MXPA06009627A

MXPA06009627A - Aryl and heteroaryl-piperidinecarboxylate derivatives, the preparation and the use thereof in the form of faah enzyme inhibitors

Info

Publication number: MXPA06009627A
Application number: MXPA/A/2006/009627A
Authority: MX
Inventors: Abouabdellah Ahmed; Almario Garcia Antonio; Hoornaert Christian; Lardenois Patrick; Marguet Frank
Original assignee: Sanofisynthelabo
Priority date: 2004-02-26
Filing date: 2006-08-23
Publication date: 2007-04-10

Abstract

The invention relates to compounds of general formula (I), wherein m, n=1 to 3 and m + n=2 to 5 p=1 A 7;A=single bond or X, Y and/or Z;X=methylene possibly substituted;Y=C2-alkenylene possibly substituted or C2-alkynylene;Z=C3-7-cycloalkyl;R1 is an aryl or heteroaryl group;R2 is a hydrogen or fluoride atom, a hydroxyl, C1-6-alkoxy or NR8R9 group;R3 is a hydrogen atom or a C1- 6-alkyl group;R4 is a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl group. Said compounds can be embodied in the form of a base, an acid addition salt, a hydrate or a solvate and can be used in the form of FAAH enzyme inhibitors.

Description

DERIVATIVES OF ARIL AND HETEROARIL- PIPERIDINCARBOXILATOS, ITS PREPARATION AND ITS APPLICATION AS INHIBITORS OF ENZYME FAAH The subject of the invention is the derivatives of aryl and heteroaryl-piperidinecarboxylates, their preparation and their application in therapy. There are known derivatives of phenylalkylcarbamates, of dioxan-2-alkylcarbamates and of the aryloxyalkylcarbamate type, described respectively in documents FR2850377 A, WO2004 / 020430 A2 and PCT / FR2005 / 00028, inhibitors of the FAAH enzyme (Fatty Acid Amido Hydrolase). There is still a need to find and develop products inhibiting the FAAH enzyme. The compounds of the invention respond to this objective. The compounds of the invention correspond to the general formula (I): (I) where: m and n represent integers ranging from 1 to 3 so that m + n is an integer ranging from 2 to 5; p represents an integer ranging from 1 to 7; A represents a single link or is chosen from one or more groups X, Y and / or Z; X represents a methylene group optionally substituted with one or two C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl C 1-3 alkyne groups; Y represents either a C2-alkenylene group optionally substituted with one or two C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl- C-3 alkylene groups; either an alkynylene-C2 group; Z represents a group of formula: or represents an integer ranging from 1 to 5; r and s represent integers and are defined so that r + s - is a number ranging from 1 to 5; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen or fluorine atom, hydroxyl group. C1-C6 alkoxy or NR8Rg; R3 represents a hydrogen atom or a C6-alkyl group; R 4 represents a hydrogen atom or a C-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-3 alkyl group. R5 represents a group chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, quinolinyl, / tetrahydroquinolinyl , isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl, furopyridinyl , thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R6 represents a halogen atom or cyano group, nitro, C6-6 alkyl, C3-7 cycloalkyl, C6-6 alkoxy, hydroxyl, C1-6 thioalkyl, C1-6 fluoroalkyl, C1-6 fluoroalkoxy , fluorothioalkyl-C1 -6, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CON R8R9, SO2R8, SO2NR8R9, -O-Calkylene-d. 3) -O or a cycle selected from the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, piperazine cycles, this cycle optionally being substituted with a C-6-alkyl or benzyl group; R7 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group; the R7 group (s) having one or more R6 groups identical or different from one another may be substituted; R8 and R9 independently represent a hydrogen atom or an alkyl-C-? -6 group independently of one another. In the context of the invention, the compounds of general formula (I) can therefore comprise several A groups identical or different from each other. Among the compounds of general formula (I), a first subgroup of compounds consists of compounds for which: m and n represent integers equal to 1 or 2 so that m + n is an integer ranging from 2 to 4; p represents a number equal to 1 to 3; A represents a single bond, a methylene or alkynylene-C2 group; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen atom or a hydroxyl group; R3 represents a hydrogen atom or a C1-C6 alkyl group; R represents a hydrogen atom or a C1-C6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkyl group; R5 represents a group selected from phenyl, pyridinyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthalenyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl or pyrrolopyridinyl; R 6 represents a halogen atom, more particularly bromine, chlorine or fluorine, or a cyano group, C 1-6 alkyl, more particularly methyl, butyl or isobutyl, C 3-7 cycloalkyl, more particularly cyclopentyl, C 6 alkoxy, more particularly methoxy or ethoxy, fluoroalkyl-C? -6, more particularly trifluoromethyl, or a pyrrolidine or piperidine cycle, this cycle being optionally substituted with a C? -6 alkyl group, more particularly isopropyl; R7 represents a phenyl group which may be substituted with one or more R6 groups identical or different from one another. Among the compounds of general formula (I), a second subgroup of compounds consists of compounds for which: m and n represent integers equal to 1 or 2 so that m + n is an integer ranging from 2 to 4; p represents an integer ranging from 1 to 3; A represents a single bond, a methylene or alkynylene-C2 group; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen atom or a hydroxyl group; R3 represents a hydrogen atom or a C1-6 alkyl group; R represents a hydrogen atom or a C1-C6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl-C1-3 alkyl group; R 5 represents a group selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, isoxazolyl, naphthalenyl or isoquinolinyl; R 6 represents a halogen atom, more particularly bromine, chlorine or fluorine, or a cyano group, C 1-6 alkyl, more particularly methyl, butyl or isobutyl, C 3-7 cycloalkyl, more particularly cyclopentyl, C 6 alkoxy. , more particularly methoxy or ethoxy, fluoroalkyl-C 1-6, more particularly trifluoromethyl, or a pyrrolidine or piperidine cycle, this cycle being optionally substituted with a group more particularly isopropyl; R7 represents a phenyl group which may be substituted with one or more R6 groups identical or different from one another.

Among the compounds of general formula (I), a third subgroup of compounds consists of compounds for which: m, n, p, A and Ri are as defined in the first subgroup defined above; R3 represents a hydrogen atom; R 4 represents a hydrogen atom or a C 1-6 alkyl group, more particularly methyl. Among the compounds of the subgroups defined above, the following compounds may be mentioned: -4-. { 5- [4- (Trifluoromethyl) phenyl] pyridin-2-yl} piperidin-1-2- (methylamino) -2-oxoethyl-4-carboxylate (4'-chlorobiphen i-4-yl) -4-h idroxypiperid i n-1-2- (methylamino) -2-carboxylate -oxoethyl 4- (4'-ethoxy b ifen l-4-yl) -4-h id roxi pi perid i n-1-2- (methylamino) -2-oxoethyl-4-carboxylate 4- (3 ') , 4'-d icio robifen i l-4-il) -4-h id roxi pi perid i n-1 -carboxy lato 2- (methylamino) -2-oxoetilo -4- (3'-chloro-4 ' -fluorob ifen i l-4-yl) -4-h id roxi pi perid i n-1-2- (methylamino) -2-oxoethyl-4 - [(6-cyclopentylpyridin-2-yl) methyl] piperidin carboxylate 2- (Methylamino) -2-oxoethyl-2- (2- (3-chlorophenyl) ethyl] piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-2- (2- (4-carboxylic acid) -carboxylate chlorophenyl) ethyl] piperidin-1-2- (methylamino) -2-oxoethyl-4-carboxylate. { 2- [3- (trifluoromethyl) phenyl] ethyl} piperidin-1-2- (methylamino) -2-oxoethyl-4-carboxylate. { 2- [4- (trifluoromethyl) phenyl] ethyl} piperid i n-1-2- (methylamino) -2-oxoethyl-2- (2-biphenyl-3-ylethyl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-4-carboxylate 2- [2- 2- (Methylamino) -2-oxoethyl-2- (2-methylamino) -2-oxoethyl (2- (2-naphthyl) ethyl] piperidin-1-carboxylic acid (1-naphthyl) ethyl] piperidin-1-carboxylate -4- [2- (6-Cyclopentyl-pyridin-2-yl) ethyl] piperidin-1-carboxylate 2- (methylamino) -2-oxoethyl-4- [2- (6-pyrrolidin-1-ylpyrid n-2-yl) ethyl] piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-2- (2-isoquinolin-1-ylethyl) piperidin-1-carboxylate 2- (methylamino) -2-oxoethylcarboxylate -4- [3- (3-chlorophen i I) propi I] pi perid in-1-2- (methylamino) -2-oxoethyl-4- [3- (4-chlorophen-yl) propyl] piperid n-carboxylate -1-2- (methylamino) -2-oxoethyl-4-carboxylate. { 3- [3- (trifluoromethyl) phenyl] propyl} piperidin-1-2- (methylamino) -2-oxoethyl-4-carboxylate. { 3- [4- (trifluoromethyl) phenyl] propyl} piperid i n-1-2- (methylamino) -2-oxoethyl-4- (3- (3-cyanophenyl) propyl] piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-4-carboxylate 2- (Methylamino) -2-oxoethyl-3- (3-biphenyl-3-ylpropyl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-2-oxoethyl-piperidin-1-carboxylate 4- [3- (1-naphthyl) propyl] piperidin-1-carboxylic acid 2- (meth) lamino or) -2-oxoethyl-4- [3- (2-naphthyl) propyl] piperidin-1-carboxylate of 2 - (Methyl lamethyl) -2-oxoethyl 4- [3- (1, 3-thiazol-2-yl) propyl] piperidin-1-carboxylate 2- (methylamino) -2-oxoethyl -4- [ (3-Chlorophen-yl) ethynyl] piperid-n-1-2- (methylamino) -2-oxoethyl-4 - [(4-chlorophenyl) ethynyl] piperidin-1-carboxylate 2- (methylamino) -2- carboxylate oxoethyl 4- (biphenyl-3-ylethynyl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl -4- (1 -naphthyltin) piperid i n-1 -carboxylate 2- (methylamino) -2-oxoethyl -4- (2-naphthi letin i I) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl-4- (3-biphenyl-2-ylprop-2-yn-1-yl) piperidin-1 - 2- (Methylamino) -2-oxoethyl 2- [(6-pyrrolidin-1-ylpyridin-2-yl) methyl] piperidin-1-carboxylate 2- (methylamino) -2-oxoethyl carboxylate. Among the compounds of general formula (I), a subfamily of compounds consists of compounds that correspond to the general formula (I '): where m and n represent integers ranging from 1 to 3 so that m + n is an integer ranging from 2 to 5; p represents an integer ranging from 1 to 7; A represents a single link or is chosen from one or more groups X, Y and / or Z; X represents a methylene group optionally substituted with one or two C 1-6 -alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1-3 -alkylene groups; Y represents either a C2-alkenylene group optionally substituted with one or two C5-C, C6-C3, C3-7 cycloalkyl or C3-7 cycloalkyl-C-C3-alkylene groups; either an alkylene-C2 group; Z represents a group of formula: or represents an integer ranging from 1 to 5; r and s represent integers and are defined so that r + s is a number ranging from 1 to 5; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen or fluorine atom, hydroxyl group. C1-C6 alkoxy or NR8R9; R3 represents a hydrogen atom or a C1-C6 alkyl group; R4 represents a hydrogen atom or an alkylene-C6-6 cycloalkyl-C3-7 or cycloalkyl-C3-7-alkyl-C -3 group. R 5 represents a group chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, indolinyl, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R 6 represents a halogen atom or a cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, C 1-6 thioalkyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 1-6 fluorothioalkyl group , NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CONR8R9, SO2R8, SO2N R8R9 or -O- (alkylene-C1-3) -O; R7 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group; the R7 group (s) having one or more R6 groups identical or different from one another may be substituted; R8 and R9 independently represent a hydrogen atom or a C1-C6 alkyl group independently of one another, or form with the atom (s) that contain them a cycle selected from an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine, optionally substituted with an alkyl-C1-6 group or benzyl. Among the compounds of general formula (I1), a first subgroup of compounds consists of compounds for which: m and n represent integers equal to 1 or 2 so that m + n is an integer ranging from 2 to 4; p represents an integer equal to 1 or 2; A represents a single bond or a methylene group; R represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen or fluorine atom, hydroxyl group. C1-C6 alkoxy or NR8R9; R3 represents a hydrogen atom or a C1-C6 alkyl group; R 4 represents a hydrogen atom or an a-C 1 -C 6 -alkyl, a C 3-7 cycloalkyl or a C 3-7 cycloalkyl-C 1-3 -alkyl group. R 5 represents a group selected from phenyl, midazolyl, naphthalenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, indolinyl, benzimidazolyl, benzotriazolyl or pyrrolopyridinyl; R6 represents a halogen atom, more particularly bromine, chlorine or fluorine, or a C1-C6 alkyl group, more particularly methyl or butyl, C6-alkoxy, more particularly methoxy or ethoxy, fluoroalkyl-C6-6, more particularly trifluoromethyl; R7 represents a phenyl group which may be substituted with one or more R6 groups identical or different from one another. Among the compounds of general formula (I1), a second subgroup of compounds consists of compounds for which: m, n, p, A and R-i are as defined in the first subgroup defined above; R3 represents a hydrogen atom; R 4 represents a hydrogen atom or a C 1-6 alkyl group, more particularly methyl. Among the compounds of general formula (V), mention may be made of the following compounds: 2-amino-2-oxoethyl-4-phenylpiperidin-1-carboxylate; 2- (Methylamino) -2-oxoethyl-4-phenylpiperidin-1-carboxylate; -4- [3- (trifluoromethyl) phenyl] pipepdin-1-2-amino-2-oxoethyl carboxylate; -4- [3- (trifl or o-romethyl) phenyl] piperid-n-1-2- (methylamino) -2-oxoethyl carboxylate; -4- (4-phenyl-1H-imidazol-1-yl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; -4- (1 H-1, 2,3-benzotriazol-1-yl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; -4- (4-Bromophenyl) -4-hydroxypiperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; -4- (4'-fluorobifen i-l-4-yl) -4-h id roxy p i perid i n-1-2- (methylamino) -2-oxoethyl carboxylate; -4- (4'-chlorobiphenyl-4-yl) -4-hydroxy-piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; 2- (Methylamino) -2-oxoethyl-4-hydroxy-4- (4'-methylbiphenyl-4-yl) piperidin-1-carboxylate; -4- (4 .'-Butylbiphenyl-4-yl) -4-hydroxypiperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; 4-hydroxy 4- [4 '- (trifluoromethyl) b.phenyl-4-yl] piperidin-1-carboxylate 2- (methylamino) -2-oxoethyl; -4-h id roxi-4- [4 '- (m ethi loxi) b ifen i l-4-i I] p i perid in-1-2- (methylamino) -2-oxoethyl carboxylate; -4- [4 '- (Ethyloxy) biphenyl-4-yl] -4-hydroxypiperidin-1-carboxylate 2- (methylamino) -2-oxoethyl; -4- (3 ', 4'-dichlorobiphenyl-4-yl) -4-hydroxypiperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester; -4- [3'-fluoro-4 '- (methyloxy) bifen i-l-4-yl] -4-h idroxypiperidin-1-carboxylate of 2- (methylamino) -2-oxoethyl; -4- (3'-Chloro-4'-fluorobiphenyl-4-yl) -4-hydroxypiperidine-1-carboxylate of 2- (methylamino) -2-oxoethyl; -4- (2- (methylamino) -2-oxoethyl-naphthalen-2-ylmethyl) piperidin-1-carboxylate; -4- (biphenyl-4-ylmethyl) piperidin-1-carboxylate of 2- (methyl lamin) -2-oxoethyl; -4- (1 H-indol-1-ylmethyl) piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- (2,3-dihydro-1 H -indol-1-ylmethyl) piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- (3,4-dihydroquinolin-1 (2H) -ylmethyl) piperidin-1-carboxylic acid of 2-amino-2-oxoethyl; -4- (2-amino-2-oxoethyl 3,4-dihydroisoquinolin-2 (1 H) -ylmethyl) piperidin-1-carboxylate; -4- (1 H-pyrrolo [2,3-b] pyridin-1-ylmethyl) piperidin-1-carboxylic acid of 2-amino-2-oxoethyl; -4- (1 H-benzimidazol-1-ylmethyl) piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4 - [(4-phenyl-1 H-imidazol-1-yl) methyl] piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -3- (2-phenylethyl) pyrrolidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- [2- (3,4-dihydroquinolin-1 (2H) -yl) ethyl] piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- [2- (3,4-dihydroisoquinolin-2 (1 H) -yl) ethyl] piperidin-1-carboxylate of 2-amino-2-oxoethyl; -4- [2- (1 H-indol-1-yl) ethyl] piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- [2- (2,3-dihydro-1 H -indol-1-yl) ethyl] piperidin-1-2-amino-2-oxoethyl carboxylate; -4- [2- (1 H-pyrrolo [2,3-b] pyridin-1-yl) ethyl] piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- [2- (1 H-benzimidazol-1-yl) ethyl] piperidin-1-carboxylic acid 2-amino-2-oxoethyl ester; -4- [2- (4-phenyl-1 H-imidazol-1-yl) ethyl] piperidin-1-carboxylic acid of 2-amino-2-oxoethyl. The compounds of general formula (I) may comprise one or more asymmetric carbons. They can exist in the form of enantiomers or diastereoisomers. These enantiomers and 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 acid addition salts. Said addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, although the salts of other acids useful, for example, for the purification or isolation of the compounds of the formula (I) also form part of the invention. The compounds of the general formula (I) can be present in the form of hydrates or solvates, that is to say in the form of combinations or combinations with one or more water molecules or with a solvent. Said hydrates and solvates are also part of the invention. In the context of the invention, it is meant by: Ct-Z where tyz can have the values from 1 to 7, a carbon chain which can have from carbon atoms, for example, C -? - 3 a carbon chain that can have from 1 to 3 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C 1-6 alkyl group represents a carbon chain of 1 to 6 carbon atoms, straight or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl or hexyl; alkylene, a linear or branched saturated divalent alkyl group, for example, an alkylene-C1-3 group represents a divalent carbon chain of 1 to 3 carbon atoms, straight or branched, more particularly methylene, ethylene, 1-methylethylene or propylene; cycloalkyl, a cyclic alkyl group, for example, a C3-7 cycloalkyl group represents a cyclic carbon chain of 3 to 7 carbon atoms, more particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; alkenylene, a 2-carbon aliphatic, divalent unsaturated group, more particularly ethylene; Alkynylene-C2, a group -C = C-; alkoxy, a linear or branched saturated aliphatic chain-O-alkyl group; thioalkyl, a saturated or straight or branched aliphatic chain -S-alkyl group; fluoroalkyl, an alkyl group in which one or several hydrogen atoms have been replaced by a fluorine atom; - fluoroalkoxy, an alkoxy group in which one or several hydrogen atoms have been replaced by a fluorine atom; fluorothioalkyl, a thioalkyl group in which one or several hydrogen atoms have been replaced by a fluorine atom; halogen atom, fluorine, chlorine, bromine or iodine. The compounds of the invention can be prepared according to the method illustrated by the following scheme.

Scheme (ll) (IV) The compounds of the invention can be prepared by reacting an amine of the general formula (II), in which Ri, A, R2, p, myn are as defined in the general formula (I), with a carbonate of the general formula (III), in which Z represents a hydrogen atom or a nitro group, R3 is as defined in the general formula (I) and R represents a methyl or ethyl group, in a solvent such as toluene, dichloroethane or acetonitrile, or a mixture of these solvents, at a temperature comprised between 0 ° C and 80 ° C. The carbamate esters of the general formula (IV) obtained in this way are converted into compounds of the general formula (I), by aminolysis by an amine of the general formula R 4 NH 2 wherein R 4 is as defined in the general formula (I ). The aminolysis reaction can be carried out in a solvent such as methanol or ethanol, or in a mixture of solvents such as methanol and tetrahydrofuran. The compounds of general formula (I) or (IV), in which Ri represents a group of the aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl type, can also be prepared by reaction of the compounds of the general formula ( I) or (IV), for which R5 is substituted with a chlorine, bromine, iodine or with a triflate group in the position in which the R7 group must be introduced, with an aryl or heteroaryl boronic acid derivative following the reaction conditions of Suzuki (Chem. Rev. 1 995, 95, 2457-2483) or with an aryl or heteroaryl-alkylatannane derivative following the reaction conditions of Stille (Angew.Chem. Int. Ed. , 25, 504-524). The carbonates of the general formula (III) can be prepared according to any method described in the literature, for example, by reacting an alcohol of the general formula HOCH R3COOR in which R represents a methyl or ethyl group with phenyl chloroformate or 4-nitrophenyl , in the presence of a base such as triethylamine or diisopropylethylamine. The compounds of general formula (II), as well as the amines of general formula R4N H2, when their mode of preparation is not described, are commercially available or are described in the literature or can be prepared according to different methods described in the literature or known by the expert in the art. The compounds of general formula (IV) in which R1; A, R2, R3, p, m and n are as defined in the general formula (I) and R represents a methyl or ethyl group are new and also form part of the invention. They are useful as synthesis intermediates for the preparation of compounds of general formula (I). The examples that follow illustrate the preparation of some compounds of the invention. These examples are not limiting and only serve to illustrate the invention. The microanalyses, the spectra of I. R. and R. M. N. and / or analyzes by LC-MS (Liquid Chromatography coupled with Mass Spectrometry) confirm the structures and purities of the obtained compounds. PF (° C) represents the melting point in degrees Celsius. The numbers indicated in parentheses in the titles of the examples correspond to those in the first column of the following table.

The nomenclatu ra U ICPA (International Union of Pure Chemistry and Applied -I U PAC in English) has been used for the naming of the compounds in the following examples. For example, for the biphenyl group, the following numbering has been respected: '6' 6 5 Example 1 (compound No. 14) 4- (4-phenyl-1 H-imidazol-1-yl) piperidin-1-carboxylic acid 2- (methylamino) -2-oxoethyl 1 .1. 4 - [(Methylsulfonyl) oxy] piperidine-1-carboxylate 1,1-dimethylethyl With stirring, 1.4 ml (1.7 mmol) of methanesulfonyl chloride are added dropwise to a solution of 3.0 g (14.9 mmol) of 1,1-dimethylethyl 4- hydroxypiperidine-1-carboxylate and 2.2 ml (17.9 mmol) of triethylamine in 60 ml of dichloromethane cooled in an ice bath. Stirring is maintained for one hour at 0 ° C and then 4 hours at room temperature. The reaction mixture is diluted with 100 ml of dichloromethane and washed successively with 1 00 ml of an aqueous solution of sodium hydrogencarbonate., with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate to dryness. The residue is triturated in a 50/50 mixture of cyclohexane and diethylether to obtain 3.7 g of product as a white solid. 1 .2. 4- (4-phenyl-1H-imidazol-1-yl) piperidin-1-carboxylate 1,1-dimethylethyl ester To a suspension of 1.1 g (27.9 mmoles) of sodium hydride (60% suspension) in oil) in 30 ml of? /,? / - dimethylformamide cooled in an ice bath, a solution of 4.0 g (27.9 mmoles) of 4-phenylimidazole in 40 ml of N -dimethylformamide is added dropwise. . The mixture is stirred at room temperature for 1 hour, cooled to 0 ° C and 2.6 g (9.3 mmol) of 4 - [(methylsulfonyl) oxy] piperidine-1-carboxylate are added dropwise. 1, 1 -dimethylethyl obtained in stage 1 .1. , in solution in 20 ml of N-N-dimethylformamide. It is then heated at 80 ° C for 2 hours. The reaction mixture is cooled to room temperature and diluted with 50 ml of water and 150 ml of ethyl acetate. Decant and extract the aqueous phase twice with 100 ml of ethyl acetate. The organic phases are washed twice with 100 ml of water and with 100 ml of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate to dryness. The residue is purified by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol to obtain 1.0 g of product as a yellow oil. 1 .3. 4- (4-phenyl-1 / - / - imidazol-1-yl) piperidine 5.6 ml (76.3 mmoles) of trifluoroacetic acid are added dropwise to a solution of 1.0 g (3.05 mmol) ) of 1,1-dimethylethyl 4- (4-phenyl-1H-imidazol-1-yl) piperidin-1-carboxylate obtained in step 1 .2. , in 60 ml of dichloromethane cooled in an ice bath. Stir one hour at room temperature and evaporate to dryness. The residue is taken up in 25 ml of water and 2 ml of a 30% aqueous solution of sodium hydroxide are added. The mixture is stirred for 30 minutes and extracted four times with 80 ml of dichloromethane. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness to obtain 0.7 g of product in the form of a yellow oil, which is used as such in the next step. 1 .4. 4- (4-phenyl-1 - / - imidazol-1-yl) piperidin-1-2- (ethyloxy) -2-oxoethylcarboxylate. Heat at 60 ° C overnight, a solution of 1.0 g ( 4.4 mmol) of 4- (4-phenyl-1-imidazol-1-yl) piperidine prepared according to step 1 .3. and 1.18 g (5.2 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate (J. Med. Chem, 1 999, 42, 277-290) in 50 ml of toluene. It is evaporated to dryness and the residue is taken up in 80 ml of ethyl acetate and 80 ml of water. Decant and extract the aqueous phase three times with 80 ml of ethyl acetate. The organic phases are washed with 80 ml of a saturated aqueous solution of sodium chloride. Dry over sodium sulfate and evaporate to dryness. The remainder is purified by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol to obtain 0.35 g of product. fifteen. 2- (Methylamino) -2-oxoethyl 4- (4-phenyl-1-imidazol-1-yl) piperidin-1-carboxylate 0.35 g (0.98 mmol) of 4 (4-phenyl) are dissolved. 1 / - -imidazol-1-yl) piperidin-1-2- (ethyloxy) -2-oxoethyl carboxylate obtained in step 1 .4. , in 7 ml of methanol. 1.5 ml (3 mmol) of a 2 M solution of methylamine in tetrahydrofuran are added. After 16 hours at room temperature, 1 ml (2 mmoles) of a 2 M solution of methylamine in tetrahydrofuran is added and allowed to react for an additional 6 hours. It is evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a mixture 98/2, 97/3, 96/4 and 95/5 of dichloromethane and methanol. Triturate in diethyl ether to obtain 0.20 g of product as a white solid. Melting Point (° C): 1 92-1 94 LC / MS: M + H = 343 NMR-1H (CDCl 3) d (ppm): 7.75 (d, 2H); 7.60 (s, 1 H); 7.40 (m, 2H); 7.25 (m, 2H); 6.05 (broad s, 1 H); 4.65 (s, 2H); 4.35 (m, 2H); 4, 15 (m, 1 H); 3.05 (m, 2H); 2.90 (d, 3H); 2.20 (m, 2H); 2.05-1, 85 (m, 2H). Example 2 (compound No. 32) 2- (methylamino) -2-oxoethyl 4- (4-bromophenyl) -4-hydroxypiperidin-1-carboxylate 2. 1 . 4- (4-Bromophenyl) -4-hydroxypiperidin-1-carboxylic acid 2- (ethyloxy) -2-oxyethyl ester. A mixture of 2.24 g (10 mmol) of [(phenyloxycarbonyl) is heated at 50 ° C for 20 hours. ) oxy] ethyl acetate and 2.56 g (10 mmol) of 4- (4-bromophenyl) -4-piperidinol in solution in 40 ml of toluene. The solution is evaporated to dryness in a water bath under reduced pressure.

An oil is obtained that is used directly in the next stage. 2. 2. 2- (Methylamino) -2-oxoethyl 4- (4-bromophenyl) -4-hydroxypiperidine-1-carboxylate 4- (4-bromophenyl) -4-hydroxypiperidin-1-carboxylate of 2- (ethyloxy) - 2-Oxyethyl obtained in step 2.1. , it is stirred for 3 hours in a solution of 33% methylamine in methanol. The solution is concentrated in a water bath under reduced pressure. The remainder is purified by chromatography on silica gel eluting with ethyl acetate. 2.6 g of product are obtained in the form of an oil that solidifies progressively, Melting point (° C): 57-60 LC-MS: M + H = 371 NMR-1 H (DMSO-de) d (ppm): 7.55 (broad s, 1 H); 7.50 (d, 2H); 7.40 (d, 2H); 5.20 (s, 1 H); 4.40 (s, 2H); 3.80 (m, 2H); 3.20 (m, 2H); 2.60 (d, 3H); 1, 90 -1, 50 (m, 4H). Example 3 (compound No. 40) 4- (3 ', 4'-d, chlorobif in i-4-yl) -4-h id roxy pi perid i n-1 -carboxylate of 2- (methylamino) - 2-oxoethyl 0.1 g (0.27 mmol) of 2- (methylamino) -2-oxoethyl 4- (4-bromophenyl) -4-hydroxypiperidin-1-carboxylate obtained following example 2, 0.077 g (0.4 mmoles) of 3,4-dichlorophenylboronic acid, 10 mg of tetrakis- (triphenylphosphine) palladium (0), 2 ml of 2 M aqueous solution of sodium carbonate, 0.5 ml of ethanol and 4 ml of previously degassed toluene with nitrogen. Heat at 80 ° C with stirring for 20 hours. It is filtered hot on a hydrophobic cartridge, washed with tetrahydrofuran (THF) and evaporated to dryness. The remainder was purified by LC-MS chromatography on silica phase eluting with a gradient of cyclohexane / ethyl acetate / methanol to obtain 0.069 g of crystalline product. Melting Point (° C): 1 56-1 58 LC-MS: M + H = 438 RM N-1 H (DMSO-de) d (ppm): 7.95 (s, 1 H); 7.80 (m, 1 H); 7.70 (m, 4H); 7.60 (m, 2H); 5.20 (s, 1 H); 4.45 (s, 2H); 4.00 (m, 2H); 3.25 (m, 2H); 2.60 (d, 3H); 1.95 (m, 2H); 1.65 (m, 2H). Example 4 (compound No. 43) 4- (naphthalene-2-i I meti) pi perid i n-1-2- (methylamino) -2-oxoethyl carboxylate 4. 1 . 4- (1,1-dimethylethyl) -naphthalene-2-ylmethyl) piperidin-1-carboxylate. Under an argon atmosphere, 8.0 ml of a 0.5 N solution is added. (4 mmol) of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran to a solution of 0.789 g (4 mmol) of 4-methylidene piperadin-1-1,1-dimethylethyl carboxylate (Tetrahedron Letters 1 996, 37 ( 30), 5233-5234) in solution in 5 ml of tetrahydrofuran. Heat to reflux for 3 hours. Cool to room temperature and add 0.787 g (3.8 mmol) of 2-bromonaphthalene in solution in 9 ml of N, N-dimethylformamide, 0.829 g (6.0 mmol) of potassium carbonate in solution in 1 ml. ml of water and 0.1.6 g (0.20 mmol) of complex [1, 1'-bis (diphenylphosphine) -ferrocene] dichloropalladium (II) -dichloromethane). Heat to reflux overnight. The reaction mixture is diluted with 50 ml of ethyl acetate and 50 μl of water. The organic phase is decanted and washed with 25 ml of water and 25 ml of a saturated aqueous solution of sodium chloride. Dry over magnesium sulfate and evaporate in vacuo. The remainder was purified by chromatography on silica gel eluting with a 99/1, 95/5 and 90/1 0 mixture of cyclohexane and ethyl acetate to obtain 0.79 g of product as a colorless viscous liquid. 4.2. 4- (naphthalen-2-ylmethyl) piperidine 0.79 g (2.43 mmol) of the 4- (naphthalen-2-ylmethyl) piperidin-1-carboxylate 1,1-dimethylethyl obtained in step 4.1 are dissolved. in 1 ml of dichloromethane and 2 ml (25 mmol) of trifluoroacetic acid are added. It is stirred for 3 hours at room temperature. It evaporates under reduced pressure, add 4 ml of 1,2-dichloroethane and evaporate again. The residue is taken up in a mixture of 50 ml of dichloromethane and 15 ml of a 1% aqueous solution of sodium hydroxide. The organic phase is decanted and the aqueous phase is extracted twice with 25 ml of dichloromethane. The organic phases are washed with 15 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo to give 0.52 g of product as an orange oil, which is used as such in step following. 4.3. 2- (Ethoxy) -2-oxoethyl 4- (naphthalen-2-ylmethyl) piperidin-1-carboxylate. It is heated at 60 ° C overnight, a mixture of 0.52 g (2.3 mmol) of 4- (naphthalen-2-ylmethyl) piperidine obtained in step 4.2., and from 0.69 g (3.1 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate in 10 ml of toluene and 5 ml of acetonitrile. It evaporates in vacuum. The remainder is purified by chromatography on silica gel eluting with a 90/10, 85/1 5 and 80/20 mixture of cyclohexane and ethyl acetate to obtain 0.56 g of product as a colorless viscous liquid. 4.4. 2- (Methylamino) -2-oxoethyl 4- (naphthalen-2-ylmethyl) piperidin-1-carboxylate 0.54 g (1.52 mmol) of 4- (naphthalen-2-ylmethyl) are dissolved in 3 ml of methanol. ) 2- (ethoxy) -2-oxoethyl piperidine-1-carboxylate obtained in step 4.3. and 3 ml (6.0 mmol) of a solution of 2 M methylamine in tetrahydrofuran is added. It is left to react overnight at room temperature, 1.5 g of silica are added and evaporated. The remainder is purified by chromatography on silica gel eluting with a 98.5 / 1, 5 and 97/3 mixture of dichloromethane and methanol. It is recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain 0.43 g of product as a white solid. Melting Point (° C): 150-152 LC / MS: M + H 341 NMR-1H (CDCl 3) d (ppm): 7.80 (m, 3H); 7.60 (s, 1H); 7.45 (m, 2H); 7.30 (d, 1H); 6.10 (m, 1H); 4.60 (s, 2H); 4.15 (m, 2H); 2.85 (d, 3H); 2.85-2.75 (m + d, 4H); 1.90-1.70 (m, 3H); 1.35-1.15 (m, 2H). Example 5 (compound No. 107) 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidine-1-carboxylate 2- (methylamino) -2-oxoethyl . 1.4- (2-Oxoethyl) piperidine-1-carboxylic acid tere-butyl ester To a solution of 30.4 g (132 mmol) of 4- (2-hydroxyethyl) piperidine-1-carboxylate ferric-butyl ester in 150 mL of dichloromethane After cooling to 0 ° C, 70.9 g (167 mmol) of (1, 1, 1 -tris (acetyloxy) -1,1-dihydro-1,2-benziodoxol-3- (7 / -) are added. ) -one (Dess-Martin reagent), stir 2 hours at room temperature, add 150 μL of a 1% aqueous solution of sodium thiosulfate (Na2S2O3) and stir for an additional 30 minutes. decant the organic phase, wash with a saturated aqueous solution of sodium carbonate, dry over sodium sulfate and evaporate to dryness to obtain 30.1 g (132 mmol) of product in the form of a colorless oil which is used as is. in the next step 5.2 4- (3,3-dibromoprop-2-en-1-yl) piperidin-1-tert-butylcarboxylate To a solution of 1 39.4 g (531 mmol) of triphenylphosphine in 440 mL of toluene, cooled to -20 ° C, 47.6 are added mL (531 mmoles) of tribromomethane and 59.6 g (531 mmoles) of potassium fer-butylate. Stirring is maintained at -20 ° C for 1 5 minutes and a solution of 30.1 g (31 mmoles) of 4- (2-oxoethyl) piperidin-1-ferrobutylcarboxylate prepared in the stage is added. 5.1. , in 240 mL of toluene. Stir at room temperature for 3 hours. 300 mL of diethyl ether is added, the formed solid is filtered and the filtrate is evaporated. The residue is purified by chromatography on silica gel eluting with dichloromethane to obtain 32.6 g (85 mmol) of product as a yellow oil. 5.3 4-prop-2-yn-1-ylpiperidin-1-ferrobutylcarboxylate 32.6 g (85 mmol) of 4- (3,3-dibromoprop-2-en-1-yl) piperidine are dissolved. 1-fer-butylcarboxylate, prepared in step 5.2. , in 420 mL of anhydrous tetrahydrofuran. The mixture is cooled to -78 ° C and, with good stirring, 1 06 μL of a 1.6 M solution of n-butyllithium (1 70 mmol) in hexane dissolved in 1 00 μL of anhydrous tetrahydrofuran are added dropwise. Stirring is maintained at -78 ° C for 3 hours and at -20 ° C for 1 hour. It is cooled to -78 ° C and 1 30 mL of a 1.25 M hydrochloric acid solution in ethanol are added. It is reheated at room temperature for one hour. Water and ethyl acetate are added. The organic phase is decanted, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel eluting with dichloromethane and with a 98/2 mixture of dichloromethane and methanol to obtain 32.4 g (85.2 mmol) of product as a colorless oil. . 4. 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidin-1-tert-butylcarboxylate 2.29 g (9.6 mmoles) of 1-chloro-4- are dissolved iodine-benzene and 1.7 mL (12 mmol) of triethylamine in 5 mL of tetrahydrofuran. Under argon, 0.076 g (0.40 mmol) of cuprous iodide and 0.168 g (0.24 mmol) of bis (triphenylphosphine) palladium dichloride complex are added and dropwise, a solution of 1.78 g ( 8 mmoles) of 4-prop-2-yn-1-ylpiperidin-1-ferrobutylcarboxylate, prepared in step 5.3. , in 3 μL of tetrahydrofuran. Stirring is maintained overnight. 25 μL of water and 1 00 mL of ethyl acetate are added. The organic phase is decanted, washed successively with 25 mL of 10% ammonia, 25 mL of water and mL of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The remainder was purified by chromatography on silica gel eluting with a 95/5 and 90/1 0 mixture of cyclohexane and ethyl acetate to obtain 2.15 g (6.44 mmol) of product as a yellow oil. 5.5 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidine 2.13 g (6.38 mmol) of 4- [3- (4-chlorophenyl) prop-2-in are dissolved. 1-yl] piperidin-1-fer-butylcarboxylate obtained in step 5.4. , in 15 mL of dichloromethane. A solution of 4.9 mL is added dropwise (63.8 mmol) of trifluoroacetic acid in 5 mL of dichloromethane. It is left to react overnight at room temperature and evaporated to dryness. 25 mL of dichloroethane are added and the mixture is again evaporated to dryness. The remainder is collected in a mixture of 70 μL of ethyl acetate, 10 mL of a 1 N aqueous solution of sodium hydroxide and 10 mL of 30% ammonia. The organic phase is decanted, washed twice with 10 mL of water and with 10 mL of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness to obtain 1.39 g (5.94 mmol). ) of product in the form of brown oil, which is used as it is in the next step. 5.6. 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidin-1-2-ethoxy-2-oxoethylcarboxylate A solution of 1.39 g is heated at 70 ° C for 5 hours. 5.94 mmol) of 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidine, prepared in step 5.5. and 1.86 g (8.33 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate in 1 mL of toluene. It is evaporated to dryness and the residue is purified by chromatography on silica gel eluting with a 90/10 mixture and 80/20 of cyclohexane and ethyl acetate to obtain 1.89 g (5.19 mmoles) of product in the form of a viscous oil. 5.7. 2- (Methylamino) -2-oxoethyl 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidin-1-carboxylate Dissolve 0.91 g (2.51 mmol) of 4- [3- (4-chlorophenyl) prop-2-yn-1-yl] piperidin-1-carboxylic acid 2-ethoxy-2-oxoethyl ester, prepared in step 5.6. in 4 μL of methanol. 2.5 M L (25 mmoles) of a 33% methylamine solution in ethanol are added and left overnight at room temperature. It is evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a mixture of 99.5 / 0.5, 98/2 and 96/4 of dichloromethane and methanol. It is crystallized from hexane and dried under vacuum to obtain 0.50 g (1.43 mmol) of product as a white powder. Melting Point (° C): 1 01 -1 03 LC / MS: M + H = 349 RM N-1 H (CDCl 3) d (ppm): 7.20 (m, 4H); 6.30 (m, 1 H); 4.50 (broad s, 2H); 4, 1 0 (broad d, 2H); 2.75 (m + d, 5H), 2.30 (d, 2H); 1, 85-1, 60 (m, 3H); 1, 35-1, 15 (m, 2H). Example 6 (compound No. 83) 4- [3- (4-chlorophen I) propi I] 2- (methylamino) -2-oxoethyl piperidin-1-carboxylate 0.158 g (0.448 mmol) of 4- (3- (4-chlorophenyl) prop-2-yn-1-yl] piperidin-1-2- (methylamino) -2-oxoethyl carboxylate, prepared following the procedure, are dissolved. example 5, in 2 μL of ethanol. 16 mg of platinum dioxide are added. It is stirred under hydrogen atmosphere at room temperature and pressure for 2 hours and at 40 ° C for 2 more hours. It is filtered over celite and the filtrate is evaporated. The remainder is purified by HPLC chromatography on Nucleosil gel eluting with a gradient from 70/30/0 to 0/80/20 hexane, ethyl acetate and methanol to obtain 0.108 mg (0.306 mmol) of product as a white solid. . Melting Point (° C): 118-120 LC-MS: M + H = 353 NMR-1H (CDCl 3) d (ppm): 7.25 (d, 2H); 7.10 (d, 2H); 6.05 (m, 1H); 4.60 (s, 2H); 4.10 (broad d, 2H); 2.90 (d, 3H); 2.80 (broad t, 2H); 2.60 (t, 2H); 1.75-1.55 (m, 4H); 1.45 (m, 1H); 1.35-1.05 (m, 4H). Example 7 (Compound No. 74) 4- (2-isoquinol i n-1 -i leti I) -1- (2-methylamino) -2-oxoethyl piperidinecarboxylate 7. 1,4- (Iodomethyl) -1-piperidinecarboxylic acid-butyl ester To a solution of 10 g (46.45 mmol) of 4- (hydroxymethyl) -1-piperidinecarboxylate of fer-butyl, of 15.84 g (60.38 mmol) ) of triphenylphosphine and 4.74 g (69.67 mmol) of imidazole in 200 ml of dichloromethane, cooled to about 0 ° C, 14.15 g (55.74 mmoles) of iodine are added in small fractions ( 12) maintaining the temperature of the reaction medium between 0 ° C and 5 ° C. Stirring is maintained at 0 ° C for 1 hour, and then at room temperature for 4 hours. 1 00 ml of water and 300 ml of ethyl acetate are added. The organic phase is decanted, washed successively with a saturated aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with a 90/10 mixture of cyclohexane and ethyl acetate. 1.70 g (42.1 mmol) of product are obtained in the form of a colorless oil. 7.2. 4- (2-Isoquinolin-1-ylethyl) -1-piperidinecarboxylate of fer-butyl To a solution of 2.202 g (1 5.38 mmol) of 1-methylisoquinoline in 150 ml of tetrahydrofuran, cooled to about -70 ° C , 10 ml (20 mmol) of a solution (2 M) of lithium diisopropylamide (LDA) in a mixture of tetrahydrofuran and n-hexane are added dropwise. Stirring is maintained at -70 ° C for 10 minutes and a solution of 5 g (15.38 mmol) of 4- (iodomethyl) -l-piperidinecarboxylate of fer-butyl obtained in step 7.1 is added slowly. , in 30 ml of tetrahydrofuran. After 30 minutes of stirring at -70 ° C, 1 00 ml of a saturated aqueous solution of ammonium chloride is added. Allow it to reach room temperature, separate the aqueous phase and extract 3 times with ethyl acetate. The organic phases are washed together with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with a 99/1 and 98/2 mixture of dichloromethane and methanol. 1.80 g (5.29 mmoles) of product are obtained in the form of a yellow oil. 7.3. (2-piperidin-4-ylethyl) -1-isoquinoline To a solution of 1.60 g (4.70 mmol) of 4- (2-isoquinolin-1-ylethyl) -1-piperidinecarboxylate of fer-butyl, obtained in stage 7.2. , in 1 5 ml of 1,4-dioxane, 3.90 ml (23.50 mmol) of a solution of hydrochloric acid (6 N) in isopropanol are added at room temperature. The reaction mixture is brought to approximately 60 ° C for 1 2 hours.

It is concentrated to dryness under reduced pressure. The hydrochloride obtained is taken up in 5 ml of water and a 20% aqueous solution of sodium hydroxide is added slowly with stirring until pH 9. The aqueous phase is extracted twice with chloroform, the organic phases are washed together with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. You get 0, 400 g (1.66 mmol) of product in the form of a brown oil. 7.4. 2- (2-ethoxy-2-oxoethyl) 4- (2-isoquinolin-1-ylethyl) -1-piperidinecarboxylate. A solution of 0.320 g (1.33 mmol) of (2-piperidine) is heated at 70 ° C for 18 hours. 4-ylethyl) -1-isoquinoline, obtained in step 7.3. and 0.388 g (1.73 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate in 10 ml of toluene. Allow it to reach room temperature, concentrate under reduced pressure and purify the residue obtained in this way by chromatography on silica gel eluting with a 40/60 mixture of ethyl acetate and cyclohexane. 0.390 g (1.05 mmol) of product are obtained in this manner in the form of a viscous oil. 7.5. 2- (Methylamino) -2-oxoethyl 2- (2-isoquinolin-1-ylethyl) -1-piperidinecarboxylate To a solution of 0.380 g (1.03 mmol) of 4- (2-isoquinolin-1-ylethyl) - 2-Ethoxy-2-oxoethyl 1-piperidinecarboxylate, prepared in step 7.4., In 10 ml of methanol, 2.60 ml (5.13 mmol) of a solution of methylamine (2 M) in tetrahydrofuran are added. Stirring is maintained at room temperature for 12 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel eluting with a 95/5 mixture of dichloromethane and methanol. A solid is obtained which is recrystallized from a mixture of ethyl acetate and diisopropyl ether. 0.315 g (0.88 mmol) of product are obtained in the form of a white solid in this manner. LC-MS: M + H = 356 Melting Point (° C): 126-128 NMR1H (CDCl 3) d (ppm): 8.50 (d, 1H); 8.15 (d, 1H); 7.90 (d, 1H); 7.70 (m, 2H); 7.55 (d, 1H); 6.10 (broad s, 1H); 4.60 (broad s, 2H); 4.20 (m, 2H); 3.35 (dd, 2H); 2.90 (m + d, 5H); 1.90 (m, 4H); 1.65 (m, 1H); 1.30 (m, 2H). The following table illustrates the chemical structures and physical properties of some compounds according to the invention. In this table: -all the compounds are in the form of a free base, -n-butyl represents a linear butyl group. Table 62. 4-CHs-phenyl (CH2): H H -CHr 117-119 63. 4-CHsO-phenyl (CH2): H H H 123-125 64. 4-CH 3 O-phenyl (CH 2) 2 H H -CH; 122-124 65. 2-phenyl-phenyl (CH2); H H -CHr (381) 66. 3-phenyl-phenyl (CH 2) 2 H H -CH; 113-115 67. Naphthalene-1-yl (CH2): H H -CH 112-114 68. naphthalene-2-yl (CH 2) 2 H H -CH; 106-108 69. pyrimidin-2-yl (CH 2) 2 H H -CH; 160-170 70. pyrimidin-5-yl (CH2): H H -CH; 123-125 71, 6-cyclopentyl- (CH 2), H H -CH; (374) The compounds of the invention have been the target of pharmacological tests that allow to determine their inhibitory effect on the FAAH (Fatty Acid amido Hydrolase) enzyme. The inhibitory activity has been demonstrated in a radioenzymatic assay based on the determination of the product of hydrolysis (ethanolamine [1 -3H]) of anandamide [ethanolamine 1 -3H] by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). Thus, mouse brains (minus the cerebellum) are removed and stored at -80 ° C. The membrane homogenates are prepared extemporaneously by homogenizing the tissues with a Polytron in a 10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. The enzymatic reaction is then carried out in 70 μl of buffer containing bovine serum albumin without fatty acids (1 mg / ml). Subsequently, the compounds tested in different concentrations were added, anandamide [ethanolamine 1 -3H] (specific activity 15-20 Ci / mmol) diluted to 1 μM with cold anandamide and the membrane preparation (400 μg of tissue frozen by test). After 15 minutes at 25 ° C, the enzymatic reaction is stopped by the addition of 140 μL of chloroform / methanol (2: 1). The mixture is stirred 10 minutes and centrifuged for 15 minutes at 3500g. An aliquot (30 μL) of the aqueous phase containing the ethanolamine [1 -3 H] is counted by liquid scintillation. Under these conditions, the most active compounds of the invention have values of Cl50 (concentration that inhibits 50% of the control enzymatic activity of the FAAH) comprised between 0.001 and 1 μM. For example, compounds No. 39 and 40 of the table have Cl50 of respectively 0.095 and 0.098 μM. It thus appears that the compounds according to the invention have an inhibitory activity on the FAAH enzyme. The in vivo activity of the compounds of the invention has been evaluated in an analgesic assay. Thus, the intraperitoneal (ip) administration of PBQ (phenylbenzoquinone, 2 mg / kg in a 0.9% sodium chloride solution containing 5% ethanol) to OF1 male rats from 25 to 30 g, causes abdominal stretches, Twists or contractions of average during the period of 5 to 1 5 minutes after the injection. The tested compounds are administered orally (p.o.) or intraperitoneally (i.p.) in suspension in 0.5% Tween 80, 60 minutes or 120 minutes before administration of PBQ. Under these conditions, the most potent compounds of the invention reduce from 35 to 70% the number of stretches induced by PBQ, in a dose range comprised between 1 and 30 mg / kg. For example, compound No. 57 of the table reduces 37% and 74% the number of stretches induced by PBQ, at the dose 3 mg / kg p.o. respectively at 60 minutes and 120 minutes. The FAAH enzyme (Chemistry and Physics of Lipids, (2000), 108, 1 07-121) catalyzes the hydrolysis of the endogenous derivatives of amides and esters of different fatty acids such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, α / - oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert different pharmacological activities interacting, among others, with the cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue rate of these endogenous substances. They can be used in this way in the prevention and treatment of pathologies in which the endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme are involved. For example, the following diseases and conditions can be mentioned: Pain, mainly acute or chronic pains of neurogenic type: migraine, neuropathic pain including the forms associated with the herpes virus and diabetes; Acute or chronic pains associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness, vomiting, nausea in particular those resulting from chemotherapy; eating behavior disorders in particular anorexia and cachexia of different natures; neurological and psychiatric pathologies: tremors, dyskinesias, dystonia, spasticity, compulsive and obsessive behaviors, Tourette syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychosis; Acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, H untington chorea, lesions linked to cerebral ischemia and cranial and spinal injuries; epilepsy; sleep disorders including sleep apneas; cardiovascular diseases in particular hypertension, cardiac arrhythmias, arteriosclerosis, cardiac crisis, cardiac ischemia; renal ischemia; cancers: benign skin tumors, papillomas and brain tumors, tumors of the prostate, brain tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependiomas, oligodendrogliomas, plexus tumor, neuroepitheliomas, tumor the epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas); disorders of the immune system, mainly autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connectivitis, Sjögren's syndrome, ankylosing spondylitis, undifferentiated spondylarthritis, Behçet's disease, autoimmune hemolytic anemias, plaque sclerosis, amyotrophic lateral sclerosis , amyloidosis, rejection of grafts, diseases that affect the plasmocitary line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; infectious parasitic, viral or bacterial diseases: AIDS, meningitis; inflammatory diseases, mainly joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome; osteoporosis; ocular conditions: ocular hypertension, glaucoma; pulmonary conditions: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema; gastro-intestinal diseases: irritable bowel syndrome, inflammatory bowel disorders, ulcers, diarrhea; urinary incontinence and bladder inflammation. The use of a compound of formula (I), in the form of a base, of salt, of hydrate or of solvate acceptable from a pharmaceutical point of view, for the preparation of a medicament intended to treat the pathologies mentioned above forms an integral part of the invention. The invention also relates to medicaments comprising a compound of formula (I), or a salt, or else a pharmaceutically acceptable hydrate or solvate of the compound of formula (I). These drugs find application in therapy, mainly in the treatment of the aforementioned pathologies. According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or a salt, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and optionally one or more pharmaceutically acceptable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, among 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, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of formula (I) above, or its optional salt, solvate or hydrate, can be administered in unit dosage form or mixed with conventional pharmaceutical excipients, animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned above. The appropriate unit dosage forms comprise the oral forms, such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms, and forms of rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions. By way of example, a unitary form of administration of a compound according to the invention in the tablet form can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223, 75 mg Croscarmellose sodium 6.0 mg Corn starch 15 , 0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Said unit forms are dosed to allow a daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the galenic form. There may be particular cases in which higher or lower doses are appropriate, said doses also belonging to the invention. According to the usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient. The invention according to another of its aspects, also refers to a method of treatment of the pathologies indicated above comprising the administration of an effective dose of a compound according to the invention, of one of its pharmaceutically acceptable salts, of a solvate or a hydrate of said compound.

Claims

CLAIMS 1. A compound that responds to the formula (I) (i) where m and n represent integers ranging from 1 to 3 so that m + n is an integer ranging from 2 to 5; p represents a whole number ranging from 1 to 7; A represents a single link or is chosen from one or more groups X, Y and / or Z; X represents a methylene group optionally substituted with one or two C 1 -C 6 -alkyl, C 3-7 cycloalkyl or C 3 -cycloalkyl-C 1 -3 alkylene; Y represents either a C 2 -alkenylene group optionally substituted with one or two C 1 -C 6 alkyl, C 3 7 cycloalkyl or C 3 7 cycloalkyl C 1-3 alkyl group; either an alkynylene-C2 group; Z represents a group of formula: or represents a whole number ranging from 1 to 5; r and s represent integers and are defined so that r + s is a number ranging from 1 to 5; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R 2 represents a hydrogen or fluorine atom, hydroxyl group, C 1 -C 6 alkoxy or N R 8 Rg; R3 represents a hydrogen atom or a C -6 alkyl group; R 4 represents a hydrogen atom or a C-6-alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkyl-C 1 -C 3 -alkyl group. R 5 represents a group chosen from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthalenyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, ndolinilo, indazolyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, pyrrolopyridinyl, furopyridinyl , thienopyridinyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl or isothiazolopyridinyl; R6 represents a halogen atom or cyano group, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, hydroxyl, C 1-6 thioalkyl, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy , fluorothioalkyl-C1 -6, NR8Rg, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CONR8R9, SO2R8, SO2NR8Rg, -O-alkylene-d. 3) -O or a cycle selected from the azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, piperazine cycles, this cycle optionally being substituted with a C-α-6-alkyl or benzyl group; R7 represents a phenyl, phenyloxy, benzyloxy, naphthalenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl group; the R7 group (s) having one or more R6 groups identical or different from one another may be substituted; R8 and R9 represent. independently of one another a hydrogen atom or an alkyl-C-α-6 group; in the form of a base, of addition salt with an acid, hydrate or solvate. 2. Compound of formula (I) according to claim 1, characterized in that: m and n represent integers equal to 1 or 2 so that m + n is an integer ranging from 2 to 4; p represents an integer equal to 1 to 3; A represents a single bond, a methylene or alkynylene-C2 group; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen atom or a hydroxyl group; R3 represents a hydrogen atom or a C1-6 alkyl group; R4 represents a hydrogen atom or a C3-7 cycloalkyl or C3-7 cycloalkyl-C-? -3 alkyl group; R5 represents a group chosen from phenyl, pyridinyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthalenyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl or pyrrolopyridinyl; R 6 represents a halogen atom or a cyano group, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 fluoroalkyl or a pyrrolidine or piperidine cycle, this cycle optionally being substituted with an alkyl group -Ci-ß ', R7 represents a phenyl group which may be substituted with one or more R6 groups identical or different from each other; in the form of a base, of addition salt with an acid, hydrate or solvate. Compound of formula (I) according to any of claims 1 or 2, characterized in that: m and n represent integers equal to 1 or 2 so that m + n is an integer ranging from 2 to 4; p represents an integer ranging from 1 to 3; A represents a single bond, a methylene or alkynylene-C2 group; R-i represents a group R5 optionally substituted with one or more groups R6 and / or R7; R2 represents a hydrogen atom or a hydroxyl group; R3 represents a hydrogen atom or a C1-C6 alkyl group; R represents a hydrogen atom or an alkyl-C? D, C3-7 cycloalkyl or C3-7-cycloalkyl-C1-3 alkyl group; R 5 represents a group selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, isoxazolyl, naphthalenyl or isoquinolinyl; R6 represents a halogen atom or a cyano group, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy, fluoroalkyl-C6-6 or a pyrrolidine or piperidine cycle, this cycle optionally being substituted with a group alkyl-C? -6; R7 represents a phenyl group which may be substituted with one or more R6 groups identical or different from one another. 4. Compound of formula (I) according to any of claims 1 to 3, characterized in that: R3 represents a hydrogen atom; R4 represents a hydrogen atom or a C1-C6 alkyl group; in the form of a base, of addition salt with an acid, hydrate or solvate. 5. Process for the preparation of a compound of formula (I) according to any of claims 1 to 4, comprising the step of transforming the carbamate ester of the general formula (IV) wherein R ^ A, R2, R3, p, m and n are as defined in formula (I) according to claim 1 and R represents a methyl or ethyl group, by aminolysis by an amine of general formula R4NH2 in the that R4 is as defined in formula (I) according to the claim

1 . 6. Compound that corresponds to the general formula (IV), wherein R-i, A, R2, R3, p, m and n are such as defined in formula (I) according to claim 1 and R represents a methyl or ethyl group. Pharmaceutical composition containing at least one compound of formula (I) according to any of claims 1 to 4, in the form of a base, salt, hydrate or solvate acceptable from a pharmaceutical point of view and optionally one or more excipients acceptable from a pharmaceutical point of view. 8. Compound of formula (I) according to any of claims 1 to 4, in the form of a base, salt, hydrate or solvate acceptable from a pharmaceutical point of view, for use as a medicine. 9. Use of a compound of formula (I) according to any one of claims 1 to 4, in pharmaceutically acceptable base, salt, hydrate or solvate form, for the preparation of a medicament intended for prevent or treat a pathology in which endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme are involved. 1 0. Use of a compound of formula (I) according to any of claims 1 to 4, in the form of a base, salt, hydrate or solvate acceptable from a pharmaceutical point of view, for the preparation of a medicament intended to prevent or treat acute or chronic pain, dizziness, vomiting, nausea, eating behavior disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, disorders of the immune system, allergic diseases, infectious parasitic, viral or bacterial diseases, inflammatory diseases, osteoporosis, ocular affections, pulmonary affections, gastro-intestinal diseases or urinary incontinence.