WO2008087367A2 - Substituted (phenylthiazolyl)-phenyl-propan-1-one and (phenyloxazodyl)-phenyl-propan-1-one derivatives, preparations and uses of same - Google Patents

Substituted (phenylthiazolyl)-phenyl-propan-1-one and (phenyloxazodyl)-phenyl-propan-1-one derivatives, preparations and uses of same Download PDF

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WO2008087367A2
WO2008087367A2 PCT/FR2007/052635 FR2007052635W WO2008087367A2 WO 2008087367 A2 WO2008087367 A2 WO 2008087367A2 FR 2007052635 W FR2007052635 W FR 2007052635W WO 2008087367 A2 WO2008087367 A2 WO 2008087367A2
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yl
phenyl
trifluoromethyl
phenoxy
thiazol
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WO2008087367A3 (en
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Jean-François DELHOMEL
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Genfit
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24Radicals substituted by oxygen atoms

Abstract

The invention relates to substituted (phenylthiazolyl)-phenyl-propan-1-one and phenyloxazolyl)-phenyl-propan-1-one derivative compounds, pharmaceutical compositions comprising same, and therapeutic uses thereof, especially in the fields of human and animal health.

Description

DERIVATIVES (PHENYLTHIAZOLYL) phenyl-propan-I -ONE AND

(Phenyloxazolyl) -phenyl-PROPAN-I -ONE DERIVATIVES,

PREPARATIONS AND USES

The invention relates to novel compounds (phénylthiazolyl) - phenyl-propan-1-one and (phenyloxazolyl) -phenyl-propan-i-one derivatives, pharmaceutical compositions comprising them and their therapeutic applications, particularly in the areas human and animal health.

The inventors have shown, surprisingly, that the compounds of the invention possess intrinsically agonist property PPAR (Peroxisome Proliferator-Activated Receptor).

The molecules described in the invention are therefore of particular interest to treat complications associated with metabolic syndrome, atherosclerosis, cardiovascular disease, insulin resistance, obesity, hypertension, diabetes, dyslipidemia , inflammatory diseases (asthma, etc.), cerebral ischemia, autoimmune diseases, neurodegenerative diseases (Alzheimer's, etc.), cancers, etc., and to enable the reduction of overall cardiovascular risk. Preferably, the compounds of the invention are useful for the treatment of dyslipidemia and improving the overall risk of atherosclerosis.

Diabetes, obesity and dyslipidemia (plasma levels of LDL cholesterol and high triglycerides, low plasma levels of HDL cholesterol, etc.) are part of the cardiovascular risk factors clearly identified that predispose an individual to develop a cardiovascular pathology (Mensah M, 2004). These risk factors add to the risk factors related to lifestyle such as smoking, physical inactivity and unhealthy diets. A synergistic effect between these different factors: the simultaneous presence of several of them led to a dramatic worsening of cardiovascular risk and it is then necessary to speak of overall risk ( "global risk") for cardiovascular disease. The prevalence of dyslipidemias reached 43.6% of the population in 2004 in the major developed countries. The prevalence of diabetes, now clearly increasing, is becoming increasingly significant in the epidemiology of cardiovascular disease: the prevalence of diabetes is indeed estimated at 7.6% of the population in 2010 (Fox-Tucker J, 2005).

According to the International Atherosclerosis Society (International Atherosclerosis Society, 2003), cardiovascular diseases are the leading cause of death in industrialized countries and are becoming increasingly common in developing countries. These diseases include coronary heart disease, cerebral ischemia and peripheral arterial disease. These data justify the adoption of strong measures to significantly reduce morbidity and mortality due to cardiovascular diseases and the need to find effective treatments, complementary to a change in lifestyle, acting on risk factors cardiovascular diseases and their consequences is a global emergency.

The compounds according to the invention, agonists of PPAR properties are of particular interest for the treatment of pathologies related to deregulations of lipid and / or carbohydrate metabolism, such as diabetes, obesity, dyslipidemia or inflammation and for the reduction of overall cardiovascular risk.

PPAR (α, γ and δ) are indeed known to be involved in this type of pathologies (BP Kota et al., 2005): ligands of these receptors are therefore marketed to treat such pathologies (Lefebvre P et al. , 2006) and many PPAR modulators, agonists or antagonists, selective or not, are currently in advanced pharmaceutical development. A PPAR modulator having beneficial effects on insulin resistance, obesity, dyslipidemia, hypertension and / or inflammation could be used in the treatment of metabolic syndrome (or syndrome X) (Y Liu and Miller A, 2005). The family includes three PPAR isoforms, designated α, γ and δ

(Also called β), each encoded by a different gene. These receptors belong to the superfamily of nuclear receptors and transcription factors that are activated by the binding of certain fatty acids and / or their lipid metabolites. Activated PPARs form heterodimers with the receptors of the 9-cis retinoic acid (RXR or Retinoid X Receptor) and bind to specific response elements (PPRE or Peroxisome Proliferator Response Element) in the promoter of target genes, allowing the control of transcription.

PPARa mainly controls lipid metabolism (liver and muscle) and glucose homeostasis, for direct control of the transcription of genes encoding proteins involved in lipid homeostasis. It exerts anti-inflammatory and anti-proliferative and pro-atherogenic effects prevents the accumulation of cholesterol in macrophages by stimulating cholesterol efflux (Lefebvre P, G Chinetti, Fruchart Staels JC and B, 2006). Fibrates (fenofibrate, bezafibrate, ciprofibrate, gemfibrozil), through PPARa, and are used clinically in the treatment of certain dyslipidemias by lowering triglycerides and increasing plasma levels of HDL (High Density Lipoprotein).

PPAR gamma is involved in lipid metabolism of mature adipocytes (a key regulator of adipogenesis) in glucose homeostasis (including insulin resistance), in inflammation, in the accumulation of cholesterol in and macrophages in cell proliferation (Lehrke M and Lazar MA, 2005). PPARgamma therefore plays a role in the pathogenesis of obesity, insulin resistance and diabetes. Thiazolidinediones (rosiglitazone, troglitazone, etc.) are PPAR receptor ligands useful in the treatment of type 2 diabetes.

There are currently PPARδ ligands in clinical development (eg GW501516 (CAS Registry Number 317318-70-0)), but no PPARδ ligand is currently used as medication. This receptor is an attractive target for the development of drugs used in the treatment of risk factors associated with metabolic syndrome and atherosclerosis such as dyslipidemia, obesity, inflammation and insulin resistance. PPARδ is indeed involved in controlling lipid and glucose metabolism in energy balance, in the proliferation and differentiation of neurons and in the inflammatory response (Gross B et al., 2005). Beyond the direct role of PPAR ligands on the regulation of metabolism of fats and carbohydrates, these molecules have a pleiotropic spectrum of action due to the great diversity of PPAR target genes. These multiple properties make the PPARs interesting therapeutic targets for the treatment of various diseases including cardiometabolic diseases (ie cardiovascular and metabolic diseases) and to enable the reduction of overall cardiovascular risk.

PPAR ligands have a neuroprotective role in Alzheimer's disease, multiple sclerosis, Parkinson's disease and more generally in any pathology involving neuronal degeneration or death, whether neurons of the central nervous system or device, a death or degeneration of oligodendrocyte death or degeneration of glial cells, inflammation of glial cells (ie astrocytes, microglia or oligodendrocytes) or Schwann cells. Thus, it was recently shown that PPARδ agonists allowed to preserve learning and memory in rats in which Alzheimer's disease was induced (SM Monte et al., 2006). It was also shown that oral administration of PPARδ agonists reduced the clinical symptoms and the activation of astroglial and microglial inflammation in a model of multiple sclerosis (Polak, 2005).

The compounds of the invention, by their PPAR agonist properties, thus represent an advantageous therapeutic tool for improving pathologies associated with disturbances of lipid and / or glucose for lowering global cardiovascular risk as well as for neuroprotection.

The compounds according to the invention in particular have PPARδ agonist properties and PPARa and therefore are of value in the treatment of metabolic diseases such as metabolic syndrome (whose characteristics are obesity (especially abdominal obesity), an abnormal concentration blood lipids (high triglycerides and / or low HDL cholesterol (dyslipidemia)), high blood glucose and / or insulin resistance, and hypertension) and in the treatment of dyslipidemia. The invention relates to new compounds of general formula (I):

Figure imgf000006_0001

(I) wherein: X1 is halogen, a group R1, -OR1 or -SR1; X2 represents a group R2; X3 represents a halogen, an R3 group, -SR 3 or -OR 3; X4 represents a halogen or a group R 4, -SR 4 or -OR 4; X5 represents a group R5, -OR5 or -SR5; X6 represents halogen, a group R 6, -SR 6 or -OR 6; X7 represents a halogen, a group R 7, -OR 7 or -SR 7; X8 represents a sulfur or oxygen atom;

R1, R3, R4, R6 and R7, identical or different, representing hydrogen or alkyl;

R2 is hydrogen or an alkyl group substituted or not by at least one cycloalkyl group, heterocycloalkyl, aryl or heteroaryl;

R5 representing an alkyl group substituted by one or more substituent (s) of group 1 or group 2;

R5 can, in addition to the one or more substitutions described above, be substituted with a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; A represents:

(I) a carbonyl group (C = O),

(Ii) an oxime group (C = NOH) or oxime ether (C = NO-R11), (iii) a group -CR9R10, R9 and R10, different, representing a hydrogen, an alkyl group or a group -OR 11 R11 being as defined below,

R11 representing a hydrogen or an aryl, heterocycloalkyl, heteroaryl, or heterosubstituted alkyl, unsubstituted or substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

B represents:

(i) an unsubstituted, saturated alkyl group having two carbon atoms (CH 2 -CH 2), (ii) an unsubstituted alkene group having two carbon atoms

(CH = CH),

the substituents from group 1 are selected from -COOR12 and -CONR12R13;

the substituents from group 2 are selected from -SO 3 H and -SO 2 NRI 2R13;

R12 and R13, identical or different, representing a hydrogen or an unsubstituted alkyl radical;

their stereoisomers (diastereoisomers, enantiomers), pure or mixed, their racemic mixtures, their geometrical isomers, tautomers, salts, hydrates, solvates, solid forms and mixtures thereof.

In the context of the present invention: - the term "alkyl" denotes a saturated hydrocarbon radical, linear, branched, halogenated or not, having more particularly from 1 to 24 carbon atoms, preferably 1 to 10, and having particular 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Mention may be made, for example, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl or n-hexyl.

In particular, an alkyl or alkenyl radical having 1 to 4 carbon atoms is preferably selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl tert-butyl and their unsaturated derivatives having at least one double bond (such as in particular: CH = CH).

- the term "cycloalkyl" denotes an alkyl group as defined above and forming at least one ring. Mention may be made, by way of cycloalkyl groups having from 3 to 8 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

- the term "heterocycloalkyl" denotes a saturated or unsubstituted alkyl group and forming at least one ring is interrupted by one or more heteroatoms selected from N, O, S or P. It may be mentioned, as heterocycloalkyl groups, aziridine, the pyrrolidine, tetrahydrothiophene, imidazoline, piperidine, piperazine and morpholine.

- the term "aryl" refers to aromatic groups preferably comprising 5 to 14 carbon atoms, preferably 6 to 14 carbon atoms (eg 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon carbon). They are generally mono- or bi-cyclic. There may be mentioned for example phenyl, benzyl, α-naphthyl, β-naphthyl, anthracenyl or fluorenyl. In the context of the present invention, aryl groups may be substituted by one or more substituents the same or different. Among the substituents of aryl groups that may be mentioned by way of example, halogen, alkyl (as defined above), the alkyloxy groups (defined as an alkyl chain (as defined above) linked to the molecule via an oxygen (ether bond)), alkylthio groups (defined as an alkyl chain (as defined above) bonded to the molecule via a sulfur (thioether linkage)) such as methyl, trifluoromethyl, methoxy and trifluoromethoxy, methylthio and trifluoromethylthio, amines, nitro, hydroxy, aryl, heteroaryl and heterocycle. - the term "heteroaryl" refers to aromatic groups preferably comprising 3 to 14 carbon atoms, preferably 3 to 8 carbon atoms (ie 3, 4, 6, 7 or 8 carbon atoms), interrupted by one or more heteroatoms selected from N, O, S or P. it may be mentioned include, by way of heteroaryl groups having 3 to 8 carbon atoms, pyrrole, imidazole and pyridine.

Among the substituents of heteroaryl groups include for example, halogen, alkyl (as defined above), the alkyloxy groups (defined as an alkyl chain (as defined above) linked to the molecule via an oxygen (ether bond)), alkylthio groups (defined as an alkyl chain (as defined above) bonded to the molecule via a sulfur (thioether linkage)) . Examples of such substituents are methyl, trifluoromethyl, methoxy and trifluoromethoxy, methylthio and trifluoromethylthio, amines, nitro, hydroxy, aryl, heteroaryl and heterocycle.

The halogen atoms are chosen from bromine, fluorine, iodine, chlorine, preferably from bromine, chlorine and fluorine.

A particular aspect of the invention relates to compounds of general formula (I) wherein A represents a carbonyl group (CO).

Another particular aspect of the invention relates to compounds of general formula (I) wherein A represents an oxime group (C = NOH) or oxime ether (C = NO-RH), R11 representing a linear or branched alkyl group include an alkyl group having 1 to 7 carbon atoms, unsubstituted or substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl. Preferably, R11 represents a methyl group.

In a particular embodiment, when A represents a group C = NO-RH, R11 is an alkyl group having 1 to 7 carbon atoms substituted by an aryl group, especially a phenyl group. More preferably, R11 is a methyl group substituted by a phenyl group, in other words R11 is a benzyl group. The alkyl or aryl groups may optionally be halogenated.

Another particular aspect of the invention relates to compounds of general formula (I) wherein A represents a -CR9R10 group, R9 represents hydrogen and R10 represents a hydroxy group, an alkyl group or a -OR11 group, R11 representing a group linear or branched alkyl, unsubstituted or substituted by cycloalkyl, especially cyclohexyl, heterocycloalkyl, aryl, in particular phenyl, or a heteroaryl group, especially a pyridyl group. Said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally halogenated.

In particular, R11 represents an alkyl group, linear or branched, having 1 to 7 carbon atoms, linear or branched, preferably having 1, 2, 3 or 4 carbon atoms, preferably 1 or 2 carbon atoms, preferably R11 represents methyl or ethyl.

Advantageously, R11 is substituted by cycloalkyl, especially cyclohexyl, aryl, especially phenyl, a heterocyclic or heteroaryl group, in particular pyridinyl, said cycloalkyl, aryl, heterocyclic or heteroaryl groups is optionally halogenated. Even more preferably, R11 represents an alkyl group, preferably comprising a carbon atom substituted by a phenyl group, iodophenyl, cyclohexyl or pyridinyl.

Another particular aspect of the invention relates to compounds of general formula (I) wherein A represents a -CR9R10 group, R9 represents hydrogen and R10 represents a hydroxy group.

Another preferred aspect of the invention relates to compounds of general formula (I) wherein A represents a -CR9R10 group, R9 represents hydrogen and R10 represents a -OR11 group, R11 being as defined above. In particular, R11 represents a linear or branched alkyl group having preferably 1, 2, 3 or 4 carbon atoms. R11 preferably is substituted by cycloalkyl, especially cyclohexyl, aryl, especially phenyl, heterocyclic, or heteroaryl, in particular pyridinyl group. Even more preferably, R11 represents an alkyl group, preferably comprising a carbon atom substituted by a phenyl group, iodophenyl, cyclohexyl or pyridinyl.

A particular aspect of the invention relates to compounds of general formula (I) wherein B represents unsubstituted, saturated alkyl group comprising two carbon atoms (CH2-CH2).

Another particular aspect of the invention relates to compounds of general formula (I) wherein X5 represents a group R5, -OR5 or -SR5, R5 represents an alkyl group substituted by a substituent group 1. Even more preferably, X5 represents a -OR5 group wherein R5 represents an alkyl group substituted by a substituent from group 1. preferably, the substituent group 1 is -COOR12.

Preferably, R5 represents an alkyl group formed of a linear, saturated carbon chain having 1 to 4 carbon atoms, said chain being connected by its end opposite the phenyl group (III), a substituent group 1. Said chain may be branched with at least one alkyl or alkenyl group having 1 to 4 carbon atoms, or susbtituée by cycloalkyl, especially cyclohexyl, or an aryl group, notably phenyl.

Preferably, R12 and R13, identical or different, represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

Preferably, the substituent from group 1 is -COOR12 type R12 being as defined above and preferably represents hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, in particular a tert-butyl group.

In a particular aspect of the invention X5 is selected from the groups -OC (CH 3) 2 COOR12, -OCH 2 COOR 2, -OCH (CH 2 CH 3) COOR 2, -OCH (CH 2 CH 2 CH 2 CH 3) COOR ^, -O (CH 2) 3 C (CH 3) 2 COOR12 and

-OCH (CeH 5) COOR 2. Advantageously, R12 can be chosen from hydrogen and -CH 3, -C (CH 3) 3 and -CH 2 CH 3.

Even more preferably, X5 represents a -OC (CH 3) 2 COOH, -OC (CH 3) 2 COOC (CH 3) 3, -OCH (CH 2 CH 3) COOC (CH 3) 3, -OCH (CH 2 CH 3) COOH, -OCH 2 COOH, -OCH 2 COOC (CH S) 3, -OCH (C 4 H 9) COOH, -OCH (C 4 H 9) COO (CHs) 3, -OCH (C 6 H 5) COO (CHs) 3, or -OCH (C 6 H 5) COOH.

A particular aspect of the invention relates to compounds of general formula (I) wherein R2 represents a hydrogen atom.

A particular aspect of the invention relates to compounds of general formula (I) wherein R2 represents an alkyl group not subtitué. Preferably, the alkyl group has 1 to 4 carbon atoms.

According to another aspect of the invention, the compounds of general formula (I) have at least one of X3, X4, X6 and X7 denotes a halogen atom or an alkyl group having 1 to 4 carbon atoms. And, optionally, the (s) group (s) remaining (that is to say, the (s) group (s) non-halogen (s) or non-alkylated (s) chosen (s) of X3, X4, X6 and X7) denotes (s) one (or more) atom (s) hydrogen.

Advantageously, X4 is a halogen atom, particularly a bromine atom.

Another particular object of the invention relates to compounds of general formula (I) wherein X3 and / or X4 are identical or different, represent a halogen, preferably chlorine or fluorine.

Preferably, X3 and X4 are identical and represent a halogen, preferably chlorine or fluorine, more preferably chlorine.

Another particular object of the invention relates to compounds of general formula (I) wherein X3 represents a hydrogen atom and X4 represents a bromine or fluorine atom.

Another particular object of the invention relates to compounds of general formula (I) wherein X4 and X6 represent an alkyl group, preferably a methyl group, and X3 and X7 are hydrogen atoms.

Another particular object of the invention relates to compounds of general formula (I) wherein X6 and X7 represents a hydrogen atom.

Preferably, X6 and X7 are hydrogen and X3 and / or X4 are identical or different, represent a halogen, preferably chlorine or fluorine.

Another preferred aspect relates to compounds of general formula (I) wherein X1 is R1 or -OR1 group, R1 representing a hydrogen or an alkyl group. Preferably, R1 represents an alkyl group having 1 to 4 carbon atoms, in particular 1, 2 or 3 carbon atoms, more preferably halogen. Another preferred aspect relates to the compounds of general formula (I) wherein X1 represents a halogen, preferably a bromine or chlorine atom.

In a particular embodiment of the invention, X1 is selected from a trifluoromethyl group, a bromine atom, a chlorine atom, a methylthio group, a methyloxy group and a trifluoromethoxy group. Optionally X 1 is -CF 3, -OCF 3, -SCH 3, preferably a -CF 3.

In a particular embodiment of the preferred invention, X1 represents a trifluoromethyl group located in the para position relative to the cycle II.

Another particular aspect of the invention relates to compounds of general formula (I) wherein R1 represents an alkyl group having 1 to 4 carbon atoms, optionally halogenated, R3, R4, R6 and R7, identical or different, represent a hydrogen or an alkyl group having 1 to 4 carbon atoms and R2 represents an alkyl group having 1 to 4 carbon atoms, for example methyl. Another particular object of the invention relates to compounds of general formula (I) wherein at least one of X3, X4, X6 and X7 is a halogen atom or an alkyl group, preferably methyl. (S) group (s) remaining one of X3, X4, X6 and X7 means (nt), preferably a (the) atom (s) hydrogen.

In particular, X3 and X4 are both halogen or methyl groups. Eventually, X3 and X4 may be identical. Halogen may be chlorine or fluorine.

Alternatively X4 may be a bromine atom.

Another particular object of the invention relates to compounds of general formula (I) wherein X8 represents a sulfur atom. Another particular object of the invention relates to compounds of general formula (I) wherein ring I is substituted with the X1 group in position C 4.

Even more preferably, the invention relates to the compounds of general formula (I) wherein at least one of the following conditions, preferably all conditions is met:

X6 and X7, are identical and represent hydrogen; and or

X3 and / or X4 are identical or different, represent a halogen, preferably chlorine or fluorine; and or

R2 represents a hydrogen atom or an unsubstituted alkyl groupemement; and or

X8 is oxygen or sulfur, preferably sulfur; and / or X5 represents a group R5, -OR5 or -SR5, R5 represents an alkyl group substituted by a substituent from group 1; and / or ring I is substituted with the X1 group in position C 4; and / or X 1 is halogen, R 1 group, -SR1 or -OR1, R1 is a hydrogen or an alkyl group, preferably halogen; and or

A represents:

(I) a carbonyl group (CO), (ii) an oxime group (C = NOH) or oxime ether (C = NO-R11),

(Iii) a group -CR9R10 different R9 and R10 representing a hydrogen, an alkyl group or a -OR11 group, R11 being as defined below,

R11 representing a hydrogen or an aryl, heterocycloalkyl or heteroaryl as defined below or an alkyl group, unsubstituted or substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl as defined above; and or

B represents an unsubstituted, saturated alkyl group comprising two carbon atoms (CH 2 -CH 2) or an unsubstituted alkene group having two carbon atoms (CH = CH).

In a particularly preferred embodiment, the invention relates to compounds of general formula (I):

Figure imgf000015_0001

(I) wherein:

X1 represents halogen, a group R1, -OR1 or -SR1; X2 represents a group R2;

X3 represents a halogen, an R3 group, -SR 3 or -OR 3; X4 represents a halogen or a group R 4, -SR 4 or -OR 4; X5 represents a group R5, -OR5 or -SR5; X6 represents halogen, a group R 6, -SR 6 or -OR 6; X7 represents a halogen, a group R 7, -OR 7 or -SR 7; X8 represents a sulfur or oxygen atom;

R1 representing an alkyl group having 1 to 4 carbon atoms, optionally halogenated;

R3, R4, R6 and R7, identical or different, representing a hydrogen or an alkyl group having 1 to 4 carbon atoms;

R2 represents an alkyl group having 1 to 4 carbon atoms, for example methyl; R5 represents an alkyl group formed of a linear, saturated carbon chain having 1 to 4 carbon atoms, preferably 1 carbon atom, said carbon chain is:

- linked, by its end opposite the phenyl group (III), with a substituent selected from -COOR12 and -CONR12R13, with R12 and R13, identical or different, representing a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and

- unbranched or branched with at least one alkyl or alkenyl having 1 to 4 carbon atoms, or substituted by cycloalkyl, especially cyclohexyl, or an aryl group, including phenyl;

A represents:

(I) a carbonyl group (C = O),

(Ii) an oxime group (C = NOH) or oxime ether (C = NO-RH), with R11 selected from hydrogen, an alkyl group (linear or branched) having 1 to 7 carbon atoms, unsubstituted or substituted aryl, especially a phenyl group; said alkyl and aryl groups being optionally halogenated, or

(Iii) a -CR9R10 group, R9 representing a hydrogen atom and R10 represents a -OR11 group, R11 being chosen from a hydrogen atom, an alkyl group (linear or branched) having 1 to

7 carbon atoms, preferably having 1 carbon atom, said alkyl group being unsubstituted or substituted by cycloalkyl, especially cyclohexyl, aryl, in particular phenyl or heteroaryl, in particular pyridinyl, said alkyl, cycloalkyl, aryl or heteroaryl being optionally halogenated,

B is (i) an unsubstituted alkyl group and saturated two carbon atoms (CH 2 -CH 2), or

(Ii) an unsubstituted alkene group, to two carbon atoms (CH = CH).

A variant of particularly preferred embodiment of the invention relates to compounds of general formula (I) wherein A represents a carbonyl group (C = O).

Another variant of the particularly preferred embodiment of the invention relates to compounds of general formula (I) wherein A represents a -CH (ORH), R11 is preferably selected from a hydrogen atom, a methyl group, ethyl, cyclohexylmethyl, benzyl, iodobenzyl and pyridinylmethyl.

An additional variant of the particularly preferred embodiment of the invention relates to compounds of general formula (I) wherein A represents an oxime group or oxime ether (C = NO-RH), the group R11 is preferably chosen from a hydrogen atom, a methyl, ethyl, cyclohexylmethyl, benzyl, iodobenzyl, pyridinylmethyl, even more preferably from hydrogen and methyl.

In another variant of the preferred embodiment, the invention relates to compounds of general formula (I) wherein X5 is an -OR5 group or an bioisomère of this group, e.g. -SR5, where R5 denotes an alkyl radical said carbon chain is linked to a substituent -COOR 12.

Advantageously, X5 is selected from the groups: -OC (CH 3) 2 COOR12, -OCH 2 COOR 2, -OCH (CH 2 CH 3) COOR 2,

-OCH (CH 2 CH 2 CH 2 CH 3) COOR 2, -O (CH 2) 3 C (CH 3) 2 COOR12 and

-OCH (C 6 H 5) 2 COOR.

Advantageously, R12 is selected from hydrogen and the groups - CH 3, -C (CH 3) 3 and -CH 2 CH 3.

The X1 group may be in any position of the cycle I, that is to say in the ortho, meta or para to the ring II. In a particular embodiment of the invention, X1 is meta or para position, preferably in the para position relative to the ring II.

In a particular embodiment of the invention, X1 is selected from a trifluoromethyl group, a bromine atom, a chlorine atom, a methylthio group, a methyloxy group and a trifluoromethoxy group. According to a preferred embodiment of the invention, X1 represents a trifluoromethyl group located in the para position relative to the cycle II.

According to another preferred embodiment of the invention, X1 represents a halogen atom, in particular chlorine, positioned para or ortho with respect to the cycle II.

In another variant of the preferred embodiment of the invention, the compounds according to the invention at least one of X3, X4, X6 and X7 denotes a halogen atom or an alkyl group having 1 to 4 carbon carbon. And, optionally, the (s) group (s) remaining (that is to say, the (s) group (s) non-halogen (s) or non-alkylated (s) chosen (s) of X3, X4, X6 and X7) denotes (s) one (or more) atom (s) hydrogen.

For example, it may include compounds in which X4 is a bromine atom. It can also include compounds for which X3 and X4 are identical and are either halogen atoms (chlorine, fluorine, bromine or iodine) or methyl groups. In particular, X3 and X4 may be identical and correspond to chlorine atoms or fluorine.

In a particular aspect of the invention, in the particularly preferred embodiment of the invention, X4 and / or X6 denotes (s) an alkyl group, in particular X4 and X6 are both methyl, and X3 and X7 groups are atoms 'hydrogen.

Preferably, the compounds of the invention are selected from:

- 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2 -méthylpropanoate tert-butyl;

- 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) acetate tert-butyl;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) acetic acid; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) hexanoate tert-butyl;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) hexanoic acid;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate ;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) butanoate; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) butanoic acid;

- 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate ; - 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;

- 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque; - 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque;

- 2- (4- (3- (benzyloxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) -2,3-dichlorophenoxy) -2 -méthylpropanoïque;

- 2- (2,3-dichloro-4- (3-hydroxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate;

- 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate

- 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) butanoic acid; - 2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2-methylpropanoate tert-butyl;

- racide-2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) -2- methylpropanoic;

- 2- (4- (3- (4-iodobenzyloxy) -3 (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) -2,3-dichlorophenoxy ) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;

- 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-hydroxypropyl) phenoxy) -2-methylpropanoic acid;

- 2- (4- (3- (benzyloxy) -3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) - propyl) -2,3-dichlorophenoxy) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2 -méthylpropanoate tert-butyl;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3-oxo-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate ; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;

- 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate;

- 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid;

- 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate;

- 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (cyclohexylmethoxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid;

- 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate ;

- 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;

- 2- (2,3-dichloro-4- (3- (hydroxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (methoxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;

- 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-phenylacetate of ethyl;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-phenylacetic acid ; - 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2,2-dimethylpentanoate methyl;

- 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2,2 -diméthylpentanoïque; - 2-methyl-2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) propanoate;

- 2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy-2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3- (pyridin-3-ylmethoxy) propyl ) phenoxy) -2-methylpropanoic acid;

- 2- (2,3-dichloro-4- (3-methoxy-3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque;

- 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate ; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;

- 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;

- 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid;

- 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate ;

- 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid .

The compounds of the present invention include their stereoisomers (diastereoisomers, enantiomers), pure or mixed, their racemic mixtures, their geometrical isomers, tautomers, salts, hydrates, solvates, solid forms and mixtures thereof.

The compounds of the invention may contain one or more asymmetric centers. The invention includes stereoisomers (diastereoisomers, enantiomers), pure or mixed, as well as racemic mixtures and geometric isomers. When an enantiomerically pure mixture (or enriched) is desired, it may be obtained either by purification of the final product or chiral intermediates or by asymmetric synthesis according to methods known to the skilled worker (for example using the reagents and catalysts chiral). The compounds of the invention can have different shapes stable and all these forms tautomers and mixtures thereof are included in the invention.

The invention also relates to the salts "pharmaceutically acceptable" compounds of formula (I) according to the invention. Generally speaking, this term refers to little or nontoxic salts derived from bases or acids, organic or inorganic. These salts can be obtained during the final purification step of the compounds of the invention or by incorporating the salt on the already purified compounds.

Certain compounds of the invention and their salts could be stable in several solid forms. The present invention includes all of the solid forms of the compounds according to the invention, including amorphous forms, polymorphs, mono- and poly-crystalline.

The compounds of the invention can exist in free form or solvated form, for example, with pharmaceutically acceptable solvents such as water (hydrates) or ethanol.

The compounds according to the invention may optionally be labeled with one or more isotopes (radioactive or not). Examples of isotopes that can be included in the structure of compounds according to the invention may be selected from hydrogen, carbon, oxygen, sulfur such as 2 H, 3 H, 13 C, 14 C, 18 O , 17 0, 35 S, respectively. Radioactive isotopes 3 H and 14 C are preferred as easy to prepare and detect in bioavailability studies under in vivo substances. Heavy isotopes (such as H 2) are particularly preferred; They are especially used as internal standards in analytical studies. The present invention also relates to a synthesis of compounds of general formula method (I) which comprises:

1. a step of contacting in basic medium or in acidic medium at least one compound of formula (C) with at least one compound of formula (D):

Figure imgf000024_0001

wherein X1, X2, X3, X4, X6, X7 and X8 are as defined above,

Y5 represents a group R5, -SR5, -OR5, hydroxy or thiol, R 5 being as defined above;

2. possibly a reduction step of the compounds obtained in step

(1),

And optionally 3. a step of inserting functional groups.

The conditions of implementation of step (1) in acidic or basic medium and in step (2) are known to those skilled in the art and may vary to a large extent. The synthetic protocols may be particularly presented in the "examples" of the present invention.

The contacting of these two compounds is advantageously carried out stoichiometrically. It is preferably carried out at a suitable temperature (between about 18 ° C and 100 0 C) and preferably at atmospheric pressure.

In basic medium, the reaction is preferably performed in the presence of a strong base, such as an alkali metal hydroxide such as sodium hydroxide or an alkali metal alkoxide such as sodium ethoxide. In acidic medium, the reaction is preferably performed in the presence of a strong acid, such as hydrochloric acid.

The resulting compounds can be isolated by conventional methods known in the art.

The present invention also relates to the compounds as described hereinbefore, as medicaments.

The present invention also relates to a compound as described hereinbefore, for the treatment of complications associated with metabolic syndrome, atherosclerosis, cerebral ischemia, autoimmune diseases, cardiovascular diseases, insulin resistance, obesity, hypertension, diabetes, dyslipidemias, inflammatory diseases (such as asthma), neurodegenerative diseases (particularly multiple sclerosis, Parkinson's disease, Alzheimer's disease , tauopathies (frontotemporal dementias, Pick's disease, corticobasal degeneration, progressive supranuclear palsy), cortical dementias, spinal amyotrophies, mild cognitive impairment (MCI mild cognitive Impairment) synucleopathies, the body pathologies Lewy, Huntington's chorea, epilepsy, amyotrophic lateral sclerosis, prion disease (Creutzfeldt-Jakob disease), syndrome Down, Friedreich's Ataxia, spinocerebellar ataxia cerebellar disease Charcot-Marie-Tooth disease, neurological complications associated with AIDS, chronic pain, cerebellar degeneration, cerebellar hypoxia, neuropathies associated with diabetes) cancers, as well as allowing the reduction of overall cardiovascular risk.

Preferably, the invention relates to a compound as described hereinbefore, for treating cardiovascular risk factors related to deregulations of lipid and / or carbohydrate (including hyperlipidemia, type II diabetes, obesity, etc. .) allowing the reduction of overall cardiovascular risk. Even more preferably, the invention relates to a compound as described above, for the treatment of diabetes or dyslipidemia.

The present invention also relates to a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, at least one compound as described above, optionally in combination with one or more other therapeutic active ingredients and / or cosmetic. It is advantageously a pharmaceutical composition for the treatment of complications associated with metabolic syndrome, atherosclerosis, cerebral ischemia, autoimmune diseases, cardiovascular disease, insulin resistance, obesity , hypertension, diabetes, dyslipidemias, inflammatory diseases (such as asthma), neurodegenerative diseases (particularly multiple sclerosis, Parkinson's disease, Alzheimer's disease, tauopathies (frontotemporal dementias -temporales, Pick's disease, corticobasal degeneration, progressive supranuclear palsy), cortical dementias, spinal amyotrophies, mild cognitive impairment (MCI mild cognitive Impairment) synucleopathies, pathologies with Lewy bodies, chorea of Huntington, epilepsy, amyotrophic lateral sclerosis, prion disease (Creutzfeldt-Jakob disease), Down's syndrome, Ataxia Friedrei ch, ataxia spinocerebellar, disease Charcot-Marie-Tooth disease, neurological complications associated with AIDS, chronic pain, cerebellar degeneration, cerebellar hypoxia, neuropathies associated with diabetes), cancer, and for allow the reduction of overall cardiovascular risk. II preferably is a pharmaceutical composition for treating cardiovascular risk factors related to deregulations of lipid and / or carbohydrate (including hyperlipidemia, type II diabetes, obesity, etc.) allowing the reduction of overall cardiovascular risk.

Even more preferably, the pharmaceutical composition of the invention is for the treatment of dyslipidemia.

Another object of the invention relates to a nutritional composition comprising at least one compound as described above. The present invention also relates to the compounds as described hereinbefore, as cosmetics.

Another object of the invention is the use of at least one compound as described above for the preparation of pharmaceutical compositions for the treatment of various pathologies as defined above, particularly related to metabolic disorders carbohydrate and / or lipid including dyslipidemia may be mentioned. More generally, the invention is the use object of at least one compound as described above for the preparation of pharmaceutical compositions for treating the risk factors for cardiovascular disease related to lipid metabolism disorders and / or carbohydrates and intended and reduce overall cardiovascular risk.

For example (and without limitation), the compounds according to the invention may advantageously be administered in combination with one or more other therapeutic and / or cosmetic agents, marketed or in development, such as:

- anti-diabetics: the insulin secretors (sulfonylureas (glibenclamide, glimepiride, gliclazide, etc.) and meglitinides (repaglinide, nateglinide, etc.)), inhibitors of alpha-glucosidase, PPAR gamma agonists (thiazolidinediones such as rosiglitazone, pioglitazone), mixed agonists PPARa / PPAR (tesaglitazar, muraglitazar), pan-PPAR (compounds simultaneously activating three PPAR isoforms), biguanides (metformin), inhibitors of dipeptidyl Peptidase IV (sitagliptin, vildagliptin), agonists of Glucagon-Like Peptide-1 (GLP-1) (exenatide), etc.,

- insulin,

- molecules hypolipidemic and / or hypocholesterolemic: fibrates (fenofibrate, gemfibrozil), the HMG CoA reductase inhibitor or hydroxylméthylglutaryl Coenzyme A reductase (statins such as atorvastatin, simvastatin, fluvastatin), cholesterol absorption inhibitors ( ezetimibe, phytosterols), the CETP inhibitors or Cholesteryl Ester Transfer Protein (torcetrapib), inhibitors of ACAT or Acyl-Coenzyme A cholesterol acyltransferase (Avasimibe, eflucimibe), MTP inhibitors (Microsomal Triglyceride Transfer Protein), agents bile acid sequestrants (cholestyramine), vitamin E, polyunsaturated fatty acids, omega 3 fatty acids, nicotinic acid derivatives (niacin), etc.,

- antihypertensive agents and hypotensive agents: ACE inhibitors (Angiotensin-Converting Enzyme) inhibitors (captopril, enalapril, ramipril or quinapril), antagonists of the angiotensin II receptor antagonist (losartan, valsartan, telmisartan, eposartan, irbesartan, etc.), beta blockers (atenolol, metoprolol, labetalol, propranolol), thiazide and non-thiazide diuretics (furosemide, indapamide, hydrochlorothiazide, anti- aldosterone), vasodilators, calcium channel blockers (nifedipine, felodipine or amlodipine , diltiazem or verapamil), etc.

- antiplatelet agents aspirin, ticlopidine, dipyridamole, clopidogrel, flurbiprofen, etc.

- anti-obesity agents: sibutramine, lipase inhibitors (orlistat), PPARδ agonists and antagonists, antagonists of the cannabinoid CB1 receptor (rimonabant), etc.,

- anti-inflammatory agents, eg, corticosteroids (prednisone, betamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, etc.), NSAIDs or anti-inflammatory drugs indole derivatives (indomethacin, sulindac), NSAIDs the aryl carboxylic group (tiaprofenic acid, diclofenac, etodolac, flurbiprofen, ibuprofen, ketoprofen, naproxen, nabumetone, alminoprofen), the NSAID derivatives of oxicam (meloxicam, piroxicam, tenoxicam), NSAIDs group of the fenamates, selective inhibitors COX2 (celecoxib, rofecoxib), etc.

- of antioxidants: for example probucol, etc.

- agents used in the treatment of heart failure: thiazide diuretics or not thiazide (furosemide, indapamide, hydrochlorothiazide, anti-aldosterone), the ACE inhibitors (captopril, enalapril, ramipril and quinapril), digitalis ( digoxin, digitoxin), beta blockers (atenolol, metoprolol, labetalol, propranolol), inhibitors of phosphodiesterases (enoximone, milrinone), etc.,

- agents used for the treatment of coronary insufficiency: beta-blockers (atenolol, metoprolol, labetalol, propranolol), calcium channel blockers (nifedipine, felodipine or amlodipine, bepridil, diltiazem or verapamil), donors agents NO (nitroglycerine, isosorbide dinitrate, molsidomine), amiodarone, etc.

- anticancer: cytotoxic agents (agents interacting with DNA, alkylating agents, cisplatin and derivatives), cytostatic agents (GnRH analogues (Gonatropin-releasing hormone), somatostatin analogues, progestogens, anti-estrogens , the aromatase inhibitors, etc.), modulators of the immune response (interferons, IL-2, etc.), etc.

- anti-asthmatic agents such as bronchodilators (beta 2 agonists), corticosteroids, cromoglycate, receptor antagonists to leukotrienes (montelukast), etc.,

- corticosteroids used in the treatment of skin diseases such as psoriasis and dermatitis,

- vasodilators and / or anti-ischemic agents (buflomedil, Ginkgo Biloba extract, naftidrofuryl, pentoxifylline, piribedil), etc.,

The invention also relates to a method of treating various pathologies as defined above, in particular related to lipid metabolism disorders and / or carbohydrate, comprising administering to a subject, particularly human, an effective amount of a compound or a pharmaceutical composition as defined above.

For the purposes of the invention, the term "effective amount" refers to an amount of the compound sufficient to produce the desired biological result. The term "subject" means a mammal and particularly a human.

The term "treatment" means the curative, symptomatic and / or preventive. The compounds of the present invention can thus be used in subjects (such as mammals, particularly humans) with a declared disease. The compounds of the present invention can also be used to delay or slow the progression or prevent further progression of the disease, improving the condition of the subjects. The compounds of the present invention may finally be given to non-diseased subjects, but that might normally develop the disease or who have a high risk of developing the disease.

The pharmaceutical compositions according to the invention advantageously comprise one or more excipients or carriers, pharmaceutically acceptable plan. These include, for example, saline, physiological, isotonic, buffered, etc., compatible with pharmaceutical use and known to the skilled person. The compositions may contain one or more agents or vehicles selected from among dispersants, solubilisers, stabilizers, preservatives, etc. Agents or vehicles used in the formulations (liquid and / or injectable and / or solid) are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, the acacia, liposomes, etc. The compositions may be formulated as suspensions for injection, gels, oils, tablets, suppositories, powders, capsules, aerosols, etc, possibly by means of pharmaceutical forms or devices ensuring prolonged and / or delayed release. For this type of formulation used is advantageously an agent such as cellulose, carbonates or starches.

The compounds or compositions according to the invention can be administered in different ways and in different forms. Thus, they may for example be administered systemically, orally, parenterally, by inhalation or by injection, such as intravenous, intramuscular, subcutaneous, transdermal, intra-arterially, etc. For injections, the compounds are generally packaged in the form of liquid suspensions that can be injected through syringes or by infusion, for example. It is understood that the flow rate and / or the injected dose can be adapted by the skilled person depending on the patient, the pathology, the mode of administration, etc. Typically, the compounds are administered at doses ranging from 1 .mu.g to 2 g per administration, preferably from 0.01 mg to 1 g per administration. Administrations may be repeated daily or even several times a day, if necessary. Furthermore, the compositions of the invention may also comprise other agents or active ingredients.

LEGENDS OF FIGURES

Abbreviations used in Figures and Tables:

- Cpd = compound - Ctrl = control

- mpk = mg / kg / day.

- LDL-cholesterol = Low Density Lipoprotein cholesterol

- HDL cholesterol = High Density Lipoprotein Cholesterol

- VLDL-cholesterol = Very Low Density Lipoprotein Cholesterol - Free fatty acids Free fatty acids =

Figures 1-1 to 1-4: In vitro evaluation of PPARδ activating properties of the compounds of the invention by measuring the expression of target genes of PPARδ in murine myocytes The stimulatory effects of lipid metabolism, carbohydrate and expenditure energy of the compounds according to the invention were evaluated by measuring the expression of the pyruvate Dehydrogenase Kinase 4 (PDK4) of Carnitine Palmotoyl Transferase Ib, the uncoupling protein 2 (UCP2) and Uncoupling Protein 3 (UCP3) by murine myocytes treated for 24 hours with the compounds according to the invention. It is disclosed that the regulation of the expression of these genes is directly controlled by PPARδ in this cell type. More gene expression is increased, the more the compound of the invention is PPARδ activator and thus stimulating the metabolism in the muscle cells. The expression levels shown were normalized to the expression level of the reference gene 36B4.

- Figure 1-1: Expression of PDK4 in human myocytes, treated for 24 hours with the compound 8 according to the invention in dosage effect of from 5 to 50OnM;

- Figure 1-2: Expression of CPTI b in human myocytes, treated for 24 hours with the compound 8 according to the invention in dosage effect of from 5 to

50OnM; - Figure 1-3: Expression of UCP2 in human myocytes, treated for 24 hours with the compound 8 according to the invention in dosage effect of from 5 to 50OnM;

- Figure 1-4: Expression of UCP3 in human myocytes, treated for 24 hours with the compound 8 according to the invention in dosage effect of from 5 to

50OnM.

Figures 2-1 to 2-7: In vivo evaluation in mice E2 / E2, of hvpolipémiantes and stimulatory properties of synthetic HDL-cholesterol compounds of the invention by lipid assays and measuring the expression of genes involved in lipid and carbohydrate metabolism and energy dissipation.

The lipid-lowering effect of the compounds according to the invention were evaluated in vivo in the mouse E2 / E2 (E2 humanized isoform apolipoprotein E) by analyzing the distribution of cholesterol in the various fractions lipoprotéigues plasmatigues, and by measuring triglycerides plasmatigues after 7 days of oral treatment. These rates were compared to those obtained with control animals (not treated with the compounds according to the invention): the measured difference shows the hypolipidemic effect of the compounds according to the invention.

- Figure 2-1: distribution of cholesterol in the various fractions lipoprotéigues plasmatigues after 7 days of treatment with Compound # 8 administered at 20 mpk;

- Figure 2-2: Triglycerides plasmatigues after 7 days of treatment with compound 8, administered at 20 mpk.

The effectiveness of the compounds of the invention was also evaluated by measuring in hépatigues and muscle tissue (sguelettigues), the expression of genes in metabolism impligués lipidigue, glucidigue and energy dissipation. Chague levels of gene expression were normalized to the expression level of 36B4 reference genes in 18S hépatigue or tissue in the gastrocnemius muscle sguelettigue. The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, is then calculated. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group. - Figure 2-3: Expression of PDK4 (Pyruvate Dehydrogenase Kinase isoform 4) in liver tissue in mice E2 / E2 after 7 days of treatment with Compound # 8 (20 mpk);

- Figure 2-4: Expression of Acoxi in the hepatic tissue, in the E2 / E2 mouse, after 7 days of treatment with Compound # 8 (20 mpk); - Figure 2-5: Expression of ApoCIII in liver tissue in mice

E2 / E2 after 7 days of treatment with Compound # 8 (20 mpk);

- Figure 2-6: Expression of UCP2 (uncoupling protein 2) in skeletal muscle, in the E2 / E2 mouse, after 7 days of treatment with Compound # 8 (20 mpk); - Figure 2-7: Expression of UCP3 (Uncoupling protein 3) in skeletal muscle in mice E2 / E2 after 7 days of treatment with Compound # 8 (20 mpk).

Figures 3-1 to 3-13: Evaluation in vivo, in C57BI6 mice, hvpolipémiantes and stimulatory properties of synthetic HDL-cholesterol compounds of the invention by lipid assays and measuring the expression of genes involved in the lipid and carbohydrate metabolism and energy dissipation.

The effect of the compounds according to the invention was evaluated in vivo in C57BI6 mice by measuring plasma levels of HDL-cholesterol, triglycerides and free fatty acids after 7 and 14 days of oral treatment. These rates were compared to those obtained with control animals (not treated with the compounds according to the invention): the measured difference shows the hypolipidemic effect of the compounds according to the invention. - Figure 3-1: plasma total cholesterol level after 7 and 14 days of treatment with compound 8, administered at 50 mpk;

- Figure 3-2: plasma HDL-cholesterol level after 7 and 14 days of treatment with compound 8, administered at 50 mpk; - Figure 3-3: Plasma triglyceride levels after 7 and 14 days of treatment with compound 8, administered at 50 mpk;

- Figure 3-4: Rate of plasma free fatty acids after 7 and 14 days of treatment with Compound # 8 administered at 50 mpk; - Figure 3-5: plasma total cholesterol level after 7 and 14 days of treatment with compound 14, administered at 50 mpk.

The effectiveness of the compounds of the invention was also evaluated by measuring, in liver and muscle tissues (skeletal), the expression of genes involved in lipid metabolism, carbohydrate and energy dissipation. The expression levels of each gene were normalized relative to the 36B4 level of expression of reference genes in liver tissue or 18S in the gastrocnemius skeletal muscle. The induction factor was then calculated. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

- Figure 3-6: Expression of PDK4 (Pyruvate dehydrogenase isoform 4) in the hepatic tissue, in the C57BI6 mice, after 14 days of treatment with Compound # 8 (50 mpk); - Figure 3-7: Expression of the Acoxi (Acyl coenzymeA oxidase) in the hepatic tissue, in the C57BI6 mice, after 14 days of treatment with Compound # 8 (50 mpk);

- Figure 3-8: Expression of PDK4 (Pyruvate dehydrogenase isoform 4) in the hepatic tissue, in the C57BI6 mice, after 14 days of treatment with compound 14 (50 mpk);

- Figure 3-9: Expression of the Acoxi (Acyl coenzymeA oxidase) in the hepatic tissue, in the C57BI6 mice, after 14 days of treatment with compound 14 (50 mpk);

- Figure 3-10: Expression of CPTIa (Carnitine palmitoyltransferase 1A) in the hepatic tissue, in the C57BI6 mice, after 14 days of treatment with compound 14 (50 mpk); - Figure 3-11: Expression of UCP2 (uncoupling protein 2) in skeletal muscle, in the C57BI6 mice, after 14 days of treatment with Compound # 8 (50 mpk);

- Figure 3-12: Expression of UCP2 (uncoupling protein 2) in skeletal muscle, in the C57BI6 mice, after 14 days of treatment with compound 14 (50 mpk);

- Figure 3-13: Expression of UCP3 (Uncoupling protein 3) in skeletal muscle, in the C57BI6 mice, after 14 days of treatment with compound 14 (50 mpk).

Figures 4-1 to 4-8: In Vivo Evaluation, in the db / db mice, the hypolipidemic properties, antidiabetic and activator of PPAR compounds according to the invention. The effect of compounds according to the invention was evaluated in vivo in the db / db mouse plasma cholesterol measurement and blood glucose levels after 14 and 28 days of oral treatment with the compound of the invention. These rates were compared to those obtained with control animals (not treated with the compound according to the invention): the measured difference shows the hypolipidemic effect and insulin resistance of the compound of the invention. - Figure 4-1: plasma total cholesterol after 14 and 28 days of treatment with compound 8, administered at 50 mpk;

- Figure 4-2: Blood Glucose after 14 and 28 days of treatment with Compound # 8 administered at 50 mpk.

The efficacy of the compound of the invention was also evaluated by measuring, in liver and muscle tissue expression of genes involved in glucose metabolism, lipid, and energy dissipation. The levels of expression of each gene were normalized to the expression level of 36B4 reference genes in the liver and 18S in the skeletal muscle. The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, is then calculated. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

- Figure 4-3: Expression of PDK4 (Pyruvate Dehydrogenase Kinase isoform 4) in the hepatic tissue, in the db / db mice after 28 days of treatment with Compound # 8 administered at 50 mpk; - Figure 4-4: Expression of ApoCIII (Apolipoprotein C3) in the hepatic tissue, in the db / db mice after 28 days of treatment with Compound # 8 administered at 50 mpk;

- Figure 4-5: Expression of CPTI b (carnitine palmitoyl transferase 1b) in the hepatic tissue, in the db / db mice after 28 days of treatment with Compound # 8 administered at 50 mpk;

- Figure 4-6: Expression of CPTI b (carnitine palmitoyl transferase 1b) in muscle tissue, in the db / db mice after 28 days of treatment with Compound # 8 administered at 50 mpk;

- Figure 4-7: Expression of UCP2 (Uncoupling Protein 2) in muscle tissue, in the db / db mice after 28 days of treatment with Compound # 8 administered at 50 mpk;

- Figure 4-8: Expression of UCP3 (uncoupling protein 3) in muscle tissue, in the db / db mouse, after 28 days of treatment with compound 8, administered at 50 mpk.

Figure 5: In vitro evaluation of the metabolic properties of the compounds according to the invention by measuring the β-oxidation of fatty acids in myocvtes

The stimulatory effects of the compounds according to the invention were evaluated by measuring the β-oxidation of fatty acids in myocytes pretreated for 24 hours with the compounds according to the invention. More induction of β-oxidation of fatty acids is increased, the more the compounds of the invention are stimulators of breakdown of fatty acids into muscle cells. Figure 6: In vitro evaluation of activating properties of reverse cholesterol transport of the compounds according to the invention by measuring the expression of the ABCA1 gene in macrophages.

The effect of compounds of the invention on cholesterol reverse transport was assessed by measuring expression of the gene ABCA1 (ATP-binding cassette, sub-family A, member 1; membrane transporter involved in the efflux of ) cholesterol in macrophages. More expression ABCAL is increased, the more the compound of the invention stimulates reverse cholesterol transport.

Figures 7-1 to 7-3: In vitro evaluation of anti-inflammatory properties of the compounds according to the invention by measuring the secretion and expression of MCP1 and MMP9 by monocytes treated with the compounds of the invention and stimulated PMA

The anti-inflammatory effects of compounds of the invention were evaluated by measuring the secretion and expression of Monocyte Chemoattractant

Protein-1 (MCP1) and by measuring the expression of matrix metalloproteinase 9 (MMP9) by monocytes treated for 24 hours with the compounds of the invention and stimulated with PMA (phorbol 12-myristate 13-acetate , which causes an inflammatory response of the cells). Plus the amount of MCP1 secreted is decreased, the more the compound of the invention inhibits the inflammatory response. Similarly, the greater the expression of MCP1 and MMP9 genes is inhibited, the more the compound according to the invention is anti-inflammatory.

- Figure 7-1: Secretion of MCP1 (monocyte chemoattractant protein-1) in human monocytes treated with compound 8 according to the invention at 1 .mu.M;

- Figure 7-2: Expression of MCP1 (monocyte chemoattractant protein-1) in human monocytes treated with compound 8 according to the invention at 1 .mu.M;

- Figure 7-3: Expression of MMP9 (matrix metalloproteinase 9) in human monocytes treated with compound 8 according to the invention at 1 .mu.M. Figures 8-1 to 8-3: In vitro evaluation of anti-inflammatory properties of the compounds according to the invention by measuring the secretion and expression of IL6 and MCP1 macrophages pretreated with the compounds of the invention and stimulated with LPS anti-inflammatory effects of compounds of the invention were evaluated by measuring the secretion and expression of interleukin-6 (IL-6) and by measuring the expression of monocyte chemoattractant protein 1 (MCP1) by macrophages pretreated for 24 hours with the compounds of the invention and stimulated for 6 hours with LPS (lipopolysaccharide, which causes an inflammatory response of the cells). The greater the amount of secreted IL-6 is decreased, the more the compound of the invention inhibits the inflammatory reaction. Similarly, over expression of IL-6 and MCP-1 genes is inhibited, the more the compound according to the invention is anti-inflammatory.

- Figure 8-1: Secretion of IL-6 (interleukin 6) by human macrophages, treated with compound 14 according to the invention at 10 .mu.M;

- Figure 8-2: Expression of IL-6 (interleukin 6) in human macrophages treated with the compounds 8 and 14 according to the invention at 10 .mu.M;

- Figure 8-3: Expression of MCP1 (monocyte chemoattractant protein-1) in human macrophages treated with Compound # 8 according to the invention at 10 .mu.M;

Other advantages and aspects of the invention will appear on reading the following examples, which should be considered as illustrative and not restrictive.

STATISTICAL ANALYZES

The statistical studies consist of a student's t-test and / or analysis of variance univariate (ANOVA) followed by Tukey test. The results are compared with the control group according to the value of the parameter p: *: p <0.05;**: p <0.01;*** P <0.001. EXAMPLES

The reagents and conventional catalysts are commercially available (Aldrich,

Alfa Aesar, Acros, Fluka or Lancaster as appropriate), In these examples, various analyzes are performed for the identification of compounds,

melting points (mp) are given in degrees Celsius,

The purity of the product was checked by Thin Layer Chromatography

(TLC) and / or by HPLC (high performance liquid chromatography), Infra-Red (IR) spectra were performed on an inert support (crystal

Germanium),

Mass spectra were acquired by ESI-MS (Electrospray Ionization -

Mass Spectroscopy), Q-TOF (Quadripol - Time of Flight) or MALDI-TOF (Matrix

Assisted Laser Desorption / Ionization - Time of Flight) Spectra Nuclear Magnetic Resonance Proton (1 H NMR) were recorded on a Bruker AC300P, chemical shifts are expressed in ppm (parts per million) and multiplicities by common abbreviations.

Example 1: Description of general protocols for synthesis of the invention

General Procedure A

The thiobenzamide and the halogenated derivative (1, 3 eq.) Are dissolved in ethanol (1 to 15 g, from 0.5 to 3.2 mol / L). The medium is stirred at 180 0 C for 3 hours in a sealed tube. The solvent was removed by evaporation under reduced pressure. The evaporation residue is purified by crystallization in ethanol.

General Procedure B:

The thiobenzamide and the halogenated derivative (1 eq.) Are dissolved in ethanol (1 14 g, 0.1 1, 2 mol / L) and then a solution of hydrochloric acid is added (2.5 to 6 eq.). The mixture is stirred at 80 0 C for 18 hours. The solvent was removed by evaporation under reduced pressure. The evaporation residue is purified by crystallization in ethanol.

General Procedure C: The ketone (1 eq.) and aldehyde (1 eq.) are dissolved (0.4 to 14 g, 0.1 to 0.7 mol / L) in a saturated ethanol solution of gaseous hydrochloric acid.

General procedure D:

The propenone and triethylsilane (2.25 eq.) Are dissolved (0.3 to 3 g, 0.1 to 0.2 mol / L) in dichloromethane. Trifluoroacetic acid (7.6 eq.) Was added dropwise. After stirring for 16 hours at room temperature, the reaction medium is washed with water, the solvent is removed by evaporation under reduced pressure and the evaporation residue is purified by flash chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1 to 8/2 gradient, silica 40-63μm.

General Procedure E:

Prop-2-en-1-one is dissolved in a 2: 1 chloroform / methanol (0.2 to 5 g, 0.02 to 0.1 mol / L) and a catalytic amount of palladium on charcoal ( 10 Wt%) was added. The assembly is placed under a hydrogen atmosphere at atmospheric pressure.

General procedure F:

The propenone was dissolved in tetrahydrofuran (0.2 to 0.4 g, 0.1 mol / L) and catecholborane was added. After stirring for 16 hours at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is diluted with ethyl acetate then, washed sequentially with a 2N sodium hydroxide solution, and a citric acid solution (pH = 6). The organic phase is concentrated under reduced pressure and the evaporation residue is purified by chromatography on silica gel. General Procedure G:

The phenol or thiophenol is dissolved in the appropriate solvent (0.1 to 5 g, 0.1 to 0.8 mol / L) and the halogenated derivative (3 to 10 eq.) And potassium carbonate (3-12 eq.) are added. The reaction medium is maintained under vigorous stirring at the appropriate temperature.

General procedure H:

The tert-butyl ester is dissolved in dichloromethane (0.1 to 7 g, 0.2 to 2 mol / L), trifluoroacetic acid is added. Stirring is maintained at room temperature.

General procedure I:

The propanone was dissolved in the appropriate solvent (0.1 to 6 g, 0.1 to 0.3 mol / L). Sodium borohydride is added. The whole is kept under stirring at room temperature.

General procedure J:

The alcohol is dissolved in N, N-dimethylformamide (0.1 to 7 g, 0.1 mol / L), the whole is cooled to 0 0 C and sodium hydride is added. After 15 minutes of stirring, the appropriate alkyl bromide was added and the mixture is stirred.

General procedure K:

The propanone was dissolved in pyridine (0.3 g, 0.1 mol / L). Hydrochloride O-alkylhydroxylamine (10 equivalents) was added. After 16 h of reflux, the mixture is evaporated under reduced pressure and the evaporation residue is purified by flash chromatography on silica gel. The oil obtained is crystallized from methanol.

General Procedure L:

The ester is dissolved in ethanol (0.2 to 0.4 g, 0.05 to 0.1 mol / L) and then 2N sodium hydroxide solution is added. After 18h stirring at room temperature the mixture is concentrated under reduced pressure and then acidified with dilute aqueous hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure.

EXAMPLE 2 Synthesis of the raw materials involved in the synthesis of the compounds according to the invention:

Raw material 1: 3,5-diméthv-4-hvdroxvbenzaldéhyde

Figure imgf000043_0001

2,6-dimethylphenol (0.34 g / mL) and hexamethylenetetramine (2 eq.) Are dissolved in acetic acid / water 2/1. The whole is heated at 100 0 C for 4 hours. The reaction medium is cooled to room temperature poured onto water / ice mixture. The precipitate is drained.1 H NMR (300MHz, CDCl 3, δ in ppm): 2.33 (s, 6H); 5.90 (s, 1H); 7.55 (s, 2H); 9.81 (s, 1H).

raw material 2: 2,3-dichloro-4-hvdroxvbenzaldéhyde

Figure imgf000043_0002
Sodium carbonate (3.5 eq.), Calcium hydroxide (4.5 eq.) And 2,3-dichlorophenol (0.15 g / L) are added to water, the suspension is heated at 70 0 C for 4 hours. Chloroform (2 eq.) Is added dropwise. The whole is stirred at 70 ° C for 16 hours. The reaction medium is cooled to 0 0 C, acidified (pH = 2) with a concentrated hydrochloric acid solution. The whole is extracted with ethyl acetate; The organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by flash chromatography on silica gel. (Elution: cyclohexane / ethyl acetate: 9/1 to 7/3 gradient, silica 40-63μm). The solid obtained is recrystallized from isopropanol.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 7.20 (d, 1H, J = 8.8Hz); 7.70 (d, 1H, J = 8.8Hz); 10.13 (s, 1H).

Raw material 3: 2-chloro-4-methyl-3-oxopentanoate oo

Cl

The ethyl isobutyrylacetate (0.6 to 6 g) was cooled under an inert atmosphere at 0 0 C.

Sulfuryl chloride (1 eq.) Is added dropwise. After 1 hour of stirring at room temperature, the reaction medium is diluted with ethyl acetate and then washed with a saturated sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by flash chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 100/0 to 98/2 gradient, silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 18 (t, 6H, J = 7.0Hz); 1, 32 (t, 3H, J = 7.3Hz);

3.10 (m, 1H); 4.28 (q, 2H, J = 7.0Hz); 4.94 (s, 1H).

Raw material 4: 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone

Figure imgf000044_0001

1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone is prepared from 3-chloro-2,4-pentanedione and 4- (trifluoromethyl) thiobenzamide according to the procedure General A.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.62 (s, 3H); 2.82 (s, 3H); 7.73 (d, 2H, J = 8.2Hz); 8.12 (d, 2H, J = 8.2Hz).

Raw material 5: 1 - (4-methyl-2- (4-chlorophenyl) thiazol-5-yl) ethanone

Λ Hv

O 1- (4-methyl-2- (4-chlorophenyl) thiazol-5-yl) ethanone is prepared from 3-chloro-2,4-pentanedione and 4-chlorothiobenzamide according to General Procedure A.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.60 (s, 3H); 2.81 (s, 3H); 7.45 (d, 2H, J = 8.8Hz); 7.95 (d, 2H, J = 8.8Hz).

Raw Material 6: 4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylate ethyl

Figure imgf000045_0001
4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylate was prepared from ethyl 2-chloro-4-methyl-3-oxopentanoate and 4- (trifluoromethyl) thiobenzamide according to General procedure A. 1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 39 (m, 9H); 4.04 (m, 1H); 4.37 (q, 2H, J = 7.1 Hz); 7.71 (d, 2H, J = 8.2Hz); 8.11 (d, 2H, J = 8.2Hz).

Raw material 7: acid 4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylic

Figure imgf000045_0002

4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylate is dissolved in ethanol and a potassium hydroxide solution (2M, 3 eq.) Was added. The whole is refluxed for 2 hours with stirring. The reaction mixture is concentrated by evaporation under reduced pressure. The evaporation residue is taken up in an aqueous solution of 6N hydrochloric acid, the precipitate is drained.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 39 (d, 6H, J = 6.9Hz); 4.03 (m, 1H); 7.73 (d, 2H, J = 8.2Hz); 8.14 (d, 2H, J = 8.2Hz). Raw material 8: 1 - (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - ethanone

Figure imgf000046_0001

The 4-Isopropyl-2- (4- (trifluoromethyl) phenyl) thiazole-5-carboxylic acid and ethyl chloroformate (1 eq.) Are dissolved in anhydrous tetrahydrofuran. The reaction medium is cooled to 0 0 C and triethylamine (1 eq.) Was added dropwise. After 30 minutes of stirring, the salts are removed by filtration and the filtrate was concentrated under reduced pressure. The evaporation residue is dissolved in dry tetrahydrofuran, the whole is cooled to 0 0 C and then methylmagnesium chloride (1 eq.) Is added dropwise. After 1 hour of stirring at room temperature, the solvents are removed by evaporation under reduced pressure. The evaporation residue is purified by flash chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 36 (d, 6H, J = 7.7Hz); 2.61 (s, 3H); 3.94 (m, 1H); 7.70 (d, 2H, J = 8.3 Hz); 8.12 (d, 2H, J = 8.3Hz).

Raw material 9: 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) ethanone

Figure imgf000046_0002
1- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) ethanone is prepared from 3-chloro-2,4-pentanedione and 4- (trifluoromethyl) benzamide by the procedure General A.

The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm. 1 H NMR (300MHz, CDCl3, δ in ppm): 2.58 (s, 6H); 7.76 (d, 2H, J = 8.2Hz); 8.22

(D, 2H, J = 8.2Hz). Raw material 10: 1 - (2- (2-chlorophenyl) -4-methylthiazol-5-yl) ethanone

Figure imgf000047_0001

1- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) ethanone is prepared from 3-chloro-2,4-pentanedione and 2-chlorothiobenzamide according to General Procedure B.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.62 (s); 2.82 (s); 7.40 (m); 7.52 (m); 8.34 (m).

Raw material 11: 1 - (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) - ethanone

Figure imgf000047_0002

1- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone is prepared from 3-chloro-2,4-pentanedione and 3- (trifluoromethyl) thiobenzamide according to the procedure General B. 1 H NMR (300MHz, CDCl 3, δ in ppm): 2.61 (s, 3H); 2.82 (s, 3H); 7.61 (t, 1H, J = 7.9Hz); 7.74 (d, 1H, J = 7.9Hz); 8.16 (d, 1H, J = 7.9Hz); 8.27 (s, 1H).

Raw material 12: 1 - (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) ethanone

Figure imgf000047_0003
1- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) ethanone is prepared from

3-chloro-2,4-pentanedione and 4-méthoxythiobenzamide according to General Procedure B.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.66 (s, 3H); 3.10 (s, 3H); 3.92 (s, 3H); 7.08

(D, 2H, J = 8.4Hz); 8.41 (d, 2H, J = 8.4Hz). Raw material 13: 4-hydroxy-2,3-diméthylbenzaldéhvde

Figure imgf000048_0001

Sodium carbonate (3.5 eq.), Calcium hydroxide (4.5 eq.) And 2,3-dimethylphenol (0.11 g / L) are added to water, the suspension is heated at 70 0 C for 4 hours. Chloroform (9 eq.) Is added dropwise.

The whole is stirred at 70 0 C for 1, 5 hours.

The reaction medium is cooled to 0 0 C, acidified (pH = 1) with concentrated hydrochloric acid solution. The whole is extracted with ethyl acetate; The organic phases are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by flash chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 6/4, silica 40-63μm).

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.23 (s, 3H); 2.63 (s, 3H); 6.78 (d, 1H,

J = 8.3Hz); 7.62 (d, 1H, J = 8.3 Hz); 10.17 (s, 1H).

Example 3: Synthesis of intermediates involved in the synthesis of compounds according to the invention:

Intermediate compound 1: 3- (4-hydroxy-3,5-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000048_0002

3- (4-hydroxy-3,5-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general procedure C. After 16 hours stirring at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is crystallized in ethanol.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.32 (s, 6H); 2.9 (s, 3H); 5.05 (s, 1H); 7.14 (d, 1H, J = 15.5Hz); 7.32 (s, 2H); 7.36 to 7.78 (m, 3H); 8.15 (d, 2H, J = 8.2Hz).

Intermediate Compound 2: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000049_0001
3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C. After 16 hours stirring at 50 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is crystallized from acetonitrile.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.80 (s, 3H); 7.07 (d, 1H, J = 8.8Hz); 7.40 (d, 1H, J = 15.5Hz); 7.95 (m, 4H); 8.21 (d, 2H, J = 8.2Hz); 11, 49 (s, 1H).

Intermediate Compound 3: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000049_0002

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propan-1-one is prepared from the 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one according to general procedure D. 1 H NMR (300MHz, CDCl 3, δ in ppm): 2.82 (s, 3H); 3.18 (s, 4H); 5.66 (s, 1H); 6.92 (d, 1H, J = 8.5Hz); 7.17 (d, 1H, J = 8.5Hz); 7.72 (d, 2H, J = 8.2Hz); 8.08 (d, 2H, J = 8.2Hz).

Intermediate Compound 4: 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4-

(Trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000050_0001

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C.

After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is crystallized from acetonitrile.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 1, 33 (d, 6H, J = 6.7Hz); 3.92 (m, 1H); 7.06 (d, 1H, J = 8.8Hz); 7.35 (d, 1H, J = 15,2Hz); 7.95 (m, 4H); 8.23 (d, 2H,

J = 8.2Hz); 11, 46 (s, 1H).

Intermediate compound 5: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-isopropyl-2- (4-

(Trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000050_0002

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propan-1-one is prepared from the 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one according to general procedure D. 1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 36 (d, 6H, J = 7.0Hz); 3.17 (s, 4H); 3.95 (sep, 1H, J = 7.0Hz); 5.61 (s, 1H); 6.91 (d, 1H, J = 8.5Hz); 7.16 (d, 1H, J = 8.5Hz); 7.71 (d, 2H, J = 8.3 Hz); 8.11 (d, 2H, J = 8.3Hz). Intermediate compound 6: 3- (3-bromo-4-hydroxyphenyl) -1 - (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000051_0001
3- (3-bromo-4-hydroxyphenyl) -1 - (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 3-bromo-4-hydroxybenzaldehyde according to general procedure C. After 16 hours of stirring at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in a saturated solution of sodium hydrogencarbonate and the whole is extracted with ethyl acetate. The evaporation residue is purified by flash chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1 to 8/2 gradient. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 42 (d, 6H, J = 7.0Hz); 4.01 (m, 1H); 5.84 (s, 1H); 7.10 (d, 1H, J = 8.5Hz); 7.12 (d, 1H, J = 15,3Hz); 7.54 (dd, 1H, J = 1, 8Hz, J = 8.5Hz); 7.72 (d, 1H, J = 15,3Hz); 7.75 (d, 2H, J = 7.9Hz); 7.78 (d, 1H, J = 1, 8Hz); 8.17 (d, 2H, J = 7.9Hz).

intermediate compound 7: 1- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) prop-2-en-1-one

Figure imgf000051_0002

1- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) - prop-2-en-1-one is prepared from the 1- (4-methyl-2- (4-chlorophenyl) thiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C. After stirring for 24 hours at 60 0 C, the solvent was removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N aqueous ammonia solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from acetonitrile.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.81 (s, 3H); 5.96 (s, 1H); 7.05 (d, 1H, J = 8.9Hz); 7.16 (d, 1H, J = 15.5Hz); 7.46 (d, 2H, J = 8.8Hz); 7.63 (d, 1H, J = 8.9Hz); 7.97 (d, 2H, J = 8.8Hz); 8.16 (d, 1H, J = 15.5Hz).

Intermediate compound 8: 1 - (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) propan-1-one

Figure imgf000052_0001

1- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) - prop-2-en-1-one is prepared from 1 - (2- (4-chlorophenyl) -4-methylthiazol-5- yl) -3- (2,3-dichloro-4-hydroxyphenyl) prop-2-en-1-one and 11 wt% catalyst according to general procedure E.

After 8 hours of stirring at room temperature, the catalyst was removed by filtration and the solvent is removed by evaporation under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 7/3. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.79 (s, 3H); 3.16 (s, 4H); 5.63 (bs, 1H);

6.92 (d, 1H, J = 8.5Hz); 7.17 (d, 1H, J = 8.5Hz); 7.44 (d, 2H, J = 8.5Hz); 7.91 (d, 2H, J = 8.5Hz). Intermediate Compound 9: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4-

(Trifluoromethyl) phenyl) oxazol-5-yl) prop-2-en-1-one

Figure imgf000053_0001

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) - oxazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C.

After stirring for 10 minutes at 130 0 C (microwave), the solvent is removed by evaporation under reduced pressure. The evaporation residue is crystallized from ethanol and then diluted in ethyl acetate. This solution was successively treated with a 2N sodium hydroxide solution and citric acid solution 1 N and then, dried over magnesium sulfate and concentrated under reduced pressure.1 H NMR (300MHz, CDCI -3, δ in ppm): 2.69 (s, 3H); 5.97 (s, 1H); 7.08 (d, 1H, J = 8.8Hz); 7.38 (d, 1H, J = 15.8Hz); 7.72 (d, 1H, J = 8.8Hz); 7.79 (d, 2H, J = 8.2Hz); 8.29 (d, 2H, J = 8.2Hz); 8.30 (d, 1H, J = 15.8Hz).

Intermediate compound 10: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) propan-1-one

Figure imgf000053_0002
3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) - oxazol-5-yl) propan-1-one is prepared from the 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) prop-2-en-1-one through 8 equivalents of catecholborane according to General procedure F. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCI -3, δ in ppm): 2.58 (s, 3H); 3.18 (m, 4H); 6.87 (d, 1H, J = 8.5Hz); 7.14 (d, 1H, J = 8.5Hz); 7.75 (d, 2H, J = 8.2Hz); 8.21 (d, 2H, J = 8.2Hz). Intermediate compound 11: 3- (2-chloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000054_0001

3- (2-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4-

(Trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2-dichloro-4-hydroxybenzaldehyde according to general procedure C.

After 18 hours of stirring at 60 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from acetonitrile.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.89 (s, 3H); 5.54 (s, 1H); 6.83 (dd, 1H, J = 2.6Hz, J = 8.2Hz); 6.97 (d, 1H, J = 2.6Hz); 7.17 (d, 1H, J = 15.5Hz); 7.37 (d, 2H,

J = 8.8Hz); 7.73 (d, 2H, J = 8.2Hz); 8.11 (d, 2H, J = 8.2Hz); 8.18 (d, 1H, J = 15.5Hz).

Intermediate compound 12: 3- (2-chloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000054_0002

3- (2-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one is prepared from 3- ( 2-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one with 4 equivalents of catecholborane according to General procedure F. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 2.81 (s, 3H); 3.14 (m, 4H); 6.69 (dd, 1H, J = 2.6Hz, J = 8.2Hz); 6.89 (d, 1H, J = 2.6Hz); 7.17 (d, 1H, J = 8.2Hz); 7.71 (d, 2H, J = 8.2Hz); 8.09 (d, 2H, J = 8.2Hz). Intermediate compound 13: 3- (3-chloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000055_0001
3- (3-chloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) ethanone and 3-dichloro-4-hydroxybenzaldehyde according to general procedure C. After stirring for 18 hours at 60 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from ethanol. 1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.79 (s, 3H); 7.04 (d, 1H, J = 8.5Hz); 7.39 (d, 1H, J = 15.5Hz); 7.67 (d, 1H, J = 15.5Hz); 7.68 (d, 1H, J = 2.0Hz); 7.92 (m, 3H); 8.24 (d, 2H, J = 8.2Hz).

Intermediate compound 14: 3- (3-chloro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000055_0002

3- (3-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one is prepared from 3- ( 3-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one and 15 wt% catalyst according to General procedure E. After 18 hours at room temperature, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5 to 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCI -3 δ in ppm): 2.82 (s, 3H); 3.03 (t, 2H, J = 7.3Hz); 3.16 (t, 2H, J = 7.3Hz); 5.43 (s, 1H); 6.95 (d, 1H, J = 8.2Hz); 7.07 (dd, 1H, J = 2.0Hz J = 8.2Hz); 7.24 (d, 1H, J = 2.0Hz); 7.73 (d, 2H, J = 8.3 Hz); 8.09 (d, 2H, J = 8.3Hz).

intermediate compound 15: 3- (2,3-difluoro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000056_0001

3- (2,3-difluoro-4-hydroxyphenyl) -1 - (4-methyl-2- (4-

(Trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2,3-difluoro-4-hydroxybenzaldehyde according to general procedure C.

After 18 hours of stirring at 50 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from acetonitrile.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.79 (s, 3H); 6.87 (m, 1H); 7.39 (m, 1H); 7.65 (m, 2H); 7.91 (m, 2H); 8.22 (m, 2H).

Intermediate compound 16: 3- (2,3-difluoro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000056_0002
3- (2,3-difluoro-4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propan-1-one is prepared from the 3- (2,3-difluoro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one and 14% mass of catalyst according to General procedure E. After 2 hours at room temperature, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is purified by chromatography on silica gel

Elution: cyclohexane / ethyl acetate: 8/2. Silica 40-63μm. 1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.72 (s, 3H); 2.90 (t, 2H, J = 7.3Hz); 3.25 (t, 2H, J = 7.3Hz); 6.70 (m, 1H); 6.94 (m, 1H); 7.90 (d, 2H, J = 4.1 Hz); 8.21 (d, 2H, J = 4.1 Hz); 10.16 (s, 1H).

Intermediate compound 17: 1 - (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) prop-2-en-1-one

Figure imgf000057_0001

1- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) - prop-2-en-1-one is prepared from the 1- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C. After stirring for 16 hours at 50 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from acetonitrile.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.79 (s, 3H); 7.04 (d, 1H, J = 8.8Hz); 7.42 (d, 1H, J = 15.5Hz); 7.56 (m, 2H); 7.69 (m, 1H); 7.97 (d, 1H, J = 8.8Hz); 7.99 (d, 1H, J = 15.5Hz); 8.33 (m, 1H). Intermediate compound 18: 1 - (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) propan-1-one

Figure imgf000058_0001

1- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) - propan-1-one is prepared from 1- (2 - (2-chlorophenyl) -4-methylthiazol-5- yl) -3- (2,3-dichloro-4-hydroxyphenyl) prop-2-en-1-one and 12 wt% catalyst according to General procedure E .

After 3 hours of stirring at 40 0 C, the catalyst is removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is crystallized from ethyl acetate.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 3.01 (t, 2H, J = 7.5Hz); 3.25 (t, 2H, J = 7.5Hz); 6.90 (d, 1H, J = 8.4Hz); 7.18 (d, 1H, J = 8.4Hz); 7.51 to 7.61 (m, 2H); 7.69 (dd, 1H, J = 7.6Hz J = 1, 6Hz); 8.29 (dd, 1H, J = 7.4Hz J = 2.2Hz); 10.46 (s, 1H).

Intermediate compound 19: 3- (4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000058_0002

3- (4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one is prepared from 1- ( 4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 4-hydroxybenzaldehyde according to general procedure C.

After 18 hours of stirring at 60 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is recrystallized from acetonitrile. 1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.79 (s, 3H); 6.85 (d, 2H, J = 8.7 Hz); 7.29 (d, 1H, J = 15,2Hz); 7.70 (d, 1H, J = 15,2Hz); 7.70 (d, 2H, J = 8.7 Hz); 7.91 (d, 2H, J = 8.2Hz); 8.23 (d, 2H, J = 8.2Hz).

Intermediate compound 20: 3- (4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000059_0001

3- (4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - propan-1-one is prepared from 3- (4-hydroxyphenyl ) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one and 12 wt% catalyst according to General procedure E.

After 8 hours of stirring at room temperature, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is purified by chromatography on silica gel Elution: petroleum ether / ethyl acetate: 8/2. Silica 40-63μm.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.71 (s, 3H); 2.83 (t, 2H, J = 7.4 Hz); 3.19 (t, 2H, J = 7.4 Hz); 6.67 (d, 2H, J = 8.5Hz); 7.05 (d, 2H, J = 8.5Hz); 7.87 (d, 2H, J = 8.2Hz); 8.19 (d, 2H, J = 8.2Hz); 9.18 (s, 1H).

Intermediate compound 21: 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000059_0002

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (3- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C.

After 16 hours of stirring at 50 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate and the whole is washed with a 2N sodium hydroxide solution. After acidification (pH = 5) with a citric acid solution 1 N, the organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel, elution: cyclohexane / ethyl acetate: 8/2. Silica 40-63μm.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.82 (s, 3H); 7.06 (d, 1H, J = 8.8Hz); 7.45 (d, 1H, J = 15.5Hz); 7.78 to 7.85 (m, 1H); 7.94 to 8.03 (m, 3H); 8.29 to 8.36 (m, 2H).

Intermediate compound 22: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000060_0001

3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (3- (trifluoromethyl) phenyl) - thiazol-5-yl) propan-1-one is prepared from the 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one and 11% mass catalyst according to General procedure E.

After 18 hours of stirring at room temperature, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is purified by chromatography on silica gel Elution: petroleum ether / ethyl acetate: 8/2. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 2.81 (s, 3H); 3.16 to 3.21 (m, 4H); 6.90 (d, 1H, J = 8.4Hz); 7.18 (d, 1H, J = 8.4Hz); 7.56 to 7.62 (m, 1H); 7.74 (d, 1H, J = 7.6Hz); 8.15 (d, 1H, J = 7.6Hz); 8.27 (s, 1H).

Intermediate compound 23: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) prop-2-en-1-one

Figure imgf000060_0002
3- (2,3-dichloro-4-hydroxyphenyl) -1- (2- (4-methoxy-phenyl) -4-methylthiazol-5-yl) prop-2-en-1-one is prepared from 1- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure C. After stirring for 16 hours at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up with methanol and filtered.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.85 (s, 3H); 3.92 (s, 3H); 5.12 (bs, 1H); 7.18 (m, 3H); 7.48 (d, 1H, J = 15.5Hz); 7.99 to 8.08 (m, 4H).

Intermediate compound 24: 3- (2,3-dichloro-4-hydroxyphenyl) -1 - (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) propan-1-one

Figure imgf000061_0001

3- (2,3-dichloro-4-hydroxyphenyl) -1- (2- (4-methoxy-phenyl) -4-methylthiazol-5- yl) propan-1-one is prepared from 3- ( 2,3-dichloro-4-hydroxyphenyl) -1- (2-

(4-methoxy-phenyl) -4-methylthiazol-5-yl) prop-2-en-1-one and 10% by weight of catalyst according to General Procedure E.

After 1 hour at 50 0 C under 10 bar of hydrogen pressure, the catalyst is removed by filtration and the solvent was evaporated under reduced pressure. The evaporation residue is taken up in dichloromethane then filtered and used as such for carrying out the next step.

Intermediate compound 25: 3- (4-hydroxy-2,3-dimethylphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one

Figure imgf000061_0002

3- (4-hydroxy-2,3-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2-en-1-one is prepared from 1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) ethanone and 2,3-dimethyl-4-hydroxybenzaldehyde according to general procedure C.

After stirring for 48 hours at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up with ethanol and filtered.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.12 (s, 3H); 2.32 (s, 3H); 2.81 (s, 3H); 6.81 (d, 1H, J = 8.7 Hz); 7.25 (d, 1H, J = 15,7Hz); 7.67 (d, 1H, J = 8.7 Hz); 7.95 (d, 2H, J = 8.2Hz); 8.10 (d, 1H, J = 15.5Hz); 8.27 (d, 2H, J = 8.2Hz).

Intermediate compound 26: 3- (4-hydroxy-2,3-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one

Figure imgf000062_0001

3- (4-hydroxy-2,3-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propan-1-one is prepared from the 3- (4-hydroxy-2,3-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) prop-2-en-1-one according to general procedure D.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.06 (s, 3H); 2.15 (s, 3H); 2.74 (s, 3H);

2.82 to 2.89 (m, 2H); 3.08 to 3.13 (m, 2H); 6.59 (d, 1H, J = 8.4Hz); 6.83 (d, 1H,

J = 8.4Hz); 7.92 (d, 1H, J = 8.3 Hz); 8.26 (d, 2H, J = 8.3 Hz); 9.01 (s, 1H).

Example 4: Synthesis of compounds according to the invention

Compound 1: 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) - 2-methylpropanoate

Figure imgf000062_0002

2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2- methylpropanoate is prepared from 3- (4-hydroxy-3,5-dimethylphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) prop-2 -en-1-one according to general procedure G using 6 equivalents of tert-butyl bromoisobutyrate and 12 equivalents of potassium carbonate in acetonitrile. After 10 hours of stirring at 70 0 C, the solvents are removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a dilute hydrochloric acid solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 48 (s, 6H); 1, 54 (s, 9H); 2.30 (s, 6H); 2.89 (s, 3H); 7.17 (d, 1H, J = 15.1 Hz); 7.29 (s, 2H); 7.74 (d, 2H, J = 8.2Hz); 7.75 (d, 1H, J = 15.1 Hz); 8.15 (d, 2H, J = 8.2Hz).

Compound 2: 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy ) -2-methylpropanoic acid

Figure imgf000063_0001

2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) - 2-methylpropanoic acid is prepared from 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1- enyl) phenoxy) -2-methylpropanoate according to general procedure H using 20 equivalents of trifluoroacetic acid.

After 48 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 1, 39 (s, 6H); 2.22 (s, 6H); 2.80 (s, 3H);

7.38 (d, 1H, J = 15.5Hz); 7.53 (s, 2H); 7.65 (d, 1H, J = 15.5Hz); 7.92 (d, 2H,

J = 8.2Hz); 8.24 (d, 2H, J = 8.2Hz).

Mass (APCI "): 502 (M-1) mp: 179.6 to 181, 9 ° C Compound 3:.. 2- (2,3-dichloro-4- (3- (4-methyl-2- ( 4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) acetate tert-butyl

Figure imgf000064_0001
2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-prop-1-enyl) phenoxy) acetate t-butyl is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) prop-2-en -1-one according to general procedure G using 3 equivalents of tert-butyl bromoacetate and 3 equivalents of potassium carbonate in acetonitrile.

After 10 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 52 (s, 9H); 2.89 (s, 3H); 4.70 (s, 2H); 6.79 (d, 1H, J = 8.8Hz); 7.15 (d, 1H, J = 15.5Hz); 7.62 (d, 1H, J = 8.8Hz); 7.74 (d, 2H, J = 8.1 Hz); 8.13 (d, 2H, J = 8.1 Hz); 8.18 (d, 1H, J = 15.5Hz).

Compound 4: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy )acetic

Figure imgf000064_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) -phenoxy) -acetic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy ) tert-butyl acetate according to general procedure H using 20 equivalents of trifluoroacetic acid. After 48 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 2.81 (s, 3H); 5.00 (s, 2H); 7.19 (d, 1H, J = 9.1 Hz); 7.50 (d, 1H, J = 15.5Hz); 7.94 (d, 2H, J = 8.2Hz); 7.97 (d, 1H, J = 15.5Hz); 8.07 (d, 1H, J = 9.1 Hz); 8.23 (d, 2H, J = 8.2Hz). Mass (ES "): 514 (M-1) mp 225 ° C..

Compound 5: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) hexanoate tert-butyl

Figure imgf000065_0001

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) hexanoate was prepared from tert-butyl 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to General procedure G using 3 equivalents of tert-butyl 2-bromohexanoate and 3 equivalents of potassium carbonate in acetonitrile. After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up chlodichlorométhane washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: gradient 95/5 to 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 0.94 (m, 3H); 1, 32-1, 46 (m, 11H); 1, 51-1, 61 (m, 2H); 1, 98 (m, 2H); 2.80 (s, 3H); 3.17 (s, 4H); 4.49 (m, 1H); 6.65 (d, 1H, J = 8.6 Hz); 7.13 (d, 1H, J = 8.6 Hz); 7.39 (d, 2H, J = 8.2Hz); 8.07 (d, 2H, J = 8.2Hz). Compound 6: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) hexanoic acid

Figure imgf000066_0001

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) hexanoic acid was prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) hexanoate tert according to general procedure H using 56 equivalents of trifluoroacetic acid.

After 72 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel (preparative HPLC, lichrospher (Merck) RP18

100A 12 .mu.m, column: 25 * 250 mm).

Elution: gradient water, methanol + 0.1% trifluoroacetic acid: 22/78 to 10/90.1 H NMR (300MHz, CDCl 3, δ in ppm): 0.94 (t, 3H, J = 7.0Hz); 1, 39 (m, 2H); 1, 56

(M, 2H); 2.06 (m, 2H); 2.81 (s, 3H); 3.19 (s, 4H); 4.69 (t, 1H, J = 6.7Hz); 6.72 (d, 1H,

J = 8.5Hz); 7.18 (d, 1H, J = 8.5Hz); 7.72 (d, 2H, J = 8.3 Hz); 8.08 (d, 2H, J = 8.3Hz).

Mass (ES "): 572/574 (M-1).

F = 153 ° C.

Compound 7: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoate butyl

Figure imgf000066_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to the procedure General G using 10 equivalents of tert-butyl bromoisobutyrate and 10 equivalents of potassium carbonate in acetonitrile.

After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in dichloromethane, washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: gradient 95/5 to 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 45 (s, 9H); 1, 59 (s, 6H); 2.80 (s, 3H); 3.17

(S, 4H); 6.80 (d, 1H, J = 8.5Hz); 7.09 (d, 1H, J = 8.5Hz); 7.69 (d, 2H, J = 8.3 Hz); 8.07 (d, 2H, J = 8.3Hz).

Compound 8: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoic

Figure imgf000067_0001
2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate tert-butyl according to general procedure H using 45 equivalents of trifluoroacetic acid. After stirring for 16 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel (preparative HPLC, lichrospher (Merck) RP18 12 .mu.m 100A, column 25 * 250 mm). Elution: gradient water, methanol + 0.1% trifluoroacetic acid: 22/78 to 10/90.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 65 (s, 6H); 2.82 (s, 3H); 3.22 (s, 4H); 6.96

(D, 1H, J = 8.5Hz); 7.20 (d, 1H, J = 8.5Hz); 7.72 (d, 2H, J = 8.2Hz); 8.09 (d, 2H,

J = 8.2Hz).

Mass (ES "): 544/546 (M-1) mp 155 ° C Compound 9:. 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) butanoate

Figure imgf000068_0001

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) butanoate was prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to General procedure G using 3 equivalents of tert-butyl 2-bromobutanoate and 3 equivalents of potassium carbonate in acetonitrile. After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: gradient 95/5 to 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 12 (t, 3H, J = 7.3Hz); 1, 44 (s, 9H); 2.03 (m, 2H); 2.81 (s, 3H); 3.17 (s, 4H); 4.46 (t, 1H, J = 6.1 Hz); 6.65 (d, 1H, J = 8.5Hz); 7.13 (d, 1H, J = 8.5Hz); 7.71 (d, 2H, J = 8.2Hz); 8.08 (d, 2H, J = 8.2Hz).

Compound 10: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) butanoic acid

Cl O

h O

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) butanoic acid was prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) butanoate according to general procedure H using 25 equivalents of trifluoroacetic acid. After 72 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel (preparative HPLC, lichrospher (Merck) RP18 12 .mu.m 100A, column 25 * 250 mm).

Elution: gradient water, methanol + 0.1% trifluoroacetic acid: 22/78 to 10/90.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 15 (t, 3H, J = 7.6Hz); 2.11 (m, 2H); 2.81 (s, 3H); 3.19 (s, 4H); 4.67 (t, 1H, J = 5.9Hz); 6.74 (d, 1H, J = 8.6 Hz); 7.18 (d, 1H, J = 8.6 Hz); 7.72 (d, 2H, J = 8.3 Hz); 8.08 (d, 2H, J = 8.3Hz). Mass (ES "): 544/546 (M-1) mp 88 ° C..

Compound 11: 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate butyl

Figure imgf000069_0001

2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to general procedure G using 10 equivalents of tert-butyl bromoisobutyrate and 3 equivalents of potassium carbonate in acetonitrile.

After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm.1 H NMR (300MHz, CDCI -3 δ in ppm): 1, 36 (d, 6H, J = 6.7Hz); 1, 46 (s, 9H); 1, 58 (s, 6H); 3.18 (s, 4H); 3.95 (sep, 1H, J = 6.7Hz); 6.80 (d, 1H, J = 8.7 Hz); 7.09 (d, 1H, J = 8.7 Hz); 7.71 (d, 2H, J = 8.2Hz); 8.11 (d, 2H, J = 8.2Hz). Compound 12: 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoic

Figure imgf000070_0001

2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate tert-butyl according to general procedure H using 22 equivalents of trifluoroacetic acid.

After 2 hours stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 36 (d, 6H, J = 6.7Hz); 1, 65 (s, 6H); 3.21 (s,

4H); 3.97 (m, 1H); 6.95 (d, 1H, J = 8.5Hz); 7.18 (d, 1H, J = 8.5Hz); 7.71 (d, 2H,

J = 8.2Hz); 8.11 (d, 2H, J = 8.2Hz). Mass (ES "): 572/574 (M-1).

F = 75 ° C.

Compound 13: 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic

Figure imgf000070_0002

2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) -2- methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy ) -2-methylpropanoic acid according to general procedure I using 3 equivalents of sodium borohydride in methanol.

After 72 hours of stirring at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in an aqueous solution of hydrochloric acid and the precipitate is filtered and washed with water.

1 H NMR (300MHz, DMSO-d 6, δ in ppm): 1, 52 (s, 6H); 1, 94 (m, 2H); 2.35 (s, 3H); 2.64 to 2.85 (m, 2H); 4.93 (m, 1H); 5.98 (s, 1H); 6.84 (d, 1H, J = 8.8Hz); 7.23 (d, 1H, J = 8.8Hz); 7.82 (d, 2H, J = 8.1 Hz); 8.11 (d, 2H, J = 8.1 Hz); 13.26 (s, 1H). Mass (ES "): 546/548 (M-1) mp: 90-95 ° C..

Compound 14: 2- (2,3-dichloro-4- (3-ethoxy-3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque

Figure imgf000071_0001

2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) -2- methylpropanoic acid is solubilized in ethanol / water: 2/1 and 0.1% of trifluoroacetic acid are added. The mixture is heated 16 hours at reflux.

The ethanol was removed by evaporation under reduced pressure, the resulting aqueous phase is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 24 (m, 3H); 1, 59 (s, 6H); 2.02 (m, 1H); 2.19 (m, 1H); 2.42 (s, 3H); 2.74 to 2.96 (m, 2H); 3.36 to 3.56 (m, 2H); 4.55 (m, 1H); 6.89 (d, 1H, J = 8.5Hz); 7.01 (d, 1H, J = 8.5Hz); 7.66 (d, 2H, J = 8.3 Hz); 7.99 (d, 2H, J = 8.3Hz). Mass (ES "): 574/576 (M-1) Compounds 14a and 14b.:

Figure imgf000072_0001

The two enantiomers of compound 40 are separated by semi-preparative HPLC on chiral column Chiralpak®AD-H (250 * 20mm, 5 .mu.m, Chiral Technologies Europe) at room temperature. Elution was carried out isocratically with a mobile phase n-heptane-ethanol (96-4) supplemented with 0.1% trifluoroacetic acid at a flow rate of 16-18 ml / min.

The enantiomeric purity of each enantiomer obtained is controlled by analytical HPLC: column Chiralpak®AD-H (250 * 46mm, 5 .mu.m, Daicel Chemical Industries, LTD) at 30 0 C; isocratic elution with mobile phase n-heptane-isopropanol (95-5) with 0.1% trifluoroacetic acid; flow rate 1 ml / min; UV detection at 205 nm. Compound 40a: tR = 14.6 min, ee = 100%, mp 61-63 ° C. Compound 40b: tR = 19.0 min, ee = 100%, mp 55-57 ° C.

Compound 15: 2- (4- (3- (benzyloxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) -2,3-dichlorophenoxy) - 2-methylpropanoic

Figure imgf000072_0002

2- (4- (3- (benzyloxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - propyl) -2,3-dichlorophenoxy) -2 -méthylpropanoïque is prepared from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) -thiazol-5-yl) propyl) phenoxy) -2-methylpropanoic acid according to general procedure J using 3 equivalents of sodium hydride and two equivalents of benzyl bromide. After stirring for 16 hours at room temperature, the reaction medium is diluted with ethyl acetate and washed with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is dissolved in ethanol in the presence of 2N sodium hydroxide (20 eq.). After 16 hours stirring the solvents are evaporated under reduced pressure. The evaporation residue is acidified with dilute hydrochloric acid and then extracted with dichloromethane. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 63 (s, 6H); 2.01 to 2.12 (m, 1H); 2.24 to 2.31 (m, 1H); 2.39 (s, 3H); 2.72 to 2.84 (m, 1H); 2.93 to 3.03 (m, 1H); 4.36 (d, 1H,

J = 11, 8Hz); 4.62 (d, 1H, J = 11, 8Hz); 4.62 to 4.65 (m, 1H); 6.91 (d, 1H, J = 8.5Hz); 6.99

(D, 1H, J = 8.5Hz); 7.32-7.40 (m, 5H); 7.71 (d, 2H, J = 8.0Hz); 8.05 (d, 2H, J = 8.0Hz).

Mass (ES ') 636/637/638 (M-1).

Mp 51-53 ° C.

Compound 16: 2- (2,3-dichloro-4- (3-hydroxy-3- (4-isopropyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) butanoate

Figure imgf000073_0001

2- (2,3-dichloro-4- (3-hydroxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) butanoate was prepared from 2- (2,3-dichloro-4- (3-oxo-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propyl) phenoxy) butanoate according to General procedure I by 1, 1 equivalent of sodium borohydride in ethanol.

After 30 minutes of stirring at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in dilute aqueous hydrochloric acid and extracted with dichloromethane.

The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 13 (t, 3H, J = 7.3Hz); 1, 32-1, 37 (m, 6H); 1, 45 (s, 9H); 2.01 to 2.25 (m, 4H); 2.7 to 2.85 (m, 2H); 3.03 to 3.13 (m, 1H); 4.46 (m, 1H); 5.05 to 5.15 (m, 1H); 6.68 (d, 1H, J = 8.5Hz); 7.06 (d, 1H, J = 8.5Hz); 7.68 (d, 2H, J = 8.2Hz); 8.05 (d, 2H, J = 8.2Hz).

Compound 17: 2- (2,3-dichloro-4- (3-ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) butanoate

Figure imgf000074_0001

2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propyl) phenoxy) butanoate was synthesized from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propyl) phenoxy) butanoate according to General procedure J by means of two equivalents of sodium hydride and one equivalent of iodoethane. After stirring for 16 hours at room temperature, the reaction medium is washed with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: heptane / ethyl acetate: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 13 (t, 3H, J = 7.3Hz); 1, 23 (t, 3H, J = 7.0Hz); 1, 35 (d, 3H, J = 6.9Hz); 1, 31 (d, 3H, J = 6.9Hz); 1, 44 (s, 9H); 1, 99 to 2.09 (m, 3H); 2.11 to 2.25 (m, 1H); 2.72 to 2.95 (m, 2H); 2.98 to 3.09 (m, 1H); 3.35 to 3.57 (m, 2H); 4.46 (m, 1H); 4.57 to 4.64 (m, 1H); 6.68 (d, 1H, J = 8.6 Hz); 7.04 (d, 1H, J = 8.6 Hz); 7.68 (d, 2H, J = 8.2Hz); 8.05 (d, 2H, J = 8.2Hz).

Compound 18: 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) butanoic acid

Figure imgf000074_0002
2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoic acid is prepared from 2- (2,3-dichloro-4- (3-ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propyl) phenoxy) butanoate according General procedure H using 10 equivalents of trifluoroacetic acid.

After stirring for 16 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 12 (t, 3H, J = 7.1 Hz); 1, 23 (t, 3H, J = 6.9Hz); 1, 31 (d, 3H, J = 6.7Hz); 1, 35 (d, 3H, J = 6.7Hz); 1, 95 to 2.25 (m, 4H); 2.65 to 2.81 (m, 1H); 2.83 to 2.97 (m, 1H); 3.01 to 3.15 (m, 1H); 3.35 to 3.59 (m, 2H); 4.55 to 4.71 (m, 2H); 6.71 (d, 1H, J = 7.9Hz); 7.05 (d, 1H, J = 7.9Hz); 7.67 (d, 2H, J = 8.3 Hz); 8.04 (d, 2H, J = 8.3Hz).

Mass (ES "): 602/603/604 (M-1).

Compound 19: 2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) -2- methylpropanoate

Figure imgf000075_0001

2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-prop-1-enyl) phenoxy) -2- methylpropanoate is prepared from 3- (3-bromo-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) prop-2-en-1 -one according to general procedure G using 5 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate in N, N-dimethylformamide.

After stirring for 16 hours at 70 0 C, the reaction mixture is cooled, ethyl acetate added, the whole is washed with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 42 (d, 6H, J = 6.7Hz); 1, 46 (s, 9H); 1, 67 (s, 6H); 4.00 (sep, 1H, J = 6.7Hz); 6.88 (d, 1H, J = 8.8Hz); 7.11 (d, 1H, J = 15,2Hz); 7.44 (dd, 1H, J = 2.0Hz, J = 8.8Hz); 7.69 (d, 1H, J = 15,2Hz); 7.73 (d, 2H, J = 7.9Hz); 7.87 (d, 1H, J = 2.0Hz); 8.16 (d, 2H, J = 7.9Hz).

Compound 20: Acid-2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoic acid

Figure imgf000076_0001

2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2- methylpropanoic acid is prepared from 2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoate according to general procedure H using 10 equivalents of trifluoroacetic acid.

After stirring for 16 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is crystallized from diethyl ether.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 42 (d, 6H, J = 6.7Hz); 1, 74 (s, 6H); 3.99 (m, 1H); 7.04 (d, 1H, J = 8.5Hz); 7.14 (d, 1H, J = 15.5Hz); 7.48 (dd, 1H, J = 1, 8Hz, J = 8.5Hz); 7.71 (d, 1H, J = 15.5Hz); 7.75 (d, 2H, J = 8.2Hz); 7.89 (d, 1H, J = 1, 8Hz); 8.17 (d, 2H, J = 8.2Hz). Mass (MALDI-TOF): 581. mp: 172-174 ° C. Compound 21: 2- (4- (3- (4-iodobenzyloxy) -3 (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) -2,3-dichlorophenoxy ) -2-methylpropanoic acid

Figure imgf000077_0001

The 2- (4- (3- (4-iodobenzyloxy) -3 (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) -2,3-dichlorophenoxy) - 2-methylpropanoic acid is synthesized from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl ) propyl) phenoxy) -2-methylpropanoic acid according to general procedure J using 3 equivalents of sodium hydride and 3 equivalents of 4-iodobenzyl bromide. After stirring for 48 hours at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is dissolved in ethanol in the presence of 2N sodium hydroxide (20 eq.). After 16 hours stirring the solvents are evaporated under reduced pressure. The evaporation residue is acidified with dilute hydrochloric acid and then extracted with dichloromethane. The solvent was removed by evaporation under reduced pressure, the evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 99/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 59 (s, 6H); 1, 98 to 2.12 (m, 1H); 2.15 to 2.18 (m, 1H); 2.39 (s, 3H); 2.67 to 2.82 (m, 1H); 2.86 to 2.99 (m, 1H); 4.29 (d, 1H, J = 12.0Hz); 4.51 (d, 1H, J = 12.0Hz); 4.63 (dd, 1H, J = 5.7Hz, J = 7.7Hz); 6.88 (d, 1H, J = 8.3 Hz); 6.93 (d, 1H, J = 8.3 Hz); 7.07 (d, 2H, J = 8.2Hz); 7.69 (d, 4H, J = 8.2Hz); 8.02 (d, 2H, J = 8.2Hz). Mass (ES +): 764/766 (M + 1). Mp 74-76 ° C. Compound 22: 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000078_0001

The (2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) - phenoxy) -2-methylpropanoate was prepared from 1- (2- (4- chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) propan-1-one according to general procedure G using 5 equivalents tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate in N, N-dimethylformamide. After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. the evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 45 (s, 9H); 1, 59 (s, 6H); 2.78 (s, 3H); 3.16 (s, 4H); 6.81 (d, 1H, J = 8.6 Hz); 7.1 (d, 1H, J = 8.6 Hz); 7.44 (d, 2H, J = 8.5Hz); 7.91

(D, 2H, J = 8.5Hz).

Compound 23: 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000078_0002

2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) - phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (2- (4- chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate according to general procedure H using 10 equivalents of trifluoroacetic acid.

After stirring for 16 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is crystallized from diethyl ether.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 64 (s, 6H); 2.79 (s, 3H); 3.19 (s, 4H); 6.95 (d, 1H, J = 8.5Hz); 7.19 (d, 1H, J = 8.5Hz); 7.44 (d, 2H, J = 8.5Hz); 7.91 (d, 2H, J = 8.5Hz).

Mass (ES +): 512/514 (M + 1). F = 169-171 ° C.

Compound 24: 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) - 3-hydroxypropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000079_0001

2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-hydroxy-propyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid according to the procedure I generally by 3 equivalents of sodium borohydride in ethanol.

After 2 hours of stirring at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in dilute aqueous hydrochloric acid and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 61 (s, 6H); 2.01 to 2.21 (m, 2H); 2.35 (s, 3H); 2.71 to 2.98 (m, 2H); 4.97 (m, 1H); 6.88 (d, 1H, J = 8.5Hz); 7.01 (d, 1H, J = 8.5Hz);

7.37 (d, 2H, J = 8.5Hz); 7.78 (d, 2H, J = 8.5Hz).

Mass (MALDI-TOF) 513/515 /. 517

Mp 89-91 ° C. Compound 25: 2- (4- (3- (benzyloxy) -3- (2- (4-chlorophenyl) -4-methylthiazol-5- yl) propyl) -2,3-dichlorophenoxy) -2-methylpropanoic acid

Figure imgf000080_0001

2- (4- (3- (benzyloxy) -3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) propyl) -2,3-dichlorophenoxy) -2-methylpropanoic acid was synthesized from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4-chlorophenyl) thiazol-5-yl) propyl) phenoxy) -

2-methylpropanoic acid according to general procedure J using 2.1 equivalents of sodium hydride and 2.1 equivalents of benzyl bromide.

After stirring for 16 hours at room temperature, the solvent is removed by evaporation under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

The oil obtained is solubilized in ethanol in the presence of 2N sodium hydroxide (20 eq.). After 16 hours stirring, the solvents are removed by evaporation under reduced pressure. The evaporation residue is acidified with dilute hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 62 (s, 6H); 1, 99 to 2.10 (m, 1H); 2.19 to 2.31 (m, 1H); 2.36 (s, 3H); 2.71 to 2.81 (m, 1H); 2.90-3.00 (m, 1H); 4.34 (d, 1H,

J = 11, 7 Hz); 4.57 to 4.65 (m, 2H); 6.9 (d, 1H, J = 8.5Hz); 6.98 (d, 1H, J = 8.5Hz); 7,29-

7.42 (m, 7H); 7.86 (d, 2H, J = 8.5Hz).

Mass (MALDI-TOF): 603.

Mp 50-55 ° C. Compound 26: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) - 2-methylpropanoate

Figure imgf000081_0001

The (2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-prop-1-enyl) phenoxy) -2-methylpropanoate was prepared from 3-

(2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) -thiazol-5-yl) prop-2-en-1-one according to General Procedure G using 3 equivalents of tert-butyl bromoisobutyrate and 3 equivalents of potassium carbonate in N, N-dimethylformamide. After stirring for 16 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 48 (s, 9H); 1, 68 (s, 6H); 2.90 (s, 3H); 6.86 (d, 1H, J = 8.9Hz); 7.15 (d, 1H, J = 15.5Hz); 7.55 (d, 1H, J = 8.9Hz); 7.74 (d, 2H,

J = 8.0Hz); 8.13 (d, 2H, J = 8.0Hz); 8.18 (d, 1H, J = 15.5Hz).

Compound 27: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy ) -2-methylpropanoic acid

Figure imgf000081_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) - 2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1- enyl) phenoxy) -2-methylpropanoate according to general procedure H using 25 equivalents of trifluoroacetic acid.

After 48 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel (preparative HPLC, lichrospher (Merck) RP18 12 .mu.m 100A, column 25 * 250 mm).

Elution: gradient water, methanol + 0.1% trifluoroacetic acid: 22/78 to 10/90.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 74 (s, 6H); 2.90 (s, 3H); 7.01 (d, 1H, J = 8.7 Hz); 7.17 (d, 1H, J = 15.5Hz); 7.60 (d, 1H, J = 8.7 Hz); 7.74 (d, 2H, J = 8.5Hz); 8.13 to 8.22 (m, 3H). Mass (ES "): 542 (M-1) mp 194 ° C..

Compound 28: 2- (2,3-dichloro-4- (3-oxo-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate

Figure imgf000082_0001

2- (2,3-dichloro-4- (3-oxo-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propyl) phenoxy) butanoate was prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to General procedure G using 5 equivalents of tert-butyl 2-bromobutanoate and 5 equivalents of potassium carbonate in N, N-dimethylformamide. After stirring for 16 hours at 70 0 C, the reaction mixture is cooled, ethyl acetate added, the whole is washed with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 8/2. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 12 (t, 3H, J = 7.3Hz); 1, 36 (d, 6H, J = 6.4Hz); 1, 45 (s, 9H); 2.01 to 2.07 (m, 2H); 3.18 (s, 4H); 3.94 (m, 1H); 4.46 (t, 1H, J = 6.0Hz); 6.67 (d, 1H, J = 8.5Hz); 7.15 (d, 1H, J = 8.5Hz); 7.73 (d, 2H, J = 8.3 Hz); 8.12 (d, 2H, J = 8.3Hz). Compound 29: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate butyl

Figure imgf000083_0001

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) propan-1-one according to the procedure General G using 5 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate in N, N-dimethylformamide. After 22 hours of stirring at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 85/15. Silica 40-63μm.

1 H NMR (300MHz, CDCI -3 δ in ppm): 1, 46 (s, 9H); 1, 57 (s, 6H); 2.59 (s, 3H); 3.15 (m, 2H); 3.25 (m, 2H); 6.80 (d, 1H, J = 8.5Hz); 7.09 (d, 1H, J = 8.5Hz); 7.75 (d, 2H, J = 8.2Hz); 8.21 (d, 2H, J = 8.2Hz).

Compound 30: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - oxazol-5-yl) -3-oxopropyl) phenoxy) -2 -méthylpropanoïque

Figure imgf000083_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate tert-butyl according to general procedure H using 17 equivalents of trifluoroacetic acid. After stirring for 18 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 64 (s, 6H); 2.60 (s, 3H); 3.24 (m, 4H); 6.95 (d, 1H, J = 8.5Hz); 7.18 (d, 1H, J = 8.5Hz); 7.76 (d, 2H, J = 8.1 Hz); 8.21 (d, 2H, J = 8.1 Hz).

Mass (MALDI-TOF): 529. mp: 178-179 ° C.

Compound 31: 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000084_0001
2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate is prepared from 3- (2-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to General procedure G with 5 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate in N, N-dimethylformamide.

After 26 hours of stirring at 70 0 C, the reaction mixture is cooled, ethyl acetate added, the whole is washed with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5. Silica 40-63μm.1 H NMR (300MHz, CDCI -3 δ in ppm): 1, 46 (s, 9H); 1, 55 (s, 6H); 2.81 (s, 3H); 3.13 (m, 4H); 6.71 (dd, 1H, J = 2.6Hz J = 8.5Hz); 6.90 (d, 1H, J = 2.6Hz); 7.15 (d, 1H, J = 8.5Hz); 7.72 (d, 2H, J = 8.2Hz); 8.09 (d, 2H, J = 8.2Hz). Compound 32: 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000085_0001

2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate according to general procedure H using 92 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 61 (s, 6H); 2.81 (s, 3H); 3.17 (m, 4H); 6.79 (dd, 1H, J = 2.3Hz J = 8.5Hz); 7.00 (d, 1H, J = 2.3Hz); 7.21 (d, 1H, J = 8.5Hz);

7.72 (d, 2H, J = 8.2Hz); 8.08 (d, 2H, J = 8.2Hz).

Mass (ES +): 512 (M + 1).

Compound 33: 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000085_0002

2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate is prepared from 3- (3-chloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to General procedure G with 5 equivalents of tert-butyl bromoisobutyrate and 5 equivalents of potassium carbonate in N, N-dimethylformamide. After 6 hours of stirring at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: petroleum ether / ethyl acetate: 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCI -3 δ in ppm): 1, 49 (s, 9H); 1, 55 (s, 6H); 2.81 (s, 3H); 3.00 (t, 2H, J = 7.2Hz); 3.15 (t, 2H, J = 7.2Hz); 6.89 (d, 1H, J = 8.4Hz); 7.02 (dd, 1H, J = 2.1 Hz J = 8.4Hz); 7.26 (m, 1H); 7.72 (d, 2H, J = 8.2Hz); 8.09 (d, 2H, J = 8.2Hz).

Compound 34: 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000086_0001

2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate according to general procedure H using 112 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 98/2. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 62 (s, 6H); 2.81 (s, 3H); 3.04 (m, 2H); 3.18 (m, 2H); 7.03 (d, 1H, J = 8.5Hz); 7.10 (dd, 1H, J = 2.1 Hz J = 8.5Hz); 7.31 (d, 1H,

J = 2.1 Hz); 7.73 (d, 2H, J = 8.4Hz); 8.10 (d, 2H, J = 8.4Hz).

Mass (ES +): 512 (M + 1).

F = 127 ° C. Compound 35: 2- (2,3-dichloro-4- (3- (cyclohexylmethoxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic

Figure imgf000087_0001

2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) -2- methylpropanoic acid is solubilized in a mixture cyclohexanemethanol / water: 2/1 in the presence of a catalytic amount of trifluoroacetic acid. The assembly is placed under microwave irradiation for 5 minutes at 160 0 C.

The reaction mixture is concentrated by evaporation under reduced pressure and the evaporation residue is purified by chromatography on silica gel.

Elution: ethyl acetate and then dichloromethane / methanol: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 0.95 (m, 2H); 1, 24 (m, 4H); 1, 63 (s, 6H);

1, 65 (m, 5H); 2.01 (m, 1H); 2.15 (m, 1H); 2.41 (s, 3H); 2.82 (m, 1H); 2.92 (m, 1H);

3.14 (m, 1H); 3.24 (m, 1H); 4.51 (dd, 1H, J = 5.1 Hz J = 8.0Hz); 6.93 (d, 1H, J = 8.5Hz); 7.02 (d, 1H, J = 8.5Hz); 7.67 (d, 2H, J = 8.2Hz); 8.01 (d, 2H, J = 8.2Hz).

Mass (ES "): 642 (M-1).

Mp 62-64 ° C.

Compound 36: 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoate butyl

Figure imgf000087_0002

2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from the

3- (2,3-difluoro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to general procedure G by 3 equivalents of tert-butyl bromoisobutyrate and 3 equivalents of potassium carbonate in N, N-dimethylformamide.

After stirring for 12 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 7/3. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 47 (s, 9H); 1, 56 (s, 6H); 2.81 (s, 3H); 3.10 (m, 2H); 3.18 (m, 2H); 6.71 (m, 1H); 6.81 (m, 1H); 7.73 (d, 2H, J = 4.0Hz); 8.10 (d, 2H, J = 4.0Hz).

Compound 37: 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoic

Figure imgf000088_0001

2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate tert-butyl according to general procedure H using 99 equivalents of trifluoroacetic acid.

After 6 hours of stirring at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 61 (s, 6H); 2.81 (s, 3H); 3.10 (m, 2H);

3.19 (m, 2H); 6.81 (m, 1H); 6.94 (m, 1H); 7.72 (d, 2H, J = 4.1 Hz); 8.10 (d, 2H,

J = 4.1 Hz).

Mass (ES "): 512 (M-1) mp 133-134 ° C Compound 38:.. 2- (2,3-dichloro-4- (3- (hydroxyimino) -3- (4-methyl- 2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) -2-methylpropanoic acid

Figure imgf000089_0001

2- (2,3-dichloro-4- (3- (hydroxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl ) phenoxy) -2-methylpropanoic acid and hydroxylamine hydrochloride according to general procedure K.

Elution: dichloromethane / methanol: 97/3. Silica 40-63μm.1 H NMR (300MHz, Acetone-d 6, δ in ppm): 1, 55 (s, 6H); 2.56 (s, 3H); 3.10 (s, 4H);

6.98 (d, 1H, J = 8.6 Hz); 7.20 (d, 1H, J = 8.6 Hz); 7.83 (d, 2H, J = 8.2Hz); 8.15 (d, 2H,

J = 8.2Hz).

Mass (ES +): 564 (M + 1).

F = 198-199 ° C.

Compound 39: 2- (2,3-dichloro-4- (3- (methoxyimino) -3- (4-methyl-2- (4-

(Trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) -2-methylpropanoic acid

Figure imgf000089_0002

2- (2,3-dichloro-4- (3- (methoxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl ) phenoxy) -2-methylpropanoic acid and O-methyl hydroxylamine hydrochloride according to general procedure K. Elution: dichloromethane / methanol: 95/5. Silica 40-63μm.1 H NMR (300MHz, Acetone-d 6, δ in ppm): 1, 56 (s, 6H); 2.58 (s, 3H); 3.31 (s, 4H); 3.94 (s, 3H); 6.96 (d, 1H, J = 8.5Hz); 7.18 (d, 1H, J = 8.5Hz); 7.84 (d, 2H, J = 8.1 Hz); 8.16 (d, 2H, J = 8.1 Hz). Mass (ES +): 575 (M + 1). F = 197-199 ° C.

Compound 40: 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000090_0001
2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) - phenoxy) -2-methylpropanoate was prepared from 1- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3- (2,3-dichloro-4-hydroxyphenyl) propan-1-one according to general procedure G using 3 equivalents tert-butyl bromoisobutyrate and 3 equivalents of potassium carbonate in N, N- dimethylformamide.

After stirring for 12 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 7/3. Silica 40-63μm.1 H NMR (300MHz, DMSO-d 6, δ in ppm): 1, 37 (s, 9H); 1, 52 (s, 6H); 2.73 (s, 3H); 3.06 (m, 2H); 3.26 (m, 2H); 6.83 (d, 1H, J = 8.6 Hz); 7.31 (d, 1H, J = 8.6 Hz); 7.56 (m, 2H); 7.69 (m, 1H); 8.30 (m, 1H). Compound 41: 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000091_0001

2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) - phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (2- (2- chlorophenyl) -4-methylthiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate according to general procedure H using 71 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 73 (s, 6H); 2.82 (m, 4H); 3.22 (s, 3H); 6.95 (d, 1H, J = 8.5Hz); 7.19 (d, 1H, J = 8.5Hz); 7.40 (m, 2H); 7.50 (m, 1H); 8.32 (m,

1H).

Mass (ES +): 510/512 (M + 1).

Mp 165 ° C.

Compound 42: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-phenylacetate d 'ethyl

Figure imgf000091_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-phenylacetate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to General procedure G using 3 equivalents of ethyl 2-bromophenylacetate and 3 equivalents of potassium carbonate in N, N-dimethylformamide.

After 10 minutes of stirring at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 18 (m, 3H); 2.81 (s, 3H); 3.18 (s, 4H); 4.16 (m, 2H); 5.64 (s, 1H); 6.75 (d, 1H, J = 8.5Hz); 7.14 (d, 1H, J = 8.5Hz); 7.45 (m, 3H); 7.62 (m, 2H); 7.70 (d, 2H, J = 8.2Hz); 8.10 (d, 2H, J = 8.2Hz).

Compound 43: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2- phenylacetic

Figure imgf000092_0001

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-phenylacetic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-phenylacetate ethyl according to general procedure L using 13 equivalents of 2N sodium hydroxide solution.

The evaporation residue is purified by chromatography on silica gel (preparative HPLC, Lichrospher (Merck) RP18 12 .mu.m 100A, column 25 * 250 mm). Elution: gradient water, methanol + 0.1% trifluoroacetic acid: 14/86 to 10/90.1 H NMR (300MHz, CDCl 3, δ in ppm): 2.79 (s, 3H); 3.16 (s, 4H); 5.68 (s, 1H); 6.74 (d, 1H, J = 8.6 Hz); 7.12 (d, 1H, J = 8.6 Hz); 7.42 (m, 3H); 7.61 (m, 2H); 7.72 (d, 2H, J = 8.2Hz); 8.05 (d, 2H, J = 8.2Hz). Mass (ES +): 594 (M + 1). Compound 44: 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2,2 methyl dimethylpentanoate

Figure imgf000093_0001

5- (2,3-dichloro-4- (3-oxo-3- (5- (4- (trifluoromethyl) phenyl) thien-2-yl) propyl) - phenoxy) -2,2-dimethylpentanoate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) propan-1-one according to the procedure General G using 3 equivalents of 5-iodo-2,2-dimethylpentanoate methyl and 3 equivalents of potassium carbonate in N, N-dimethylformamide. After 10 minutes of stirring at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 22 (s, 6H); 1, 73 (m, 4H); 2.79 (s, 3H); 3.16 (m, 4H); 3.66 (s, 3H); 3.97 (m, 2H); 6.75 (d, 1H, J = 8.5Hz); 7.16 (d, 1H, J = 8.5Hz); 7.69 (d, 2H, J = 8.2Hz); 8.07 (d, 2H, J = 8.2Hz).

Compound 45: 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2, 2-dimethylpentanoic

Figure imgf000093_0002

The 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2,2 dimethylpentanoic acid was prepared from 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2 , methyl 2-dimethylpentanoate according to general procedure L using 7 equivalents of 2N sodium hydroxide solution. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 7/3 dichloromethane / methanol: 85/15. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 27 (s, 6H); 1, 74 (m, 2H); 1, 84 (m, 2H); 2.81 (s, 3H); 3.18 (s, 4H); 4.01 (m, 2H); 6.78 (d, 1H, J = 8.5Hz); 7.17 (d, 1H, J = 8.5Hz); 7.72 (d, 2H, J = 8.2Hz); 8.09 (d, 2H, J = 8.2Hz). Mass (ES +): 588 (M + 1). F = 172-173 ° C.

Compound 46: 2-methyl-2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) propanoate

Figure imgf000094_0001

2-methyl-2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy) propanoate was prepared from 3- (4-hydroxyphenyl) -1 - (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to general procedure G using 5 equivalents bromoisobutyrate tert-butyl and 5 equivalents of potassium carbonate in N, N- dimethylformamide. After stirring for 12 hours at 70 0 C, the solvent is removed by evaporation under reduced pressure. The evaporation residue is taken up in ethyl acetate. The organic phase is washed with a saturated solution of ammonium chloride, water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel, elution: cyclohexane / ethyl acetate: 8/2. Silica 40-63μm.1 H NMR (300MHz, DMSO-d 6, δ in ppm): 1, 33 (s, 9H); 1, 40 (s, 6H); 2.66 (s, 3H); 2.88 (t, 2H, J = 7.4 Hz); 3.10 (t, 2H, J = 7.4 Hz); 6.65 (d, 2H, J = 8.5Hz); 7.04 (d, 2H, J = 8.5Hz); 7.71 (d, 2H, J = 8.2Hz); 8.07 (d, 2H, J = 8.2Hz). Compound 47: 2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy-2-methylpropanoic

Figure imgf000095_0001

The 2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) - phenoxy -2-methylpropanoic acid is prepared from 2- methyl-2- (4- (3- (4-methyl-

2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) propanoate according to general procedure H using 65 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is washed with water. The organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 95/5. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 59 (s, 6H); 2.81 (s, 3H); 3.07 (m, 2H); 3.17 (m, 2H); 6.89 (m, 2H); 7.16 (m, 2H); 7.72 (d, 2H, J = 4.1 Hz); 8.09 (d, 2H,

J = 4.1 Hz).

Mass (ES "): 476 (M-1).

F = 115-116 ° C.

Compound 48: 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) -3- (pyridin-3-ylmethoxy) propyl) phenoxy) -2-methylpropanoic acid

Figure imgf000095_0002

2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- (pyridin-3-ylmethoxy) propyl ) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol -5-yl) propyl) phenoxy) -2-methylpropanoic acid according to general procedure J using 8 equivalents of sodium hydride and 2 equivalents of bromo hydride 3- (bromomethyl) pyridine.

After stirring for 16 hours at room temperature, the reaction medium is diluted with a hydrochloric acid solution dliuée then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 58 (s, 6H); 2.09 to 2.33 (m, 2H); 2.38 (s, 3H); 2.77 to 2.95 (m, 2H); 4.35 (d, 1H, J = 12.4Hz); 4.55 (d, 1H, J = 12.5Hz); 4.65 to 4.70

(M, 1H); 6.91 (d, 1H, J = 8.3 Hz); 6.98 (d, 1H, J = 8.3 Hz); 7.39-7.43 (m, 1H); 7,66-

7.74 (m, 3H); 8.02 (d, 2H, J = 8.3 Hz); 8.42 (s, 1H); 8.56 (m, 1H).

Mp 74-76 ° C.

Compound 49: 2- (2,3-dichloro-4- (3-methoxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic

Figure imgf000096_0001

2- (2,3-dichloro-4- (3-methoxy-3- (4-methyl-2- (4- (trifluoro-methyl) phenyl) - thiazol-5-yl) propyl) phenoxy) - 2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) -thiazol-5-yl ) propyl) phenoxy) -2-methylpropanoic acid according to general procedure J using 5 equivalents of sodium hydride and 2 equivalents of iodomethane. After stirring for 16 hours at room temperature, the reaction medium is diluted with a hydrochloric acid solution dliuée then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: dichloromethane / methanol: 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 64 (s, 6H); 1, 97 to 2.28 (m, 2H); 2.44 (s, 3H); 2.75 to 2.98 (m, 2H); 3.32 (s, 3H); 4.47 (dd, 1H, J = 5.7Hz, J = 7.7Hz); 6.95 (d, 1H, J = 8.4Hz); 7.05 (d, 1H, J = 8.4Hz); 7.69 (d, 2H, J = 8.3 Hz); 8.03 (d, 2H, J = 8.3Hz). Mp 56-58 ° C.

Compound 50: 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoate butyl

Figure imgf000097_0001
2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to the procedure General G using 4 equivalents of tert-butyl bromoisobutyrate and 4 equivalents of potassium carbonate in acetonitrile. After 22 hours of stirring at 80 0 C, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel. Elution: cyclohexane / ethyl acetate: 95/5 to 8/2. Silica 40-63μm.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 45 (s, 9H); 1, 59 (s, 6H); 2.80 (s, 3H); 3.16 (s, 3H); 6.78 (d, 1H, J = 8.3 Hz); 7.08 (d, 1H, J = 8.3 Hz); 7.56 to 7.62 (m, 1H); 7.72 (d, 1H, J = 7.7Hz); 8.12 (d, 1H, J = 7.6Hz); 8.25 (s, 1H).

Compound 51: 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoic

Figure imgf000097_0002
2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) -thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoate according to general procedure H using 20 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is washed with water and the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is taken up in acetone and then filtered.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 54 (s, 6H); 2.81 (s, 3H); 3.19 (s, 3H); 6.94 (d, 1H, J = 8.4Hz); 7.18 (d, 1H, J = 8.4Hz); 7.55 to 7.62 (m, 1H); 7.72 (d, 1H, J = 7.6Hz); 8.12 (d, 1H, J = 7.7Hz); 8.23 (s, 1H). F = 143-145 ° C.

Compound 52: 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000098_0001

2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxopropyl) - phenoxy) -2-methylpropanoate was prepared from 3- (2,3-dichloro-4-hydroxyphenyl) -1- (2- (4-methoxy-phenyl) -4-methylthiazol-5-yl) propan-1-one according to general procedure G by 6 equivalents of tert-butyl bromoisobutyrate and 6 equivalents of potassium carbonate in N, N-dimethylformamide.

After 3.5 hours of stirring at 120 0 C, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 95/5 to 9/1. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 45 (s, 9H); 1, 59 (s, 6H); 2.78 (s, 3H); 3.15 (s, 4H); 3.88 (s, 3H); 6.80 (d, 1H, J = 8.4Hz); 6.95 (d, 2H, J = 8.6 Hz); 7.10 (d, 1H, J = 8.4Hz); 7.92 (d, 2H, J = 8.6Hz).

Compound 53: 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid

Figure imgf000099_0001

2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoate according to general procedure H with 20 equivalents of trifluoroacetic acid.

After stirring for 18 hours at room temperature, the reaction medium is diluted with ethyl acetate then washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is taken up in acetone and then filtered.

1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 55 (s, 6H); 2.69 (s, 3H); 3.02 (m, 2H);

3.22 (m, 2H); 3.82 (s, 3H); 6.87 (d, 1H, J = 8.4Hz); 7.09 (d, 2H, J = 8.5Hz); 7.31 (d,

1H, J = 8.4Hz); 7.95 (d, 2H, J = 8.5Hz). F = 176-178 ° C.

Compound 54: 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluorométhvQphénv0thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoate

Figure imgf000099_0002
2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate is prepared from 3- (4-hydroxy-2,3-dimethylphenyl) -1- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propan-1-one according to the procedure General G by 8 equivalents of tert-butyl bromoisobutyrate and 8 equivalents of potassium carbonate in acetonitrile.

After 48 hours of stirring at 80 0 C, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by chromatography on silica gel.

Elution: cyclohexane / ethyl acetate: 9/1 to 8/2. Silica 40-63μm.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 46 (s, 9H); 1, 54 (s, 6H); 2.19 (s, 3H); 2.24

(S, 3H); 2.81 (s, 3H); 2.99 to 3.11 (m, 4H); 6.58 (d, 1H, J = 8.3 Hz); 6.87 (d, 1H,

J = 8.3Hz); 7.72 (d, 2H, J = 8.4Hz); 8.09 (d, 2H, J = 8.4Hz).

Compound 55: 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoic

Figure imgf000100_0001

2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) -thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid is prepared from 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2- methylpropanoate according to general procedure H using 20 equivalents of trifluoroacetic acid.

After 1 hour of stirring at room temperature, the reaction medium is washed with water and the dichloromethane is removed by evaporation under reduced pressure. The evaporation residue is taken up in acetone and then filtered.1 H NMR (300MHz, CDCl 3, δ in ppm): 1, 58 (s, 6H); 2.19 (s, 3H); 2.26 (s, 3H); 2.80 (s, 3H); 3.01 to 3.13 (m, 4H); 6.68 (d, 1H, J = 8.4Hz); 6.94 (d, 1H, J = 8.4Hz); 7.69 (d, 2H, J = 8.4Hz); 8.05 (d, 2H, J = 8.4Hz). F = 150-152 ° C. Example 5: In Vitro Evaluation of PPAR activating properties of the compounds according to the invention - Method 1

Principle The activation of PPAR has been evaluated in vitro on a line of monkey kidney fibroblasts (COS-7) by measuring the transcriptional activity of chimeras composed of the binding domain to the DNA of the Gal4 transcription factor yeast and the ligand binding domain of the different PPARs. Compounds were tested at doses of between 10 "4 and 100 .mu.m on chimeric Gal4 PPARa, γ or δ.

Protocol

Cell Culture

COS-7 cells obtained from the ATCC and were cultured in 10% DMEM supplemented medium (vol / vol) fetal calf serum, 100 U / ml penicillin (Gibco, Paisley, UK) and 2 mM L-Glutamine (Gibco, Paisley, UK). The cells were incubated at 37 ° C in a humid atmosphere containing 5% CO 2.

Description of plasmids used in transfection

The plasmids Gal4 (RE) _TkpGL3, pGal4-hPPARα, hPPARγ-pGal4, pGal4 hPPARδ and pGal4-φ have been described in the literature (Raspe E et al., 1999). Constructions pGal4-hPPARα, pGal4-hPPARγ and pGal4-hPPARδ were obtained by cloning into the vector pGal4-φ of DNA fragments amplified by PCR corresponding to the DEF domains of the nuclear receptor PPARa, PPAR gamma and human PPARδ.

transfection

COS-7, suspended cells were transfected with 150 ng of DNA per well with a ratio pGal4-PPAR / Gal4 (RE) _TkpGL3 1/10 in the presence of 10% fetal calf serum. The cells were then seeded in 96-well plates (4x10 4 cells / well) and incubated for 24 hours at 37 ° C. Activation with the test compounds is carried out during 24 h at 37 ° C in serum free medium. At the end of the experiment, cells were lysed and luciferase activity was determined using the Steady-Lite ™ HTS (Perkin Elmer) according to manufacturer's recommendations.

Results

Unexpectedly, the inventors have demonstrated a significant increase in dose-dependent luciferase activity in cells transfected with the pGal4-hPPAR plasmids and treated with the compounds according to the invention. The experimental data are summarized in Table 1 below, which shows the EC50 measured for each PPAR isoform, as well as the maximum response rate achieved by each test compound in relation to the reference (fenofibric acid for PPARa, Rosiglitazone for PPAR gamma and GW501516 for PPARδ).

The measured activities differ depending on the test compound and also was observed from the compounds of the invention more or less than vis-à-vis isoform PPAR selectivity:

- some compounds according to the invention are selective with respect to a subtype of PPAR. - other compounds of the invention are simultaneously activating two or three subtypes.

Figure imgf000103_0001

Table 1

Conclusion: These results show that the compounds of the invention bind and activate the receptor hPPARα, hPPARγ and / or significantly hPPARδ. The activity of compounds according to the invention is variable depending on the chemical structure of the test compound and according to the subtype of PPAR studied.

Example 6 In Vitro Evaluation of PPAR activating properties of the compounds according to the invention - Method 2

In this example, the principle, the cells and plasmids used in Example 5 were taken. Only the implementation of the transfection step is slightly different. It is detailed below.

The adherent COS-7 cells were transfected with 40 ug of DNA per flask of 225 cm 2, with a ratio pGal4-PPAR / Gal4 (RE) _TkpGL3 1/10 in the presence of 10% fetal calf serum. Cells were then detached and seeded in the absence of serum in 384-well plates (2x10 4 cells / well) and incubated for 4 hours at 37 ° C. The compounds are then diluted in a 96 well plate and then transferred into the 384-well plate. Activation with the test compounds is carried out for a further 24 h at 37 ° C in the presence of 1% of synthetic serum Ultroser ™ (Biosepra) without lipids. These two last steps are automated using a Genesis Freedom 200 ™ station (Tecan). After the experiment, the cells are lysed and luciferase activity is determined using the Steady-Lite ™ HTS (Perkin Elmer) according to manufacturer's recommendations.

Results

Unexpectedly, the inventors have demonstrated a significant increase in dose-dependent luciferase activity in cells transfected with the pGal4-hPPAR plasmids and treated with the compounds according to the invention.

The collected experimental data are summarized in Table 2 below, which shows the EC50 measured for each PPAR isoform, as well as the maximum response rate achieved by each test compound in relation to the reference (fenofibric acid for PPARa, Rosiglitazone for PPARgamma and GW501516 for PPARδ).

The measured activities differ depending on the test compound and also was observed from the compounds of the invention more or less than vis-à-vis isoform PPAR selectivity:

- some compounds according to the invention are selective with respect to a subtype of PPAR.

- other compounds of the invention are simultaneously activating two or three subtypes.

Figure imgf000105_0001

Table 2

Conclusion: These results show that the compounds of the invention bind and activate the receptor hPPARα, hPPARγ and / or significantly hPPARδ. The activity of compounds according to the invention is variable depending on the chemical structure of the test compound and according to the subtype of PPAR studied.

Example 7: In vitro evaluation of PPARδ activating properties of the compounds according to the invention by measuring the expression of target genes of PPARδ in mvocvtes

Principle stimulatory effects of lipid metabolism, carbohydrate and energy expenditure of the compounds of the invention were evaluated by measuring the expression of Pyruvate Dehydrogenase Kinase 4 (PDK4) of Carnitine Transferase Palmotoyl Ib (SCIT b) , the uncoupling protein 2 (UCP2) and the uncoupling protein 3 (UCP3) by myocytes treated for 24 hours with the compounds according to the invention. It is disclosed that the regulation of the expression of these genes is directly controlled by PPARδ in this cell type. More gene expression is increased, the more the compound of the invention is stimulating the metabolism in the muscle cells. Protocol

Differentiation C2C12 cells into myocytes

The murine cell line C2C12 (from ECACC) were cultured in DMEM medium (Gibco, 41965-039) supplemented with 1% L-Glutamine (Gibco, 25030), 1% penicillin / streptomycin (VWR; BWSTL0022 / 100) and 10 % fetal calf serum decomplemented (FCS Gibco;. 10270-106).

Cells are seeded onto 24-well plates at a density of 50.10 3 cells / well. At confluence, the medium was replaced with differentiation medium (basal culture medium supplemented with 2% horse serum (Gibco; 26050- 088)) and then incubated at 37 ° C and 5% CO2 for 4 days to differentiate into myocytes.

Treatment

After 5 days of differentiation, cells are placed in a deprivation of medium (serum-free basal culture medium) for 6 hours. Afterwards the cells are treated with the compounds according to the invention in the culture medium of deprivation. Compound 8 according to the invention has been tested at doses of 5, 50 and 50OnM, corresponding to 1x, 10x and 100x its EC50 PPARδ. Compound 8 according to the invention is dissou in dimethyl sulfoxide (DMSO, Sigma; D5879). Cells were treated for 24 h at 37 ° C, 5% CO2. The effect of compound 8 according to the invention is compared with the effect of DMSO alone.

1 RNA extraction and reverse transcription quantitative PCR. After treatment, total RNA was extracted from cells using the NucleoSpin kit 96 RNA ® (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions.

1 ug of total RNA (quantified by spectrophotometer reading at UV) was then retro-transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30 microliters containing 1X buffer (Invitrogen), 1 , 5mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen). The experiences of quantitative PCR were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, M rn-l-Coquette, France) and were performed using the kit iQ SYBR Green Supermix as recommended supplier, in 96-well plates, on 5 .mu.l of retro-transcription reactions diluted with a hybridization temperature of 60 0 C. primer pairs specific for the genes and PDK4 CPTI b studied were used:

• hPDK4: sense primer: 5'-CCCGAGAGGTGGAGCATTTC-3 '(SEQ ID NO: 15) and antisense primer δ'-TGTTGGCGAGTCTCACAGGC-S' (SEQ ID NO: 16) • hCPTI b: sense primer: δ'-CTTCTTCTTCCGCCAAACCC-S '(SEQ ID NO: 7) and antisense primer: δ'-ACACATAGCCCAGATCCTGG-S' (SEQ ID No. 8)

• hUCP2: sense primer: 5'-CAGCACAGTTGACAATGGC-3 '(SEQ ID NO: 31) and antisense primer: 5'-CTCGGGAAGTGCAGGCAGC-3' (SEQ ID No. 32)

• hUCP3: sense primer: δ'-CCATCCAGGAGCGACAGAAAATAC-S '(SEQ ID 33) and antisense primer: δ'-GCACAGTTGACGATAGCATTCCTC-S'

(SEQ ID No. 34)

The amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different retro-transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points. The expression levels of the genes of interest were then normalized relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: δ'-CATGCTCAACATCTCCCCCTTCTCC-S '(SEQ ID No. 27) and antisense primer: δ'-GGGAAGGTGTAATCCGTCTCCACAG-S '(SEQ ID No. 28)). The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, was then calculated. More this factor, the higher the compounds of the invention have an activating nature of gene expression. The end result is represented as an average of the induction values ​​in each experimental group.

Results The inventors also demonstrated, on myocytes in vitro, the compound 8 according to the invention has the stimulatory effects of the expression of genes involved in glucose metabolism, lipid and thermoregulation. The results shown in Figure 1-1 show that compound 8 according to the invention, as soon 5OnM, induces a significant increase and dose-dependent expression of PDK4 in myocytes. The results shown in Figure 1-2 show that compound 8 according to the invention, as soon 5OnM, induces a significant increase and dose dependent expression of CPTI b in myocytes. The results presented in Figure 1 -3 show that compound 8 according to the invention, as soon 5OnM, induces a significant increase and dose dependent expression of UCP2 in the myocytes. The results shown in Figure 1-4 show that compound 8 according to the invention, from 5 nM, induces a significant increase and dose dependent expression of UCP3 in the myocytes.

Conclusion

Unexpectedly, the experimental data presented show that compound 8 according to the invention has a metabolic action in human myocytes by activation of PPARδ.

Example 8: In vivo evaluation in mice E2 / E2, hypolipidemic and stimulatory properties of the synthesis of HDL cholesterol of the compounds according to the invention

Principle The hypolipidemic properties and stimulator of the synthesis of HDL-cholesterol compounds of the invention were assessed in vivo by measurement of plasma lipid analysis of the distribution of cholesterol in the various plasma lipoprotein fractions and measuring the expression of PPAR target genes in the liver and skeletal muscle in mice E2 / E2 dyslipidemic.

The murine model used is the type of ApoE2 / E2, mice transgenic for the E2 isoform of human apolipoprotein E (Sullivan PM et al., 1998). In humans, this apolipoprotein, lipoprotein component of low and very low density (VLDL-LDL) is present in three isoforms E2, E3 and E4. E2 form has a mutation on an amino acid at position 158, which significantly weakens the affinity of this protein for the LDL receptor. Clearance of VLDL is therefore almost zero. This produces an accumulation of low density lipoproteins and a so-called mixed hyperlipidemia type III

(Cholesterol and triglycerides).

PPARa regulates the expression of genes involved in lipid transport (apolipoproteins such as Apo AI, Apo AII and Apo CIII, membrane transporters such as FAT) or catabolism of lipids (ACOX1, CPT-I or CPT-II enzymes the β-oxidation of fatty acids). Treatment with the PPARa activators therefore results in humans as in rodents, by a decrease in circulating levels of triglycerides and free fatty acids. The measurement of lipid and plasma free fatty acids after treatment with the compounds according to the invention is thus an indicator of the agonist character of the PPARs and therefore the nature of lipid-lowering compounds according to the invention. PPARa agonists properties of the molecules according to the invention previously measured in vitro to be translated in the liver by a modulation of the expression of target genes directly under the receiver control PPARa: genes that have been studied in this experiment were the genes encoding PDK4 (Pyruvate dehydrogenase kinase isoform 4, enzyme of carbohydrate metabolism), the Acoxi (the Acoxi present in mice corresponds to the ACO gene in humans (Acyl Co-enzymeA oxidase, a key enzyme in the β-oxidation mechanism of fatty acids)) and Apo CIII (apolipoprotein involved in lipid metabolism). Treatment with PPARδ activators is reflected in man as in rodents, in an increase in plasma HDL-cholesterol levels. The analysis of the distribution of cholesterol after treatment with the compounds of the invention therefore highlight the stimulatory nature of the synthesis of HDL cholesterol of the compounds of the invention.

The PPARδ agonistic properties of the molecules of the invention previously measured in vitro should also result in skeletal muscle by over-expression of target genes directly under the control of the PPARδ receptor: the genes that were studied in this experiment are genes encoding UCP2 and UCP3 (Uncoupling Protein 2 and 3, mitochondrial transporters involved in thermoregulation).

The measurement of the transcriptional activity of PPAR target genes after treatment with the compounds of the invention is also an indicator of character of lipid-lowering compounds of the invention.

Protocol

Animal Treatment

Transgenic mice Apo E2 / E2 were kept on a light / dark cycle of 12/12 hours at a constant temperature of 20 ± 3 ° C. After acclimation for one week, the mice were weighed and divided into groups of 6 animals selected so that the distribution of their body weights and their plasma lipid levels determined once before the experiment are consistent. The test compounds were suspended in carboxymethylcellulose (Sigma C4888) and administered by intragastric gavage at a rate of once a day for 7 days at the selected dose. The animals had free access to water and food (standard diet). After the experiment, the animals were anesthetized after fasting for 4 hours, a blood sample was taken using anticoagulant (EDTA) then the mice were weighed and euthanized. The plasma was separated by centrifugation at 3000 rev / min for 20 minutes, the samples were stored at 4 ° C.

Samples of liver and skeletal muscle tissue were taken and frozen immediately in liquid nitrogen and stored at -80 0 C for further analysis. Analysis of the distribution of cholesterol in plasma lipoprotein fractions.

The various lipid fractions (VLDL, LDL, HDL) plasma were separated by chromatography Gel - Filtration. Cholesterol concentrations were then measured in each fraction by enzyme assays (bioMérieux-Lyon-France) following the supplier's recommendations.

Measurement of Plasma Lipids Plasma triglyceride concentrations were measured by enzyme assays (bioMérieux-Lyon-France) following the supplier's recommendations.

qénique expression analysis by quantitative RT-PCR Hepatic Tissue

Total RNA was extracted from liver fragments by using the kit

NucleoSpin® 96 RNA (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions.

Fabric souelettigue Total RNA was extracted from gastrocnemius skeletal muscle fragments by using the kit RNeasy ® Fibrous Tissue kit (Qiagen) according to manufacturer's instructions.

1 ug of total RNA (quantified by spectrophotometry) was then reverse transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30μl containing 1X buffer (Invitrogen), 1, 5 mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen).

Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the kit iQ SYBR Green Supermix according to the supplier's recommendations, in 96-well plates, on 5 .mu.l of diluted reverse transcription reaction with an annealing temperature of 60 0 C. primer pairs specific for the genes PDK4, Acoxi, ApoCIII, UCP2 and UCP3 studied were used:

• mPDK4: sense primer: δ'-TACTCCACTGCTCCAACACCTG-S '(SEQ ID NO: 17) and antisense δ'-GTTCTTCGGTTCCCTGCTTG primer-S' (SEQ ID No. 18)

• mACOXI: sense primer: 5'GAAGCCAGCGTTACGAGGTG-3 '(SEQ ID NO: 3) and antisense primer: 5'TGGAGTTCTTGGGACGGGTG-3' (SEQ ID NO: 4) • mApoCIII: sense primer: δ'-CTCTTGGCTCTCCTGGCATC-S '(SEQ ID NO: 5) and antisense primer 5'-GCATCCTGGACCGTCTTGGA-3' (SEQ ID NO: 6)

• mUCP2: sense primer: δ'-GTCGGAGATACCAGAGCACTGTCG-S '(SEQ ID NO: 19) and antisense primer: 5'-CACATCAACAGGGGAGGCGA-3' (SEQ ID No. 20)

• mUCP3: sense primer: 5'-GCACCGCCAGATGAGTTTTG-3 '(SEQ ID NO: 21) and antisense primer: δ'-GACGCTGGAGTGGTCCGCTC-S' (SEQ ID No. 22)

In both cases (liver tissue and skeletal muscle tissue), the amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different reverse transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points.

The expression levels of the genes of interest were then normalized in liver tissue relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: 5'CATGCTCAACATCTCCCCCTTCTCC-3 '(SEQ ID NO: 27) and antisense primer: 5'GGGAAGGTGTAATCCGTCTCCACAG-3 '(SEQ ID No. 28)) and in skeletal muscle tissue relative to the expression level of the reference gene 18S (including the specific primers are: sense primer: 5'-

CGGACACGGACAGGATTGACAG-3 '(SEQ ID No. 29) and the antisense primer: 5'-

AATCTCGGGTGGCTGAACGC-3 '(SEQ ID No. 30).

The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group was then calculated for each sample. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

Results

Analysis of the distribution of cholesterol in plasma lipoprotein fractions and measurement of plasma triglycerides

Figure 2-1 shows the distribution of cholesterol in the various lipoprotein fractions of plasma mouse E2 / E2 controls or treated for 7 days with the compound 8 to 20 mpk. Surprisingly, the rate of HDL plasma cholesterol was increased by treatment with compound 8, administered at a dose of 20 mpk.

Figure 2-2 compares the plasma triglyceride levels after 7 days of treatment with Compound # 8 at 20 mpk against the levels obtained with the control animals. Unexpectedly, plasma triglycerides were significantly reduced by the treatment.

Analysis of gene expression by quantitative RT-PCR The inventors have also demonstrated in vivo that the compounds according to the invention are regulators of the expression of target genes of PPAR. The results presented in Figures 2-3 to 2-7 show that compound 8 according to the invention, administered at 20 mpk for 7 days to E2 / E2 mice, induces a significant increase in hepatic expression of genes encoding for PDK4 (Figure 2-3), the Acoxi (Figure 2-4), a decrease in hepatic expression of the gene encoding ApoCIII (Figure 2-5) and a significant increase in skeletal muscle genes encoding UCP2 (Figure 2-6), and UCP3 (Figure 2- 7). These genes encode enzymes deeply involved in the metabolism of lipids and carbohydrates as well as the power dissipation and the fact that their expression is modulated by the compounds according to the invention reinforces the idea that these compounds are of major interest in As part of metabolic diseases.

Conclusion

Unexpectedly, the experimental in vivo data show that the compounds according to the invention stimulate the synthesis of HDL-cholesterol while having a hypolipidemic effect (decrease in plasma triglyceride levels). In addition, experimental data show that the compounds of the invention modulate the expression of genes regulated by PPAR; or those involved in the metabolism of fats and carbohydrates and energy dissipation.

Example 9: In vivo evaluation in mice C57BI6, hypolipidemic and stimulatory properties of the synthesis of HDL cholesterol of the compounds according to the invention

Principle

The hypolipidemic properties and stimulating the synthesis of HDL-cholesterol compounds of the invention were assessed in vivo by measurement of serum lipids and by measuring the expression of PPAR target genes in liver tissue and skeletal muscle after oral therapy in C57BI6 mice.

Protocol

Animal Treatment

C57BI6 female mice were maintained on a light / dark cycle of 12/12 hours at a constant temperature of 20 ± 3 ° C. After acclimation for one week, the mice were weighed and divided into groups of 6 animals selected so that the distribution of their body weight and their plasma lipid levels determined once before the experiment are consistent. The test compounds were suspended in carboxymethylcellulose (Sigma C4888) and administered by intragastric gavage at a rate of once a day for 14 days at the selected dose. The animals had free access to water and food (standard diet). After the experiment, the animals were anesthetized after fasting for 4 hours, a blood sample was taken using anticoagulant (EDTA) then the mice were weighed and euthanized. The plasma was separated by centrifugation at 3000 rev / min for 20 minutes, the samples were stored at 4 ° C. Samples of skeletal muscle and liver tissues were harvested and immediately frozen in liquid nitrogen and stored at -80 0 C for further analysis.

Measurement of total plasma cholesterol

Plasma concentrations of total cholesterol were measured by enzymatic assays (bioMérieux-Lyon-France) following the supplier's recommendations.

Measurement of HDL-cholesterol

Low density lipoproteins (VLDL and LDL) are precipitated by phosphotungstate. The precipitate is removed by centrifugation. HDL-cholesterol in the supernatant is quantitated by enzymatic assays (bioMérieux-Lyon-France) according to the supplier's recommendations.

Measurement of plasma triglyceride

Plasma triglyceride concentrations were measured by enzyme assays (bioMérieux-Lyon-France) following the supplier's recommendations.

qénique expression analysis by quantitative RT-PCR Hepatic Tissue

Total RNA was extracted from liver fragments by using the kit NucleoSpin 96 RNA ® (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions. Fabric squelettigue Total RNA was extracted from gastrocnemius skeletal muscle fragments by using the kit RNeasy ® Fibrous Tissue kit (Qiagen) according to manufacturer's instructions.

1 ug of total RNA (quantified by spectrophotometry) was then reverse transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30μl containing 1X buffer (Invitrogen), 1, 5 mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen).

Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the kit iQ SYBR Green Supermix according to the supplier's recommendations, in 96-well plates, on 5 .mu.l of diluted reverse transcription reaction with an annealing temperature of 60 0 C. primer pairs specific for the genes PDK4, Acoxi, CPTIa, UCP2 and UCP3 studied were used:

• mPDK4: sense primer: δ'-TACTCCACTGCTCCAACACCTG-S '(SEQ ID NO: 17) and antisense δ'-GTTCTTCGGTTCCCTGCTTG primer-S' (SEQ ID No. 18)

• mACOXI: sense primer: δ'-GAAGCCAGCGTTACGAGGTG-S '(SEQ ID NO: 3) and antisense primer: δ'-TGGAGTTCTTGGGACGGGTG-S' (SEQ ID No. 4)

• mCPTIa: sense primer: δ'-CCTGGAAGAAGAAGTTCATCCG-S '(SEQ ID NO: 23) and antisense primer: δ'-AGAGGACGCCACTCACGATG-S' (SEQ ID No. 24)

• mUCP2: sense primer: δ'-GTCGGAGATACCAGAGCACTGTCG-S '(SEQ ID NO: 19) and antisense primer: 5'-CACATCAACAGGGGAGGCGA-3' (SEQ ID NO: 20) • mUCP3: sense primer: 5'-GCACCGCCAGATGAGTTTTG-3 '(SEQ ID NO: 21) and antisense primer: δ'-GACGCTGGAGTGGTCCGCTC-S' (SEQ ID No. 22) in both tissues (liver and skeletal muscle), the amount of fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different reverse transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points. The expression levels of the genes of interest were then normalized in liver tissue relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: 5'CATGCTCAACATCTCCCCCTTCTCC-3 '(SEQ ID NO: 27) and antisense primer: 5'GGGAAGGTGTAATCCGTCTCCACAG-3 '(SEQ ID No. 28)) and, in muscle tissue relative to the expression level of the reference gene 18S (including the specific primers are: primer meaning: δ'-CGGACACGGACAGGATTGACAG- 3 '(SEQ ID No. 29) and the antisense primer: 5'-AATCTCGGGTGGCTGAACGC-3' (SEQ ID No. 30)).

The induction factor was then calculated for each sample. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

Results

Measurement of Plasma Lipids Figures 3-1 and 3-5 compare the lipid profile after 7 and 14 days of treatment with Compound # 8 at 50 mpk and 14 to the values ​​of control animals. Unexpectedly, the lipid profile was significantly improved by treatment.

Figure 3-2 compares the plasma HDL-cholesterol after 7 and 14 days of treatment with compound 8 at 50 mpk against the levels obtained with the control animals. Unexpectedly, the circulating levels of HDL cholesterol were very significantly increased by treatment. Figures 3-3 and 3-4 compare the plasma triglycerides and free fatty acids after 7 and 14 days of treatment with compound 8 at 50 mpk against the levels obtained with the control animals. Unexpectedly, the circulating levels of triglycerides and free fatty acids were very significantly decreased by treatment.

Unexpectedly, the circulating levels of total cholesterol were very significantly increased by treatment.

Analysis of gene expression by quantitative RT-PCR The inventors have also demonstrated in vivo that the compounds according to the invention are regulators of the expression of target genes of PPAR. The results presented in Figures 3-6 to 3-13 show that the compounds 8 and 14 according to the invention, administered at 50 mpk for 14 days to C57BI6 mice, induced in the liver a significant increase in gene expression encoding PDK4, and Acoxi CPTIa (Figs 3-6 to 3-10) and a significant increase in skeletal muscle of the expression of genes encoding for UCP2 and UCP3 (Figs 3-11 to 3-13). These genes encode enzymes deeply involved in the metabolism of lipids, carbohydrates and the power dissipation and the fact that their expression is modulated by the compounds according to the invention reinforces the idea that these compounds are of major interest in As part of metabolic diseases.

Conclusion

Unexpectedly, the experimental in vivo data show that the compounds according to the invention stimulate the synthesis of HDL-cholesterol while having a marked hypolipidemic effect (decrease in plasma triglycerides and free fatty acids). In addition, experimental data show that the compounds of the invention modulate the expression of genes regulated by the

PPARs: those involved in the metabolism of fats and carbohydrates and energy dissipation. Example 10: In Vivo Evaluation, in the db / db mice, antidiabetic and stimulatory properties of the synthesis of HDL-cholesterol compounds of the invention.

Principle

Properties on insulin resistance of the compounds according to the invention were evaluated in vivo by measuring the plasma glucose after oral treatment in mice db / db. Moreover, the stimulating action of the synthesis of HDL cholesterol of the compounds of the invention was demonstrated by the determination of plasma cholesterol and analysis of the expression of PPAR target genes in the liver and muscle tissue .

Protocol

Treatment of animals The db / db mice females were kept on a light / dark cycle of 12/12 hours at a constant temperature of 20 ± 3 ° C. After acclimation for one week, the mice were weighed and divided into groups of 8 animals selected such that the distribution of their body weight and their plasma lipid levels determined once before the experiment are consistent. The test compounds were suspended in carboxymethylcellulose (Sigma C4888) and administered by intragastric gavage at a rate of once a day for 28 days at the selected dose. The animals had free access to water and food (standard diet). Food intake and weight gain are recorded throughout the experiment. After the experiment, the animals were anesthetized after fasting for 4 hours, a blood sample was taken using anticoagulant (EDTA) then the mice were weighed and euthanized. The plasma was separated by centrifugation at 3000 rev / min for 20 minutes, the samples were stored at 4 ° C. Samples of liver and muscle tissues were collected and immediately frozen in liquid nitrogen and stored at -80 0 C for further analysis. Measurement of total plasma cholesterol

Plasma concentrations of total cholesterol were measured by enzymatic assays (bioMérieux-Lyon-France) following the supplier's recommendations.

Measurement of plasma glucose

The glucose assay was performed by enzyme assays (bioMérieux

Lyon-France) following the supplier's recommendations.

qénique expression analysis by quantitative RT-PCR

liver tissue

Total RNA was extracted from liver fragments by using the kit

NucleoSpin® 96 RNA (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions.

muscle tissue

Total RNA was extracted from muscle fragments using the kit

® RNeasy Fibrous Tissue kit (Qiagen) according to manufacturer's instructions.

1 ug of total RNA (quantified by UV spectrophotometry) was then retro-transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30μl containing 1X buffer (Invitrogen), 1, 5 mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen).

Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the kit iQ SYBR Green Supermix according to the supplier's recommendations, in 96-well plates, on 5 .mu.l of diluted retro-transcription reaction with an annealing temperature of 60 0 C. the primer pairs specific for the genes studied are as follows. • mPDK4: sense primer: δ'-TACTCCACTGCTCCAACACCTG-S '(SEQ ID NO: 17) and antisense δ'-GTTCTTCGGTTCCCTGCTTG primer-S' (SEQ ID No. 18)

• mApoCIII: sense primer: δ'-CTCTTGGCTCTCCTGGCATC-S '(SEQ ID NO: 5) and antisense primer δ'-GCATCCTGGACCGTCTTGGA-S' (SEQ ID No. 6)

• mCPT1 b: sense primer: δ'-GGACTGAGACTGTGCGTTCCTG-S '(SEQ ID NO: 9) and antisense primer: δ'-AGTGCTTGGCGGATGTGGTT-S' (SEQ ID NO: 10) • mUCP2: sense primer: 5'GTCGGAGATACCAGAGCACTGTCG- 3 '

(SEQ ID NO: 19) and antisense primer: 5'CACATCAACAGGGGAGGCGA-3 '(SEQ ID No. 20)

• mUCP3: sense primer: 5'GCACCGCCAGATGAGTTTTG-3 '(SEQ ID NO: 21) and antisense primer: 5'GACGCTGGAGTGGTCCGCTC-3' (SEQ ID No. 22)

The amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different retro-transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points. The expression levels of the genes of interest were then normalized in liver tissue relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: 5'CATGCTCAACATCTCCCCCTTCTCC-3 '(SEQ ID NO: 27) and antisense primer: 5'GGGAAGGTGTAATCCGTCTCCACAG-3 '(SEQ ID No. 28)) and, in muscle tissue relative to the expression level of the reference gene 18S (including the specific primers are: primer sense: 5'-CGGACACGGACAGGATTGACAG- 3 '(SEQ ID No. 29) and the antisense primer: 5'-AATCTCGGGTGGCTGAACGC-3' (SEQ ID No. 30)). The induction factor was calculated for each sample. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

Results Measurement of Plasma total cholesterol

Figure 4-1 compares the plasma total cholesterol after 14 and 28 days of treatment with compound 8, administered at 50 mpk with the rates obtained for the control animals. Unexpectedly, total cholesterol was significantly increased by treatment with the compound of the invention. This increase in total cholesterol reflects an increase in the synthesis of HDL cholesterol by the action of compound 8 according to the invention in this animal model.

Blood glucose measurement Figure 4-2 compares the plasma glucose levels after 14 and 28 days of treatment with compound 8, administered at 50 mpk against the levels obtained with the control animals. Unexpectedly, blood glucose was significantly reduced after 28 days of treatment of animals with the compound 8 according to the invention.

Analysis qénique expression quantitative RT-PCR

The inventors have also demonstrated in vivo that the compounds according to the invention are regulators of the expression of target genes of PPAR. The results presented in Figures 4-3 to 4-5 show that compound 8 according to the invention administered at 50 mpk for 28 days in db / db mice, induced in the liver a significant increase in the expression of genes encoding for PDK4 (Figure 4-3), CPTI b (Figure 4-5) and a significant decrease in expression of the gene encoding the ApoCIII (Figure 4-4). These genes encode enzymes involved in the metabolism of lipids and carbohydrates, and are recognized as PPARa target genes in the liver. The fact that their expression is modulated by the compound 8 according to the invention reinforces the idea that this compound has a major interest in the context of metabolic diseases. On the other hand, the inventors have also demonstrated in vivo that the compound 8 according to the invention is a regulator of expression of PPARδ to target genes in skeletal muscle. The results shown in Figures 6-6 to 6-8 show that compound 8 administered at 50 mpk for 28 days in db / db mice, induced in skeletal muscle significantly increased the expression of genes coding for SCIT b (Figure 4-6), UCP2 (Figure 4-7) and UCP3 (Figure A-8). These genes encode enzymes involved in lipid metabolism and thermoregulation, and are known as target genes of PPARδ in the muscle. The fact that their expression is modulated by the compound 8 according to the invention reinforces the idea that this compound has a major interest in the context of metabolic diseases.

Conclusion

Unexpectedly, the experimental data presented show that compound 8 according to the invention induces in vivo improved insulin sensitivity. In addition, experimental data show that the compounds of the invention modulate the expression of genes regulated by the activation of PPAR that encode enzymes involved in the metabolism of lipids, carbohydrates and thermoregulation.

Example 11: In vitro evaluation of the metabolic properties of the compounds according to the invention in a model of myocytes

The principle compounds stimulatory effects of the invention were evaluated by measuring the β-oxidation of fatty acids by myocytes pretreated for 24 hours with the compounds according to the invention. More induction of β-oxidation of fatty acids is increased, the more the compound of the invention is for stimulating the metabolism in the muscle cells. The objective is to measure the amount of tritiated water formed during the mitochondrial oxidation of fatty acids labeled with 3 H. Protocol

Differentiation C2C12 cells into myocytes

The murine cell line C2C12 (from ECACC) were cultured in DMEM medium (Gibco, 41965-039) supplemented with 1% L-Glutamine (Gibco, 25030), 1% penicillin / streptomycin (VWR; BWSTL0022 / 100) and 10 % fetal calf serum decomplemented (FCS Gibco;. 10270-106).

Cells are seeded onto 48-well plates at a density of 25.10 3 cells / well. At confluence, the medium was replaced with differentiation medium (basal culture medium supplemented with 2% horse serum (Gibco; 26050- 088)) and then incubated at 37 ° C and 5% CO 2 for 4 days to differentiate into myocytes.

Treatment

After 4 days of differentiation, cells were treated with the compounds according to the invention added the differentiation culture medium. The compounds of the invention have been tested at doses of 1 microM. The compounds according to the invention are dissolved in dimethyl sulfoxide (DMSO, Sigma; D5879). Cells were treated for 24 h at 37 ° C, 5% CO2. The effect of compounds according to the invention is compared with the effect of DMSO alone.

Measurement of β-oxidation

After 24 hours of treatment, the culture medium was replaced with a medium

DMEM 1g / l glucose (Gibco, 21885-025) supplemented with 1% L-Glutamine (Gibco;

25030), 1% penicillin / streptomycin (VWR; BWSTL0022 / 100) and 1 mM L-carnitine (Alfa Aefar; A 17618). The cells are then incubated with the complex tritiated palmitate / BSA (0.1 mM) at 37 ° C in the presence of 5% CO 2. The reaction was stopped after 1, 2 and 3 hours and proteins were precipitated with TCA 10% distribution.

Initially, the counting of tritium is performed on 100 .mu.l of precipitated culture supernatant.

In a second step, 50 .mu.l of supernatant precipitate is carried evaporation for 2 days then the residual tritium measured to assess the amount of tritiated palmitate unconverted water. A standard range is prepared by successive dilutions of the complex tritiated palmitate / BSA to determine the amount of palmitate transformed into water. For each time kinetics, 1 h, 2h and 3h, the amount in nanomoles palmitate oxidized is calculated by linear regression. The areas under the curve are determined for each condition and the results are normalized to DMSO. The end result is represented as an average of the induction values ​​in each experimental group.

Results The inventors have also evidenced, on myocytes in vitro, the compounds of the invention have stimulatory effects of the β-oxidation of fatty acids. The results presented in Figure 5 show that the compounds 8, 12, 14 and 15 according to the invention, 1 .mu.M, induce a significant increase of the β- oxidation of fatty acids in the myocytes.

Conclusion

Unexpectedly, the experimental data presented show that the compounds according to the invention have a metabolic action in murine myocytes by inducing catabolism of fatty acids.

Example 12 In Vitro Evaluation activating properties of reverse cholesterol transport of the compounds according to the invention

Principle

The effect of compounds of the invention on cholesterol reverse transport was assessed by measuring expression of the gene ABCA1 (ATP-binding cassette, sub-family A, member 1; membrane transporter involved in the efflux of ) cholesterol in macrophages. More expression ABCAL is increased, the more the compound of the invention stimulates reverse cholesterol transport. Protocol

Differentiation of THP-1 cells into macrophages.

The human monocyte cell line THP1 (from ATCC) was cultured in RPMI1640 medium supplemented with 25 mM Hepes (Gibco, 42401-018), 1% glutamine (Gibco; 25030-24), 1% penicillin / streptomycin (Biochrom AG; A 2213 ) and 10% fetal calf serum decomplemented (FBS Gibco;. 26050-088). Cells are seeded onto 24-well plates (Primaria BD Falcon) at a density of 3.10 5 cells / well and incubated at 37 ° C and 5% CO2 for 72h in the presence of 30 ng / ml phorbol 12-myristate 13 acetate (PMA) to differentiate into macrophages.

Treatment

The differentiation medium is aspirated and replaced with the treatment medium

(Same composition as the culture medium without fetal calf serum and 1% Ultroser (Pall Life Science, P / N267051)).

The compounds according to the invention are dissolved in dimethyl sulfoxide (DMSO, Fluka; 41640). Compound 8 according to the invention was tested at the dose of 1 microM. Cells were treated for 24 h at 37 ° C, 5% CO2. The effect of compounds according to the invention is compared with the effect of DMSO alone.

1 RNA extraction and reverse transcription quantitative PCR.

After treatment, total RNA was extracted from cells using the NucleoSpin ® kit

96 RNA (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions.

1 ug of total RNA (quantified by spectrophotometer reading) was then reverse-transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 20 microliters containing 1X buffer (Invitrogen), 1, 5 mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen).

Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the kit iQ SYBR Green Supermix according to the supplier's recommendations, in 96-well plates, on 5 .mu.l of reverse transcription reactions diluted with a hybridization temperature of 60 0 C. primer pairs specific for the ABCA1 gene studied were used:

• HABCal: sense primer: δ'-CTGAGGTTGCTGCTGTGGAAG-S '(SEQ ID NO: 1) and reverse primer: δ'-CATCTGAGAACAGGCGAGCC-S' (SEQ ID NO: 2)

The amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few .mu.l of different reverse transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points. The expression levels of the genes of interest were then normalized relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: δ'-CATGCTCAACATCTCCCCCTTCTCC-S '(SEQ ID NO: 27 ) and antisense primer: δ'-GGGAAGGTGTAATCCGTCTCCACAG-S '(SEQ ID No. 28)). The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, was then calculated. More this factor, the higher the compound has a gene expression enhancer character. The end result is represented as an average of the induction values ​​in each experimental group.

Results

The inventors have demonstrated in macrophage cultures that the inventive compounds are stimulators of reverse cholesterol transport. The results presented in Figure 6 show that the compounds 8 and 14 according to the invention at the dose of 1 .mu.M, induce a significant increase in the expression of the gene encoding ABCA1 in macrophages. Conclusion

Unexpectedly, the experimental data presented show that the compounds according to the invention stimulate reverse cholesterol transport.

Example 13: In vitro evaluation of anti-inflammatory properties of the compounds according to the invention in a model of monocvtes

Principle

The anti-inflammatory effects of compounds of the invention were evaluated by measuring the secretion and expression of Macrophage Chemoattractant

Protein (MCP1) and Matrix metalloproteinase 9 (MMP9) by monocytes treated for 24 hours with the compounds of the invention and stimulated with

PMA (phorbol 12-myristate 13-acetate, causes an inflammatory response of the cells). Plus the amount of MCP1 secreted is reduced, Furthermore, the compounds of the invention inhibit the inflammatory reaction. Similarly, the greater the expression of genes coding for MCP1 and MMP9 is inhibited, the more compounds of the invention are anti-inflammatory.

Protocol Culture of THP-1 cells

The human monocyte cell line THP1 (from ATCC) was cultured in RPMI1640 medium supplemented with 25 mM Hepes (Gibco, 42401-018), 1% glutamine (Gibco; 25030-24) 1% penicillin / streptomycin (Biochrom AG, A 2213) and 10% decomplemented fetal calf serum (FCS Gibco;. 10270-106).

Treatment

Cells are seeded onto 24-well plates (BD Falcon Primaria) at a density of 8,70.10 5 cells / well in the treatment medium (same composition as the culture medium but with 0.2% serum decomplemented fetal calf) and in the presence of 5 ng / mL phorbol 12-myristate 13-acetate (PMA) to induce inflammatory response. Compound 8 according to the invention was tested at 1 .mu.M, and dissou in dimethyl sulfoxide (DMSO, Fluka; 41640). Cells were treated for 24 h at 37 ° C, 5% CO2. The effect of the compound according to the invention is compared with the effect of DMSO alone.

Measuring the secretion of MCP1

The treatment medium is recovered and the concentration of MCP-1 was measured using the ELISA kit "Human MCP1 Elisa set" (BD OptEIA; 555179) according to manufacturer's recommendations. A monoclonal human anti-MCP1 antibody is fixed on a plate, and the supernatants containing the MCP1 secreted by the cells are distrubés. A biotinylated anti-MCP-1 antibody will then bind to the complex. A third and conjugated antibody coupled to a peroxidase enzyme enables the presence of substrate to initiate a réactionenzymatique which results in a proportional amount of staining MCP1 fixed and can be measured by spectrophotometry. A range is produced from a point of known concentration and used to calculate the MCP1 concentration of each sample. The induction factor, that is to say the ratio between the signal induced by the compound according to the invention and the control signal group, was then calculated. More this factor is, the more the compound has an inhibitory character of the secretion of MCP1. The end result is represented as average of the induction values ​​in each experimental group.

1 RNA extraction and reverse transcription quantitative PCR. After treatment, total RNA was extracted from cells using the NucleoSpin kit 96 RNA ® (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions.

1 ug of total RNA (quantified by spectrophotometer reading at UV) was then retro-transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30 microliters containing 1X buffer (Invitrogen), 1 , 5mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen). The experiences of quantitative PCR were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, M rn-l-Coquette, France) and were performed using the kit iQ SYBR Green Supermix as recommended supplier, in 96-well plates, on retro-transcription reaction of 5 .mu.l diluted with a hybridization temperature of 60 0 C. primer pairs specific for the MCP1 and MMP9 genes studied were used:

• hMCP1: sense primer: δ'-AGGAAGATCTCAGTGCAGAGG-S '(SEQ ID NO: 11) and antisense primer: δ'-AGTCTTCGGAGTTTGGGTTTG-S' (SEQ ID NO: 12) • hMMP9: sense primer: δ'-TGGCACCACCACAACATCAC-S '(SEQ ID NO: 25) and antisense primer: δ'-ACCACAACTCGTCATCGTCG-S' (SEQ ID No. 26)

The amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different retro-transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points.

The expression levels of the genes of interest were then normalized in liver tissue relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: 5'CATGCTCAACATCTCCCCCTTCTCC-3 '(SEQ ID NO: 27) and antisense primer: 5'GGGAAGGTGTAATCCGTCTCCACAG-3 '(SEQ ID No. 28)). The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, was then calculated. More this factor is, the more the compound has an inhibitory nature of gene expression. The end result is represented as an average of the induction values ​​in each experimental group. Results

The inventors have also demonstrated, on monocytes in vitro, the inventive compounds have anti-inflammatory effects. The results presented in Figure 7-1 show that compound 8 according to the invention, 1 .mu.M, induced a significant decrease in MCP-1 secretion in human monocytes. The results presented in Figures 7-2 and 7-3 show that compound 8 according to the invention, 1 .mu.M, induced a significant decrease in the expression of MCP1 and MMP9 in human monocytes.

Conclusion

Unexpectedly, the experimental data presented show that compound 8 according to the invention have antiinflammatory action in monocytes stimulated with PMA.

Example 14: In vitro evaluation of anti-inflammatory properties of the compounds according to the invention in a model of macrophages

Principle

The anti-inflammatory effects of compounds of the invention were evaluated by measuring the secretion of interleukin-6 (IL-6) by human macrophages pretreated for 24 hours with the compounds of the invention and stimulated for 6 hours with LPS (lipopolysaccharide, causes an inflammatory response of the cells). The greater the amount of secreted IL-6 is decreased, the more the compound of the invention inhibits the inflammatory reaction.

Protocol

Differentiation of THP-1 cells into macrophages.

The human monocyte cell line THP1 (from ATCC) was cultured in RPMI1640 medium supplemented with 25 mM Hepes (Gibco, 42401-018), 1% glutamine (Gibco; 25030-24) 1% penicillin / streptomycin (Biochrom AG, A 2213) and 10% decomplemented fetal calf serum (FCS Gibco;. 10270-106). Cells are seeded onto 24-well plates (BD Falcon Primaria) at 3,75.10 density of 5 cells / well and incubated at 37 ° C and 5% CO2 for 72h in the presence of 30 ng / mL phorbol 12- myristate 13-acetate (PMA) to differentiate into macrophages.

Treatment differentiation medium was aspirated and replaced with treatment medium (same composition as the culture medium without fetal calf serum and 1% Ultroser (Pall Life Science, P / N267051)).

The compounds of the invention were tested at 10 .mu.M. The compounds according to the invention are dissolved in dimethyl sulfoxide (DMSO, Fluka; 41640). Cells were treated for 24 h at 37 ° C, 5% CO2. After 24h of incubation, the inflammatory response is induced by adding 0.1 micrograms / ml of lipopolysaccharide (LPS, Sigma, L4005) for 6 hours. The effect of compounds according to the invention is compared with the effect of DMSO alone.

Measuring the secretion of IL-6

The treatment medium is recovered and the concentration of IL-6 was measured using the ELISA kit "Human IL-6 Elisa set" (BD OptEIA; 555220) according to manufacturer's recommendations. IL-6 is fixed on a plate and recognized by an anti-IL-6 specific antibody. The antibody is, in turn, specifically recognized by a second type of antibody coupled to a peroxidase enzyme. The resulting coloring of the enzyme activity is proportional to the amount of IL-6 fixed and can be measured by spectrophotometry. A range is produced from a point of known concentration and used to calculate the concentration of IL-6 of each sample. The induction factor, that is to say the ratio between the signal induced by the compound according to the invention and the control signal group, was then calculated. More this factor is, the more the compound has an inhibitory character of the secretion of IL-6. The end result is represented as average of the induction values ​​in each experimental group.

1 RNA extraction and reverse transcription quantitative PCR.

After treatment, total RNA was extracted from cells using the NucleoSpin ® kit

96 RNA (Macherey Nagel, Hoerdt, France) according to manufacturer's instructions. 1 ug of total RNA (quantified by spectrophotometer reading at UV) was then retro-transcribed into complementary DNA by reaction for 1 hour at 37 ° C in a total volume of 30 microliters containing 1X buffer (Invitrogen), 1 , 5mM DTT, 0,18mm dNTPs (Promega), 200 ng of pdN6 (Amersham), 3or RNase inhibitor (Promega) and 1 .mu.l of MMLV-RT (Invitrogen).

Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the kit iQ SYBR Green Supermix according to the supplier's recommendations, in 96-well plates, on retro-transcription reaction of 5 .mu.l diluted with a hybridization temperature of 60 0 C. primer pairs specific for the MCP1 and MMP9 genes studied were used:

• lhL6: sense primer: 5'-AATGCCAGCCTGCTGACGAAG-3 '(SEQ ID NO: 13) and antisense primer: 5'-TTTGCCGAAGAGCCCTCAGG-3' (SEQ ID No. 14)

• hMCP1: sense primer: δ'-AGGAAGATCTCAGTGCAGAGG-S '(SEQ ID NO: 11) and antisense primer: δ'-AGTCTTCGGAGTTTGGGTTTG-S' (SEQ ID NO: 12)

The amount of emitted fluorescence is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during the PCR. For each target investigated, a range is produced by successive dilutions of a pool consisting of a few microliters of different retro-transcription reactions. The relative levels of expression of each target are thus determined by using efficiency curves obtained with the range points.

The expression levels of the genes of interest were then normalized in liver tissue relative to the expression level of the reference gene 36B4 (whose specific primers are: sense primer: 5'CATGCTCAACATCTCCCCCTTCTCC-3 '(SEQ ID NO: 27) and antisense primer: 5'GGGAAGGTGTAATCCGTCTCCACAG-3 '(SEQ ID No. 28)). The induction factor, that is to say the ratio between the relative signal (induced by the compound according to the invention) and the average of the relative values ​​of the control group, was then calculated. More this factor is, the more the compound has an inhibitory nature of gene expression. The end result is represented as an average of the induction values ​​in each experimental group.

Results

The inventors have also identified, in human macrophages in vitro, the inventive compounds have anti-inflammatory effects. The results presented in Figure 8-1 show that compound 14 according to the invention, to 10 .mu.M, induced a significant decrease in MCP-1 secretion in human macrophages. The results shown in Figure 8-2 and 8-3 show that the compounds 8 and 14 according to the invention to 10 .mu.M, induce a significant decrease in the expression of NL6 and MCP1 in human macrophages.

Conclusion Unexpectedly, the experimental data presented show that the compounds according to the invention have anti-inflammatory action in macrophages stimulated with LPS.

Conclusion The inventors have shown that the compounds of the invention have stimulatory properties of HDL-cholesterol synthesis and lipid lowering properties (lowering plasma triglycerides and free fatty acids). In addition, the inventors have demonstrated that the compounds of the invention are regulators of the expression of genes encoding enzymes involved in the metabolism of lipids, carbohydrates and the power dissipation. These results, obtained in vivo demonstrate the therapeutic potential of the compounds vis-à-vis invention major pathologies associated with metabolic syndrome such as dyslipidemia, obesity, atherosclerosis, etc. On the other hand, the inventors have demonstrated the character activating PPAR in different cell models reflected especially by regulators of the expression of genes encoding enzymes strongly involved in the metabolism of fats, carbohydrates and thermoregulation and as an anti-inflammatory action. BIBLIOGRAPHY

Monte SM, et al, Therapeutic rescue of neurodegeneration in experimental type 3 diabetes. Relevance to Alzheimer's disease, J Alzheimers Dis 2006, 10 (1), 89-109

Fox-Tucker J, The cardiovasular Market Outlook to 2010, BUSINESS INSIGHTS REPORTS, 2005, 1-174

Gross B et al, peroxisome proliferator-activated receptor b / d. A novel target for the reduction of atherosclerosis, DRUG DISCOVERY TODAY: THERAPEUTIC STRATEGIES, 2005, 2 (3), 237-243

International Atherosclerosis Society Harmonized Clinical. Guidelines on Prevention of Atherosclerotic Vascular Disease, 2003

Kota BP, et al., An overview on Biological Mechanisms of PPARs, Pharmacol Res, 2005, 51 (2), 85-94

Lefebvre P, et al. Sorting out the roles of PPARalpha in energy metabolism and vascular homeostasis, J Clin Invest, 2006, 116 (3), 571-580

Lehrke M and Lazar MA, The many faces of PPARgamma, IECI, 2005, 123 (6), 993-9

Liu Y and Miller A, Ligands to peroxisome proliferator-activated receptors as therapeutic options for metabolic syndrome, DRUG DISCOVERY TODAY: THERAPEUTIC STRATEGIES, 2005, 2 (3), 165-169

Mensah M, The Atlas of Heart Disease and Stroke 2004, Polak, Oral administration of the selective agonist GW0742 PPARd Reduced clinical symptoms and Reduces astroglial and microglial inflammatory activation in a model of EAE, J Neuroimmunol, 2005

Raspe E, et al., Modulation of rat liver apolipoprotein gene Expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation, J Lipid Res, 1999, 40 (11) 2099-110

Sullivan PM, et al., Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting and from gene replacement of mouse with human Apoe Apoe * 2, J Clin Invest, 1998, 102 (1), 130-5

Claims

1. Compounds of general formula (I):
Figure imgf000137_0001
(I) wherein:
X1 represents halogen, a group R1, -OR1 or -SR1;
X2 represents a group R2;
X3 represents a halogen, an R3 group, -SR 3 or -OR 3; X4 represents a halogen or a group R 4, -SR 4 or -OR 4;
X5 represents a group R5, -OR5 or -SR5;
X6 represents halogen, a group R 6, -SR 6 or -OR 6;
X7 represents a halogen, a group R 7, -OR 7 or -SR 7;
X8 represents a sulfur or oxygen atom;
R1 representing an alkyl group having 1 to 4 carbon atoms, optionally halogenated;
R3, R4, R6 and R7, identical or different, representing a hydrogen or alkyl group having 1 to 4 carbon atoms; R2 represents an alkyl group having 1 to 4 carbon atoms;
R5 represents an alkyl radical consisting of a linear, saturated carbon chain having 1 to 4 carbon atoms, said carbon chain is:
- linked, by its end opposite the phenyl group (III), with a substituent selected from -COOR12 and -CONR12R13, with R12 and R13, identical or different, representing a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and
- unbranched or branched with at least one alkyl or alkenyl having 1 to 4 carbon atoms, or substituted by cycloalkyl, especially cyclohexyl, or an aryl group, including phenyl;
A is (i) a carbonyl group (C = O),
(Ii) an oxime group (C = NOH) or oxime ether (C = NO-R11), with
R11 selected from a hydrogen atom, an alkyl group
(Linear or branched) having 1 to 7 carbon atoms, substituted or unsubstituted aryl group, in particular phenyl; said alkyl and aryl groups being optionally halogenated, or
(Iii) a -CR9R10 group, R9 representing a hydrogen atom and
R10 represents a -OR11 group, R11 being chosen from a hydrogen atom, an alkyl group (linear or branched) having 1 to 7 carbon atoms, said alkyl group being unsubstituted or substituted by a cycloalkyl group, especially a cyclohexyl group , an aryl group, especially a phenyl or heteroaryl group, in particular pyridinyl, said alkyl, cycloalkyl, aryl or hétéroayle being optionally halogenated,
B is (i) an unsubstituted alkyl group and saturated two carbon atoms (CH 2 -CH 2), or
(Ii) an unsubstituted alkene group, to two carbon atoms (CH = CH),
their stereoisomers (diastereoisomers, enantiomers), pure or mixed, their racemic mixtures, their geometrical isomers, tautomers, salts, hydrates, solvates, solid forms and mixtures thereof.
2. Compounds according to claim 1, characterized in that X 5 represents a group -OR5, where R5 is an alkyl radical in which said carbon chain is linked to a substituent -COOR 12.
3. Compounds according to claim 1 or 2, characterized in that
X5 is selected from the groups: -OC (CH 3) 2 COOR12, -OCH 2 COOR 2, -OCH (CH 2 CH 3) COOR 2, -OCH (CH 2 CH 2 CH 2 CH 3) COOR 2,
-O (CH 2) 3 C (CH 3) 2 COOR12 and -OCH (C 6 H 5) 2 COOR.
4. A compound according to one of claims 1 to 3, characterized in that A represents a carbonyl group C = O.
5. A compound according to one of claims 1 to 3, characterized in that A represents a -CH (ORH), with R11 selected from hydrogen, methyl, ethyl, cyclohexylmethyl, benzyl, iodobenzyl, pyridinylmethyl .
6. Compounds according to any of claims 1 to 3, characterized in that A represents a group C = NO-RH, with R11 selected from hydrogen and methyl.
7. Compounds according to any of claims 1 to 6, characterized in that X1 is selected from a trifluoromethyl group, a bromine atom, a chlorine atom, a methylthio group, a methyloxy group and a trifluoromethoxy group.
8. Compounds according to any of claims 1 to 7, characterized in that X1 represents a trifluoromethyl group located in the para position relative to the ring II.
9. Compounds according to any of claims 1 to 8, characterized in that at least one of X3, X4, X6 and X7 is a halogen atom or an alkyl group.
10. Compounds according to any of claims 1 to 9, characterized in that X3 and X4 are identical and represent halogen or methyl.
11. Compounds according to any of claims 1 to 10, characterized in that X3 and X4 are identical and correspond to chlorine atoms or fluorine.
12. Compounds according to any of claims 1 to 9, characterized in that
X4 is a bromine atom.
13. Compounds according to any of claims 1 to 12, characterized in that at least one of X3, X4, X6 and X7 is a halogen atom or a methyl group, and (s) group (s) remaining one of X3, X4, X6 and X7 denotes (s) one (or more) atom (s) hydrogen.
14. Compounds according to any of claims 1 to 13, characterized in that they are chosen from:
- 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxoprop-1-enyl) phenoxy) -2 -méthylpropanoate tert-butyl;
- 2- (2,6-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -
3-oxoprop-1-enyl) phenoxy) acetate tert-butyl;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy) acetic acid;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) hexanoate tert-butyl;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) hexanoic acid; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate ;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -
3-oxopropyl) phenoxy) butanoate;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) butanoic acid;
- 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoate ;
- 2- (2,3-dichloro-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;
- 2- (2,3-dichloro-4- (3-hydroxy-3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque;
- 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-methyl-2- (4- (trifluoromethyl) phenyl) -thiazol-5-yl) propyl) phenoxy) -2 - methylpropanoic;
- 2- (4- (3- (benzyloxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) -2,3-dichlorophenoxy) -2 -méthylpropanoïque;
- 2- (2,3-dichloro-4- (3-hydroxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate;
- 2- (2,3-dichloro-4- (3-Ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate - 2- (2,3-dichloro-4- (3-ethoxy-3- (4-isopropyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) butanoic acid;
- 2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxoprop-1-enyl) phenoxy) -2-methylpropanoate tert-butyl;
- racide-2- (2-bromo-4- (3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxoprop-1-enyl) phenoxy) -2- methylpropanoic;
- 2- (4- (3- (4-iodobenzyloxy) -3 (4-methyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) -2,3-dichlorophenoxy ) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;
- 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) -3-hydroxypropyl) phenoxy) -2-methylpropanoic acid;
- 2- (4- (3- (benzyloxy) -3- (2- (4-chlorophenyl) -4-methylthiazol-5-yl) - propyl) -2,3-dichlorophenoxy) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxoprop-1-enyl) phenoxy) -2 -méthylpropanoate tert-butyl;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxoprop-1-enyl) phenoxy) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3-oxo-3- (4-isopropyl-2- (4- (trifluoromethyl) phenyl) - thiazol-5-yl) propyl) phenoxy) butanoate - 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -
3-oxopropyl) phenoxy) -2-methylpropanoate;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) oxazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;
- 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate;
- 2- (3-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoic acid;
- 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoate; - 2- (2-chloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -
3-oxopropyl) phenoxy) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3- (cyclohexylmethoxy) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid;
- 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate ;
- 2- (2,3-difluoro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5- yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ; - 2- (2,3-dichloro-4- (3- (hydroxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3- (methoxyimino) -3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) propyl) phenoxy ) -2-methylpropanoic acid; - 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;
- 2- (2,3-dichloro-4- (3- (2- (2-chlorophenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-phenylacetate of ethyl;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-phenylacetic acid ;
- 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2,2-dimethylpentanoate methyl; - 5- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol
5-yl) -3-oxopropyl) phenoxy) -2,2-dimethylpentanoic acid;
- 2-methyl-2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- oxopropyl) phenoxy) propanoate;
- 2- (4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxo-propyl) phenoxy-2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3- (pyridin-3-ylmethoxy) propyl ) phenoxy) -2-methylpropanoic acid;
- 2- (2,3-dichloro-4- (3-methoxy-3- (4-methyl-2- (4- (trifluoromethyl) - phenyl) thiazol-5-yl) propyl) phenoxy) -2 -méthylpropanoïque; - 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) -
3-oxopropyl) phenoxy) -2-methylpropanoate;
- 2- (2,3-dichloro-4- (3- (4-methyl-2- (3- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid ;
- 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3-oxo-propyl) phenoxy) -2-methylpropanoate;
- 2- (2,3-dichloro-4- (3- (2- (4-methoxyphenyl) -4-methylthiazol-5-yl) -3- oxopropyl) phenoxy) -2-methylpropanoic acid; - 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) - 3-oxopropyl) phenoxy) -2-methylpropanoate ;
- 2- (2,3-dimethyl-4- (3- (4-methyl-2- (4- (trifluoromethyl) phenyl) thiazol-5-yl) -3-oxopropyl) phenoxy) -2-methylpropanoic acid .
15. Compounds according to any one of claims 1 to 14, as medicaments.
16. A pharmaceutical composition comprising, in a carrier acceptable pharmaceutically, at least one compound as defined in claims 1 to 14, optionally in combination with one or more other active principles therapeutic and / or cosmetic.
17. A pharmaceutical composition comprising, in a carrier acceptable pharmaceutically, at least one compound as defined in one of claims 1 to 14 in combination with one or more compounds selected from the list below: an anti-diabetic , insulin - a lipid-lowering molecule and / or cholesterol-lowering, antihypertensive or hypotensive agent, an anti-platelet agent,
- an anti-obesity agent,
- an anti-inflammatory agent - an antioxidant agent,
- an agent used in the treatment of heart failure, an agent used for the treatment of coronary insufficiency, an anticancer agent, an anti-asthmatic, - a corticosteroid used in the treatment of diseases of the skin,
- a vasodilator and / or an anti-ischemic agent.
18. A pharmaceutical composition according to claim 16 or 17, for the treatment of complications associated with metabolic syndrome, ADE insulin resistance, diabetes, dyslipidemias, atherosclerosis, cardiovascular diseases, obesity, the hypertension, inflammatory diseases, cerebral ischemia, autoimmune diseases, neurodegenerative diseases or cancers.
19. A pharmaceutical composition according to claim 16 or 17, for the treatment of dyslipidemia.
20. A pharmaceutical composition according to claim 16 or 17, for the treatment of diabetes.
21. A pharmaceutical composition according to claim 16 or 17, for treating cardiovascular risk factors related to deregulations of lipid and / or carbohydrate.
PCT/FR2007/052635 2006-12-29 2007-12-28 Substituted (phenylthiazolyl)-phenyl-propan-1-one and (phenyloxazodyl)-phenyl-propan-1-one derivatives, preparations and uses of same WO2008087367A2 (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101870642A (en) * 2009-04-21 2010-10-27 赢创德固赛有限责任公司 Method for producing substituted 1,4 chinonmethides
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013186089A2 (en) 2012-06-14 2013-12-19 Basf Se Pesticidal methods using substituted 3-pyridyl thiazole compounds and derivatives for combating animal pests
CN103588767A (en) * 2013-11-20 2014-02-19 苏州明锐医药科技有限公司 Preparation method of dabrafenib

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2770494A1 (en) * 2009-08-14 2011-02-17 Ronald Barbaras Use of ppar delta ligands for the treatment or prevention of inflammation or energy metabolism/production related diseases

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002050048A1 (en) * 2000-12-20 2002-06-27 Glaxo Group Limited Thia- and oxazoles and their use as ppars activators
WO2002059098A1 (en) * 2000-12-20 2002-08-01 Glaxo Group Limited Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
EP1310494A1 (en) * 2000-08-11 2003-05-14 Nippon Chemiphar Co., Ltd. PPAR (delta) ACTIVATORS
EP1371650A1 (en) * 2001-03-23 2003-12-17 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor
EP1424330A1 (en) * 2001-08-10 2004-06-02 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-responsive receptor delta
EP1666472A1 (en) * 2003-09-22 2006-06-07 Ono Pharmaceutical Co., Ltd. Phenylacetic acid derivative, process for producing the same, and use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310494A1 (en) * 2000-08-11 2003-05-14 Nippon Chemiphar Co., Ltd. PPAR (delta) ACTIVATORS
WO2002050048A1 (en) * 2000-12-20 2002-06-27 Glaxo Group Limited Thia- and oxazoles and their use as ppars activators
WO2002059098A1 (en) * 2000-12-20 2002-08-01 Glaxo Group Limited Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
EP1371650A1 (en) * 2001-03-23 2003-12-17 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-activated receptor
EP1424330A1 (en) * 2001-08-10 2004-06-02 Nippon Chemiphar Co., Ltd. Activator for peroxisome proliferator-responsive receptor delta
EP1666472A1 (en) * 2003-09-22 2006-06-07 Ono Pharmaceutical Co., Ltd. Phenylacetic acid derivative, process for producing the same, and use

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101870642B (en) * 2009-04-21 2015-07-29 赢创德固赛有限责任公司 The substituted 1,4-quinone methide prepared
CN101870642A (en) * 2009-04-21 2010-10-27 赢创德固赛有限责任公司 Method for producing substituted 1,4 chinonmethides
WO2011107494A1 (en) 2010-03-03 2011-09-09 Sanofi Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof
WO2011157827A1 (en) 2010-06-18 2011-12-22 Sanofi Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases
WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013186089A2 (en) 2012-06-14 2013-12-19 Basf Se Pesticidal methods using substituted 3-pyridyl thiazole compounds and derivatives for combating animal pests
CN103588767A (en) * 2013-11-20 2014-02-19 苏州明锐医药科技有限公司 Preparation method of dabrafenib
CN103588767B (en) * 2013-11-20 2016-01-20 苏州明锐医药科技有限公司 Feeney preparation Dara

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