FR2948119A1 - 5,6-BISARYL-2-PYRIDINE CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE AS ANTAGONISTS OF UROTENSIN II RECEPTORS - Google Patents

Abstract

The compounds according to the present invention correspond to the formula (I): in which: A represents a (C 1 -C 4) alkyl group; - W represents a halogen atom; E represents a CR3 link in which R3 represents a halogen atom or a hydrogen atom, or E represents a nitrogen atom; B represents a group -NR R in which R represents a hydrogen atom or a (C -C) alkyl and R represents a (C -C) alkyl group; - V represents a hydrogen atom, a halogen atom or a (C -C) alkyl group; Z represents an oxygen atom or a -CH- group; or its acid or base addition salt. Preparation process and therapeutic application

Description

The present invention relates to 5,6-bis-3-baryl-2-pyridinecarboxamide derivatives, their preparation and their therapeutic application as anti-gonadamide receivers. preparation and their therapeutic application as Urotensin II receptor antagonists.

Urotensin II is a cyclic peptide consisting of 11 amino acids and considered to be one of the most potent vasoconstrictor agents known to date (Ames et al., 1999, Nature 401, 282-286). Its biological activity is mediated by the activation of a GPR14-transmembrane protein-coupled receptor, GPR14, renamed UT (Urotensin Il Receptor) by the International Union of Basic and Clinical Pharmacology (IUPHAR). Activation of the Urotensin II receptor induces intracellular calcium mobilization. Urotensin II and its receptor are strongly expressed in the cardiovascular system, but also in the renal, cerebral and endocrine systems (Richards and Charles, 2004, Peptides 25, 1795-1802). On isolated vessels, human Urotensin II causes vasoconstriction, the intensity of which varies according to the territory and the species concerned (Douglas et al., 2000, Br. J. Phamacol, 131, 1262-1274). The administration of Urotensin II in the anesthetized primate induces an increase in peripheral vascular resistance and a deterioration of contractility and cardiac output, which can lead to high doses to a cardiovascular collapse and ultimately to the death of the animal (Ames et al., 1999, Nature 401, 282-286). In addition, Urotensin II stimulates the proliferation of vascular smooth muscle cells and acts in synergy with the mitogenic activity of serotonin and oxidized LDL (Low Density Lipoproteins) (Watanabe et al., 2001, Circulation 104; 16-18). . On cardiomyocytes in culture, Urotensin II induces cellular hypertrophy and increased extracellular matrix synthesis (Tzanidis A., et al, 2003, Circ Res 93, 246-253). The plasma and urinary levels of Urotensin II have been reported to be increased in a number of cardiovascular, renal and metabolic pathologies in humans. These conditions include high blood pressure, heart failure, renal failure, diabetes, and hepatic cirrhosis (Richards and Charles, 2004, Peptides 25, 1795-1802, Doggrell, 2004, Expert Opin Investig Drugs 13, 479- 487). Central effects of Urotensin II have also been described (Matsumoto Y. et al., Neurosci Lett, 2004, 358, 99).

Finally, it has been shown that certain tumor cell lines overexpress the Urotensin II receptor (Takahashi K., et al., Peptides, 2003, 24, 301). Urotensin II receptor antagonists may be useful for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac fibrosis and hypertrophy, coronary artery disease and atherosclerosis. systemic and pulmonary arterial hypertension, portal hypertension and hepatic fibrosis, post-angioplasty restenosis, acute and chronic renal insufficiency of diabetic and / or hypertensive origin, diabetes, vascular inflammation, and aneurysms. In addition, Urotensin II receptor antagonists may be useful for the treatment of disorders of the central nervous system, including neurodegenerative diseases, stroke, stress, anxiety, aggression, depression, schizophrenia. but also vomiting and sleeping sickness. Finally, the antagonists of the Urotensin II receptors may also be useful for the treatment of certain cancers. Derivatives of 5,6-bisaryl-2-pyridine carboxamide are described in International Application WO 2008/020124 as GPR14 receptor antagonists. wherein: - A represents a (C1-C4) alkyl group; - W represents a halogen atom; E represents a CR3 linkage in which R3 represents a halogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a group (C1 -C4) alkyl; The compounds according to the present invention correspond to formula (I): ## STR1 ## where V represents a hydrogen atom, a halogen atom or a (C 1 -C 4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or - E represents a CR3 linkage in which R3 represents a hydrogen atom, and: V represents a halogen atom or a (C1-C4) alkyl group; B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a (C1-C4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or where V represents a hydrogen atom; B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a (C1-C4) alkyl group; Z is -CH2-; or where V represents a hydrogen atom; B represents a group -NR1R2 wherein R1 represents a hydrogen atom and R2 represents a (C1-C4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or - E represents a nitrogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a (CIC4) alkyl group; V represents a hydrogen atom or a halogen atom; Z represents an oxygen atom or a -CH 2 - group. The compounds of formula (I) may have one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. The compounds of formula (I) may exist in the form of bases or salified by acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids or bases, but the salts of other acids or bases useful, for example, for the purification or the isolation of the compounds of formula (I), are also part of invention.

By (Ci-C4) alkyl is meant a linear or branched alkyl radical of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. By halogen atom is meant a bromine, chlorine, fluorine or iodine atom.

According to the present invention, the following are distinguished in the base state or in the salified state by a base or an acid: the compounds of formula (IA) in which E represents a chain CR 3 in which R 3 represents a halogen atom ; compounds of formula (IB) in which E represents a chain CR3 in which R3 represents a hydrogen atom; compounds of formula (IC) in which E represents a nitrogen atom; the other substituents being as defined for the compounds of formula (I).

For the compounds of formula (IA), the substituents are as follows: A represents a (C 1 -C 4) alkyl group; - W represent a halogen atom; E represents a link CR3 in which R3 represents a halogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a group (C1- C4) alkyl; V represents a hydrogen atom, a halogen atom or a (C 1 -C 4) alkyl group; Z represents an oxygen atom or a -CH 2 - group.

Within the compounds (IA), the compounds in which: A represents a methyl group are preferred; - W represent a chlorine atom; E represents a CR3 link in which R3 represents a fluorine atom, and: B represents a group -NR1R2, in which R1 represents a hydrogen atom or a methyl group and R2 represents a methyl group; V represents a hydrogen atom, a fluorine atom or a methyl group; Z represents an oxygen atom or a -CH 2 - group; in the base state or in the salified state with a base or an acid. For the compounds of formula (IB), the substituents are as follows: A represents a (C 1 -C 4) alkyl group; - W represent a halogen atom; E represents a link CR3 in which R3 represents a hydrogen atom, and: V represents a halogen atom or a (C1-C4) alkyl group; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl and R 2 represents a (C 1 -C 4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl and R 2 represents a (C 1 -C 4) alkyl group; Z is -CH2-; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom and R 2 represents a (C 1 -C 4) alkyl group; Z represents an oxygen atom or a -CH 2 - group.

Within the compounds of formula (IB), the compounds in which: A represents a methyl group are preferred; - W represent a chlorine atom; E represents a CR3 linkage in which R3 represents a hydrogen atom, and: V represents a fluorine atom or a methyl group; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a methyl group and R 2 represents a methyl group; Z represents an oxygen atom or a -CH 2 - group; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a methyl group and R 2 represents a methyl group; Z is -CH2-; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom and R 2 represents a methyl group; Z represents an oxygen atom or a -CH 2 - group; in the base state or in the salified state with a base or an acid. For the compounds of formula (IC), the substituents are as follows: A represents a (C 1 -C 4) alkyl group; - W represent a halogen atom; E represents a nitrogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a (C1-C4) alkyl group; V represents a hydrogen atom, a halogen atom or a (C 1 -C 4) alkyl group; Z represents an oxygen atom or a -CH 2 - group.

Within the compounds of formula (IC), those compounds are preferred in which: A represents a methyl group; - W represents a chlorine atom; E represents a nitrogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a methyl group and R2 represents a methyl group; V represent a hydrogen atom, a fluorine atom or a methyl group; Z represents an oxygen atom or a -CH 2 - group; or an addition salt thereof to an acid or a base.

For the compounds of formula (I), the radical V is preferably in the 5-position of the phenyl group; and the other substituents are as defined for the compounds of formulas (I), (IA), (IB) and IC).

For the compounds of formula (I) the radical A is preferably in position 2 of the phenyl group; and the other substituents are as defined for the compounds of formulas (I), (IA), (IB) and IC). Among the compounds which are the subject of the invention, mention may notably be made of the following compounds in base form or one of their addition salts with a base or an acid: IUPAC name Chemical Structure Acid 1 - ({[6- {4 3-chloro-3- [3- [1H] -NO (methylamino) propoxy] phenyl} -5- (2-NH methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid. 1 - ({[6- {4-chloro-3- [3-HIC I / N NH (dimethylamino) propoxy] -5-fluorophenyl} -5- (2H-OH methylphenyl) pyridine 2-yl] carbonyl) amino) cyclohexanecarboxylic acid. 1 - ({[6- {4-chloro-3- [4- (dimethlaminobutyl) -2-N-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid. ## STR2 ## yl} carbonyl) amino] cyclohexanecarboxylic acid. 0 N ~ CH3 N (? OH 1 ci CHi Name IUPAC Chemical Structure Acid 1 - ({[6- {4-chloro-3- [3- H3C I / N o (dimethylamino) propoxy] -2-fluorophenyl} -5 - (2-Methylphenyl) pyridin-2-yl] carbonyl) amino) cyclohexanecarboxylic acid CH3 o ~ / N CH3 1 - ({[6- {4-chloro-3- [3- H3C]) acid / N (dimethylamino) propoxy] -5-methylphenyl} -5- (2-H3CNiCl methylphenyl) pyridin-2-o (OH) yl] carbonyl} amino) cyclohexanecarboxylic acid Hs o ~ / N CH3 It should be noted that the above compounds have been named in IUPAC nomenclature via the ACD / Name software, version10.0, Advanced Chemistry Development, Inc.: Toronto ON, Canada, www.acdlabs.com, 2006.

In what follows, a protecting group (GP) is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis. Examples of protecting groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 4th Edition (John Wiley & Sons, Inc., New York), 2007.

By leaving group (Tf) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic link, with the departure of an electronic pair. This group can thus be easily replaced by another group during a nucleophilic substitution reaction or during an organometallic coupling reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as references for their preparation are given in Advances in Organic Chemistry, M. B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, p. 496-501. In accordance with the present invention, compounds of formula (IA) and (IB) wherein E is a CR3 linker and compounds of formula (IC) wherein E is a nitrogen atom, and Z is oxygen atom according to process (A) characterized in that A.1) is reacted with an acid or a functional derivative of this acid of formula: wherein A, B, E, V and W are as defined above for a compound of formula (I), with an amine of formula: OMe 10 to obtain a compound of formula: A.2) the compound of formula (IV) thus obtained is reacted with a strong base to obtain the compound of formula: (I) Optionally the compound of formula (I) thus obtained is converted into one of its salts.

In step A.1) of the process, when a compound of formula (III) is treated with the acid of formula (II), the reaction is carried out in the presence of a coupling agent used in peptide chemistry such as 3-dicyclohexylcarbodiimide or benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (1H-benzotriazol-1-tetrafluoroborate yl) -1,1,3,3-tetramethyl uronium or N- [3- (dimethylamino) propyl-N'-ethyl carbodiimide hydrochloride, in the presence of a base such as triethylamine, N, N-diisopropylethylamine; or 4-dimethylaminopyridine, in a solvent such as dichloromethane, dichloroethane, N, N-dimethylformamide, tetrahydrofuran or acetonitrile at a temperature between -10 ° C and the reflux temperature of the solvent.

As functional derivative of the acid of formula (II), it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, an activated ester for example, p-nitrophenyl ester. Thus, in the process according to the invention, the chloride of the acid obtained can also be reacted by reaction of thionyl chloride or oxalyl chloride with the acid of formula (II), with the compound of formula (III ), in a solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N, N-dimethylformamide for example) under an atmosphere inert, at a temperature between 0 ° C and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine. One variant consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in doing so react with the compound of formula (III) in a solvent such as dichloromethane under an inert atmosphere at room temperature in the presence of a base such as triethylamine. In step A.2) of process (A), the compounds of formula (IV) are saponified with a strong base such as, for example, sodium hydroxide (NaOH) in a binary mixture. such as, for example, water / methanol maintained at room temperature or heated at reflux to conduct, after acidification, the acids of formula (I). According to the present invention, the compounds of formula (IA), (IB) and (IC) in which E represents a CR3 linkage or a nitrogen atom can be prepared, and Z represents a -CH2- group according to the process ( B) characterized in that:

B.1) is reacted with an acid or a functional derivative of this acid of the formula: wherein A, B, E, V and W are as defined above for a compound of formula (I), with a amine of formula (III) to obtain a compound of formula: B.2) the compound of formula (VI) thus obtained is reduced to obtain a compound of formula: ## STR2 ## the compound of formula (VII) with a strong base to obtain the compound of formula (I). Optionally, the compound of formula (I) thus obtained is converted into one of its salts. In step B.1) of the process (B), the procedure is as in step A.1) of the process (A). In step B.2), the hydrogenation with a catalytic amount of palladium deposited on carbon under an atmosphere of 3 bar of hydrogen and in a solvent such as methanol leads to the compounds (I) according to the present invention. In step B.3) of the process (B), the procedure is as in step A.2) of the process (A).

The compounds of formula (I) thus obtained may subsequently be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography. The compounds of formula (II) in which E represents a CR3 linkage are prepared according to SCHEME I below in which A, B, E, V, and R3 are as defined for a compound of formula (I) and Bn represents a benzyl radical.

The OH function of the starting compound (VIII) is protected in step (i) by a group GP, GP representing, for example, a benzyl group substituted with one or more alkoxy groups using the corresponding alkoxy benzyl chloride and a base such as triethylamine (TEA) and in a solvent such as dichloromethane ( DCM) to yield the compound of formula (IX).

This is then transformed into a stanyl derivative of formula (X) in step (ii) using hexabutyltin in the presence of a catalytic amount of palladium derivative such as [1,1bis bis] dichloride. (Cyclopentadienyldiphenylphosphino) ferrocene] palladium (II) [PdCl2 (dppf)] and in an aprotic polar solvent such as N-methylpyrrolidinone (NMP) at a temperature of 90 ° C. The compound (X) reacts with the compound (XI) ), Q representing a bromine or iodine atom or a trifluoromethanesulfonyl group, by a STILLE type organopalladic coupling reaction described in step (iii) in the presence of a catalytic amount of palladium derivative such as tetrakis ( triphenylphosphine) palladium (0) [Pd (PPh3) 4] and copper iodide (Cul) and a salt such as lithium chloride in a solvent such as dioxane at the temperature of 90 ° C to lead to compound (XII). In step (iv), the use of an acid such as trifluoroacetic acid (TFA) or hydrogen chloride dissolved in DCM makes it possible to selectively remove the GP group without affecting the benzyloxy function (OBn ) of the compound (XII). Compound (XIII) is thus obtained. Alternatively, in step (vi), it is possible to reverse the reactivity for the assembly of the two aromatic rings by directly reacting the compound (VIII) with the compound (XIV) by an organopalladic coupling reaction of the following type: - either SUZUKI (R = B (OH) 2) in the presence of a catalytic amount of palladium derivative such as PdCl2 (dppf) in the presence of a base such as potassium phosphate and in an aprotic polar solvent such as dimethylformamide ( DMF) at a temperature of 90 ° C; or STILLE (R = SnBu3) in the presence of a catalytic amount of a palladium derivative such as bis (triphenylphosphine) palladium (II) dichloride [Pd (PPh 3) 2 Cl 2] and in a solvent such as toluene, the temperature of 95 ° C. The compound (XIV) is itself obtained from the compound (XI) in step (v): either by borylation (R represents -B (OH) 2) in a sequence: o 1 ° metal-halogen exchange (Q = 1) using isopropylmagnesium chloride in a solvent such as tetrahydrofuran (THF) at the temperature of -78 ° C; o 2 ° substitution on a borate such as triisopropyl borate at a temperature between -20 and 0 ° C; 3 ° acidolysis with an acid such as 1 N hydrochloric acid at room temperature. or by stanylation (R = Bu3Sn) according to the same process as in step (ii). Compound (XIV) is thus obtained. The OH function of the compound (X111) is then converted into a leaving group such as trifluoromethanesulphonate (OTf), in step (vii), using trifluoromethanesulphonic anhydride in the presence of a base such as TEA, in a solvent such as DCM and at a temperature of -20 ° C to yield the compound of formula (XV). The trifluoromethanesulphonate group thus obtained allows the step (viii), thanks to its reactivity, to introduce the 2-methylphenyl ring by a second reaction of SUZUKI type in the same manner as that described in step (vi) but in replacing PdCl2 (dppf) with Pd (PPh3) 4 and obtaining the compound of formula (XVI). In step (ix), the deprotection of the phenol function of the compound of formula (XVI) by boron tribromide at -78 ° C. in DCM followed by the re-esterification of the intermediate acid with the aid of thionyl chloride (SOCl2) in methanol leads to the compound of formula (XVII). The introduction of the group - (CH2) 3-B in step (x) is carried out by alkylation of the compound (XVII) with a chlorinated derivative Cl- (CH2) 3-B in the presence of a weak mineral base such that cesium carbonate, a catalytic amount of sodium iodide (NaI) and in an aprotic polar solvent such as acetonitrile at a temperature between 80 and 100 ° C, such as 90 ° C. The compound of formula (XVIII) thus obtained is then saponified in step (xi), using a strong mineral base such as potassium hydroxide (KOH) in a water / methanol mixture maintained at room temperature or heated under reflux, to conduct, after acidification with a strong acid such as hydrochloric acid (HCl) IN, the compound (II).

The compounds of formula (II) in which E represents a nitrogen atom are prepared according to Scheme II below in which A, B, V and W are as defined for a compound of formula (I) and Bn represents a benzyl radical. ## STR2 ## The halogenation of the compound (XIX) in the step (II) (i) using an N-halosuccinimide of formula (XX) in a solvent such as acetonitrile at a temperature of 80 ° C leads to compound (XXI). In step (ii), the introduction of the monobenzylated alkanediol of formula (XXII) in the presence of a strong mineral base such as KOH in a solvent such as toluene at a temperature of 120 ° C. leads to the compound ( XXIII). The SANDMEYER reaction carried out in step (iii) at 0 ° C using sodium nitrite (NaNO 2) in trifluoromethanesulfonic acid gives the compound (XXIV).

The trifluoromethanesulphonate group thus generated allows stage (iv), thanks to its reactivity, to carry out a STILLE type organopalladiated reaction with a stanyl derivative of formula (XXV) as described previously in Scheme I and to give the compound of formula (XXVI).

In step (v), the selective GP group deprotection, triflatation and SUZUKI coupling sequences described in SCHEMA I and applied to the derivative (XXVI) lead to the compound of formula (XXVII). In step (vi), debenzylation of the hydroxyalkyl function using bromine tribromide in a solvent such as DCM at room temperature followed by re-esterification of the intermediate acid with thionyl chloride in methanol leads to the compound (XXVIII). The iodination in step (vii) carried out using iodine in the presence of triphenylphosphine in a solvent such as DCM leads to the compound (XXIX). In step (viii), the nucleophilic substitution of the iodine atom by secondary amines HB in a protic polar solvent such as methanol followed by saponification with a strong mineral base such as sodium hydroxide in a solvent such as methanol at a temperature of 70 ° C. and then acidification with a strong acid such that 1N hydrochloric acid leads to the derivative (II).

The compounds of formula (V) in which E represents a CR3 or a nitrogen atom and Z represents a -CH2- group are prepared according to SCHEME III below, in which A, B, E, V, and W are as defined for a compound of formula (I). SCHEMA III Br w (XXXII) (HO) 2B V

(iii) OG'P W (XXXIII) OGP Br (XXX) OR (i) HO OMe Br (VIII) ## STR2 ## In step (i), the reduction of the ester (XXX) with a hydride such as lithium aluminum hydride in a solvent such as THF leads to benzyl alcohol (XXXI). In step (ii), the deprotonation at 0 ° C of the benzyl alcohol (XXXI) with a base such as sodium hydride (NaH) in a solvent such as THF followed by protection by a group G P (representing a benzyl group optionally substituted by one or more alkoxy groups) with the aid of the corresponding (alkoxy) benzyl chloride or bromide leads to the compound (XXXII). In step (iii), the metal-halogen exchange with butyllithium at -78 ° C in a solvent such as THF followed by the borylation and hydrolysis sequences described in Scheme I and applied to derivative (XXXII) lead to boronic acid (XXXIII). In step (iv), SUZUKI coupling sequences for assembling the 2 aromatic nuclei, triflating, second SUZUKI coupling to introduce the 2-methylphenyl group and deprotection described in SCHEMA I and applied to the derivative (XXXIII) ) make it possible to obtain the compound (XXXIV). In step (v), the oxidation of the benzyl alcohol function of the derivative (XXXIV) with the aid of an oxidant such as pyridinium chlorochromate (PCC) in a solvent such as DCM at room temperature leads to aldehyde (XXXV).

In step (vi), the WITTIG reaction carried out with the phosphines of formula (XXXVI) in the presence of a strong organic base such as lithium bis (trimethylsilyl) amide (LiHMDS) and in a solvent such as THF at a temperature of 0 ° C. followed by saponification with a strong mineral base such as sodium hydroxide and then acidification with a strong acid such as 1N hydrochloric acid leads to the olefinic compound (V). The starting compounds and the reagents, when their methods of preparation are not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or which are known to the human being. job.

In the context of the present invention, ambient temperature means a temperature between 20 and 25 ° C. The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the exemplified compounds refer to those given in the tables below, which illustrate the chemical structures and the physical properties of some compounds according to the invention.

The following abbreviations and crude formulas are used: AcOEt AcOH Ass DCM Dl EA DMF DMSO EDC. HCI EtOH h iPrMgCI MCPBA min MeOH HCl K2CO3 KOAc KOH K3PO4 NaOH Na2CO3 NH4Cl NaHCO3 NaHSO3 Na2SO4 NMP PCC PdCl2 (dppf)

Pd (PPh3) 4 PdCl2 (PPh3) 2 TBTU

TEA TFA Ethyl acetate Acetic acid Copper iodide Dichloromethane N, N-diisopropylethylamine Dimethylformamide Dimethyl sulfoxide N- [3- (dimethylamino) propyl-N'-ethyl carbodiimide hydrochloride Ethanol hour (s) Isopropylmagnesium chloride Meta-chloroperbenzoic acid minute (s) Methanol Hydrochloric acid Potassium carbonate Potassium acetate Potassium hydroxide Potassium phosphate or tripotassium tetraoxophosphate Sodium hydroxide Sodium carbonate Ammonium chloride Sodium hydrogencarbonate Sodium hydrogen sulphate Sodium sulphate N-methylpyrrolidinone Pyridinium chlorochromate Dichloride [1,1'bis (cyclopentadienyldiphenylphosphino) ferrocene] palladium (II) Tetrakis (triphenylphosphine) palladium (0) Dichloride of bis (triphenylphosphine) palladium (II) N - [(1H-benzotriazol-1-yloxy) tetrafluoroborate (dimethylamino) ) methylidene] -N-methylmethanaminium. N, N-diethylethanamine trifluoroacetic acid THF Tetrahydrofuran TA Ambient temperature.

The compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry). The characteristic molecular peak (MH +) and the retention time (tr) are measured in minutes (min). The mass spectra are obtained under the following LC / MS coupling conditions: Column: Kromasil 50x2.1 mm 6.5 μm Eluents: A = CH3CN / TFA (1000 / 0.5) B = H2O / CH3CN / TFA (1000 / 30 / 0.5) t (mm)% A% B Flow rate (ml / mm) 0 0 100 0.5 12 100 0 0.5 100 0 0.5 The magnetic resonance spectra of the proton (1 H NMR), such as as described below, are recorded at 400MHz in DMSO-d6, using the peak of DMSO-d6 as a reference. The chemical shifts are expressed in parts per million (ppm). The signals observed are expressed as follows: s = singlet; d = doublet; t = triplet; m = solid or broad singlet; H = proton.

Example 1: 1- ({[6- {4-Chloro-3- [3- (methylamino) propoxy] phenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino acid hydrochloride) cyclohexanecarboxylic acid 1.a. 1-Chloro-4-iodo-2 - [(4-methoxybenzyl) oxylbenzène

A suspension of 300 g of 2-chloro-5-iodophenol, 184 g of 1- (chloromethyl) -4-methoxybenzene and 195.5 g of anhydrous K 2 CO 3 in 1.2 l of anhydrous DMF is stirred for 5 hours at 70 ° C. C then brought back to TA. The reaction medium is then partitioned in 3 l of a 2: 1 ether / water mixture. The organic phase is washed with 2 × 1 l of water, dried over Na 2 SO 4 and concentrated under reduced pressure and the residue obtained is crystallized in pentane. After filtration and drying under reduced pressure, 406 g of expected compound are obtained. Gradients 1 .b. {4-Chloro-34 (4-methoxybenzyl) oxylphenyl} boronic acid

To a solution of 145 g of the compound obtained in the preceding step in 1.2 l of anhydrous THF placed under argon and stirred at -50 ° C., 220 ml of a 2N solution of iPrMgCl in the reaction medium are added dropwise. THF keeping the temperature between -40 and -50 ° C. After 2h at -40 ° C, the reaction mixture is allowed to return to -10 ° C in 1h. 94 ml of triisopropyl borate are then added and the reaction mixture is slowly allowed to warm to 0 ° C. After stirring for 2 h, the mixture is treated with 500 ml of a 1N aqueous HCl solution and then extracted with ether. The organic phase is washed with water, dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue obtained is formed in 300 ml of pentane, filtered and washed with 200 ml of pentane. After drying under reduced pressure, 96 g of the expected compound are obtained. 1 C. Methyl 6-f 4-Chloro-3-f- (4-methoxybenzyl) oxyphenyl) -5-hydroxypyridine-2-carboxylate

A solution of 80 g of methyl 6-bromo-5-hydroxypyridine-2-carboxylate, the synthesis of which is carried out according to a process already described in the literature (J. Org. Chem., 1996, 4623-4633), and of 146 g of compound obtained in the preceding step in 1600 ml of anhydrous dioxane is stirred for 15 min under argon bubbling. 143 g of anhydrous K2CO3 and 14 g of PdCl2 (dppf) are then added. The reaction medium is stirred for 10 h at 95 ° C. under argon, cooled to RT and then distributed in 2 l of AcOEt and 350 ml of a 1N aqueous HCl solution. The organic phase is washed with 300 ml of a solution. 1N aqueous HCl and 600 ml of water. After drying over Na 2 SO 4 and concentration under reduced pressure, the precipitate is taken up in 500 ml of a pentane / DCM mixture 7: 3, filtered and washed with 200 ml of pentane. 105 g of the expected compound are thus obtained. 1.d. Methyl 6-f 4-Chloro-3-f- (4-methoxybenzyl) oxylphenyl) -5- (trifluoromethyl) sulfonyloxy-pyridine-2-carboxylate

To a mixture of 115 g of the compound of the preceding step in 1200 ml of DCM are added 121.3 ml of TEA. The mixture gradually dissolves and is then cooled to -20 ° C. under argon. 54.5 ml of trifluoromethanesulphonic anhydride are added dropwise while maintaining the temperature at -20 ° C. After 3h at -10 ° C, the reaction medium is taken up in 11 of DCM and washed with 2 times 11 of water, dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a pentane / AcOEt gradient from 0 to 30% AcOEt. After concentration under reduced pressure, 138 g of the expected compound are obtained. 1.e. Methyl 6- {4-chloro-3-f- (4-methoxybenzyl) oxylphenyl} -5- (2-methylphenyl) pyridine-2-carboxylate

A solution of 26.5 g of the compound of the preceding step and 8.8 g of 2-methylphenylboronic acid in 200 ml of anhydrous DMF is stirred for 15 min under argon bubbling and then 12.7 g of Anhydrous K 3 PO 4 and 5.76 g of Pd (PPh 3) 4 and the reaction mixture is stirred for 18 h at 90 ° C. under argon. The reaction medium is then distributed in 600 ml of a 1: 1 ether / AcOEt mixture and 600 ml of water. After extraction, the aqueous phase is re-extracted with 100 ml of AcOEt, the organic phases are combined and washed with water, dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a heptane / AcOEt gradient from 0 to 20% AcOEt. After concentration under reduced pressure, 18 g of expected compound are obtained. 1f. Methyl 6-f 4-Chloro-3- (4-hydroxy) phenyl} -5- (2-methylphenyl) pyridine-2-carboxylate

To a solution of 20.3 g of the compound of the previous step in 500 ml of anhydrous DCM cooled to -10 ° C, hydrogen chloride was bubbled for 2 min. After stirring for 2 hours at 0 ° C., the reaction medium is concentrated under reduced pressure and the residue is crystallized in 200 ml of ether. After filtration and washing with a pentane / ether mixture 1: 1, 14.1 g of the expected compound are obtained. 1.g. (3-chloropropyl) tert-butyl methylcarbamate

To a solution of 2 g of 3-chloro-N-methylpropan-1-amine hydrochloride in 50 ml of DCM are added 2.34 ml of TEA and 3.33 g of di-tert-butyl dicarbonate. The reaction mixture is stirred for 3 hours at RT and then diluted in 100 ml of an ether / AcOEt 8: 2 mixture. The organic phase is washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column eluting with a cyclohexane / AcOEt gradient from 0 to 10% AcOEt. After concentration under reduced pressure, 2.8 g of expected compound are obtained.

1. h. 6- (3- {3 - [(tert-Butoxycarbonyl) (methyl) aminolpropoxy} -4-chlorophenyl) -5- (2-methylphenyl) pyridine-2-carboxylic acid

To a suspension of 2.1 g of the compound obtained in step 1.f. and 3.77 g of cesium carbonate in 30 ml of acetonitrile stirred at 80 ° C are added 1.2 g of compound obtained in step 1.g. and 130 mg of sodium iodide. The reaction medium is stirred for 18 h at 80 ° C., cooled and filtered. The filtrate is concentrated under reduced pressure and the residue taken up in 100 ml of DCM and 100 ml of a 5% aqueous solution of citric acid. The organic phase is washed with 20 ml of water and 20 ml of brine then dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is then purified by chromatography on a column of silica gel, eluting with a DCM / MeOH gradient of 0 to 10% MeOH, which makes it possible to obtain, after concentration under reduced pressure, 1.5 g of the expected compound.

1.i Methyl 20- (6- {3- (3-tert-butoxycarbonyl) (methyl) aminolpropoxy) -4-chlorophenyl) -5- (2-methylphenyl) pyridin-2-ylcarbonyl} aminomo) cyclohexanecarboxylate a solution of 1.5 g of compound obtained in the preceding step in 10 ml of acetonitrile is added 1.28 ml of DIEA and 570 mg of methyl 2-amino-2-cyclohexanecarboxylate hydrochloride. 1.13 g of TBTU are then added to the suspension, stirred at 0 ° C., and the reaction mixture is stirred for 2 hours at RT and then diluted in 10 ml of AcOEt and 10 ml of ether. The organic phase is washed successively with 10 ml of water, 10 ml of a saturated aqueous solution of NaHCO 3 and 10 ml of brine. After drying over Na 2 SO 4 and concentration under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 30% AcOEt. After concentration under reduced pressure, 780 mg of the expected compound are obtained.

1.j. 1- (f [6-F4-Chloro-3- [3- (methylamino) propoxylphenyl) -5- (2-methylphenyl) pyridin-2-ylcarbonyl) amino) cyclohexane carboxylic acid hydrochloride To a solution of 1.22 g of compound obtained in the preceding step in 20 ml of a 1: 1 THF / MeOH mixture are added 0.63 ml of a 12N aqueous sodium hydroxide solution. The reaction medium is stirred for 4 hours at 60 ° C., cooled and then diluted in 100 ml of AcOEt and 100 ml of a 5% by weight aqueous solution of citric acid. After extraction, the organic phase is washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is taken up in 100 ml of DCM and stirred at 0 ° C., hydrogen chloride is bubbled for 2 min. After stirring for 15 minutes at 10 ° C., the solution is filtered and the solid is taken up in 100 ml of AcOEt and 100 ml of a saturated aqueous solution of NaHCO3. After extraction, the organic phase is dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column eluting with a DCM / MeOH gradient of 0 to 35% MeOH. After concentration under reduced pressure, the residue is taken up in 10 ml of ether and 1 ml of MeOH. To the cooled solution at 0 ° C. is added 1 ml of a solution of 2N hydrogen chloride in ether and the precipitate obtained is rinsed with anhydrous ether. After drying under reduced pressure, 500 mg of the expected compound are obtained.

Example 2: 1- ({[6- {4-Chloro-3- [3- (dimethylamino) propoxy] -5-fluorophenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} hydrochloride friend no) cyclohexanecarboxylic

2.a. 2-Fluoro-6-methoxyaniline To a solution of 15 g of 2-fluoro-6-methoxybenzoic acid in 70 ml of anhydrous tert-butanol is added 12.8 ml of TEA and 25.46 g of diphenylphosphoryl azide. The reaction medium is heated for 5 h at 100 ° C., cooled and then concentrated under reduced pressure. The residue is taken up in 300 ml of AcOEt and the organic phase is washed successively with 150 ml of an aqueous solution of 1N HCl, 150 ml of a saturated aqueous solution of NaHCO 3 and 150 ml of brine. After drying over Na 2 SO 4 and concentration under reduced pressure, the residue is taken up in 150 ml of DCM and 40 ml of a solution of 4N hydrogen chloride in dioxane. The mixture is stirred for 18 h at RT and then concentrated under reduced pressure. The residue is taken up in 200 ml of AcOEt and the organic phase is washed with 150 ml of a saturated aqueous solution of NaHCO3. After drying over Na 2 SO 4 and concentration under reduced pressure, 12 g of expected compound are obtained.

21. To a solution of 12 g of the compound obtained in the previous step in 150 ml of acetic acid cooled at 5 ° C., are dissolved in a solution of chloroform. 4 ml of bromine were added dropwise. The suspension is stirred for 2 h at 5 ° C. and then filtered. The solid is washed with ether and then taken up in 300 ml of ether. 200 ml of a saturated aqueous NaHCO 3 solution are added to the strongly stirred suspension. After the end of the evolution of gas, the organic phase is washed with 100 ml of brine, dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 12 g of expected compound. 2.c. 5-Bromo-2-chloro-1-fluoro-3-methoxybenzene

To a suspension of 2.2 g of the compound obtained in the previous step in 10 ml of an aqueous solution of 12N HCl cooled to 0 ° C is added dropwise a solution of 760 mg of sodium nitrite in ml of water. After 30 min at 0 ° C., the clear solution is poured into a solution also cooled at 0 ° C. with 1.04 g of cuprous chloride in 10 ml of an aqueous 12N HCl solution. After 2 h at RT, the reaction medium is poured into 50 ml of water and the aqueous phase is extracted with ether. The organic phase is then washed with twice 50 ml of water and 50 ml of brine then dried over Na 2 SO 4 and concentrated under reduced pressure. 2 g of the expected compound are thus obtained.

2.d Methyl 6-bromo-54 (4-methoxybenzyl) oxylpyridine-2-carboxylate

To a solution of 50 g of methyl 6-bromo-5-hydroxypyridine-2-carboxylate in 600 ml of DCM is added 32 ml of TEA. The solution obtained is cooled to 0 ° C. and 31 ml of 4-methoxybenzyl chloride are added. The reaction mixture is stirred for 18 h at RT and then extracted with water. After drying over Na 2 SO 4 and concentration under reduced pressure, the residue is purified by chromatography on a silica column eluting with a cyclohexane / AcOEt gradient from 0 to 10% AcOEt. After concentration under reduced pressure, 20 g of expected compound are obtained.

2.e. Methyl 5-f (4-methoxybenzyl) oxyl-6- (tributylstannanyl) pyridine-2-carboxylate

In a screw tube, 10 g of the compound obtained in the preceding step, 15 ml of hexabutyltin and 60 ml of anhydrous NMP are introduced. After bubbling argon for 10 min, 8.4 g of anhydrous KOAc and 1.1 g of PdCl 2 (dppf) were added. The tube is closed and the reaction mixture is brought to 90 ° C with stirring for 18h. After cooling, the reaction medium is poured into 600 ml of AcOEt / 10% by weight aqueous potassium fluoride solution 1: 1 and the mixture is stirred for 15 min. After filtration on celite, the organic phase is washed with 300 ml of water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column eluting with a cyclohexane / AcOEt gradient from 0 to 10% AcOEt. After concentration under reduced pressure, 16 g of expected compound are obtained. 2 F. Methyl 6- (4-chloro-3-fluoro-5-methoxyphenyl) -5- (4-methoxybenzyl) oxylpyridine-2-carboxylate

In a screw tube is introduced 1.12 g of compound obtained in the previous step, 480 mg of compound obtained in step 2.c. and 10 ml of anhydrous dioxane. To the stirred solution was bubbled argon for 10 minutes, then 476 mg of copper iodide, 170 mg of anhydrous lithium chloride and 116 mg of Pd (PPh 3) 4 were added. The tube is closed and the reaction medium is heated for 4 h at 90 ° C., cooled and then poured into 100 ml of AcOEt. The organic phase is washed with 50 ml of an aqueous solution of potassium fluoride at 5% by mass, filtered on a cake of celite and again washed with 100 ml of brine. After drying over Na 2 SO 4 and concentration under reduced pressure, the residue is purified by chromatography on a silica column eluting with a cyclohexane / AcOEt gradient from 0 to 50% AcOEt. After concentration under reduced pressure, 350 mg of expected compound is obtained.

2.g. Methyl 6- (4-chloro-3-fluoro-5-methoxyphenyl) -5-hydroxypyridin-2-carboxylate

To a solution of 340 mg of the compound obtained in the preceding step in 20 ml of anhydrous DCM cooled to 0 ° C. is added 0.6 ml of TFA. The solution is stirred for 2 hours at RT and then concentrated under reduced pressure. The residue is taken up in 20 ml of AcOEt and washed with water and 20 ml of brine. After drying over Na 2 SO 4 and concentration under reduced pressure, 240 mg of the expected compound is obtained 2.h. Methyl 6- (4-Chloro-3-fluoro-5-methoxyphenyl) -5- (2-methylphenyl) pyridine-2-carboxylate

According to the SUZUKI triflatation / reaction sequence described in Examples 1.d. and 1.e. respectively, from 240 mg of compound obtained in the preceding step, 271 mg of expected compound are obtained. Methyl 2- (4-chloro-3-fluoro-5-yloxy-p-phenyl) -5- (2-methylphenyl) -2-methylcarboxylate

To a solution of 270 mg of the compound obtained in the preceding step in 8 ml of DCM cooled at -75 ° C. under argon is added 3 ml of a solution of 1 N boron tribromide in DCM and the reaction medium is then stirred 5h at RT. Another 1 ml of 1 N bromine tribromide is then added to the DCM and the reaction is maintained for 18 hours at RT with stirring. After cooling to -75 ° C, 10 ml of methanol are added dropwise and the mixture is then concentrated under reduced pressure. The residue is taken up in 10 ml of methanol and 55 μl of thionyl chloride are added. The mixture is heated for 3 h at 60 ° C. and then stirred for 18 h at RT. After concentration under reduced pressure, the residue is taken up in 50 ml of AcOEt and the organic phase is washed with 50 ml of a saturated aqueous solution of NaHCO3. After drying over Na 2 SO 4 and concentration under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 50% AcOEt, which makes it possible to obtain, after concentration under pressure. reduced, 200 mg of expected compound. 2.J. 6-F4-Chloro-3- [3- (dimethylamino) propoxyl-5-fluorophenyl} -5- (2-methylphenyl) pyridine-2-carboxylic acid

To a suspension of 200 mg of the compound obtained in the preceding step and of 350 mg of cesium carbonate in 5 ml of acetonitrile stirred at 80 ° C., a solution of 89 mg of 3-chloropropyl hydrochloride is added dropwise. N, N-dimethylamine and 12 mg of sodium iodide in 2 ml of acetonitrile. The reaction medium is stirred for 2 hours at 80 ° C., cooled and filtered. The filtrate is concentrated under reduced pressure and the residue taken up in 20 ml of AcOEt. The organic phase is washed with 20 ml of water and 20 ml of brine then dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is then dissolved in 3 ml of a 2: 1 THF / MeOH mixture to which 2.16 ml of a 1N aqueous sodium hydroxide solution are added. After stirring for 2 hours at RT, 2.16 ml of a 1N aqueous HCl solution are added and the reaction mixture is extracted with DCM. The organic phase is dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is triturated in 10 ml of ether, which gives, after filtration, 200 mg of expected compound. 2.K. Methyl 1- (f-6-chloro-3-yl) (dimethylamino) propoxyl-5-fluorophenyl) -5- (2-methylphenyl) pyridin-2-ylcarbonyl) amino) cyclohexanecarboxylate According to the procedure described in US Pat. Example 1.i., the peptide coupling carried out between 220 mg of the compound obtained in the preceding step and 106 mg of methyl 2-amino-2-cyclohexanecarboxylate hydrochloride makes it possible, after concretion in the ether, to obtain 220 mg. of the expected compound hydrochloride. 2.1. 1- (f [6- [4-Chloro-3- [3- (dimethylamino) propoxyl-5-fluorophenyl) -5- (2-methylphenyl) pyridin-2-ylcarbonyl) amino) cyclohexane carboxylic acid hydrochloride to a solution of 220 mg of the compound obtained in the preceding step in 3 ml of a 2: 1 THF / MeOH mixture are added 0.12 ml of a 12N aqueous sodium hydroxide solution. The reaction medium is stirred for 5 hours at 40 ° C., cooled to RT and then neutralized with 1.44 ml of a 1N aqueous HCl solution. After concentration under reduced pressure, the residue is taken up in 3 ml of methanol and 2 ml. of a 1N aqueous HCl solution and purified by reverse phase chromatography (RP18) eluting with a 10-2N aq HCl / acetonitrile gradient from 0 to 80% acetonitrile in 40 min. After concentration under reduced pressure and lyophilization, 164 mg of the expected compound are obtained in the form of a white powder.

Example 3: 1 - ({[6- {4-Chloro-3- [4- (dimethylamino) butyl] phenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid hydrochloride

3.a. (5-Bromo-2-chlorophenyl) methanol

To a solution of 13.2 g of ethyl 5-bromo-2-chlorobenzoate in 100 ml of anhydrous THF and cooled to 5 ° C are added dropwise 50 ml of a solution of lithium aluminum hydride 1 N in THF. After stirring for 1 hour at RT, 20 ml of water are added dropwise and at 0 ° C. The reaction medium is then poured into 200 ml of AcOEt and the organic phase is extracted with 100 ml of water and 100 ml of brine, dried over Na 2 SO 4 and concentrated under reduced pressure.

11 g of the expected compound are obtained. 3. b. 4-Bromo-1-chloro-2 - [(4-methoxybenzyl) oxylmethyl} benzene To a solution of 13 g of the compound obtained in the preceding step in 120 ml of DMF cooled at 0 ° C., 2.6 g are added. a 60% sodium hydride dispersion in paraffin oil. After stirring for 30 minutes, 9.7 g of 4-methoxybenzyl chloride are added at 0 ° C. and the reaction mixture is stirred for 2 hours at RT and then diluted in 200 ml of ether and 200 ml of water. The organic phase is washed with water and 100 ml of brine then dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with DCM. After concentration under reduced pressure, 20 g of expected compound are obtained. 3c (4-Chloro-3-ff (4-methoxybenzyl) oxylmethyl) phenyl) boronic acid

To a solution of 17 g of the compound obtained in the preceding step in 100 ml of anhydrous THF cooled to -75 ° C., 31.25 ml of a 1.6M solution of n-butyllithium in THF are added dropwise. the temperature does not exceed -65 ° C. After 5 min at -70 ° C., 12.8 ml of triisopropyl borate are added and the reaction medium is stirred for 2 h at 0 ° C. and then poured into 500 ml of a 1N aqueous HCl solution and 300 ml of AcOEt. The organic phase is washed with 2 times 100 ml of water, dried over Na 2 SO 4 and concentrated under reduced pressure, which makes it possible to obtain 12 g of expected compound.

3.d Methyl 6- (4-chloro-3-ff (4-methoxybenzyl) oxylmethyl) phenyl) -5-hydroxypyridine-2-carboxylate According to the method described in Example 1.c., the SUZUKI reaction carried out between 2 g of the product obtained in the preceding step and 5.8 g of methyl 6-bromo-5-hydroxypyridine-2-carboxylate yielded 8 g of the expected compound.

3.e. Methyl 6- [4-chloro-3- (hydroxymethyl) phenyl] -5- (2-methylphenyl) pyridine-2-carboxylate

According to the triflatation / SUZUKI / deprotection sequence, described in Examples 1.d., 1.e. and 1.f. respectively, from 8 g of compound obtained in the preceding step, 5 g of expected compound are obtained. 3.f. Methyl 6- (4-chloro-3-formylphenyl) -5- (2-methylphenyl) pyridine-2-carboxylate To a solution of 1.12 g of the compound obtained in the preceding step in 15 ml of DCM is added. mg of PCC and the reaction medium is stirred for 2 hours at RT. After filtration on a cake of celite, the organic phase is chromatographed on a column of silica gel, eluting with a DCM / MeOH 98: 2 mixture, which makes it possible to obtain, after concentration under reduced pressure, 1 g of the expected compound. 3.g. 644-Chloro-34 (1E) -4- (dimethylamino) but-1-en-1-yllphenyl) -5- (2-methylphenyl) pyridine-2-carboxylic acid hydrochloride

To a solution of 1.58 g of 3-triphenylphosphinopropyl-N, N-dimethylamine bromide in 10 ml of anhydrous THF is added at 0 ° C and under argon 3.7 ml of 1 N LiHMDS solution in THF. . The reaction medium is stirred for 1 h at RT and the orange suspension obtained is added dropwise at 0 ° C a solution of 900 mg of compound obtained in the previous step in 16 ml of anhydrous THF. After stirring for 3 h at RT, the reaction medium is diluted with 30 ml of methanol and 9 ml of a 1N aqueous sodium hydroxide solution are added. After stirring for 1 hour at 30 ° C., 9 ml of a solution are added. aqueous solution of 1N HCl and the reaction medium is extracted with 100 ml of DCM. The organic phase is dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is then taken up in 10 ml of methanol and 3 ml of a 1N aqueous HCl solution and purified by reverse phase HPLC (RP18), eluting with a 10-2N HCL / acetonitrile gradient of 5 to 100% by weight. acetonitrile. After concentration under reduced pressure, 400 mg of expected compound are obtained.

3.h. 1- (f [6- [4-Chloro-3-f (1E) -4- (dimethylamino) but-1-en-1-yl] phenyl} -5- (2-methylphenyl) pyridin-2-ylcarbonyl} amino); methyl cyclohexanecarboxylate

According to the process described in Example 1 i, the peptide coupling carried out between 400 mg of the compound obtained in the preceding step and 173 mg of methyl 1-aminocyclohexanecarboxylate hydrochloride gives 480 mg of the expected compound. 3. Methyl 1- (ff 6 -f4-Chloro-3-yl- (dimethylamino) butylphenyl) -5- (2-methylphenyl) pyridin-2-ylcarbonyl) amino) cyclohexanecarboxylate In a Parr flask 480 mg of compound obtained in the preceding step, 15 ml of AcOEt, 0.25 ml of a solution of 4N HCl in dioxane and 210 mg of a dispersion of 10% palladium in charcoal. The suspension is stirred for 30 min under a pressure of 2 bar of hydrogen, filtered and then washed with 50 ml of a saturated aqueous solution of NaHCO 3. The organic phase is dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel eluting with a DCM / MeOH gradient of 0 to 10% MeOH. After concentration under reduced pressure, 300 mg of expected compound is obtained. 3.j 1- (6-Fluoro-3- [4- (dimethylamino) butyl] phenyl} -5- (2-methylphenyl) pyridin-2-ylcarbonyl) amino) cyclohexanecarboxylic acid hydrochloride

According to the procedure described in Example 2.1., The saponification of 300 mg of the compound obtained in the preceding step leads, after purification by reverse phase chromatography (RP18) and lyophilization, to 190 mg of the expected compound. Example 4: 1 - [({5'-Chloro-6 '- [3- (dimethylamino) propoxy] -3- (2-methylphenyl) -2,2'-bipyridin-6-yl} carbonyl) hydrochloride) friend no] cyclohexanecarboxylic

4.a. 6-Bromo-5-chloropyridin-2-amine A mixture of 20 g of 2-amino-6-bromopyridine and 16.2 g of 1-chloropyrrolidine-2,5-dione in 140 ml of acetonitrile is brought to 80 ° With stirring for 5h. After cooling, the mixture is concentrated under reduced pressure and the residue is taken up in 500 ml of AcOEt. The organic phase is washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 30% AcOEt. After concentration under reduced pressure, 19.7 g of expected compound are obtained. 4.b. 6-3- (Benzyloxy) propoxyl-5-chloropyridin-2-amine

A mixture of 7 g of the compound obtained in the preceding step, 7.3 g of 3- (benzyloxy) propan-1-ol, 7.57 g of KOH, 3.31 g of KOAc and 1.09 g of tris (3,6-dioxaheptyl) amine in 340 ml of toluene is heated at 120 ° C with stirring for 5h. After cooling with T.A., the mixture is poured into 200 ml of AcOEt and the organic phase is washed with 200 ml of brine. After drying and concentration under reduced pressure, the residue is purified by chromatography on a silica gel column eluting with a cyclohexane / AcOEt gradient from 0 to 30% AcOEt. After concentration under reduced pressure, 5.29 g of expected compound is obtained.

4.c 643- (benzyloxy) propoxyl-5-chloropyridin-2-yl trifluoromethanesulfonate A solution of 2.76 g of the compound obtained in the preceding step and 12 ml of trifluoromethanesulphonic acid in 15 ml of anhydrous DMF are added in small portions 1.3 g of potassium nitrite. The reaction medium is stirred at RT for 1 h 30 and then poured into 100 ml of AcOEt. The organic phase is washed successively with water, with 100 ml of a 1N aqueous sodium hydroxide solution and 100 ml of water and then dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 30% AcOEt. After concentration under reduced pressure, 2.3 g of expected compound are obtained. 4.d. Methyl 6'-f3- (Benzyloxy) propoxyl-5'-chloro-3-f- (4-methoxybenzyl) oxyl-2,2'-bipyridine-6-carboxylate

According to the procedure described in Example 3f, the STILLE reaction carried out between 2.17 g of compound obtained in step 4.c. and 3.18 g of compound prepared and obtained in step 2.e. of Example 2 gives 1.62 g of the expected compound.

4.e. Methyl 6'-f3- (Benzyloxy) propoxyl-5'-chloro-3- (2-methylphenyl) -2,2'-bipyridine-6-carboxylate According to the deprotection / triflatation / reaction sequence of SUZUKI described in the examples , 1d, respectively, we obtain, from 1.75 g of compound obtained in the previous step, 1 g of expected compound. 4.f. Methyl 5'-chloro-6 '- (3-hydroxypropoxy) -3- (2-methylphenyl) -2,2'-bipyridine-6-carboxylate

According to the procedure described in Example 2.i., the deprotection of 800 mg of the compound obtained in the preceding step with 6.4 ml of a solution of 1 N boron tribromide in DCM makes it possible to obtain 460 mg of expected compound. 4.g. Methyl 5'-chloro-6 '- (3-iodopropoxy) -3- (2-methylphenyl) -2,2'-bipyridine-6-carboxylate

To a solution of 410 mg of the compound obtained in the preceding step in 2 ml of anhydrous DCM placed under argon are added successively 312 mg of triphenylphosphine, 81 mg of 1 H-imidazole and 302 mg of iodine. The reaction mixture is stirred for 2 hours at RT and then diluted with 10 ml of DCM. The organic phase is washed with 10 ml of water and 10 ml of brine then dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel eluting with a cyclohexane / AcOEt gradient from 0 to 100% ACOEt. After concentration under reduced pressure, 465 mg of expected compound are obtained.

4.h. 5'-Chloro-6'-β- (dimethylamino) propoxyl-3- (2-methylphenyl) -2,2'-bipyridine-6-carboxylic acid hydrochloride To a solution of 403 mg of the compound obtained in step Previously in 1.5 ml of methanol are added 0.4 ml of a solution of 2N dimethylamine in methanol. The reaction medium is heated for 2 hours 30 minutes at 70 ° C. and then concentrated under reduced pressure. The residue is taken up in 1.5 ml of THF and 0.77 ml of a 2N aqueous sodium hydroxide solution are added. The reaction mixture is stirred for 1 hour at RT and then concentrated under reduced pressure. The residue is taken up in 3 ml of water and 3 ml of methanol, 1 ml of 6N aqueous HCl solution is added and purified by reverse phase HPLC (RP18), eluting with a 10-2N HCl gradient. acetonitrile 5% to 80% acetonitrile. After concentration under reduced pressure and lyophilization, 224 mg of expected compound are obtained.

4.i. 1 - [(5'-Chloro-6'-β- (dimethylamino) propoxyl-3- (2-methylphenyl) -2,2'-bipyridin-6-yl) carbonyl) aminolcyclohexanecarboxylic acid

According to the peptide coupling / saponification sequence described in step 1.i. and 2.1., from 224 mg of the compound obtained in the preceding step and 103 mg of methyl 2-amino-2-cyclohexanecarboxylate hydrochloride, 39 mg of the expected compound are obtained.

Tables 1 and 2 indicate the chemical structures of some compounds according to the invention as well as their physical properties (analysis by LC / UV / MS coupling: liquid chromatography / UV detection / mass spectrometry). These compounds are exemplified above or prepared according to procedures similar to those of the exemplified compounds (Examples 1 to 4). In these tables, Me represents a methyl group.

Tables 1 and 2 indicate the chemical structures of some compounds according to the invention as well as their physical properties (analysis by LC / UV / MS coupling: liquid chromatography / UV detection / mass spectrometry). These compounds are exemplified above or prepared according to procedures similar to those of the exemplified compounds (Examples 1 to 4). In these tables, Me represents a methyl group.

OH Compound A R3 V W Z B F ° C No MH +; tr (min) 1M HCl ClO NHMe 205,536; 1.06 2HeClF O NMeZ 162,568; 1.07 Me HCl Cl CH2 NMe2 548,157; 1H NMR (CDCl3, d6-DMSO, 400MHz): 9.00 (s, 1H); 8.90 (s, 1H); 8.45 (s, 1H); 8.05 (d, 1H); 7.95 (d, 1H); 7.40-7.20 (m, 6H); 7.05 (d, 1H); 3.95-3.75 (m, 2H); 3.00 (t, 2H); 2.60 (s, 3H); 2.20 (m, 2H); 1.95 (m, 2H); 1.90 (s, 3H); 1.85 (t, 5H); 1.60 (m, 3H); 1.55-1.25 (m, 3H).

Ex 2: 1H NMR (ppm, d 6 -DMSO, 400MHz): 12.40 (s, 1H); 8.55 (s, 1H); 8.10 (d, 1H); 8.00 (d, 1H); 7.40-7.25 (m, 4H); 7.10 (m, 2H); 4.00-3.80 (m, 2H); 3.15 (t, 2H); 2.80 (s, 6H); 2.25 (m, 2H); 2.10 (m, 2H); 1.95 (s, 3H); 1.85 (t, 2H); 1.75 - 1.30 (m, 6H).

Ex 3: 1H NMR (ppm, d6-DMSO, 400MHz): 10.20 (s, 1H); 8.40 (s, 1H); 8.10 (d, 1H); 7.95 (d, 1H); 7.40 (s, 2H); 7.35-7.20 (m, 5H); 3.00 (m, 2H); 2.75 (s, 6H); 2.55 (t, 2H); 2.20 (m, 2H); 1.90 (s, 3H); 1.85 (t, 2H); 1.65 (m, 5H); 1.50 (m, 2H); 1.35 (m, 3H).

OH Compound No. A V W Z B F ° C MH +; tr (min) 6191M HClO NMe2 551; 1.05 Ex. 4: 1H NMR (ppm, d 6 -DMSO, 400MHz): 10.35 (s, 1H); 8.40 (s, 1H); 8.10 (d, 1H); 8.05 (d, 1H); 7.95 (d, 1H); 7.90 (d, 1H); 7.25 (m, 3H); 7.05 (d, 1H); 3.45 (t, 2H); 3.00 (m, 2H); 2.75 (s, 6H); 2.20 (m, 2H); 1.95 (s, 3H); 1.90 (m, 4H); 1.70 - 1.25 (m, 6H).

GPR14 is a receptor with 7 transmembrane domains coupled to G (Gq) proteins. Its activation by a specific ligand causes an increase of Ca2 + in the cell via the PLC (Phospholipase C), 1P3 (Inositol-1,4,5-triphosphate) and DAG (Diacylglycerol) pathway. The increase in the amount of Ca2 + in the cell is measured using a Fluo-4AM permeant probe that when it binds to Ca2 +, emits at 520 nm. The non-Ca2 + bound probe is non-fluorescent. The affinity, or inhibitory activity, of the compounds of formula (I) according to the invention for human GPR14 receptors was determined in vitro using an intracellular calcium mobilization test (FlipR test) as described in S. Flohr et al. J. Med. Chem., 2002, 45, 1799-1805. For this test, CHO cells transfected with the human GPR14 gene were used.

Cell Seeding CHOGPR14 cells are cultured in 96-well plates for use at D + 1, or 40,000 cells per well for use at D + 2. Charging CHOGPR14 cells with the Fluo-4AM probe After washing the wells with the measurement buffer the cells are loaded with Fluo-4AM (20 mM) in the presence of pluronic acid. The cells are incubated for the time necessary for charging, protected from light in the presence of 5% CO2. The cells are washed with the measurement buffer to remove excess probe.

Adding Products to the FlipR and Measuring After stabilizing the plates at room temperature away from light, they are placed in the FlipR to perform a fluorescence measurement. After a period of stabilization of the signal, the compounds of formula (I) according to the invention are injected by FlipR, in serial dilution at 10 different concentrations per compound. After pretreatment with the compounds of formula (I) according to the invention, the GPR14 receptor agonist, Urotensin II, is added to the FlipR at a concentration equal to the EC50 of the agonist. Data logging is continuous throughout the duration of the experiment. Data processing In each plate, a series of 16 control wells are treated with Urotensin II alone. For the other wells of the plate, the cells are first pre-treated with the compounds of formula (I) according to the invention in concentration-response range and then with Urotensin II. For the control wells, the fluorescence values measured just before the injection of Urotensin II (min) as well as those of the fluorescence measured at the peak of the effect of Urotensin II (max) are averaged and the amplitude The average of the signa is calculated according to the following formula: Aur ° ä = (average of the maximum fluorescence values) û (average of the minimum fluorescence values). The procedure is the same for each well treated with the compound of formula (I) according to the invention (Aur ° ii + cl). The percent inhibition of Urotensin II binding to its GPR14 receptor for each product concentration is calculated as described below: Urotensin II binding inhibition / GPR14 receptor: 0 x pro II) - / pro II + CI) 38 (Uro II) The tested compounds have a C150 in the FlipR test of the order of 10 6M. Preferably, the C150 is less than 200nM.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular drugs which inhibit Urotensin 11 receptors. Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or base of the compound of formula (I).

These drugs find use in therapy, particularly in the treatment and / or prevention of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac fibrosis and hypertrophy, coronary heart disease and atherosclerosis, systemic arterial hypertension, pulmonary hypertension, portal hypertension, liver fibrosis, post-angioplasty restenosis, renal insufficiency and more particularly acute and chronic diabetic origin and / or or hypertensive, diabetes, inflammation in general, fibrosis in general and aneurysms. These drugs are also used in therapeutics, in the treatment and / or prevention of disorders of the central nervous system, including neurodegenerative diseases, stroke, stress, anxiety, aggression, depression, schizophrenia or sleeping sickness. Drugs comprising Urotensin II antagonist compounds such as the compounds according to the invention also find use in therapy, in the treatment and / or prevention of vomiting.

These drugs are also used therapeutically in the treatment of certain cancers. These drugs are also used in therapy, in the treatment and / or prevention of asthma and respiratory diseases.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts, or an enantiomer, a diastereoisomer or a racemic mixture of this compound.

Claims (16)

REVENDICATIONS1. A compound of formula (I): OH wherein: - A represents a (C 1 -C 4) alkyl group; - W represents a halogen atom; E represents a CR3 linkage in which R3 represents a halogen atom, and B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a group (Ci -C4) alkyl wherein V represents a hydrogen atom, a halogen atom or a (C1-C4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or - E represents a CR3 linkage in which R3 represents a hydrogen atom, and: V represents a halogen atom or a (C1-C4) alkyl group; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl and R 2 represents a (C 1 -C 4) alkyl group or Z represents an oxygen atom or a -CH 2 - group; Or wherein V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl and R 2 represents a (C 1 -C 4) alkyl group Z represents a group -CH 2 - or where V represents a hydrogen atom; B represents a group -NR1R2 in which R1 represents a hydrogen atom and R2 represents a (C1-C4) alkyl group; Z represents an oxygen atom or a -CH 2 - group; or - E represents a nitrogen atom, and: B represents a group -NR1R2 in which R1 represents a hydrogen atom or a (C1-C4) alkyl and R2 represents a (C1-C4) alkyl group; V represents a hydrogen atom or a halogen atom; Z represents an oxygen atom or a group -CH 2, or its addition salt with an acid or a base. 2. Compounds of formula (I) according to claim 1 wherein E represents a chain CR3 in which R3 represents a halogen atom, or its addition salt with an acid or a base. 3. Compounds of formula (I) according to claim 1 wherein E represents a chain CR3 in which R3 represents a hydrogen atom, or its addition salt with an acid or a base. 4. Compounds of formula (I) according to claim 1 wherein E represents a nitrogen atom, or its addition salt with an acid or a base. 25 5. Compound of formula (I) according to claim 2 wherein: - A represents a methyl group; - W represent a chlorine atom; - E represents a CR3 link in which R3 represents a fluorine atom, and - B represents a group -NR1R2, in which R1 represents a hydrogen atom or a methyl group and R2 represents a methyl group; V represents a hydrogen atom, a fluorine atom or a methyl group; Z represents an oxygen atom or a -CH 2 - group; or its acid or base addition salt. 41New page 42 6. Compound of formula (I) according to claim 3 wherein: - A represents a methyl group; - W represent a chlorine atom; E represents a CR3 linkage in which R3 represents a hydrogen atom, and: V represents a fluorine atom or a methyl group; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a methyl group and R 2 represents a methyl group; Z represents an oxygen atom or a -CH 2 - group; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a methyl group and R 2 represents a methyl group; Z is -CH2-; or where V represents a hydrogen atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom and R 2 represents a methyl group; Z represents an oxygen atom or a -CH 2 - group; or its acid or base addition salt. 7. A compound of formula (I) according to claim 4 wherein: - A represents a methyl group; - W represents a chlorine atom; B represents a group -NR 1 R 2 in which R 1 represents a hydrogen atom or a methyl group and R 2 represents a methyl group; V represent a hydrogen atom or a fluorine atom; Z represents an oxygen atom or a -CH 2 - group; or an addition salt thereof to an acid or a base. 8. Compound of formula (I) according to any one of claims 1 to 7 wherein the radical V is preferably in position 5 of the phenyl group, or an addition salt thereof to an acid or a base. 9. Compound of formula (I) according to any one of claims 1 to 7 wherein the radical A is preferably in position 2 of the phenyl group, or an addition salt thereof to an acid or a base. 43 10. Compound of formula (I) according to any one of claims 1 to 9 selected from: - 1 - ({[6- {4-chloro-3- [3- (methylamino) propoxy] phenyl} -5- (2-Methylphenyl) pyridin-2-yl] carbonyl) amino) cyclohexanecarboxylic acid; 1- ({[6- {4-Chloro-3- [3- (dimethylamino) propoxy] -5-fluorophenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid; 1- ({[6- {4-Chloro-3- [4- (dimethylamino) butyl] phenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid; 1 - [({5'-chloro-6 '- [3- (dimethylamino) propoxy] -3- (2-methylphenyl) -2,2'-bipyridin-6-yl} carbonyl) amino] cyclohexanecarboxylic acid; 1- ({[6- {4-Chloro-3- [3- (dimethylamino) propoxy] -2-fluorophenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid; 1- ({[6- {4-Chloro-3- [3- (dimethylamino) propoxy] -5-methylphenyl} -5- (2-methylphenyl) pyridin-2-yl] carbonyl} amino) cyclohexanecarboxylic acid; or an addition salt thereof to an acid or a base. 11. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 10, characterized in that A.1) is reacted with an acid or a functional derivative of this acid of formula: Wherein A, B, E, V, and W are as defined for a compound of formula (I) in claim 1, with an amine of formula (III): ## STR5 ## to obtain a compound of formula (IV) 10A.2) the compound of formula (IV) thus obtained is reacted with a strong base to obtain the compound of formula (I). 12. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 10, characterized in that: B.1) is reacted an acid or a functional derivative of this acid of formula ( V): wherein A, B, E, V and W are as defined for a compound of formula (I) in claim 1, with an amine of formula (III) to obtain a compound of formula (VI): 15B.2) the compound of formula (VI) thus obtained is reduced to give a compound of formula (VII): W B.3) the compound of formula (VII) is reacted with a strong base to obtain the compound of formula (I). 13. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 10, or a salt of addition of this compound to a pharmaceutically acceptable acid or base. 14. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 10, or a salt of addition of this compound to a pharmaceutically acceptable acid or base, and at least one pharmaceutically acceptable excipient. 15 15. Use of a compound of formula (I) according to any one of claims 1 to 10 for the preparation of a medicament for the treatment and / or prevention of congestive heart failure, cardiac ischemia , myocardial infarction, cardiac fibrosis and hypertrophy, coronary heart disease and atherosclerosis, systemic and pulmonary arterial hypertension, portal hypertension, liver fibrosis of postmenopausal restenosis. angioplasty, acute and chronic renal insufficiency of diabetic and / or hypertensive origin, diabetes, inflammation, fibrosis and aneurysms, disorders of the central nervous system, including neurodegenerative diseases, cerebrovascular accidents, stress, anxiety, aggression, depression, schizophrenia or sleeping sickness and cancers or respiratory diseases, asthma. 30 16. Use of a compound of formula (I) according to any one of claims 1 to 10 for the preparation of a medicament for the treatment and / or prevention of vomiting. E V '1 ~ (CH B 10