 (d, 2H), 7. 83 (d, 2H), 5. 66 (t, 1H), 4. 67 (d, 2H), 2. 37 (s, 3H).

 Intermediate 3

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

 MS [M] +=284. 1 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

 The title compound was prepared using p-fluorobenzoic acid amide as a crude material. MS [M] += 223. 3 m/e

 Intermediate 5

标题化合物以对甲氧基苯甲酰胺为原料如一般操作 A所述制 备， 得浅黄色固体。 MS [M] +=235. 3 m/e

The title compound was prepared using p-methoxybenzamide as a crude material. MS [M] +=235. 3 m/e

 Intermediate 6

 The title compound was obtained from the title compound (m.p.

 Intermediate 7

 The title compound was obtained as a crude material. MS [M] += 274. 2 m/e

 Intermediate 8

 The title compound was prepared from p-tert-butyl benzamide as a general procedure A to give a pale yellow solid. MS [M] +=261. 4 ra/e

标题化合物以 2-噻吩甲酰胺为原料如一般操作 A所述制备: 得浅黄色固体。 MS [M] +=211. 3 ra/e Intermediate 9

The title compound was prepared from 2-thiophenecarboxamide as described in General Procedure A. MS [M] +=211. 3 ra/e

Intermediate 10

 The title compound was prepared using 3-thiophene amide as a crude material. MS [M] +=211. 3 m/e

 Intermediate 11

 The title compound was prepared using 2-naphthylcarboxamide as a crude material. MS [M] +=255. 3 ra/e

 Intermediate 12

 The title compound is based on piperonamide.

Light yellow solid. MS [M] +=249. 2 ra/e

 Intermediate 13

In a solution of 2.42 g (l Oramol) 4-p-ethylphenylphenol in 50 ml of dry acetone After adding 15 mmol of KOH, 1.88 g (10 lbs) of 1,2-dibromoethane was slowly added dropwise, and reacted at 50 ° C for 8 hours, followed by filtration, concentration, and column separation (elution system: n-hexane / ethyl acetate) The intermediate 13 was obtained as an oil, and the yield was 45%. MS [M] +=305.2 m/e Intermediate 14

1.99 g (10 mmol) of phenothiazine was dissolved in 50 ral of anhydrous butanone, 0.94 g (16.7 mmol) of potassium hydroxide powder was added, and cooled, and kept at 0 ° C for 2 hours, and dissolved in 0.79 g (18 mmol) of ethylene oxide. 15 ml of anhydrous butanone, (TC reaction after 2 hours, the temperature was raised to 50-60 ° C for 2 hours, after cooling, filtration, concentration, column separation (elution system: n-hexane / ethyl acetate) to obtain 1.85 g of product. Yield 76% MS [M] +=243.3 m/e Intermediate 15

After 8.8 g (80 mmol) of catechol and 20.8 g (256 mmol) of sodium thiocyanate in 100 ml of methanol were dropped to 0 ° C, 4.4 ml of bromine (80 mmol) and 8.24 g (480 mmol) of sodium bromide were slowly added dropwise. 100 ml of methanol solution, kept at 0. C After 3 hours, 300ml of water was added to terminate the reaction, a saturated NaHC0 ₃ aqueous solution was adjusted near neutral, extracted with ethyl acetate, dried, concentrated, and column separation (elution system: n-hexane / ethyl acetate / acetic acid) to give a white solid The product was 12.73 g, the yield was 95.3%, and the rap: 133.0-134.5 °C.

MS [M]+=167.1 m/e; 'H-NMR (400 MHz, DMSO) δ 9.66 (d, 2H), 7.00 (s, 1H), 6.93 (dd, 1H), 6.84 (d, 1H).

Intermediate 16

In a 150ml round bottom bottle, add 4-sulfonitrile catechol (intermediate 15) 7.5g (44.9mraol), triethyl orthoformate. 98g (67.4mraol), acidic ion exchange resin 0.5g, 4A molecular sieve 0.8 g, 100 ml of anhydrous benzene, refluxing for 72-96 hours, filtration, concentration, and column separation (eluting system: n-hexane/ethyl acetate = 25:1) yielding 7.24 g of lightly buttery product, yield 72.3%. MS [M] +=223.2 m/e; 'H-NMR (400MHz, CDC1 ₃ ) δ 7.12 (d, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 6.90 (dd, 1H), 3.73 (q, 2H), 1.28 (t, 3H).

 Preparation of 4-[(2-aryl-4-methylthiazol-5-yl)methylthio]-1,2-catechol from 2-aryl-4-methyl-5-hydroxymercaptothiazole General operation B

(I) 2-Aromatic 4-methyl-5-hydroxymercaptothiazole (5 匪ol) was dissolved in 20 ml of dry chloroform, 5 ml of SOCl _{2 was} added dropwise, and after 3-5 hours, it was distilled, and evaporated to dryness under reduced pressure. The product is ready for use.

(II) Add 6-leg ol 4-cyanothio catechol (intermediate 16) protected with triethyl orthoformate in a 100 ml round bottom flask, 35 ml absolute ethanol, N ₂ protection, slowly add NaBH ₄ (6.6 mmol) After refluxing for 10-15 minutes, the temperature is lowered to room temperature. After adding cesium carbonate, the reaction product of (I) is added dropwise, reacted at room temperature, N ₂ overnight, filtered, washed with ethyl acetate, concentrated, and separated by column (elution system: Alkyl/ethyl acetate) gave the product as a yellow oil.

(III) The reaction product of (II) is dissolved in 40 ml of 90% aqueous methanol, added After reacting 500 mg of p-toluenesulfonic acid at room temperature for 12-24 hours, concentrating, and separating by column (elution system: chloroform/methanol) to give pale yellow to yellow 4-[(2-aryl-4-mercaptothiazol-5-yl) )Methylthio] - 1, 2-catechol.

 Intermediate 17

The title compound was prepared using Intermediate 1 as a crude material. MS [M] += 329. 4 m/e; 'H-NMR (400 MHz, DMSO) δ 9. 10 (d, 2 Η), δ 7. 84 (in, 2H), 7. 46 (ra, 3H) , 6. 77 (s, 1H), 6. 67 (s, 2H), 4. 20 (s, 2H), 2. 12 (s, 3H).

 The title compound was prepared from Intermediate 2 as a crude material. MS [M] +=397. 3 m/e; 'H-NMR (400MHz, DMSO) δ 9. 11 (d, 2Η), δ 8. 05 (d, 2H), 7. 82 (d, 2H) , 6. 76 (s, 1H), 6. 66 (s, 2H), 4. 21 (s, 2H), 2. 12 (s, 3H).

 Intermediate 19

The title compound was prepared from Intermediate 3 using mp. MS [M] += 408. 3 m/e; 'H-NMR (400 MHz, DMSO) δ 9. 11 (d, 2Η), δ 7. 77 (d, 2H), 7. 66 (d, 2H), 6. 77 (s, 1H), 6. 67 (s 2H), 4. 21 (s, 2H), 2. 14 (s, 3H).

Intermediate 20

 The title compound was prepared from Intermediate 4 using EtOAc m. MS [M] +=347. 4 m/e; ^-NMR (400MHz, DMSO) δ 9. 11 (d, 2Η), δ 7. 88 (m, 2H), 7. 31 (m, 2H), 6. 77 (s, 1H), 6. 67 (s, 2H), 4. 20 (s, 2H), 2. 12 (s, 3H).

Intermediate 21

 The title compound was prepared from Intermediate 5 using EtOAc (EtOAc) MS [M] +=359. 5 m/e

Intermediate 22

 The title compound was prepared from Intermediate 6 using EtOAc (EtOAc) MS [M] +=389. 3 m/e

Intermediate 23

 The title compound was prepared from Intermediate 7 using EtOAc (EtOAc) MS [M] +=398. 3 m/e

Intermediate 24

 The title compound was prepared from Intermediate 8 using EtOAc (m.). MS [M] +=385. 5 m/e

Intermediate 25

 The title compound was prepared from Intermediate 9 using EtOAc (m.) MS [M] +=335. 4 ra/e

Intermediate 26

 The title compound was prepared from Intermediate 10 using EtOAc (EtOAc) MS [M] +-335. 4 m/e

Intermediate 27

-28-

 The title compound was prepared from Intermediate 11 using EtOAc (EtOAc) MS [M] +=379.5 m/e

Intermediate 28

 The title compound was obtained from the title compound (yield: m. MS [M] +=373.4 ra/e

Intermediate 29

Add 1.34 g (6 mmol) of 4-cyanothio catechol (intermediate 16) protected with triethyl orthoformate to a 100 ml round bottom flask, protect with 35 ml of absolute ethanol, N ₂ and slowly add NaBH ₄ (0.24 g, 6.6 mmol), after refluxing for 10 minutes, the temperature was lowered to room temperature. After adding 0.55 g (9.9 mmol) of K0H, 1.52 g (5 mmol) of chloroform solution of intermediate 13 was added dropwise, and the mixture was refluxed with N _{2 and} then filtered, ethyl acetate. Washing, concentrating, and column chromatography (eluting: hexane/ethyl acetate) afforded product as yellow oil (yield of triethyl orthoformate to afford intermediate 29). This oil was dissolved in 40 ml of a 90% aqueous methanol solution, and 500 rag of p-toluenesulfonic acid was added, and the mixture was concentrated at room temperature for 24 hours, and then concentrated to give a pale yellow solid (yield: 0.712 g). MS [M] +=366.3 m/e

2-(carbazol-9-yl)ethanol (purchased from ACR0S) (1.06g, 5mmol) was dissolved in 2 Oral dry chloroform, 5ml of S0C1 _{2 was} added dropwise, refluxed for 4h, distilled, evaporated under reduced pressure, the product was ready for use .

Add 1.34 g (6 mmol) of 4-cyanothiocatechol (intermediate 16) protected with triethyl orthoformate in a 100 ml round bottom flask, 35 ml absolute ethanol, N ₂ protection, slowly add NaBE O.24 g, 6.6 Ment), after refluxing for 10 minutes, the temperature was lowered to room temperature. After adding 0.55 g (9.9 mmol) of K0H and 50 mg of KI, the chloro product obtained above was added dropwise, N _{2 was} refluxed for 6 hours, filtered, washed with ethyl acetate, concentrated, and separated. (elution system: n-hexane / ethyl acetate) to give the product as a yellow oil (yield intermediate 30 protected by triethyl orthanoate).

 The yellow product obtained above was dissolved in a 40 rpm 90% aqueous methanol solution, and after adding 500 mg of p-toluenesulfonic acid, the reaction was carried out at room temperature for 24 hours, concentrated, and separated by column (elution system: chloroform/methanol) to obtain a yellow 4-[2-( Oxazol-9-yl)ethylthio]-1,2-catechol 0.605 g. MS [M] +=335.4 ra/e

Intermediate 31

The intermediate 14 was used as a starting material to give the title compound (yield: 4-[2-(phenothiazine-10-yl)ethylthio]- 1, 2-catechol. MS [M] +=367.5 m/e

Intermediate 32

 2.8 g (40 mmol) of propiolic acid and 6.9 g (50 mmol) of p-methoxybenzyl alcohol were dissolved in 4 Oral dry dichloromethane, and after cooling to -20 ° C, 9.28 g (45 mraol) DCC and 0.37 g were slowly added dropwise. (3 leg ol) DMAP (4-N, N-dimethylaminopyridine) in 100 ml of dry dichloromethane, after 30 minutes, warm to room temperature for 12 hours, filter, concentrate, and column separation (elution system: N-hexane/ethyl acetate) gave 4.95 g of pale yellow oil, yield 65.1%.

^-NMR (400MHz, CDC1 ₃ ) δ 7.32 (d, 2Η), 6.90 (d, 2H), 5.16 (s, 2H), 3.82 (s, 3H), 2.87 (s, 1H). Example

Example 1: 2-{5-[(4-Methyl-2-phenyl-1,3-thiazol-5-yl)-methylthio]-1,3-benzodioxole } - acetic acid

 0.44 g (1.22 mmol) of intermediate 17 and 0.223 g (1.83 mmol) of DMAP (4-N,N-dimethylaminopyridine) were dissolved in 20 ml of dry acetonitrile, and 0.254 g (l.34) was slowly added dropwise. Leg ol) a solution of propiolic acid to benzyloxybenzyl ester (intermediate 32) in 5 liters of dry acetonitrile, which was reacted at room temperature for 2 h, concentrated and purified by column (eluting system: n-hexane / ethyl acetate) to give 0.573 g of oil. 2-{5-[(4-Methyl-2-phenyl- 1, 3-thiazol-5-yl)-methylthio]-1,3-benzodioxole}-acetic acid Methoxybenzyl ester, yield 90.2 ° /. .

0.573 g (1.1 mmol) of 2-{5-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)-methylthio]-1,3-benzodioxine dioxol} - acetic acid was dissolved in 16ml methoxybenzyl ester in dichloromethane was added 0. ⁸² ml (llramol) trifluoroacetic acid was stirred at rt 4.5h, concentration, column separation (elution system: methylene chloride / decyl alcohol), 2-{5-[(4-methyl-2-phenyl-1, 3-thiazole) as a pale yellow amorphous solid -5-yl)-methylthio]- 1, 3-benzodioxole}-acetic acid 0.325 g, yield 74.0%.

MS [M]+= 400. Ora/e; ^-NMR (400MHz, DMS0-d ₆ ) δ 12.79 (brs, 1H,), 7.85 - 7.82 (m, 2H), 7.48 - 7.45 (m, 3H), 7.04 (d, 1H), 6.85 (d, 2H), 6.52 (t, 1H), 4.35 (s, 2H), 2.96 (d, 2H), 2.20 (s, 3H) Example 2: 2-(5- {[4-Methyl-2-(4-trifluoromethylphenyl)-1, 3-thiazole-5-yl]-methylthio}-1,3-benzodioxole) -acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

18, 2-(5-{[4-methyl-2-(4-trifluoromethylphenyl)-1, 3-thiazole-5-yl]-methylthio}- 1, 3-benzodioxole)-acetic acid.

MS [M]+= 468. Ora/e; ^- MR (400MHz, DMS0-d ₆ ) δ 12, 77 (brs, 1H,), 8.05 (d, 2H), 7.82 (d, 2H) , 7.04 ( d, 1H), 6.85 (ra, 2H), 6.52 (t, 1H), 4.38 (s, 2H), 2.96 (d, 2H), 2.23 (s, 3H) Example 3: 2- (5- {[ 4-mercapto-2-(4-bromophenyl)-1,3-thiazol-5-yl]-methylthio}-1,3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

19, obtained as a pale yellow amorphous solid: 2-(5-{[4-methyl-2-(4-bromophenyl)-l,3-thiazol-5-yl]-methylthio}-l, 3-benzodioxole)-acetic acid.

MS [M]+= 478. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) 7.78 (d, 2H), 7.65 (d, 2H), 6.96 (d, 1H), 6.82-6.76 (m, 2H), 6.46 (s, 1H), 4.32 (s, 2H), 2.64 (s, 2H), 2.18 (s, 3H) Example 4: 2-(5-{[4-methyl-2-(4) -fluorophenyl)-1,3-thiazol-5-yl]-indole sulfur }}-1,3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 20 to give 2-(5-{[4-methyl-2-(4-fluorophenyl)-l as a pale yellow amorphous solid. , 3-thiazole-5-yl]-methylthio}-l,3-benzodioxole)-acetic acid.

MS[M]+= 418. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) 12.67 (brs, 1H), 7.88 (m, 2H), 7.29 (ra, 2H) , 7.03 (d, 1H) , 6.84 (d, 2H),

6.52 (t, 1H), 4.34 (s, 2H), 2.96 (d, 2H), 2.19 (s, 3H) Example 5: 2- (5- {[4-methyl-2-(4-methoxy) Phenyl) -1,3-thiazole-5-yl]-methylthio}-1,3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 21 to give 2-(5-{[4-methyl-2-(4-methoxyphenyl) as a pale yellow amorphous solid. -1,3-thiazol-5-yl]-indolyl}-1,3-benzodioxole)-acetic acid.

MS [M]+= 430. Om/e; ^-NMR (400MHz, DMS0-d ₆ ) 7:77 (d, 2H),

7.1 (m, 3H), 6.83 (m, 2H) 6: 2-(5- {[4 -Methyl-2-(3,5-dimethoxyphenyl)-1,3-thiazole-5-yl]-methylthio}- 1, 3-benzene P-dioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 22 to give a pale yellow amorphous solid of 2-(5-{[4-mercapto-2-(3,5-didecyloxy). Phenyl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzodioxole)-acetic acid.

MS [M] += 460. lm/e; ^-NMR (400MHz, DMS0-d ₆ ) 7.01 (s, 1H), 6.94 (d, 2H), 6.82 (s, 2H) , 6.58 (t, 1H) , 6.50 (s, 1H), 4.33 (s, 2H), 3.80 (s, 6H), 2.86 (s, 2H), 2.19 (s, 3H) Example 7: 2- (5- {[4-曱-2- (2, 4-dichlorophenyl)- 1, 3 -thiazol-5-yl- 曱thio}- 1, 3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

23, 2-(5-{[4-methyl-2-(2,4-dichlorophenyl)- 1, 3-thiazole-5-yl]-methylthio}- 1, 3-benzodioxole)-acetic acid.

MS [M]+= 468. Om/e; 'H-NMR (400MHz, DMSO-d ₆ ) 8.17 (d, 1H), 7.79 (d, 1H), 7.54 (dd, 1H), 6.96 (d, 1H) ), 6.81 (dd, 1H), 6.77 (d, 1H), 6.46 (s, 1H), 4.36 (s, 2H), 2.67 (s, 2H), 2.23 (s, 3H) Example 8: 2- ( 5- {[4-Methyl-2-(4-tert-butylphenyl)-1,3-thiazole-5-yl]-indolyl 3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

24, 2-(5-{[4-indolyl-2-(4-tert-butylphenyl)-1,3-thiazol-5-yl]-indenylthio}-1 as a pale yellow amorphous solid , 3-benzodioxole)-acetic acid.

MS [M] += 456. Om/e; ^-NMR (400MHz, DMSO-d ₆ ) 7.75 (d, 2H), 7.47 (d, 2H), 6.97 (s, 1H), 6.83 - 6.77 (m, 2H), 6.47 (s, 1H), 4.31 (s, 2H), 2.71 (s, 2H), 2.18 (s, 3H), 1.29 (s, 9H) Example 9: 2- (5- {[4- Methyl-2-(thiophen-2-yl)- 1, 3-thiazol-5-yl]-methylthio}-1,3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

25, 2-(5-{[4-methyl-2-(thiophen-2-yl)-1,3-thiazol-5-yl]-methylthio}- 1, 3 as a pale yellow amorphous solid - benzodioxole) - acetic acid.

MS [M]+= 406. Om/e; 'H-NMR (400MHz, DMSO-d ₆ ) 7.66 (d, 1H), 7.55 (d, 1H), 7.12 (t, 1H), 6.98 (s, 1H) ), 6.83-6.78 (m, 2H), 6.47 (s, 1H), 4.30 (s, 2H), 2.73 (s, 2H), 2.13 (s, 3H) Example 10: 2-(5- {[4-Methyl-2-(thiophen-3-yl)-1,3-thiazol-5-yl]-indenyl}} 1,1-benzophenanthrene Oxephthalene)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 26 to give 2-(5-{[4-indolyl-2-(thiophen-3-yl)-1) as a pale yellow amorphous solid. , 3-thiazole-5-yl]-indolyl}-1,3-benzodioxole)-acetic acid.

MS [M]+= 406. Oin/e; 'H-NMR (400MHz, D S0-d ₆ ) 8.03 (s, 1H),

7.65 (m, 1H), 7.48 (d, 1H), 6.97 (s, 1H), 6.83-6.77 (m, 2H), 6.47 (s, 1H), 4.30 (s, 2H), 2.74 (s, 2H) , 2.15 (s, 3H) Example 11: 2-(5- {[4-Methyl-2-(naphthalen-2-yl)-1,3-thiazole-5-yl]-methylthio}-1 , 3-benzodioxole)-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to an intermediate.

27, 2-(5-{[4-indolyl-2-(cai-2-yl)-1,3-thiazole-5-yl]-methylthio}-1, 3 as a pale yellow amorphous solid - benzodioxole) - acetic acid.

MS [M] += 450. Om/e; 'H-NMR ( 00MHz, DMS0-d ₆ ) 8.43 (s, 1H),

8.08-7.94 (m, 4H), 7.57 (ra, 2H), 7.06 (s, 1H), 6.89-6.84 (m, 2H), 6.52 (t, 1H), 4.38 (s, 2H), 2.97 (d, 2H), 2.24 (s, 3H) Example 12: 2-(5- {[4-Methyl-2-(1,3-benzodioxol-5-yl)- 1, 3 -thiazole-5-yl]-methylthio}-1,3-benzodioxole)-acetic acid, using the preparation method of Example 1, the intermediate 17 was changed to an intermediate

28, a pale yellow amorphous solid of 2-(5-{[4-methyl-2-(1,3-benzodioxole-5-yl)-1, 3-thiazole-5 -yl]-methylthio}-1,3-benzodioxole)-acetic acid.

MS [M] += 444. Om/e; 'H-NMR (400MHz, DMS0-d ₆ ) 12.77 (brs, 1H), 7.35-7.33 (m, 2H), 7.02-6.97 (ra, 2H), 6.84 (s, 2H), 6.52 (t, 1H), 6.09 (s, 2H), 4.31 (s, 2H), 2.96 (d, 2H), 2.16 (s, 3H) Example 13: 2- [5- (2- {4-〖 (4-ethyl)phenyl]phenoxy}ethylthio)-1,3-benzodioxole]-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 29 to give 2-[5-(2-{4-[(4-ethyl)phenyl]phenoxy) as a pale yellow amorphous solid. Base} ethylthio)- 1, 3-benzodioxole]-acetic acid.

MS [M]+= 437. Om/e; ^J H-NMR (400MHz, DMS0-d ₆ ) 7.44-7.36 (m 4H), 7.15 (d, 2H), 6.98 (s, 1H), 6.85-6.79 ( Ra, 4H), 6.47 (s, 1H), 4.26 (t, 2H), 3.15 (t, 2H), 2.74 (s, 2H), 2.55 (q, 2H), 1.18 (t, 3H) Example 14: 2-{5- [2-(carbazol-9-yl)ethylthio]-1,3-benzodioxole}-acetic acid

 Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 30 to give 2-{5-[2-(carbazol-9-yl)ethylthio]-1 as a pale yellow amorphous solid. 3-benzodioxole}-acetic acid.

MS[M]+= 406. Ora/e; 'H-NMR ( 00MHz, CDC1 ₃ ) 8.07 (m, 2H), 7.47 (ra, 4H), 7.25 (m, 2H), 6.96(s, 1H), 6.80 (ra, 2H), 6.44 (s, 1H), 4.21 (t, 2H), 3.28 (t, 2H), 2.70 (s, 2H) Example 15: 2- {5- [2- (phenothiazine) -10-yl)ethylthio]- 1, 3-benzodioxole}-acetic acid

Using the preparation method of Example 1, the intermediate 17 was changed to the intermediate 31 to give 2-{5-[2-(phenothiazine-10-yl)ethylthio]-1 as a pale yellow amorphous solid. , 3-benzodioxole}-acetic acid. MS [M] += 438. Om/e; ^-NMR (400MHz, CDC1 ₃ ) 7. 38-7. 03 (m, 8H), 6. 97 (s, 1H) , 6. 82 (m, 2H ), 6. 46 (s, 1H), 4. 18 (t, 2H), 3. 24 (t, 2H), 2. 72 (s, 2H). Example 16: Partial agonistic effects of the compounds of the invention on PPAR

The 293- T cells were seeded into 48-well plates at a cell density of 2-4xl 0 ⁴ / well, culture was 10% defatted fetal calf serum (FCS) in phenol red-free 1640 medium without antibiotics. 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. Rluc three kinds of shield granules were co-transfected into 293-T cells, and administered 24 hours later. The double agonist GW409544 was used as a positive control for α and γ subtypes, and GW501516 was used as a positive control for δ subtype. The intensity of luciferase was measured 24 hours after administration, and the results were expressed as PPAR activation energy (value relative to control drug (100%)) and EC _5Q value for PPAR6, as shown in Tables 1 and 2, respectively.

Table 1. Some of the agonistic effects of the compounds of the invention on PPAR

表 2.部分本发明化合物对 ΡΡΑΙΙδ的 EC₅。值 化合物 实施例 1 实施例 2 实施例 3 实施例 4 实施例 5

Table 2. Partial EC _{5 of the} compounds of the invention for ΡΡΑΙΙδ. Value Compound Example 1 Example 2 Example 3 Example 4 Example 5

EC50 (uM) 0. 396 0. 084 0. 092 0. 416 0. 149 Compound Example 7 Example 9 Example 10 Example 11 Example 12

BC50 (uM) 0. 147 1. 042 0. 684 0. 117 0. 454

Claims

Rights request A compound of the formula I, a racemate or an optical isomer thereof or a pharmaceutically acceptable salt or solvate thereof,

among them: a linear or branched alkyl group selected from H, dC ₆ , optionally a benzyl group substituted by one or more substituents on the benzene ring, said substituent being selected from a linear or branched alkoxy group of dC ₆ , d -C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, C ₃ -C ₆ cycloalkyl, halogen, nitrile, trifluoromethyl, trifluoroox base; R _{2 is} selected from H, halogen, d-C ₆ linear or branched alkyl, C ₂ - C ₆ straight or branched alkenyl, C ₃ - C ₆ cycloalkyl, 5-6 aromatic carbon a ring or an aromatic heterocyclic ring, the aromatic heterocyclic ring comprising 1 to 3 hetero atoms selected from 0, S, N, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted with 1 to 5 substituents selected from the group consisting of Base replacement: ! 3⁄4, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d-C ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, d- Alkoxy, C ₂ - (alkenyloxy, phenoxy, benzyloxy, carboxy or amino;  m and n are each independently selected from 0, 1, 2, 3, 4, 5 and 6; Xi, X ₂ and X ₃ are each independently absent or are 0, S, NR ₃ , NR ₄ C(=0), S0, S(0) ₂ , C0, C(=N-0R ₅ ), CH ( 0R ₆ ), (CH ₂ ) _Y , OC, C≡C, wherein R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from a hydrogen atom or a straight or branched alkyl group of dC ₆ , Y selected From 1, 2 and 3; A is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a single ring or a double a ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 hetero atoms selected from 0, N, and S, and the aromatic carbocyclic ring or aromatic heterocyclic ring is optional. Substituted by 1-5 substituents selected from the group consisting of: i3⁄4, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, d-C ₆ straight or branched alkyl, C ₂ - straight or branched alkenyl, d-C ₄ alkoxy, C ₂ -C ₄ alkenoxy, phenoxy, benzyloxy, carboxy or amino; Ar _{2 is} selected from a H atom, an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1 to 4 a hetero atom selected from 0, N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted with from 1 to 5 substituents selected from the group consisting of: 素, nitro, hydroxy, hydroxymethyl, trifluoro Methyl, trifluoromethoxy, d-C ₆ straight or branched alkyl, C ₂ - straight or branched alkenyl, (^-( ₄ methoxy, C ₂ -alkenyloxy, phenoxy) Base, benzyloxy, carboxyl or amino. 2. The compound of claim 1 having the following formula II:

 II  among them:  m, n are independently selected from 0, 1, 2, 3, 4, 5 and 6; X, X ₂ and X ₃ are each independently absent or are 0, S, NR ₃ , NR ₄ C(=0), S0, S(0) ₂ , C0, C(=N—0R ₅ ), CH ( 0R ₆ ), (CH ₂ ) _Y , C=C, C≡C, wherein R ₃ , R ₄ , R ₅ and R ₆ are each independently selected from a hydrogen atom or a linear or branched fluorenyl group of d-, Y is selected from 1, 2 and 3; Ar is an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, and the aromatic heterocyclic ring includes 1-4 selected a hetero atom from 0, N, S, and the aromatic carbocyclic or aromatic heterocyclic ring may be optionally substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl , trifluoromethoxy, dC ₆ straight or branched alkyl, C ₂ -C ₆ straight or branched alkenyl, d-C ₄ alkoxy, C ₂ -C ₄ alkenoxy, phenoxy Or a benzyloxy group, a carboxyl group or an amino group; Ar _{2 is} selected from a H atom, an aromatic carbocyclic ring or an aromatic heterocyclic ring, wherein the ring may be a monocyclic ring, a bicyclic ring or a tricyclic ring; each ring is composed of 5 to 6 atoms, The aromatic heterocyclic ring includes 1 to 4 hetero atoms selected from 0, N, S, and the aromatic carbocyclic ring or aromatic heterocyclic ring may be optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen, nitrate Base, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC^ straight or branched alkyl, C ₂ - (linear or branched alkenyl, d- ( ₄ alkoxy, C ₂ - (alkenyloxy, phenoxy, benzyloxy, carboxy or amino.  3. A compound according to claim 1 or 2 which is selected from the group consisting of:  2-{5-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)-methylthio]-1,3-benzodioxole}-acetic acid; 2- (5- {[4-methyl - 2- (4-trifluoromethylphenyl) -1, ³ - thiazol ^--5-- yl] - methylsulfanyl-yl} - from 1, 3-benzodioxol Heterocyclopentene)-acetic acid;  2-(5- {[4-methyl-2-(4-bromophenyl)-1,3-thiazole-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;  2-(5- {[4-Methyl-2-(4-fluorophenyl)-1,3-thiazol-5-yl]-methylthio}-1,3-benzodioxole Alkene)-acetic acid;  2-(5- { [4-Methyl-2-(4-methoxyphenyl)-1,3-thiazole-5-yl]-methylthio}-1,3-benzo-dioxa Cyclopentene)-acetic acid;  2-(5- { [4-methyl-2-(3, 5-dimethoxyphenyl)-1,3-thiazole-5-yl]-methylthio-3-benzodioxole Pentene)-acetic acid;  2-(5- { [4-indolyl-2-(2,4-dichlorophenyl)-1,3-thiazol-5-yl]-methylthio}-1,3-benzodioxane Heterocyclic pentene)-acetic acid; 2-(5- { [4-indolyl-2-(4-tert-butylphenyl)-1,3-thiazol-5-yl]-methyl sulfide Base}- 1, 3-benzodioxole)-acetic acid;  2-(5- { [4-methyl-2-(thiophen-2-yl)-1,3-thiazol-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;  2-(5- { [4-methyl-2-(thiophen-3-yl)-1,3-thiazol-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;  2-(5- {[4-Methyl-2-(naphthalen-2-yl)-1,3-thiazol-5-yl]-methylthio}- 1, 3-benzodioxole Alkene)-acetic acid;  2-(5- { [4-methyl-2-(1,3-benzodioxole-5-yl)-1,3-thiazol-5-yl]-methylthio} 1, 3-benzodioxole)-acetic acid;  2-[5-(2- {4- [(4-ethyl)phenyl]phenoxy}ethylthio)-1,3-benzodioxole]-acetic acid;  2-{5-[2-(carbazol-9-yl)ethylthio]- 1, 3-benzodioxole }-acetic acid;  2-{5- [2-(phenothiazine-10-yl)ethylthio]-1,3-benzodioxol}-acetic acid;  Or a pharmaceutically acceptable salt or solvate thereof. 4. A method of preparing a compound of any of claims 1-3, comprising the steps of: 1) reacting catechol with sodium thiocyanate in the presence of bromine and sodium bromide to give a compound of formula III, reacting a compound of formula III with triethyl orthoformate to provide a compound of formula IV;

 III IV 2) Reduction of the compound of formula IV with sodium borohydride followed by intermediate with formula V The reaction of the body in the presence of a base such as sodium hydroxide, cesium carbonate or potassium carbonate

 V Wherein, Ar, Ar ₂ , X ₂ , X ₃ , n are as defined in claim 1, and X is a halogen to give a compound of formula VI:

 VI Wherein, Α _Γι , Ar ₂ , X ₂ , X ₃ , n are as defined in claim 1; 3) Deprotecting the compound of formula VI in the presence of p-toluenesulfonic acid to give a compound of formula VII which is S.

4) reacting a compound of formula VII with a compound of formula VIII:

VIII Wherein I, R _{2 are} as defined in claim 1, but 1^ is not H, to obtain a compound of the formula I wherein ra-l is S:

Wherein, Ar _{l 5} Ar ₂ , X ₂ , X ₃ , n, 1^ and R ₂ are as defined in claim 1, but not H;  Optionally, the above-obtained compound of the formula I which is not H is reacted with an alkali metal hydroxide or with an acid such as dilute hydrochloric acid or trifluoroacetic acid, and hydrolyzed to obtain m = l, which is S, ! ^ is a compound of formula H:

X ₂ , X ₃ , n, R ₂ are defined as claimed in claim 1 5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a racemate or an optical isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, Diluent or excipient. 6. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and/or prophylaxis of hPPAR mediated diseases, risk factors or disorders. 7. The use according to claim 6, wherein the disease, risk factor or condition is dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type I diabetes, type II diabetes, insulin resistance , Diabetes complications, glucose intolerance, X syndrome, heart failure, cardiovascular disease, obesity, anorexia - bulimia and bulimia nervosa. 8. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for activating hPPAR. A method of treating or preventing a hPPAR-mediated disease, a risk factor or a condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention according to any one of claims 1-3.