HK1166231A - Carbamate derivatives of alkyl-heterocycles, preparation thereof and therapeutic use thereof - Google Patents

Description

Carbamate derivatives containing alkyl-heterocycles, preparation and therapeutic use thereof

Technical Field

The present invention relates to carbamate derivatives containing alkyl-heterocycles, their preparation and therapeutic use.

Background

There is still a need to find and develop products that inhibit the enzyme FAAH (fatty acid amide hydrolase). The compounds of the present invention meet this object. These compounds should have metabolic, pharmacokinetic and toxicological properties that allow their use as pharmaceuticals. Among these properties, mention may be made in particular of the inhibitory action on cytochrome P450 and more particularly on the isoenzyme CYP3a 4.

Document WO 2004/099176 describes compounds having inhibitory activity on the enzyme FAAH, which contain a 2-hydroxyacetamide (glycoamide) carbamate group.

Disclosure of Invention

The compounds of the invention correspond to the general formula (I):

wherein

R₂Represents a hydrogen or fluorine atom or a hydroxyl group, a cyano group, a trifluoromethyl group, C_1-6Alkyl radical, C_1-6-alkoxy or NR₈R₉A group;

n represents an integer equal to 1, 2 or 3 and m represents an integer equal to 1 or 2;

a represents a covalent bond or a group C_1-8-An alkylene group;

R₁represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, and naphthyridinyl;

R₆represents a halogen atom or a cyano group, -CH₂CN, nitro, hydroxy, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6Alkylthio radical, C_1-6-haloalkyl group, C_1-6-haloalkoxy, C_1-6-haloalkylthio, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3Alkylene radical, C_3-7-cycloalkyl-C_1-3alkylene-O-, NR₈R₉、NR₈COR₉、NR₈CO₂R₉、NR₈SO₂R₉、NR₈SO₂NR₈R₉、COR₈、CO₂R₈、CONR₈R₉、SO₂R₈、SO₂NR₈R₉or-O- (C)_1-3-alkylene) -O-group;

R₇represents a group selected from: furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, phenyloxy, benzyloxy, and pyrimidinoxy; or a radical R₇May be substituted by one or more radicals R₆Said R is₆May be the same or different from each other;

R₃represents a hydrogen or fluorine atom, a group C_1-6-alkyl or trifluoromethyl;

R₄represents a group selected from: furyl, pyrrolyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl;

said group being optionally substituted with one or more substituents selected from: halogen atom, group C_1-6Alkyl radical, C_1-6-haloalkyl group, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3Alkylene radical, C_1-6Haloalkoxy, cyano, NR₈R₉、NR₈COR₉、NR₈CO₂R₉、NR₈SO₂R₉、NR₈SO₂NR₈R₉、COR₈、CO₂R₈、CONR₈R₉、CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁)、SO₂R₈、SO₂NR₈R₉、-O-(C_1-3-alkylene) -O-, phenyl, phenyloxy, benzyloxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl, or pyrimidinyl; the phenyl, phenoxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl and pyrimidinyl may be substituted with one or more substituents selected from the group consisting of: halogen atom and cyano, nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6Alkylthio radical, C_1-6-haloalkyl group, C_1-6-haloalkoxy, C_1-6-haloalkylthio, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkylene group;

R₈、R₉、R₁₀and R₁₁Independently of one another, represents a hydrogen atom or a group C_1-6-alkyl, or at NR₈R₉In the case of (a) form, with the atoms they carry, a ring selected from: azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepineOxygen and nitrogen heteroAnd a piperazine ring, said ring being optionally substituted with a group C_1-6-alkyl or benzyl;

at NR₈COR₉A lactam ring is formed; at NR₈CO₂R₉In the case of (A) form oxazolidinones, oxazinones or oxaziridinesA ketone ring; at NR₈SO₂R₉Form a sultam ring; at NR₈SO₂NR₈R₉In the case of (A) or (B) forms a thiazolidine dioxide or thiadiazine dioxide ring.

Of the compounds of formula (I), a first subclass of compounds is formed by the following compounds: wherein R is₂Represents a hydrogen or fluorine atom or a hydroxyl group, C_1-6-alkyl or NR₈R₉A group. More specifically, R₈And R₉Represents a group C_1-6-an alkyl group.

Of the compounds of formula (I), the second subclass of compounds is formed by the following compounds: wherein R is₂Represents a hydrogen atom.

Of the compounds of formula (I), the third subclass of compounds is formed by the following compounds: wherein n represents an integer equal to 2 and m represents an integer equal to 2.

Of the compounds of formula (I), the fourth subclass of compounds is formed by the following compounds: wherein A represents a group C_1-8Alkylene, more particularly ethylene, propylene or ethylene groups.

Of the compounds of formula (I), the fifth subclass of compounds is formed by the following compounds: wherein A represents a covalent bond.

Among the compounds of the general formula (I), the compounds of the sixth subclass are formed by the following compounds: wherein

R₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, phthalazinyl or quinoxalinyl;

R₆represents nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-haloalkoxy or-O- (C)_1-3-alkylene) -O-groups or halogen atoms, more particularly chlorine or fluorine atoms;

R₇represents phenyl, whichMay be substituted by one or more radicals R₆Said R is₆May be the same or different from each other.

Among the compounds of the general formula (I), the seventh subclass of compounds is formed by the following compounds: wherein

R₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, phthalazinyl or quinoxalinyl;

R₆represents nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-haloalkoxy or-O- (C)_1-3-alkylene) -O-groups or halogen atoms, more particularly chlorine or fluorine atoms;

R₇represents phenyl which may be substituted by one or more radicals R₆Said R is₆May be the same or different from each other.

Among the compounds of the general formula (I), the eighth subclass of compounds is formed by the following compounds: wherein

R₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents phenyl, pyridyl, pyrazinyl or quinolyl;

R₆represents a halogen atom, more particularly a chlorine or fluorine atom;

R₇represents phenyl which may be substituted by one or more radicals R₆Said R is₆May be the same or different from each other.

Among the compounds of the general formula (I), the ninth subclass of compounds is formed by the following compounds: wherein R is₃Represents trifluoromethyl, C_1-6-alkyl, further havingBulk isopropyl groups or hydrogen atoms.

Among the compounds of the general formula (I), the tenth subclass of compounds is formed by the following compounds: wherein R is₃Represents a hydrogen atom.

Among the compounds of the general formula (I), the eleventh subclass of compounds is formed by the following compounds: wherein

R₄Represents a group selected from: oxazolyl, isoxazolyl, furanyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl;

said group being optionally substituted with one or more substituents selected from: group C_1-6Alkyl, more particularly methyl, ethyl, isopropyl or tert-butyl, COOR₈、CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁)、CONR₈R₉A phenyl group; the phenyl group may be substituted with one or more substituents selected from: halogen atoms, more particularly chlorine or fluorine atoms, group C_1-6-alkoxy, more particularly methoxy;

R₈and R₉Independently of one another, represents a hydrogen atom or a group C_1-6-alkyl, more particularly methyl or ethyl, or together with the atoms they carry form a piperazine ring,

R₁₀and R₁₁Independently of one another, represents a hydrogen atom or a group C_1-6-an alkyl group.

Among the compounds of the general formula (I), the twelfth subclass of compounds is formed by the following compounds: wherein

R₄Represents a group selected from: oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl;

said group being optionally substituted with one or more substituents selected from: group C_1-6Alkyl, more particularly methyl, ethyl, isopropyl or tert-butyl, COOR₈、CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁)、CONR₈R₉Or phenyl; the phenyl group may be substituted with one or more substituents selected from: halogen atoms, more particularly chlorine or fluorine atoms, or groups C_1-6-alkoxy, more particularly methoxy;

R₈and R₉Independently of one another, represents a hydrogen atom or a group C_1-6-alkyl, more particularly methyl or ethyl, or together with the atoms they carry form a piperazine ring,

R₁₀and R₁₁Independently of one another, represents a hydrogen atom or a group C_1-6-an alkyl group.

Among the compounds of the general formula (I), the compounds of the thirteenth subclass are formed by: wherein R is₄Represents a group selected from: oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl or triazolyl; said group being optionally substituted with one or more substituents selected from: group C_1-6Alkyl, more particularly methyl, ethyl, isopropyl or tert-butyl, CONR₈R₉A phenyl group; the phenyl group may be substituted with one or more substituents selected from: a halogen atom, more particularly a chlorine or fluorine atom, and a radical C_1-6-alkoxy, more particularly methoxy;

R₈and R₉Independently of one another, represents a hydrogen atom or a group C_1-6-alkyl, more particularly methyl.

Among the compounds of the general formula (I), the fourteenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 3-carbamoylisoxazol-5-yl.

Among the compounds of the general formula (I), the fifteenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 2-methyl-2H- [1, 2, 4]Triazol-3-yl.

Among the compounds of the general formula (I), the sixteenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 3- (4-chlorophenyl) ("2")1，2，4]Oxadiazol-5-yl.

Among the compounds of the general formula (I), the seventeenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 3- (4-chlorophenyl) isoxazol-5-yl.

Among the compounds of the general formula (I), the eighteenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 3-ethyl [1, 2, 4]]Oxadiazol-5-yl.

Among the compounds of the general formula (I), the nineteenth subclass of compounds is formed by the following compounds: wherein R is₄Represents 5-methyl-3-phenylisoxazol-4-yl.

Among the compounds of the general formula (I), the twentieth subgroup of compounds is formed by the following compounds: wherein R is₄Represents 3-isopropyl [1, 2, 4]]Oxadiazol-5-yl.

Of the compounds of formula (I), the twenty-first subclass of compounds is formed from the following compounds: wherein R is₄Represents 1-methyl-1H-pyrazol-3-yl.

Among the compounds of general formula (I), the twenty-second subclass of compounds is formed by the following compounds: wherein R is₄Is represented by [1, 2, 3]]Thiadiazol-4-yl.

Among the compounds of the general formula (I), the compounds of the twenty-third subclass are formed by the following compounds: wherein R is₄Represents 5-tert-butyl [1, 3, 4]]Thiadiazol-2-yl.

Among the compounds of the general formula (I), the twenty-fourth subclass of compounds is formed by the following compounds: wherein R is₄Represents 5-isopropyl [1, 2, 4]]Oxadiazol-3-yl.

Of the compounds of formula (I), the twenty-fifth subclass of compounds is formed from the following compounds: wherein R is₄Represents 5- (4-fluorophenyl) [1, 3, 4]]Oxadiazol-2-yl.

Among the compounds of general formula (I), the twenty-sixth subclass of compounds is formed by the following compounds: wherein R is₄Represents 5- (4-chlorophenyl) [1, 3, 4]]Oxadiazol-2-yl.

Among the compounds of the general formula (I), a twenty-seventh subclass of compounds is formed from: wherein R is₄Represents 5- (4-methoxyphenyl) [1, 3, 4]]Oxadiazol-2-yl.

Among the compounds of the general formula (I), the twenty-eighth subclass of compounds is formed by the following compounds: wherein R is₄Represents 3- (4-fluorophenyl) [1, 2, 4]]Oxadiazol-5-yl.

Among the compounds of general formula (I), the twenty-ninth subclass of compounds is formed from the following compounds: wherein R is₄Represents 3- (3-fluorophenyl) [1, 2, 4]]Oxadiazol-5-yl.

Among the compounds of the general formula (I), the thirtieth subclass of compounds is formed by the following compounds: wherein R is₄Represents 5- (4-chlorophenyl) [1, 2, 4]]Thiadiazol-3-yl.

Among the compounds of the general formula (I), the thirty-first subclass of compounds is formed by the following compounds: wherein R is₄Represents 3-methylcarbamoylisoxazol-5-yl.

Of the compounds of general formula (I), the thirty-second subclass of compounds is formed by the following compounds: wherein R is₄Represents 4-carbamoyloxazol-2-yl.

Among the compounds of the general formula (I), the compounds of the thirteenth subclass are formed by: wherein R is₄Represents 3-dimethylcarbamoylisoxazol-5-yl.

Of the compounds of formula (I), the thirty-fourth subclass of compounds is formed by the following compounds: wherein R is₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents phenyl, pyridyl, pyrazinyl or quinolyl; r₆Represents a halogen atom, more particularly a chlorine or fluorine atom;

R₇represents phenyl which may be substituted by one or more radicals R₆Said R is₆May be the same or different from each other.

R₂And R₃Represents a hydrogen atom; r₄Represents 3-carbamoylisoxazol-5-yl; n represents an integer equal to 2 and m represents an integer equal to 2;

a represents an alkylene group.

Of the compounds of formula (I), the thirty-fifth subclass of compounds is formed by the following compounds: wherein R is₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, phthalazinyl or quinoxalinyl;

R₆represents nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-haloalkoxy or-O- (C)_1-3-alkylene) -O-groups or halogen atoms, more particularly chlorine or fluorine atoms;

R₇represents phenyl which may be substituted by one or more radicals R₆Said R is₆May be the same or different from each other;

R₂and R₃Represents a hydrogen atom;

R₄represents a group selected from: furyl, pyrrolyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl, said groups being optionally substituted with CONR₈R₉Wherein R is₈And R₉Independently of one another, represents a hydrogen atom or a group C_1-6-an alkyl group;

n represents an integer equal to 2 and m represents an integer equal to 2; a represents an alkylene group.

Among the compounds of formula (I), the thirty-sixth subclass of compounds is represented by formula (I)I) Formation of a compound in which R₁And/or R₂And/or R₃And/or R₄And/or n and/or m and/or A are simultaneously as defined in the groups mentioned above.

Among the compounds of general formula (I), mention may be made of the following compounds in base form or in acid addition salt form (IUPAC nomenclature, produced by AutoNom software):

1.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

2.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 2-methyl-2H- [1, 2, 4] triazol-3-ylmethyl ester

3.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3- (4-chlorophenyl) isoxazol-5-ylmethyl ester

4.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3- (4-chlorophenyl) [1, 2, 4] oxadiazol-5-ylmethyl ester

3-Ethyl [1, 2, 4] oxadiazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

6.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 5-methyl-3-phenylisoxazol-4-ylmethyl ester

3-isopropyl [1, 2, 4] oxadiazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

1-methyl-1H-pyrazol-3-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

[1, 2, 3] thiadiazol-4-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

5-tert-butyl [1, 3, 4] thiadiazol-2-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

12.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 5- (4-fluorophenyl) [1, 3, 4] oxadiazol-2-ylmethyl ester

13.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 5- (4-chlorophenyl) [1, 3, 4] oxadiazol-2-ylmethyl ester

14.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 5- (4-methoxyphenyl) [1, 3, 4] oxadiazol-2-ylmethyl ester

15.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3- (4-fluorophenyl) [1, 2, 4] oxadiazol-5-ylmethyl ester

16.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3- (3-fluorophenyl) [1, 2, 4] oxadiazol-5-ylmethyl ester

17.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 5- (4-chlorophenyl) [1, 2, 4] thiadiazol-3-ylmethyl ester

18.2- [1- (6-Chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid [1, 2, 3] thiadiazol-4-ylmethyl ester

3-carbamoylisoxazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

20.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 4-carbamoyloxazol-2-ylmethyl ester

3-methylcarbamoylisoxazol-5-ylmethyl 2- [6 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

23.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

3-carbamoylisoxazol-5-ylmethyl 2- [6 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

25.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

26.2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

3-dimethylcarbamoylisoxazol-5-ylmethyl 2- [6 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

3-carbamoylisoxazol-5-ylmethyl 2- [5 '- (3-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

29.2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

3-dimethylcarbamoylisoxazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

31.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-dimethylcarbamoyl-isoxazol-5-ylmethyl ester

32.2- {1- [6- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl } ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

3-carbamoylisoxazol-5-ylmethyl (2- {1- [6- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl ] ethylcarbamate

3-dimethylcarbamoylisoxazol-5-ylmethyl (2- {1- [6- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl ] ethylcarbamate

3-methylcarbamoylisoxazol-5-ylmethyl (2- {1- [5- (4-fluorophenyl) pyrimidin-2-yl ] piperidin-4-yl ] ethylcarbamate

3-dimethylcarbamoylisoxazol-5-ylmethyl (2- {1- [5- (4-fluorophenyl) pyrimidin-2-yl ] piperidin-4-yl ] ethylcarbamate

{2- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

{2- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoyl-isoxazol-5-ylmethyl ester

(2- {1- [5- (4-fluorophenyl) pyrimidin-2-yl ] piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-dimethylcarbamoylisoxazol-5-ylmethyl ester

(2- {1- [6- (4-fluorophenyl) pyridazin-3-yl ] piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3- (2-dimethylaminoethylcarbamoyl) isoxazol-5-ylmethyl ester

[2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [5 '- (2, 2-dimethylpropyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

45.[2- (5 '-m-tolyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3- (4-methylpiperazin-1-carbonyl) isoxazol-5-ylmethyl ester

{2- [5 '- (3-trifluoromethoxyphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [5 '- (3-chlorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [5 '- (3-fluoro-5-methoxyphenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

[2- (5 '-benzo [1.3] dioxol-5-yl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

51.5- [ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ylmethylcarbamoyloxymethyl ] isoxazole-3-carboxylic acid ethyl ester

{3- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] propylcarbamic acid 1-methyl-1H-pyrazol-3-ylmethyl ester

53.5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid

[1- (6-Chloroquinoxalin-2-yl) piperidin-4-yl ] methylcarbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

[1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] methylcarbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

56.5- [1- (6-chloroquinolin-2-yl) -4-fluoropiperidin-4-ylmethylcarbamoyloxymethyl ] isoxazole-3-carboxylic acid ethyl ester

[ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] methylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester 57

58.[1- (4-Nitro-2-trifluoromethylphenyl) piperidin-4-yl ] methylcarbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

[1- (4-Chlorophthalazin-1-yl) piperidin-4-yl ] methylcarbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

{2- [ 3-dimethylamino-1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

61.{2- [ 4-Ethyl-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

{2- [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

63.{2- [1- (4-chlorophthalazin-1-yl) -3-dimethylaminoazetidin-3-yl ] ethyl } carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester

{2- [1- (6-Chloroquinoxalin-2-yl) -4-ethylpiperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

65.{2- [1- (6-chloroquinoxalin-2-yl) -4-isobutylpiperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

66.{2- [ 4-isobutyl-1- (4-nitro-2-trifluoromethylphenyl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

(1-Isoquinolin-1-ylpiperidin-4-ylmethyl) carbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

68.(2- {1- [5- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl } ethyl) carbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

3-methylcarbamoylisoxazol-5-ylmethyl (2- {1- [5- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl } ethyl) carbamate

[1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

71.5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid ethyl ester

{2- [ 4-methyl-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

73.{2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester

(±) [1- (4-trifluoromethylpyrimidin-2-yl) azepan-4-yl ] carbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

[1- (4-chlorophthalazin-1-yl) piperidin-4-yl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester

76.[1- (4-nitro-2-trifluoromethylphenyl) piperidin-4-yl ] carbamic acid 3-methylcarbamoyl-isoxazol-5-ylmethyl ester

77.[1- (6-chloroquinoxalin-2-yl) piperidin-4-yl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

78.{2- [1- (6-chloroquinoxalin-2-yl) -4-methylpiperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

79.(±) [1- (4-chlorophthalazin-1-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoyl-isoxazol-5-ylmethyl ester

80.{2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 1- (furan-3-yl) -3-methylbutyl ester

{2- [6 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } carbamic acid 1- (furan-3-yl) -3-methylbutyl ester

82.{2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

{2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

(-) - [1- (4-chloro-pyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoyl-isoxazol-5-ylmethyl ester

85.(+) [1- (4-chloro-pyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester.

The compounds of formula (I) may include one or more asymmetric carbons. They may exist as enantiomers or diastereomers. The compounds of the general formula (I) may also exist in the form of the cis (Z) or trans (E) stereoisomers. These stereoisomers, enantiomers and diastereomers and mixtures thereof (including racemic mixtures) form part of the present invention.

The compounds of formula (I) may exist in the form of a base or in the form of an acid addition salt. Such addition salts form part of the present invention.

These salts are advantageously prepared with the use of the pharmaceutical acids, but the use of salts of other acids, for example for the purification or isolation of the compounds of formula (I), also forms part of the invention.

In the context of the present invention, the following definitions apply:

-C_t-zwhere t and z may have values of1 to 8, and the carbon chain may contain t to z carbon atoms, e.g. C_1-3Is a carbon chain which may contain 1 to 3 carbon atoms;

-alkyl means a linear or branched saturated aliphatic group; e.g. C_1-6Alkyl represents a linear or branched carbon chain of1 to 6 carbon atoms, more particularly methyl, ethylPropyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl;

alkylene means a linear or branched saturated divalent alkyl radical, e.g. C_1-3Alkylene represents a linear or branched divalent carbon chain of1 to 3 carbon atoms, more particularly methylene, ethylene, 1-methylethylene or propylene;

cycloalkyl means a cyclic alkyl radical, e.g. C_3-7-cycloalkyl represents a cyclic carbon group of 3 to 7 carbon atoms, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

-alkoxy means an-O-alkyl group containing a linear or branched, saturated aliphatic chain;

alkylthio means an-S-alkyl group containing a linear or branched, saturated aliphatic chain;

haloalkyl refers to an alkyl group wherein one or more hydrogen atoms are replaced by halogen atoms;

haloalkoxy means an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms;

haloalkylthio means an alkylthio group in which one or more hydrogen atoms are replaced by halogen atoms;

halogen atom means fluorine, chlorine, bromine or iodine.

The compounds of the present invention can be prepared according to various methods as exemplified in the following schemes.

Thus, the first approach (scheme 1) comprises: reacting an amine of the formula (II) (wherein A, R₁、R₂M and n are as defined in formula (I) as defined above) and a carbonate of formula (III) wherein Z represents a hydrogen atom or a nitro group, and R₃And R₄As defined in formula (I) as defined above) in the presence of a base such as triethylamine, pyridine, N-dimethylaminopyridine or diisopropylethylamine in a solvent such as toluene or 1, 2-dichloroethane at room temperature and solvent returnThe reaction is carried out at a temperature between the stream temperatures.

Scheme 1

One variant for obtaining the compounds of general formula (I) (scheme 1) comprises: the reaction of an amine of formula (II) as defined above with phenyl chloroformate or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as dichloromethane or tetrahydrofuran at a temperature between 0 ℃ and room temperature gives carbamate derivatives of formula (IV) wherein A, R₁、R₂M and n are as defined in general formula (I) as defined above, and Z represents a hydrogen atom or a nitro group. The carbamate derivative of general formula (IV) thus obtained is then subjected to the general formula HOCHR as defined above₃R₄The action of the alcohol of (IIIa) is converted in the presence of a base such as triethylamine, pyridine, N-dimethylaminopyridine or diisopropylethylamine in a solvent such as toluene or dichloroethane at a temperature between room temperature and the reflux temperature of the solvent to the compound of formula (I).

The second approach (scheme 2) yields compounds of general formula (I) wherein R₁Represents a group R₅Which is especially substituted by C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3A group R of alkylene type₆Or substituted with a group R as defined in formula (I) as defined above₇。

Scheme 2

Thus, the first step comprises: reacting an amine of the formula (IIa) (wherein A, R₂M and n are as defined in formula (I) as defined above and PG represents a protecting group such as Boc (tert-butyloxycarbonyl), CBz (benzyloxycarbonyl), benzyl or benzhydryl) and a derivative of formula (V) wherein R is₅As defined above, U₁Represents a halogen atom or an O-triflate group and U₂Representing a chlorine, bromine or iodine atom or an O-triflate group) by aromatic or heteroaromatic nucleophilic substitution or Buchwald N-arylation or N-heteroaromatization, for example using a palladium or copper catalyst, to give intermediates of the general formula (IVa) in which A, R₂、R₅、m、n、U₂And PG is as defined above. The compound (IVa) thus obtained is used in a first stage in a deprotection reaction, for example in the presence of a solution of trifluoroacetic acid or hydrogen chloride (5N) in isopropanol or dioxane, followed by a condensation reaction with a carbonate of general formula (III) as defined above under the conditions as described in scheme 1 above to give a carbamate derivative of general formula (IVb), wherein A, R₂、R₅、m、N、U₂And Z is as defined above. The compound of formula (IVb) thus obtained is then subjected to the general formula HOCHR as defined above₃R₄The action of the alcohol of (IIIa) is converted in the presence of a base such as triethylamine, pyridine, N-dimethylaminopyridine or N, N-diisopropylethylamine in a solvent such as toluene or dichloroethane at a temperature between room temperature and the reflux temperature of the solvent into the carbamate derivative of general formula (Ia). The final step involves the preparation of intermediates of formula (Ia) (wherein A, R₂、R₃、R₄、R₅M, n and U₂As defined above, U₂When desired introduced into the radical R₆Or R₇In position (s)) with a transition metal (such as palladium (0)) to catalyze the following coupling reaction:

via reactions of the Suzuki type, for example using alkyl, cycloalkyl, aryl or heteroaryl boronic acids,

or according to a Stille type reaction, for example using aryl or heteroaryl trialkyltin derivatives,

or by a Negishi type reaction, for example using alkyl, cycloalkyl, aryl or heteroaryl halide zincate derivatives.

Scheme 3

The third process (scheme 3) comprises reacting in a first stage an amine of formula (IIb) (wherein A, R₂M and N are as defined in formula (I) as defined above and PG is as defined above) with a carbonate of formula (III) as defined above under the conditions described above for the reaction of the amine of formula (II) with the carbonate of formula (III) followed by a deprotection reaction, for example in the presence of a solution of hydrogen chloride (5N) in isopropanol or dioxane, to give an intermediate of formula (Ia) wherein A, R₂、R₃、R₄M and n are as defined in formula (I).

One variant (scheme 3, route a variant) to obtain intermediates of general formula (Ib) comprises reacting an amine of general formula (IIa) as described above with phenyl chloroformate or 4-nitrophenylchloroformate under conditions as described for the reaction of a compound of formula (II) with a compound of formula (IV) (scheme 1, variant) to obtain a carbamate derivative of general formula (IVc), wherein A, R₂M and n are as defined in formula (I) as defined above and PG and Z are as defined above. The carbamate derivative of formula (IVc) thus obtained is then subjected to a reaction of formula HOCHR₃R₄The action of the alcohol of (IIIa) is converted to the compound of general formula (Ia) under the conditions described above for the reaction of the compound of formula (IV) with the compound of formula (IIIa) (scheme 1, variation).

Followed by reacting a compound of formula (Ib) with a derivative of formula (Va) (wherein R is₁And U₁As defined in formula (I) using aromatic or heteroaromatic nucleophilic substitution reaction conditions, e.g., using a base such as triethylamine, diisopropylethylamine, pyridine or N, N-dimethylaminopyridine in a solvent such as dichloromethane, dichloroethane, acetonitrile,N, N-dimethylformamide, dioxane or tetrahydrofuran) at a temperature between 0 ℃ and the reflux temperature of the solvent to give the compound of the general formula (I). The conversion may also be carried out using Buchwald N-arylation or N-heteroaromatization reaction conditions, for example using palladium or copper catalysts.

Compounds of formula (I) (wherein R is₁Represents a group R₅Which is especially substituted by C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3A group R of alkylene type₆Or substituted with a group R as defined in formula (I) as defined above₇) Also according to the formula (Ia) (wherein A, R)₂、R₃、R₄、R₅M, n, o and p are as defined in formula (I) and U₂Represents a chlorine, bromine or iodine atom or a triflate group, U₂When desired introduced into the radical R₆Or R₇According to the reaction conditions used for the conversion of the compound of formula (Ia) to the compound of formula (I) (see scheme 2) a coupling reaction catalysed with a transition metal, for example palladium (0) is carried out.

By reacting an amine of the general formula (Ib) as defined above with a derivative of the general formula (Vb) in which R₅、U₁And U₂As defined above) under the conditions described above for the reaction of a compound of formula (IIa) with a compound of formula (V) to give a compound of formula (IVa) in scheme 2 above to give first an intermediate of general formula (Ia) as defined above.

One variant (scheme 3, route B variant) to obtain intermediates of formula (Ia) comprises reacting an amine of formula (IIb) (wherein A, R) in a first stage₅、R₂M and n are as defined in formula (I) as defined above, and U₂As defined above) with a carbonate of the general formula (III) as defined above under the conditions described for the reaction of an amine of the general formula (II) with a carbonate of the general formula (III) as defined above to give an intermediate of the general formula (Ia) wherein A, R₅、R₂、R₃、R₄M and n are as defined in formula (I) and U₂As defined above。

Another subject of the invention relates to intermediates of formula (Ib) below:

pyrrolidin-3-ylmethylcarbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester hydrochloride

m.p.(℃)：187-189，LC-MS：M+H＝283

¹H NMR(DMSO)δ(ppm)：8.70(bs，1H)；8.00(m，2H)；6.80(m，1H)；5.25(s，2H)；3.60(m，1H)；3.45(m，1H)；3.30(m，1H)；3.10(m，1H)；2.90(m，2H)；2.80(s，3H)；2.50(m，1H)；2.05(m，1H)；1.70(m，1H)

[2- (4-methylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester

m.p.(℃)：188-190，LC-MS：M+H＝361

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.50 (broad singlet, 1H); 7.45 (broad singlet, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.00(m, 6H); 2.75(d, 3H); 1.60-1.40(m, 6H); 0.95(m, 3H)

[2- (4-Isobutylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

LC-MS：M+H＝367

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.50 (broad singlet, 1H); 7.40(m, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.00(m, 6H); 2.75(d, 3H); 1.70(m, 1H); 1.50(m, 6H); 1.30(m, 2H); 0.90(d, 6H)

[2- (4-ethylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester hydrochloride

m.p.(℃)：222-224，LC-MS：M+H＝339

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 2H); 7.40(t,1H)；6.80(s，1H)；5.20(s，2H)；2.95(m，6H)；2.75(d，3H)；1.55(q，2H)；1.45(t，2H)；1.35(m，4H)；0.80(t，3H)

piperidin-4-ylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

LC-MS：M+H＝283

¹H NMR(DMSO)δ(ppm)：8.80(bs，1H)；8.70(m，1H)；7.75(m，1H)；6.80(s，1H)；5.25(s，1H)；3.65(m，1H)；3.25(m，2H)；3.00(m，2H)；2.80(d，3H)；1.95(m，2H)；1.70(m，2H).

Piperidin-4-ylmethyl carbamic acid 5-isopropyl [1, 2, 4] oxadiazol-3-ylmethyl ester

LC-MS：M+H＝282

¹H NMR(DMSO)δ(ppm)：7.25(bt，1H)；4.90(s，2H)；2.80(m，2H)；2.70(m，2H)；2.30(m，2H)；1.40(m，2H)；1.30(m，1H)；1.10(d，6H)；0.85(m，2H).

[2- (3-dimethylaminoazetidin-3-yl) ethyl ] carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester hydrochloride

¹H NMR (DMSO) δ (ppm): 12.50 (broad singlet, 1H); 10.00 (broad singlet, 1H); 9.20 (broad singlet, 1H); 8.30(t, 1H); 7.60(s, 1H); 7.30(s, 1H); 6.80(m, 1H); 4.50(m, 2H); 4.10(m, 2H); 3.90(s, 3H); 3.40(m, 2H); 2.70(s, 6H); 2.15(m, 2H)

[2- (3-dimethylaminoazetidin-3-yl) ethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester hydrochloride

m.p.(℃)：210-212℃

¹H NMR (DMSO) δ (ppm): 12.50 (broad singlet, 1H); 9.80 (broad singlet, 1H); 9.20 (broad singlet, 1H); 8.80 (broad singlet, 1H); 7.80 (broad singlet, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.50(m, 2H);4.10(m，2H)；3.40(m，2H)；2.80(s，3H)；2.55(s，6H)；2.10(t，2H)

5- (4-Fluoropiperidin-4-ylmethylcarbamoyloxymethyl) isoxazole-3-carboxylic acid ethyl ester trifluoroacetate

1-methyl-1H-pyrazol-3-ylmethyl (3-piperidin-4-ylpropyl) carbamate

LC-MS：M+H＝281

¹H NMR(DMSO)δ(ppm)：9.10(bs，1H)；8.85(bs，1H)；7.65(s，1H)；7.15(bs，1H)；6.20(s，1H)；4.90(s，2H)；3.80(s，3H)；3.20(m，2H)；3.00(m，2H)；2.80(m，2H)；1.80(m，2H)；1.50-1.20(m，6H).

Azepan-4-ylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester.

Another subject of the invention relates to intermediates of formula (II) below:

[1- (4-trifluoromethylpyrimidin-2-yl) pyrrolidin-3-yl ] methylamine

4- (2-aminoethyl) -1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ol

¹H NMR(CDCl₃) δ (ppm): 8.40(d, 1H); 6.60(d, 1H); 4.50(m, 2H); 3.50-3.20(m, 2H); 3.20(m, 2H); 2.90-2.60 (broad singlet, 2H); 1.70(m, 2H); 1.50-1.30(m, 4H).

2- [5 '- (3-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylamine

2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethylamine

LC-MS：M+H＝299

¹H NMR(DMSO)δ(ppm)：7.60(m，2H)；7.50(d，2H)；7.25(m，2H)；7.00(d，2H)；3.75(m，2H)；2.85(m，2H)；2.75(m，2H)；1.70(m，2H)；1.50(m，1H)；1.35(m，2H)；1.25(m，2H)

2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylamine

LC-MS：M+H＝262

¹H NMR(CDCl₃)δ(ppm)：8.00(m，1H)；7.30(m，1H)；6.65(d，1H)；4.25(m，2H)；2.80(m，4H)；2.35(d，2H)；1.80(m，3H)；1.60(m，1H)；1.45(m，2H)；1.30(m，4H)；0.90(d，6H)

2- {1- [6- (4-fluorophenyl) pyridazin-3-yl ] piperidin-4-yl } ethylamine

2- [5 '- (2, 2-dimethylpropyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylamine

2- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethylamine

2- {1- [6- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl } ethylamine

2- {1- [5- (4-fluorophenyl) pyrimidin-2-yl ] piperidin-4-yl } ethylamine

2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethylamine

LC-MS：M+H＝247

¹H NMR(CDCl₃)δ(ppm)：8.50(d，1H)；6.80(d，1H)；4.30(m，2H)；3.90(m，2H)；2.85(m，1H)；2.75(m，2H)；1.85(m，2H)；1.30(bs，2H)。

Another subject of the invention relates to intermediates of formula (IIa) below:

4- (2-aminoethyl) -4-ethylpiperidine-1-carboxylic acid tert-butyrate

4- (2-aminoethyl) -4-isobutylpiperidine-1-carboxylic acid tert-butyl ester

3- (2-aminoethyl) -3-dimethylaminoazetidine-1-carboxylic acid tert-butyl ester

Another subject of the invention relates to intermediates of formula (IV) below:

4-Nitrophenyl {2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } carbamate

4-Nitrophenyl {2- [5 '- (3-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } carbamate

[2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethyl ] carbamic acid 4-nitrophenyl ester

{2- [1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 4-nitrophenyl ester

4-Nitrophenyl (2- {1- [6- (4-fluorophenyl) pyrazin-2-yl ] piperidin-4-yl } ethyl) carbamate

4-Nitrophenyl (2- {1- [5- (4-fluorophenyl) pyrimidin-2-yl ] piperidin-4-yl } ethyl) carbamate

4-Nitrophenyl [2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamate.

Other compounds of the general formulae (II), (IIa), (III), (IIIa) and (V) and other reagents are commercially available or described in the literature or can be prepared according to the methods described herein or known to the person skilled in the art.

In particular, the carbonates of formula (III) can be prepared according to any of the methods described in the literature, for example by reacting a compound of formula HOCHR₃R₄Alcohol of (IIIa) (wherein R₃And R₄As defined in formula (I) as defined above) with phenyl chloroformate or 4-nitrophenyl chloroformate in the presence of a base such as triethylamine, N-methylmorpholine or diisopropylethylamine in a solvent such as dichloromethane or tetrahydrofuran at a temperature between 0 ℃ and room temperature.

The following examples illustrate the preparation of various compounds of the present invention. These examples are not limiting and are merely illustrative of the present invention. Microanalysis and IR, NMR and/or LC-MS (liquid chromatography coupled with mass spectrometry) spectroscopy confirmed the structure and purity of the resulting compound.

The method A comprises the following steps: UPLC/TOF-gradient 3 min-H₂O/ACN/TFA T0: 98% A-T1.6 to T2.1 min: 100% B-T2.5 to T3 min: 98% A pathway A: h₂O + 0.05% TFA; route B: ACN + 0.035% TFA flow rate: 1.0mL/min-T ° -40 ℃ -2 μ L of Acquisty BEHC18 (50X 2.1 mm; 1.7 μm) column was injected; 220 nm.

The method B comprises the following steps: HPLC/ZQ-gradient 10 min-CH₃COONH₄5mM/ACN T0: 100% A-T5.5 to T7 min: 100% B-T7.1 to T10 min: 100% A route A: CH (CH)₃COONH₄+ 3% ACN; route B: ACN flow rate: 0.8 mL/min-T.degree 40 deg.C-5. mu.L Kromasil C18 (50X 2.1 mm; 3.5 μm) column was injected; 220 nm.

m.p. (° c) denotes the melting point in degrees celsius.

The numbers given in parentheses in the example titles correspond to the numbers in the first column of the table below.

IUPAC (international union of theory and applied chemistry) nomenclature is used to name the compounds in the examples below.

Detailed Description

Example 1 (Compound 9)

[1, 2, 3] thiadiazol-4-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

1.1.2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethanol

A solution of 11.00g (46.43mmol) of 2, 5-dibromopyridine, 6.00g (46.43mmol) of piperidin-4-ylethanol and 6.74g (48.76mmol) of potassium carbonate in 8mL of DMSO was placed in an autoclave. The mixture was then heated at 160 ℃ for 20 hours.

The reaction mixture was cooled to room temperature and then taken up in ethyl acetate and water. The aqueous phase was separated and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure.

This gave 11.00g of product in the form of an oil which was used in the next step without further purification.

1.2.2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethanol

3.60g (12.62mmol) of 2- (5 ' -bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' prepared in step 1.1 are reacted under inert atmosphere ']Bispyridin-4-yl) ethanol, 3.53g (25.25mmol) of 4-fluorophenylboronic acid, 5.23g (37.87mmol) of potassium carbonate and 4.88g (15.15mmol) of tetrabutylammonium bromide were introduced in the form of a suspension into 20mL of water. Then 0.142g (0.63mmol) of Pd (OAc) were added₂. The reaction mixture was refluxed for 24 hours.

The mixture was cooled to room temperature, the salts were separated off by filtration over celite, the filtrate was taken up in ethyl acetate, the aqueous phase was separated off and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the obtained residue was purified by silica gel chromatography (eluting with 50/50 mixture of ethyl acetate and cyclohexane), thereby obtaining 1.6g of the product in the form of a white powder.

m.p.(℃)＝118-120℃

1.3.2- {2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } isoindole-1, 3-dione

To a solution of 2.00g (6.66mmol) of 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethanol prepared in step 1.2, 2.096g (7.99mmol) of triphenylphosphine and 1.077g (7.32mmol) of phthalimide in 40mL of tetrahydrofuran was added dropwise a solution of 1.61g (7.99mmol) of diisopropyl azodicarboxylate (DIAD) in 4mL of tetrahydrofuran, cooled to about-2 ℃ under an inert atmosphere, while maintaining the temperature of the reaction medium between-2 ℃ and 0 ℃. Stirring was continued at 0 ℃ for 1 hour and then at room temperature for 12 hours.

The mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane and water. The aqueous phase was separated off and then extracted twice with dichloromethane. The organic phases were combined and washed successively with aqueous hydrochloric acid (1N), saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by chromatography on silica gel (elution with 20/80 mixture of ethyl acetate and cyclohexane), thus obtaining 2.1g of the desired product in the form of a white powder.

m.p.(℃)＝180-182℃

1.4.2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylamine

To a solution of 1.3g (3.03mmol) of 2- {2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } isoindol-1, 3-dione prepared in step 1.3 in 30mL ethanol at room temperature was slowly added 0.485g (15.13mmol) of hydrazine monohydrate. The reaction mixture was then refluxed for 3 hours.

The mixture was cooled to room temperature, the insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was taken up in 20mL of diethyl ether and stirred at room temperature for 1 hour. The insoluble material was separated again and the filtrate was concentrated under reduced pressure.

This gives 0.70g of the desired product in the form of a white powder.

m.p.(℃)＝88-94℃

¹H NMR(CDCl₃) δ (ppm): 8.3(d, 1H); 7.55(dd, 1H); 7.35(m, 2H); 7.05(d, 1H); 7.1(d, 1H); 6.65(d, 1H); 4.25 (broad doublet, 2H); 3.0-2.8(m, 4H); 1.8(m, 2H); 1.6-1.1(m, 5H).

4-Nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

To a solution of 5g (16.7mmol) of 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylamine prepared in step 1.4, 4.32g (33.40mmol) of N, N-diisopropylethylamine and 0.10g (0.84mmol) of N, N-dimethylaminopyridine in 50mL of dichloromethane cooled to about 0 deg.C was added dropwise 3.7g (18.37mmol) of 4-nitrophenyl chloroformate. Stirring was continued for 1 hour at 0 ℃ and then for 2 hours at room temperature.

Water was added to the reaction medium, the aqueous phase was separated off and extracted several times with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure.

This gave 4.6g of product in the form of an amorphous beige solid, which was used in the next step without further purification.

LC-MS：M+H＝465

¹H NMR(DMSO)δ(ppm)：8.40(s，1H)；8.30(d，2H)；8.10(bt，1H)；7.80(m，1H)；7.70(m，2H)；7.45(d，2H)；7.25(m，2H)；6.90(d，1H)；4.35(m，2H)；3.20(m，2H)；2.80(m，2H)；1.80(m，2H)；1.65(m，1H)；1.50(m，2H)；1.20(m，2H).

1.6.2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid [1, 2, 3] thiadiazol-4-ylmethyl ester

A solution of 0.50g (0.50mmol) of 4-nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate prepared in step 1.5, 0.128g (0.99mmol) of N, N-diisopropylethylamine, 0.030g (0.25mmol) of N, N-dimethylaminopyridine and 0.079g (0.5mmol) of [1, 2, 3] thiadiazol-4-ylmethanol (Acta pharmaceutical Suecica (1973), 10(4), 285-96) in 5mL of1, 2-dichloroethane is heated in a reaction tube at 80 ℃ for 12 hours.

The mixture was cooled to room temperature. The residue is taken up in dichloromethane and 1N aqueous sodium hydroxide solution, the aqueous phase is separated off and extracted twice with dichloromethane, and the combined organic phases are washed with 1N aqueous sodium hydroxide solution, then with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (elution with 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia), thus obtaining 0.23g of pure product in the form of a white powder.

m.p.(℃)：139-141℃；LC-MS：M+H＝442

¹H NMR (DMSO) δ (ppm): 9.15(s, 1H); 8.4(s, 1H); 7.8(d, 1H); 7.7(dd, 2H); 7.40 (broad triplet, 1H); 7.25(t, 2H); 6.90(d, 1H); 5.5(s, 2H); 4.35 (broad doublet, 2H); 3.1(m, 2H); 2.85 (broad triplet, 2H); 1.75 (broad doublet, 2H); 1.55(m, 1H); 1.4(m, 2H); 1.15(m, 2H).

Example 2 (Compound 5)

3-Ethyl [1, 2, 4] oxadiazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

The process was carried out according to the procedure described in example 1 (step 1.6.). Starting from 0.23g (0.5mmol) of 4-nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate, 0.128g (0.99mmol) of N, N-diisopropylethylamine, 0.030g (0.25mmol) of N, N-dimethylaminopyridine and 0.067g (0.50mmol) of 3-ethyl [1, 2, 4] oxadiazol-5-yl methanol as described in example 1 (step 1.5.) and, after purification by chromatography on silica gel (elution with an 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.138g of pure product is obtained in the form of a white powder.

m.p.(℃)：110-112℃，LC-MS：M+H＝454

¹H NMR (DMSO) δ (ppm): 8.40(s, 1H); 7.8(d, 1H); 7.7(dd, 2H); 7.65 (broad triplet, 1H); 7.30(t, 2H); 6.90(d, 1H); 5.30(s, 2H); 4.35 (broad doublet, 2H); 3.1(m, 2H); 2.85 (broad triplet, 2H); 2.75(q, 2H); 1.75 (broad doublet, 2H); 1.60(m, 1H); 1.45(m, 2H); 1.25(t, 3H); 1.15(m, 2H).

Example 3 (Compound 26)

3-methylcarbamoylisoxazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

The process was carried out according to the procedure described in example 1 (step 1.6.). Starting from 0.20g (0.43mmol) of 4-nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate, 0.122g (0.95mmol) of N, N-diisopropylethylamine, 0.026g (0.22mmol) of N, N-dimethylaminopyridine and 0.074g (0.47mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol described in example 1 (step 1.5.) and, after purification by chromatography on silica gel (elution with an 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.170g of pure product is obtained in the form of a white powder.

m.p.(℃)：191-193℃，LC-MS：M+H＝482

¹H NMR (DMSO) δ (ppm): 8.7 (broad singlet, 1H); 8.40(s, 1H); 7.85(d, 1H); 7.65(dd, 2H); 7.45 (broad triplet, 1H); 7.30(t, 2H); 6.90(d, 1H); 6.8(s, 1H); 5.20(s, 2H); 4.35 (broad doublet, 2H); 3.10(m, 2H); 2.80(m, 5H); 1.75 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 4 (Compound 19)

3-carbamoylisoxazol-5-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

A solution of 0.25g (0.54mmol) of 4-nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate, prepared in step 1.5, 0.139g (1.08mmol) of N, N-diisopropylethylamine, 0.033g (0.27mmol) of N, N-dimethylaminopyridine and 0.084g (0.59mmol) of 3-carbamoylisoxazol-5-ylmethanol in 5mL of1, 2-dichloroethane is heated in a sealed tube at 90 ℃ for 12 hours.

The mixture was cooled to room temperature. The precipitate formed in the reaction medium was filtered through a sintered funnel and then rinsed thoroughly with ether and water. The solid was then dried under vacuum at about 80 ℃ overnight.

This gives 0.202g of pure product in the form of a white powder.

m.p.(℃)：202-204℃，LC-MS：M+H＝468

¹H NMR (DMSO) δ (ppm): 8.45(s, 1H); 8.15 (broad singlet, 1H); 7.85(m, 2H); 7.70(dd, 2H); 7.45 (broad triplet, 1H); 7.30(t, 2H); 6.90(d, 1H); 6.8(s, 1H); 5.20(s, 2H); 4.40 (broad doublet, 2H); 3.10(m, 2H); 2.85 (broad triplet, 2H); 1.80 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 5 (Compound 21)

4-carbamoyl-oxazol-2-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

5.1.2-acetoxymethyloxazole-4-carboxylic acid methyl ester

To a solution of 1.2g (4.20mmol) of methyl 2-bromomethyloxazole-4-carboxylate (US 2005/215577) in 42mL of acetonitrile was added 0.453g (4.62mmol) of potassium acetate at room temperature, followed by stirring at room temperature for 12 hours.

After concentration under reduced pressure, the residue was taken up in dichloromethane and water. The aqueous phase was separated off and then extracted twice with dichloromethane. The organic phases were combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

This gives 1.1g of the desired product in the form of an oil which can be used in the next step without further purification.

5.2.4-carbamoyl-oxazol-2-yl-methanols

20mL (352mmol) of 28% aqueous ammonia are added to a round-bottom flask containing 0.60g (3.01mmol) of methyl 2-acetoxymethyloxazole-4-carboxylate prepared in step 5.1 and the reaction medium is then stirred at room temperature for 24 hours.

After concentration under reduced pressure, the resulting residue was purified by silica gel chromatography (eluting with 90/10/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia), whereby 0.230g of pure product was in the form of a white powder.

m.p.(℃)：148-150℃

4-carbamoyloxazol-2-ylmethyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

The process was carried out according to the procedure described in example 4. Starting from 0.25g (0.54mmol) of 4-nitrophenyl 2- [5 '- (4-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate, 0.139g (1.08mmol) of N, N-diisopropylethylamine, 0.033g (0.27mmol) of N, N-dimethylaminopyridine and 0.084g (0.59mmol) of 4-carbamoyloxazol-2-ylmethanol prepared in step 5.2 as described in example 1 (step 1.5.) 162g of pure product are obtained in the form of a white powder.

m.p.(℃)：206-208℃，LC-MS：M+H＝468

¹H NMR (DMSO) δ (ppm): 8.60(s, 1H); 8.40(s, 1H); 7.80(dd, 1H); 7.65(m, 3H); 7.45(m, 2H); 7.25(t, 2H); 6.85(d, 1H); 5.10(s, 2H); 4.30 (broad doublet, 2H); 3.10(m, 2H); 2.75 (broad triplet, 2H); 1.75 (broad doublet, 2H); 1.55(m, 1H);1.35(m，2H)；1.10(m，2H).

example 6 (Compound 1)

2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

6.1. Methanesulfonic acid 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl ester

To a solution of 4.00g (13.76mmol) of 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] -ethanol (WO 2004/099176), 3.55g (27.51mmol) of N, N-diisopropylethylamine and 0.84g (6.88mmol) of N, N-dimethylaminopyridine in 30mL of dichloromethane is added dropwise, under an inert atmosphere, a solution of 2.36g (20.63mmol) of methyl chloride in 3mL of dichloromethane. Stirring was continued for 2 hours at 0 ℃ and then for 1 hour at room temperature.

Water was added to the reaction medium, the aqueous phase was separated off and extracted several times with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure.

This gives 5.1g of product in the form of an oil which can be used in the next step without further purification.

6.2.2- [4- (2-azidoethyl) piperidin-1-yl ] -6-chloroquinoline

A solution of 5g (13.55mmol) of 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl methanesulfonate prepared in step 6.1 and 1.76g (27.11mmol) of sodium azide in 30ml of N, N-dimethylformamide was refluxed under an inert atmosphere for 4 hours.

The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in dichloromethane and water, the aqueous phase was separated off and extracted twice with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, 3.8g of product are obtained in the form of an oil, which is used in the next step without further purification.

6.3.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylamine

To a solution of 3.50g (11.08mmol) of 2- [4- (2-azidoethyl) piperidin-1-yl ] -6-chloroquinoline obtained in step 6.2 in 100mL of THF/water (1/1) was added dropwise 4.36g (16.62mmol) of triphenylphosphine at room temperature. Stirring was continued at room temperature for 10 hours.

The mixture was concentrated under reduced pressure. Ethyl acetate was added, the aqueous phase was separated and extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. After purification by chromatography on silica gel (elution with 90/10/1 mixture of dichloromethane, methanol and 28% aqueous ammonia), 1.77g of pure product are obtained in the form of an oil which crystallizes at room temperature.

m.p.(℃)：68-70℃

¹H NMR(CDCl₃) δ (ppm): 7.70(d, 1H); 7.50(m, 2H); 7.35(m, 1H); 6.95(d, 1H); 4.45 (broad doublet, 2H); 2.90 (broad three-panel doublet, 2H); 2.70(t, 2H); 1.70(m, 2H); 1.60-1.10(m, 5H).

6.4.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 4-nitrophenyl ester

The process was carried out according to the method described in example 1 (step 1.5.). Starting from 5.00g (17.25mmol) of 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylamine prepared in step 6.3, 3.825g (18.98mmol) of 4-nitrophenyl chloroformate, 4.46g (34.51mmol) of N, N-diisopropylethylamine and 0.105g (0.86mmol) of N, N-dimethylaminopyridine, and after trituration from a mixture of diisopropylether and hexane, 7.8g of pure product are obtained in the form of a white powder.

m.p.(℃)：80-84℃

6.5.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 4. Starting from 0.50g (1.10mmol) of 4-nitrophenyl 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamate obtained in step 6.4, 0.284g (2.2mmol) of N, N-diisopropylethylamine, 0.067g (0.55mmol) of N, N-dimethylaminopyridine and 0.156g (1.1mmol) of 3-carbamoylisoxazol-5-ylmethanol, 0.250g of pure product are obtained in the form of a white powder.

m.p.(℃)：220-222℃；LC-MS：M+H＝468

¹H NMR (DMSO) δ (ppm): 8.15 (broad singlet, 1H); 8.0(d, 1H); 7.85 (broad singlet, 1H); 7.75(d, 1H); 7.50(q, 2H); 7.45 (broad triplet, 1H); 7.30(d, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.50 (broad doublet, 2H); 3.10(m, 2H); 2.90 (broad triplet, 2H); 1.80 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 7 (Compound 20)

2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

7.1.5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-ylethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid ethyl ester

The process was carried out according to the procedure described in example 1 (step 1.7.). Starting from 0.5g (1.1mmol) of 4-nitrophenyl 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamate, 0.311g (2.2mmol) of N, N-diisopropylethylamine, 0.067g (0.55mmol) of N, N-dimethylaminopyridine and 0.188g (1.1mmol) of ethyl 5-hydroxymethylisoxazole-3-carboxylate as described in example 6 (step 6.4.) and, after purification by chromatography on silica gel eluting with an 98/2 mixture of dichloromethane and methanol, 0.4g of pure product is obtained in the form of a white powder.

m.p.(℃)：113-115℃

¹H NMR(CDCl₃)δ(ppm)：7.70(d，1H)；7.50(m，1H)；7.45(m，1H)；7.35(m，1H) (ii) a 6.90(d, 1H); 6.65(s, 1H); 5.20(s, 2H); 4.70(m, 2H); 4.50-4.30(m, 5H); 3.20(m, 2H); 2.90 (broad triplet, 2H); 1.80 (broad doublet, 2H); 1.60-1.20(m, 6H).

7.2.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

To a solution of 0.17g (0.35mmol) of ethyl 5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-ylethylcarbamoyloxymethyl } isoxazole-3-carboxylate prepared in step 7.1 in 5mL of an 5/1 mixture of methanol and dichloromethane was added at room temperature 1mL (6.98mmol) of a solution of methylamine (7M) in tetrahydrofuran. Stirring was continued for 2 hours at about 50 ℃.

The mixture was cooled to room temperature and then cooled in an ice bath. The precipitate thus formed was filtered off and then rinsed well with diethyl ether. After drying at about 70 ℃ in vacuo, 0.12g of pure product is obtained in the form of a white powder.

m.p.(℃)：200-202℃，LC-MS：M+H＝472

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.0(d, 1H); 7.80(s, 1H); 7.55(q, 2H); 7.45 (broad triplet, 1H); 7.30(d, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.50 (broad doublet, 2H); 3.10(m, 2H); 2.90 (broad triplet, 2H); 2.80(d, 3H); 1.80 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 8 (Compound 23)

2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

8.1.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid tert-butyl ester

2.18g (9.64mmol) of 2-bromo-6-fluoroquinoline, 2.00g (8.76mmol) of tert-butyl 2-piperidin-4-ylethylcarbamate, 2.08g (26.28mmol) of pyridine and 15mL of acetonitrile are introduced into a sealed tube. The mixture was then heated at 80 ℃ for 12 hours.

The mixture was cooled to room temperature and then cooled in an ice bath. The precipitate thus formed was filtered off and then rinsed well with diethyl ether. After drying at about 50 ℃ in vacuo, 2.00g of pure product are obtained in the form of a white powder.

m.p.(℃)：127-129℃

8.2.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylamine hydrochloride

To a solution of 1.9g (5.09mmol) of tert-butyl 2- [1- (6-fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamate in 6mL of dichloromethane obtained in step 8.1, cooled in an ice/water bath, was slowly added 10mL (40mmol) of a 4N hydrogen chloride in dioxane. Stirring was continued at room temperature for 2 hours.

After evaporation under reduced pressure, 0.9g of the product was obtained as the hydrochloride salt, which was used without further purification in step 8.4 below.

8.3.4-Nitrophenyl carbonate 3-carbamoylisoxazol-5-ylmethyl ester

To a solution of 2.00g (14.07mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71mL (21.11mmol) of pyridine and 0.172g (1.41mmol) of N, N-dimethylaminopyridine in 15mL of dichloromethane cooled to about 0 deg.C was added dropwise 2.84g (14.07mmol) of 4-nitrophenyl chloroformate. Stirring was continued for 1 hour at 0 ℃ and then for 1 hour at room temperature.

The precipitate thus formed was filtered off and then rinsed well with diisopropyl ether. After drying at about 60 ℃ in vacuo, 3.12g of product were obtained as a white solid, which was used in the next step without further purification.

m.p.(℃)：143-145℃

¹H NMR (DMSO) δ (ppm): 8.40(d, 2H); 8.25 (broad singlet, 1H); 7.90 (broad singlet, 1H); 7.65(d, 2H); 7.0(s, 1H); 5.50(s, 2H).

8.4.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 1 in step 1.6. Starting from 0.30g (0.87mmol) of 2- [1- (6-fluoroquinolin-2-yl) piperidin-4-yl ] ethylamine hydrochloride obtained in step 8.2, 0.266g (0.87mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 8.3, 0.367g (2.6mmol) of N, N-diisopropylethylamine and 0.053g (0.43mmol) of N, N-dimethylaminopyridine, 0.260g of pure product are obtained in the form of a white powder.

m.p.(℃)：200-202℃，LC-MS：M+H＝442

¹H NMR (DMSO) δ (ppm): 8.15 (broad singlet, 1H); 8.05(d, 1H); 7.80 (broad singlet, 1H); 7.55(dd, 1H); 7.50(dd, 1H); 7.40(m, 2H); 7.30(d, 1H); 6.75(s, 1H); 5.20(s, 2H); 4.50 (broad doublet, 2H); 3.10(m, 2H); 2.90 (broad triplet, 2H); 1.75 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 9 (Compound 25)

2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

9.1.4-Nitrophenyl carbonate 3-methylcarbamoyl isoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 8 (step 8.3.). Starting from 2g (12.81mmol) of 3-methylcarbamoylisoxazol-5-ylmethanol, 2.58g (12.81mmol) of 4-nitrophenyl chloroformate, 1.52g (19.21mmol) of pyridine and 0.157g (1.28mmol) of N, N-dimethylaminopyridine, 2.6g of pure product are obtained in the form of a white powder.

m.p.(℃)：166-168℃

¹H NMR(CDCl₃)δ(ppm)：8.40(d, 2H); 7.50(d, 2H); 7.0(s, 1H); 6.90 (broad singlet, 1H); 5.50(s, 2H); 3.10(d, 3H).

9.2.2- [1- (6-Fluoroquinolin-2-yl) piperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 1 (step 1.6.). Starting from 0.310g (1.13mmol) of 2- [1- (6-fluoroquinolin-2-yl) piperidin-4-yl ] ethylamine obtained in step 8.2, 0.383g (1.19mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.1 and 0.32g (2.27mmol) of N, N-diisopropylethylamine, 0.33g of pure product is obtained in the form of a white powder.

m.p.(℃)：180-182℃，LC-MS：M+H＝456

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.0(d, 1H); 7.55(dd, 1H); 7.50(dd, 1H); 7.40(m, 2H); 7.30(d, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.50 (broad doublet, 2H); 3.10(m, 2H); 2.85 (broad triplet, 2H); 2.75(d, 3H); 1.75 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 10 (Compound 28)

3-carbamoylisoxazol-5-ylmethyl 2- [5 '- (3-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamate

10.1.2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamic acid tert-butyl ester

10.37g (43.80mmol) of 2, 5-dibromopyridine, 10.00g (43.80mmol) of tert-butyl 2-piperidin-4-ylethylcarbamate and 6.05g (43.80mmol) of potassium carbonate were placed in an autoclave. The mixture was then heated at 130 ℃ for 12 hours.

The reaction mixture was cooled to room temperature and then taken up in chloroform and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted twice with chloroform, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure.

After purification by chromatography on silica gel (elution with 95/5 mixture of dichloromethane and methanol), 6.9g of pure product are obtained in the form of a white powder.

m.p.(℃)：108-110℃

10.2.2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylamine

To a solution of 6.90g (17.95mmol) of tert-butyl 2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamate obtained in step 10.1 in 100mL of dichloromethane cooled in an ice/water bath was slowly added 20.47g (179.54mmol) of trifluoroacetic acid. Stirring was continued at room temperature for 2 hours. The reaction mixture was poured into a mixture of ice-water and 28% aqueous ammonia. The phases were separated by settling, the aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.

4.9g of product are obtained in the form of an oil which is used in the next step without further purification.

[2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamic acid 4-nitrophenyl ester

The process was carried out according to the method described in example 1 (step 1.5.). Starting from 3.00g (10.56mmol) of 2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) -ethylamine prepared in step 10.2, 2.34g (11.61mmol) of 4-nitrophenyl chloroformate, 3.41g (26.39mmol) of N, N-diisopropylethylamine and 0.129g (1.06mmol) of N, N-dimethylaminopyridine, and trituration in diisopropylether, 3.27g of the product are obtained as an amorphous solid.

3-carbamoylisoxazol-5-ylmethyl 2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamate

The process was carried out according to the procedure described in example 4. Starting from 1.00g (2.23mmol) of 4-nitrophenyl [2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylcarbamate obtained in step 10.3, 0.575g (4.45mmol) of N, N-diisopropylethylamine, 0.136g (1.11mmol) of N, N-dimethylaminopyridine and 0.381g (2.67mmol) of 5-hydroxymethylisoxazole-3-carboxamide, and trituration with ether gives 0.740g of pure product in the form of a white powder.

m.p.(℃)：164-166℃

10.5.2- [5 '- (3-fluorophenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid carbamoylisoxazol-5-ylmethyl ester

0.735g (1.63mmol) of 2- (5 ' -bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2 ' obtained in step 10.4 ']Bipyridin-4-yl) ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester, 0.256g (1.83mmol) of 3-fluorophenylboronic acid and 1.493g (4.58mmol) of cesium carbonate in 8mL 9/1 mixture of tetrahydrofuran and water were placed under an inert atmosphere. Then 0.125g (0.15mmol) of PdCl are added₂dppf.CH₂Cl₂. The mixture was then heated at about 80 ℃ for 18 hours.

The mixture was cooled to room temperature, the salts were separated off by filtration over celite, the filtrate was taken up in ethyl acetate and water, the aqueous phase was separated off and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, a brown gum was obtained, which was triturated in diisopropyl ether. The resulting green solid was then filtered off and dried under vacuum at about 80 ℃.

0.651g of product was obtained.

m.p.(℃)：172-176℃，LC-MS：M+H＝468

¹H NMR (DMSO) δ (ppm): 8.50(s, 1H); 8.15 (broad singlet, 1H);7.90(dd, 1H); 7.80 (broad singlet, 1H); 7.70-7.40(m, 4H); 7.15(m, 1H); 6.90(d, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.35 (broad doublet, 2H); 3.10(m, 2H); 2.85 (broad triplet, 2H); 1.80 (broad doublet, 2H); 1.60(m, 1H); 1.40(m, 2H); 1.15(m, 2H).

Example 11 (Compound 53)

2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid

{2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl } carbamic acid tert-butyl ester

A solution of 2.00g (8.76mmol) of tert-butyl (2-piperidin-4-ylethyl) carbamate (commercially available), 1.73g (8.76mmol) of 2, 6-dichloroquinoline (commercially available) and 1.27g (36.79mmol) of potassium carbonate in 11mL of DMSO was introduced into a sealed tube. The mixture was then heated at 130 ℃ for 12 hours. The reaction mixture was cooled to room temperature and then taken up in dichloromethane and water. The aqueous phase was separated and extracted twice with dichloromethane, and the combined organic phases were washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (elution with 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia) to yield 3.40g of pure product in the form of a powder.

LC-MS：M+H＝390

m.p.(℃)：120-122℃

¹H NMR(CDCl₃) δ (ppm): 7.80(d, 1H); 7.65(d, 1H); 7.60(s, 1H); 7.40(d, 1H); 7.00(d, 1H); 4.50 (broad doublet, 3H); 3.25(m, 2H); 2.90(m, 2H); 1.90(d, 2H); 1.65(m, 1H); 1.45(m, 11H); 1.25(m, 2H).

11.2.2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylamine

To a solution of 10.95g (28.08mmol) of tert-butyl {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethyl } carbamate in 10mL of dioxane obtained in step 11.1 cooled in an ice/water bath was slowly added 28mL (112.00mmol) of a 4N solution of hydrogen chloride in dioxane. Stirring was continued at room temperature for 3 hours. After filtration through a sintered funnel, the product is obtained in the form of the hydrochloride salt, which is then basified by treatment with 35% sodium hydroxide. After extraction with dichloromethane, dried over sodium sulfate and evaporated to dryness, 8.13g of a white powder was obtained.

LC-MS：M+H＝290

m.p.(℃)：118-120℃

¹H NMR(CDCl₃) δ (ppm): 7.80(d, 1H); 7.65(d, 1H); 7.60(s, 1H); 7.45(d, 1H); 7.00(d, 1H); 4.50 (broad doublet, 2H); 3.00(m, 2H); 2.80(t, 2H); 1.85(d, 2H); 1.65(m, 1H); 1.50(m, 2H); 1.30-1.10(m, 4H).

11.3.5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid ethyl ester

To a solution of 3.54g (20.70mmol) of ethyl 5-hydroxymethylisoxazole-3-carboxylate (commercially available), 7.88mL (41.41mmol) of N, N-diisopropylethylamine and 1.26g (10.35mmol) of N, N-dimethylaminopyridine in 120mL of dichloromethane cooled to 0 deg.C was added dropwise 4.17g (20.70mmol) of p-nitrophenyl chloroformate. The mixture was stirred at 10 ℃ for 2 hours and then evaporated to dryness. The residue obtained is taken up in 120mL of1, 2-dichloroethane, followed by addition of 6.00g (20.70mmol) of 2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylamine obtained in step 11.2 and 5mL (26.27mmol) of N, N-diisopropylethylamine. The mixture was heated at 70 ℃ for 12 hours.

After cooling to room temperature, the insoluble matter was filtered off and 1N aqueous sodium hydroxide solution was added to the filtrate. The product was then extracted with dichloromethane. The combined organic phases were washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. After drying the organic phase over sodium sulfate, the resulting solution was concentrated under reduced pressure. After purification on a silica gel column (elution with 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia), the product was triturated in diisopropyl ether to give 5.10g of the desired product as a white solid.

m.p.(℃)：113-115℃

¹H NMR(CDCl₃) δ (ppm): 7.70(d, 1H); 7.50(m, 1H); 7.45(m, 1H); 7.35(m, 1H); 6.90(d, 1H); 6.65(s, 1H); 5.20(s, 2H); 4.70(m, 2H); 4.50-4.30(m, 5H); 3.20(m, 2H); 2.90 (broad triplet, 2H); 1.80 (broad doublet, 2H); 1.60-1.20(m, 6H).

11.4.5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylic acid

To a solution of 1.00g (2.05mmol) of ethyl 5- {2- [1- (6-chloroquinolin-2-yl) piperidin-4-yl ] ethylcarbamoyloxymethyl } isoxazole-3-carboxylate obtained in step 11.3 in 51mL of ethanol was added 10.27mL (10.27mmol) of aqueous sodium hydroxide solution (1N). The mixture was stirred at room temperature for 2 hours. After evaporation to dryness, the residue is taken up in a minimum amount of water, followed by addition of 1N aqueous hydrochloric acid at 0 ℃ to reach pH 4-5. After separation of the phases by settling, the resulting oil was triturated in acetone to give 0.45g of the desired product in the form of a white solid.

m.p.(℃)：180-182℃，LC-MS：M+H＝459

¹H NMR (DMSO) δ (ppm): 8.40 (broad singlet, 1H); 8.00 (broad singlet, 2H); 7.85 (broad singlet, 1H); 7.75(d, 1H); 7.55(d, 1H); 6.85(s, 1H); 5.20(s, 2H); 4.50 (broad doublet, 2H); 3.55(m, 2H); 3.10(m, 2H); 1.90(m, 2H); 1.70(m, 1H); 1.40(m, 2H); 1.25(m, 2H).

Example 12 (Compound 60)

{2- [ 3-dimethylamino-1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

12.1.3-cyanomethyl-3-dimethylaminoazetidine-1-carboxylic acid tert-butyl ester

1.20g (6.18mmol) of tert-butyl 3-cyanomethyleneazetidine-1-carboxylate (WO2009/064835) were dissolved in 15mL of methanol in a sealed tube. 6.18mL (12.36mmol) of dimethylamine in methanol are added and the reaction medium is stirred for 3 hours at 80 ℃.

The mixture was cooled to room temperature and then evaporated to dryness. The residue obtained is purified by chromatography on a column of silica gel (elution with 97/3/0.3 mixture of dichloromethane, methanol and 28% aqueous ammonia) to give 1.32g of the desired product in the form of an oil.

LC-MS：M+H＝240

¹H NMR(DMSO)δ(ppm)：3.75(m，4H)；2.90(s，2H)；2.15(s，6H)；1.40(s，9H).

12.2.3- (2-aminoethyl) -3-dimethylaminoazetidine-1-carboxylic acid tert-butyl ester

To a solution of 1.30g (5.43mmol) of 3-cyanomethyl-3-dimethylamino-azetidine-1-carboxylic acid tert-butyl ester obtained in the preceding step in 27mL of methanol was added 1.59g (27.16mmol) of Raney Nickel (Raney Nickel). The reaction medium is placed in a Parr bomb (Parr bomb) under a hydrogen atmosphere (70psi) at 50 ℃ and held for 6 hours. The resulting mixture was filtered through a buchner funnel, and the filtrate was concentrated under reduced pressure. This gave 1.28g of the desired product as a colorless oil.

¹H NMR(CDCl₃)δ(ppm)：3.90(d，2H)；3.60(d，2H)；2.90(m，2H)；2.25(s，6H)；2.10(m，2H)；1.90(m，2H)；1.40(s，9H).

12.3.3-dimethylamino-3- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl ] azetidine-1-carboxylic acid tert-butyl ester

A solution containing 0.60g (2.47mmol) of tert-butyl 3- (2-aminoethyl) -3-dimethylaminoazetidine-1-carboxylate obtained in step 12.2, 0.87g (2.71mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.2, 860. mu.L (4.93mmol) of N, N-diisopropylethylamine and 0.15g (1.23mmol) of N, N-dimethylaminopyridine in 12mL1, 2-dichloroethane was heated at 80 ℃ for 3 hours.

Water was added to the reaction medium, the aqueous phase was separated off and extracted several times with dichloromethane, and the combined organic phases were washed with aqueous sodium hydroxide solution (1N) and then with saturated aqueous ammonium chloride solution. The resulting solution was dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (elution with 97/3/0.3 mixture of dichloromethane, methanol and 28% aqueous ammonia) to give 0.64g of the desired product in the form of a wax.

LC-MS：M+H＝426

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 7.40 (broad singlet, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.80(m, 2H); 3.60(m, 2H); 3.10(m, 2H); 2.80(s, 3H); 2.15(s, 6H); 1.80(m, 2H); 1.40(s, 9H).

[2- (3-dimethylaminoazetidin-3-yl) ethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester hydrochloride (2: 1)

The process was carried out according to the procedure described in example 11 (step 11.2.) starting from 0.58g (1.36mmol) of tert-butyl 3-dimethylamino-3- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl ] azetidine-1-carboxylate obtained in step 12.3 and 4mL (16mmol) of 4N hydrogen chloride in dioxane and, after trituration with diethyl ether, giving 1.27g of the desired product in the form of a white powder.

m.p.(℃)：210-212℃

¹H NMR (DMSO) δ (ppm): 12.50 (broad singlet, 1H); 9.80 (broad singlet, 1H); 9.20 (broad singlet, 1H);8.80 (broad singlet, 1H); 7.80 (broad singlet, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.50(m, 2H); 4.10(m, 2H); 3.40(m, 2H); 2.80(s, 3H); 2.55(s, 6H); 2.10(t, 2H).

3-methylcarbamoylisoxazol-5-ylmethyl {2- [ 3-dimethylamino-1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamate

0.40g (1.00mmol) of [2- (3-dimethylaminoazetidin-3-yl) ethyl ] prepared in the preceding step]Carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester hydrochloride (2: 1), 0.20g (1.10mmol) of 2-chloro-4-trifluoromethylpyrimidine and 700. mu.L (4.02mmol) of N, N-diisopropylethylamine in a microwave reactor (Biotage Initiator)^TM2.0 model) in 5mL of acetonitrile. The reaction medium is subjected to microwave irradiation at 130 ℃ for 10 minutes.

The mixture was cooled to room temperature and then water was added to the reaction medium. The aqueous phase was separated and extracted several times with dichloromethane and the combined organic phases were washed with saturated aqueous ammonium chloride solution. The resulting solution was dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

The residue obtained is purified by chromatography on silica gel (elution with an 97/3/0.3 mixture of dichloromethane, methanol and 28% aqueous ammonia) and, after trituration in diisopropyl ether and filtration, 0.38g of the desired product is obtained in the form of a white powder.

m.p.(℃)：154-156℃，LC-MS：M+H＝472

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 2H); 7.45(t, 1H); 7.10(m, 1H); 6.80(s, 1H); 5.20(s, 2H); 4.10(d, 2H); 3.80(d, 2H); 3.10(m, 2H); 2.80(s, 3H); 2.20(s, 6H); 1.90(m, 2H).

Example 13 (Compound 63)

{2- [1- (4-Chlorophthalazin-1-yl) -3-dimethylaminoazetidin-3-yl ] ethyl } carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester

13.1.3-dimethylamino-3- {2- [2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethoxycarbonylamino ] ethyl } azetidine-1-carboxylic acid tert-butyl ester

To a solution of 0.60g (2.47mmol) of tert-butyl 3- (2-aminoethyl) -3-dimethylaminoazetidine-1-carboxylate prepared in step 12.2, 0.95g (7.40mmol) of N, N-diisopropylethylamine and 0.06g (0.49mmol) of N, N-dimethylaminopyridine in 12mL of1, 2-dichloroethane cooled to about 0 deg.C was added dropwise a solution of 0.497g (2.47mmol) of 4-nitrophenyl chloroformate in 3mL1, 2-dichloroethane. Stirring was continued at room temperature for 1 hour. Then 0.488g (2.71mmol) of 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethanol (commercially available) and 0.47g (3.70mmol) of N, N-diisopropylethylamine were added. The mixture was heated at 80 ℃ for 12 hours.

After cooling to room temperature, water was added to the reaction medium, the aqueous phase was separated off and extracted several times with dichloromethane, and the combined organic phases were washed with aqueous sodium hydroxide solution (1N) and then with saturated aqueous ammonium chloride solution. The resulting solution was dried over sodium sulfate and the filtrate was concentrated under reduced pressure.

After purification on a silica gel column (elution with an 97/3/0.3 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.71g of the desired product is obtained in the form of a wax.

LC-MS：M+H＝450

¹H NMR(DMSO)δ(ppm)：7.85(t，1H)；7.25(s，1H)；7.00(s，1H)；6.45(m，1H)；3.75(m，5H)；3.50(m，2H)；3.10(m，2H)；2.15(s，6H)；1.85(t，2H)；1.40(s，9H).

[2- (3-dimethylaminoazetidin-3-yl) ethyl ] carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester hydrochloride (2: 1)

The process was carried out according to the procedure described in example 11 (step 11.2.) starting from 0.71g (1.58mmol) of tert-butyl 3-dimethylamino-3- {2- [2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethoxycarbonylamino ] ethyl } azetidine-1-carboxylate obtained in step 13.1 and 3.90mL (15.75mmol) of a solution of 4N hydrogen chloride in dioxane and trituration with diethyl ether gave 0.84g of the desired product as an amorphous solid.

¹H NMR (DMSO) δ (ppm): 12.50 (broad singlet, 1H); 10.00 (broad singlet, 1H); 9.20 (broad singlet, 1H); 8.30(t, 1H); 7.60(s, 1H); 7.30(s, 1H); 6.80(m, 1H); 4.50(m, 2H); 4.10(m, 2H); 3.90(s, 3H); 3.40(m, 2H); 2.70(s, 6H); 2.15(m, 2H).

{2- [1- (4-chlorophthalazin-1-yl) -3-dimethylaminoazetidin-3-yl ] ethyl } carbamic acid 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl ester

The process was carried out according to the procedure described in example 12 (step 12.5.), starting from a solution of 0.50g (1.09mmol) of 2, 2, 2-trifluoro-1- (1-methyl-1H-imidazo-2-yl) ethyl [2- (3-dimethylaminoazetidin-3-yl) ethyl ] carbamate hydrochloride (2: 1) obtained in the preceding step 13.2, 0.26g (1.31mmol) of1, 4-dichlorophthalazine (commercially available) and 0.70g (5.45mmol) of N, N-diisopropylethylamine in 5.45mL of acetonitrile, giving 0.185g of the desired product in the form of a powder.

m.p.(℃)：168-170℃，LC-MS：M+H＝512，

¹H NMR (DMSO) δ (ppm): 8.20(m, 2H); 8.05(m, 1H); 7.90(m, 1H); 7.80 (broad singlet, 1H); 7.20(m, 1H); 6.90(s, 1H); 6.40(m, 1H); 4.40 (broad singlet, 2H); 4.20 (broad singlet, 2H); 3.70(s, 3H); 3.20(m, 2H); 2.30(m, 6H); 1.95(m, 2H).

Example 14 (Compound 56)

5- [1- (6-Chloroquinolin-2-yl) -4-fluoropiperidin-4-ylmethylcarbamoyloxymethyl ] isoxazole-3-carboxylic acid ethyl ester

14.1.5- (4-Nitrophenoxycarbonyloxymethyl) isoxazole-3-carboxylic acid ethyl ester

The process was carried out according to the procedure described in example 8 (step 8.3.), starting from 3.00g (17.53mmol) of ethyl 5-hydroxyisoxazole-3-carboxylate, 3.71g (18.40mmol) of 4-nitrophenyl chloroformate, 2.07g (26.29mmol) of pyridine and 0.214g (1.75mmol) of N, N-dimethylaminopyridine, to give 3.80g of the desired product in the form of a white powder.

m.p.(℃)：85-87℃，LC-MS：M+H＝337

¹H NMR(DMSO)δ(ppm)：8.40(d，2H)；7.60(d，2H)；7.10(s，1H)；5.55(s，2H)；4.40(q，2H)；1.40(t，3H).

14.2.4- [ (3-ethoxycarbonylisoxazol-5-ylmethoxycarbonylamino) methyl ] -4-fluoropiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 1 (step 1.6.) starting from 0.70g (3.01mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercially available) and 1.11g (3.31mmol) of ethyl 5- (4-nitrophenoxycarbonyloxymethyl) isoxazole-3-carboxylate obtained in step 14.1 to give 0.33g of pure product in the form of an orange oil.

¹H NMR (DMSO) δ (ppm): 7.75 (broad triplet, 1H); 6.90(s, 1H); 5.25(s, 2H); 4.40(q, 2H); 3.80(m, 2H); 3.00(m, 2H); 3.25(m, 2H); 1.75-1.45(m, 4H); 1.40(s, 9H); 1.30(t, 3H).

14.3.5- (4-Fluoropiperidin-4-ylmethylcarbamoyloxymethyl) isoxazole-3-carboxylic acid ethyl ester trifluoroacetate salt

To a solution of 0.90g (2.10mmol) of tert-butyl 4- [ (3-ethoxycarbonylisoxazol-5-ylmethoxycarbonylamino) methyl ] -4-fluoropiperidine-1-carboxylate obtained in step 14.2 in 10mL of dichloromethane cooled in an ice/water bath was slowly added a solution of 1.06mL (12.57mmol) of trifluoroacetic acid. Stirring was continued at room temperature for 3 hours.

After evaporation under reduced pressure, 0.46g of product was obtained in the form of the trifluoroacetate salt, which was used without further purification in step 14.4 described below.

14.4.5- [1- (6-chloroquinolin-2-yl) -4-fluoropiperidin-4-ylmethyl ] isoxazole-3-carboxylic acid ethyl ester

A solution of 0.465g (1.05mmol) of ethyl 5- (4-fluoropiperidin-4-ylmethylcarbamoyloxymethyl) isoxazole-3-carboxylate trifluoroacetate obtained in step 14.3, 0.23g (1.15mmol) of 2, 6-dichloroquinoline and 730. mu.L (4.20mmol) of N, N-diisopropylethylamine in 5mL of acetonitrile is introduced into a sealed tube. The mixture was then heated at 120 ℃ for 12 hours. The mixture is cooled to room temperature, the reaction medium is then taken up in ethyl acetate, the aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is purified by chromatography on a column of silica gel (elution with 99/1 mixture of dichloromethane and methanol), thus obtaining 0.07g of pure product in the form of a white powder.

m.p.(℃)：132-134℃，LC-MS：M+H＝491，

¹H NMR(DMSO)δ(ppm)：8.05(d，1H)；7.90-7.70(m，2H)；7.60-7.50(m，2H)；7.35(d，1H)；6.90(s，1H)；5.25(m，2H)；4.45-4.30(m，4H)；3.40-3.20(m，4H)；1.90-1.60(m，4H)；1.35(t，3H).

Example 15 (Compound 57)

[ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] methylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

15.1.5- [ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ylmethylcarbamoyloxymethyl ] isoxazole-3-carboxylic acid ethyl ester

The process was carried out according to the procedure described in example 14 (step 14.4.), starting from 0.46g (1.05mmol) of ethyl 5- (4-fluoropiperidin-4-ylmethylcarbamoyloxymethyl) isoxazole-3-carboxylate trifluoroacetate obtained in step 14.3, 0.21g (1.15mmol) of 2-chloro-4-trifluoromethylpyrimidine and 730. mu.L (4.20mmol) of N, N-diisopropylethylamine in 5mL of acetonitrile, whereby 0.22g of pure product was obtained in the form of a white powder.

m.p.(℃)：136-138℃，LC-MS：M+H＝476

¹H NMR(DMSO)δ(ppm)：8.70(d，1H)；7.75(t，1H)；7.00(d，1H)；6.90(s，1H)；5.25(s，2H)；4.50-4.30(m，4H)；3.40-3.15(m，4H)；1.90-1.50(m，4H)；1.30(t，3H).

[ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] methylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

A solution of 0.14g (0.29mmol) of ethyl 5- [ 4-fluoro-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ylmethylcarbamoyloxymethyl ] isoxazole-3-carboxylate prepared in step 15.1 in 1.10mL (8.83mmol) of methylamine in ethanol was stirred in a sealed tube at room temperature for 1h 30 min. The resulting mixture was evaporated to dryness. The residue obtained is triturated in ether and filtered. After drying at about 60 ℃ in vacuo, 0.12g of pure product is obtained in the form of a white powder.

m.p.(℃)：187-189℃，LC-MS：M+H＝461

¹H NMR(DMSO)δ(ppm)：8.70(m，2H)；7.75(m，1H)；7.00(m，1H)；6.80(s，1H)；5.20(m，2H)；4.45(m，2H)；3.40-3.20(m，4H)；2.80(m，3H)；1.90-1.55(m，4H).

Example 16 (Compound 43)

[2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

[2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethyl ] carbamic acid ethyl ester

The process was carried out according to the method described in example 1 (step 1.5.), starting from 4.52g (15.90mmol) of 2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) -ethylamine prepared in step 10.2, 1.89g (17.49mmol) of ethyl chloroformate, 5.13g (39.76mmol) of N, N-diisopropylethylamine and 0.19g (1.59mmol) of N, N-dimethylaminopyridine, and, after purification on a silica gel column (elution with 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia), 3.87g of the desired product are obtained in the form of a powder.

m.p.(℃)：87-89℃

¹H NMR (DMSO) δ (ppm): 8.00(m, 1H); 7.30(m, 1H); 6.40(d, 1H); 4.45 (broad singlet, 1H); 4.15-3.90(m, 4H); 3.10(m, 2H); 2.60(m, 2H); 1.65(m, 2H); 1.55-1.25(m, 3H); 1.20-0.95(m, 5H).

{2- [5 '- (2-methylpropenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } carbamic acid ethyl ester

The process was carried out according to the method described in example 10 (step 10.5.), starting from 1.00g (2.81mmol) of [2- (5 '-bromo-3, 4, 5, 6-tetrahydro-2H- [1, 2']Bipyridin-4-yl) ethyl]Ethyl carbamate, 0.61g (3.37mmol) of 2-methyl-1-propenylboronic acid pinacol ester (commercially available), a suspension of 2.74g (8.42mmol) of cesium carbonate in 18mL of 9/1 mixture of tetrahydrofuran and water, and 0.23g (0.28mmol) of PdCl₂dppf.CH₂Cl₂And after purification on a silica gel column (elution with an 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.75g of the desired product is obtained in the form of a wax.

¹H NMR(CDCl₃) δ (ppm): 8.10(m, 1H); 7.40(m, 1H); 6.65(d, 1H); 6.10(m, 1H); 4.65 (broad singlet, 1H); 4.40-4.10(m, 4H); 3.25(m, 2H); 2.85(m, 2H); 1.90-1.75(m, 8H); 1.70-1.40(m, 4H); 1.35-1.20(m, 4H).

[2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethyl ] carbamic acid ethyl ester

To a solution of 0.74g (2.23mmol) of ethyl {2- [5 '- (2-methylpropenyl) -3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethyl } carbamate obtained in the preceding step in 30mL of methanol was added 0.10g (0.94mmol) of palladium on charcoal. The reaction medium is placed in a parr cylinder at room temperature under a hydrogen atmosphere (10psi) and held for 1 hour 30 minutes. The resulting mixture was filtered through a buchner funnel, and the filtrate was concentrated under reduced pressure. This gives 0.74g of the desired product in the form of a powder.

m.p.(℃)：78-80℃

¹H NMR(CDCl₃) δ (ppm): 8.00(m, 1H); 7.30(m, 1H); 6.65(d, 1H); 4.65 (broad singlet, 1H); 4.35-4.05(m, 4H); 3.30(m, 2H); 2.80(m, 2H); 2.35(d, 2H); 1.90-1.75(m, 2H); 1.70-1.45(m, 2H); 1.35-1.20(m, 3H); 0.90(d, 6H).

16.4.2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylamine

To a solution of 0.64g (1.93mmol) of ethyl [2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethyl ] carbamate obtained in step 16.3 in 9.70mL of ethanol/water (1/1) was added 2.17g (38.68mmol) of potassium hydroxide at room temperature. The mixture was then heated at 110 ℃ for 12 hours. 2.17g (38.68mmol) of potassium hydroxide are added and the mixture is stirred for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The reaction medium is taken up in dichloromethane, the aqueous phase is separated off and extracted twice with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation under reduced pressure, 0.37g of the desired product is obtained in the form of a yellow wax.

LC-MS：M+H＝262

¹H NMR(CDCl₃)δ(ppm)：8.00(m，1H)；7.30(m，1H)；6.65(d，1H)；4.25(m，2H)；2.80(m，4H)；2.35(d，2H)；1.80(m，3H)；1.60(m，1H)；1.45(m，2H)；1.30(m，4H)；0.90(d，6H).

[2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl ] ethylcarbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 1, step 1.6, starting from 0.37g (1.42mmol) of 2- (5 '-isopropyl-3, 4, 5, 6-tetrahydro-2H- [1, 2' ] bipyridinyl-4-yl) ethylamine obtained in step 16.4, 0.52g (1.70mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 8.3, 0.62mL (3.54mmol) of N, N-diisopropylethylamine and 0.087g (0.71mmol) of N, N-dimethylaminopyridine in 14mL of1, 2-dichloroethane, to give 0.42g of pure product in the form of a white powder.

m.p.(℃)：168-170℃，LC-MS：M+H＝430

¹H NMR(DMSO)(ppm)：8.10(m，1H)；7.95-7.75(m，2H)；7.50-7.25(m，2H)；6.75(m，2H)；5.20(m，2H)；4.20(m，2H)；3.10(m，2H)；2.70(m，2H)；2.30(d，2H)；1.85-1.65(m，3H)；1.60-1.30(m，3H)；1.10(m，2H)；0.85(m，6H).

Example 17 (Compound 72)

{2- [ 4-methyl-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

17.1.4- (2-aminoethyl) -4-methylpiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.2.), starting from a solution of 1.40g (5.87mmol) of tert-butyl 4-cyanomethyl-4-methylpiperidine-1-carboxylate (WO 2006/001752) and 1.72g (29.37mmol) of Raney nickel in 20mL of methanol at 45 ℃ under a hydrogen atmosphere (70psi), to give 1.35g of the desired product in the form of a wax.

LC-MS：M+H＝243

¹H NMR(CDCl₃)δ(ppm)：3.60-3.40(m，2H)；3.30-3.10(m，2H)；2.75(m，2H)；1.50(s，9H)；1.40-1.25(m，6H)；0.95(s，3H).

17.2.4-methyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl 1-piperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.3.) starting from 0.54g (2.22mmol) of tert-butyl 4- (2-aminoethyl) -4-methylpiperidine-1-carboxylate and 0.78g (2.45mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.2, 580. mu.L (3.34mmol) of N, N-diisopropylethylamine and 0.13g (1.11mmol) of a solution of N, N-dimethylaminopyridine in 22mL of1, 2-dichloroethane, to give 0.94g of the desired product in the form of a wax.

LC-MS：M+H＝425

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 7.40 (broad singlet, 1H); 6.75(s, 1H); 5.20(s, 2H); 3.40(m, 2H); 3.20(m, 2H); 3.05(m, 2H); 2.80(d, 3H); 1.40(m, 11H); 1.25(m, 4H); 0.95(s, 3H).

[2- (4-methylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester hydrochloride

The process was carried out according to the procedure described in example 11 (step 11.2.), starting from 0.97g (2.30mmol) of tert-butyl 4-methyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl ] piperidine-1-carboxylate obtained in step 17.2 and 5.74mL (22.97mmol) of 4N hydrogen chloride in dioxane and, after trituration with diethyl ether, giving 0.73g of the desired product in the form of a white powder.

m.p.(℃)：188-190，LC-MS：M+H＝361

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.50 (broad singlet, 1H); 7.45 (broad singlet, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.00(m, 6H); 2.75(d, 3H); 1.60-1.40(m, 6H); 0.95(m, 3H).

{2- [ 4-methyl-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 12 (step 12.5.) starting from 0.30g (0.83mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2- (4-methylpiperidin-4-yl) ethyl ] carbamate hydrochloride, 0.23g (1.25mmol) of 2-chloro-4-trifluoromethylpyrimidine and 430 μ L (2.49mmol) of N, N-diisopropylethylamine in 2.77mL of acetonitrile to give 0.29g of the desired product in the form of a powder.

m.p.(℃)：160-162℃，LC-MS：M+H＝471

¹H NMR(DMSO)δ(ppm)：8.80-8.60(m，2H)；7.45(m，1H)；6.95(m，1H)；6.80(s，1H)；5.20(s，2H)；3.95(m，2H)；3.60(m，2H)；3.10(m，2H)；2.80(s，3H)；1.50(m，2H)；1.40(m，4H)；1.00(s，3H).

Example 18 (Compound 64)

{2- [1- (6-Chloroquinoxalin-2-yl) -4-ethylpiperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

18.1.4- (Cyanoethoxycarbonylmethyl) -4-ethylpiperidine-1-carboxylic acid tert-butyl ester

To a solution of 2.00g (6.79mmol) of tert-butyl 4- (cyanoethoxycarbonylmethylene) piperidine-1-carboxylate (WO 2006/001752) in 33mL tetrahydrofuran was added 4.53mL (13.59mmol) of a solution of 3M ethylmagnesium bromide in diethyl ether dropwise at-5 ℃ under argon. The reaction medium is then stirred at room temperature for 12 hours. Ethyl acetate was added and the medium was cooled in an ice/water bath, followed by addition of saturated ammonium chloride solution. The aqueous phase was separated and extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 95/5 mixture of cyclohexane and ethyl acetate) to give 1.63g of pure product in the form of a white powder.

LC-MS：M+H＝325

¹H NMR(CDCl₃)δ(ppm)：4.25(s，1H)；4.20(q，2H)；3.50-3.15(t，4H)；1.60(q，2H)；2.50-1.55(t，2H)；1.40(s，9H)；1.20(t，3H)；0.85(t，3H).

18.2.4-Cyanomethyl-4-ethylpiperidine-1-carboxylic acid tert-butyl ester

To a solution of 1.30g (4.01mmol) of tert-butyl 4- (cyanoethoxycarbonylmethyl) -4-ethylpiperidine-1-carboxylate obtained in the preceding step in 14mL of dimethyl sulfoxide were added 0.09g (1.60mmol) of sodium chloride and 0.14g (8.01mmol) of water. The reaction medium is stirred for 1 hour at 150 ℃. Diethyl ether and water were added. The aqueous phase was separated and extracted three times with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 95/5 mixture of cyclohexane and ethyl acetate) to give 0.96g of pure product in the form of a wax.

LC-MS：M+H＝253

¹H NMR(CDCl₃)δ(ppm)：3.30(t，4H)；2.60(s，2H)；1.45(q，2H)；1.40(t，4H)；1.35(s，9H)；0.80(t，3H).

18.3.4- (2-aminoethyl) -4-ethylpiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.2.), starting from a solution of 0.96g (3.83mmol) of tert-butyl 4-cyanomethyl-4-ethylpiperidine-1-carboxylate and 1.12g (19.15mmol) of Raney nickel in 50mL of methanol at 50 ℃ under an atmosphere of hydrogen (70psi), and after purification by chromatography on a silica gel column (elution with an 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.71g of the desired product are obtained in the form of a wax.

LC-MS：M+H＝257

¹H NMR(CDCl₃)δ(ppm)：3.30(m，4H)；2.50(m，2H)；1.35(t，2H)；1.40(s，9H)；1.30(q，2H)；1.25(m，4H)；0.80(t，3H).

18.4.4-Ethyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl ] piperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.3.), starting from 0.71g (2.78mmol) of tert-butyl 4- (2-aminoethyl) -4-ethylpiperidine-1-carboxylate, 0.98g (3.06mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.1, 730. mu.L (4.17mmol) of N, N-diisopropylethylamine and 0.17g (1.39mmol) of a solution of N, N-dimethylaminopyridine in 27mL of1, 2-dichloroethane, to give 0.94g of the desired product in the form of a powder.

LC-MS：M+H＝439

¹H NMR(CDCl₃)δ(ppm)：8.70(d，1H)；7.40(t，1H)；6.75(s，1H)；5.20(s，2H)；3.30(q，2H)；3.25(m，4H)；2.80(d，3H)；1.50-1.20(m，8H)；1.10(s，9H)；0.80(t，3H).

[2- (4-ethylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester hydrochloride

The process was carried out according to the procedure described in example 11 (step 11.2.), starting from 0.94g (2.14mmol) of tert-butyl 4-ethyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl ] piperidine-1-carboxylate obtained in step 18.4, 2.68mL (10.72mmol) of a solution of 4N hydrogen chloride in dioxane and trituration in ether gave 0.76g of the desired product in the form of a white powder.

m.p.(℃)：222-224，LC-MS：M+H＝339

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 2H); 7.40(t, 1H); 6.80(s, 1H); 5.20(s, 2H); 2.95(m, 6H); 2.75(d, 3H); 1.55(q, 2H); 1.45(t, 2H); 1.35(m, 4H); 0.80(t, 3H).

{2- [1- (6-Chloroquinoxalin-2-yl) -4-ethylpiperidin-4-yl ] ethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process is carried out according to the procedure described in example 12 (step 12.5.) starting from 0.30g (0.89mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2- (4-ethylpiperidin-4-yl) ethyl ] carbamate hydrochloride, 0.26g (1.33mmol) of 2, 6-dichloroquinoxaline and 460. mu.L (2.66mmol) of N, N-diisopropylethylamine in 3mL of acetonitrile to give 0.29g of the desired product in the form of a yellow powder.

m.p.(℃)：158-160℃，LC-MS：M+H＝501

¹H NMR(DMSO)δ(ppm)：8.80(s，1H)；8.70(m，1H)；7.90(s，1H)；7.60(s，2H)；7.40(m，1H)；6.80(s，1H)；5.20(s，2H)；3.90-3.60(m，4H)；3.00(m，2H)；2.80(m，3H)；1.50-1.30(m，8H)；0.80(t，3H).

Example 19 (Compound 65)

{2- [1- (6-Chloroquinoxalin-2-yl) -4-isobutylpiperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

19.1.4- (Cyanoethoxycarbonylmethyl) -4-isobutylpiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 18 (step 18.1.) starting from a solution of 5.00g (16.99mmol) of tert-butyl 4- (cyanoethoxycarbonylmethylene) piperidine-1-carboxylate (WO 2006/001752) in 56mL of tetrahydrofuran and 16.99mL (33.97mmol) of a solution of 2M isopropylmagnesium bromide in diethyl ether to give 1.46g of pure product in the form of a wax.

LC-MS：M+H＝353

¹H NMR(CDCl₃)δ(ppm)：4.25(q，2H)；3.80(s，1H)；3.45(m，2H)；3.30(m，2H)；1.75(m，5H)；1.60(m，2H)；1.40(s，9H)；1.30(t，3H)；0.90(d，6H).

19.2.4-Cyanomethyl-4-isobutylpiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 18 (step 18.2.) starting from a solution of 1.46g (4.16mmol) of tert-butyl 4- (cyanoethoxycarbonylmethyl) -4-isobutylpiperidine-1-carboxylate obtained in the preceding step in 14mL of dimethyl sulfoxide, 0.097g (1.66mmol) of sodium chloride and 0.15g (8.31mmol) of water to give 1.10g of pure product in the form of a wax.

LC-MS：M+H＝281

¹H NMR(CDCl₃)δ(ppm)：3.50-3.30(m，4H)；2.45(m，2H)；2.40(s，2H)；1.70(m，2H)；1.60(m，3H)；1.40(s，9H)；0.90(d，6H).

19.3.4- (2-aminoethyl) -4-isobutylpiperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.2.), starting from a solution of 1.10g (3.95mmol) of tert-butyl 4-cyanomethyl-4-isobutylpiperidine-1-carboxylate and 1.16g (19.75mmol) of Raney nickel in 13mL of methanol at 45 ℃ under a hydrogen atmosphere (70psi), and after chromatographic purification on a silica gel column eluting with an 96/4/0.4 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.50g of the desired product was obtained in the form of an oil.

LC-MS：M+H＝285

¹H NMR(CDCl₃)δ(ppm)：3.50-3.30(m，4H)；2.45(m，2H)；1.70(m，1H)；1.60(m，4H)；1.40(s，9H)；1.35(m，4H)；1.25(m，2H)；0.90(d，6H).

19.4.4-isobutyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) ethyl 1-piperidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 12 (step 12.3.), starting from 0.49g (1.73mmol) of tert-butyl 4- (2-aminoethyl) -4-isobutylpiperidine-1-carboxylate, 0.61g (1.91mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.2, 450. mu.L (2.60mmol) of N, N-diisopropylethylamine and a solution of 0.10g (0.87mmol) of N, N-dimethylaminopyridine in 17mL of1, 2-dichloroethane, to give 0.73g of the desired product in the form of a wax.

LC-MS：M+H＝467

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 7.40(m, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.40-3.15(m, 4H); 3.00(m, 2H); 2.80(d, 3H); 1.70(m, 1H); 1.50(m, 2H); 1.40(s, 9H); 1.30(m, 4H); 1.20(m, 2H); 0.90(d, 6H).

[2- (4-isobutylpiperidin-4-yl) ethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 11 (step 11.2.) starting from 0.71g (1.53mmol) of tert-butyl 4-ethyl-4- [2- (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) isobutyl ] piperidine-1-carboxylate obtained in step 19.4 and 3.83mL (15.30mmol) of 4N hydrogen chloride in dioxane and triturating with diethyl ether gave 0.60g of the desired product as an oil.

LC-MS：M+H＝367

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 8.50 (broad singlet, 1H); 7.40(m, 1H); 6.80(s, 1H); 5.20(s, 2H); 3.00(m, 6H); 2.75(d, 3H); 1.70(m, 1H); 1.50(m，6H)；1.30(m，2H)；0.90(d，6H).

{2- [1- (6-Chloroquinoxalin-2-yl) -4-isobutylpiperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 12 (step 12.5.), starting from 0.30g (0.74mmol) of 3-methylcarbamoylisoxazol-5-ylmethyl [2- (4-ethylpiperidin-4-yl) isobutyl ] carbamate hydrochloride obtained in the preceding step, 0.22g (1.12mmol) of 2, 6-dichloroquinoxaline and 390. mu.L (2.23mmol) of N, N-diisopropylethylamine in 2.50mL of acetonitrile, to give 0.29g of the desired product in the form of a yellow powder.

m.p.(℃)：144-146℃，LC-MS：M+H＝530

¹H NMR(DMSO)δ(ppm)：8.80(s，1H)；8.70(m，1H)；7.90(s，1H)；7.60(s，2H)；7.40(m，1H)；6.80(s，1H)；5.20(s，2H)；3.90(m，2H)；3.70(m，2H)；3.10(m，2H)；2.80(m，3H)；1.80(m，1H)；1.60-1.40(m，6H)；1.30(m，2H)；0.90(d，6H).

Example 20 (Compound 62)

{2- [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

20.1.4-ethoxycarbonylmethyl-4-hydroxypiperidine-1-carboxylic acid benzyl ester

To a solution of 5.00g (56.75mmol) of ethyl acetate in 140mL of diethyl ether at-78 deg.C under argon was slowly added 28.38mL (56.75mmol) of a solution of lithium diisopropylamide (2N). After stirring for 30 minutes, a solution of 12.57g (53.91mmol) of benzyl 4-oxopiperidine-1-carboxylate in 140mL of diethyl ether is added dropwise at-78 ℃ under argon. The reaction medium is then stirred at room temperature for 2 hours. Ethyl acetate was added and the medium was cooled in an ice/water bath, followed by addition of saturated ammonium chloride solution. The aqueous phase was separated and extracted three times with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 85/15 mixture of cyclohexane and ethyl acetate) to give 13.00g of pure product in the form of an oil.

LC-MS：M+H＝322

¹H NMR (DMSO) δ (ppm): 7.50-7.30(m, 5H); 5.10(s, 2H); 4.70(s, 1H); 4.10(q, 2H); 3.70(m, 2H); 3.20 (broad singlet, 2H); 2.40(s, 2H); 1.60(m, 4H); 1.20(t, 3H).

Ethyl (4-hydroxypiperidin-4-yl) acetate hydrobromide

To a solution of 2.00g (6.22mmol) of benzyl 4-ethoxycarbonylmethyl-4-hydroxypiperidine-1-carboxylate in 31mL of dichloromethane obtained in the preceding step, cooled in an ice/water bath, was slowly added 5.46mL (31.12mmol) of a 5.7N solution of hydrogen bromide in acetic acid. Stirring was continued at room temperature for 2 hours. The resulting mixture was evaporated to dryness by adding 50mL of toluene. The residue was triturated in ether. After filtration through a sinter funnel, 1.50g of the desired product are obtained in the form of the hydrobromide salt.

¹H NMR (DMSO) δ (ppm): 8.45 (broad singlet, 2H); 4.10(q, 2H); 3.40 (broad singlet, 1H); 3.10(m, 4H); 2.40(m, 2H); 1.80(m, 4H); 1.20(t, 3H).

[ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] acetic acid ethyl ester

The process was carried out according to the procedure described in example 12 (step 12.5.), starting from a solution of 1.21g (4.51mmol) of ethyl (4-hydroxypiperidin-4-yl) acetate hydrobromide, 0.90g (4.96mmol) of 2-chloro-4-trifluoromethylpyrimidine and 1.65mL (9.48mmol) of N, N-diisopropylethylamine in 10mL of acetonitrile obtained in the preceding step and purified by chromatography on silica gel (elution with 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia) to give 1.33g of the desired product in the form of a wax.

¹H NMR(CDCl₃) δ (ppm): 8.40(d, 1H); 6.60(d, 2H); 4.45(m, 2H); 4.10(q, 2H); 3.65 (broad singlet, 1H); 3.40-3.20(m, 2H); 2.40(s, 2H); 1.75(m, 2H); 1.60-1.30(m, 2H); 1.20(t, 3H).

20.4.4- (2-hydroxyethyl) -1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ol

To a solution of 1.30g of ethyl [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] acetate in 39mL of tetrahydrofuran obtained in the preceding step was added 0.15g of lithium aluminum hydride dropwise at-10 ℃. The mixture was then stirred at room temperature for 1 hour. The reaction medium is cooled to about 0 ℃ and then 15mL of aqueous sodium hydroxide solution (1M) are slowly added. The resulting mixture was stirred at room temperature for 30 minutes, followed by dropwise addition of wet sodium sulfate. The salt was separated off, filtered over celite and the phases were separated by settling. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel (elution with an 97/3/0.3 mixture of dichloromethane, methanol and 28% aqueous ammonia) to yield 0.64g of the desired product in the form of a wax.

¹H NMR(CDCl₃) δ (ppm): 8.40(d, 1H); 6.60(d, 1H); 4.45(m, 2H); 4.00(q, 2H); 3.60-3.30(m, 2H); 3.20 (broad singlet, 1H); 2.50 (broad singlet, 1H); 1.80(m, 4H); 1.65-1.40(m, 2H).

20.5.4, 5, 6, 7-tetrachloro-2- {2- [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } isoindole-1, 3-dione

The process was carried out according to the procedure described in example 1 (step 1.3.), starting from 0.63g (2.16mmol) of 4- (2-hydroxyethyl) -1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ol, 0.62g (2.38mmol) of triphenylphosphine, 0.69g (2.38mmol) of 4, 5, 6, 7-tetrachloroisoindole-1, 3-dione and a solution of 0.41g (2.38mmol) of diethyl azodicarboxylate (DEAD) in 10mL of tetrahydrofuran, obtained in the preceding step, to give 0.38g of the desired product.

¹H NMR(CDCl₃)δ(ppm)：8.40(d，1H)；6.70(d，1H)；4.50(m，2H)；3.90(m，2H)；3.60-3.30(m，2H)；1.90(m，2H)；1.70-1.40(m，4H).

20.6.4- (2-aminoethyl) -1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ol

The process was carried out according to the procedure described in example 1 (step 1.4.), starting from a solution of 0.38g (0.68mmol) of 4, 5, 6, 7-tetrachloro-2- {2- [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } isoindol-1, 3-dione) obtained in the preceding step in a mixture of acetonitrile/tetrahydrofuran/water (2/1/1) and 0.18g (3.06mmol) of ethylenediamine in 4.50mL of ethanol, and after purification by chromatography on silica gel (eluting with a 90/10/1 mixture of dichloromethane, methanol and 28% aqueous ammonia), 0.15g of the desired product was obtained in the form of a wax.

¹H NMR(CDCl₃) δ (ppm): 8.40(d, 1H); 6.60(d, 1H); 4.50(m, 2H); 3.50-3.20(m, 2H); 3.20(m, 2H); 2.90-2.60 (broad singlet, 2H); 1.70(m, 2H); 1.50-1.30(m, 4H).

{2- [ 4-hydroxy-1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

The process was carried out according to the procedure described in example 12 (step 12.3.), starting from 0.13g (0.45mmol) of 4- (2-aminoethyl) -1- (4-trifluoromethylpyrimidin-2-yl) piperidin-4-ol obtained in the preceding step, 0.187g (0.58mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate obtained in step 9.1, 200. mu.L (1.12mmol) of N, N-diisopropylethylamine and 0.027g (0.22mmol) of N, N-dimethylaminopyridine in 2.20mL of1, 2-dichloroethane to give 0.165g of the desired product in the form of a powder.

m.p.(℃)：138-140℃，LC-MS：M+H＝473

¹H NMR(DMSO)δ(ppm)：8.70(m，2H)；7.35(t，1H)；6.95(m，1H)；6.80(s，1H)；5.20(m，2H)；4.50(s，1H)；4.30(m，2H)；3.40(m，2H)；3.20(m，2H)；2.80(m，3H)；1.90(m，4H)；1.45(m，2H).

Example 21 (Compound 29)

{2- [1- (4' -Fluorobiphenyl-4-yl) piperidin-4-yl ] ethyl } carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

{2- [1- (4-bromo-phenyl) piperidin-4-yl ] ethyl } carbamic acid tert-butyl ester

A suspension of 6.19g (21.90mmol) of 1-bromo-4-iodobenzene, 5.00g (21.90mmol) of tert-butyl (2-piperidin-4-ylethyl) carbamate, 9.98g (60.66mmol) of cesium carbonate and 0.54g (0.88mmol) of BINAP (2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl) in 100mL of toluene was placed under an inert atmosphere. Then 0.098g (0.44mmol) of palladium diacetate was added. The reaction mixture was then refluxed for 6 hours. 0.045g (0.20mmol) of palladium diacetate and 0.25g (0.40mmol) of BINAP were added and the mixture was stirred at reflux for 12 hours. The reaction medium is cooled and ethyl acetate and water are added. The aqueous phase was separated and extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is purified by chromatography on silica gel (elution with 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia) to yield 1.66g of the desired product in the form of a white solid.

m.p.(℃)：120-122℃，LC-MS：M+H＝384

¹H NMR (DMSO) δ (ppm): 7.30(d, 2H); 6.90(d, 2H); 6.70 (broad singlet, 1H); 3.70(m, 2H); 2.95(m, 2H); 2.60(m, 2H); 1.70(m, 2H); 1.40(s, 9H); 1.35(m, 3H); 1.20(m, 2H).

{2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethyl } carbamic acid tert-butyl ester

The process was carried out according to the procedure described in example 10 (step 10.5.) starting from1.50g (3.91mmol) of {2- [1- (4-bromophenyl) piperidin-4-yl ] obtained in the preceding step]Tert-butyl ethyl carbamate, 0.66g (4.70mmol) of 4-fluorophenylboronic acid, a solution of 3.82g (11.74mmol) of cesium carbonate in 40mL of 9/1 mixture of tetrahydrofuran and water, and 0.32g (0.39mmol) of PdCl₂dppf.CH₂Cl₂And after purification by chromatography on silica gel (elution with an 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia), 1.23g of the desired product are obtained in the form of a white solid.

m.p.(℃)：173-175℃，LC-MS：M+H＝399

¹H NMR (DMSO) δ (ppm): 7.60(m, 2H); 7.50(d, 2H); 7.20(m, 2H); 6.95(d, 2H); 6.75 (broad singlet, 1H); 3.70(m, 2H); 2.95(m, 2H); 2.70(m, 2H); 1.70(m, 2H); 1.40(s, 9H); 1.35(m, 3H); 1.20(m, 2H).

21.3.2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethylamine

The process was carried out according to the procedure described in example 14 (step 14.3.), starting from a solution of 1.10g (2.76mmol) of tert-butyl {2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethyl } carbamate and 2.11mL (25.09mmol) of trifluoroacetic acid in 20mL of dichloromethane obtained in the preceding step and, after basification by treatment with 35% sodium hydroxide, extraction with dichloromethane, drying over sodium sulfate and evaporation to dryness, 0.74g of the desired product was obtained in the form of an amorphous orange solid.

LC-MS：M+H＝299

¹H NMR(DMSO)δ(ppm)：7.60(m，2H)；7.50(d，2H)；7.25(m，2H)；7.00(d，2H)；3.75(m，2H)；2.85(m，2H)；2.75(m，2H)；1.70(m，2H)；1.50(m，1H)；1.35(m，2H)；1.25(m，2H).

3-methylcarbamoylisoxazol-5-ylmethyl {2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethyl } carbamate

The process was carried out according to the procedure described in example 12 (step 12.3.), starting from 0.27g (0.90mmol) of 2- [1- (4' -fluorobiphenyl-4-yl) piperidin-4-yl ] ethylamine obtained in the preceding step, 0.29g (0.90mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate and 320. mu.L (1.81mmol) of N, N-diisopropylethylamine in 10mL1, 2-dichloroethane obtained in step 9.1 and, after trituration in ether, 0.26g of the desired product was obtained in the form of a white powder.

m.p.(℃)：212-215℃，LC-MS：M+H＝481

¹H NMR (DMSO) δ (ppm): 8.70 (broad singlet, 1H); 7.60(m, 2H); 7.50(m, 2H); 7.45 (broad singlet, 1H); 7.25(m, 2H); 7.00(m, 2H); 6.90(s, 1H); 5.20(s, 2H); 3.75(m, 2H); 3.10(m, 2H); 2.80(s, 3H); 2.70(m, 2H); 1.75(m, 2H); 1.45(m, 3H); 1.25(m, 2H).

Example 22 (Compound 79)

(±) - [1- (4-chlorophthalazin-1-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoyl isoxazol-5-ylmethyl ester

22.1 (. + -.) -3- [ (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester

The process was carried out according to the procedure described in example 1 (step 1.6.), starting from 2.00g (9.99mmol) of (. + -.) -1-Boc-3- (aminomethyl) pyrrolidine (commercially available), 3.52g (10.98mmol) of 3- (methylcarbamoyl) isoxazol-5-ylmethyl 4-nitrophenylcarbonate solution obtained in step 9.2, 2.61mL (14.98mmol) of N, N-diisopropylethylamine and 0.61g (4.99mmol) of dimethylaminopyridine in 100mL of1, 2-dichloroethane and, after purification by chromatography on silica gel (elution with a mixture 100/0/0 to 98/2/0.2 of dichloromethane, methanol and 28% aqueous ammonia), 1.32g of the desired product were obtained in the form of a wax.

LC-MS：M+H＝383

¹H NMR(DMSO)δ(ppm)：8.70(bs，1H)；7.00(bs，1H)；6.80(s，1H)；5.25(s，2H)；3.40(m，3H)；3.00(m，3H)；2.80(s，3H)；2.20(m，1H)；1.90(m，1H)；1.60(m，1H)；1.40(s，9H).

22.2 (. + -.) -pyrrolidin-3-ylmethylcarbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester hydrochloride

The process was carried out according to the procedure described in example 11 (step 11.2.) and, starting from a solution of 1.30g (3.40mmol) of tert-butyl 3- [ (3-methylcarbamoylisoxazol-5-ylmethoxycarbonylamino) methyl ] pyrrolidine-1-carboxylate and 4.25mL of 4N hydrogen chloride in dioxane, and trituration in ether, 0.82g of a white powder was obtained.

m.p.(℃)：187-189℃，LC-MS：M+H＝283

¹H NMR(DMSO)δ(ppm)：8.70(bs，1H)；8.00(m，2H)；6.80(m，1H)；5.25(s，2H)；3.60(m，1H)；3.45(m，1H)；3.30(m，1H)；3.10(m，1H)；2.90(m，2H)；2.80(s，3H)；2.50(m，1H)；2.05(m，1H)；1.70(m，1H).

3-methylcarbamoylisoxazol-5-ylmethyl 3(±) - [1- (4-chlorophthalazin-1-yl) pyrrolidin-3-ylmethyl ] carbamate

The process was carried out according to the procedure described in example 12 (step 12.5.), starting from 0.19g (0.60mmol) of pyrrolidin-3-ylmethyl carbamate 3-methylcarbamoylisoxazol-5-ylmethyl ester hydrochloride, 0.17g (0.89mmol) of1, 4-dichlorophthalazine and 0.21mL (0.15mmol) of N, N-diisopropylethylamine (15 min, 150 ℃) and after purification by chromatography on silica gel (elution with a mixture of dichloromethane, methanol and 28% aqueous ammonia 100/0/0 to 98/2/0.2), 0.09g of the desired product was obtained in the form of a white powder.

m.p.(℃)：159-161℃，LC-MS：M+H＝445

¹H NMR(DMSO)δ(ppm)：8.80(m，1H)；8.40(m，1H)；8.15(m，1H)；8.05(m，2H)；7.80(m，1H)；6.80(s，1H)；5.25(s，2H)；3.65(m，1H)；3.50(m，2H)；3.30(m，1H)；3.20(m，2H)；2.80(m，4H)；2.05(m，1H)；1.70(m，1H).

Example 23 (Compound 82)

{2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamic acid 3-carbamoylisoxazol-5-ylmethyl ester

23.1{2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamic acid tert-butyl ester

The process was carried out according to the procedure described in example 14 (step 14.4.) starting from 3.00g (12.57mmol) of tert-butyl (2-azetidin-3-ylethyl) carbamate (commercially available), 3.00g (16.47mmol) of 2-chloro-4-trifluoromethylpyrimidine and 7.73mL (44.35mmol) of N, N-diisopropylethylamine and purifying by silica gel chromatography (eluting with a mixture of dichloromethane, methanol and 28% aqueous ammonia 100/0/0 to 98/2/0.2) to give 4.00g of product in the form of an orange powder.

m.p.(℃)：95-97℃

23.22- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethylamine

The process was carried out according to the procedure described in example 11 (step 11.2.) starting from 3.67g (10.60mmol) of tert-butyl {2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamate and 10.60mL (42.38mmol) of a solution of 4N hydrogen chloride in dioxane and purified by silica gel chromatography eluting with a mixture 100/0/0 to 90/10/1 of dichloromethane, methanol and 28% aqueous ammonia to give 1.75g of the product as a yellow oil.

LC-MS：M+H＝247

¹H NMR(CDCl₃)δ(ppm)：8.50(d，1H)；6.80(d，1H)；4.30(m，2H)；3.90(m，2H)；2.85(m，1H)；2.75(m，2H)；1.85(m，2H)；1.30(bs，2H).

3-carbamoylisoxazol-5-ylmethyl {2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethyl } carbamate

The process was carried out according to the procedure described in example 1 (step 1.6.) starting from 0.30g (1.22mmol) of 2- [1- (4-trifluoromethylpyrimidin-2-yl) azetidin-3-yl ] ethylamine, 0.45g (1.46mmol) of 3-carbamoylisoxazol-5-ylmethyl 4-nitrophenylcarbonate, 0.53mL (3.05mmol) of diisopropylethylamine and 0.07g (0.61mmol) of dimethylaminopyridine as described in example 8 (step 8.3.), and after purification by chromatography on silica gel (elution with a mixture of 100/0/0 to 98/2/0.2 of dichloromethane, methanol and 28% aqueous ammonia), 0.41g of product was obtained in the form of a white powder.

m.p.(℃)：163-165℃，LC-MS：M+H＝415

¹H NMR(DMSO)δ(ppm)：8.65(d，1H)；8.15(bs，1H)；7.85(bs，1H)；7.50(bt，1H)；7.05(d，1H)；6.80(s，1H)；5.20(s，2H)；4.20(s，2H)；3.70(m，2H)；3.10(m，2H)；2.75(m，1H)；1.80(m，2H).

Example 24 (Compound 84)

(-) - [1- (4-chloro-pyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

0.32g (. + -.) [1- (4-chloropyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester was separated by preparative HPLC chromatography (Chiralpak AD 20 μm 50X 220mm) eluting with a mixture of propanol/n-heptane 25/75 ratio to give 0.070g of product in the form of a base.

t_R: 45 minutes

m.p.(℃)：114.4-118.3℃，LC-MS：M+H＝429

[α]^20℃-9.88(c＝0.333，DMSO，589nm)

¹H NMR(DMSO)δ(ppm)：8.70(bs，1H)；8.60(bs，1H)；8.05(m，1H)；7.00(m，1H)；6.80(s，1H)；5.25(s，2H)；3.45(m，2H)；3.30(m，3H)；3.10(m，1H)；2.80(m，3H)；2.50(m，1H)；2.00(m，1H)；1.70(m，1H).

Example 25 (Compound 85)

(+) - [1- (4-chloro-pyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester

0.32g (. + -.) [1- (4-chloropyrimidin-2-yl) pyrrolidin-3-ylmethyl ] carbamic acid 3-methylcarbamoylisoxazol-5-ylmethyl ester was separated by preparative HPLC chromatography (Chiralpak AD 20 μm 50X 220mm) eluting with a mixture of propanol/n-heptane 25/75 ratio to give 0.090g of the product in the form of a base.

t_R: 52 minutes

m.p.(℃)：114.4-118.3℃，LC-MS：M+H＝429

[α]^20℃+9.55(c＝0.222，DMSO，589nm)

¹H NMR(DMSO)δ(ppm)：8.70(bs，1H)；8.60(bs，1H)；8.05(m，1H)；7.00(m，1H)；6.80(s，1H)；5.25(s，2H)；3.45(m，2H)；3.30(m，3H)；3.10(m，1H)；2.80(m，3H)；2.50(m，1H)；2.00(m，1H)；1.70(m，1H).

Table 1 below illustrates the chemical structures and physical properties of various compounds of the present invention.

In this table:

-all compounds are in the form of a base;

the column "m.p. (° c)", gives the melting point of the product in degrees celsius (° c);

the term "rot." denotes the levorotatory or dextrorotatory nature of a compound;

the dotted chemical bond "- - -" represents the chemical bond linking the substituent to the rest of the molecule.

TABLE 1

The following Table 2 shows the compounds of Table 1¹Results of H NMR analysis and LC-MS analysis. In the table, the RT column indicates the retention time.

TABLE 2

The compounds of the invention were subjected to pharmacological tests which allowed their inhibitory effect on the enzyme FAAH (fatty acid amide hydrolase).

Scheme 1:this inhibitory activity was demonstrated using a radioenzymatic assay to measure anandamide [ ethanolamine 1-³H]Hydrolysis products with FAAH (Life Sciences (1995), 56, 1999 2005 and Journal of Biochemical and Biophysical Methods (2004), 60(2), 171-177). Thus, mouse brains (without cerebellum) were removed and stored at-80 ℃. Membrane homogenate by usingThe instrument was prepared extemporaneously by homogenizing tissues in reaction buffer (10mM Tris-HCl, pH 8, 150mM NaCl, and 1mM ethylenediaminetetraacetic acid (EDTA)). The enzymatic reaction was performed on 96-well Multiscreen filter plates in a final volume of 70. mu.L. Reaction buffer supplemented with fatty acid free bovine serum albumin (BSA, 1mg/ml) was used for the enzymatic reaction and to dilute the compound and cannabinoid [ ethanolamine 1-³H]. Reaction buffer containing BSA (43. mu.L/well), diluted test compounds at different concentrations (7. mu.L/well with 1% DMSO) and membrane preparations (10. mu.L/well, i.e.200. mu.g of tissue per assay) were added sequentially to the wells. After pre-incubation of the compound with the enzyme at 25 ℃ for 20 minutes, by adding the cannabinoid [ ethanolamine 1-³H](specific activity 15-20Ci/mmol, diluted with cold cannabinoid (10. mu.L/well, final concentration 10. mu.M, 0.01. mu. Ci per test)). After incubation at 25 ℃ for 20 minutes, the enzymatic reaction was stopped by adding 5M charcoal solution prepared in 1.5M NaCl buffer and 0.5M HCl (50. mu.L/well). The mixture was stirred for 10 minutes and then the mixture containing ethanolamine [1-³H]The aqueous phase was recovered by vacuum filtration and counted by liquid scintillation.

Scheme 2:this inhibitory activity was confirmed by fluorescence techniques in an enzymatic assay based on the measurement of the fluorescent product of the hydrolysis of arachidoyl 7-amino-4-methylcoumarin amide (AAMC) with FAAH (Analytical Biochemistry (2005), 343: 143-. Thus, mouse brains (without cerebellum) were removed and stored at-80 ℃. Brain homogenate is obtained by usingThe instrument was prepared extemporaneously by homogenizing tissues in reaction buffer (10mM tris-HCl, pH 8, 150mM NaCl, and 1mM ethylenediaminetetraacetic acid (EDTA)). The enzymatic reaction was performed in a final volume of 50. mu.L on a black polystyrene 384-well plate. Reaction buffer supplemented with bovine serum albumin without fatty acids (BSA, 1mg/ml) was used for the enzymatic reaction and to dilute the compound and AAMC. Reaction buffer containing BSA (25 μ L/well), diluted test compounds at different concentrations (5 μ L/well, containing 1% DMSO) and membrane preparations (10 μ L/well, i.e. 200 μ g tissue per assay) were added sequentially to the wells. After pre-incubation of the compound with the enzyme at 25 ℃ for 20 minutes, the reaction was started by adding 10. mu.L of substrate per well (AAMC, 10. mu.M final concentration). After 40 minutes of incubation, the produced Aminomethylcoumarin (AMC) was measured by fluorescence counting (Envision plate reader).

Under these conditions, the most active compounds of the invention have an IC between 0.001 and 1. mu.M₅₀Value (concentration of 50% control enzyme activity that inhibited FAAH). Some compounds have an IC of less than 50nM and more specifically less than 15nM₅₀The value is obtained.

Table 3 shows the IC obtained with the compounds of the invention₅₀The value is obtained.

TABLE 3

Compound numbering	IC50(nM)	Application protocol
			1	1	1
2	40	1
			5	2	1
9	2	1
			12	47	1
19	1	1
			29	0.7	2
38	2	1
			41	0.6	1
46	16	1
			52	28	1
64	3	1

Therefore, the compounds of the present invention are considered to have inhibitory activity against the enzyme FAAH.

The in vivo activity of the compounds of the invention was evaluated in an analgesic assay.

Thus, intraperitoneal (i.p.) administration OF PBQ (benzoquinone, 2mg/kg in 0.9% sodium chloride solution containing 5% ethanol) to male OF1 mice (25 to 30g body weight) caused abdominal traction (abdominal stretching), averaging 30 twisting or contraction movements within 5 to 15 minutes after injection. Test compounds suspended in 0.5% Tween 80 were administered orally (p.o.) or intraperitoneally (i.p.) 60 minutes or 120 minutes prior to PBQ administration. Under these conditions, the most potent compounds of the invention reduced the number of PBQ-induced pulls by 30% to 80% in the dose range of1 and 30 mg/kg.

For example, compounds 1 and 19 in the table reduced PBQ-induced pull-ups by 55% and 30%, respectively, at a dose of 30mg/kg p.o. when administered over 120 minutes.

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, for example N-arachidonic acid ethanolamine (N-arachidonoyl ethanolamine), N-palmitoyl-ethanolamine, N-oleoylethanolamide, oleamide or 2-arachidoyl glycerol. These derivatives have different pharmacological activities through interaction with cannabinoid (cannabinoid) and capsaicin (vanilloid) receptors.

The compounds of the invention prevent this breakdown pathway and increase the tissue level of these endogenous substances. They may therefore be used in the prevention and treatment of pathologies associated with endogenous cannabinoids and/or any other substrate involved in the metabolism by the enzyme FAAH. The following diseases and conditions may be mentioned, for example:

pain, in particular acute or chronic neuropathic pain: migraine, neuropathic pain, including forms associated with herpes viruses 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, particularly nausea caused by chemotherapy; eating disorders, in particular anorexia and cachexia of various nature; neurological and psychiatric conditions: tremor, movement disorders, dystonia, spasticity, obsessive-compulsive disorder (complex and obsessive compulsive), tourette's syndrome, depression and anxiety of any nature or origin in all forms, mood disorders, psychotic disorders; acute and chronic neurodegenerative diseases: parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, injuries associated with cerebral ischemia and with cranial and myeloid trauma; epilepsy; sleep disorders, including sleep apnea; cardiovascular diseases, in particular hypertension, arrhythmias, arteriosclerosis, heart attacks, cardiac ischemia; renal ischemia; cancer: benign cutaneous, papilloma and cerebroma, prostate tumor, brain tumorTumors (glioblastomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, ependymomas, oligodendrogliomas, reticulomas (plexus tumor), neuroepitheliomas, pineal tumors, ependymomas, malignant meningiomas, sarcomas, malignant melanomas, schwennomas); diseases of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or collagen diseases, sjogren's syndrome: (syndrome), ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, diseases affecting the plasma cell line; allergic diseases: immediate and delayed hypersensitivity reactions, allergic rhinitis or allergic conjunctivitis, contact dermatitis; parasitic, viral or bacterial infection diseases; AIDS; meningitis; inflammatory diseases, in particular joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, crohn's disease, irritable bowel syndrome; osteoporosis; eye diseases: intraocular hypertension, glaucoma; pulmonary diseases: respiratory diseases, bronchospasm, cough, asthma, chronic bronchitis, chronic airway obstruction, emphysema; gastrointestinal diseases: irritable bowel syndrome, inflammatory bowel disease, ulcers, diarrhea; urinary incontinence and bladder inflammation.

The use of the compounds of the invention in the form of the base or of the pharmaceutically acceptable acid addition salts, hydrates or solvates for the preparation of a medicament for the treatment of the above-mentioned pathologies forms an integral part of the present invention.

Another subject of the invention is a medicament comprising a compound of formula (I) or an acid addition salt of a compound of formula (I), or alternatively a pharmaceutically acceptable hydrate or solvate of a compound of formula (I). These medicaments are used in therapy, in particular for the treatment of the above-mentioned conditions.

According to another aspect, the invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions comprise an effective amount of a compound of the present invention or a pharmaceutically acceptable acid addition salt, hydrate or solvate of said compound and optionally one or more pharmaceutically acceptable excipients.

Depending on the pharmaceutical dosage form and the desired method of administration, the excipients are selected from the group of commonly used excipients known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (topical), topical, intrathecal, intranasal, transdermal, pulmonary, intraocular or rectal administration, the active ingredient of the compound of formula (I) above, or a possible acid addition salt, solvate or hydrate thereof, can be administered in unit dosage form to humans and animals as a mixture with standard pharmaceutical excipients for the prevention or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral dosage forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, or dosage forms for administration by inhalation, dosage forms for subcutaneous, intramuscular or intravenous administration, and dosage forms for rectal or vaginal administration. For topical administration, the compounds of the invention may be used in creams, ointments or lotions.

For example, a unit dosage form of administration of a compound of the invention in the form of a tablet may comprise the following components:

the unit dosage forms comprise a dose which can be administered daily in the range from 0.01 to 20mg of active ingredient per kg of body weight, depending on the pharmaceutical dosage form.

There are many specific cases where higher or lower doses are appropriate; such dosages are also within the scope of the present invention. According to common practice, the dosage suitable for each patient is determined by the clinician according to the mode of administration, the weight and response of the patient in question.

According to another aspect, the present invention also relates to a method for treating the above-mentioned pathologies, which comprises the administration of an effective dose of a compound according to the invention, of a pharmaceutically acceptable acid addition salt thereof or of a solvate or hydrate of said compound.

Claims (15)

1. A compound of formula (I) in base form or in acid addition salt form

Wherein

R₂Represents a hydrogen or fluorine atom or a hydroxyl group, a cyano group, a trifluoromethyl group, C_1-6Alkyl radical, C_1-6-alkoxy or NR₈R₉A group;

n represents an integer equal to 1, 2 or 3 and m represents an integer equal to 1 or 2;

a represents a covalent bond or C_1-8-an alkylene group;

R₁represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents a group selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, and naphthyridinyl;

R₆represents a halogen atom or a cyano group, -CH₂CN, nitro, hydroxy, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6Alkylthio radical, C_1-6-haloalkyl group, C_1-6-haloalkoxy, C_1-6-haloalkylthio, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3Alkylene radical, C_3-7-cycloalkyl-C_1-3alkylene-O-, NR₈R₉、NR₈COR₉、NR₈CO₂R₉、NR₈SO₂R₉、NR₈SO₂NR₈R₉、COR₈、CO₂R₈、CONR₈R₉、SO₂R₈、SO₂NR₈R₉or-O- (C)_1-3-alkylene) -O-group;

R₇represents a group selected from: furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridyl, furopyridyl, thienopyridinylA group selected from the group consisting of imidazopyridinyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl, thiazolopyridyl, phenyloxy, benzyloxy and pyrimidinyloxy; or a radical R₇May be substituted by one or more radicals R₆Said R is₆May be the same or different from each other;

R₃represents a hydrogen or fluorine atom, a group C_1-6-alkyl or trifluoromethyl;

R₄represents a group selected from: furyl, pyrrolyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl and tetrazolyl; said group being optionally substituted with one or more substituents selected from: halogen atom, group C_1-6Alkyl radical, C_1-6-haloalkyl group, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-3Alkylene radical, C_1-6Haloalkoxy, cyano, NR₈R₉、NR₈COR₉、NR₈CO₂R₉、NR₈SO₂R₉、NR₈SO₂NR₈R₉、COR₈、CO₂R₈、CONR₈R₉、CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁)、SO₂R₈、SO₂NR₈R₉、-O-(C_1-3-alkylene) -O-, phenyl, phenyloxy, benzyloxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl, or pyrimidinyl; said phenyl, phenyloxy, pyridyl, pyrazinyl, pyridazinyl, triazinyl and pyrimidinyl being optionally substituted with one or more substituents selected from the group consisting of: halogen atom and cyano, nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6Alkylthio radical, C_1-6-haloalkyl group, C_1-6-haloalkoxy, C_1-6-haloalkylthio, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-3-an alkylene group;

R₈、R₉、R₁₀and R₁₁Independently of one another, represents a hydrogen atom or a group C_1-6-an alkyl group,

or at NR₈R₉In the case of (a) form, with the atoms they carry, a ring selected from: azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepineOxygen and nitrogen heteroAnd a piperazine ring, said ring being optionally substituted with a group C_1-6-alkyl or benzyl;

or at NR₈COR₉A lactam ring is formed; at NR₈CO₂R₉In the case of (A) form oxazolidinones, oxazinones or oxaziridinesA ketone ring; at NR₈SO₂R₉Form a sultam ring; at NR₈SO₂NR₈R₉In the case of (A) or (B) forms a thiazolidine dioxide or thiadiazine dioxide ring.

2. A compound of formula (I) according to claim 1, characterized in that R is in the form of the base or of an acid addition salt₂Represents a hydrogen or fluorine atom or a hydroxyl group, C_1-6-alkyl or NR₈R₉A group.

3. A compound of formula (I) according to claim 1 or 2, in base form or in acid addition salt form, characterized in that n represents an integer equal to 2 and m represents an integer equal to 2.

4. A compound of formula (I) according to any one of claims 1 to 3, characterized in that a represents a group C_1-8-An alkylene group.

5. A compound of formula (I) according to any one of claims 1 to 4, characterized in that R is₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, phthalazinyl or quinoxalinyl;

R₆represents nitro, C_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6-haloalkoxy, -O- (C)_1-3-alkylene) -O-or a halogen atom;

R₇represents phenyl, optionally substituted with one or more radicals R₆Said R is₆May be the same or different from each other.

6. A compound of formula (I) according to any one of claims 1 to 5, characterized in that R is in the form of the base or of an acid addition salt₃Represents trifluoromethyl, C_1-6-an alkyl group or a hydrogen atom.

7. A compound of formula (I) according to any one of claims 1 to 6, characterized in that R is in the form of the base or of an acid addition salt₄Represents a group selected from: oxazolyl, isoxazolyl, furanyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and triazolyl; said group being optionally substituted with one or more substituents selected from: group C_1-6-alkyl, COOR₈、CON(R₈)(C_1-3-alkylene-NR₁₀R₁₁)、CONR₈R₉A phenyl group; said phenyl group being optionally substituted with one or more substituents selected from: halogen atom and group C_1-6-an alkoxy group;

R₈and R₉Independently of one another, represents a hydrogen atom or a group C_1-6-alkyl, or together with the atoms they carry, form a piperazine ring,

R₁₀and R₁₁Independently of one another, represents a hydrogen atom or a group C_1-6-an alkyl group.

8. A compound of formula (I) according to any one of claims 1 to 7, characterized in that it is in base form or in acid addition salt form

R₁Represents a group R₅Optionally substituted with one or more radicals R₆And/or one or more radicals R₇；

R₅Represents phenyl, pyridyl, pyrazinyl or quinolyl; r₆Represents a halogen atom;

R₇represents phenyl, optionally substituted with one or more radicals R₆Said R is₆May be the same or different from each other;

R₂and R₃Represents a hydrogen atom;

R₄represents 3-carbamoylisoxazol-5-yl;

n represents an integer equal to 2 and m represents an integer equal to 2;

a represents an alkylene group.

9. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 8, comprising the step of reacting an amine of formula (II) with a carbonate of formula (III) in the presence of a base in a solvent at a temperature between room temperature and the reflux point of the solvent,

an amine of the general formula (II):

a, R therein₁、R₂M and n are as defined in formula (I) of claim 1,

a carbonate of the general formula (III):

wherein Z represents a hydrogen atom or a nitro group, and R₃And R₄As defined in formula (I) according to claim 1.

10. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 8, comprising the steps of: reacting an amine of the general formula (II) with phenyl chloroformate or 4-nitrophenyl chloroformate in the presence of a base in a solvent at a temperature between 0 ℃ and room temperature to give a carbamate derivative of the general formula (IV), and subjecting the thus obtained carbamate derivative of the general formula (IV) to a reaction of the general formula HOCHR₃R₄The action of the alcohol of (IIIa) is converted in a solvent in the presence of a base at a temperature between room temperature and the reflux point of the solvent into the compound of formula (I),

an amine of the general formula (II):

a, R therein₁、R₂M and n are as defined in formula (I) of claim 1,

carbamate derivatives of general formula (IV):

a, R therein₁、R₂M and n are as defined in general formula (I) of claim 1, and Z represents a hydrogen atom or a nitro group;

in the general formula HOCHR₃R₄In the alcohol of (IIIa), R₃And R₄As defined in formula (I) according to claim 1.

11. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 8, wherein R is₁Represents a group R₅Which is especially substituted by C_1-6Alkyl radical, C_3-7-cycloalkyl orC_3-7-cycloalkyl-C_1-3A group R of alkylene type₆Or substituted by a group R as defined in formula (I)₇The method comprises the following steps: subjecting a compound of general formula (Ia) to a transition metal catalyzed reaction selected from:

-Suzuki type reactions using alkyl, cycloalkyl, aryl or heteroaryl boronic acids,

a Stille-type reaction using aryl or heteroaryl trialkyltin derivatives,

-a Negishi type reaction using alkyl halide zincate derivatives, cycloalkyl halide zincate derivatives, aryl halide zincate derivatives or heteroaryl halide zincate derivatives,

a compound of the general formula (Ia):

a, R therein₂、R₃、R₄、R₅N and m are as defined in formula (I) of claim 1, and U₂Represents a chlorine, bromine or iodine atom or an O-trifluoromethanesulfonate group, U₂When desired introduced into said group R₆Or R₇In the position of (a).

12. A compound of formula (I) according to any one of claims 1 to 8 in base form or in pharmaceutically acceptable acid addition salt form for use as a medicament.

13. Pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 8 in base form or in pharmaceutically acceptable acid addition salt form, and optionally one or more pharmaceutically acceptable excipients.

14. Use of a compound of formula (I) as claimed in any one of claims 1 to 8 in base form or in pharmaceutically acceptable acid addition salt form, for the manufacture of a medicament for the prevention or treatment of a condition in which endocannabinoid and/or any other substrate metabolized by the enzyme FAAH is implicated.

15. Use of a compound of formula (I) in the form of a base or a pharmaceutically acceptable acid addition salt according to any one of claims 1 to 8 for the preparation of a medicament for the prevention or treatment of acute or chronic pain; vertigo; vomiting; nausea; eating disorders; neurological and psychiatric conditions; acute or chronic neurodegenerative diseases; epilepsy; sleep disorders; cardiovascular diseases; renal ischemia; cancer; diseases of the immune system; allergic diseases; parasitic, viral or bacterial infectious diseases; inflammatory diseases; osteoporosis; eye diseases; pulmonary diseases; use in the treatment of gastrointestinal disorders or urinary incontinence.