MXPA06007301A - Derivatives of 1-piperazine- and 1-homopiperazine-carboxylates, preparation method thereof and use of same as inhibitors of the faah enzyme - Google Patents

Abstract

The invention relates to a compound having general formula (I), wherein:m represents an integer equal to 1 or 2;R1 represents an aryl- or heteroaryl-type group that is optionally substituted by one or more R3 or R4 groups;R2 represents a group having general formula CHR5CONHR6;R3 represents a halogen atom or a hydroxy, cyano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, -O-(C2-3-alkylene)-, -O-(C1-3-alkylene)-O-, C1-6-fluorothioalkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylene, piperidinyl, benzyloxy, piperazinyl, pyrrolidinyl, morpholinyl, phenyloxy, NR7R8, NHCOR7, NHSO2R7, COR7, C02R7, CONR7R8, SO2R7 or SO2NR7R8 group;R4 represents an aryl- or heteroaryl-type group, whereby the R4 group(s) can be substituted by one or more identical or different R3 groups;R5 represents a hydrogen atom or a C1-3-alkyl group;R6 represents a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene group;and R7 and R8 represent, independently of each other, a hydrogen atom, a C1-3-alkyl group or a phenyl group, said compound taking the form of a base, an acid addition salt, a hydrate or a solvate. The compounds are inhibitors of the FAAH enzyme, which can be used for the treatment of pain, eating disorders, neurological and psychiatric pathologies, etc.

Description

DERIVATIVES OF 1-PIPERAZIN AND 1 -HOMOPIPERAZIN CARBOXYLATES, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS The invention has as its object the derivatives of 1-piperazin and 1-homopiperazine carboxylates, their preparation and their application in therapy. The compounds of the invention correspond to the general formula (I): ( wherein: m represents an integer equal to 1 or 2; Ri represents a group selected primarily from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl. , benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihydro-furopyridinyl, thienopyridinyl, dihydrothienopyridinyl, midazopiridinilo, midazopirir? idinilo, pyrazolopyridinyl, oxazolopiri-dinilo, isoxazolopyridinyl , thiazolopyridinyl or isothiazolopyridinyl, this group being optionally substituted with one or more R3 groups identical or different from each other or with a group R; R 2 represents a group of the general formula CHR 5 -CONHR 6, R 3 represents a halogen atom or a hydroxy, cyano, nitro, C 1 -C 4 alkyl, C 1 alkoxy, C 1 -C 6 thioalkyl, C 1 -C fluoroalkyl group, fluoroalkoxy-C? _6, -0- (alkylene-C2.3) -, -O-alkylene-C ^ JO-, fluorothioalkyl-C-? - 6, cycloalkyl-C3-7, cycloalkyl-C3-7-alkylene- C3.3, piperidinyl, benzyloxy, piperazinyl, pyrrolidinyl, morpholinyl, phenyloxy, NR7R8, NHCOR7, NHS02R7, COR7, C02R7, CONR7R8, SO2R7 or SO2NR7R8, R4 represents a group selected primarily from phenyl, benzofuranyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl , cinnolinyl, imidazolpirimidinilo, benzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihidrofuropiridinilo, thienopyridinyl, dihydrothienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pirazopiridinilo, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl or isothiazolopyridinyl; the R group (s) having one or more R3 groups identical or different from one another may be substituted; R5 represents a hydrogen atom or a C- ^ alkyl group; Re represents a hydrogen atom or a C alquilo alquilo alkyl group, C3.7 cycloalkyl or cycloalkyl-Cs-T-alkylene-CLa; R7 and R8 represent, independently of one another, a hydrogen atom, a C alquilo .3 alkyl group or a phenyl group. Among the compounds of general formula (I), a first sub-group of compounds consists of compounds for which: m represents an integer equal to 1 or 2; and / or Ri represents a group selected primarily from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, benzisoxazolyl, thienopyridinyl, this group being optionally substituted with one or more groups R3, more particularly with one or two identical R3 groups or different from each other; and / or R2 represents a group of general formula CHR5CONHR6; I R3 represents a halogen atom, more particularly chlorine, bromine or fluorine, or a cyano group, more particularly methyl, ethyl, n-propyl, isobutyl, alkoxy-Ci.β, more particularly methoxy, fluoroalkyl-C? .6, more particularly CF3, more particularly -OCH2CF3, -0- (C2.3 alkylene) -, more particularly -O- (CH2) 3-, phenyloxy; and / or R5 represents a hydrogen atom; and / or Re represents a hydrogen atom or a group more particularly methyl. Among the compounds of general formula (I), a second subgroup of compounds consists of compounds for which: m equals 1; and / or Ri represents a group chosen primarily from pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, this group being optionally substituted with a group R3; and / or R2 represents a group of general formula CHR5CONHR6; I R3 represents a halogen atom, more particularly chlorine, or a C1-C6 alkyl group, more particularly methyl, ethyl, n-propyl, isobutyl, C1-C6 alkoxy, more particularly methoxy, more particularly CF3; and / or R5 represents a hydrogen atom; and / or R6 represents a hydrogen atom or an alkyl-C ^ e group, more particularly methyl. Among the compounds of general formula (I), a third subgroup of compounds consists of compounds for which: m represents an integer equal to 1 or 2; and / or R-i represents a group chosen primarily from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or thiadiazolyl, this group optionally being substituted with a group R4; and / or R4 represents a group selected primarily from phenyl, benzofuranyl or naphthyl; the group R 4 can be substituted with one or more groups R 3 identical or different from one another, more particularly with one or two R 3 groups identical or different from one another; and / or R2 represents a group of general formula CHR5CONHR6; I R3 represents a halogen atom, more particularly chlorine, bromine or fluorine, or a nitro group, more particularly methyl, isopropyl, C 1 -C 6 alkoxy, more particularly methoxy, ethoxy, fluoroalkyl-C 6 -6, more particularly CF 3, fluoroalkoxy-C 6, more particularly OCF 3, -O-alkylene-C ^^ -O-, more particularly -O- CH2-0- or benzyloxy; and / or R5 represents a hydrogen atom; and / or R 6 represents a hydrogen atom or a C 1 -C alkyl group, more particularly methyl or ethyl, or C 3-7 cycloalkyl-C 1 -3 alkylene, more particularly cyclopropyl-CH 2 -. Among the compounds of general formula (I), a fourth sub-group of compounds consists of compounds for which: m equals 1; and / or Ri represents a group selected primarily from phenyl, pyridinyl, pyridazinyl or pyrimidinyl, this group being optionally substituted with a group R; and / or R4 represents a group selected primarily from phenyl, benzofuranyl or naphthyl; the group R can be substituted with one or more R3 groups identical or different from one another, more particularly with one or two R3 groups identical or different from one another; and / or R2 represents a group of general formula CHR5CONHR6; I R 3 represents a halogen atom, more particularly chlorine, bromine or fluorine, or a nitro group, C 1 -alkyl, more particularly methyl, isopropyl, C 1 -alkoxy, more particularly methoxy, ethoxy, fluoroalkyl-Cß-β, more particularly CF3, fluoroalkoxy-C1-6, more particularly OCF3, -O-alkylene-C ^ sJ-O-, more particularly -O-CH2-0- or benzyloxy; and / or R5 represents a hydrogen atom; and / or R6 represents a hydrogen atom or an alkyl-C ^ e group, more particularly methyl or ethyl. The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention. The compounds of formula (I) may exist in the form of bases or acid addition salts. Said addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, although salts of other acids useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention. The compounds of the general formula (I) can be present in the form of hydrates or solvates, that is to say in the form of combinations or combinations with one or more water molecules or with a solvent. Said hydrates and solvates are also part of the invention. In the context of the invention, it is meant by: Ct.z where t and z can have the values of 1 to 7, a carbon chain that can have from t to z carbon atoms, by example C? _3 a carbon chain which may have from 1 to 3 carbon atoms, alkyl, a saturated, linear or branched aliphatic group, for example, an alkyl-C? -3 group represents a carbon chain of 1 to 3 carbon atoms carbon, linear or branched, more particularly methyl, ethyl, propyl or 1-methylethyl, alkylene, a saturated, linear or branched divalent alkyl group, for example an alkylene-C ^ group represents a divalent carbon chain of 1 to 3 carbon atoms , linear or branched, more particularly methylene, ethylene, 1-methylethylene or propylene, cycloalkyl, a cyclic alkyl group, for example a C3.5 cycloalkyl group represents a cyclic carbon group of 3 to 5 carbon atoms, more particularly cyclopropyl, cyclobutyl or cyclopentyl, -alkoxy, a linear or branched saturated aliphatic chain-O-alkyl group, thioalkyl, a linear or branched saturated aliphatic chain -S-alkyl group, fluoroalkyl, an alkyl group in the l that one or several hydrogen atoms have been substituted with a fluorine atom, fluoroalkoxy, an alkoxy group in which one or more hydrogen atoms have been substituted with a fluorine atom, fluorothioalkyl, a thioalkyl group in which one or several hydrogen atoms have been substituted with a fluorine atom, - halogen atom, a fluorine, chlorine, bromine or iodine.

The compounds of the invention can be prepared according to different methods illustrated by the following schemes. Thus, a first preparation method (scheme 1) consists in reacting an amine of general formula (II), in which R, and m are as defined in the general formula (I), with a carbonate of the general formula (III), in which Z represents a hydrogen atom or a nitro group and R2 is as defined in the general formula (I), in a solvent such as toluene or dichloroethane, at a temperature comprised between 0 and 80 ° C. Scheme 1 (ll) The carbonates of the general formula (III) can be prepared according to any method described in the literature, for example, by reacting an alcohol of the general formula HOR2 with phenyl chloroformate or 4-nitrophenyl, in the presence of a base such as triethylamine or diisopropylethylamine. , at a temperature between 0 ° C and the reflux temperature of the solvent. According to a second method (scheme 2), the compounds of general formula (I) can be prepared by reacting an amine of general formula (II), as defined above, with a carbonate of general formula (Illa) in which Z represents a hydrogen atom or a nitro group, R5 is as defined in the general formula (I) and R represents a methyl or ethyl group. The carbamate ester of the general formula (la) obtained in this way is converted into a compound of the general formula (I), by aminolysis by an amine of the general formula R6NH2 in which R6 is as defined in the general formula ( I). The aminolysis reaction can be carried out in a solvent such as methanol or in a mixture of solvents such as methanol and tetrahydrofuran or methanol and dioxane.

Scheme 2 (U) (the) The carbonates of the general formula (Illa) can be prepared according to any method described in the literature, for example, by reacting an alcohol of the general formula HOCHR5COOR where R represents a methyl or ethyl group, with phenyl chloroformate or 4-nitrophenyl, presence of a base such as triethylamine or diisopropylethylamine. The compounds of general formula (I), in which Ri represents a group substituted with a R3 group of the alkyl-Ci-6, cycloalkyl-C3,7 or cycloalkyl-Cs ^ -alkylene-Ci-3 type, or with a group R4 as defined in general formula (I), can also be prepared by a Suzuki-type reaction carried out on the compounds of corresponding general formula (I), in which R ^ is substituted with a chlorine, bromine, iodine atom or with a triflate group in the position where the R3 or R4 group must be introduced, for example, by a boronic acid of alkyl, cycloalkyl, aryl or heteroaryl. For the compounds of general formula (I), in which Ri represents a group substituted with a group R3 of the C 1 -C 6 alkylcycloalkyl-C 3,7 type or C 1 -C 7 alkylene-alkylene-C 1 al so with a R 4 group as defined in the general formula (I), and R2 represents more particularly a group of the general formula CHR5CONHR6, the Suzuki reaction described above can be carried out on the carbamate ester of the general formula (la) as defined above . The action of an amine of general formula R6NH2 as defined above on the carbamate ester obtained in this manner makes it possible to obtain the compounds of general formula (I). The compounds of general formula (II), when their mode of preparation is not described, are commercially available or are described in the literature, or can be prepared according to the methods described herein or that are known to the person skilled in the art. The amines of the general formula RSNH2 are commercially available. The invention, according to another of its aspects, also has as its object the compounds of formula (la). These compounds are useful as synthesis intermediates of the compounds of formula (I). The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and only serve to illustrate the invention. The microanalyses, the spectra of I.R. and R.M. N. and / or analyzes by LC-MS (Liquid Chromatography coupled with Mass Spectrometry) confirm the structures and purities of the obtained compounds. PF (° C) represents the melting point in degrees Celsius. The numbers indicated in parentheses in the titles of the examples correspond to those in the first column of the following table. Example 1 (Compound No. 44) 4-. { 4 '- [(trifluoromethyl) oxy] -4-biphenylyl} -1-piperazinecarboxylate 2- (methylamino) -2-oxoethyl 1. 1. [(Phenyloxycarbonyl) oxy] ethyl acetate To a solution of 25 g (240 mmoles) of ethyl glycolate and 55 ml (315 mmoles) of diisopropylethylamine in 500 ml of toluene, 32 ml (256 mmoles) of phenyl chloroformate are slowly added at room temperature. Stirring is maintained at room temperature for 2 hours. The salt formed is separated and the filtrate is concentrated under reduced pressure. 53.7 g of oily product are obtained which is used as is in the next stage. 1 .2. 4- (4-bromophenyl) -1-piperazine carboxylic acid 2- (ethyloxy) -2-oxoethyl ester. A solution of 5.81 g 5 (24.08 mmol) of 1 - is heated at 80 ° C for 12 hours. 4-bromophenyl) piperazine and 6 g (26.76 mmoles) of ethyl [(phenyloxycarbonyl) oxy] acetate, obtained in step 1 .1. , in 50 ml of toluene. It is allowed to reach room temperature, concentrated under reduced pressure and the residue obtained in this way is purified by chromatography on silica gel eluting with a 20/80 and 30/70 mixture of ethyl acetate and cyclohexane. In this way 7.75 g of pure product are obtained in the form of an oil that crystallizes at room temperature. PF (° C): 80-82 ° C 5 1 .3. 4-. { 4 '- (trifluoromethyl) oxy] -4-biphenylyl} 2- (Ethyoxy) -2-oxoethyl-1-piperazinecarboxylate Under an inert atmosphere, 2 g (5.39 mmol) of 2- (ethyloxy) -2-oxoethyl 4- (4-bromophenyl) -1-piperazinecarboxylate are introduced. , obtained in stage 1 .2. 3.33 g (16.16 mmol) of 4- (trifluoromethoxy) phenyl or boronic acid and 4.57 g (21.55 mmol) of hydrated potassium phosphate in suspension in 18 ml of 1,2-dimethoxyethane. Then 0.62 g (0.54 mmoles) of palladium tetrakis (triphenylphosphine) are added. The reaction mixture is brought to approximately 80 ° C for 12 hours. It is concentrated under reduced pressure. The residue is taken up with 5 dichloromethane and water, the aqueous phase is separated, extracted twice with dichloromethane, the combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. The residue obtained in this way is purified by chromatography on silica gel eluting with a 30/70 mixture of ethyl acetate and cyclohexane. 5 1.65 g of product are obtained in the form of a white solid. PF (° C): 1 12-1 16 ° C 1.4. 4-. { 4 '- [(trifluoromethyl) oxy] -4-biphenylyl} 2- (Methylamino) -2-oxoethyl-1-piperazinecarboxylate To a solution of 1.60 g (3.54 mmol) of 4-. { 4'-0 [(trifluoromethyl) oxy] -4-biphenylyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazine carboxylate, prepared in step 1 .3. , in 14 ml of methanol, 7.10 ml (14.15 mmoles) of a solution of methylamine (2M) in tetrahydrofuran are added. Stirring is maintained at room temperature for 12 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. A solid is obtained which is recrystallized from a mixture of ethyl acetate and diisopropyl ether. In this way, 0.86 g of pure product is obtained in the form or a white solid. LC-MS: M + H = 438 PF (° C): 187-189 ° C 1 H NMR (CDCl 3) d (ppm): 2.90 (d, 3H); 3.25 (m, 4H); 3.70 (m, 4H); 4.60 (s, 2H); 6, 10 (broad s, 1 H); 7.0 (d, 2H); 7.30 (d, 2H); 7.50 (d, 5 2 H); 7.60 (d, 2H).

Example 2 (Compound No. 37) 4- [3 '- (trifluoromethyl) -4-biphenylyl] -1-piperazin carboxylate 2- (methylamino) -2-oxoethyl carboxylate 2. 1. 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate To a suspension of 2.62 g (29.4 mmoles) of 2-hydroxy-N-methylacetamide and 16.5 g (58.7 mmoles) of Diisopropylethylamine in the support (Argonaut Ps-DIEA, loading = 3.56 mmol / g) in 250 ml of dichloromethane, 5.93 g (29.4 mmol) of 4-nitrophenyl chloroformate are added in small portions at room temperature. Orbital shaking is maintained at room temperature for 16 hours. The resin is filtered, washed with 150 ml of dichloromethane and the filtrate is concentrated under reduced pressure. 6 g of product are obtained in the form of a light yellow solid (estimated purity of 70%) which is used as it is in the next step. 2.2. 4- (4-bromophenyl) -1-piperazincarboxylic acid 2- (methylamino) -2-oxoeti! O To a solution of 1.47 g (4 mmol) of 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate , obtained in step 2.1., in 18 ml of 1,2-dichloroethane, are added 1.17 g (4.85 mmol) of 1- (4- bromophenyl) piperazine. This reaction mixture is heated at 65 ° C for 2.25 hours. It is allowed to reach room temperature and then concentrated under reduced pressure. The yellow oily residue is taken up in dichloromethane and washed successively with soda (1 N), water, a 5% citric acid solution, water and then concentrated salt solution. This organic phase is dried over sodium sulfate and concentrated under reduced pressure. After washing with diisopropyl ether, 1.3 g of product are obtained in the form of a white solid. 2.3. Synthesis of the palladium catalyst incorporated in the Merrifield resin Under an inert atmosphere, to a suspension of 5 g (3.5 mmoles) of Merrifield resin (Fluka, 200-400 Mesh, cross-linked with 2% divinylbenzene (DVB), Load = 0 , 7 mmole / g) in 50 ml of anhydrous tetrahydrofuran (THF), 54.6 ml (27.3 mmoles) of a solution of commercially available lithium diphenylphosphide 0.5 M in THF are introduced. Orbital shaking is maintained at room temperature for 24 hours and 60 ml of acetone and 20 ml of water are added. The resin is filtered, washed successively with water, acetone, THF, a mixture THF / H20 (2/1), THF, toluene, dichloromethane and ethyl ether and dried in vacuum for 2 hours. A suspension of the resin obtained in this way in 47 ml of ethanol and 23 ml of toluene is heated at 70 ° C for 24 hours. After filtering, the resin is washed successively with acetone, THF and ethyl ether. In total, this treatment is repeated four times to eliminate the soluble fractions of the polymer. The resin obtained from this is dried empty way for 2 hours. To a suspension of this resin in 60 ml of toluene, 0.18 g (0.16 mmol) of palladium tetrakis (triphenylphosphine) are added and this reaction mixture is brought to 95 ° C for 24 hours. 5 Allow it to reach room temperature, filter the resin and wash successively with acetone, THF and ethyl ether. 5. 135 g of resin is obtained which is used as such in the next step. 2.4. 4- [3 '- (trifluoromethyl) -4- biphenyl-1-yl-2- (methylamino) -2-oxoethyl-piperazincarboxylate 0 0.18 g (0.5 mmol) of 4- (4-bromophenyl) are introduced. -1- 2- (methylamino) -2-oxoethyl piperazinecarboxylate, obtained in step 2.2. , 0.21 g (1.1 mmol) of 3- (trifluoromethyl) phenyl boronic acid and 0.16 g (1.5 mmol) of sodium carbonate in suspension in 3 ml of toluene and 0.3 ml of ethanol. Next, 0.14 g (~ 10 mol%) of palladium supported catalyst obtained in step 2.3 are added. and the orbital agitation is maintained at 80 ° C for 48 hours. Allow to reach room temperature, filter the resin, wash with dichloromethane and concentrate the filtrate under reduced pressure. The remainder is taken up in 5 ml of dichloromethane and washed with water and a saturated aqueous solution of sodium bicarbonate. The organic phase is filtered in a hydrophobic cartridge and the filtrate is concentrated under reduced pressure. An oily residue is obtained which crystallizes in diisopropyl ether. 5 0.15 g of white crystals are obtained.

LC-MS: M + H = 422 PF (° C): 129-130 ° C 1 H NMR (CDCl 3) d (ppm): 2.95 (d, 3H); 3.20-3.35 (m, 4H); 3.65-3.80 (m, 4H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 7.05 (d, 2H); 7.50-7.60 (m, 4H); 7.65-7.80 (m, 2H) Example 3 (Compound No. 76) 4-. { 5- [3- (trifluoromethyl) phenyl] -2-pyridinyl} 2- (methylamino) -2-oxoethyl -1-piperazincarboxylate 3. 1 . 4- (5-bromo-2-pyridinyl) -1-piperazine carboxylate 1,1-dimethylethyl ester In an autoclave, 29.2 g (157 mmol) of 1,1-dimethylethyl 1-piperazinecarboxylate, 37 g ( 157 mmoles) of 2,5-dibromopyridine and 21.7 g (157 mmoles) of potassium carbonate in suspension in 27 ml of dimethylsulfoxide (DMSO). It is then heated at 150 ° C for 21 hours. Allow it to reach room temperature, collect the reaction mixture with ethyl acetate and water and remove the insoluble portion by filtration. The aqueous phase is separated, extracted twice with ethyl acetate, the organic phases are washed together with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, sodium and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with a 99/1 mixture of dichloromethane and methanol. In this way 44 g of product are obtained in the form of a white solid. PF (° C): 83-85 ° C 3.2. 1- (5-bromo-2-pyridinyl) piperazine To a solution of 18.60 g (54.40 mmol) of 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate 1,1-dimethylethyl , obtained in stage 3.1. , in 100 ml of 1,4-dioxane, are added at room temperature, 49 ml (272 mmoles) of a solution of hydrochloric acid (6N) in isopropanol.

The reaction mixture is brought to approximately 60 ° C for 3 hours. It is concentrated to dryness under reduced pressure. The dihydrochloride obtained is taken up in 200 ml of dichloromethane and 200 ml of water and 10 g of sodium hydrogencarbonate are added in small portions with stirring. Decant, extract the aqueous phase twice with dichloromethane, wash the organic phases together with a saturated aqueous solution of sodium chloride, dry over sodium sulfate and concentrate the filtrate under reduced pressure. 12 g of product are obtained in the form of a white solid. PF (° C): 72 ° C 3.3. 4- (5-Bromo-2-pyridinyl) -1-piperazinecarboxylic acid 2- (ethyloxy) -2-oxoethyl ester The procedure is as described in example 1 (step 1.2.). From 6 g (24.80 mmol) of 1- (5-bromo-2-pyridinyl) piperazine, obtained in stage 3.2. , and 10.88 g (48.52 mmol) of ethyl [(phenyloxycarbonyl) oxy] acetate, prepared in step 1 .1. of Example 1, and after chromatography on silica gel eluting with a 15/85 and 30/70 mixture of ethyl acetate and cyclohexane, 6.70 g of product are obtained as an oil which crystallizes from a white solid. 3.4. 4-. { 5- [3- (trifluoromethyl) phenyl] -2-pyridinyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in Example 1 (step 1 .3.). From 3 g (8.06 mmol) of 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate of 2- (ethyloxy) -2-oxoethyl, obtained in step 3.3. , of 4.59 g (24.17 mmoles) of 3- (trifluoromethyl) phenyl boronic acid, 6.84 g (32.23 mmoles) of hydrated potassium phosphate and 0.93 g (0.806 mmoles) of palladium tetrakis (triphenylphosphine), and after chromatography on silica gel eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.22 g of product are obtained as a white solid. 3.5. 4-. { 5- [3- (trifluoromethyl) phenyl] -2-pyridinyl} 2- (Methylamino) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in example 1 (step 1 .4.). From 1.50 g (3.43 mmol) of 4-. { 5- [3- (trifluoromethyl) phenyl] -2-pyridinyl} 2- (Ethyloxy) -2-oxoethyl-1-piperazinecarboxylate, obtained in step 3.4. and 8.6 m (17.15 mmoles) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel eluting with a 97/3 mixture of dichloromethane and methanol, followed by a wash with diisopropylether. , HE they obtain 1.18 g of product in the form of a white solid. LC-MS: M + H = 423 PF (° C): 158-160 ° C 1 H NMR (CDCl 3) d (ppm): 2.90 (d, 3H); 3.75 (broad s, 8H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 6.75 (d, 1 H); 7.50-7.80 (broadband, 5H); 8.50 (d, 1 H). Example 4 (Compound No. 79) 4-. { 5- [4- (Trifluoromethyl) phenyl] -2-pyridinyl} 2- (methylamino) -2-oxoethyl -1-piperazinecarboxylate 4. 1. 4- { 5- [4- (Trifluoromethyl) phenyl] -2-pyridinyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in Example 1 (step 1.3.). From 4 g (10.75 mmoles) of 2- (ethyloxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate, obtained in step 3.3. of Example 3, 5.50 g (28.96 mmol) of 4- (trifluoromethyl) phenyl boronic acid, of 9, 12 g (42.99 mmol) of potassium hydrous phosphate and of 1.24 g (1, 07 mmoles) of palladium tetrakis (triphenylphosphine), and after chromatography on silica gel eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.78 g of product are obtained as a white solid. 4. 2. 4-. { 5- [4- (Trifluoromethyl) phenyl] -2-pyridinyl} 2- (Methylamino) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in example 1 (step 1 .4.). From 2.77 g (6.33 mmoles) of 4-. { 5- [4- (Trifluoromethyl) phenyl] -2-pyridinyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate, obtained in step 4.1. and of 15.80 ml (31.67 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel eluting with a 97/3 mixture of dichloromethane and methanol, followed by recrystallization from acetate of ethyl, 1.69 g of product are obtained in the form of a white solid. LC-MS: M + H = 423 PF (° C): 206-209 ° C 1 H NMR (CDCl 3) d (ppm): 2.90 (d, 3H); 3.70 (broad s, 8H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 6.75 (d, 1 H); 7.60-7, 75 (m, 4H); 7.80 (dd, 1 H); 8.50 (d, 1 H). Example 5 (Compound No. 83) 4- (5- { 4 - [(trifluoromethyl) oxy] phenyl] -2-pyridinium) -1-piperazinecarboxylic acid 2- (methylamino) -2-oxoethyl . 1 . 2- (Methylamino) -2-oxoethyl-1,4-piperazine dicarboxylate 1,1-dimethylethyl ester To a solution cooled to 0 ° C of 1.1 g (3 mmol) of 2- (methylamino) -2- nitrophenylcarbonate. oxoethyl, prepared in step 2.2. from Example 2, in 10 ml of 1,2-dichloroethane, a solution of 0.53 g (2.85 mmol) of 1,1-dimethylethyl-1-piperazinecarboxylate is added dropwise at about 0 ° C. ml of 1,2-dichloroethane. Stirring is maintained at 0 ° C for 1 hour, and then at room temperature for 3 hours. Concentrate under reduced pressure and purify the residue obtained by chromatography on silica gel eluting with a 20/80 mixture of ethyl acetate and cyclohexane. The gradient is progressively increased to terminate the elution with ethyl acetate. An oily residue is obtained which crystallizes in diisopropyl ether. 0.61 g of product are obtained in the form of a white solid which is used as such in the next step. 5.2. 2- (Methylamino) -2-oxoethyl 1-piperazinecarboxylate hydrochloride To a solution of 2.68 g (8.9 mmoles) of 1,1-dimethylethyl 1, 4-piperazin dicarboxylic acid 2- (methylamino) -2-oxoethyl, obtained according to step 5.1. 25 ml of a 6 N hydrochloric acid solution in isopropanol are added in 25 ml of dichloromethane. Stirring is maintained at room temperature for 1 hour. The organic phase is removed by filtration through a Hydrophobic cartridge and the aqueous acid phase is concentrated under reduced pressure. After crystallization from isopropanol, 2.05 g of product are obtained in the form of a white solid which is used as it is in step 5 below. PF (° C): 167-169 ° C 5.3 2- (Methylamino) -2-oxoethyl 4- (5-nitro-2-pyridinyl) -1-piperazinecarboxylate To a solution of 2.05 g (8.62 mmol) ) of 2- (methylamino) -2-oxoethyl piperazinecarboxylate hydrochloride, obtained in step . 2. and 3.85 ml (22.4 mmol) of N, N-diisopropylethylamine in 55 ml of 1,2-dichloroene are added 1.84 g (1.1 mmol) of 2-chloro-5-nitropyridine. .

This reaction mixture is brought to 70 ° C for 5 hours. Allow to reach room temperature, concentrate under reduced pressure and purify the residue obtained in this way by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol. 2.48 g of product are obtained in the form of a light yellow solid which is used as such in the next step. or 5.4. 2- (Methylamino) -2-oxoethyl 4- (5-amino-2-pyridinyl) -1-piperazinecarboxylate To a suspension of 0.64 g (1.98 mmol) of 4- (5-nitro-2) 2- (methylamino) -2-oxoethyl-pyridinyl) -1-piperazinecarboxylate, prepared in step 5.3. , in 90 ml of ethyl acetate, 0.24 g of 10% palladium on carbon are added. Stirring is maintained at room temperature under a 60 psi hydrogen atmosphere for 14 hours. After filtering the catalyst, the filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol. 0.47 g of product are obtained in the form of a violet oil which is used as it is in the next step. 5.5 2- (Methylamino) -2-oxoethyl 4- (5-iodo-2-pyridinyl) -1-piperazincarboxylate To a solution cooled to 0 ° C of 0.47 g (1.5 mmoles) of 4-0 (5 2- (methylamino) -2-oxoety! -amino-2-pyridinyl) -1-piperazinecarboxylate, prepared in step 5.4. , in 15 ml of an aqueous solution of sulfuric acid (0.33 N), a solution of 0.16 g (2.2 mmol) of dissolved sodium nitrite in 3.5 ml of water is slowly added. Stirring is maintained at about 0 ° C for 0.5 hours and slowly adding 0.83 g (5 mmol) of potassium iodide. Stirring is maintained at this temperature for 0.5 hour and the reaction mixture is brought to 85 ° C for 2 hours. After cooling to room temperature, the reaction medium is basified to pH = 14, by the addition of a saturated aqueous solution of sodium bicarbonate. The aqueous phase is extracted three times with dichloromethane, the organic phases are washed together with an aqueous solution of thiosulfite at 35%, water, concentrated salt solution and dried over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. After washing with diisopropyl ether, 0.35 g of product are obtained in the form of a beige solid which is used as such in the next step. 5.6. 4- (5- { 4 - [(trifluoromethyl) oxy] phenyl] -2-pyridinyl) -1-piperazinecarboxylic acid 2- (methylamino) -2-oxoethyl The procedure is followed according to the procedure described in example 2 (step 2.4.). From 0.250 g (0.61 mmol) of 2- (methylamino) -2-oxoethyl 4- (5-iodo-2-pyridinyl) -1-piperazinecarboxylate, obtained in step 5.5. , of 0.51 g (2.44 moles) of 4- (trifluoromethoxy) phenyl boronic acid, of 0.61 g (~ 8% by mole) of solid supported palladium catalyst, prepared in step 2.1. from Example 2, and from 2.9 ml (7.32 mmol) of an aqueous solution of sodium carbonate (2.5 M) in suspension in 12 ml of toluene and 3 ml of ethanol, and after chromatography on silica gel. silica eluting with a 98/2 mixture of dichloromethane and methanol, followed by a wash with diisopropyl ether, gave 0.092 g of product as a white solid. LC-MS: M + H = 439 PF (° C): 188-190 ° C 1 H NMR (CDCl 3) d (ppm): 2.90 (d, 3H); 4.70 (broad s, 8H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 6, 75 (dd, 1 H); 7.30 (d, 2H); 7.55 (d, 2H); 7.75 (dd, 1 H); 8.45 (dd, 1 H). Example 6 (Compound No. 63) 4- [5- (2-methylpropyl) -2-pyridinyl-J-1-piperazine carboxylate of 2- (methylamine) -2-oxoethyl 6. 1 . 2- (Methylamino) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate The procedure is as described in example 1 (step 1 .4.). From 2.20 g (5.91 mmol) of 2- (ethyloxy) -2-oxoethyl 4- (5-bromo-2-pyridinyl) -1-piperazinecarboxylate, obtained in step 3.3. of example 3and of 14.80 ml (29.55 mmoles) of a solution of methylamine (2M) in tetrahydrofuran, and after crystallizing from diisopropyl ether, 1.974 g of pure product are obtained in the form of a white solid. 6.2. 4- [5- (2-methylpropyl) -2-pyridinyl] -1-piperazin carboxylate of 2- 2- (methylamino) -2-oxoethyl. Under inert atmosphere, 0.88 g (2.47 mmol) of (2- (methylamino) -2-oxoethyl (5-bromo-2-pyridinyl) -1-piperazin carboxylate, obtained in step 6.1. 0.33 g (3.22 mmol) of isobutylboronic acid, 1.16 g (5.44 mmol) of hydrated potassium phosphate and / or 0.07 g (0.25 mmol) of tricyclohexylphosphine in suspension in 11 ml of toluene Then 0.028 g (0.12 mmol) of palladium diacetate are added. The reaction mixture is brought to reflux for 3 hours. Allow it to reach room temperature and add 15 ml of water and 15 ml of ethyl acetate. The salts are separated by filtration on a frit, decanted, the aqueous phase is extracted twice with ethyl acetate. ethyl acetate, the organic phases are washed together with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After evaporating the solvent, the residue obtained is purified by chromatography on silica gel eluting with a 97/3 mixture of dichloromethane and methanol. 0.17 g of product are obtained in the form of a white solid after crystallization from diisopropyl ether. LC-MS: M + H = 335 PF (° C): 127-129 ° C 1 H NMR (CDCl 3) d (ppm): 0.90 (d, 6H); 1.80 (m, 1 H); 2.35 (d, 2H); 2, 90 (d, 3H); 3.60 (m, 8H); 4.65 (s, 2H); 6, 10 (broad s, 1 H); 6.60 (d, 1 H); 7.35 (dd, 1 H); 8.0 (d, 1 H). Example 7 (Compound No. 85) 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridinyl} 2- (Methylamino) -2-? Xoethyl-1-piperazinecarboxylate 7. 1 . 4- (3-pyridinyl) -1-piperazincarboxylate 1,1-dimethyl ethyl ester Under an inert atmosphere, 7.07 g (44.74 mmoles) of 3-bromopyridine, 10 g (53.69 mmoles) of 1,1-dimethylethyl-1-piperazinecarboxylate, 6.02 g (62.64 mmoles) are introduced. of sodium tert-butylate and 0.836 g (1.34 mmol) of (2,2'-bis (diphenylphosphino) -1,1-biphenyl) (BI NAP) in suspension in 100 ml of toluene. 0.41 g (0.45 mmol) of [dipalladium tris (dibenzylideneacetone)] (Pd2 (dba) 3). The reaction mixture is brought to reflux for 22 hours. It is allowed to reach room temperature, the salts are separated by filtration in glass fiber and the filtrate is concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and 100 ml of water, the aqueous phase is separated, extracted several times with ethyl acetate, the organic phases are washed together with a saturated aqueous solution of sodium chloride, dried on sodium sulfate and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with a 98/2 mixture and 95/5 dichloromethane and methanol. 9.80 g of product are obtained in the form of an oil which crystallizes at room temperature. 7.2. 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylic acid 1,1-dimethylethyl ester To a solution of 4 g (15.19 mmol) of 4- (3-pyridinyl) -1-piperazinecarboxylate of 1.1 - dimethylethyl, obtained in step 7.1. , in 50 ml of acetonitrile, cooled to approximately 0 ° C, 2.70 g (15, 19 mmoles) of N-bromosuccinimide are added in small fractions.

(NBS) Stirring is maintained at 0 ° C for 15 minutes, and then at room temperature for 2 hours. 100 ml of an aqueous solution of sodium hydroxide (1 M) and 100 ml of ethyl acetate are added to the reaction medium. The aqueous phase is separated, extracted twice with ethyl acetate, the organic phases together with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and the filtrate is concentrated under reduced pressure. 5.16 g of product are obtained in the form of a yellow-orange solid used as such in the next step. 7.3. 1- (6-bromo-3-pyridinyl) piperazine To a suspension of 5.16 g (15.08 mmol) of 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate of 1,1-dimethylethyl, obtained in the stage 7. 2. in 70 ml of dichloromethane, 1 1, 20 ml (150.77 mmol) of trifluoroacetic acid are slowly added. Stirring is maintained at room temperature for 16 hours. It is concentrated under reduced pressure, the residue is taken up in 40 ml of chloroform and 4 ml of an aqueous solution of sodium hydroxide (10 M) are slowly added. The aqueous phase is separated and extracted two times with chloroform. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. In this way, 5.16 g of product are obtained in the form of an orange oil that crystallizes at room temperature. This product is used as it is in the next stage. 7.4. 2- (Ethyloxy) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate The procedure is as described in example 1 (step 1 .2.). From 3.57 g (14.76 mmoles) of 1- (6-bromo-3-pyridinyl) piperazine, obtained in step 7.3. , and of 3.97 g (17.71 mmoles) of [(Phenyloxycarbonyl) oxy] ethyl acetate, prepared in step 1 .1. of Example 1, and after chromatography on silica gel eluting with a 99/1 and 98/2 mixture of dichloromethane and methanol, 3.75 g of product are obtained in the form of a yellow oil which crystallizes at room temperature. 7.5. 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridinyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in Example 1 (step 1 .3.). From 1.28 g (3.43 mmol) of 4- (6-bromo-3-pyridinyl) -1-piperazine carboxylate of 2- (ethyloxy) -2-oxoethyl, obtained in step 7.4. , of 1.96 g (10.29 mmol) of 3- (trifluoromethyl) phenyl boronic acid, 2.91 g (13.72 mmol) of hydrated potassium phosphate and 0.40 g (0.34 mmol) of palladium tetrakis (triphenylphosphine), and after chromatography on silica gel eluting with a 35/65 mixture of ethyl acetate and cyclohexane, 0.98 g of pure product is obtained in the form of an oil which crystallizes at room temperature. 7.6. 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridinium} 2- (Methylamino) -2-oxoeti-piperazinecarboxylate (or The mode of operation described in Example 1 is used (step 1 .4.). From 0.60 g (1.37 mmoles) of 4 - { 6- [3- (trifluoromethyl) phenyl] -3-pyridinyl.} -1- piperazine carboxylate of 2- (ethyloxy) -2-oxoethyl, obtained in step 7.5., And of 3.40 ml (6.86 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel eluting with a 98/2 and 97/3 mixture of dichloromethane and methanol, followed by a washing with diisopropyl ether, they obtain 0.36 g of pure product in the form of a white solid. LC-MS: M + H = 423 PF (° C): 146-150 ° C 1 H NMR (CDCl 3) d (ppm): 2.90 (d, 3H); 3.35 (m, 4H); 3.80 (m, 4H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 7.30 (m, 1 H); 7.65 (m, 2H); 7.70 (d, 1 H); 8, 10 (d, 1 H); 8.25 (s, 1 H); 8.45 (d, 1 H). Example 8 (Compound No. 86) 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridi ni I.}. - 2-amino-2-oxoethyl 1-piperazinecarboxylate To a solution of 0.30 g (0.69 mmol) of 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridinyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazine carboxylate, obtained in step 7.5. of Example 7, in 6 ml of a 1/1 mixture of methanol and tetrahydrofuran, 5.90 ml (41.40 mmol) of a solution of ammonia (7 N) in methanol are added. Stirring is maintained at room temperature for 22 hours. After concentrating under reduced pressure, the residue obtained is purified by chromatography on silica gel eluting with a 96/4 mixture of dichloromethane and methanol, followed by a wash with diisopropyl ether. 0.19 g of pure product are obtained in the form of a solid yellow. LC-MS: M + H = 409 PF (° C): 155-157 ° C 1 H NMR (CDCl 3) d (ppm): 3.35 (m, 4H); 3.75 (m, 4H); 4.70 (s, 2H); 5.50 (broad s, 1 H); 6.0 (broad s, 1 H); 7.30 (m, 1 H); 7.55 (m, 2H); 7.70 (d, 1 H); 8, 10 (d, 1 H); 8.25 (s, 1 H); 8.40 (d, 1 H). Example 9 (Compound No. 66) 4- [6- (2-methylpropyl) -3-pyridinyl] -1-piperazinecarboxylate 2- (methylamino) -2-oxoethyl 9. 1 . 2- (Methylamino) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazinecarboxylate The operation mode described in Example 1 is used (step 1 .4.). From 2.35 g (6.32 mmol) of 2- (ethyloxy) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazine carboxylate, obtained in step 7.4. of Example 7, and of 15.80 ml (31.61 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel eluting with a 98/2 and 97/3 mixture of dichloromethane and methanol , 1,779 g of product are obtained in the form of a white solid. PF (° C): 164 ° C 9.2. 4- (6- (2-methylpropyl) -3-pyridinyl] -1-piperazine carboxylate of 2- (methylamino) -2-oxoethyl Under an inert atmosphere, 1.25 g (3.50 mmol) of 2- (methylamino) -2-oxoethyl 4- (6-bromo-3-pyridinyl) -1-piperazine carboxylate, prepared in step 9.1, are introduced. , and 0.12 g (0.17 mmoles) of palladium dichloro bis (triphenylphosphine) (Pd (PPh3) 2Cl2) in suspension in 7 ml of tetrahydrofuran. 17 are added, 50 ml (8.74 mmoles) of a solution of bromoisobutyl) zinc (0.5 M) in tetrahydrofuran. Stirring is maintained at room temperature for 19 hours. The reaction mixture is poured into 25 ml of water and 25 ml of ethyl acetate. The insoluble part in fiberglass is filtered. Decant, extract the aqueous phase twice with ethyl acetate, dry the organic phases together over sodium sulfate and concentrate the filtrate under reduced pressure. The residue obtained is purified by chromatography on silica gel eluting with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether. 0.36 g of pure product are obtained in the form of a brown solid. LC-MS: M + H = 335 PF (° C): 87-89 ° C 1 H NMR (CDCl 3) d (ppm): 0.90 (d, 6H); 2.05 (m, 1 H); 2.60 (d, 2H); 2.90 (d, 3H); 3.20 (m, 4H); 3.70 (m, 4H); 4.65 (s, 2H); 6.05 (broad s, 1 H); 7.0-7.20 (m, 2H); 8.25 (d, 1 H). Example 10 (Compound No. 87) 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridanyl} 2- (methylamino) -2-oxoethyl -1-piperazinecarboxylate . 1 . 4- (6-chloro-3-pyridazinyl) -1-piperazinecarboxylate of 2- (ethy! Oxy) -2-oxoethyl The procedure is as described in example 1 (step 1 .2.). From 1.60 g (8.05 mmol) of 3-chloro-6- (1-piperazinyl) pyridazine (J. Med. Chem., 18, 2002, 401 1-4017) and from 1.99 g (8.86 mmol) of [(phenyloxycarbonyl) oxy] ethyl acetate, prepared in step 1 .1. of Example 1, and after chromatography on silica gel eluting with a 98/2 mixture of dichloromethane and methanol, 1.70 g of product are obtained as a white solid. PF (° C): 149-151 ° C 10.2. 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridanyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate The procedure is followed according to the procedure described in Example 1 (step 1 .3.). From 1.15 g (3.50 mmol) of 2- (ethyloxy) -2-oxoethyl 4- (6-chloro-3-pyridazinyl) -1-piperazinecarboxylate, obtained in step 10.1. , of 1.99 g (10.49 mmol) of 3- (trifluoromethyl) phenyl boronic acid, 2.97 g (13.99 mmol) of potassium phosphate hydrate and 0.40 g (0.35 mmol) of palladium tetrakis (triphenylphosphine) r and after chromatography on silica gel eluting with a 35/65 and 45/55 mixture of ethyl acetate and cyclohexane, 0.67 g of pure product is obtained in the form of a solid.

PF (° C): 126-128 ° C 10.3. 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridanyl} 2- (Methylamino) -2-oxoethyl-piperazinecarboxylate The operation mode described in Example 1 is used (step 1 .4.). From 0.66 g (1.51 mmol) of 4-. { 6- [3- (trifluoromethyl) phenyl] -3-pyridanyl} 2- (Ethyloxy) -2-oxoethyl -1-piperazinecarboxylate, obtained in step 10.2. and of 3 ml (6.02 mmol) of a solution of methylamine (2 M) in tetrahydrofuran, and after chromatography on silica gel eluting with a 96/4 mixture of dichloromethane and methanol, followed by a wash with diisopropyl ether, 0.50 g of product are obtained in the form of a white solid. LC-MS: M + H = 424 PF (° C): 151-153 ° C 1 H NMR (DMSO) d (ppm): 2.60 (d, 3H); 3.55 (m, 4H); 3.75 (m, 4H); 4.45 (s, 2H); 7.40 (d, 1 H); 7.80 (m, 3H); 8, 10 (d, 1 H); 8.35 (m, 2H). Example 1 1 (Compound No. 103) 4- (5- { 4 - [(trifluoromethyl) oxy] phenyl] -2- pyridinyl) -1,4-diazepane-1-carboxylate of 2- (methylamino) -2-oxoethyl 1 1 .1. 4- (5-bromo-2-pyridinif) -1,4-diazepane-1-carboxylate 1,1-dimethylethyl In an autoclave, 1.03 g (5 mmol) of 1,4-diazepane-1-carboxylate 1,1-dimethylethyl, 1.19 g (5 mmol) of 2,5-dibromopyridine are introduced. and 0.7 g (5 mmol) of potassium carbonate in suspension in 0.90 ml of dimethyl sulfoxide (DMSO). Heat at 150 ° C for 22 hours. Allow to reach room temperature, collect the reaction mixture with ethyl acetate, wash with water and concentrated salt solution, and dry over sodium sulfate. The filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica gel eluting with a 99.5 / 0.5 mixture of dichloromethane and methanol. 1.63 g of product are obtained in the form of oil which is used as such in the next step. 1 1 .2. 1- (5-bromo-2-pyridinyl) -1,4-diazepam To a solution of 1.63 g (4.4 mmol) of 4- (5-bromo-2-pyridinyl) -1,4-diazepam 1-1,1-dimethylethyl carboxylate, obtained in step 1 1.1. , in 12 ml of dioxane and 4 ml of ethanol, add 6 ml of a solution of hydrochloric acid (6N) in isopropanol. This reaction mixture is brought to 70 ° C for 3 hours. It is allowed to reach room temperature and then concentrated under reduced pressure. 1.32 g of a white solid are obtained after crystallization from acetone. Collect these crystals in 10 ml of dichloromethane and basify the reaction medium to pH = 14, by adding a 28% ammonia solution. The organic phase is recovered by filtration through a hydrophobic cartridge and the filtrate is concentrated under reduced pressure. 0.96 g of product are obtained in the form of an oil which is used as it is in the next step. 1 1 .3. 4- (5-bromo-2-pyridinyl) -1, 2- (methylamino) -2-oxoethyl 4-diazepane-1-carboxylate The procedure is as described in example 1 (step 1.2.). From 0.95 g (3.70 mmoles) of 1- (5-bromo-2-pyridinyl) -1,4-diazepam, 0 obtained in step 1 1 .2. , and of 0.94 g (3.70 mmol) of 2- (methylamino) -2-oxoethyl-4-nitrophenol carbonate, prepared in step 2.2. of Example 2, and after chromatography on silica gel eluting with a 30/70 mixture of ethyl acetate and cyclohexane and then with a 95/5 mixture of dichloromethane and methanol, followed by a crystallization from diisopropyl ether, gives 0, 97 g of product in the form of a white solid. 1 1 .4. 4- (5- { 4 - [(trifluoromethyl) oxy] phenyl} -2-pyridinyl) -1,4-diazepane-1-carboxylic acid 2- (methylamino) -2-oxoethyl ester In a Pyrex reactor , 0.12 g (0.3 mmol) of 4- (5-bromo-2-pyridi or I) -1,4-diazepane-1-carboxylate of 2- (methylamino) -2- or oxoethyl are introduced, prepared in stage 1 1.3. 0.25 g (1.2 mmoles) of 4- (trifluoromethoxy) phenyl boronic acid and 0.9 ml (1.8 mmoles) of an aqueous solution of sodium carbonate (2M), in suspension in 3.5 ml of toluene and 0.8 ml of ethanol. Then 0.07 g (0.06 mmoles) of palladium tetrakis (triphenylphosphine) are added and, after sealing the reactor, it is brought to 150 ° C for 15 minutes under microwave irradiation.

The organic phase is recovered by decantation and the filtrate is concentrated under reduced pressure. The residue obtained in this way is purified by chromatography on silica gel eluting with a 30/70/5 mixture of ethyl acetate, cyclohexane and methanol. After crystallizing from diisopropyl ether, 0.078 g of product are obtained in the form of a white solid. LC-MS: M + H = 452 PF (° C): 191 -193 ° C 1 H-NMR (DMSO) d (ppm): 1.70-2.00 (m, 2H); 2.55 (d, 3H); 3.25-3.40 (m, 2H); 3.40-3.90 (m, 6H); 4.35 (d, 2H); 6.75 (d, 1 H); 7.35 (d, 2H); 7.70 (broad d, 2H + NH); 7.80 (dd, 1 H); 8.45 (d, 1 H). Table 1 below illustrates the chemical structures and physical properties of some compounds according to the invention. In the column "base or salt", "base" represents a compound in the form of librßi base while "HCl" represents a compound in the form of hydrochloride. In the table, OMe represents a methoxy group. In the column "PF (° C) or M + H", PF (° C) is the melting point of the compound in degrees Ceisius and M + H is the value of the mass of the compound protonated by a hydrogen atom (mass of compound + 1), determined by LC-MS (Liquid Chromatography - Spectroscopy of Masses). Table 1 (i) fifteen twenty 1 CH2CONHCH3 base 180-181 CH2CONHCH3 base 175-176 CH2CONHCH3 base 197-198 CH2CONHCH3 base 129-130 CH2CONHCH3 base 207-208 CH2CONHCH3 base 123-124 CH2CONHCH3 base 202-203 CH2CONHCH3 base 157-158 CH2CONHCH3 base 139-140 CH2CONHCH3 base 215-216 CH2CONHCH3 base 187-189 CH2CONH2 base 193-195 CH2CONHCH3 HCl 199-200 CH2CONHCH3 base 181 -182 CH2CONHCH3 base 164-165 CH2CONHCH3 base 183-184 The compounds of the invention have been the object of pharmacological tests that allow to determine their inhibitory effect of the FAAH enzyme (Amido-Hydrolase of Fatty Acids). The inhibitory activity has been demonstrated in a radioenzymatic assay based on the determination of the product of hydrolysis (ethanolamine [1 -3H]) of anandamide [ethanolamine 1-3H] by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). Thus, the brains of mice (minus the cerebellum) are removed and stored at -80 ° C. The homogenates of the membranes are prepared extemporaneously by homogenization of the tissues in a Polytron in a buffer solution of 10mM Tris-HCl (pH 8) containing 150mM NaCl and 1mM EDTA. The enzymatic reaction is then carried out in 70 μL of buffer containing bovine serum albumin without fatty acids (1 mg / ml). Subsequently, the compounds tested in different concentrations were added, anandamide [ethanolamine 1 -3H] (specific activity of 15-20 Ci / mmol) diluted to 10 μM with cold anandamide and the membrane preparation (400 μg of tissue frozen by test). After 15 minutes at 25 ° C, the enzymatic reaction is stopped by the addition of 140 μL of chloroform / methanol (2: 1). The mixture is stirred 10 minutes and centrifuged for 15 minutes at 3500g. An aliquot (30 μL) of the aqueous phase containing the ethanolamine [1-3H] is counted by liquid scintillation. Under these conditions, the most active compounds of the invention have values of Cl50 (concentration that inhibits in 50% the control enzymatic activity of the FAAH) comprised between 0.001 and 1 μM. Table 2 below shows the Cl50 of some compounds according to the invention. Table 2 It appears, therefore, that the compounds according to the invention have an inhibitory activity on the FAAH enzyme. The in vivo activity of the compounds of the invention has been evaluated in an analgesic assay. Thus, the intraperitoneal (ip) administration of the PBQ (phenylbenzoquinone, 2 mg / kg in a 0.9% sodium chloride solution containing 5% ethanol) to OF1 male rats from 25 to 30 g, causes abdominal stretches , 30 twists or contractions on average during the period of 5 to 15 minutes after the injection. The compounds tested are administered orally in Tween 80 at 0, 5%, 60 minutes or 120 minutes before PBQ administration. Under these conditions, the most potent compounds of the invention reduce from 35 to 70% the number of stretches induced by the PBQ, in a dose range comed between 1 and 30 mg / kg. Table 3 below presents the results of the analgesia test for some compounds according to the invention. Table 3 (a) 1 mg / kg p.o. to 2 hours.

The FAAH enzyme (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of the endogenous derivatives of amides and esters of different fatty acids, such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamine, N-Oleoylethanolamine, oleamide or 2-arachidonoylglycerol. These derivatives exert different pharmacological activities interacting, among others, with the cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the rate of these endogenous substances in the tissue. They can be used in the prevention and treatment of pathologies in which endogenous cannabinoids and / or other substrates metabolized by the FAAH enzyme are involved. For example, the following diseases and conditions can be mentioned: pain, mainly acute or chronic neurogenic pains: migraine, neuropathic pain including the forms associated with the herpes virus and diabetes; Acute or chronic pains associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness; vomiting; nausea, particularly those due to chemotherapy; eating behavior disorders in particular anorexia and cachexia of different natures; neurological and psychiatric pathologies: tremors, dyskinesias, dystonias, spasticity, compulsive and obsessive behaviors, Tourette syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychosis; Acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions linked to cerebral ischemia and cranial and spinal cord injuries; epilepsy; sleep disorders including sleep apneas; cardiovascular diseases in particular hypertension, cardiac arrhythmias, arteriosclerosis, cardiac crisis, cardiac ischemia; renal ischemia; cancers: benign skin tumors, papillomas and brain tumors, tumors of the prostate, brain tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependiomas, oligodendrogliomas, plexus tumor, neuroepitheliomas, tumor the epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas); disorders of the immune system, mainly autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue disease, Sjógrer syndrome, ankylosing spondylitis, undifferentiated spondylarthritis, Behcet's disease, hemolytic autoimmune anemias, plaque sclerosis, amyotrophic lateral sclerosis, amyloidosis , rejection of implants, diseases that affect the plasmocitary line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; infectious parasitic, viral or bacterial diseases: SI DA, meningitis; inflammatory diseases, mainly joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease, colon syndrome irritable; osteoporosis; ocular conditions: ocular hypertension, glaucoma; pulmonary conditions: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema; gastrointestinal diseases: irritable bowel syndrome, inflammatory bowel disorders, ulcers, diarrhea; urinary incontinence and bladder inflammation. The use of the compounds according to the invention, in the form of a base, of pharmaceutically acceptable acid addition, hydrate or solvate salt, for the preparation of a medicament intended to treat the aforementioned pathologies forms part of the process. integrant of the invention. The invention also relates to medicaments comprising a compound of formula (I), or an acid addition salt or a pharmaceutically acceptable hydrate or solvate of the compound of formula (I). These drugs find application in therapy, mainly in the treatment of the aforementioned pathologies. According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or an acid addition salt, or a hydrate, or a pharmaceutically acceptable solvate of said compound, and optionally one or more excipients acceptable from a point of view. from pharmaceutical view Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, among the usual excipients which are known to the person 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) above, or its salt of addition of acid, solvate or optional hydrate, can be administered in unitary form of administration, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms comprise oral forms, such as tablets, soft or hard capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms of subcutaneous, intramuscular or intravenous administration, and forms of rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions. By way of example, a unitary form of administration of a compound according to the invention in the tablet form can comprise the following components: Compound according to the invention 50.0 mg Mannitol 223,75 mg Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2,25 mg Magnesium stearate 3,0 mg These unit forms are dosed to allow daily administration of 0.01 to 20 mg of active ingredient per kg of body weight, according to the galenical form. There may be particular cases in which higher or lower doses are appropriate, such doses also belong to the invention. According to the usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the weight and the response of said patient. The invention according to another of its aspects, also refers to a method of treating the aforementioned pathologies comprising the administration of an effective dose of a compound according to the invention, of one of its acid addition salts acceptable from a point of pharmaceutical view, a solvate or a hydrate of said compound.

Claims (10)

1. CLAIMS 1. Compound that corresponds to the formula (I) (i) wherein: m represents an integer equal to 1 or 2; R 1 represents a group selected primarily from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl, benzofuranyl, 5 dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihidrofuropiridinilo, thienopyridinyl, dihydrothienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, oxazolopyridinyl, isoxazolopyridinyl, or thiazolopyridinyl or isothiazolopyridinyl, this group being optionally substituted with one or more R3 groups identical or different from each other or with a group R; R2 represents a group of the general formula CHR5CONHR6, R3 represents a halogen atom or a hydroxy, 5 cyano, nitro, C-alkyl6, fluoroalkyl-C ^ ß,
2. C3.7-cycloalkyl, C3.7-cycloalkyl-C1.3-alkylene, piperidinyl, benzyloxy, piperazinyl, pyrrolidinyl, morpholinyl, phenyloxy, NR7R8, NHCOR7, NHS02R7, COR7, C02R7, CONR7R8, S02R7 or S02NR7R8, R represents a group selected primarily from phenyl, benzofuranyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinolinyl , imidazolpirimidinilo, benzothienyl, ndolilo, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, furopyridinyl, dihidrofuropiridinilo, thienopyridinyl, dihydrothienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pirazopiridinilo, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl or isothiazolopyridinyl; the R4 group (s) having one or more R3 groups identical or different from one another may be substituted; R5 represents a hydrogen atom or a C ^ alkyl group; R6 represents a hydrogen atom or an amino-Ct.6l-cycloalkyl-C3-7 or cycloalkyl-C3-7-alkenyl-C1.3 group; > R7 and R8 represent, independently of one another, a hydrogen atom, a C ^ alkyl group or a phenyl group; in the form of a base, of addition salt of acid, hydrate or solvate. 2. Compound of formula (I) according to claim 1, characterized in that m represents an integer equal to 1 or 2; R-i represents a group chosen primarily from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, benzisoxazolyl or thienopyridinyl, this group optionally being substituted with one or more R3 groups identical or different from one another; R2 represents a group of general formula CHR5CONHR6; R 3 represents a halogen atom or a cyano group, C 1 -C 6 alkyl, C 6 alkoxy, fluoroalkoxy-Ci-β, -0- (C 2-3 alkylene) -, phenyloxy; R5 represents a hydrogen atom; R6 represents a hydrogen atom or an alkyl-C ^ e group.
3. 3. Compound of formula (I) according to any of claims 1 or 2, characterized in that m is equal to 1; R1 represents a group selected primarily from pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl or isoquinolinyl, this group optionally being substituted with a group R3; R2 represents a group of general formula CHR5CONHR6; R3 represents a halogen atom, or a C ^ alkyl group, fluoroalkyl-Ci-β; R5 represents a hydrogen atom; R6 represents a hydrogen atom or a group
4. 4. Compound of formula (I) according to claim 1, characterized in that m represents an integer equal to 1 or 2; Ri represents a group selected primarily from phenyl, pyridinyl, pyridazinyl, pyrimidinyl or thiadiazolyl, this group optionally being substituted with a group R; R 4 represents a group selected primarily from phenyl, benzofuranyl or naphthyl; the group R4 being able to be substituted with one or more R3 groups identical or different from one another; R2 represents a group of general formula CHR5CONHR6; R3 represents a halogen atom or a nitro group, alkylC? 6, fluoroalkoxy-CLβ, -O-alkylene-Ci-s) - © -o-benzyloxy; R5 represents a hydrogen atom; R6 represents a hydrogen atom or a group or cycloalkyl-C3.7-C1-3 alkylene.
5. 5. Compound of formula (I) according to any of claims 1 or 4, characterized in that m is equal to 1; Ri represents a group selected primarily from phenyl, pyridinyl, pyridazinyl or pyrimidinyl, this group optionally being substituted with a group R4; R 4 represents a group selected primarily from phenyl, benzofuranyl or naphthyl; the group R4 being able to be substituted with one or more R3 groups identical or different from one another; R2 represents a group of general formula CHR5CONHR6; R3 represents a halogen atom or a nitro group, alkyl- or benzyloxy; R5 represents a hydrogen atom; R6 represents a hydrogen atom or a C-alkyl group.
6. 6. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, comprising the step of reacting an amine of general formula (II), (ll) wherein R ^ and m are as defined in the general formula (I) according to claim 1, with a carbonate of the general formula (ll l), wherein Z represents a hydrogen atom or a nitro group and R2 is as defined in the general formula (I) according to claim 1.
7. 7. Process for the preparation of a compound of the formula (!) according to any one of Claims 1 to 5, which comprises the step consisting in transforming the carbamate ester of the general formula (the) (la) wherein m, Ri and R5 are as defined in general formula (I) according to claim 1 and R represents a methyl or ethyl group, by aminolysis by an amine of general formula R6NH2 wherein R6 is as defined in the general formula (I) according to claim 1.
8. 8. Compound that corresponds to the general formula (III), which is 2- (methylamino) -2-oxoethyl 4-nitrophenyl carbonate.
9. 9. Compound that responds to the general formula (la): /the. wherein m, R and R5 are as defined in the general formula (I) according to claim 1 and R represents a methyl or ethyl group.
10. 10. Compound of formula (I) according to any one of claims 1 to 5, in the form of a base, of pharmaceutically acceptable acid, hydrate or solvate addition salt for use as a medicament. eleven . A pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 5, in the form of a base, of acid addition, hydrate or solvate salt acceptable from a pharmaceutical point of view and optionally one or 5 various excipients acceptable from a pharmaceutical point of view. 12. Use of a compound of formula (I) according to any one of claims 1 to 5, in the form of a base, of pharmaceutically acceptable acid, hydrate or solvate addition salt, for the preparation of a medicine intended to prevent or treat a pathology in which endogenous cannabinoids and / or any other substrate metabolized by the FAAH enzyme are involved. 13. Use of a compound of formula (I) according to any one of claims 1 to 5, in the form of a base, salt, hydrate or solvate acceptable from a pharmaceutical point of view, for the preparation of a medicament intended to prevent or treat acute or chronic pain, dizziness, vomiting, nausea, eating behavior disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, or sleep disorders, cardiovascular diseases, renal ischemia, cancers, system disorders immune, allergic diseases, infectious parasitic, viral or bacterial diseases, inflammatory diseases, osteoporosis, ocular affections, pulmonary affections, gastrointestinal diseases or urinary incontinence.