FR2955580A1 - New heterocyclic alkyl carbamate derivatives are fatty acid amide hydrolase inhibitors useful for treating or preventing e.g. nausea, eating disorders, renal ischemia, cancer, osteoporosis, senile dementia, lung diseases and dyskinesia - Google Patents

Abstract

Heterocyclic alkyl carbamate derivatives (I) and their base or acid addition salts are new. Heterocyclic alkyl carbamate derivatives of formula (I) and their base or acid addition salts are new. R2 : H, F, OH, CN, CF 3, 1-6C alkyl, 1-6C alkoxy or NR8R9; n, m : 1-3, provided that the sum of m and n is at most equal to 5; A : a covalent bond, O, 1-6C-alkylene or -O-1-6C-alkylene in which the end represented by an oxygen atom is related to the group R1; R1 : R5 group (optionally substituted by one or more R6 and/or R7 groups); R5 : phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzoxadiazolyl, indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, triazolopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrrolotriazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, furopyridazinyl, furotriazinyl, oxazolopyridinyl, oxazolopyrimidinyl, oxazolopyrazinyl, oxazolopyridazinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyrazinyl, isoxazolopyridazinyl, oxadiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyle, thienotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, isothiazolopyridinyl, isothiazolopyrimidinyl, isothiazolopyrazinyl, isothiazolopyridazinyl or thiadiazolopyridinyl; R6 : halo, CN, -CH 2CN, nitro, OH, 1-8C alkyl, 1-6C alkoxy, 1-6C thioalkyl, 1-6C haloalkyl, 1-6C haloalkoxy, 1-6C halothioalkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C alkylene, 3-7C cycloalkyl-1-3C-alkylene-O-, -(CH 2) p-NR8R9, -NR8COR9, -NR8CO 2R9, -NR8SO 2R9, -NR8SO 2NR8R9, -COR8, -CO 2R8, -(CH 2) p-CONR8R9, -SO 2R8, -SO 2NR8R9 or -O-(1-3C-alkylene)-O-; R7 : phenyl, phenyl-1-4C-alkylene, phenyl-(CH 2) p-O-, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadazolyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl or thiazolopyridinyl (all optionally substituted by one or more R6); p : 0-3; R3 : F, H, 1-6C alkyl or CF 3; R4 : 5-membered heterocyclic ring (comprising furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl or tetrazolyl), which is optionally substituted by one or more halo, 1-6C alkyl, 1-6C haloalkyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-3C-alkylene, 1-6C-haloalkoxy, CN, -NR8R9, -NR8C(O)R9, -NR8CO 2R9, NR8SO 2R9-, -NR8SO 2NR8R9, -C(O)R8, -CO 2R8, C(O)NR8R9, -C(O)N(R8)(1-3C-alkylene-NR10R11), -SO 2R8, SO 2NR8R9, or -O-(1-3C-alkylene)-O-; either R8, R9 : H or 1-6C-alkyl; or NR8R9 : azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, azepine, or oxazepine (all optionally substituted by 1-6C-alkyl or benzyl); or NR8COR9 : lactam ring; or NR8CO 2R9 : oxazolidinone, oxazinone or oxazepinone ring; or NR8SO 2R9 : sultam ring; or NR8SO 2NR8R9 : thiazolidine dioxide or thiadiazinane dioxide; and R10, R11 : H or 1-6C alkyl. Provided that (I) excludes: 4-hydroxy-4-(4-chloro-phenyl)-piperidine-1-carboxylate of 5-methyl-isoxazol-3-ylmethyl. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Analgesic; Antiemetic; Eating-Disorders-Gen.; Neuroprotective; Neuroleptic; Anticonvulsant; Hypnotic; Cardiovascular-Gen.; Nephrotropic; Vasotropic; Cytostatic; Antiallergic; Antiparasitic; Virucide; Antibacterial; Antiinflammatory; Osteopathic; Ophthalmological; Respiratory-Gen.; Gastrointestinal-Gen.; Uropathic; Antimigraine; Antiparkinsonian; Nootropic; Antipsoriatic; Antiarthritic; Antirheumatic; Immunosuppressive; Antianemic.Muscular-Gen.; Muscle relaxant; Tranquilizer. MECHANISM OF ACTION : Fatty acid amide hydrolase (FAAH) inhibitor. The ability of (I) to inhibit FAAH was tested in mouse brains using radioenzymatic test. The result showed that (+)-(S)-3-(naphthalen-2-yloxymethyl)-pyrrolidine-1-carboxylate of 3-carbamoyl-isoxazol-5-ylmethyl exhibited an IC 50value of 8 nM.

Description

1 Derivatives of alkyl-heterocycle carbamates, their preparation and their therapeutic application

The subject of the invention is derivatives of alkyl-5-heterocycle carbamates, their preparation and their therapeutic application. There is still a need to find and develop products that inhibit the enzyme FAAH (Fatty Acid Amide Hydrolase). The compounds of the invention fulfill this purpose. In addition, these compounds must have metabolic, pharmacokinetic and safety index properties for their use as drugs. The compounds of the invention correspond to the general formula (I): (I)

wherein: R2 is hydrogen, fluorine or hydroxyl, cyano, trifluoromethyl, C1-alkyl, C1-alkoxy, NR8R9; n and m represent, independently of one another, an integer equal to 1, 2 or 3, it being understood that the sum of m + n is at most equal to 5; A represents a covalent bond, an oxygen atom, a C2-6 alkylene group or a -O-C1-6-alkylene group in which the end represented by an oxygen atom is bonded to the R1 group; R1 represents a group R5 optionally substituted with 2 or more R6 and / or R7 groups; R5 representing a group selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzoxadiazolyl, indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyle, imidazopyridazinyl, triazolopyridinyl, pyrrolopyridinyl pyrrolopyrimidinyl, pyrrolopyrazinyle, pyrrolopyridazinyle, pyrrolotriazinyle, pyrazolopyridinyle, pyrazolopyrimidinyl, pyrazolopyrazinyle, pyrazolopyridazinyle, furopyridinyl, furopyrimidinyle, furopyrazinyle, furopyridazinyle, furotriazinyle , oxazolopyridinyl, oxazolopyrimidinyl, oxazolopyrazinyl, oxazolopyridazinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyrazinyl, isoxazolopyridazinyl, ox adiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thienotriazinyl, triazolopyridinyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, isothiazolopyridinyl, isothiazolopyrimidinyl, isothiazolopyrazinyl, isothiazolopyridazinyl, thiadiazolopyridinyl; R6 represents a halogen atom, a cyano group, CH2CN, nitro, hydroxyl, C1-8-alkyl, C1-6-alkoxy, C1-6 thioalkyl, C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1_3; -alkylene, C 3-7 -cycloalkyl-C 1-3 alkylene-O-, - (CH 2) p -NR 8 R 9 - NR 8 COR 9, -NR 8 CO 2 R 9, -NR 8 SO 2 R 9, -NR 8 SO 2 NR 8 R 9, -COR 8, -CO 2 R 8, - (CH 2) p-CONR 8 R 9 -SO 2 R 8, SO2NR8R9 or -O- (C1-3alkylene) -O-; Wherein R 7 is selected from phenyl, 3-phenyl-C 1-4 -alkylene-, phenyl- (CH 2) p -O-, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl; , tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadazolyle, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, pyrazolopyridinyle, oxazolopyridinyl, isoxazolopyridinyle, thiazolopyridinyl ; the group or groups R7 may be substituted by one or more groups R6 identical to or different from each other; p representing a number that can have the value 0, 1, 2 or 3; - R3 represents a hydrogen atom, fluorine, a C1-6-alkyl group or a trifluoromethyl group; - R4 represents a 5-chain heterocycle selected from furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl, tetrazolyl; this heterocycle being optionally substituted by one or more substituents chosen from a halogen atom, a C1_6-alkyl, C1-6-haloalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1_3-alkylene, C1_6-haloalkoxy, cyano, -NR8R9r-NRBC group; (0) R9, -NR8CO2R9, -NR8SO2R9, -NR8SO2NR8R9, -C (O) R8, -CO2R8, -C (O) NR8R9r -C (O) N (R8) (C1-3alkylene-NR1oR1), -SO2R8r -SO2NR8R9 0- (C1-3alkylene) -O-; R8 and R9 independently of one another represent a hydrogen atom or a C1_6-alkyl group, or forming with the nitrogen atom (s) thereof, in the case of NR8R9r a ring selected from azetidine rings; pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine, this ring being optionally substituted by a C 2-6 alkyl or benzyl group; in the case of NR8COR9r a lactam ring; in the case of NR8CO2R9r, an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR8SO2R9r a sultame cycle; in the case of NR8SO2NR8R9r a thiazolidine dioxide or thiadiazinane dioxide ring; R10 and Rn independently of one another represent a hydrogen atom or a C2-6alkyl group; excluding the following compound: 5-methyl-isoxazol-3-ylmethyl 4-hydroxy-4- (4-chloro-phenyl) -piperidine-1-carboxylate.

Among the compounds of general formula (I), a first subgroup of compounds is composed of compounds for which R 2 represents a hydrogen atom.

Among the compounds of general formula (I), a second subgroup of compounds is composed of compounds for which m and n represent, independently of each other, the value 1 or 2.

Among the compounds of general formula (I), a third subgroup of compounds is composed of compounds for which m and n each represent the value 2.

Among the compounds of general formula (I), a fourth subgroup of compounds is composed of compounds for which A represents a group -O-C1-alkylene in which the end represented by an oxygen atom is linked to the RI group. , in particular a -O- (CH 2) 2 group, also called ethylenoxy.

Among the compounds of general formula (I), a fifth subgroup of compounds is composed of compounds for which A represents a group -O-C16-alkylene in which the end represented by an oxygen atom is bonded to the group RI, in particular a -O-CH2- group, also called methyleneoxy.

Among the compounds of general formula (I), a sixth subgroup of compounds is composed of compounds for which R 1 represents a group R 5 optionally substituted with one or more R 6 and / or R 7 groups; R5 representing a group selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl, benzothiophenyl; indazolyl, indolizinyl, indolyl, isoindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl; R 6 represents a halogen atom, a cyano group, CH 2 CN, nitro, hydroxyl, C 1-8 alkyl, C 1-6 alkoxy, C 1-6 -thioalkyl, C 1-6 -haloalkyl, C 1-6 -haloalkoxy, C 1-6 -halothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl- C1-3alkylene, C3-7cycloalkyl-C1-3alkylene-O-, - (CH2) p -NR8R9r -NR8COR9, -NR8CO2R9, -NR8SO2R9, -NR8SO2NR8R9, -COR8, -CO2R8, (CH2) p-CONR8R9r -SO2R8, - SO2NR8R9 or -O- (C1-3alkylene) -O-; R7 represents a group selected from phenyl, phenyl-C1-4alkylene-, phenyl- (CH2) p-O-, pyridinyl, pyridazinyl, isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyrimidinyl, thiazolyl, pyrazinyl, triazinyl, benzoxazolyl; the group or groups R7 may be substituted by one or more groups R6 6 identical to or different from each other as defined above; p representing a number that can have the value 0, 1, 2 or 3; R 8 and R 9 independently of one another represent a hydrogen atom or a C 1-6 -alkyl group or, together with the nitrogen atom (s) carrying them in the case of NR 8 R 9, form a ring selected from the group consisting of azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine rings, this ring being optionally substituted by a C1-6 alkyl or benzyl group; in the case of NR8COR9r a lactam ring; in the case of NR8CO2R9r, an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR8SO2R9r a sultame cycle; in the case of NR8SO2NR8R9r a thiazolidine dioxide or thiadiazinane dioxide ring.

Among the compounds of general formula (I), a seventh subgroup of compounds is composed of compounds for which R 1 represents a group R 5 optionally substituted by one or more R 6 and / or R 7 groups; R5 representing a group selected from phenyl, benzothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl; R6 represents a halogen atom, a cyano group, CH2CN, nitro, hydroxyl, C1-8alkyl, C1-6alkoxy, C1_thioalkyl, C1_6-haloalkyl, C1_6-haloalkoxy, C1-6-halothioalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1_3; Alkylene, C 3-7 -cycloalkyl-C 1-3 alkylene-O-, - (CH 2) p -NR 8 R 9 7 - NR 8 CORR 9 -NR 8 CO 2 R 9, -NR 8 SO 2 R 9, -NR 8 SO 2 NR 8 R 9, -COR, -CO 2 R 8, - (CH 2) p -CONR 8 R 9, O -SO 2 R 8 -SO2NR8R9 or -O- (C1-3alkylene) -O-; R7 represents a group selected from phenyl, phenyl-C1-4alkylene-, phenyl- (CH2) p -O-, pyridinyl, pyridazinyl, isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyrimidinyl, thiazolyl, pyrazinyl, triazinyl, benzoxazolyl; the group or groups R7 may be substituted by one or more groups R6 identical to or different from each other; p representing a number that can have the value 0, 1, 2 or 3; R8 and R9 represent, independently of one another, a hydrogen atom or a C1-C6 alkyl group, or form, with the nitrogen atom which, in the case of NR8R9, carries them, a ring chosen from the azetidine, pyrrolidine rings; piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine, this ring being optionally substituted by a C1_6-alkyl or benzyl group; in the case of NR8COR9r a lactam ring; in the case of NR8CO2R9r, an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR8SO2R9r a sultame cycle; in the case of NR8SO2NR8R9r a thiazolidine dioxide or thiadiazinane dioxide ring.

Among the compounds of general formula (I), an eighth subgroup of compounds is compounds for which R 1 represents a group selected from phenyl, benzothiazolyl, naphthalenyl, quinolinyl, isoquinolinyl, indolyl, optionally substituted by one or more groups R6 and / or R7; Wherein R6 is halogen, cyano, C1-8alkyl, C1-6alkoxy, C1-6alkyl, C1-6alkyloxy, C3-7cycloalkyl, - (CH2) p -NR8R9r -NR8COR9, -CO2R8, - (CH2) ) p-CONR8R9r ° SO2R8r-SO2NR8R9; R7 represents a group selected from phenyl, phenyl-C1-4alkylene-, phenyl- (CH2) p -O-, isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl, benzoxazolyl; the group or groups R7 may be substituted by one or more groups R6 identical to or different from each other, as defined above; p represents a number which can have the value 0 or 1 R8 and R9 represent, independently of one another, a hydrogen atom, a C1-6-alkyl group; or R8 and R9 forming with the nitrogen atom which carries them in the case of -NR8R9r a morpholine ring; in the case of -NR8COR9r a lactam ring.

Among the compounds of general formula (I), a ninth subgroup of compounds is composed of compounds for which R3 represents a hydrogen atom.

Among the compounds of general formula (I), a tenth subgroup of compounds is composed of compounds for which R 4 represents a 5-membered heterocycle selected from pyrazolyl, imidazolyl, thiazolyl, isothiazole, oxazolyl, isoxazolyl; this heterocycle being optionally substituted by one or more substituents -C (O) NR8R9 in which R8 and R9 each represent a hydrogen atom.

Among the compounds of general formula (I), an eleventh subgroup of compounds is composed of compounds for which R 4 represents a 5-membered heterocycle chosen from a thiazolyl or isoxazolyl; this heterocycle being optionally substituted by one or more substituents -C (O) NR8R9 in which R8 and R9 each represent a hydrogen atom.

Among the compounds of general formula (I), there may be mentioned a twelfth subgroup represented by the compounds of formula (Ii): ## STR1 ## wherein R 1, A, R 4, n and m are as defined above.

Other subgroups consisting of compounds of formula (Ii) are also part of the present invention.

Thus, among the compounds of the abovementioned general formula (Ii), a subgroup of compounds is composed of the compounds for which A represents a group -O- (CH 2) 2- •

Among the compounds of general formula (Ii) mentioned above, a subgroup of compounds is composed of compounds for which A represents a -O-CH 2 - group.

Among the compounds of general formula (I), there may be mentioned a thirteenth subgroup represented by the compounds of formula (Iii): embedded image in which R 1, A, n and m are as defined above.

Other subgroups consisting of the compounds of formula (Iii) are also part of the present invention.

Thus, among the compounds of the abovementioned general formula (III), a subgroup of compounds is composed of the compounds for which A represents a group -O- (CH 2) 2- • Thus, among the compounds of the aforementioned general formula (Iii) a subgroup of compounds are compounds for which A is -O-CH2-.

Among the compounds of general formula (I), a fourteenth subgroup consists of compounds of general formula (I) in which: R2 represents a hydrogen atom; m and n independently of one another are 1 or 2; A represents a group -O-CI-6-alkylene in which the end represented by an oxygen atom is bonded to the RI group, in particular an ethylenoxy or methylenoxy group; R1 represents a group selected from phenyl, benzothiazolyl, naphthalenyl, quinolinyl, isoquinolinyl, indolyl, optionally substituted with one or more R6 and / or R7 groups; R6 represents: - a halogen atom, especially a chlorine, fluorine, bromine; a cyano group; C2-2alkyl, especially methyl, isopropyl, 1,1,3,3-tetramethylbutyl, tert-butyl; C1-alkoxy, especially methoxy, hexyloxy, butoxy, ethoxy; C1-6-haloalkyl, especially trifluoromethyl, pentafluoroethyl; C1-C6-haloalkoxy, especially trifluoromethoxy, difluoromethoxy; C 3-7 -cycloalkyl, especially cyclopentyl; a group - (CH2) p -NR8R9r in which p is 0 or 1; R8 and R9 each represent a hydrogen atom or R8 and R9 each represent a methyl, or R8 and R9 together with the nitrogen atom carrying them a morpholine ring; a group -NR8COR9r in which R8 represents a hydrogen atom and R9 represents a methyl, or else R8 and R9 form with the nitrogen atom which carries them a lactam ring, in particular 5-lactam; a group -CO2R8r wherein R8 is methyl; a group - (CH2) p-CONR8R9r in which p is 0 or 1; R8 and R9 each represent a hydrogen atom; a group -SO2R8r in which R8 represents a methyl; a group -SO 2 NR 8 R 9 in which R 8 and R 9 each represent a hydrogen atom; R7 represents a group selected from a phenyl group; phenyl-C 1-4 -alkylene, especially 1,1-dimethyl-1-phenylmethylene, benzyl; a phenyl- (CH 2) p -O- group in which p is 0 or 1; isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl, thiazolyl, benzoxazolyl; the group or groups R7 may be substituted by one or more groups R6 identical to or different from each other, as defined above, such as a halogen atom, a cyano group. R 3 represents a hydrogen atom R 4 represents a 5-membered heterocycle selected from thiazolyl, isoxazolyl; this heterocycle being optionally substituted by one or more substituents -C (O) NR8R9 in which R8 and R9 each represent a hydrogen atom.

Among the compounds of general formula (I), a fifteenth subgroup of compounds is constituted by the compounds of general formula (I) in which both R1 and / or R2 and / or R3 and / or R4 and / or n and / or m and / or A are as defined in the subgroups above.

Among the compounds of general formula (I), the following compounds may be mentioned (IUPAC nomenclature generated by AutoNom software): 1,4- [2- (4-Chloro-naphthalen-1-yloxy) -ethyl] -piperidine-1-carboxylate Thiazol-2-ylmethyl 2. 4- [2- (4-Fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate thiazol-2-ylmethyl 3. 4- [2- (4-Fluoro-phenoxy) Thiazol-4-ylmethyl 4,4-thiazol-4-ylmethyl 4-thiazol-4-ylmethyl] -4- [2- (4-trifluoromethyl-phenoxy) -ethyl] -piperidine-1-carboxylic acid-1-carboxylate. Thiazol-4-ylmethyl 2- (4-chloro-phenoxy) -ethyl] -piperidine-1-carboxylate 6. Thiazol-4- [2- (4-fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate 5-ylmethyl 4- [2- (4-Chloro-phenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-5-ylmethyl 8. 4- [2- (4-Trifluoromethyl-phenoxy) -ethyl] Thiazol-5-ylmethyl-piperidine-1-carboxylate 13 9. Thiazol-4-ylmethyl 4- [2- (7-methoxy-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate [2- (4-Cyano-ph thiazol-4-ylmethyl 11 (+/-) - (6-Methoxy-Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylate thiazol-4-ylmethyl enoxy) -ethyl] -piperidine-1-carboxylate 12 Thiazol-4-ylmethyl (+/-) - 3- (3,4-dichlorophenoxymethyl) (+/-) -3- (7-methoxy-naphthalen-2-yloxymethyl) pyrrolidine-1-carboxylate ) Thiazol-4-ylmethyl pyrrolidine-1-carboxylate 14. Thiazol-4-ylmethyl 4- [2- (6-methoxy-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 15. 4- [(+/-) -3- (4-Chloro-Naphthalen-1-yloxymethyl) pyrrolidine-1 [2- (naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylic acid thiazol-4-ylmethyl ester Thiazol-4-ylmethyl carboxylate 17. (+/-) - 3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid thiazol-4-ylmethyl 18. 4- [2- (4'-Fluoro- thiazol-4-ylmethyl biphenyl-4-yloxy) -ethyl] -piperidine-1-carboxylate 19. Thiazol-4-ylmethyl 4- [2- (quinolin-6-yloxy) -ethyl] -piperidine-1-carboxylate and its hydrochloride 20. 4- [2- (Isoquinolin-6-yloxy) -ethyl] -piperid thiazol-4-ylmethyl ine-1carboxylate and its thiazol-4-ylmethyl 21 (+/-) -3- (3'-cyano-biphenyl-3-yloxymethyl) pyrrolidine-1-carboxylate hydrochloride (+ Thiazol-4-ylmethyl (-) -3- (4'-fluoro-biphenyl-4-yloxymethyl) pyrrolidine-1-carboxylate 23. (+/-) -3- (5-Chloro-Naphthalen-2-yloxymethyl) ) thiazol-4-ylmethyl 4- (3-trifluoromethoxy-phenoxymethyl) -pyrrolidine-1-carboxylate thiazol-4-ylmethyl thiazol-4-ylmethyl pyrrolidine-1-carboxylate 1. (+/-) Thiazol-4-ylmethyl 26 (+/-) - 3- (Quinolin-3-yloxymethyl) -3- [4- (1-methyl-1-phenyl-ethyl) -phenoxymethyl] -pyrrolidine-1-carboxylate thiazol-4-ylmethyl thiazol-4-ylmethyl pyrrolidine-1-carboxylate 27. (+/-) - 3- (Isoquinolin-6-yloxymethyl) -pyrrolidine-1-thiazol-4-ylmethylcarboxylate 28. (+/-) - 3- (Quinolin) Thiazol-4-ylmethyl 29 (+/-) - 3- (Isoquinolin-7-yloxymethyl) -pyrrolidine-4-ylmethyl thiazol-4-ylmethyl-7-yloxymethyl) pyrrolidine-1-carboxylate (+/- ) -3- (4-Chloro-3-trifluoromethyl-phenoxymethyl) Thiazol-4-ylmethyl 31 (+/-) -3- (5-fluoro-naphthalen-2-yloxymethyl) pyrrolidine-1-carboxylate thiazol-4-ylmethyl pyrrolidine-1-carboxylic acid-1-pyrrolidine-4-ylmethyl. 2- (2,4-Dimethylphenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl 33. 4- [2- (2,3-Dichloro-phenoxy) -ethyl] -piperidine-1- Thiazol-2-ylmethyl carboxylate 34. Thiazol-2-ylmethyl 4- [2- (2,4-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 35. 4- [2- (2,5- Thiazol-2-ylmethyl thiazol-2-ylmethyl dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 36. Thiazol-2-ylmethyl 4- [2- (3,4-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 37. Thiazol-2-ylmethyl 4- [2- (3,5-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 38. 4- [2- (4-Cyclopentyl-phenoxy) -ethyl] -piperidine Thiazol-2-ylmethyl carboxylate 39. Thiazol-2-ylmethyl 4- [2- (2-benzoazazol-2-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 40. 4- [2 - (4-Benzyloxy-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl 41. 4- [2- (4-C) Thiazol-2-ylmethyl 4- [2- (quinolin-7-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-2-ylmethyl arbamoylmethylphenoxy) ethyl] -piperidine-1-carboxylate and its trifluoroacetate 43. Thiazol-2-ylmethyl 4- [2- (quinolin-6-yloxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 44. 4- [2- (4-Cyano-3-fluoro-phenoxy) ) Thiazol-2-ylmethyl 45-thiazol-2-ylmethyl] -piperidine-1-carboxylate 45. Thiazol-2-ylmethyl 45. 4- [2- (biphenyl-2-yloxy) -ethyl] -piperidine-1-carboxylate 46. 4- [ 2- (2-Isopropyl-5-methyl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl ester 47. 4- [2- (3-Trifluoromethyl-phenoxy) -ethyl] -piperidine-1-one Thiazol-2-ylmethyl carboxylate 48. Thiazol-2-ylmethyl 49 {4- [2- [4- (1,1,3,3-tetramethyl-butyl) -phenoxy] -ethyl} -piperidine-1-carboxylate 49. 4- [2- (4-Benzyl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl ester 50. 4- [2- (4-Pyrrol-1-yl-phenoxy) -ethyl] -piperidine Thiazol-2-ylmethyl carboxylate and its trifluoroacetate 51. 4- [2- (4-Carbamoyl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl ester 52. 4- [2- (3-Cyano-phenoxy) -ethyl] -piperidine- 1- Thiazol-2-ylmethyl carboxylate 53. Thiazol-2-ylmethyl 54 [4- [2- (3,5-di-tert-butyl-phenoxy) -ethyl] -piperidine-1-carboxylate. 2- [2- (2-Benzyl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl ester 55. 4- [2- (8-Acetylamino-naphthalen-2-yloxy) -ethyl] -piperidine-1-one Thiazol-2-ylmethyl carboxylate 56. Thiazol-2-ylmethyl 57- [2- (3-methoxycarbonyl-Naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 57. 4- [2- (3- Phenoxy-phenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-2-ylmethyl 58. Thiazol-2-ylmethyl 4- [2- (Isoquinolin-7-yloxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 59. Thiazol-2-ylmethyl 60- [2- (3-butoxy-phenoxy) -ethyl] -piperidine-4- [2- (4-Hexyloxy-phenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-2-ylmethyl 1-carboxylate 61. 4- [2- (Quinolin-5-yloxy) -ethyl] -piperidine thiazol-2-ylmethyl-ridin-1-carboxylate and its trifluoroacetate 62. Thiazol-2-ylmethyl 4- [2- (3-pentafluoroethyl-phenoxy) -ethyl] -piperidine-1-carboxylate 63. 4- [2- Thiazol-2-ylmethyl (5-acetylamino-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 64. 4- [2- (5-Bromo-2-chloro-phenoxy) -ethyl] -piperidine- Thiazol-2-ylmethyl 1-carboxylate 65. Thiazol-2-ylmethyl 4- [2- (2-methyl-quinolin-6-yloxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 17 66. 4- Thiazol-2-ylmethyl [2- (4'-cyano-biphenyl-3-yloxy) -ethyl] -piperidine-1-carboxylate 67. 4- [2- (6-Cyano-Naphthalen-2-yloxy) -ethyl) Thiazol-2-ylmethyl 68-thiazol-2-ylmethyl] -piperidine-1-carboxylate 68. Thiazol-2-ylmethyl 69 [4- (2- (4-thiazol-2-yl-phenoxy) -ethyl] -piperidine-1-carboxylate. Thiazol-2-ylmethyl [2- (biphenyl-3-yloxy) -ethyl] -piperidine-1-carboxylate 70. Thiazol 4- [2- (biphenyl-4-yloxy) ethyl] -piperidine-1-carboxylate -2-ylmethyl 71. 4- [2- (2-Cyano-quinolin-8-yloxy) -ethyl] -piper thiazol-2-ylmethyl eridine-1-carboxylate and its trifluoroacetate 72. Thiazol-2-ylmethyl 4- [2- (4-chloro-2-cyano-phenoxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 73. Thiazol-2-ylmethyl 4- [2- (2-methyl-benzothiazol-5-yloxy) -ethyl] -piperidine-1-carboxylate 74. 4- [2- (4'-Cyano-biphenyl) -4- thiazol-2-ylmethyl yloxy) -ethyl] -piperidine-1-carboxylate 75. Thiazol-2-ylmethyl 4- [2- (2-morpholin-4-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 76. 4- [2- (4-Chloro-2-isoxazol-5-yl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-2-ylmethyl ester 77. 4- [2- (2,4-Dimethyl) Phenoxy) -ethyl] -piperidine-1-carboxylic acid Thiazol-4-ylmethyl 78. Thiazol-4-ylmethyl 4- [2- (2,3-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 79 Thiazol-4-ylmethyl 4- [2- (naphthalen-1-yloxy) -ethyl] -piperidine-1-carboxylate 80. 4- [2- (3-Dimethylamino-phenoxy) -ethyl] -piperidine-1 thiazol-4-ylmethyl carboxylate and its trifluoroacetate 81. 4- [2- (3-Tr thiazol-4-ylmethyl trifluoromethyl-phenoxy) -ethyl] -piperidine-1-carboxylate 82. Thiazol-4-ylmethyl 4- [2- (4-benzyl-phenoxy) -ethyl] -piperidine-1-carboxylate 83. 4- [2- (2-Ethoxy-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-4-ylmethyl ester 84. 4- {2- [4- (1-Methyl-1-phenyl-ethyl) -phenoxy) thiazol-4-ylmethyl] -ethyl] -piperidine-1-carboxylate 85. Thiazol-4-ylmethyl 4- [2- (4-phenoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 2- (2-Bromo-4-fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl 87. 4- [2- (2-Benzyl-phenoxy) -ethyl] -piperidine-1- thiazol-4-ylmethyl carboxylate 88. Thiazol-4-ylmethyl 89. 4- [2- (4-hexyloxyphenoxy) 4- [2- (3-phenoxyphenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-4-ylmethyl-thiazol-4-ylmethyl ethyl-piperidine-1-carboxylate 90. Thiazol-4-ylmethyl 91- [2- (3-butoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 91. 4- [2 Thiazol (4-chloro-5-isopropyl-2-methyl-phenoxy) -ethyl] -piperidine-1-carboxylate 4-ylmethyl 92. Thiazol-4-ylmethyl 4- [2- (3-pentafluoroethyl-phenoxy) -ethyl] -piperidine-1-carboxylate 93. 4- [2- (5-Acetylamino-naphthalen-2-yloxy)) Thiazol-4-ylmethyl-ethyl] -piperidine-1-carboxylate 94. Thiazol-4-ylmethyl 4- [2- (5-bromo-2-chloro-phenoxy) -ethyl] -piperidine-1-carboxylate 95 Thiazol-4-ylmethyl 4- [2- (4'-cyano-biphenyl-3-yloxy) -ethyl] -piperidine-1-carboxylate 96. 4- [2- (6-Cyano-naphthalen-2-yloxy) ) thiazol-4-ylmethyl 97-thiazol-4-ylmethyl 4-thiazol-4-ylmethyl] -piperidine-1-carboxylate 97. Thiazol-4-ylmethyl 4- [2- (4-Thiazol-2-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 98 4- [2- (Biphenyl-3-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl 99. 4- [2- (Biphenyl-4-yloxy) -ethyl] -piperidine-1- thiazol-4-ylmethyl carboxylate 100. 4- [2- (4-Chloro-2-cyano-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-4-ylmethyl ester 101. 4- [2- (2- Thiazol-4-ylmethyl methyl-benzothiazol-5-yloxy) -ethyl] -piperidine-1-carboxylate 102. 4- [2- (4'-Cyano-biphenyl) Thiazol-4-ylmethyl 4-yloxy) -ethyl] -piperidine-1-carboxylate 103. Thiazol-4 4- [2- (2-Morpholin-4-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 4-Methylmethyl and its trifluoroacetate 104. 4- [2- (4-Chloro-2-isoxazol-5-yl-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-4-ylmethyl ester 105. 4- [2- ( Thiazol-2-ylmethyl 4-dimethylaminomethyl-phenoxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 106. Thiazol-4- [2- (naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 2-ylmethyl 107. Thiazol-2-ylmethyl 4- [2- (naphthalen-1-yloxy) -ethyl] -piperidine-1-carboxylate 108. 4- [2- (7-Methoxy-naphthalen-2-yloxy) Thiazol-2-ylmethyl) -ethyl] -piperidine-1-carboxylate 109. Thiazol-4-ylmethyl 4- [2- (2-Cyclopentyl-phenoxy) -ethyl] -piperidine-1-carboxylate 110. 4- [ Thiazol-4-ylmethyl 2- (2-benzyloxy-phenoxy) -ethyl] -piperidine-1-carboxylate 111. Thiazol-4- [2- (Isoquinolin-7-yloxy) -ethyl] -piperidine-1-carboxylate 4-ylmethyl and its trifluoroac ethanol 112. 4- [2- (Quinolin-5-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl and its trifluoroacetate 113. 4- [2- (2-Methyl-quinolin-6-yloxy) Thiazol-4-ylmethyl) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 114. 4- [2- (2-Cyano-quinolin-8-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-4 1-methylmethyl and its trifluoroacetate 115. 4- [2- (2,4-Dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl 116. 4- [2- (4-Cyclopentylphenoxy) Thiazol-4-ylmethyl ethyl-1-piperidine-1-carboxylate 117. Thiazol-4-ylmethyl 4- [2- (2-benzoazazol-2-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 118. Thiazol-4-ylmethyl 4- [2- (4-cyano-3-fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate 119. 4- {2- [4- (1,1,3,3- Thiazol-4-ylmethyl 120 tetramethyl-butyl) -phenoxy] -ethyl} -piperidine-1-carboxylate 120. 4- [2- (4-Pyrrol-1-yl-phenoxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl and its trifluoroacetate 21 121. 4- [2- (3,5-Di-tert) Thiazol-4-ylmethyl 122. 4- [2- (4-dimethylaminomethyl-phenoxy) -ethyl] -piperidine-1-carboxylate thiazol-4-ylmethyl 4-butyl-phenoxy) -ethyl] -piperidine-1-carboxylate and its thiazol-4-ylmethyl 4- [2- (2-methyl-quinolin-8-yloxy) -ethyl] -piperidine-1-carboxylate trifluoroacetate and its trifluoroacetate 124. 4- [2- (3-Cyano- thiazol-5-ylmethyl 125. 4- (2-Phenoxy-ethyl) -piperidine-1-carboxylate thiazol-4-ylmethyl phenoxy) -ethyl] -piperidine-1-carboxylate 126. 4- [2- (Biphenyl) -2- Thiazol-5-ylmethyl 4-yloxy) -ethyl] -piperidine-1-carboxylate 127. Thiazol-5-ylmethyl 4- [2- (4-carbamoyl-phenoxy) -ethyl] -piperidine-1-carboxylate 128. Thiazol-5-ylmethyl 4- [2- (4-fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate 129. 4- [2- (2,4-Dimethyl-phenoxy) -ethyl] -piperidine-1 Thiazol-5-ylmethyl carboxylate 130. Thiazol-5-ylmethyl 4- [2- (4-dimethylaminomethyl-phenoxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 131. 4- [2- (2, 3-Dichl Thiazol-5-ylmethyl 132. 4- [2- (2,4-Dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-5-ylmethyl-13- [2- (2,4-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate, oro-phenoxy) -ethyl] -piperidine-1-carboxylate 133. Thiazol-5-ylmethyl 4- [2- (2,5-dichloro-phenoxy) -ethyl] -piperidine-1-carboxylate 134. 4- [2- (3,5-Dichloro-phenoxy) -ethyl) ] thiazol-5-ylmethyl] -piperidine-1-carboxylate 135. Thiazol-5-ylmethyl 136. 4- [2- (4-Cyclopentylphenoxy) -ethyl] -piperidine-1-carboxylate 136. 4- [2- ( Naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylic acid thiazol-5-ylmethyl 137. 4- [2- (Naphthalen-1-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-5-ylmethyl 138. Thiazol-5-ylmethyl 4- [2- (2-methylquinolin-8-yloxy) -ethyl] -piperidine-1-carboxylate 139. 4- [2- (2-Benzooxazol-2-yl-phenoxy) - Thiazol-5-ylmethyl ethyl] -piperidine-1-carboxylate 140. Thiazol-5-ylmethyl 141 [4- (2- (4-Benzyloxy-phenoxy) -ethyl] -piperidine-1-carboxylate. Thiazol-5-ylmethyl (4-sulfamoyl-phenoxy) -ethyl] -piperidine-1-carboxylate 142. 4- [2- (Isoquinolin-5-yloxy) -ethyl] -piperidine-1-thiazol-5-ylmethylcarboxylate 143. 4- [2- (4-Carbamoylmethylphenoxy) -ethyl] -piperidine-1- Thiazol-5-ylmethyl carboxylate 144. 4- [2- (Quinolin-7-yloxy) -ethyl] -piperidine-1-carboxylic acid thiazol-5-ylmethyl 145. 4- [2- (Quinolin-6-yloxy) 1-Thiazol-5-ylmethyl-thiazol-5-ylmethyl-4-thiazol-5-ylmethyl] -4- [2- (Quinolin-8-yloxy) -ethyl] -piperidine-1-carboxylic acid-1-carboxylate 147. 4- [2] Thiazol-5-ylmethyl (3-dimethylamino-phenoxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 238. 4- [2- (4-Cyano-3-fluoro-phenoxy) -ethyl] -piperidine Thiazol-5-ylmethyl 1,1-carboxylate 149. Thiazol-5-ylmethyl 150 [4- (2- (biphenyl-2-yloxy) -ethyl] -piperidine-1-carboxylate 150. 4- [2- (Biphenyl-3 Thiazol-5-ylmethyl-thiazol-5-ylmethyl-thiazol-5-ylmethyl 5-ylmethyl] -piperidine-1-carboxylate 151. Thiazol-5-ylmethyl-15 [4- (2- (3-trifluoromethyl-phenoxy) -ethyl] -piperidine-1-carboxylate - [2- (4-Benzyl-phenoxy) -ethyl] -piperidine-1-c Thiazol-5-ylmethyl arboxylate 153. Thiazol-5-ylmethyl 4- [2- (2-ethoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 154. 4- [2- (2-Cyclopentylphenoxy) Thiazol-5-ylmethyl ethyl-piperidine-1-carboxylate 155. Thiazol 4- {2- [4- (1-methyl-1-phenyl-ethyl) -phenoxy] -ethyl} -piperidine-1-carboxylate 15- [4- (2- (4-Phenoxy-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-5-ylmethyl ester 157. 4- [2- (2-Bromo-4-fluoro-phenoxy) -5-ylmethyl ) Thiazol-5-ylmethyl 158. 4- [2- (4-Pyrrol-1-yl-phenoxy) -ethyl] -piperidine-1-carboxylate Thiazol-5-ylmethyl 159. 4-thiazol-5-ylmethyl-piperidine-1-carboxylate. Thiazol-5-ylmethyl [2- (3-cyano-phenoxy) -ethyl] -piperidine-1-carboxylate 160. 4- [2- (3,5-Di-tert-butyl-phenoxy) -ethyl] - Thiazol-5-ylmethyl piperidine-1-carboxylate 161. Thiazol-5-ylmethyl 162. 4- [2- (2-Benzyl-phenoxy) -ethyl] -piperidine-1-carboxylate 162. 4- [2- (2-) Thiazol-5-ylmethyl benzyloxy-phenoxy) -ethyl] -piperidine-1-carboxylate 24 163. 4- [2- (2-Cyano-quinolin) Thiazol-5-ylmethyl 8-yloxy) -ethyl] -piperidine-1-carboxylate 164. Thiazol-5 4- [2- (3-methoxycarbonyl-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate Methyl 165. 4- [2- (3-Phenoxy-phenoxy) -ethyl] -piperidine-1-carboxylic acid thiazol-5-ylmethyl ester 166. 4- [2- (4-Chloro-2-cyano-phenoxy) - thiazol-5-ylmethyl ethyl] -piperidine-1-carboxylate 167. Thiazol-5-ylmethyl 168. 4- [2- (Isoquinolin-7-yloxy) -ethyl] -piperidine-1-carboxylate 4-8. Thiazol-5-ylmethyl (4-hexyloxy-phenoxy) -ethyl] -piperidine-1-carboxylate 169. Thiazol-5- [4- (2- (3-butoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 170. Thiazol-5-ylmethyl 17? 4- [2- (4-chloro-5-isopropyl-2-methyl-phenoxy) -ethyl] -piperidine-1-carboxylate. 4- [2- (2-Methyl) -2- Thiazol-5-ylmethyl thiazol-5-ylmethyl benzothiazol-5-yloxy) -ethyl] -piperidine-1-carboxylate 172. Thiazol-5-ylmethyl 4- [2- (quinolin-5-yloxy) -ethyl] -piperidine-1-carboxylate 173. 4- [2- (3-Pentafluoroethyl-phenoxy) -ethyl] -piperidine-1-carbo thiazol-5-ylmethyl xylate 174. thiazol-5-ylmethyl 4- [2- (5-bromo-2-chloro-phenoxy) -ethyl] -piperidine-1-carboxylate 175. 4- [2- (4- Thiazol-5-ylmethyl difluoromethoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 176. Thiazol-5-ylmethyl-4- [2- (4'-cyano-biphenyl-3-yloxy) -ethyl] -piperidine-1-carboxylate 5-ylmethyl 177. Thiazol-5-ylmethyl 4- [2- (6-cyano-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 178. 4- [2- (4-Thiazol-2 1-thiazol-5-ylmethyl 17-thiazol-5-ylmethyl-4-thiazol-5-ylmethyl] -piperidine-1-carboxylate 179. Thiazol-5-ylmethyl 179. 4- [2- (7-Methoxy-Naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate 5-ylmethyl 180. Thiazol-5-ylmethyl 181. 4- [2- (4-Chloro-2-isoxazol-5-yl-phenoxy) -ethyl] -piperidine-1-carboxylate 181. 4- [2- (2- Thiazol-5-ylmethyl carbamoyl-4-chloro-phenoxy) -ethyl] -piperidine-1-carboxylate 182. 4- [2- (5-Acetylamino-naphthalen-2-yloxy) -ethyl] -piperidine-1-carboxylate Thiazol-5-ylmethyl 183. 4- [2- (4'-Cyano-biphenyl-4-yloxy) -ethyl] -piperidine-1-carboxylate thiazol-5-ylmethyl 184. thiazol-5-ylmethyl 4- [2- (4-methanesulfonyl-phenoxy) -ethyl] -piperidine-1-carboxylate 185. 4- [2- (5-Acetylamino-2-propyl) thiazol-5-ylmethyl phenyl) -ethyl] -piperidine-1-carboxylate 186. Thiazol-5-ylmethyl-4- [2- (1H-indol-6-yloxy) -ethyl] -piperidine-1-carboxylate 187. 4 Thiazol-5-ylmethyl {1- (4-fluoro-2- (1H-pyrazol-3-yl) -phenoxy] -ethyl} -piperidine-1-carboxylate 188. 4- [2- (4-Cyano- Thiazol-5-ylmethyl 2-fluoro-phenoxy) -ethyl] -piperidine-1-carboxylate 189. Thiazol 4- [2- (2-Isopropyl-5-methyl-phenoxy) -ethyl] -piperidine-1-carboxylate 5-ylmethyl 190. Thiazol-5-ylmethyl 4- [2- (2-morpholin-4-yl-phenoxy) -ethyl] -piperidine-1-carboxylate and its trifluoroacetate 191. 4- [2- (2- Thiazol-5-ylmethyl methyl-quinolin-6-yloxy) -ethyl] -piperidine-1-carboxylate 192. 4- {2- [4- (2-Oxo-pyrrolidin-1-yl) -phenoxy] -ethyl Thiazol-5-ylmethyl 19β-piperidine-1-carboxylate 193. 4- [2- (3-Tetrazol-1-yl-phenoxy) -ethyl] -piperidine Thiazol-5-ylmethylcarboxylate 194. (R) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid thiazol-2-ylmethyl ester (Enantiomer I) 195. (S) -3- (Naphthalene) 2-yloxymethyl) -pyrrolidine-1-thiazol-2-ylmethyl ester (enantiomer II) 196. (+/-) -3- (5-Chloro-Naphthalen-2-yloxymethyl) pyrrolidine-1-carboxylic acid thiazol 2-ylmethyl 197. (+/-) - 3- (4'-Fluoro-biphenyl-4-yloxymethyl) -pyrrolidine-1-carboxylic acid thiazol-2-ylmethyl 198. 4- [2- (4-Fluoro-phenoxy) 3-carbamoyl-isoxazol-5-ylmethyl) -ethyl-3-carbamoyl-isoxazol-5-ylmethyl] -piperidine-1-carboxylate 199. 3-carbamoyl-isoxazol-4-a [4- (4-trifluoromethoxy-phenoxy) -ethyl] -piperidine-1-carboxylate 5-ylmethyl 200. (-) - (R) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid 3-carbamoyl-isoxazol-5-ylmethyl (enantiomer I) 201. (+/-) - 3-Carbamoyl-isoxazol-5-ylmethyl 3- (6-methoxy-naphthalen-2-yloxymethyl) pyrrolidine-1-carboxylate 202. (+) - (S) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine -1-Carboxyl carboxylate yl-isoxazol-5-ylmethyl (enantiomer II).

The compounds of general formula (I), (Ii) and (Iii) can comprise one or more asymmetric carbons. They can exist as enantiomers or diastereoisomers.

These enantiomers and diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

The compounds of formula (I), (Ii) and (Iii) can exist in the form of bases or of addition salts with acids. Such addition salts are part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids useful, for example, for the purification or isolation of the compounds of formulas (1), (Ii) and (III) are also part of the invention.

In the context of the invention, the following terms are understood: where Z and z can take the values from 1 to 8, a carbon chain which may have from t to z carbon atoms, for example C 1 -C 3 a carbon chain which may have from 1 to 3 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a C1-C6 alkyl group represents a linear or branched carbon chain of 1 to 6 carbon atoms, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl; alkylene, a saturated divalent linear or branched alkyl group, for example a C 1-3 alkylene group, represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, more particularly a methylene, ethylene, 1-methylethylene, propylene ; cycloalkyl, a cyclic alkyl group, for example a C 3-7 -cycloalkyl group represents a cyclic carbon group of 3 to 7 carbon atoms, more particularly a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; alkoxy, a saturated, linear or branched aliphatic chain -O-alkyl group; thioalkyl, a -S-alkyl group with saturated aliphatic chain, linear or branched; haloalkyl, an alkyl group of which one or more hydrogen atoms have been substituted with a halogen atom; haloalkoxy, an alkoxy group of which one or more hydrogen atoms have been substituted by a halogen atom; halothioalkyl, a thioalkyl group of which one or more hydrogen atoms have been substituted with a halogen atom; halogen atom, fluorine, chlorine, bromine or iodine; TFA: trifluoroacetic acid; - ACN: acetonitrile.

Within the meaning of the present invention, it should be noted that the terms "from to" and "between and" mean that the terminals are also considered.

Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, comprising the step of reacting an amine derivative, compound of general formula (II) which follows: R2 NH RI ùA (II) wherein R1, R2, A, n and m are as defined in formula (I) defined above, with a carbonate of general formula (III), which follows: ## STR2 ## (III) wherein Z represents a hydrogen atom or a nitro group, R3 and R4 are as defined in the general formula (I) defined above, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or N, N-diisopropylethylamine in an organic solvent such as toluene, acetonitrile or dichloroethane at a temperature between room temperature and the reflux temperature of the solvent.

The compounds of the invention may further be prepared according to different methods, illustrated by the following diagrams. These methods, as well as the intermediate compounds used, are also an object of the present invention.

If appropriate, a compound of formula (II) may be protected, in particular at its amine function, according to methods well known to those skilled in the art.

As examples of protecting groups as well as protection and deprotection methods, mention may be made of Protective Groups in Organic Synthesis, Green et al., 2nd Edition (John Wiley Sons, Inc. New York). . A preparation process using a compound of formula (II) protected is described, for example, in Scheme 1 which follows.

As regards more particularly the compounds of general formula (I) in which A represents more particularly an oxygen atom or a -O-C1-6-alkylene group, they can also be prepared according to the procedure described in scheme 1 which follows. Diagram 1 (IIa) R2 1) R1OH or R1X HONG NGP (IV) (IVa) / O ~ XN 2) deprotection R ((I) deprotection HOC This method of preparation (diagram 1) consists in reacting, in a first time, an alcohol of general formula (IIa), wherein R2, m and n are as defined in the general formula (I) defined above, G represents a part of the group A as defined in the general formula (I ) namely either a covalent bond or the C 1-6 -alkylene portion of the -O-C 1-6 -alkylene group, and GP represents a protecting group such as a Boc (tert-butyloxycarbonyl), a Cbz (benzyloxycarbonyl), a benzyl or a benzhydrile; or with an alcohol derivative of general formula (IV), in which R 1 is as defined above using the reaction conditions of Mitsunobu (Synthesis, 1981, 1-28), or with a halogenated derivative of general formula (IVa), wherein RI is as defined above and X represents a fluorine, chlorine, bromine or iodine using aromatic, heteroaromatic or O-arylation nucleophilic substitution reactions, Buchwald O-heteroarylation, for example by Palladium or copper catalyst; followed by a deprotection reaction, for example in the presence of trifluoroacetic acid or a solution of hydrochloric acid in isopropanol or dioxane, to yield the amine of general formula (IIb) in which G, R2, m and n are as defined in the amine of formula (IIa) above and R1 is as defined in the general formula (I) defined above. An alternative to the Mitsunobu reaction consists in reacting an alcohol derivative of general formula (IV) with a compound of general formula (IIe) and derived from the activation of the alcohol function of a compound of general formula (IIa) by a tosylate group. The derivative of general formula (IIb) thus obtained is then converted into a compound of general formula (I) according to a condensation reaction with a carbonate of general formula (III) as defined above, under the conditions described above.

An alternative for obtaining the compounds of general formula (I) (Scheme 1) in which A represents more particularly an oxygen atom or a -O-C1-6-alkylene group, consists in deprotecting an alcohol of general formula (IIa) such as defined above, according to a deprotection reaction as defined above in order to obtain an aminoalcohol of general formula (IIc) and then to react that aminoalcohol of general formula (IIc) in which R2, m and n are such defined in the general formula (I) defined above, and G represents a part of the group A as defined in the general formula (I), namely either a covalent bond or the C1_6-alkylene part of the group -0- C1_6-alkylene, with a carbonate of general formula (III) as defined above, under the conditions described above, to yield the carbamate derivative of general formula (Ia), wherein R2, R3, R4, 32 m and n are as defined in the general mule (I) defined above and G represents a part of the group A as defined in the general formula (I), namely either a covalent bond or the C 1-6 -alkylene portion of the -O-C 1-6 -alkylene group. The carbamate derivative (Ia) thus obtained is then converted into a compound of general formula (I) by the action of an alcohol of general formula RIOH (IV) as defined above, using the reaction conditions of Mitsunobu or by action of a halogenated derivative of the general formula R1X (IVa) as defined above using the aromatic nucleophilic, heteroaromatic or O-arylation substitution reactions, O-heteroarylation of Buchwald, for example by means of a catalyst with Palladium or Copper.

As regards more particularly the compounds of general formula (I) in which R 1 represents a group R 5 substituted in particular by a R 6 group of the C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-3 alkylene type, or by an R 7 group as defined in the general formula (I) defined above, they may also be prepared according to the procedure described in Scheme 2 which follows.

Diagram 2 O R3 OO R4 (III) and R5 A R5 NH Suzuki or Stille or Negishi 33

. Thus, the first step consists in reacting an amine of general formula (IId), in which A, R2, R5, m and n are as defined in the general formula (I) defined above and U1 represents an atom of chlorine, bromine, iodine or a triflate group, with a carbonate of general formula (III) as defined above, under the conditions described above, to yield the carbamate derivative of general formula (Ib), in wherein A, R2, R3, R4, R5, m and n are as defined in the general formula (I) defined above and U1 is as defined above. The catalyzed coupling reaction using a transition metal such as Palladium (0) is then carried out on the key intermediate of general formula (Ib) as defined above, U1 being in the position where it is desired introduce the group R6 or R7 (scheme 2): either by a Suzuki type reaction, for example by means of an alkyl boronic acid, cycloalkyl, aryl or heteroaryl, or according to a reaction of Stille type, for example using a trialkylstannyl derivative of aryl or heteroaryl - either by a Negishi reaction, for example using a zincate derivative of alkyl halide, cycloalkyl, aryl or heteroaryl.

Alternatively, the other compounds of general formulas (II), IIa, IIb, IIc, IId, III, IV and IVa and the other reagents are commercially available or Described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art. Another object of the present invention relates to compounds of the general formula (Ia). Wherein R 2, R 3, R 4, m and n are as defined in the general formula (I), and G represents a portion of the group A as defined in the general formula (I), i.e. a covalent bond is the C1-alkylene portion of the -O-Cl-6-alkylene group.

Among these compounds, mention may be made of: • Thiazol-2-ylmethyl 4- (2-hydroxy-ethyl) -piperidine-1-carboxylate • Thiazol-4-ylmethyl 3-hydroxymethyl-pyrrolidine-1-carboxylate Another object of the present invention relates to compounds of general formula (II). NH (II) wherein A, R1, R2, m and n are as defined in general formula (1).

Among these compounds, mention may be made of: • 4- [2- (4-Chloro-naphthalen-1-yloxy) -ethyl] -piperidine • 3- (6-Methoxy-naphthalen-2-yloxymethyl) -pyrrolidine 25 • 3 ' - (Pyrrolidin-3-ylmethoxy) -biphenyl-3-carbonitrile • 3- (5-chloro-naphthalen-2-yloxymethyl) -pyrrolidine • 3- (3-Trifluoromethoxy-phenoxymethyl) -pyrrolidine • 3- [4- ( 1-Methyl-1-phenylethyl) -phenoxymethyl] -pyrrolidine • 7- (Pyrrolidin-3-ylmethoxy) -quinoline • 3- (Pyrrolidin-3-ylmethoxy) -quinoline • 3- (4-Chloro-3-trifluoromethyl) phenoxymethyl) -pyrrolidine • 7- (Pyrrolidin-3-ylmethoxy) -isoquinoline • 3- (5-Fluoro-naphthalen-2-yloxymethyl) -pyrrolidine • 3- (4'-Fluoro-biphenyl-4-yloxymethyl) -pyrrolidine

The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and only illustrate the invention. R.M.N. spectra and / or LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirm the structures and purities of the compounds obtained. PF (° C) represents the melting point in degrees Celsius. Rf indicates the retention time obtained by TLC analysis (Thin Layer Chromatography).

The numbers given in parentheses in the titles of the examples correspond to those in the first column of the tables below.

The IUPAC (International Union of Pure and Applied Chemistry - IUPAC) nomenclature was used for the naming of the compounds in the examples below.

Example 1 (Compound No. 17) Thiazol-4-ylmethyl 3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylate Thiazol-4-ylmethyl 3-hydroxymethyl-pyrrolidine-1-carboxylate To a solution of 1.13 g (11.24 mmol) of pyrrolidin-3-ylmethanol (commercial) in 20 mL of methanol is added at room temperature a solution of 3.00 g (10.70 mmol) of Thiazol-4-ylmethyl nitro-phenylcarbonate in 20 ml of dichloromethane via an addition funnel. The solution is stirred for 15 hours. The water is then added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed with a 1M aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution. After drying the organic phases over sodium sulfate, the mixture is filtered and the filtrate is evaporated to dryness. In this way 0.56 g of desired product is obtained in the form of an oil after purification on a column of silica gel, eluting with a dichloromethane / metahnol mixture (97/3 to 95/5).

Thiazol-4-ylmethyl 3- (naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylate 0.25 g (1.03 mmol) 3-hydroxymethyl-pyrrolidine-1-carboxylic acid thiazol-4-ylmethyl ester are used. solution in 8 mL of toluene. 0.35 g (1.34 mmol) of triphenylphosphine and 0.16 g (1.13 mmol) of naphthalen-2-ol are added, then the medium is cooled to 0 ° C. for slow addition of a solution of 0 27 g (1.34 mmol) of diisopropylazodicarboxylate in 2 mL of toluene. The medium is stirred for 14 hours at room temperature. The residue obtained is taken up in water and extracted twice with 37 dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel, eluting with a 99/1 to 98/2 mixture of dichloromethane and methanol. 0.15 g of expected product is obtained in the form of powder. Mp (° C): 90-92 LC-MS: M + H = 369 1H NMR (DMSO) δ (ppm): 9.10 (s, 1H); 7.85 (m, 3H); 7.70 (m, 1H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) Example 2 (Compound No. 22) Thiazol-4-ylmethyl 3- (4'-Fluoro-biphenyl-4-yloxymethyl) -pyrrolidin-1-carboxylate o SN o 2.1 3- (4'- Tert-Butyl Fluoro-biphenyl-4-yloxymethyl) -pyrrolidine-1-carboxylate The same procedure as in Example 1 (step 1.2) is carried out starting from 1.50 g (7.45 mmol) of tert-butyl (commercial) hydroxymethylpyrrolidine-1-carboxylate, 2.15 g (11.18 mmol) of 4'-fluoro-biphenyl-4-ol, 2.93 g (11.18 mmol) of triphenylphosphine and 2.26 g (11.18 mmol) of diisopropylazodicarboxylate. After purification by column chromatography on silica gel eluting with dichloromethane, 1.55 g of the expected product in the form of oil.

2.2 3- (4'-Fluoro-biphenyl-4-yloxymethyl) -pyrrolidine 20 1.55 g (4.17 mmol) of 3- (4'-fluoro-biphenyl-4-yloxymethyl) -pyrrolidine-1-carboxylate tert-butyl is dissolved in 40 ml of dichloromethane and then at 0 ° C., then 6.00 ml (80.77 mmol) of trifluoroacetic acid are added. After stirring for two hours at room temperature, the mixture is concentrated to dryness and the residue is taken up in water and dichloromethane. A saturated solution of sodium hydrogencarbonate is added and the aqueous phase is then extracted with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. 0.98 g of product is obtained in the form of the oil used as in the following step. 2.3 Thiazol-4-ylmethyl 3- (4'-Fluoro-biphenyl-4-yloxymethyl) -pyrrolidine-1-carboxylate 0.30 g (1.07 mmol) 4-nitro-phenyl-thiazol-4- carbonate methyl, 0.34 g (1.28 mmol) of 3- (4'-fluoro-biphenyl-4-yloxymethyl) -pyrrolidine, 0.20 g (1.61 mmol) of N, N-diisopropylethylamine and 0.01 g (0.11 mmol) of dimethylaminopyridine are dissolved in 10 ml of 1,2-dichloroethane. The mixture is stirred at 70 ° C for 4 hours. After returning to ambient temperature, water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After drying the organic phases over sodium sulfate, the mixture is filtered and the filtrate is evaporated to dryness. After purification by column chromatography on silica gel eluting with dichloromethane and methanol (98/2), 0.16 g of the expected product in powder form. MP (° C): 115-117 LC-MS: M + H = 413 1 H NMR (DMSO) δ (ppm): 9.10 (s, 1H); 7.70 (m, 3H); 7.60 (d, 2H); 7.30 (m, 2H); 7.05 (m, 2H); 5.20 (s, 2H); 4.05 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.35 (m, 1H); 3.20 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H)

Example 3 (Compound No. 200) (-) - (R) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-10-carboxylic acid 3-carbamoyl-isoxazol-5-ylmethyl Chiral 15N 3.1 (R) - 3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylate tert-butyl The procedure is as for Example 1 (step 1.2) from 2.00 g (9.94 mmol) of Tert-butyl (R) -3-hydroxymethyl-pyrrolidine-1-carboxylate (commercial), 2.00 g (13.91 mmol) naphthalen-2-ol, 3.90 g (14.91 mmol), triphenylphosphine and 3.01 g (14.91 mmol) of diisopropylazodicarboxylate. 1.75 g of product in the form of oil are obtained after purification on a column of silica gel, eluting with dichloromethane.

3.2 (R) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine The same procedure as for Example 2 (step 2.2) is carried out from 1.75 g (5.34 mmol) of (R) Tert-Butyl 3- (naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylate, 5.00 mL (67.31 mmol) of trifluoroacetic acid. 1.20 g of product is obtained in the form of an oil. 3-carbamoyl-isoxazol-5-ylmethyl 4-nitro-phenyl-carbonate To a solution of 2.00 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71 ml (21, 11 mmol) of pyridine and 0.17 g (1.41 mmol) of N, N-dimethylaminopyridine in 15 mL of dichloromethane, cooled to about 0 ° C, are added, in small portions, 2.84 g (14, 07 mmol) of 4-nitrophenyl chloroformate. The medium is stirred at 0 ° C for 1 hour and then at room temperature for 1 hour. The precipitate formed is filtered and then rinsed thoroughly with diisopropyl ether. After drying under vacuum at about 60 ° C, 3.12 g (72%) of expected product is obtained in the form of a white solid used as it is in the next step.

Mp (° C): 143-1451H NMR (DMSO, 400MHz) b (ppm): 8.40 (d, 2H); 8.25 (broad s, 1H); 7.90 (broad s, 1H); 7.65 (d, 2H); 7.0 (s, 1H); 5.50 (s, 2H). 3.4 (-) - (R) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid 3-carbamoyl-isoxazol-5-ylmethyl 0.21 g (0.92 mmol) (R) -3 - (naphthalen-2-yloxymethyl) -pyrrolidine is dissolved in 3.80 ml of dichloromethane and then 0.31 g (1.01 mmol) of 3-carbamoyl-isoxazol-5-ylmethyl 4-nitro-phenylcarbonate and 0.15 mL (1.38 mmol) of N-methylmorpholine are added. Stirred at room temperature for 20 hours and then water is added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed three times with 1M aqueous sodium hydroxide solution and then twice with a saturated aqueous ammonium chloride solution. After drying the organic phases over sodium sulfate, the mixture is filtered and the filtrate is evaporated to dryness. 0.14 g of the desired product are thus obtained in the form of a white solid after purification on a column of silica gel, eluting with a dichloromethane / methanol mixture and then taking up in isopropyl ether. Mp (° C): 138-140 LC-MS: M + H = 396 NMR H (DMSO) δ (ppm): 8.15 (brs, 1H); 7.80 (m, 4H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 6.80 (s, 1H); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, 1H); 3.50 (m, 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) [q] 200c - 7.917 (c = 0.312, DMSO, 589 nm)

Example 4 (Compound No. 202) (+) - (S) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid 3-carbamoyl-isoxazol-5-ylmethyl ester 4.1 (S) -3- (Naphthalen) Tert-Butyl -2-yloxymethyl) -pyrrolidine-1-carboxylate The procedure is as in Example 1 (step 1.2) starting from 2.00 g (9.94 mmol) of (S) -3 tert-butyl (commercial) hydroxymethyl-pyrrolidine-1-carboxylate, 2.00 g (13.91 mmol) of naphthalen-2-ol, 3.90 g (14.91 mmol) of triphenylphosphine and 3.01 g g (14.91 mmol) of diisopropylazodicarboxylate. 2.80 g of product are obtained in the form of oil after purification on a column of silica gel, eluting with dichloromethane.

4.2 (S) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine The procedure is as for Example 2 (step 2.2) from 1.75 g (5.34 mmol) of (S) - 3- (naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester, 5.00 mL (67.31 mmol) of trifluoroacetic acid. The product is obtained in the form of an oil after purification on a column of silica gel, eluting with a dichloromethane / methanol / aqueous ammonia mixture (90/9/1). 42

4.3 (+) - (S) -3- (Naphthalen-2-yloxymethyl) -pyrrolidine-1-carboxylic acid 3-carbamoyl-isoxazol-5-ylmethyl The procedure is as for Example 3 (step 3.4) from 0.21 g (0.95 mmol) of (S) -3- (naphthalen-2-yloxymethyl) -pyrrolidine, 0.32 g (1.04 mmol) of 4-nitrophenyl carbonate of 3- carbamoyl-isoxazol-5-ylmethyl (step 4.3), 0.16 mL (1.42 mmol) of N-methylmorpholine. 0.21 g of a powder is obtained after purification on a column of silica gel, eluting with a dichloromethane / methanol mixture and trituration in isopropyl ether. Mp (° C): 139-141 LC-MS: M + H = 396 NMR H (DMSO) δ (ppm): 8.15 (brs, 1H); 7.80 (m, 4H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 6.80 (s, 1H); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, 1H); 3.50 (m, 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) [q] 200c + 9.944 (c = 0.036, DMSO, 589 nm) The following Table 1 illustrates the chemical structures and physical properties of some compounds according to the invention. In this table, the compounds are in free base or salt form. * A represents a group -O-CI_6-alkylene in which the end represented by an oxygen atom is linked to the group R.

Table 1 (I) ## EQU1 ## R 2 R 3 R 4 Base or salt 1. ci 2 2 2 -OCH 2 CH 2 -HH N ---- = - base 2. F 2 2 -OCH 2 CH 2 -HH s base 3. F 2 2 -OCH2CH2- HHN \ base J, s 4. FF 2 2 -OCH2CH2- HH jas base F 5. ci ® 2 2 -OCH2CH2-HHN \ base Jas 6. F 2 2 -OCH2CH2-HHN ~ base s 7. ci ® 2 2 -OCH2CH2- HHN ~ base 8. FF 2 2 -OCH2CH2- HHN \ base F s N ° R ~ mn A * R2 R3 R4 Base or salt 9. O.Me 2 2 - OCH2CH2-HH base 10. NC® 2 2 -OCH2CH2-HH Ns base 11. Me 21 -OCH2-HHN \ base (+/-) 12. O.Me 21 -OCH2-HHN \ base 13. ci ci 2 1 -OCH2-HHN \ base ® (+/-) 14. Me 2 2 -OCH2CH2-HHN = --- \ base o 15. 2 2 -OCH2CH2-HHN = --- \ base 16. cl Ôl * l 1 2 -OCH2- HHN = base (+/-) N ° R ~ mn A * R2 R3 R4 Base or salt 17. ® 1 2 -OCH2- HHN ~ base (+/-) 18. F 2 2 -OCH2CH2- HH jas base ® 19. I 2 2 -OCH 2 CH 2 -HH W. = S HCl N 20. I 2 2 -OCH 2 CH 2 -HHN-HCl 21. NC 1 2 -OCH 2 -HHN base 22. F 1 2 -OCH 2 -HHS base ® ~ 23. CI 1 2 -OCH2-HHN ~ base (+/-) 24. F 1 2 -OCH2- HH (+/-) base OOF ®-. Me me 1 2 -OCH2- HHN \ base (+/-) 25.01 N ° R ~ mn A * R2 R3 R4 Base or salt 26. N 1 2 -OCH2-HHN = base (+/-) 27. N 1 2 -OCH 2 -HH N - = - base (+/-) 28. 1 2 -OCH 2 -HH-base (+/-) 29. N ~ 1 2 -OCH 2 -HHN = base (+/-) 30. CI FF 1 2 -OCH 2 -HHN = base F g (+/-) 31. F% 1 2 -OCH 2 -HH ~ base ® (+/-) 32. Me 2 Me 2 2 -OCH 2 CH 2 -HH N - = - ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## Base or salt 36. c, 2 2 -OCH 2 CH 2 -HHN = base c 37. c '2 2 -OCH 2 CH 2 -HH base and 38. • 2 2 -OCH 2 CH 2 HH N - = \ base 39. N 2 2 -OCH 2 CH 2 -HH -S base 'O 40. 2 2 -OCH 2 CH 2 -HHS base 41. H2N o 2 2 -OCH 2 CH 2 -HH ~ s base 42. 2 2 -OCH 2 CH 2 -HH N - = \ CF3CO2H s 43. 2 2 -OCH2CH2- HH ~ s CF3CO2H 44. NC 2 2 -OCH2CH2- HH ~ s base F® 45. ® 2 2 -OCH2CH2- HH N - = base 46. Me 2 2 -OCH2CH2- HH -s base Me ® Me 47. FF ®. 2 2 -OCH 2 CH 2 -HH N - = \ base F v No. R ~ mn A * R2 R3 R4 Base or salt 48. Me me 2 2 -OCH2CH2- HH ~ S base MMe Me 0 49. 2 2 -OCH2CH2-HH NS base 50. 2 2 -OCH2CH2-HHN = \ CF3CO2H 51. o 2 2 -OCH2CH2-HH ~ s base H2N 52. NC 2 2 -OCH2CH2-HH N - = --- base S 53. Me Me 2 2 -OCH2CH2- HH ~ s base MeMeMeMe 54. ® 2 2 -OCH2CH2 -HH NS base \ 55. 2 2 -OCH2CH2-HHN = base 56. ~ Me 2 2 -OCH2CH2 -HH -s base 57. 2 2 -OCH2CH2-HH ~ S base no. R * mn A * R2 R3 R4 Base or salt 58. N 2 2 -OCH2CH2-HH ~ s CF3CO2H 59. Cd 6H13 2 2 -OCH2CH2-HH -s base ° ® 60. C 4 H 9 2 2 -OCH 2 CH 2 -HH ~ s base 1 ° ® 61. 2 2 -OCH 2 CH 2 -HH CF3CO2H 62. FFF 2 2 -OCH 2 CH 2 -HH N - = - - base FF 63. • N ~ o 2 2 -OCH2CH2- HH ~ s base ® 64. sr 2 2 -OCH2CH2-HH N_` base 65. Me 2 2 -OCH2CH2-HHN CF3CO2H "s ® 66. NC ® 2 2 -OCH2CH2 -HH ~ s base 67 NC 2 2 -OCH 2 CH 2 -HH N - = - base 68. (fis i® 2 2 -OCH 2 CH 2 -HH Nl` s base ~ = "No. R ~ mn A * R2 R3 R4 Base or salt 69. 2 2 -OCH2CH2- HH N --- = \ base 70. ® 2 2 -OCH2CH2- H ## STR5 ## 2 2 -OCH 2 CH 2 -HHN = OS base 74. NC 2 2 -OCH 2 CH 2 -H-base 75. 2 2 -OCH 2 CH 2 -HH-base 76. ## STR2 ## 77. Me 2 Me 2 2 -OCH 2 CH 2 -HH / base 78. ® Cl 2 2 -OCH 2 CH 2 -HH base and 79. 2 2 -OCH 2 CH 2 -HH jase base 80. Me 2 -SCH 2 CH 2 -HH jas CF 3 CO 2 H N ° R ~ mn A * R2 R3 R4 Base or salt 81.0 2 2 -OCH2CH2- HH base FFF 82.00 2 2 -OCH2CH2- HH base 83. ®, 2 2 -OCH2CH2-HH NS base OMe 84.00 2 2 -OCH2CH2 - HH js base Me Me 85.001 2 2 -OCH2CH2- HH base 86. F ®Br 2 2 -OCH2CH2- HH base 87. ®® 2 2 -OCH2CH2- HH base 88.0 2 2 -OCH2CH2-HH base o 89. CH 2 O 2 -OCH 2 CH 2 - H H base 6 13 90. C 4 H 9 O 2 2 -OCH 2 CH 2 -HH base 91. Me SMe 2 2 -OCH 2 CH 2 -HH base M.CI 92. FFF 2 2 -OCH 2 CH 2 -HH js base FF 93. NH 2 2 -OCH 2 CH 2 -HHN = --- base No. R ~ mn A * R2 R3 R4 Base or salt 94. ci 2 2 -OCH2CH2-HH base Br 95. CN 2 2 -OCH 2 CH 2 -H H jase base 96. CN 2 2 -OCH 2 CH 2 -H H jase base 97. 2 -OCH 2 CH 2 -H H N / A base N = 98.RTM. 2 2 -OCH 2 CH 2 -HH jas base 99. 2 -OCH 2 CH 2 -HHN-base 100. CN 2 2 -OCH 2 CH 2 -H 2, base 101. Me 2 -OCH 2 CH 2 -H 2, base 102. 2 - OCH2CH2-HHN = --- \ base ® CN # R ~ mn A * R2 R3 R4 Base or salt 103. (o 2 2 -OCH2CH2-HH N1 \ CF3CO2H ®NJ 104. oN 2 2 -OCH2CH2-HH base ## STR2 ## base 108.% 2 2 -OCH 2 CH 2 -HH N - = ---- \ base ® o CH3 109. • 2 2 -OCH2CH2-HH base 110.® 2 2 -OCH2CH2-HH base 111. 0 2 2 -OCH2CH2-HH CF3CO2H iN 112. 2 2 -OCH2CH2-HH CF3CO2H NN ° R ~ mn A * R2 R3 R4 Base or salt 113. N 2 2 -OCH2CH2-HH CF3CO2H CH3 114. N 2 2 -OCH2CH2- ## STR1 ## ## STR13 ## ## STR2 ## ## STR13 ## ## STR2 ## ## STR13 ## ## STR2 ## HH js base CN 119. Me me 2 2 -OCH2CH2- HH my base Me Me Me 120. 2 2 -OCH2CH2- HH jas CF3CO2H 121. Me 2 2 -OCH2CH2- HH jas bottom 122. H3C.N 2 2 -OCH2CH2- HH CF3CO2H CH3 No R ~ mn A * R2 R3 R4 Base or salt 123. N 2 2 -OCH2CH2-HH CF3CO2H Me 124. CN 2 2 -OCH2CH2-HH base 125. 2 -OCH 2 CH 2 -HHN-base S 126. 2 2 -OCH 2 CH 2 -HHN-base S 127. 0 2 2 -OCH 2 CH 2 -HH s base NH 2 128. F 2 2 -OCH 2 CH 2 HHN ~ base S 129. Me 2 2 -OCH 2 CH 2 -HHN ~ base Me ® "S 130. H3C.N 2 2 -OCH2CH2-HHN \ CF3CO2H CH3 S 131. ci 2 2 -OCH2CH2-HH base 132. ## STR1 ## wherein R4 is R3 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 Ô * 2 2 -OCH2CH2-HHN ~ base S 136. ee 2 2 -OCH2CH2-HHN ~ base s 137. SS 2 2 -OCH2CH2-HHN ~ base s 138. NN CH 3 2 2 -OCH 2 CH 2 -HHN ~ base S 139. 0 2 2 -OCH2CH2-HHN ~ base ® ~ N I_ S 140. ® 2 2 -OCH2CH2-HHN \ base S 141. ® SOZNHZ 2 2 -OCH2CH2-HHN ~ base S 142. ® 2 2 -OCH2CH2- HHS base 143. H2N 2 2 -OCH2CH2-HHN \ base o S 144. ® 2 2 -OCH2CH2-HH s base 145. ® 2 2 -OCH2CH2-HH N ~ base s No. R ~ mn A * R2 R3 R4 Base or salt 146. 2 2 -OCH2CH2- HHN ~ base S 147. ®N-Me 2 2 -OCH2CH2- HH NI ~ CF3CO2H Me S 148. F 2 2 -OCH2CH2-HHN ~ base CN S, 149. ® 2 2 -OCH2CH2-HHN ~ base S 150. ® 2 2 -OCH2CH2-HHN ~ base S 151. FF 2 2 -OCH2CH2-HHN ~ base S 152. ® 2 2 -OCH2CH2-HHN ~ base S 153. 0C2H5 2 2 -OCH2CH2-HHN \ base S 154. • 2 2 -OCH2CH2-HHN \ base S 155. Me me 2 2 -OCH2CH2-HHS base SI 156. ®o ® 2 2 -OCH2CH2-HHN ~ base 157. Br 2 2 -OCH2CH2-HHN ~ base F ® 'SN ° R ~ mn A * R2 R3 R4 Base or salt 158. 2 2 -OCH2CH2- HHN ~ base S 159. NC 2 2 -OCH2CH2-HHN ~ base S 160. Me 2 2 -OCH2CH2-HH NI_ \ S base Me Me Me am I Me 161. ® 2 2 -OCH2CH2-HHN \ base S 162. ® 2 2 -OCH2CH2-HHN \ base S 163 CN 2 2 -OCH 2 CH 2 -HHN ~ base "SI 164. oo 2 2 -OCH 2 CH 2 -HHS base 165. S 2 2 -OCH 2 CH 2 -HH base 166. CN 2 2 -OCH 2 CH 2 -HHN base S 167. 2 2 -OCH2CH2-HHS base No. R ~ mn A * R2 R3 R4 Base or salt 168. ® 2 2 -OCH2CH2-HHN ~ base C6H13O s 169. C4H9O 2 2 -OCH 2 CH 2 -HHN -base 170. Me 2 2 -OCH 2 CH 2 -HHN -base ® Me Me 171. s 2 2 -OCH 2 CH 2 -HHN ~ base Me s 172. "2 2 -OCH 2 CH 2 -HH Base 173. FFF 2 2 -OCH2CH2-HHN \ base F ® s F, 174.0 2 2 -OCH2CH2-HHN \ base c 's Br 175. Fco ® 2 2 -OCH2CH2-HHN ~ base 176.0 2 2 -OCH2CH2- HHN ~ base ®CN 177. "c 2 2 -OCH 2 CH 2 -HHN ~ base 178. 2 2 -OCH 2 CH 2 -HHN \ base SN ° R ~ mn A * R2 R3 R4 Base or salt 179. ° Me 2 2 - OCH2CH2HHN \ base s 180. ° -N 2 2 -OCH2CH2-HHN \ base C 181. ° 2 2 -OCH2CH2-HHN \ base ® "" 2 S Ci 182.0 ~ N% 2 2 -OCH2CH2- HH NI_ ~ S base H ®,, 183. ® c "2 2 -OCH2CH2-HHN ~ base 184. ® SOZMe 2 2 -OCH2CH2-HHN ~ base 185. ON • 3H7 2 2 -OCH2CH2-HHN ~ base 186. N 2 2 -OCH 2 CH 2 -HHN ~ base ® S 187. "2 2 -OCH 2 CH 2 -HHN \ base N / s ® F 188. NC F 2 2 -OCH 2 CH 2 -HHN ~ base ® s 189. Me 2 2 -OCH 2 CH 2 -HHN base Me ® Me s No R ~ mn A * R2 R3 R4 Base or salt 190. "J 2 2 -OCH2CH2-HHN \ CF3CO2H S 191. Me 2 2 -OCH2CH2-HH N - = - b 192. Name / 2 2 -OCH 2 CH 2 -HH base 193. "2 2 -OCH 2 CH 2 -HHN \ base N s 194. 1 1 2 -OCH 2 -HHN = S (R) base Enantiomer I 195. 1 2 -OCH 2 -HHN = base S (s) Enantiomer II 196. c, elel 1 2 -OCH 2 -HHN = base S (+/-) 197. F 1 2 -OCH 2 -HHS base ® (+/-) 198. F 2 2 -OCH 2 CH 2 -HH o base HZN -N 5 No R ~ mn A * R2 R3 R4 Base or salt 199. F ~ F 2 2 -OCH2CH2 -HHO base F ° HzN .N 200.% ® 2 1 -OCH 2 -HHO base HZN, N (R) (-) Enantiomer I 201. Me 2 1 -OCH 2 -HH ° base O HzN .N ° (+/-) 202. 2 1 -OCH 2 -HHO base HZN, N s (+) Enantiomer II The following table 2 gives the results of the 1H NMR analyzes, the melting points (PF) for the compounds of Table 1. Table 2 NMR 1H 400Mhz DMSO / CDCl 3 PF (° C) 8.25 (m, 2H); 7.80 (d, 1H); 7.60 (m, 2H); 7.50 (d, 1H); 7.40 (d, 1H); 6.70 1 (d, 1H); 5.45 (s, 2H); 4.20 (m, 4H); 2.90 (m, 2H); 1.80 (m; 5H); 1.30 (m, 2H oil) 2. 7.80 (d, 1H); 7.70 (d, 1H); 7.10 (m, 2H); 6.90 (m, 2H); 5.35 (s, 2H); 4.00 oil (m, 2H); 2.85 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H) δ 8.80 (s, 1H); 7.40 (s, 1H); 7.00 (m, 2H); 6.85 (m, 2H); 5.30 (s, 2H); 4.20, 76-78 (m, 2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.70 (m, 5H); 1.25 (m, 2H) 49.10 (s, 1H), 7.65 (s, 1H); 7.60 (d, 2H); 7.10 (d, 2H); 5.20 (s, 2H); 4.10 (m, oil 2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.70 (m, 5H); 1.15 (m, 2H) 9.10 (s, 1H); 7.65 (s, 1H); 7.30 (d, 2H); 6.90 (d, 2H); 5.10 (s, 2H); 3.90 (m, 53-55 4H); 2.80 (m, 2H); 1.70 (m, 4H); 1.10 (m, 2H) δ 8.80 (s, 1H); 7.90 (s, 1H); 7.00 (m, 2H); 6.80 (m, 2H); 5.30 (s, 2H); 4.20 96-98 (m, 2H); 4.00 (m, 2H); 2.80 (m, 2H); 1.75 (m, 6H); 1.20 (m, 2H)? 9.10 (s, 1H); 7.90 (s, 1H); 7.30 (d, 2H); 6.95 (d, 2H); 5.30 (s, 2H); 3.90 (m, 93-97 4H); 2.80 (m, 2H); 1.60 (m, 6H); 1.10 (m, 2H) δ 9.10 (s, 1H); 7.95 (s, 1H); 7.60 (d, 2H); 7.10 (d, 2H); 5.30 (s, 2H); 4.10 (m, 47-49 2H); 3.95 (m, 2H); 2.80 (m, 2H); 1.65 (m, 6H); 1.10 (m, 2H) 9.10 (s, 1H); 7.75 (s, 1H); 7.70 (m, 2H); 7.20 (m, 2H); 6.95 (m, 2H); 5.15 95-97 (s, 2H); 4.10 (m, 2H); 4.00 (m, 2H); 3.80 (s, 3H); 2.80 (m, 2H); 1.70 (m, 5H); 1.15 (m, 2H) 8.80 (s, 1H); 7.60 (d, 2H); 7.40 (s, 1H); 6.95 (d, 2H); 5.30 (s, 2H); 4.20 (m, 108-110, 2H); 4.05 (m, 2H); 2.80 (m, 2H); 1.75 (m, 5H); 1.20 (m, 2H); 11.80 (s, 1H); 7.65 (m, 2H); 7.40 (s, 1H); 7.10 (m, 4H), 5.30 (s, 2H); 4.05 (m, 128-130, 2H); 3.90 (s, 3H); 3.80-3.35 (m, 4H); 2.80 (m, 1H); 2.20 (m, 1H); 1.90 (m, 1H) 12.8.80 (s, 1H); 7.70 (m, 2H); 7.40 (s, 1H); 7.05 (m, 4H), 5.35 (s, 2H); 4.10 (m, 112-114, 2H); 3.90 (s, 3H); 3.80 (m, 1H); 3.65 (m, 1H); 3.55 (m, 1H); 3.40 (m, 1H); 2.80 (m, 1H); 2.20 (m, 1H); 1.90 (m, 1H) 13.8.80 (s, 1H); 7.40 (s, 1H); 7.35 (d, 1H); 7.00 (s, 1H); 6.75 (d, 1H); 5.30 (s, 78-80 2H); 3.90 (m, 2H); 3.70 (m, 1H); 3.60 (m, 1H); 3.50 (m, 1H); 3.30 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H); 14.8.80 (s, 1H); 7.65 (m, 2H); 7.40 (s, 1H); 7.10 (m, 4H); 5.30 (s, 2H); 4.20 100-102 (m, 2H); 4.10 (m, 2H); 3.90 (s, 3H); 2.80 (m, 2H); 1.80 (m, 5H); 1.25 (m, 2H) 8.80 (s, 1H); 7.80 (m, 3H); 7.45 (m, 1H); 7.40 (m, 2H); 7.15 (m, 2H); 5.30 (s, 2H); 4.25 (m, 2H); 4.20 (m, 2H); 2.90 (m, 2H); 1.85 (m, 5H); 1.25 (m, 88-90 2H) 9.10 (m, 1H); 8.50 (m, 2H); 7.95 (m, 1H); 7.85 (m, 1H); 7.75 (d, 1H); 7.70 (m, 1H); 7.00 (d, 1H); 5.60 (s, 2H); 4.40 (m, 2H); 4.10 (m, 1H); 4.00 (m, 84-86 1H); 3.85 (m, 1H); 3.70 (m, 1H); 3.20 (m, 1H); 2.50 (m, 1H); 2.30 (m, 1H) 9.10 (s, 1H); 7.85 (m, 3H); 7.70 (m, 1H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 90-92 1H); 3.30 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 8.80 (s, 1H); 7.50 (m, 4H); 7.40 (s, 1H); 7.10 (m, 2H); 6.95 (d, 2H); 5.30 (s, 18.62, 64.2H); 4.20 (m, 2H); 4.10 (m, 2H); 2.85 (m, 2H); 1.80 (m, 5H); 1.25 (m, 2H) 9.10 (s, 1H); 9.05 (m, 1H); 8.80 (d, 1H); 8.20 (d, 1H); 7.90 (m, 1H); 7.70 (m, 3H); 5.20 (s, 2H); 4.25 (m, 2H); 4.00 (m, 2H); 2.85 (m, 2H); 1.80 (m, 140-150, 5H); 1.15 (m, 2H) 9.70 (s, 1H); 9.10 (s, 1H); 8.60 (d, 1H); 8.45 (d, 1H); 8.30 (d, 1H); 7.80 (s, 20H); 7.70 (m, 2H); 5.20 (s, 2H); 4.35 (m, 2H); 4.00 (m, 2H); 2.85 (m, 2H); 150-160 1.80 (m, 5H); 1.20 (m, 2H) 9.10 (s, 1H); 8.20 (s, 1H); 8.10 (d, 1H); 7.85 (d, 1H); 7.70 (m, 2H); 7.40 (m, 1H); 7.30 (m, 2H); 7.00 (m, 1H); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, 1H); Oil 3.50 (m, 1H); 3.40 (m, 1H); 3.20 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 7.70 (m, 3H); 7.60 (d, 2H); 7.30 (m, 2H); 7.05 (m, 2H); 5.20 22 (s, 2H); 4.05 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.35 (m, 1H); 3.20 (m, 115-117 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 8.10 (d, 1H); 7.80 (d, 1H); 7.70 (m, 1H); 7.50 (m, 3H); 7.30 (d, 23H); 5.20 (s, 2H); 4.15 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 1H); 89-91 3.25 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 7.70 (s, 1H); 7.40 (m, 1H); 7.05 (m, 1H); 6.95 (m, 2H); 5.20 (s, 2H); 4.05 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.35 (m, 1H); 3.20 (m, 54-56 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 7.70 (s, 1H); 7.30-7.10 (m, 7H); 6.90 (m, 2H); 5.20 (s, 2H); 4.00 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.35 (m, 1H); 3.20 (m, 1H); 2.70 76-78 (m, 1H); 2.05 (m, 1H); 1.75 (m, 1H); 1.60 (s, 6H) 9.10 (s, 1H); 8.70 (s, 1H); 8.00 (d, 1H); 7.90 (m, 1H); 7.80 (m, 1H); 7.70 (m, 1H); 7.60 (m, 2H); 5.20 (s, 2H); 4.20 (m, 2H); 3.65 (m, 1H); 3.55 (m, 83-85 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) 9.20 (s, 1H); 9.10 (m, 1H); 8.40 (d, 1H); 8.05 (d, 1H); 7.70 (m, 2H); 7.40 (m, 1H); 7.30 (d, 1H); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, 1H); 3.50 (m, 122-124 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.75 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 8.80 (s, 1H); 8.30 (d, 1H); 7.90 (d, 1H); 7.70 (m, 1H); 7.40 (m, 28H); 7.30 (d, 1H); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 94-96 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.20 (s, 1H); 9.10 (s, 1H); 8.40 (d, 1H); 7.90 (d, 1H); 7.80 (d, 1H); 7.70 (m, 1H); 7.55 (s, 1H); 7.45 (d, 1H); 5.20 (s, 2H); 4.20 (m, 2H); 3.60 (m, 1H); 121-123 3.50 (m, 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 7.65 (m, 2H); 7.40 (s, 1H); 7.30 (d, 1H); 5.20 (s, 2H); 4.10 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 1H); 3.20 (m, 1H); 2.70 (m, 1H); 60-62 2.10 (m, 1H); 1.80 (m, 1H) 9.10 (s, 1H); 8.00 (d, 1H); 7.70 (m, 2H); 7.50 (m, 2H); 7.30 (d, 1H); 7.15 (m, 1H); 5.20 (s, 2H); 4.15 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 76-78H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) 7.90 (m, 4H); 7.75 (d, 1H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (d, 1H); 5.35, 194 (s, 2H); 4.15 (m, 2H); 3.65 (m, 1H); 3.55 (m, 1H); 3.45 (m, 1H); 3.30 (m, 100-112 1H); 2.80 (m, 1H); 2.15 (m, 1H); 1.85 (m, 1H) 7.90 (m, 4H); 7.75 (d, 1H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (d, 1H); 5.35, 195 (s, 2H); 4.15 (m, 2H); 3.65 (m, 1H); 3.55 (m, 1H); 3.45 (m, 1H); 3.30 (m, 112-114 1H); 2.80 (m, 1H); 2.15 (m, 1H); 1.85 (m, 1H), 8.10 (d, 1H), 7.85 (m, 2H); 7.75 (d, 1H), 7.50 (m, 3H); 7.40 (d, 1H); 5.35 (s, 196 2H); 4.20 (m, 2H); 3.65 (m, 1H); 3.55 (m, 1H); 3.45 (m, 1H); 3.30 (m, 1H); 100-102 2.80 (m, 1H); 2.15 (m, 1H); 1.85 (m, 1H) 7.85 (m, 1H); 7.75 (m, 1H); 7.65 (m, 2H); 7.60 (d, 2H); 7.30 (m, 2H), 7.05-195 (d, 2H); 5.40 (s, 2H); 4.10 (m, 2H); 3.60 (m, 1H); 3.50 (m, 1H); 3.40 (m, 81-83 1H); 3.30 (m, 1H); 2.70 (m, 1H); 2.10 (m, 1H); 1.80 (m, 1H) 8.15 (si, 1H); 7.85 (si, 1H); 7.15 (m, 2H); 7.00 (m, 2H); 6.80 (s, 1H); 5.25 198 106-108 (s, 2H); 4.00 (m, 4H); 2.90 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H) 8.15 (si, 1H); 7.85 (si, 1H); 7.30 (d, 2H); 7.05 (d, 2H); 6.80 (s, 1H); 5.25 (s, 199 112-115 2H); 4.05 (m, 4H); 2.85 (m, 2H); 1.70 (m, 5H); 1.10 (m, 2H) 8.15 (si, 1H); 7.80 (m, 4H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 6.80 200 (s, 1H); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, 1H); 3.50 (m, 1H); 3.40 (m, 138-140H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) 8.15 (si, 1H); 8.85 (si, 1H); 8.75 (m, 2H); 7.30 (m, 2H); 7.20 (m, 2H); 6.80, 201 (s, 1H); 5.30 (s, 2H); 4.10 (m, 2H); 3.90 (s, 3H); 3.60 (m, 1H); 3.50 (m, 193-195, 1H); 3.40 (m, 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) 8.15 (si, 1H); 7.80 (m, 4H); 7.50 (m, 1H); 7.35 (m, 2H); 7.20 (m, 1H); 6.80220 (s, 1H); 5.30 (s, 2H); 4.10 (m, 2H); 3.65 (m, 1H); 3.50 (m, 1H); 3.40 (m, 139-141 1H); 3.30 (m, 1H); 2.80 (m, 1H); 2.10 (m, 1H); 1.85 (m, 1H) Table 3 below gives the results of the M + H masses measured in LC-MS as well as the retention times for the compounds of Table 1.

LC-MS conditions: Method A: HPLC / ZQ - Gradient 10 min Moving phases: Phase A: CH3COONH4 + 3% ACN Phase B: ACN Stationary phase / column: Kromasil C18 column Dimensions: 50 * 2.1 mm; 3.5} gym Flow rate: D = 0.8 mL / min Column temperature: T = 40 ° C Injection volume: V = 5 pL Gradient: T = 0 min: 100% of A, of T = 5 , 5 min at T = 7 min: 100% B, T = 7.1 min at T = 10 min: 100% of A.

Method B: UPLC / T0F - Gradient 3 min Moving phases: Phase A: H2O + 0.05% TFA Phase B: ACN + 0.035% TFA Stationary phase / column: Acquity column BEH C18 Dimensions: 50 * 2.1 mm ; 1.7} gym Flow rate: D = 1.0 mL / min Column temperature: T = 40 ° C Injection volume: V = 2 pL Gradient: T = 0 min: 98% of A and 2% of B , T = 1.6 min at T = 2.1 min: 100% B, T = 2.5 min at T = 3 min: 9 s of A and 2% of B. Method C: LC / TRAP - Gradient 20 min Movable phases: H2O / CH3CO0NH4 / ACN Stationary phase / column: Kromasil C1830 column 67

Method D LC / ZQ - Gradient 20 min Movable phases: TFA / ACN Stationary phase / column: Kromasil C18 column

E LC / TOF Method - Gradient 20 min Movable Phases: H20 / CH3COONH4 / ACN Stationary Phase / Column: Kromasil C18 Column

Method F Stationary phase / column: Jsphere Dimensions: 33 * 2 mm; 4} Gym Gradient: H20 + 0.05% TFA: ACN + 0.05% TFA; 2:98 (1 min) to 95: 5 (5.0 min) to 95: 5 (6.25 min).

Method G Stationary phase / column: Waters XBridge C18 Dimensions: 4.6 * 50 mm; 2.5% Gym Gradient: H20 + 0.05% TFA: ACN + 0.05% TFA 95: 5 (0 min) to 95: 5 (0.3 min) to 5:95 (3.5 min) to 5:95 (4 min).

Method H: YMC Stationary phase / column: Jsphere Dimensions: 33 * 2 mm; 4} Gym Gradient: H20 + 0.1% TFA: ACN + 0.08% TFA 95: 5 (0 min) to 30 5:95 (2.5 min) to 5:95 (3 min).

Table 3 No. Method M + H RETENTION TIME 1. D 431 10.40 2. A 365 9.70 3. D 365 8.80 4. D 415 10.00 5. D 381 9.80 6. D 365 9.00 7. D 381 9.70 8. C 415 10.50 9. D 427 10.00 10. D 372 8.30 11. E 399 8.50 12. D 387 10.50 13. D 387.01 10 , 00 14. D 427 11.10 15. D 397 11.50 16. D 403 10.00 17. D 369 8.90 18. D 441 10.70 19. D 398 5.70 20. D 398 5, 80 21. D 420 9.40 22. D 413 10.00 23. D 403 10.40 24. D 403 9.60 25. D 437 11.00 26. D 370 6.00 27. D 370 5.30 28. D 370 5.20 29. D 370 5.30 30. D 421 10.10 31. D 387 9.90 32. F 375.12 4.20 33. F 414.98 4.10 34. F 414.98 4.19 35 F 414.97 4.11 36. F 414.99 4.17 37. F 415.03 4.30 38. F 415.16 4.60 39. F 464.05 3.95 40. F 453.10 4.17 41. F 404.09 2.81 42. F 398.09 2.52 43. F 398.07 2.50 44. F 390.04 3.55 45. F 423.09 4.14 46. F 403.15 4.44 47. F 415.06 4.07 48. F 459.19 4.90 49. F 437.16 4.29 50. F 412.09 3 to 93 51. F 390.10 2 to 86 52. F 372.07 3 to 72 53. F 459.21 5 to 15 54. F 437.15 4 to 27 55. H 454.41 2 to 56. F 455.09 3.89 57. F 439.09 4.19 58. F 398.08 2.51 59. F 447.16 4.73 60. F 419.15 4.29 61. F 398.07 2.55 62. F 465.04 4.27 63. F 454.08 3.17 64. F 460.92 4.14 65. F 412.08 2.51 66. F 448.07 4.04 67. F 422.06 3.78 68. F 430.01 3.65 69. F 423.12 4.24 70. F 423.11 4.22 71. F 423.05 3.39 72. F 406.01 3 , 66 73. F 418.03 3.56 74. F 448.07 3.94 75. F 432.10 2.82 76. F 448.00 3.92 77. F 375.12 4.04 78. F 415.00 3.91 79. F 397.11 4, 08 80. F 390.13 2.59 81. F 415.06 3.97 82. F 437.11 4.19 83. F 391.12 3.55 84. F 465.20 4.44 85. F 439.09 4.17 86. F 442.97 3.80 87. G 437.11 3.87 88. G 439.10 3.77 89. G 447.11 4.16 90. G 419.12 3.85 91. G 437.03 4.26 92. G 465.01 3.79 93. G 454.11 2.85 94 G 460.94 3.76 95. F 448.11 3.56 96. G 422.09 4.31 97. G 430.04 3.23 98. G 423.10 3.79 99. G 423.10 3.78 100. G 406.03 3.33 101. G 418.05 3.15 102. G 448.09 3.51 103. G 432.12 2.57 104. G 448.03 3.53 105. E 404.13 2.55 106. E 397.07 3.99 107. E 397.08 4.13 108. E 427.08 4.03 109. G 415.11 4.08 110. G 453.13 3.63 111. G 398.11 2.39 112. G 398.11 2.37 113 G 412.14 2.38 114. G 423.08 3.08 115. H 415.27 2.49 116. H 415.27 2.49 117. H 464.38 2.34 118. H 390.33 2.12 119. H 459.45 3.04 120. H 412.36 2.37 121. H 459.45 2.92 122. H 404.39 1.35 123. H 412.36 1.36 124. H 372.32 2.10 125. F 347.16 3.55 126. F 423.20 4.12 127. F 390.2 2.71 128. F 365.15 3.60 129. F 375.20 4.06 130. F 404.24 2.49 131. G 415.04 3.95 132. F 415.10 4.01 133. F 415.09 3.99 134. F 415.12 4.15 135. H 415.11 4.38 136. F 397.20 3.94 137. F 397.19 3.97 138. F 412.20 2.43 139. F 464.19 3.85 140. F 453.21 4.09 141. F 426.16 2 , 82 142. F 398.18 2.48 143. F 404.20 2.81 144. F 398.19 2.47 145. F 398.19 2.50 146. F 398.17 2.40 147. F 390.22 2.57 148. F 390.16 3, 46 149. F 423.18 4.06 150. F 423.20 4.09 151. F 415.12 3.88 152. F 437.22 4.13 153. F 391.20 3.53 154. F 415.27 4.41 155. F 465.29 4.42 156. F 439.20 4.08 157. F 443.06 3, 87 158. F 412.21 3.85 159. F 372.17 3.43 160. F 459.33 4.84 161. F 437.23 4.15 162. F 453.21 3.89 163 F 423.18 3.37 164. F 455.2 3.70 165. F 439.20 4, 05 166. F 406.13 3.55 167. F 398.18 2.49 168. F 447.29 4.55 169. F 419.27 4.25 170. F 437.23 4.56 171. F 418.15 3.37 172. F 398.18 2.52 173. F 465.15 4.07 174. F 461.03 4.08 175. F 413.15 3.69 176. F 448.20 3.86 177. F 422.07 3.76 178. F 430.14 3.53 179. F 427.21 3.88 180 F 448.15 3.81 181. F 424.15 3.04 182. F 454.23 3.11 183. F 448.20 3.99 184. F 425.16 3.00 185. F 446.13 3.44 186. F 386.2 3.36 187. F 431.19 3,19 188. F 390.15 3.36 189. F 403.28 4.34 190. F 432.22 2.72 191. F 412.20 2.49 192. F 430.21 3.05 193. F 415.20 3.17 194. D 369 4.70 195. D 369 4.73 196. A 403 5.08 197. A 413 5.00 198. B 392 1.14 199. B 458 1.28 200. B 396 1.15 201. A 426 1.13 202. B 396 1.15 The compounds of the invention were the subject of pharmacological tests for determining their inhibitory effect on the enzyme FAAH (Fatty Acid Amide Hydrolase). 1 / Radioenzymatic test The inhibitory activity was demonstrated in a radioenzymatic test based on the measurement of the hydrolysis product of anandamide [ethanolamine 1-3H] by FAAH (Life Sciences (1995), 56, 1999- 2005 and Journal of Biochemical and Biophysical Methods (2004), 60 (2), 171-177). Thus, mouse brains (minus the cerebellum) are removed and stored at -80 ° C. The membrane homogenates are prepared extemporaneously by homogenization of the tissues using a Precellys® apparatus in the reaction buffer (10 mM Tris-HCl pH = 8, 150 mM NaCl and 1 mM ethylene diamine tetraacetic acid (EDTA)). ). The enzymatic reaction is carried out in 96 μl Multiscreen filtration plates in a final volume of 70 μl. Reaction buffer supplemented with bovine serum albumin without fatty acids (BSA, 1 mg / ml) is used for the enzymatic reaction, the dilution of the compounds and anandamide [ethanolamine 1-3H]. Serially added in the wells, the reaction buffer containing BSA (431 / well), the diluted compounds tested at different concentrations (7 μl / well containing 1% DMSO) and the membrane preparation (10 1 / well or 200 μg of 74 tissue per test). After 20 minutes of preincubation of the compounds with the enzyme at 25 ° C., the reaction is started by the addition of anandamide [3H ethanolamine] (specific activity of 15-20 Ci / mmol) diluted with cold anandamide (10 μl / well, final concentration of 10 μM, 0.01 μCi per test). After incubation for 20 minutes at 25 ° C., the enzymatic reaction is stopped by addition of a solution of 5M activated charcoal prepared in a 1.5M NaCl and 0.5M HCl buffer (50 μl / well). The mixture is stirred for 10 minutes then the aqueous phase containing ethanolamine [1-3H] is recovered by vacuum filtration and counted by liquid scintillation.

Under these conditions, the most active compounds of the invention have IC 50 (concentration inhibiting by 50% the enzymatic activity controlling FAAH) of between 0.1 and 1000 nM, preferably between 0.1 and 500 nM, preferably between 0.2 and 100 nM, or even between 0.2 and 50 nM. For example, compounds No. 26, No. 38, No. 39, No. 49, No. 60, No. 90 and No. 196 and # 199, # 200 and # 202 have IC 50's of 86 nM, 14 nM, 13 nM, 19 nM, 95 nM, 92 nM, 252 nM, 350 nM, 122 nM and 8 nM, respectively.

It therefore 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 can be evaluated in an analgesia test.

2 / Analgesia test Intraperitoneal (ip) administration of PBQ (phenylbenzoquinone, 2 mg / kg in 0.9% sodium chloride solution containing 5% ethanol) in male OF1 mice from 25 to 30 g, causes abdominal stretching, 75 on average 30 twists or contractions during the period of 5 to 15 minutes after injection. Test compounds are administered orally (p.o.) or intraperitoneally (i.p.) suspended in 0.5% Tween 80, 60 minutes or 120 minutes prior to administration of PBQ. Under these conditions, the most potent compounds reduce by 30 to 80% the number of stretching induced by the PBQ, in a range of doses between 1 and 30 mg / kg.

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of endogenous derivatives of amides and esters of various fatty acids such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert different pharmacological activities by interacting, inter alia, with the cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue level of these endogenous substances. They can be used for this purpose in the prevention and treatment of pathologies in which the endogenous cannabinoids and / or any other substrates metabolized by the enzyme FAAH, are involved. For example, the following diseases and conditions may be mentioned. pain, particularly acute or chronic pain of the neurogenic type: migraine, neuropathic pain including forms associated with the herpes virus and diabetes and chemotherapy, acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis , spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome, acute or chronic peripheral pain, dizziness, vomiting, nausea especially those following 76 chemotherapy, eating disorders especially anorexia and various types of cachexia, neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and anxiety of all kinds and origins, mood disorders, psychoses , acute neuro-degenerative diseases and onics: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, brain ischemia and brain and spinal cord injury, epilepsy, sleep disorders including sleep apnea, cardiovascular disease particular hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischemia, renal ischemia, cancers: benign tumors of the skin, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medullo-epitheliomas, medulloblastomas, neuroblastomas , tumors of embryonic origin, astrocytomas, astroblastomas, ependyomas, oligodendrogliomas, plexus tumors, neuroepitheliomas, epiphysis tumors, ependymoblastomas, malignant meningiomas, sarcomatoses, malignant melanomas, schwénnomes), disorders of the immune system, especially autoimmune diseases -immunes: psoriasis, lupus erythematosus, conjunctival tissue diseases ctive or connective tissue diseases, Sjeger's syndrome, ankylosing spondylitis, undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, diseases affecting the plasma cell line, allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis, infectious diseases parasitic, viral or bacterial 77: AIDS, meningitis, inflammatory diseases, including joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome, osteoporosis, eye diseases: ocular hypertension, glaucoma, lung diseases: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic airways obstruction, emphysema, diseases gastrointestinal: irritable bowel syndrome, intestinal inflammatory disorders, ulcers, diarrhea, urinary incontinence and bladder inflammation.

The use of the compounds according to the invention, in the form of a base, of an acid addition salt, of a hydrate or of a solvate which is pharmaceutically acceptable, for the preparation of a medicament intended to treat the abovementioned pathologies mentioned is an integral part of the invention.

The subject of the invention is also medicaments which comprise a compound of formula (I), (II) or (III), or an addition salt with an acid, or a pharmaceutically acceptable hydrate or solvate of the compound of formula (1), (Ii) or (Iii). These drugs find their use in therapy, especially in the treatment of the above-mentioned pathologies.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or an acid addition salt, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and optionally one or more pharmaceutically acceptable excipients. Said excipients are selected 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, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active ingredient of formula (I ), (Ii) or (iii) above, or its acid addition salt, solvate or hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or treatment of the disorders or diseases above.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, oral forms of administration. intratracheal, intraocular, intranasal, inhalation, subcutaneous, intramuscular or intravenous administration forms and rectal or vaginal administration forms. For topical application, the compounds according to the invention can be used in creams, ointments or lotions. By way of example, a unit dosage form of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg 79 Mannitol 223.75 mg Croscaramellose 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 dosage form.

There may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

The invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of an effective dose of a compound according to the invention, one of its addition salts a pharmaceutically acceptable acid, a solvate or a hydrate of said compound.

Claims (13)

Revendications1. A compound of the general formula (I): wherein R 2 represents a hydrogen, fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy group, - NR $ R9; - Ri and m represent, independently of one another, an integer equal to 1, 2 or 3, it being understood that the sum m + n is at most equal to 5; A represents a covalent bond, an oxygen atom, a C1_6_alkylene group or a -O-C1_6-alkylene group in which the end represented by an oxygen atom is bonded to the R1 group; - R1 represents a group R5 optionally substituted with one or more groups R6 and / or R7; R5 representing a group selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzoxadiazolyl, indazolyl, indolizinyl, indolyl, isoindolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyle, imidazopyridazinyl, tria zolopyridinyle, pyrrolopyridinyl pyrrolopyrimidinyl, pyrrolopyrazinyle, pyrrolopyridazinyle, pyrrolotriazinyle, pyrazolopyridinyle, pyrazolopyrimidinyl, pyrazolopyrazinyle, pyrazolopyridazinyle, furopyridinyl, furopyrimidinyle 'furopyrazinyle, furopyridazinyle , furotriazinyl, oxazolopyridinyl, oxazolopyrimidinyl, oxazolopyrazinyl, oxazolopyridazinyl, isoxazolopyridinyl, isoxazolopyrimidinyl, isoxazolopyrazinyl, isoxazolopyridazinyl, oxadiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridazinyl, thienotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, thiazolopyrazinyl, thiazolopyridazinyl, isothiazolopyridinyl, isothiazolopyrimidinyl, isothiazolopyrazinyl, isothiazolopyridazinyl, thiadiazolopyridinyl; R6 represents a halogen atom, a cyano group, -CH2CN, nitro, hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3-7-cycloalkyl; C 3-7 cycloalkyl-C 1-3 alkylene, C 3-7 cycloalkyl-C 1-3 alkylene-O-, - (CH 2) p -NR 8 R 9 1 -NRBCOR 9, -NR 8 CO 2 R 9, -NR 8 SO 2 R 9, -NR 8 SO 2 NR 8 R 9, -COR 2, -CO 2 R 8, CH 2) p-CONRBR 9 1 -SO 2 R 8, -SO 2 NR 8 R 9 or -O- (C 1-3 alkylene) -O-; R7 representing a group selected from a. phenyl, phenyl-C1-4-alkylene-, phenyl- (CH2) .p-O-, pyridinyl, pyridazinyl, pyrimidinyl,. pyrazinyl, triazinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl,, tetrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadazolyle, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl indazolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl; the group or groups R7 which may be substituted by one or more groups R6 which are identical or different from each other p representing a number which may have the value 0, 1, 2 or 3; R3 represents a hydrogen, fluorine, C1-C6alkyl or trifluoromethyl group; - R4 represents a 5-chain heterocycle selected from furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrazolyl, oxadiazolyl, thiadiazolyl, imidazole, triazolyl, tetrazolyl; Wherein said heterocycle is optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkylene, C 1-6 haloalkoxy, cyano, NR 8 R 9, -NRBC (O) R9, -NRBCO2R9, -NR9SO2R9r -NRBSO2NRBR9, -C (O) RB, -O2R8i -C (O) NR8R9, -C (O) N (RB) (C1-3alkylene-NR10R11), - SO2R8, -SO2NRBR9, -O- (C1-3alkylene) -O-; RB and R9, independently of one another, represent a hydrogen atom or a C1-6alkyl group, or form with the nitrogen atom (s) thereof, in the case of NR8R9, a ring selected from the group consisting of azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine rings, this ring being optionally substituted by a C1-6 alkyl or benzyl group; In the case of NR8COR9, a lactam ring; in the case of NR8CO2R9, an oxazolidinone, oxazinone or oxazepinone ring; in the case of NRBS02R9, a sultame cycle; in the case of NRBSO 2 NRBR 9, a thiazolidine dioxide or thiadiazinane dioxide ring; R10 and R11 independently of one another a hydrogen atom or a C1-6alkyl group; excluding the following compound: 5-methyl-isoxazol-3-ylmethyl 4-hydroxy-4- (4-chloro-phenyl) -piperidine-2-carboxylate, base or sodium salt addition to an acid. 2. Compound of formula (1) according to claim 1, characterized in that R2 represents a hydrogen atom, in the form of a base or an addition salt with an acid. Compound of formula (I) according to claim 1 or 2, characterized in that m and n are independently of one another the value of 1 or 2; in the form of a base or an acid addition salt. 4. Compound of formula (I) according to any one of the preceding claims characterized in that A 15 represents a group -O-C1_6-alkylene in which the end represented by an oxygen atom is bonded to the group R1; in the form of a base or an acid addition salt. 5. Compound of formula (I) according to any one of the preceding claims characterized in that R1 represents a group R5 optionally substituted with one or more groups R6 and / or. R7; Wherein R 5 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, naphthyridinyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, isobenzofuranyl, benzofuranyl; benzothiophenyl, indazolyl, indolizinyl, indolyl, isoindolyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl; R6 represents a halogen atom, a cyano group, -CH2CN, nitro, hydroxyl, C1-8-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3-7-cycloalkyl; ,. C 3-7 -cycloalkyl-C 1-3 alkylene, C 3-7 cycloalkyl-C 1-3 alkylene-O-, - (CH 2) p -NR 8 R 9, -NR 8 CORR 9 -NR 8 CO 2 R 9, -NR 8 SO 2 R 9, -NR 8 SO 2 NR 8 R 9, -COR 8, -CO 2 R 8, -CH 2) p -CONRsR 9 -SO2R8, -SO2NR8R9 or -O- (C1-3alkylene) -O-; R7 represents a group selected from phenyl, phenyl-C1-4alkylene-, phenyl- (CH2) p-O-, pyridinyl, pyridazinyl, isoxazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrazolyl, pyrimidinyl, thiazolyl, pyrazinyl, triazinyl, benzoxazolyl; the group or groups R7 may be substituted by one or more groups R6 identical to or different from each other as defined above; p representing a number that can have the value 0, 1, 2 or 3; R 8 and R 9 independently of one another represent a hydrogen atom or a C 1-6 -alkyl group or, together with the nitrogen atom (s) bearing them in the case of NR 8 R 9, a ring selected from azetidine rings; pyrrolidine, piperidine, morpholine, thiomorpholine, azepine, oxazepine or piperazine, this ring being optionally substituted by a C1_6-alkyl or benzyl group; in the case of NR8COR9i a lactam ring; in the case of NR8CO2R9i, an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR8SO2R9r a sultame cycle; in the case of NR8SO2NR8R9r, a thiazolidine dioxide or thiadiazinane dioxide ring in the base state or an acid addition salt. 30 6. Compound of formula (I) according to any one of the preceding claims characterized in that R3 represents a hydrogen atom; in the form of a base or an acid addition salt. 7. Compound of formula (I) according to any one of the preceding claims, characterized in that R4 represents a 5-chain heterocycle selected from a thiazolyl, isoxazolyl; this heterocycle being optionally substituted by one or more substituents -C (.0) NR8R9 in which R8 and R9 each represent a hydrogen atom; in the form of a base or an acid addition salt. 8. Compound according to any one of the preceding claims, characterized in that the compound is of formula (Ii). Wherein R1rA, R4, n and m are as defined in any one of the preceding claims; in the form of a base or an acid addition salt. 9. Compound according to any one of the preceding claims, characterized in that the compound is of formula (Iii). Wherein R 1, A, n and m are as defined in one of claims 1 to 8; in the form of a base or an acid addition salt. A process for preparing a compound according to any one of claims 1 to 9, comprising the step of reacting an amine derivative, compound of the following general formula (II): NH (II) wherein R1i R2 , A, n and m are as defined in one of the preceding claims, with a carbonate of general formula (III), which follows: wherein Z represents a hydrogen atom or a group nitro, R3 and R4 are as defined in any one of the preceding claims, in the presence of a base such as triethylamine, pyridine, N, N-dimethylaminopyridine or N, N-diisopropylethylamine, in an organic solvent such as toluene, acetonitrile or dichloroethane, at a temperature between room temperature and the reflux temperature of the solvent. 11. A compound according to any one of claims 1 to 9 in the form of a base or a pharmaceutically acceptable acid addition salt for use as a medicament. 25 12. A pharmaceutical composition containing at least one compound according to any one of claims 1 to 9, in the form of a base or addition salt with a pharmaceutically acceptable acid, and optionally one or more pharmaceutically acceptable excipients. 13. Use of a compound according to any one of the claims. 1 to 9, in the form of a base or of a pharmaceutically acceptable acid addition salt, for the preparation of a medicament for preventing or treating acute or chronic neurogenic pain, the acute or chronic pain associated with it inflammatory diseases, acute or chronic peripheral pains, dizziness, vomiting, nausea, eating disorders,. neurological and psychiatric pathologies, acute or chronic neuro-degenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancers, disorders of the immune system, allergic diseases, parasitic infectious diseases, viral or bacterial diseases, inflammatory diseases, osteoporosis, eye diseases, lung diseases, gastrointestinal diseases, urinary incontinence or bladder inflammation.