MXPA06005308A - Beta-lactams for treatment of cns disorders - Google Patents

Abstract

The present invention relates to novel compounds of formula (I) wherein ---- represents a single or a double bond;R represents a radical selected from formulae i), ii), iii) and iv) in which R1 is halogen, cyano, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl or trifluoromethoxy and p is zero or an integer from 1 to 3;R2 represents hydrogen or C1-4 alkyl;R3 represents hydrogen, hydroxy or C1-4 alkyl;R4 represents hydrogen or R4 together with R3 represents=0 or=CH2;R5 represents phenyl, naphthyl, a 9 to 10 membered fused bicyclic heterocyclic group or a 5 or 6 membered heteroaryl group, wherein said groups are optionally substituted by 1 to 3 groups independently selected from trifluoromethyl, C1-4 alkyl, hydroxy, cyano, C 1-4 alkoxy, trifluoromethoxy, halogen or S(O)qC1-4 alkyl;R6 and R7 independently represent hydrogen, cyano, C1-4 alkyl;R8 is (CH2)rR10;R9 represents hydrogen, halogen, C3-7 cycloalkyl, hydroxy, nitro, cyano or C1-4 alkyl optionally substituted by one or two groups selected from halogen, cyano, hydroxy or C1-4 alkoxy;R10 represents hydrogen or C3-7 cycloalkyl;n represents 1 or 2;q is 0, 1 or 2;r is 0 or an integer from 1 to 4;or a pharmaceutically acceptable salt or a solvate thereof, process for their preparation and their use in the treatment of conditions mediated by tackykinins and/or by selective inhibition of the serotonin reuptake transporter protein.

Description

BETA-LACTAMAS FOR THE TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM DESCRIPTIVE MEMORY The present invention relates to lactam derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use. The present invention thus provides a compound of formula (I) where - represents a single or a double bond; R represents a radical selected from: wherein Ri is halogen, cyano, C- | 4 alkyl, C-.4 alkoxy, trifluoromethyl or trifluoromethoxy and p is zero or an integer of 1 to 3; R2 represents hydrogen or C-? - alkyl; R3 represents hydrogen, hydroxy or C1-4 alkyl; R represents hydrogen or R together with R3 represents = 0 or = CH2; Rs represents phenyl, naphthyl, a bicyclic fused heterocyclic group of 9 to 10 members or a heteroaryl group of 5 or 6 members, wherein the groups are optionally substituted with 1 to 3 groups independently selected from trifluoromethyl, C-alkyl ? -4, hydroxy, cyano, C? -4 alkoxy, trifluoromethoxy, halogen or S (0) C? -4 alkyl; R6 and R7 independently represent hydrogen, cyano, C1-4 alkyl; R8 is (CH2) rR? 0; Rg represents hydrogen, halogen, C3.7 cycloalkyl, hydroxy, nitro, cyano or C? -4 alkyl optionally substituted with one or two groups selected from halogen, cyano, hydroxy or C1-4 alkoxy; R10 represents hydrogen or C3-7 cycloalkyl; n represents 1 or 2; q is 0, 1 or 2; r is 0 or an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof. Another embodiment of the invention provides compounds of formula (I), wherein - represents a single or double bond; R represents wherein R-i is halogen, C? - alkyl, cyano, C -? - 4 alkoxy, trifluoromethyl or trifluoromethoxy p is zero or an integer of 1 to 3; R 2 represents hydrogen or C 4 -alkyl; R 3 represents hydrogen, hydroxyl or C 4 alkyl; R4 represents hydrogen or R4 together with R3 represents = 0; R5 represents phenyl, naphthyl, a bicyclic fused heterocyclic group of 9 to 10 members, or a heteroaryl group of 5 or 6 members, wherein the groups are optionally substituted with 1 to 3 groups independently selected from trifluoromethyl, C-alkyl ? -4, hydroxy, cyano, C- alkoxy, trifluoromethoxy, halogen or S (0) C1-4alkyl; R6 and R7 independently represent hydrogen, cyano, C- | 4 alkyl or R3 together with R4 represents C3 cycloalkyl.; R8 represents (CH2) rR? _; Rg represents hydrogen, halogen, C3 cycloalkyl. , hydroxy, nitro, cyano or C-M alkyl optionally substituted with one or two groups selected from halogen, cyano, hydroxy or C-? -4 alkoxy; R-io represents hydrogen or C3-7 cycloalkyl; n represents 1 or 2; q is 0, 1 or 2; r is O or an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof. A further embodiment of the invention provides compounds of formula (I), wherein - represents a single or double bond; R represents wherein Ri is halogen, C ?4 alkyl, cyano, C? -4 alkoxy, trifluoromethyl or trifluoromethoxy, p is zero or an integer from 1 to 3; R 2 represents hydrogen or C 4 alkyl; R3 represents hydrogen, hydroxy or C1-4 alkyl; R4 represents hydrogen or R4 together with R3 represents = 0; R5 represents phenyl, naphthyl, a bicyclic fused heterocyclic group of 9 to 10 members, or a heteroaryl group of 5 or 6 members, wherein the groups are optionally substituted with 1 to 3 groups independently selected from trifluoromethyl, C? -4, hydroxy, cyano, C -? - alkoxy, trifluoromethoxy, halogen or S (0) C? --alkyl; R6 and R7 independently represent hydrogen, cyano, C-? -4 alkyl; R8 represents (CH2) rR? O; Rg represents hydrogen, halogen, C3- cycloalkyl, hydroxy, nitro, cyano or C? -4 alquiloalkyl optionally substituted with one or two groups selected from halogen, cyano, hydroxy or C -? Alco alkoxy; R-io represents hydrogen or C3-7 cycloalkyl; n represents 1 or 2; q is 0, 1 or 2; r is 0 or an integer from 1 to 4; or a pharmaceutically acceptable salt and solvate thereof. The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine, the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as the acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, nitric, hydriodic, metaphosphoric or phosphoric acids, and organic acids, eg, acid succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic, formic, propionic, glycolic, gluconic, camphor sulfonic, isothionic, mucic, gentisic, isonicotinic, saccharide, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), ethanesulfonic, pantothenic, stearic, sulfinyl, alginic and galacturonic; and arylsulfonium, for example, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic; base addition salts formed with alkali metals and alkaline earth metals, and organic bases such as N, N-dibenclylethylene diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine; and salts formed internally. Certain of the compounds of formula (I) can form acid addition salts with less than one or more equivalents of the acid, for example, to form a dihydrochloride salt. The present invention includes within its scope, all possible stoichiometric and non-stoichiometric forms. Salts having a non-physiologically acceptable anion or cation are within the scope of the invention as intermediates useful for the preparation of physiologically acceptable salts and / or for use in non-therapeutic situations, for example, in vitro. Solvates can, for example, be hydrates. This invention also includes within its scope the stoichiometric hydrates and solvates, as well as the compounds containing varying amounts of water and / or solvent. The compounds of formula (I) can be prepared in crystalline or non-crystalline form, and if crystalline, they can optionally be hydrated or solvated. In addition, some of the crystalline forms of the compounds of formula may exist in alternate polymorphic forms, which are included in the present invention.

It will be appreciated by those skilled in the art that the compounds of formula (I), wherein n is 1, contain at least one chiral center (namely, the carbon atom shown as * in formula (1a) and (1)). b), and may be represented by the formulas (1a) and (1b). (1a) (1b) The wedge link indicates that the link is above the plane of the paper. The interrupted link indicates that the link is below the paper. At least two asymmetric carbon atoms are present in the compounds of formula (I), wherein Rg is different from hydrogen, and may be represented by the formula (1c), (1d), (1e) and (1f).

Additional asymmetric carbon atoms are possible when R3 and R4 are not the same group and / or when Re and R7 are not the same group and / or when - is a single bond and / or when - is a single bond and R2 is C1- alkyl. Thus, for example, at least two asymmetric carbon atoms are present when R6 and R are not the same group and - is a single bond (namely, the carbon atoms shown as ** and as *** in the formula ( 1g)).

It will be understood that all stereoisomeric forms, including all enantiomers, diastereoisomers and all mixtures thereof, including racemates, will be encompassed within the scope of the present invention, and reference to compounds of formula (I), includes all the stereoisomeric forms, unless otherwise indicated. The present invention also includes isotopically labeled compounds, which are identical to those set forth in formulas (I) and the following, except for the fact that one or more atoms are replaced by the atom having an atomic mass or a mass number different from the atomic mass or mass number usually found in nature. The exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, such as 3 H, 11 C, 14 C, 18 F, 123 I and 125 I. The compounds of the present invention and pharmaceutically acceptable salts of the aforementioned isotope-containing compounds and / or other isotopes or other atoms are within the scope of the present invention. The isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H, 14C, are incorporated, are useful in drug and / or tissue substrate distribution assays. The tritiated isotopes, ie, 3H and carbon-14, ie, 14C, are particularly preferred for their ease of preparation and detectability. The isotopes of 11C and 18F are particularly useful in PET (positron emission tomography) and the 125L isotopes are particularly useful in SPECT (single-photon emission computed tomography), all useful in brain imaging. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, can produce certain therapeutic advantages, resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, therefore, can Prefer in some circumstances. The isotopically-labeled compounds of the formula (I) and the following of this invention, can generally be prepared by carrying out the procedures described in the Reaction Schemes and / or the following Examples, substituting the isotopically-labeled reagent available for a non-isotopically labeled reagent. Where used herein, the term naphthyl, whether alone or as part of another group, is intended, unless otherwise indicated, to denote both 1-naphthyl and 2-naphthyl groups. The term "C" alkyl "as used herein as a group or as part of the group refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, tert-butyl. The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term C3.7 cycloalkyl group means a non-aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "C 1-4 alkoxy group" can be a straight-chain or branched-chain alkoxy group, for example, methoxy, ethoxy, prop-2-oxy, but-2-oxy or 2-methylprop-2-oxy. When R5 is a 5- or 6-membered heteroaryl group according to the invention, it includes furanyl, thiophenyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,3. -oxadiazolyl, 1,2,3-thiadiazolyl, 1,4-triazolyl, 3,4-oxadiazolyl, 1,4-thiadiazolyl, 1, 2,5-oxadiazolyl, 1, 2,5-thiadiazolyl, pyridyl, pyridazinyl. pyrimidinyl, pyrazinyl, 1,4-oxadiazolyl, 1, 2,5-triazinyl or 1,3,5-triazinyl and the like. The term "fused bicyclic heterocyclic group" of 9 to 10 members refers to a bicyclic ring system 5,6 or 6,6, which contains at least one heteroatom selected from oxygen, sulfur or nitrogen, which may be saturated, unsaturated or aromatic. The term "9 to 10 membered fused bicyclic heterocyclic group" also refers to a phenyl fused to a 5- or 6-membered heterocyclic group. An example of such groups includes benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, 3H-midazo [4,5-c] pyridinyl, dihydroftacinyl, 1 H-methyldazo [4,5-c] pyridin-1. -yl, imidazo [4,5-b] pyridyl, 1,3-benzo [1,3] dioxolyl, 2H-chromanyl, isochromanyl, 5-oxo-2,3-dihydro-5H- [1-3-thiazolo [3, 2-a] pyrimidyl, 1,3-benzothiazolyl, 1, 4,5,6-tetrahydropyridacil, 1, 2,3,4,7,8-hexahydropteridinyl, 2-thioxo-2,3,6,9-tetrahydro- 1 H-purin-8-yl, 3,7-dihydro-1 H-purin-8-yl, 3,4-dlhydropyrimidin-1-yl, 2,3-dihydro-1,4-benzodioxinyl, benzo [1 , 3] dioxolyl, 2H-chromenyl, chromanyl, 3,4-dihydroptalacinyl, 2,3-dihydro-1 H-indolyl, 1,3-dihydro-2H-isoindol-2-yl, 2,4,7-trioxo- 1, 2,3,4,7,8-hexahydropteridinyl, thieno [3,2-d] pyrimidinyl, 4-oxo-4,7-dihydro-3H-pyrrolo [2,3-d] pyrimidinyl, 1, 3-dimethyl-6-oxo-2-thioxo-2,3,6,9-tetrahydro-1H-purinyl, 1,2-dihydroisoquinolinyl, 2-oxo-1,3-benzoxazolyl, 2,3-dihydro- 5H-1, 3-thiazolo [3,2-a] pyrimidinyl, 5,6,7,8-tetrahydro-quinazolinyl, 4-oxochromanyl, 1, 3- benzothiazolyl, bezimidazolyl, benzotrizolyl, purinyl, furylpyridyl, thiophenyl-pyrimidyl, thiophenyl-pyridyl, pyrrolyl-pyridyl, oxazolyl-pyridyl, thiazolyl-pyridyl, 3,4-dihydropyrimidin-1-yl, imidazolium-pyridyl, qulnolyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrazolyl [3.4] plridine, 1,2-dihydroisoquinolinyl, cinolinyl, 2,3-dihydro-benzo [1,4] dioxin-6-yl, 4,5,6,7-tetrahydro-benzo [b] thiophenyl-2-yl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, 3,4-dihydro-2H-1,4-benzothiazine, 4,8-dihydroxy-quinoline, 1-oxo-1, 2- dihydro-isoquinolinoyl or 4-phenyl- [1,2-] thiadiazolyl and the like. In the compounds of formula (I) wherein n is 1 the group Rg can be in the 2, 4 or 5 position as represented in the formula (1 h) In the compounds of formula (I) wherein n is 2 the group Rg may be in the 2, 3, 5 or 6 position of the piperidine ring as represented by the formula (11) In one mode, n is 2. In a mode R represents wherein R 1 is halogen, C 4 alkyl, cyano, C 1 alkoxy, trifluoromethyl or trifluoromethoxy, p is zero or an integer from 1 to 3. In one embodiment, R is phenyl optionally substituted with one or two groups selected from halogen (e.g., fluorine), cyano, C-- 4 alkyl (e.g., methyl), C- (for example, methoxy) alkoxy, trifluoromethyl or trifluoromethoxy. In another embodiment, R is phenyl substituted by a fluorine. In one embodiment, R2 is hydrogen or methyl. In one embodiment, R3 is hydrogen, hydroxyl or methyl, or together with R4 form = 0 or = CH2. In another embodiment, R3 is hydrogen, hydroxy or methyl, or together with R form = 0. In one modality, * is hydrogen. In one embodiment, R5 is phenyl or naphthyl optionally substituted with one or two groups selected from trifluoromethyl, cyano, C? - alkyl or halogen. In one embodiment, Re is hydrogen or methyl. In one embodiment, R7 is hydrogen or methyl.

In one embodiment, R8 is (CH2) rR10 in which R-? 0 is hydrogen or C3.7 cycloalkyl (eg, cyclopropyl) and r is 0 or 1. In one embodiment, Rg is hydrogen or C? optionally substituted with one or two groups selected from halogen. In an R embodiment it is phenyl substituted with fluorine, R2, R9 and R are hydrogen, R3 is hydrogen, hydroxy or methyl, or together with R forms = 0 or = CH2, Re and R7 are independently hydrogen or methyl, R5 is phenyl or naphthyl optionally substituted by one or two groups independently selected from cyano, methyl, chloro, a bromine or fluorine atom, R8 is hydrogen, methyl or cyclopropylmethyl, and n is 2. In another embodiment R is phenyl substituted by a fluorine , R2, Rg and R4 are hydrogen, R3 is hydrogen, hydroxy or methyl, or together with R4 form = 0, Re and R are independently hydrogen or methyl, R5 is phenyl or naphthyl optionally substituted by one or two groups selected from independently of cyano, methyl, chloro, a bromine or fluorine atom, R8 is hydrogen, methyl or cyclopropylmethyl, and n is 2. Examples of the compounds of the present invention include: 1 - [(3,5-Dichlorophenol) ) methyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrole-2- ona; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 1 - . 1 - [1 - (3,5-Dichlorophenyl) etl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Enantiomer of Chain 1); 1 - [(1 S) -1 - (3-Chloro-1 -naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrole-2 ona; 1 - [(3-Chloro-1 -naphthalene] methyl) -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 4- ( { 3- [4- (4-Fluorophenyl) -4-p-peridinyl] -2-oxo-2,5-dihydro-1 H-pyrrol-1-yl} methyl) -2- naphthalenecarbonitrile; 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 2); 1 - [(1 R) -1- (3-Chloro-1-naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrole-2- ona; 1 - [1 - (3,5-Dichlorophenol) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrroi-2-one (Enantiomer of Chain 1); 1 - [(1 S) -1 - (3-Chloro-1-naphthalethylethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinium-1, 5-dihydro-2H-pyrrole-2 -one; 1 - [(3-Chloro-1 -naphthalenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrolidone 2-one: 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrole-2 -one (Chain Enantiomer 2); 1 - [(1 R) -1 - (3-Chloro-1-naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidine l] -1,5-dihydro-2H-pyrrol-2-one; 4- ( { 3- [4- (4-Fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-2,5-dihydro-1 H- pyrrol-1-yl .) methyl) -2-naphthalenecarbonitrile; 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2 hydrochloride -one (Enantiomer of Chain 1); 1- [1- (3,5-Dichlorophenol) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrole hydrochloride -2-ona (Enantiomer of Chain 1); 1 - [(3-Chloro-1 -naphthalenyl) methyl] -3- [1 - (cyclopropylmethyl) -4- (4-fluorophenyl) -4-pperidinyl] -1,5-dihydro-2H-pyrrolidone -2-ona; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone 1 - [(1 S) -1 - (3-Chloro -1-naphthalenyl) -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (diastereoisomer 1); 1 - [(1 S) -1 - (3-Chloro-1 -naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone; 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 1 Chain Enantiomer 1); 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinylj-2-pyrrolidinone (Diastereoisomer 2 Enantiomer of Chain 1); 1- [1- (3,5-Dichlorophenol) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 1 Chain Enantiomer 2); 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 2 Enantiomer of Chain 2); 4- ( { 3- [4- (4-Fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 1); 4- ( { 3- [4- (4-Fluorophenyl) -4-p-peridinyl] -2-oxo-1-pyrrolidinyl} methyl) -2- naphthalenecarbonitrile (Enantiomer 2); 7-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl] methyl) -2-naphthalenecarbonitrile (Enantiomer 2); 6-Fluoro-4- (. {3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 2); 7-Fluoro-4- (. {3- [4- (fluoroprophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl] methyl) -2-naphthalenecarbonitrile (Enantiomer 1); 6-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl}. Methyl) -2-naphthalenecarbonitrile (Enantiomer 1 ); 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone; 1 - [1 - (3-Chloro-1 -naphthalene] ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl-2-pyrrolidinone (Diastereoisomer 2 Chain Enantiomer 1); 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 1 Chain Enantiomer 1); 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 2 Enantiomer of Chain 1); 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 1 Chain Enantiomer 2); 1 - [1 - (3,5-Dichlorophenol) ethylj-3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 2 Enantiomer of Chain 2); 1 - [(3,5-D-chlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Enantiomer 1); 1 - [(3,5-Dichlorophenol) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Enantiomer 2); 4- ( { 3- [4- (4-Fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 1); 4- ( { 3- [4- (4-Fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 2); 7-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -1-methyl-4-pperpentyl] -2-oxo-1-pyrrolidinyl}. Methyl) -2-naphthalenecarbonitrile (Enantiomer 2); 6-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -1-methyl-4-piperidn] -2-oxo-1-pyrrolidin} meti) -2-naphthalenecarbonyltryl; 7-Fluoro-4- (3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 1); 6-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2 -naphthalenecarbonitrile (Enantiomer 1) -; } 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-pperidinyl] -1 H -pyrrole-2,5-dione; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-phlorophenyl) -1-methyl-4-piperidinyl] -5-methylidene-1,5-dihydro-2H-pyrrol-2-one; Or a pharmaceutically acceptable salt (for example, hydrochloride, fumarate or citrate) or a solvate or amorphous or crystalline forms thereof.

Examples of the compounds of the present invention include: 1 - [(3,5-D-chlorophenyl) methyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H- pyrrole-2-one; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1); 1 - [(1 S) -1 - (3-Chloro-1 -naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrole-2- ona; 1- [1- (3,5-Dichlorophenol) etl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrole -2-ona (Enantiomer of Chain 1); 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Enantiomer of Chain 2); 1 - [(1 R) -1 - (3-Chloro-1 -naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H- pyrrole-2-one; 4- ( { 3- [4- (4-Fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-2,5-dihydro-1H-pyrroI-1-yl} methyl) -2 -naphthalenecarbonyltrile; and pharmaceutically acceptable salts (e.g., hydrochloride, fumarate or citrate) and solvates or amorphous or crystalline forms thereof. The specific compounds of the invention are: 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H -pyrrole-2-one; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-pperidinyl] -1,5-hydroxy-2H-pyrrolidine hydrochloride -2-one; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-pperidinyl] -1,5-dihydro-2H-pyrrol-2-one fumarate; 1 - [(3,5-Dichlorophenol) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dichloride citrate -2H-pyrrol-2-one; or crystalline forms thereof. The compounds of the invention are antagonists of tachykinin receptors, including substance P and other neurokinins, both in vitro and in vivo and are therefore of use in the treatment of conditions mediated by tachykinins, including the substance P and other neurokinins. Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both inferior and advanced forms of life. In mammals' life forms, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurocynin B (NKB), which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of several human diseases. Three types of tachykinin receptors have been identified, namely NK1 (which prefers SP), NK2 (which prefers NKA) and NK3 (which prefers NKB), which are widely distributed through the central nervous system (CNS) and peripheral. Particularly, the compounds of the invention are antagonists of the NK1 receptor. The compounds of the present invention also have activity as selective inhibitors of serotonin reuptake (hereinafter referred to as SSRIs) and are therefore useful in the treatment of conditions mediated by selective inhibition of protein from the transporter of the reuptake of serotonin. Thus, the compounds of the present invention combine double activity as tachykinin antagonists, including substance P and other neurokinins, and as SSRI. In particular, the compounds of the invention combine the double activity as antagonists of the NK1 receptor and as SSRI. The receptor binding affinity of NK1 has been determined in vitro in a close scintillation binding assay (SPA) by measuring the ability of the compounds to displace the [125l] Tyr8-Substance P (SP) from the receptors of the Recombinant human NKi stably expressed in membranes of Chinese Hamster Ovary (CHO) cells prepared using a modification of the method described by Beattie DT et al. (Br. J. Pharmacol, 116: 3149-3157, 1995). Briefly, Leadseeker WGA-SPA polystyrene beads (Amersham Biosciences) were mixed with cell membranes in a bead / membrane ratio of 50: 1 (weight / weight) in assay buffer (Tris 75 mM pH 7.8, NaCl 75 mM, MnCl 2 4 mM, EDTA 1 mM, Chaps 0.05%, PMSF 1 mM). The mixture was placed on ice for 30 minutes to allow the formation of the membrane / bead complex before BSA was added to a final concentration of 1%. After a further 30 minutes of incubation on ice, the bead / membrane complex was washed twice and suspended in assay buffer. [125l] Tyr8-Substance P (2200 Ci / mmol, PerkinElmer) was added to the bead / membrane complex with a final concentration of 0.4 nM. 30 ul of the resulting mixture were then distributed to each well of a Nalgen NUNC plate of 384 wells with 1 ul of predistributed compound in DMSO. The plates were then sealed and centrifuged with pulses at 1100 rpm. After 3 hours of incubation at room temperature with shaking, the plates were centrifuged for 2 minutes at 1100 rpm and measured on a Viewiux imager (PerkinElmer) for 5 minutes with a 6.18-nm filter. Inhibition of the binding of [25l] Tyr8-Substance P to the NK-i receptors was measured by the reduction of the luminescent signal. The IC50 values of each compound were determined by an inhibition curve of the 3x dilution of 11 points. The pKi values were calculated using the KD of [125!] Tyr8-Substance P determined in a separate experiment. For the representative compounds of the invention, the binding affinity of the NK-i receptor has also been determined in vitro using conventional filtration techniques, by measuring the capacity of the Compounds for displacing the [3H] -substance P SP of the recombinant human NKi receptors expressed in membranes of CHO cells prepared as described above. Briefly, ligand binding was performed in 0.2 ml of 50 mM HEPES, pH 7.4, containing 3 mM MnCl 2, 0.02% BSA, [3 H] -Substance P 0.5 nM (30-56 Ci / mmol Amersham), a final concentration of membrane protein of 30-50 μg / ml, and the test compounds. The incubation proceeded at room temperature for 40 minutes and was stopped by filtration. The non-specific binding was determined using an excess of substance P (1 μM) and represents approximately 6-10% of the total binding. The compounds of the invention were further characterized in a functional assay using FLIPR technology for the determination of their effect to inhibit the increase of intracellular calcium induced by SP in Human-HK-i-CHO cells and in human U20S cells transduced with Bacman virus NKi Briefly, 10K-15K cells / well were seeded in a bio-one Greiner 384-well plate in culture medium (DMEM with 10% FBS), incubated overnight in C02 at 37 ° C. For human U20S cells, 1% (volume / volume) of BacMan virus carrying the NK-i gene was mixed with cells prior to emplacing. After aspirating the medium, the cells were loaded with calcium cytoplasmic dye Calcium 3 (Molecular Devices Co.) in 30ul / well of buffer (balanced Hank's salts with 20 mM Hepes) and incubated in C02 at 37 ° C for 60 minutes. Then 10ul / well of test buffer was added (exit balanced Hank with 20 mM Hepes) containing different concentrations of the compounds to the cells for another 30 minutes of incubation at 37 ° C. Finally, 10ul / SP well in assay buffer containing 0.1% BSA was added to the cells and the fluorescence signal was read in a FLIPR system. The Cl50 values of each compound were determined by an inhibition curve of the 3x dilution of 11 points. The potency of the antagonist value (value of fpKi or pKe value) was calculated from pCIso by the Cheng-Prusoff equation or was calculated from the Schild analysis. SERT binding affinity has been determined in vitro by the ability of the compound to displace [3 H] -citaIopram from cell membranes hSERT-LLCPL. For the binding reaction, a final concentration of 0.25 nM of [3 H] -citalopram (84 Ci / mmol, Amersham) was incubated with 3-5 μg (ml of cell membrane and the compound to be tested at different concentrations (7 points concentration in duplicate) in 50 mM Tris HCl, pH 7.7, containing 120 mM NaCl, 5 mM KCl, 10 μM pargyline and 0.1% ascorbic acid The reaction was carried out for 120 minutes at 22 ° C and was terminated through of a Unifilter GF / B (pre-refreshed in PEI at 0.5%) using a Cell Harvester (Tomtec). Scintillation fluid was added to each filtered spot and radioactivity was determined using a scintillation counter (TopCount (Packard)). non-specific was determined using paroxetine (10 μM) and represents approximately 2-5% of the total binding. Competent experiments were performed with determination in duplicate for each point. The Msat601 program package was used to elaborate the union data by competition. The Gl50 values were converted to K i values using the Cheng-Prusoff equation and using the KD of [3 H] citalopram determined in separate experiments. For the preferred compounds of the invention, the inhibitory activity of the compounds in the human serotonin transporter (hSERT) has been determined in vitro using porcine LLCPK cells (ATCC.) Stably transfected with the hSERT (hSERT-LLCPK). Cells have been plated in 96-well plates (10000 cells / well). After 24 hours, the cells were washed in uptake buffer (Hank's balanced salt solution + 20 mM Hepes) and preincubated for 10 minutes at 30 ° C with 50 μl of buffer containing the test compounds. 50 μl of 50 nM [3H] Serotonin (5-HT) solution (final concentration: 25 nM [3H] 5-HT) were added and the plates were incubated for 7 minutes at 30 ° C, during which time the cells captured the radiolabelled 5-HT. Aspiration of the solution and rapid washing of the cells with cold buffer completed the uptake. The amount of radioactive 5-HT incorporated into the cells has been measured by adding the scintillation cocktail directly into the cells and reading the plate in the Top Count. The data has been digitally processed to obtain the pICso values of the uptake inhibitors.

The action of the compounds of the invention on the NKi receptor and / or the serotonin transporter can be determined using conventional animal models. Thus, the ability to bind to the NK-i receptor and / or the serotonin transporter was determined using the isolation cell model of the guinea pig pup as described in Pettijohn, Psychol. Rep., 1979 and Rupniak et al., Neuropharmacology, 2000. The anti-anxiety activity obtained by the administration of a compound according to the invention can be demonstrated in the model of the social interaction of the gerbil, according to the method described by Cheeta et al. to the. (Cheeta S. et al., 2001. Brain Research 915: 170-175). The compounds of the invention are useful in the treatment of CNS disorders and psychotic disorders, in particular in the treatment or prevention of depressive states and / or in the treatment of anxiety., as defined in, but not restricted to, Statistical Diagnosis of Mental Disorder (DSM) IV Edition, edited by the American Psychiatric Association and / or National Classification of Diseases 10th revision (ICD-10).). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. The numbers in parentheses after the diseases listed below refer to the classification code in DSM-IV. Within the context of the present invention, the term psychotic disorder includes Schizophrenia including the Paranoid Type subtypes (295.30), Disorganized Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform disorder (295.40); Schizoaffective disorder (295.70) including the Bipolar Type and Depressive Type subtypes; Delusional Disorder (297.1) including subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes with Delusions and with Hallucinations; Substance Psychotic Disorder Induced by Subtypes with Delusions (293.81) and with Hallucinations (293.82); Psychotic Disorder and Not Otherwise Specified (298.9): Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Major Depressive Episodes Recurrent with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13), and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, similar to Major Depressive Episode, With Manic Features and With Mixed Features) Induced Mood Disorder Substance (including subtypes With Depressive Characteristics, With Manic Characteristics and With Mixed Characteristics) and Mood Disorder Not Otherwise Specified (296.90). The anxiety disorders include Disorder Social Anxiety, Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtypes Animal Type Natural, Type Blood-Injection-Injury, Kind Location and Other Type), Social Phobia (300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder (308.3), Anxiety Disorder Generalized (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Anxiety Disorder Induced by a Substance and Anxiety Not Otherwise Specified (300.00). The compounds of the invention are useful in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Sleep Disorders Related Breathing (780.59), Sleep Disorder of the Circadian Rhythm (307.45) and Disomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnia such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Other Mental Disorder such as Insomnia Related to Other Mental Disorder (307.42) and Hypersomnia Related to Other Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Sleep Disorder Induced by a Substance including Type Insomnia, Type Hypersomnia, Parasomnia Type and Mixed Type. The compounds of the invention may also be useful in the treatment of disorders related to Substances, including Substance Use Disorders, such as Substance Dependence, Substance Desire and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance Induced Persisting Amnestic Disorder, Substance Disorder Psychotic Substance-Induced Disorder, Substance-Induced Mood Disorder Induced Anxiety Substances, Substance-Induced Sex Dysfunction, Substance-Induced Sleep Disorder and Persistent Hallucinogenic Perception Disorder (Retrospective); Alcohol Related Disorders such as Alcohol Dependency (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Abstinence (291.81), Alcohol Intoxication Delirium, Alcohol Abstinence Delirium, Induced Persistent Dementia Alcohol, Alcohol-Induced Persistent Amnesic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol Related Disorder No Specified Otherly (291.9); Disorders Related to Amphetamines (or Amphetamine-Related) such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Delirium from Amphetamine Intoxication, Induced Psychotic Disorder Amphetamines, Amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and amphetamine-related disorder not otherwise specified (292.9); Caffeine-Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder, and Caffeine-Related Disorder Not Otherwise Specified (292.9); Related Cannabis such as Unit of Cannabis (304.30), Abuse of Cannabis (305.20), Cannabis Intoxication (292.89) Delirium, Cannabis Intoxication, disorder Psychotic Cannabis Induced, Anxiety Disorder Cannabis-Induced and Disorder Disorders Related to Cannabis Not Otherwise Specified (292.9); Cocaine Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Poisoning (292.89), Cocaine Abstinence (292.0), Cocaine Poisoning Delirium, Cocaine Induced Psychotic Disorder , Cocaine-Induced Anxiety Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-induced Sexual Dysfunction, Eating Disorder Cocaine-induced Sleep and Cocaine Related Disorder Not Otherwise Specified (292.9); Hallucinogenic Related Disorders such as Hallucinogenic Dependence (304.50), Hallucinogenic Abuse (305.30), Hallucinogenic Intoxication (292.89), Hallucinogenic Persistent Perception Disorder (Retrospective) (292.89), Delirium by Hallucinogenic Intoxication, Disorder Hallucinogenic-induced psychotic, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder, and hallucinogen-related disorders not otherwise specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Delirium by Inhalation Intoxication, Inhalant-Induced Persistent Dementia, Inhalant-induced Psychotic Disorder, Animo-induced Heid Disorder Inhalants, Anxiety Disorder Induced by Inhalants and Disorders Related to Inhalants Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0), and Nicotine-Related Disorders Not Otherwise Specified (292.9); Disorders Related to Opioids such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Delirium from Opioid Intoxication, Opioid-Induced Psychotic Disorder, Opioid-induced mood disorder, opioid-induced sexual dysfunction, sleep disorder Induced by Opioids and Disorders Related to Opioids Not Otherwise Specified (292.9); Disorders Related to Phencyclidine (or Similar to) such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-Induced Psychotic Disorder, Phencyclidine Disorder Animo Induced by Phencyclidine, Anxiety Disorder Induced by Phencyclidine and Related to Phencyclidine Not Otherwise Specified (292.9); Disorders Related to Sedatives, Hypnotics or Anxiolytics such as Dependence on Sedatives, Hypnotics or Anxiolytics (304.10), Abuse of Sedatives, Hypnotics or Anxiolytics (305.40), Sedative, Hypnotic or Anxiolytic Intoxication (292.89), Abstinence of Sedatives, Hypnotics or Anxiolytics (292.0), Delirium by Sedative, Hypnotic or Anxiolytic Intoxication, Sedative Abstinence Delirium , Hypnotic or Anxiolytic, Persistent Dementia by Sedatives, Hypnotics or Anxiolytics, Persistent Amnestic Disorder by Sedatives, Hypnotics or Anxiolytics, Psychotic Disorder Induced by Sedatives, Hypnotics or Anxiolytics, Disorder of the Animo Induced by Sedatives, Hypnotics or Anxiolytics, or Anxiety-Induced Disorder Sedatives, Hypnotics or Anxiolytics, or Sexual Dysfunction Induced by Sedatives, Hypnotics or Anxiolytics or Sleep Disorder Induced by Sedatives, Hypnotics or Anxiolytics or Disorders Related to Sedatives, Hypnotics or Anxiolytics Not Otherwise Specified (292.9); Disorders Related to Polisubstances such as Polysubstance Dependence (304.80); and Other (or Unknown) Disorders Related to Substances such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide. The compounds of the invention may also be useful in the treatment of Autistic Disorder (299.00); Attention Deficit / Hyperactivity Disorder including the Combined Type subtypes of Attention Deficit / Hyperactivity Disorder (314.01), Type Predominantly with lack of attention of the deficit of Attention / Hyperactivity (314.00), Hyperactive Type-lmpulso del Disstorno de Attention / Hyperactivity Disorder (314.01) Attention Deficit / Hyperactivity Disorder Not Otherwise Specified (314.9); Disorders Hyperkinetic; Disordered Behavior Disorders such as Behavior Disorder including subtypes of the Start Type in the Childhood (321.81), Type of Initiation in Adolescence (312.82) and Home No Specified (312.89), Oppositional Defiant Disorder (313.81) and Disordered Behavior Disorder Not Otherwise Specified; Y Tic Disorders such as Tourette's Disorder (307.23). The compounds of the invention may also be useful in the treatment of Personality Disorders, including subtypes of Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301.22), Antisocial Personality Disorder (301.7), Limit Personality Disorder (301.83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301.81), Elusive Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9). The compounds of the invention may also be useful in the treatment of eating disorders such as Anorexia Nervosa (307.1) including the subtypes of the Type of Restriction and the Type of Excess / Purge Eating; Bulimia Nervosa (307.51) including the subtypes of the Purging Type and the Non-Purging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50). The compounds of the invention may also be useful in the treatment of sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as the Female Sexual Arousal Disorder (302.72) and the Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transventetic Fetishism (302.3), Voyeurism (302.82) and Unspecified Paraphilia. Other Way (302.9); Identity disorders of the genus teles as a disorder of Gender Identity in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9). The compounds of the invention may be useful as analgesics. In particular, they may be useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus pain; chronic pain such as arthritic pain, such as occurs in bone, rheumatoid or psoriatic arthritis; neuropathic pain such as postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, neuropathy induced by chemotherapy, neuropathy induced by AIDS, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, acuminate headache; toothache; pain for cancer; pain of visceral origin; gastrointestinal pain; pain due to nervous breakdown; pain due to sports injuries; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain, for example, spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondylosis; drop; Burns; scar pain; itching and thalamic pain such as postapoplegia thalamic pain. The compounds of the invention may also be useful in the treatment or prevention of cognitive disorders. The disorders Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified. In addition, the compounds of the invention may also be useful as memory and / or cognition enhancers in healthy humans without cognitive and / or memory deficits. The improvement of memory and / or cognition includes the treatment of decreased memory and / or cognition in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive decline, for example, Alzheimer's disease. The compounds of the invention may also be useful as anti-inflammatory agents. In particular, they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and damage induced by a non-spheroidal anti-inflammatory drug; inflammatory skin diseases such as herpes and eczema; Inflammatory diseases of the bladder such as cystitis and urinary incontinence and dental inflammation. The compounds of the invention may also be useful in the treatment of superactive bladder disorders, including urinary frequency symptoms, with or without urgency, nighttime and urgency incontinence.

The compounds of the invention may also be useful in the treatment of allergic disorders, in particular allergic skin disorders such as urticaria, and allergic disorders of the airways, such as rhinitis. The compounds of the invention are also useful in the treatment of emesis, ie, nausea, vomiting and vomiting. Tmesis includes acute tmesis, delayed emesis and early tmesis. The compounds of the invention are useful in the treatment of emesis induced in any way. For example, emesis can be induced by drugs such as chemotherapeutic agents for cancer, such as alkylating agents, for example, cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, for example, dactinomycin, doxorubicin, mitomycin-C and bleomycin; antimetabolites, for example, cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, for example, etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; nausea due to radiation; radiation therapy, for example, radiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, for example, gastritis, or released by bacterial or viral infection; pregnancy; vestibular disorders, such as dizziness, vertigo, vahido and Meniere's disease; postoperative nausea; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, for example, myocardial infarction or peritonitis; migraine; increased intracranial pressure; decreased intracranial pressure (eg, altitude sickness); opioid analgesics, such as morphine; and gastroesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non-symptomatic GERD, acid indigestion, excess food or drink, stomach acid, stomach acedo, heartburn / regurgitation, acidity, such as episodic acidity, nocturnal acidity, and food-induced heartburn, dyspepsia and functional dyspepsia. The compounds of the invention are also useful in the treatment of disorders such as irritable bowel syndrome, gastroesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non-erosive GERD, acid indigestion, excess food or drink, stomach acid, stomach acedo, pyrosis / regurgitation, acidity, such as episodic acidity, nocturnal acidity, and food-induced acidity, dyspepsia, and functional dyspepsia (such as ulcer-like dyspepsia, dyspepsia similar to dysmotility, and unspecified dyspepsia), chronic constipation. ; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischemia such as cerebral vasospasm after subarachnoid hemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune improvement or suppression, such as systemic lupus erythematosus and rheumatic diseases such as fibrositis and cough.

The compounds of the invention may also be useful in premenstrual dysphoric disorders (PMDD), in chronic fatigue syndrome and in multiple sclerosis. It has been found that the compounds of the invention exhibit anxiolytic and antidepressant activity in conventional tests. For example, in vocalizations induced by separation in puppies of guinea pigs (Molewijk et al., 1996) and in the model of social interaction in gerbils, according to the method described by Cheeta et al. (Cheeta S. et 2001. Brain Research 915: 170-175). The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular, in human medicine. Also provided as a further aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medically for use in the treatment of conditions mediated by tachykinins (including substance P and other neurokinins) and / or selective inhibition of serotonin reuptake. Also provided as a further aspect of the invention, the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in the treatment of conditions mediated by tachykinins (including substance P and other neurokinins) and / or by selective inhibition of the protein of the serotonin reuptake transporter. In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of depression and / or anxiety. In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the treatment of depression and / or anxiety. In an alternate or additional aspect, a method is provided for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins and / or by selective inhibition of the protein of the serotonin reuptake transporter, comprising the administration of an effective amount of a compound of formula (I) or a pharmaceutically stable salt thereof. In a further aspect of the present invention, there is provided a method for the treatment of a mammal, including man, in particular for the treatment of depression and / or anxiety, which method comprises the administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. It will be appreciated that the reference to treatment is intended to include prophylaxis, as well as relief of established symptoms.

The compounds of formula (I) can be administered as the unpurified chemical, but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated, in conventional manner, using one or more pharmaceutically acceptable carriers or excipients. Thus, the compounds of formula (I) can be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through mouth or nose). For oral administration, the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (e.g., corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose).; fillers (for example, lactose, microcrystalline cellulose or calcium acid phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (for example, sulphate lauryl sodium). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or with another suitable vehicle before use. Such liquid preparations can be prepared by conventional means with acceptable additives such as suspending agents (eg, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, agents, colorants and sweeteners, as appropriate. Preparations for oral administration can be suitably formulated to provide controlled release of the active compound. For buccal administration, the composition can take the form of tablets or be formulated in the conventional manner. The compounds of the invention can be formulated for parenteral administration by injection of a bolus or by continuous infusion. Formulations for injection may be presented in a unit dosage form, for example, in ampoules or in containers with doses multiple, with an added conservative. The compositions may take such forms as suspensions, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds of the invention can be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g., drops for the eyes, ears or nose). The ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. Ointments for administration to the eye can be manufactured in a sterile manner using sterilized components. Lotions can be formulated with an aqueous or oily base and in general, they will also contain one or more agents. emulsifiers, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. The drops can be formulated with an aqueous or non-aqueous base, which also comprise one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a conservator. The compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, by example, which contain conventional suppository bases, such as cocoa butter or other glycerides. The compounds of the invention can also be formulated as depot preparations. Such long acting formulations can be administered by implant (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or in poorly soluble derivatives, for example, sparingly soluble salts. For intranasal administration, the compounds of the invention can be formulated as solutions via a suitable unit or metered dosing device, or alternatively, as a powder mixture with a suitable carrier for administration, using a suitable delivery device. A proposed dose of the compounds, of the Invention is 1 to about 1000 mg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will ultimately be at the discretion of the attending physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected. Thus, for parenteral administration, a daily dose will typically be in the range of 1 to about 100 mg, so Preferred 1 to 80 mg per day. For oral administration, a daily dose will typically be within a range of 1 to 300 mg, for example, 1 to 100 mg. The compounds of formula (I) and the salts and solvates thereof can be prepared by the general methods set forth hereinafter. In the following description, the groups R, R-., R2, R3, R4l R5, Re, R7, RT, R10, n, p, q and r have the meanings defined previously for the compounds of formula (I), unless otherwise indicated. The compounds of formula (I), wherein - is a single bond, R3 represents hydrogen or C? -4 alkyl and R4 represents hydrogen, can be prepared by a reductive N-alkylation of a compound of formula (III), with the carbonyl compound (II), in which Rn is C 1-4 alkyl (for example, methyl or ethyl), R 3 is hydrogen or C? -4 alkyl and R 8a has the meaning defined in formula (I) or is a nitrogen protecting group, to form an amino (IV) derivative, followed by the cyclization reaction in the presence of an alkoxy metal base, for example, methoxy sodium, and where necessary, followed by removal of the nitrogen protecting group. The reductive N-alkylation can be carried out in an aprotic solvent such as dichloroethane or acetonitrile and in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride. The cyclization reaction is conveniently carried out in a solvent such as an alkanol, for example, methanol or ethanol at a temperature within the range of 20 ° to 60 °. If desired, the compounds of formula (IV) can be isolated before the cyclization reaction takes place. The compounds of formula (I) wherein - is a single bond, R3 is hydroxy and R is hydrogen, can be prepared by oxidative cleavage of an allyl derivative of formula (V), (V) wherein R8a is defined as in formula (II), to form the aldehyde (VI), followed by in situ cyclization thereof and where necessary, followed by removal of the nitrogen protecting group.

Oxidation can be carried out using conventional oxidizing agents known in the art to convert an allyl group to a carbonyl group. Thus, for example, the oxidative cleavage to form the aldehyde (VI) is conveniently carried out using osmium tetraoxide or potassium osmate, followed by the reaction with sodium periodate in water miscible solvents (eg, tetrahydrofuran) and water, preferably at room temperature. Alternate methods include ozonolysis using ozone, followed by treatment with a suitable reducing agent, such as dimethyl sulfide or trimethyl phosphite. Clclization can be carried out by stirring the above mixture overnight at room temperature. If desired, the compounds can be isolated before cyclization takes place.

The compounds of formula (I), wherein - is a single bond and R3 together with R4 represents = 0, can be prepared by cyclization of a compound of formula (VII), wherein R8a is defined as in formula (II) and L is a suitable leaving group. The leaving groups suitable for this reaction (J. March, Advanced Organic Chemistry, 4th Edition, John Wiley and Sons, 1992, pp. 351-356) include, but are not limited to: halides, for example, chlorine, bromine, iodine; C 1 -C 4 alkoxy. The cyclization reaction is conveniently carried out in the presence of a suitable base such as NaH and in an aprotic solvent such as THF and at a temperature ranging from 0 ° C to 80 ° C. Alternatively, the compounds wherein - is a double bond, R8 represents (CH2) rR? Or wherein r is an integer from 1 to 4 and R3 together with R represents = 0, can be prepared by reductive alkylation of a compound of formula (VIIA), (V? IA) with an aldehyde, CH (O) (CH2) mR? 0 (Villa), where m is an integer from 0 to 3. Alternately, the compounds of formula (I) wherein - is a single bond can be prepared by the N-alkylation of a compound of formula (VIII), wherein R8a is defined as in formula (II) with a compound of formula (IX) in which L is a suitable leaving group as defined above. The N-alkylation can be carried out in an aprotic solvent such as dichloroethane solvent, N, N dimethyl formamide or acetonitrile and in the presence of a base such as for example sodium hydride and conveniently at a temperature within the F lter from 0 to 40 ° C. Alternatively, the compounds of formula (I) in the form of - is a double bond, R3 represents hydrogen or C1.4 alkyl and R4 is hydrogen, can be prepared by the oxidation of a compound of formula (Va) to obtain a compound of formula (Via), which can be isolated if desired, followed by cyclization with a strong acid such as sulfuric acid, trifluoroacetic acid, hydrochloric acid or p-toluenesulfonic acid, heating at room temperature between 20 ° -80 ° C.

The oxidation can be carried out using the condition described above to convert the compounds of formula (V) to the compounds of formula (VI). The compounds of formula (I) can be converted to other compounds of formula (I). Thus, for example and by way of illustration rather than limitation, the compounds of formula (I), wherein - is a double bond, R3 represents hydrogen and R4 is hydrogen, can be prepared by the reaction of a compound of formula (I) wherein it is a single bond, R3 represents hydroxy, R8 has the meaning defined in formula (I) or is a nitrogen protecting group, with an acid such as sulfuric acid, trifluoroacetic acid, hydrochloric acid or p-toluenesulfonic acid. For example, the compounds of formula (I) wherein - is a double bond and R3 is hydrogen, hydroxy, C- or R3 alkyl together with R4 represents = 0 can be prepared by a reaction of a compound of formula (I) ) where is a simple link, R8 has the defined meaning in formula (I) or is a nitrogen protecting group and R3 is hydrogen, a group protected with hydroxy, C1-4 alkyl or R3 together with R represents = 0, with a suitable twining agent, followed by treatment with a base, such as ethoxide or sodium methoxide and by the removal of any protective group. A suitable twining agent to be used in this reaction is N-bromosuccinimide. For example, in a further embodiment, the compounds of formula (I) wherein R8 is (CH2) rR? Or wherein r is an integer from 1 to 4, can be prepared by reductive alkylation of a compound of formula (I) , wherein R8 is hydrogen, with an aldehyde, CH (0) (CH2) mR-? or (Villa), where m is an integer from 0 to 3. The reductive N-alkylation can be carried out in an aprotic solvent such as dichloroethane or acetonitrile in the presence of a suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride. In a further embodiment, the compounds of formula (I), wherein R8 is (CH2) rR-] 0 wherein r is 0 and R10 is cyclgalkyl of C3.7, can be prepared by the alkylation of a compound of formula (I) ), wherein R8 is hydrogen, with a compound L-R1.0 (IX a), wherein L is a leaving group such as halogen (e.g., iodine, chlorine or bromine). The reaction is conveniently carried out in a solvent such as NN-dlmethylformamide or tetrahydrofuran. Examples of aprotic solvents are NN-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and the like.

For example, compounds of formula (I), wherein R4 together with R3 represents = CH2, can be prepared by the reaction of a compound of formula (I) in which R3 and R4 are hydrogen with formaldehyde in the presence of an agent suitable reducing agent such as sodium borohydride or sodium triacetoxyborohydride and a base such as sodium hydroxide. The compounds of formula (I) can be prepared by oxidative cleavage of an allyl compound of formula (X), wherein R8a and Rn have the meaning defined in formula (II).

(X) Oxidation is conveniently carried out in the presence of osmium tetraoxide followed by the reaction with sodium periodate. Alternate methods include ozonolysis using ozone followed by treatment with a suitable reducing agent such as dimethyl sulfide or trimethyl phosphite. The reaction is carried out in a solvent such as N, N-dimethylformamide or aqueous tetrahydrofuran at a temperature ranging from 0 to 25 ° C.

The compounds of formula (V) can be prepared by the reaction of a compound of formula (X), wherein R8a and Rn have the meaning defined in formula (II), with a strong base such as lithium hydroxide or sodium hydroxide. to obtain a carboxylic acid of formula (XI), followed by the reaction of an activated derivative thereof with a compound of formula (III) followed where necessary by the removal of any nitrogen-protecting group. Suitable activated derivatives of the carbonyl group include the acyl halide, mixed anhydride, activated ester such as thioester or the derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, eg carbonyl diimidazole, 0- (benzotrazole-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate or dicyclohexylcarbodiimide. The reaction is preferably carried out in an aprotic solvent such as a hydrocarbon, a haiohydrocarbon such as dichloromethane or an ether such as tetrahydrofuran, NN-dimethylformamide. The activated carboxylic acid derivatives (XI) can be prepared by conventional means. A particular activated derivative Suitable for use in this reaction is O- (benzotriazole-li-NNN'N'-tetramethyluronium tetrafluoroborate) The reaction is suitably carried out in a solvent such as NN-dimethylformamide The compounds of formula (VII) can be prepared from (XII) by conventional means for convert the carboxylic groups to leaving groups. Thus, for example, a compound of formula (VII) in which L is a chlorine atom can be prepared by treating a compound of formula (XII) with thionyl chloride in an appropriate solvent such as tetrahydrofuran and optionally in the presence of a base tertiary organic. The compounds of formula (VI IA) can be prepared by the reaction of a compound of formula (I) wherein R 8 is a nitrogen protecting group, - is a single bond, R is hydrogen and R 3 is hydroxy with N 2 SO 3 in the presence of an inorganic acid (for example, hydrogen chloride). The compounds of formula (XII) can be prepared by the oxidation of a compound of formula (V). Oxidation can be carried out using conventional oxidizing agents known in the art to convert an allyl group to a carboxyl group using, for example, manganese dioxide. The compounds of formula (X) can be prepared by the reaction of a compound of formula (Xlll), a a ») wherein R8a and R11 have the meaning defined in formula (II) with an allyl derivative CH2 = C (R3) HC (R2) L (XIV) wherein L is a suitable leaving group, such as halogen (for example, iodine, bromine). The reaction is conveniently carried out in an aprotic solvent such as tetrahydrofuran in the presence of a base such as lithium bis trimethylsilylamide at a temperature ranging from -70 to -60 ° C. The compounds of formula (Xlll) can be prepared by a reaction of an activated derivative of the compounds of formula (XV), wherein R8a has the meaning defined in formula (II), with methanol or ethanol.

A particular activated derivative suitable for use in this reaction is N. ^ N'.N'-tetramethyluronium tetrafluoroborate. The compounds of formula (XV) can be prepared from a cyano derivative (XVI), (XVI) wherein R8a and Rn have the meaning defined in formula (II), by reaction with an acid, such as, for example, concentrated sulfuric acid. The reaction is conveniently carried out in a solvent such as acetic acid in the presence of water and heating the reaction mixture to 150 ° C. The compounds of (XVI) can be prepared by the reaction of a compound of formula (XVll), wherein R8a and R11 have the meaning defined in formula (ll), with a compound of formula (XVlll), wherein L is a suitable halogen (ie, bromine).

(XVIII) The reaction conveniently occurs in an aprotic solvent such as a hydrocarbon (e.g., toluene), ethers (e.g., tetrahydrofuran) and at a temperature within the range of 0-25 ° C, optionally in the presence of copper salts (I), such as, for example, copper iodide. The compounds of formula (XVll) can be prepared by the reaction of a compound of formula (XIX) with a cyano derivative (XX), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group.

In a further embodiment, the compounds of formula (XI) can be prepared by a reaction of a compound of formula (XXI), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group, (XXI) with a base such as lithium bis (trimethylsilyl) amide in the presence of a catalytic amount of a Palladium (0) complex such as tetracis (triphenylphosphine) palladium. The reaction is conveniently carried out in an aprotic solvent such as tetrahydrofuran at a temperature in the range of -25 ° to 0 ° C. The compounds of formula (XXI) can be prepared by the reaction of a compound of formula (XXII), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group, (XXtlI) with an alcohol of formula (XXIII). The reaction conveniently occurs in an aprotic solvent such as a hydrocarbon (eg, toluene), or N, N-dimethylformamide by heating. The compounds of formula (XXII) can be prepared by the reaction of a compound of formula (XXIV) with a Grignard reagent of formula (XVlll).

The reaction conveniently takes place in an aprotic solvent such as a hydrocarbon (for example, toluene), ethers (for example, tetrahydrofuran) and at a temperature in the range of 0-25 ° C, optionally in the presence of salts of copper (I) such as, for example, copper iodide. The compounds of formula (XXIV) can be prepared by the reaction of a compound of formula (XIX) with an acid of Meldrums in a solvent such as an alcohol (for example, methanol). The compounds of formula (VIII) can be prepared by the cleavage of a compound of formula (XXV), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group, The reaction can be carried out in the presence of ammonium nitrate and cerium in an aprotic organic solvent such as acetonitrile.

Compounds (XXV) can be prepared by the cyclization of a compound of formula (XXVI) wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group.

The cyclization can be carried out in a solvent such as an alcohol (for example, methanol) and in the presence of a suitable base such as methoxy sodium. The compounds of formula (XXVI), wherein R 4 is hydrogen, can be prepared by reductive N-alkylation of 1- (4-methoxyphenyl) ethyl amine (XXVII) and a compound of formula (II). The reaction is conveniently carried out in an aprotic solvent such as dichloroethane or acetonitrile and in the presence of a suitable metal reducing agent, such as sodium borohydride or sodium triacetoxyborohydride. In a further embodiment, the compounds of formula (I), wherein R2, R3 and R4 are hydrogen and - is a double bond, can be prepared from alcohol derivatives of formula (XXVIII), wherein R8a has the meaning defined in Formula (I) or is a nitrogen protecting group, by conventional means, to convert a hydroxy group to a halide group, followed by its removal to form the corresponding double bond.

(XXVIII) The reaction for converting (XXVIII) to the halides can be carried out using for example the halides of the non-metal elements such as thionyl chloride, phosphorus trichloride or phosphorus tribromide. These reactions can be carried out in an aprotic solvent such as methylene chloride and at a temperature ranging from -5 ° C to 30 ° C. The compounds of formula (XXVIII) can be prepared by the reduction of a keto derivative (XXIX), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group, using the method known in the art to reduce a keto group to a hydroxy group, thus using, for example, a borohydride reducing agent such as sodium borohydride, sodium cyano borohydride. The reaction is conveniently carried out in a solvent such as alkanol, for example, in aqueous sodium propane.

The compounds of formula (XXIX) can be prepared by the decarboxylation of a compound of formula (XXX) Decarboxylation can occur in the presence of an inorganic acid such as aqueous hydrochloric acid at a temperature ranging from 58 to 106 ° C. The compounds of formula (XXX) can be prepared by cyclization of a compound of formula (XXXI), wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group.

) Cyclization is carried out in the presence of an alkoxy metal base, for example, sodium ethoxy, in a protic solvent such as alcohol (eg, ethanol), at a temperature ranging from 0 ° C to 5 °. C. The compounds of formula (XXXI) can be prepared from the esterification of an acid of formula (XXXII) (XXXII) using the conventional method to convert an acid to the methyl ester, such as, for example, by reaction with dimethyl sulfate in the presence of an organic base such as potassium carbonate. The reaction can be carried out in an aprotic solvent such as NN-dimethylformamide. The compounds of formula (XXXII) can be prepared by the reaction of a compound of formula (XXII) with a compound of formula (XXXIII) (XXX? H) The reaction is suitably carried out in an aprotic solvent such as NN dimethylformamide heating at 55 ° -58 ° C. The amines (III) and the enantiomers thereof (III) and the compounds of formulas (XIX), (XX), (XXVII) and (XXXIII) are commercially available compounds or can be prepared by methods analogous to those used for the compounds known.

It will be appreciated by those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques, such as those described in Greene T. W. Protective groups in organic synthesis, New York, Wiley (1981), may be used. Thus, for example, when R8a is a nitrogen protecting group, examples of suitable groups include alkoxycarbonyl, for example, t-butoxycarbonyl, benzyloxycarbonyl, arylsulfonyl, e.g., phenylsulfonyl or 2-trimethylsilylethoxymethyl. The carboxylic acid groups can be protected as esters. Examples of suitable hydroxy protecting reagents include acetic anhydride, benzoic anhydride or a trialkylsilyl chloride. The aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures well known in the art. For example, protecting groups such as t-butyloxycarbonyl can be removed using an acid such as hydrochloric acid or trifluoroacetic acid in a suitable solvent such as dichloromethane, diethyl ether, isopropanol or mixtures thereof. When a specific enantiomer or a compound of general formula (I) is required, it can be obtained, for example, by solving a corresponding enantiomeric mixture of a compound of formula (I), using conventional methods.

Thus, for example, specific enantiomers of the compounds of formula (I) can be obtained from the corresponding enantiomeric mixture of a compound of formula (I) using a chiral HPLC method. Alternatively, the enantiomers of a compound of general formula (I) may be synthesized from the appropriate optically active intermediates, using any of the general methods described herein. Thus, in one embodiment of the invention, the enantiomers of the compound of formula (I) can be prepared by the reaction of a chiral amine (III) using any of the procedures described above to prepare the compounds of formula (I) from the amine (III). The chiral amine (III) can be prepared from the corresponding racemic amine (III) using any conventional procedures, such as salt formation with a suitable optically active acid, such as, for example, di-p-toluoyl-D-tartaric acid, acid di-p-toluoyl-L-tartaric or using a chiral HPLC method. In a further embodiment, the enantiomers of the compound of formula (I) can be prepared by the reaction of a chiral amine (XXVII) using any of the procedures described above to prepare the compounds of formula (I) from the amine (XXVII) . Where it is desired to isolate a compound of formula (I) as a salt, for example, a pharmaceutically acceptable salt, this can be achieved reacting a compound of formula (I) in the form of a free base with an appropriate amount of a suitable acid and in a suitable solvent such as an alcohol (e.g., ethanol or methanol), an ester (e.g. ethyl) or an ether (for example, diethyl ether, tert-butyl methyl ether or tetrahydrofuran).

Biological data The affinity of the compound of the invention for the NK-j receptor was determined using the N i receptor binding affinity method (Scintillation proximity assay (SPA)) as measured in vitro by the ability of the Compounds displace the [125l] Tyr8-Substance P (SP) from the NK receptors. recombinant human expressed in the membranes of Chinese Hamster Ovary (CHO) cells. The affinity values are expressed as the negative logarithm of the inhibition constant of the displaced ligands. The pKi values obtained as the average of at least two determinations with the compounds representative of the invention are in the range of 8.6 to 6.6. Particularly, the pKi values obtained as the average of at least two determinations with Examples No. 1, 3, 5, 6, 11, 14, 15 and 16 are within the range of 8.65 to 8.07. The affinity of the preferred compounds of the invention for the NK- receptor. it was also determined using the NK-i receptor binding affinity method measured in vitro by the capacity of the Compounds displace the [3H] -substance P (SP) of the recombinant human NKi receptors expressed in the membranes of Chinese Hamster Ovary (CHO) cells. The affinity values are expressed as the negative algorithm of the inhibitor constant of the displacer ligands (pKi). The pKi values obtained as the average of at least two determinations with the compounds representative of the invention are within the range of 9.32 to 8.72. Antagonism of the compounds of the invention towards human receptors was determined in a functional assay using FLIPR technology which measures its effect to inhibit the increase of intracellular calcium by SP in Human-NK-i-CHO and human U20S cells transduced with virus BacMan of NK-i. The potency of the antagonist was expressed as fpKi or pKb. The values of fpKi obtained as the average of the last two determinations with the representative compounds of the invention are within the range of 7.83 to 5.01. Particularly, the values of fpKi obtained as the average of at least two determinations with Examples No. 1, 3, 5, 6, 11, 14, 15 and 16 are within the range of 7.83 to 5.79 with pKb values within the range from 8.65 to 6. The affinity of the compounds of the invention for the serotonin transporter was determined using the hSERT binding affinity method and measuring in vitro the ability of the compounds to displace [3H] -citalopron from the transporter of the Human Recombinant Serotonin Expressed in Epithelial Kidney LLCPK Cell Membranes Porcine. The affinity values were expressed as the negative logarithm of the inhibitor constant of the displacer ligands (pKi). The pKi values obtained as the average of at least two determinations with the representative compounds of the invention are within the range of 9.4 to 6.5. Particularly, the pKi values obtained as the average of at least two determinations with Examples No. 1, 3, 5, 6, 11, 14, 15 and 16 are within the range of 8.90 to 8.04. The potency of the compounds of the invention to inhibit the uptake of 5-HT through the serotonin transporter was determined using the hSERT uptake method and measuring in vitro the ability of the compounds to displace the uptake of [3H] -5-HT of the recombinant human serotonin transporter expressed in LLCPK cells of Porcine Kidney. The potency values are expressed as the negative logarithm of the inhibitor constant of the displacer ligands that cause the inhibition of 50% of the maximum response of 5-HT (pCI50). The weight values obtained as the average of at least two determinations with the representative compounds of the invention are within the range of 7.6 to 5.7.

EXAMPLES OF PHARMACY Tablets Tablets can be prepared by the normal method such as direct compression or wet granulation. The tablets can be coated with a film with a material that forms a suitable film such as for example Opadry, using a standard technique.

EXAMPLE A Tablet (Direct Compression V Capsules Active Ingredient 20.0 mg Calcium Dibasic Phosphate 123.253 mg Crospovidone 4.5 mg Magnesium Stearate 1.5 mg - Colloidal Silicon Dioxide 0.75 mg The active ingredient is combined with the other excipients. The combination is used to fill gelatin capsules or compressed to form tablets using appropriate punches. The tablets can be coated using suitable techniques and coatings.

EXAMPLE B Tablets / Capsules (Wet Granulation) Active Ingredient 20.0 mg PVP 3 mg Avicel 120.25 mg Crospovidone 4.5 mg Magnesium Stearate 1.5 mg Colloidal Silicon Dioxide 0.75 mg The active ingredient and the intragranular excipients (PVP, Avicel, Crospovidone) are mixed at a high main agitation (impeller) for a few minutes. The resulting mixture is moistened, adding the liquid binder (water) by spraying it in the powder while both agitators, the impeller and the cutter, are working at low speed. The particles are allowed to grow as a result of the mechanical energy provided (both agitators working at high speed) and are dried by the walls of the granulator chamber that are heated. The granules thus obtained are screened and the other extragranular excipients (Magnesium Stearate, Colloidal Silicon Dioxide) are added and then mixed. The resulting mixture is compressed to obtain tablets or encapsulated to obtain capsules.

EXAMPLE C Tablets / Capsules (Dry Granulation) Active Ingredient 20.0 mg PVP 2 mg Avicel 121 mg Crospovidone XL 4.5 mg Magnesium Stearate 1.5 mg Colloidal Silicon Dioxide 1 mg The Active Ingredient and the intragranular excipients (PVP, Avicel, Crospovidona) are mixed and the mixture is compacted by compressing with flat-face punches or passing it through two shaved rolls that turn towards each other, in order to obtain "bullets" " The other extragranular excipients (Magnesium Stearate, Colloidal Silicon Dioxide) are added and then mixed. The resulting mixture is compressed to obtain tablets or encapsulated to obtain capsules.

EXAMPLE D Infusion Active Ingredient 2-50 mg / m Buffer Solution qs to 100 ml pH 4.5 suitable for infusion (for example, sodium chloride in 0.9% NaCl or 5% dextrose) The formulation can be packaged in plastic vials or in a plastic bag. In Intermediaries and Examples, unless otherwise indicated: The melting points (map.) Were determined on a map device. Buchan and are uncorrected and t.a refers to room temperature. The infrared (IR) spectra were measured in chloroform or nujol solutions in an FT-IR instrument. The Magnetic Resonance with Proton (NMR) spectra were recorded on instruments varying at 300, 400 or 500 MHz, on a Bruker instrument at 300 MHz, the chemical shifts are reported in ppm (d) using the residual solvent line as the standard internal. The separation patterns are designated as s, singlet; d, doublet; t, triplet; c, quartet; m, multiplet; a, broad. The NMR spectra were recorded at a temperature ranging from 25 to 90 ° C; when more than one conformer was detected, the chemical shifts for the most abundant are reported. The mass spectra (MS) were taken on a Spectrometer of Quadrupole masses 4 II (Micromass UK) or an Agilent MSD 1100 Mass Spectrometer, operating in an ES (+) and ES (-) ionization mode or in an Agilent LC / MSD 1100 Mass Spectrometer, which operates in a ES (+) and ES (-) ionization mode coupled with an Agilent HPLC instrument Series 1100 Series, HPLC (LC / MS-ES / +): refers to the analyzes performed on a Supelcosil ABZ + PIus (33x4.6 mm, 3 μm) (mobile phase; 100% [water +0.1% HC02H] for 1 minute, then 100% [water +0.1% HC02H] at 5% [water + 0.1% HC02H] and 95% [CH3CN] in 5 minutes, finally under these conditions for 2 minutes; T = 40 ° C; flow = 1 mL / minute; HPLC (LC / MS-ES / -): refers to the analyzes performed on a Supelcosil ABZ + Plus (33x4.6 mm, 3 μm) (mobile phase: 100% [water + 0.05% NH3j for 1 minute, below 100% [water + 0.05% NH3 at 5% [water + 0.05% NH3] and 95% [CH3CN] in 5 minutes, finally under these conditions for 2 minutes, T = 40 ° C, flow = 1 mL / minute] In the mass spectra, only one peak in the molecular cluster is reported.The X-ray powder diffraction pattern of a crystalline form of the compound of the invention was obtained by charging the sample in the diffractometer ( X-ray Siemens D5005 equipped with q / q goniometer, scintillation counter and graphite monochromator.The diffractometer was adjusted with the following instrumental parameters: Instrumental Parameters Monochromatic Radiation: Cu-1.54056 / 1.54439 Interval 2T: 2 ° -45 ° 2T Voltage / current generator: 40kV / 50mA Step size: 0.02 ° 2T Time per step: 2 seconds-1 Rotation: on Divergence / Anti-scatter groove: variable Sample holder: round cavity or bottom plate. The spectrum obtained was analyzed using the EVA 7.0 data evaluation program. Optical rotations were determined at 20 ° C with a Jasco DIP360 instrument (1 = 10 cm, cell volume = 1 mL,? = 589 nm). Flash chromatography on silica gel was carried out on 230-400 mesh silica gel supplied by Merck AG Darmstadt, Germany or on Mega Be-Si Varian pre-packaged cartridges or on Biotage pre-packaged silica cartridges. T.l.c refers to thin layer chromatography on 0.25 mm silica gel plates (60F-254 Merck) and visualized with UV light. For phase separations performed using microfiltration devices: phase separation cartridge with polypropylene frit by means of Whatman or SCX: SCX cartridges (loading 0.75 mmol / g) by Varian. The solutions were dried over anhydrous sodium sulfate. The methylene chloride was redistilled over calcium hydride and the tetrahydrofuran was redistilled over sodium.

The following abbreviations were used in the text: AcOEt = ethyl acetate, cyclohexane, CH = cyclohexane, DCE = dichloroethane, DCM = methylene chloride, DIPEA = N, N- dlisopropylethylamine, DMF = N, N'-dimethylformamide, Et20 = diethyl ether, EtOH = ethanol, MeOH = methanol, TEA = triethylamine, THF = tetrahydrofuran, TFA = trifluoroacetic acid, CH3CN = acetonitrile, TBTU = O-Ibenzotriazole-li-NNN'N'-tetramethyluronium tetrafluoroborate, std = saturated. Enantiomer 1 or enantiomer 2 means a compound of the invention or an intermediate thereof as a single intermediate whose configuration was not determined. Enantiomer of Chain 1 or enantiomer of chain 2 refers to a compound of the invention or an intermediate thereof (ie, (Ib, (IV), (V) or (VI)) wherein R and R are not the same group, having a single indeterminate configuration at the carbon atom shown as ** in formula (Ib), (IV), ( V) or (VI).

Diastereoisomer 1 or diastereomer 2 refers to a compound of the invention or an intermediate thereof having at least two stereogenic centers and wherein - it is a single bond, having a single, but undetermined, configuration at the carbon atom shown as *** in the formula (le) INTERMEDIARY 1 [1- (3,5-Dichlorophenyl) ethinylamine A solution of 3,5-dichlorobenzaldehyde (54.3 g) in dry THF (300 mL) was added dropwise to lithium bis (trimethylsilyl) -amide (solution 1 in THF-340 mL) at -30 ° C under a nitrogen atmosphere. The resulting orange mixture was heated to -5 ° C under stirring in a nitrogen atmosphere for 1 hour, then cooled to -60 ° C and methyllithium (1.6M solution in Et20-290 mL) was added, maintaining the temperature internal of the reaction mixture < -55 ° C. The resulting dark violet reaction mixture was stirred for 1 hour at -60 ° C under a nitrogen atmosphere, then extinguished carefully at -60 ° C with an aqueous 2N hydrochloric acid solution (20 mL), followed by an aqueous solution of 6N hydrochloric acid at pH = 2. The reaction mixture was concentrated in vacuo, and the aqueous residue was washed with water. : 1 CH / Et20 (500 mL). The separated aqueous phase was then made basic (pH = 14) at 0 ° C with NaOH granules. The basic aqueous phase was extracted with Et20 (4 x 400 mL), the collected organic layers were dried and concentrated in vacuo to give the title compound (60 g) as a yellow oil. T. I. c: DCM / MeOH 9: 1, Rf = 0.5 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.25-7.15 (m, 3H); 4.05 (c, 1 H), 1.35 (d, 3H). MS (ES / +): m / z = 190 [M + H] +.

INTERMEDIARY 2 AND INTERMEDIARY 3 ri- (3,5-Dichlorophenyl) etipamine (Enantiomer 1) and T1- (3,5-DichloropheniPetillamine (Enantiomer 2) A solution of (S) -methoxyphenylacetic acid (23 g) in acetone (140 mL), was added to a solution of intermediate 1 (25 g) in acetone (140 mL). The slurry was heated at 56 ° C for 1 hour, then stirred at room temperature overnight. The suspension was filtered and the solid residue was washed with acetone (200 mL). The solid (47 g) was triturated in acetone (500 mL) by heating at reflux for 1 hour, cooling to room temperature and stirring overnight. The suspension was filtered and the solid residue (29 g) was washed with acetone (500 mL) and triturated three times as described above to provide the (S) -methoxyphenylacetic acid salt of [1- (3,5-dichloro-phenyl) - ethyl] amine (16.6 g). The solid was stirred in a mixture of saturated aqueous sodium hydrogen carbonate solution (200 mL) and DCM (200 mL). The organic phase was separated, washed with brine (200 mL), dried and concentrated in vacuo to give intermediate 2 (8.2 g) as a colorless oil. The same procedure was performed in a batch other than intermediate 1 (7.5 g), to obtain intermediate title compound 2 (1.6 g); the mother liquors from the precipitation were evaporated in vacuo to provide a residue (9.5 g), which was treated with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), and extracted with DCM (50 mL). The colorless oil thus obtained (5 g) was treated with (R) -methoxyphenylacetic acid (4.3 g) in acetone as described above (one precipitation and two triturations), to give the (R) -methoxyphenylacetic acid salt of the [1- (3,5-dichloro-phenyl) -ethyl] amine (3.26 g). The solid was stirred in a mixture of saturated aqueous sodium hydrogen carbonate solution (50 mL) and DCM (50 mL). The organic phase was washed with brine (50 mL), dried and concentrated in vacuo to provide intermediate 3 (1.6 g) as a colorless oil.

INTERMEDIARY 2: (Enantiomer 1) NMR (CDCl 3): d (ppm) 7.25-7.15 (m, 3H); 4.05 (c, 1H); 1.35 (d, 3H). MS (ES / +): m / z = 190 [M + H] +. HPLC (column: Chiral-AGP 15 cm x 2 mm, 5 μm, injection volume = 1 μL, mobile phase: 100 mM ammonium phosphate buffer pH = 4. 4 / MeOH Socratic 99/1% volume / volume; flow rate = 0.13 mL / minute; detection:? = 210 nm): retention time = 5.4 minutes; purity (a / a%) > 98%.

INTERMEDIARY 3: (Enantiomer 2) NMR (CDCl 3): (ppm) 7.25-7.15 (m, 3H); 4.05 (c, 1 H); 1.35 (d, 3H). MS (ES / +): m / z = 190 [M + H] +. HPLC (column: Chiral-AGP 15 cm x 2 mm, 5 μm, injection volume = 1 μL, mobile phase: 100 mM ammonium phosphate buffer pH = 4. 4 / MeOH Socratic 99/1% volume / volume; flow rate = 0.13 mL / minute; detection:? = 210 nm): retention time = 6.2 minutes; purity (a / a%) > 99% INTERMEDIARY 4 ri- (3-Chloro-1-naphthalenyl) etipamine A solution of 3-chloro-naphthalenecarbaldehyde (1.93 g) in dry THF (12 mL) was added dropwise to lithium bis (trimethylsilyl) -amide (1 M solution in THF-10.1 mL) at -30 ° C under an atmosphere of nitrogen. The resulting yellow mixture was stirred under a nitrogen atmosphere of -30 ° C to -5 ° C for 1 hour, then cooled to -60 ° C and methyllithium (1.6M solution in Et20-11 mL) was added, maintaining the internal temperature of the reaction mixture < -55 ° C. The resulting dark violet reaction mixture was stirred for 40 minutes at -50 ° C under a nitrogen atmosphere, then carefully quenched at -50 ° C with an aqueous 2N hydrochloric acid solution (30 mL) until pH = 2. The reaction was concentrated in vacuo and the aqueous residue was washed with 1: 1 CH / Et20 (50 mL). The separated aqueous phase was then made basic (pH = 14) at 0 ° C with NaOH granules. This basic aqueous phase was extracted with Et20 (3 x 60 mL), the collected organic layers were dried and concentrated in vacuo to give the title compound (1.12 g) as a yellow oil. T. I. c: AcOE / MeOH 8: 2, Rf = 0.25 (detection with ninhydrin). NMR (de-DMSO): d (ppm) 8.14 (dd, 1 H); 7.94-7.85 (m, 2H); 7.73 (d, 1 H); 7.58-7.50 (m, 2H); 4.80 (c, 1 H); 1.35 (d, 3H). MS (ES / +): m / z = 189 [M-NH2] +.

INTERMEDIARY 5 AND INTERMEDIARY 6 r (1R) -1- (3-Chloro-1-naphthalenedininamine and r (1S) -1- (3-Chloro-1-naphthalenyl) ethenamine To a solution of intermediate 4 (1.12 g) in acetone (10 mL), a solution of (S) -methoxyphenylacetic acid (0.9 g) in acetone (10 mL) was added. The thick solution was heated at 56 ° C for 40 minutes, then stirred at room temperature overnight. The suspension was filtered and the solid residue was washed with acetone (10 mL). The solid was triturated (0.87 g) in acetone (10 mL) by heating at reflux for 1 hour., cooling to room temperature and stirred overnight. The suspension was filtered and the solid residue (0.6 g) was washed with acetone (10 mL), and triturated once more as described above to provide the (S) -methoxyphenylacetic acid salt of [(1 R) - 1- (3-Chloro-1-naphthalenyl) ethyl] amine (0.45 g). The solid was stirred in a mixture of saturated aqueous sodium hydrogen carbonate solution (20 mL) and DCM (20 mL). The organic phase was washed with brine (20 mL), dried and concentrated in vacuo to give intermediate 5 (0.25 g) as a colorless oil. The mother liquors of the precipitation and the first trituration were collected, concentrated in vacuo, treated with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with DCM (20 mL). The colorless oil thus obtained (1 g) was treated with (R) -methoxyphenylacetic acid (0.8 g) in acetone (8 mL) as described above (one precipitation and two triturations), to provide the (R) -methoxyphenylacetic acid salt of [(1S) -1- (3-Chloro-1-naphthalenyl) ethyl] amine (0.43 g). A portion of this solid (200 mg) was stirred in a mixture of saturated aqueous sodium hydrogen carbonate solution (10 mL) and DCM (10 mL). The organic phase was washed with brine (20 mL), dried and concentrated in vacuo to provide intermediate 6 (0.100 g) as a colorless oil.

INTERMEDIARY 5 NMR (d6-DMSO): d (ppm) 8.14 (dd, 1 H); 7.94-7.85 (m, 2H); 7.73 (d, 1H); 7.58-7.50 (m, 2H); 4.80 (c, 1 H); 1.35 (d, 3H). MS (ES / +): m / z = 189 [M-NH2] +; Analytical conditions SFC (Gilson): column: Chiralcel OD 25 x 4.6 mm; mobile phase: C02 / Ethanol + 0.1% Isopropanol 92/8 volume / volume; flow rate = 2.5 mL / minute; P = 180 bars; T = 35 ° C; detection:? = 225 nm): retention time = 13.8 minutes; purity (a / a%) > 99% INTERMEDIARY 6 NMR (d6-DMSO): d (ppm) 8.14 (dd, 1 H); 7.94-7.85 (m, 2H); 7.73 (d, 1 H); 7.58-7.50 (m, 2H); 4.80 (c, 1 H); 1.35 (d, 3H). MS (ES / +): m / z = 189 [M-NH2] +; Analytical conditions SFC (Gilson): column: Chiralcel OD 25 x 4.6 mm; mobile phase: C02 / Ethanol + 0.1% Isopropanol 92/8 volume / volume; flow rate = 2.5 mL / minute; P = 180 bars; T = 35 ° C; detection:? = 225 nm): retention time = 12.4 minutes; purity (a / a%) > 99% INTERMEDIARY 7 1- (3-Chloro-1-naphthalenyl) methanamine The 3-chloro-1-naphthalenecarbaldehyde (2 g) dissolved in dry THF (12 mL) was added dropwise to the 1M lithium bis (trimethylsilyl) amide in THF (11.5 mL) previously cooled to -40 ° C. The resulting yellow mixture was stirred -40 ° C to -20 ° C for 1.5 hours; it was then cooled to -50 ° C and 1 M lithium aluminum hydride in Et2O (10.6 mL) was added; the mixture was stirred at -40 ° C for 2 hours, then quenched with 2N HCl (10 mL) and allowed to reach room temperature. The reaction mixture was diluted with an additional 2N aqueous HCl solution (20 mL), and extracted with CH / Et2O. 1/1 (50 mL). The acidic aqueous phase was made basic at 0 ° C with granules of NaOH to pH = 14, then extracted with diethyl ether (2 x 150 mL).

The organic phase was dried and concentrated in vacuo to give the title compound (1.78 g) as a white solid. T. I. c: DCM / MeOH 8: 2, Rf = 0.43 (detection with ninhydrin). MS (ES / +): m / z = 175 [M-NH2j +.

INTERMEDIARY 8 4- (Aminomethyl) -2-naphthalenecarbonitrile The 4- (hydroxymethyl) -2-naphthalenecarbonitrile (200 mg) was dissolved under an inert atmosphere, in a 3-necked flask equipped with a reflux condenser, with a mixture of solvents of DMF (4 mL) and CCI 4 (1 mL). ). PPh3 and NaN3 were added in sequence and then the reaction mixture was heated at 90 ° C for 2 hours (disappearance of the raw material). H2O (5 mL) was added, followed by AcOEt (20 mL); The phases were separated and the organic phase was washed with brine (10 mL). The crude product obtained after evaporation of the solvents was dissolved in THF (3 mL) and H20 (1 mL) and the reaction mixture was stirred overnight at room temperature before being treated by dilution with AcOEt (100 mL). and washing with H20 (15 mL); and then with brine (15 mL). The crude product obtained after evaporation of the solvents was purified by flash chromatography (DCM to DCM / MeOH, 95/5) to give 0.138 g of the desired compound as a pale yellow oil. NMR (CDCl 3): d (ppm) 8.14 (s, 1 H); 8.08 (d, 1 H); 7.89 (d, 1 H); 7.69-7.60 (m, 2H); 7.66 (s, 1 H); 4.36 (s, 2H).

INTERMEDIARY 9 4- (Bromomethyl) -2-naphthalenecarbonitrile To a solution of 4- (hydroxymethyl) -2-naphthalenecarbonyl (200 mg) in dry DCE (5 mL), CBr4 (542.8 mg) and (Ph) 3P were added, the resulting mixture was stirred at room temperature for 40 minutes and then extinguished with 40 mL of water. The aqueous phase was washed with DCM (3 x 40 mL). The combined organic extracts were dried, concentrated and purified by flash chromatography (CH / AcOEt from 8: 2 to 1: 1) to give the title compound (216 mg) as a white foam. MS (ES / +): m / z = 247 [M + H] +.

INTERMEDIARY 10 AND 11 Methyl 4-bromo-7-fluoro-2-naphthalenecarboxylate and methyl 4-bromo-6-fluoro-2-naphthalenecarboxylate Isoamyl nitrite (3.56 mL) dissolved in dimethoxyethane (18 mL) and a solution of 2-amino-4-fluorobenzoic acid (4.11 g) in dimethoxyethane (18 mL) were added in separate streams at matching speed for 90 minutes at a refluxing solution of the methyl ester of 3-bromo-crassic acid (3 g) in dimethoxyethane (25 mL) and a catalytic amount of trifluoroacetic acid (21 mg). The reaction mixture was heated under reflux for 1 additional hour at the end of the additions. Then, the temperature was lowered to 50 ° C and toluene (40 mL) was added. The mixture was then cooled to room temperature, the phases were separated and the organic phase was extracted with 0.5 M aqueous NaOH (20 mL), 5% aqueous sodium metabisulfite (20 mL), water (20 mL), aqueous HCl. 2M (20 mL) and finally water (20 mL). The solvent was removed by evaporation under reduced pressure to provide a crude product, which was purified by Biotage Instant Chromatography, eluting with CH: AcOEt = 95: 5 to provide the title compound 10 (625 mg) and the title compound 11 (547 mg) as yellow oils.

INTERMEDIARY 10 T. I. c: CH / AcOEt 7: 3, Rf = 0.67. NMR (CDCl 3): d (ppm) 8.48 (s, 1 H); 8.31 (s, 1 H); 8.27 (dd, 1 H); 7.56 (dd, 1 H); 7.46 (td, 1 H); 3.96 (s, 3H).

INTERMEDIARY 11 T. I. c: CH / AcOEt 7: 3, Rf = 0.60. NMR (CDCl 3): d (ppm) 8.53 (s, 1 H); 8.36 (s, 1 H); 7.94 (dd, 1 H); 7.88 (d, 1H); 7.34 (td, 1 H); 3.96 (s, 3H).

INTERMEDIARY 12 Acid 4-bromo-7-fluoro-2-naphthalenecarboxylic acid Intermediate 10 (970 mg) was dissolved in THF (20 mL) and water (10 L), and then LiOH "H20 (577 mg) was added. The mixture was heated at 80 ° C for 2 hours. It was then cooled to room temperature and a 2M aqueous HCl solution was added. The aqueous phase was extracted with AcOEt and the organic extracts were dried and evaporated in vacuo to give the title compound (850 mg) as a yellow solid. NMR (de-DMSO): d (ppm) 13.4 (broad s, 1 H); 8.63 (s, 1 H); 8.23 (dd, 1 H); 8.18 (s, 1 H); 8.07 (dd, 1 H); 7.71 (td, 1 H).

INTERMEDIARY 13 4-bromo-6-fluoro-2-naphthalenecarboxylic acid Intermediary 11 (3.89 g) was dissolved in THF (60 mL) and water (30 mL), and then LiOH "H20 (2.32 g) was added. The mixture was heated at 80 ° C for 2 hours. It was then cooled to room temperature and a 2M aqueous HCl solution was added. The aqueous phase was extracted with AcOEt and the organic extracts were dried and evaporated in vacuo to give the title compound (3.4 g) as a yellow solid.

HPLC (LC / MS -ES / -): tR = 4.00 minutes MS (ES / -): m / z = 267 [M-HT.

INTERMEDIARY 14 4-Bromo-7-fluoro-N-hydroxy-2-naphthalenecarboxamide Intermediate 12 (850 mg) was dissolved in DMF (3 mL) and then TBTU (1.32 g) and DIPEA (1.9 mL) were added. The mixture was stirred for 30 minutes under a nitrogen atmosphere and then hydroxylamine hydrochloride (286 mg) was added; After stirring for 2 hours, a saturated aqueous solution of NH 4 Cl was added and the aqueous phase was extracted with AcOEt. The organic phase was then washed with a saturated aqueous solution of NaHCO3, dried and evaporated in vacuo to give a crude product, which was triturated with pentane to give the title compound (360 mg) as an off-white solid. MS (ES / +): m / z = 284 [M + H] +.

INTERMEDIARY 15 4-Bromo-7-fluoro-2-naphthalenecarbonitrile Intermediate 14 (360 mg) was suspended in fluorobenzene (11 mL) under a nitrogen atmosphere at room temperature and phosphorus tribromide (358 μL) was dropped into the mixture for 5 minutes. The suspension refluxed at 80 ° C for 18 hours; it was then cooled to room temperature and a saturated aqueous solution of NaHCO 3 was added and the aqueous phase was extracted with AcOEt. The organic extracts were collected, dried and evaporated in vacuo to give a crude product, which was purified by biotage flash chromatography, eluting with CH: AcOEt = 98: 2 to give the title compound (200 mg) as a solid pale brown. NMR (d6-DMSO): d (ppm) 8.66 (s, 1 H); 8.32 (dd, 1H); 8.28 (d, 1 H); 8.01 (dd, 1 H); 7.84 (dt, 1 H).

INTERMEDIARY 16 4-Bromo-6-fluoro-2-naphthalenecarbonitrile A solution of Intermediate 13 (3.2 g), TBTU (4.58 g) and DIPEA (3.19 mL) in anhydrous DMF (50 ml) was stirred at room temperature for 1 hour under a nitrogen atmosphere. 1, 1, 1,3,3,3-Hexamethyldisilazane (5.02 mL) was added and the mixture was stirred at room temperature overnight. The mixture was washed with a 5% aqueous solution of NaHC 3, with an aqueous solution of 2M HCl, and then the organic layer was dried, concentrated in vacuo to obtain an intermediate compound (3.15 g), which was dissolved in thionyl chloride (45 mL) and refluxed for 2 hours under a nitrogen atmosphere. TO Then, the solvent was removed in vacuo to obtain the title compound as a pale brown solid (1.66 g). NMR (CDCl 3): d (ppm) 8.18 (s, 1 H); 7.94 (d, 1H); 7.93 (s, 1H); 7.91 (d, 1 H); 7.43 (td, 1 H).

INTERMEDIARY 17 4-Etenyl-7-fluoro-2-naphthalenecarbonitrile A solution of intermediate 15 (25 mg), TETRACIS (triphenylphosphine) palladium (0) (5 mg), tributyl (ethenyl) stannane (32 μL) and a crystal of dry hydroquinone in toluene (1 mL), was heated to 110 ° C for 4 hours. The mixture was then cooled to room temperature and a saturated aqueous solution of NaHCO 3 and AcOEt was added; The organic phase was separated, washed with a 10% aqueous KF solution, dried and evaporated in vacuo to give the crude product. It was then purified by flash chromatography eluting with CH: AcOEt = 9: 1, to provide the title compound (14 mg) as a yellow solid. NMR (d6-DMSO): d (ppm) 8.51 (s, 1 H); 8.40 (dd, 1 H); 7.98 (d, 1 HOUR); 7.92 (dd, 1H); 7.70 (td, 1H); 7.57 (dd, 3H); 6.07 (d, 1H); 5.65 (d, 1H).

INTERMEDIARY 18 4-Etenil-6-fluoro-2-naphtha! Encarbon8trilo A solution of intermediate 16 (1.66 g), TETRACIS (triphenylphosphine) palladium (0) (485 mg), tributyl (ethenl) stannane (2.34 mL) and a crystal of dry hydroquinone in toluene (50 mL) was heated to 110 ° C for 4 hours. The mixture was then cooled to room temperature and a saturated aqueous solution of NaHCO 3 and AcOEt was added; The organic phase was separated, washed with a 10% aqueous KF solution, dried and evaporated in vacuo to give the crude product. It was then purified by flash chromatography eluting with CH: AcOEt = 95: 5 to 9: 1, to give the title compound (1.21 g) as a yellow solid. T. I. c: CH / AcOEt 95: 5, Rf = 0.39. NMR (CDCl 3): d (ppm) 8.13 (s, 1H); 7.91 (dd, 1H); 7.72 (dd, 1H); 7. 71 (s, 1 H); 7.38 (td, 1 H); 7.25 (dd, 1 H); 5.83 (d, 1H); 5.61 (d, 1 H).

INTERMEDIARY 19 7-Fiuoro-4-formyl-2-naphthalenecarbonitrile Intermediate 17 (14 mg) was dissolved in THF (1.5 mL) and water (0.3 mL); aqueous solution of 4% osmium tetraoxide (22 μL) and sodium periodate (30 mg) was added, and the solution was stirred vigorously at room temperature and a nitrogen atmosphere for 4 hours. Then a 5% solution of sodium metabisulfite in a saturated aqueous solution of NaHCOs was added; The organic phase was extracted with AcOEt, dried and evaporated in vacuo to give the title compound (14 mg) as a pale yellow solid. NMR (d6-DMSO): d (ppm) 10.38 (s, 1 H); 9.23 (dd, 1 H); 8.90 (s, 1 H); 8.50 (s, 1 H); 8.03 (dd, 1 H); 7.87 (td, 1 H).

INTERMEDIARY 20 6-Fluoro-4-formyl-2-naphthalenecarbonyltrio Intermediate 18 (100 mg) was dissolved in THF (3 mL) and water (1 mL); 4% osmium tetraoxide aqueous solution (310 μL) and sodium periodate (217 mg) were added, and the solution was stirred vigorously at room temperature and under a nitrogen atmosphere for 4 hours. Then a 5% solution of sodium metabisulfite in a saturated aqueous solution of NaHCO3 was added; The organic phase was extracted with AcOEt, dried and evaporated in vacuo to give the title compound (99 mg) as a pale yellow solid. NMR (CDCIs): d (ppm) 10.31 (s, 1 H); 9.00 (dd, 1 H); 8.44 (s, 1 H); 8. 14 (s, 1 H); 8.01 (dd, 1 H); 7.50 (td, 1 H).

INTERMEDIARY 21 4- (Bromomethyl) -7-fluoro-2-naphthalenecarbonitrile Intermediate 19 (540 mg) was dissolved in MeOH (30 mL) under a nitrogen atmosphere, the solution was cooled to 0 ° C and NaBH4 (102 mg) was added in portions. After 1 hour, a saturated aqueous solution of NH 4 Cl was added and the solution was stirred for 1/2 hour. Then AcOEt was added and the organic phase was separated, dried and concentrated in vacuo to give a crude product, which was purified by flash chromatography with CH: AcOEt = 9: 1 to provide an intermediate compound. { MS (ES / +): m / z = 202 [M + H] +} (383 mg) as a white solid. A portion of this compound (200 mg) was suspended in DCE (10 mL) at room temperature and under a nitrogen atmosphere; then triphenylphosphine (524 mg) and carbon tetrabromide (498 mg) were added, and the solution was stirred under these conditions for 2 hours. Water was added and the aqueous phase was extracted with DCM. The organic extracts were dried and evaporated in vacuo to give a crude product, which was purified by flash chromatography eluting with CH: AcOEt = 99: 1 to 9: 1, to give the title compound (130 mg) as a solid White. NMR (CDCl 3): d (ppm) 8.2 (dd, 1 H); 8.15 (s, 1 H); 7.63 (s, 1 H); 7.56 (dd, 1 H); 7.53 (td, 1 H); 4.86 (s, 2H).

INTERMEDIARY 22 4- (Bromomethyl) -6-fluoro-2-naphthalenecarbonitrile Intermediate 20 (8300 mg) was dissolved in MeOH (50 mL) under a nitrogen atmosphere, the solution was cooled to 0 ° C and NaBH4 (158 mg) was added in portions. After 1 hour, a saturated aqueous solution of NH 4 Cl was added and the solution was stirred for 1/2 hour. Then AcOEt was added and the organic phase was separated, dried and concentrated in vacuo to give a crude product, which was purified by flash chromatography with CH: AcOEt = 9: 1 to provide an intermediate compound. { MS (ES / +): m / z = 202 [M + H] +} (383 mg) as a white solid. A portion of this compound (180 mg) was suspended in DCE at room temperature and under a nitrogen atmosphere; then triphenylphosphine (473 mg) and carbon tetrabromide (450 mg) were added, and the solution was stirred under these conditions for 2 hours. Water was added and the aqueous phase was extracted with DCM. The organic extracts were dried and evaporated in vacuo to provide a crude product, which was purified by flash chromatography eluting with CH: AcOEt = 99: 1 to 9: 1 to give the title compound (124 mg) as a white solid . NMR (CDCl 3): d (ppm) 8.2 (s, 1 H); 7.96 (dd, 1 H); 7.78 (dd, 1H); 7.7 (s, 1 H); 7.43 (td, 1H); 4.83 (s, 2H).

INTERMEDIARY 23 4- (1-Cyano-1-ethoxycarbonyl-methylene-piperidin-1-carboxylic acid) -butyl ester Ethyl cyanoacetate (13.9 mL), ammonium acetate was added (4.64 g) and acetic acid (6.9 mL), under an atmosphere of nitrogen, to a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (20 g) in anhydrous toluene (200 mL) in a bottom flask round with a Dean Stark device. The mixture was heated at 110 ° C for 2 hours, then at 85 ° C overnight and finally at 130 ° C for 4 hours. The mixture was allowed to cool to room temperature and was washed with a 1M aqueous sodium hydroxide solution, water and brine. The organic layer was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 8: 2) to give the title compound (15.54 g) as a yellow oil. T. I. c: CH / AcOEt 8: 2, Rf = 0.35 (detection with ninhydrin). IR (nujol, cm "1): 2229 (C = N), 1720 and 1694 (C = 0). NMR (CDCI3): d (ppm) 4.29 (c, 2H), 3.61 (t, 2H), 3.55 ( t, 2H), 3.13 (t, 2H), 2.78 (t, 2H), 1.49 (s, 9H), 1.36 (t, 3H), MS (ES / +): m / z = 295 [M + H] +.

INTERMEDIARY 24 4- (1-Cyano-1-ethoxycarbonyl-methyl) -4- (4-fluorophenyl) -piperidine-1-carboxylic acid tert-butyl ester A solution of 4-fluorophenyl magnesium bromide (1.0 M in THF, 49 mL), was added dropwise to a mixture of intermediate 23 (8 g) and copper iodide (1.57 g) in anhydrous THF (65 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The mixture was stirred under these conditions for 1 hour and then allowed to warm to room temperature and stirred at 23 ° C for 2 hours. The mixture was cooled to 0 ° C, treated with a 3M hydrochloric acid solution until pH = 5, and extracted with AcOEt (3 x 100 mL). The combined organic extracts were washed with a saturated aqueous solution of ammonium chloride (200 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt 85:15) to give the title compound (9.8 g) as a yellow oil. T. I. c: CH / AcOEt 6: 4, Rf = 0.35 (detection with ninhydrin). NMR (CDCIg): d (ppm) 7.31 (dd, 2H); 7.06 (t, 2H); 3.95 (c, 2H); 3.87 (broad s, 2H); 3.54 (t, 1 H); 2.85 (broad t, 2H); 2.53 (dt, 2H); 1.9 (m, 2H); 1.4 (s, 9H); 1.02 (t, 3H). MS (ES / +): m / z = 391 [M + H] +.

INTERMEDIARY 25 4-Carboxymethyl- (4-fluoro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester A mixture of intermediate 24 (0.448 g) in acetic acid (2 mL), concentrated sulfuric acid (1 mL) and water (1 mL) was heated at 140 ° C overnight. The solution was allowed to cool to room temperature and was dripped into an aqueous 2.5M sodium hydroxide solution (50 mL). Next, di-tert-butyl bicarbonate (500 mg) was added and the resulting mixture was stirred at room temperature for 5 hours. It was cooled to 0 ° C and treated with an aqueous solution of 6N hydrochloric acid until pH = 3-4 and then extracted with AcOEt (20 mL). The organic phase was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt 7: 3) to give the title compound (210 mg) as a pale yellow foam. T. I. c: CH / AcOEt 1: 1, Rf = 0.25 (detection with ninhydrin). NMR (de-DMSO): d (ppm) 11.78 (broad s, 1 H); 7.4 (dd, 2H); 7.15 (t, 2H); 3.45 (m, 2H); 3.11 (m, 2H); 2.54 (s, 2H); 2.04 (m, 2H); 1.89 (m, 2H); 1.37 (s, 9H). MS (ES / -): m / z = 336 [M-H] ".

INTERMEDIARY 26 4- (4-Fluorophenip-4-2- (methyloxy) -2-oxoetin-1-piperidinecarboxylic acid 1,1-dimethylethyl ester To a solution of intermediate 25 (20 g) in dry DCM (250 mL) under a nitrogen atmosphere at room temperature, DIPEA (26 mL) and TBTU (20.9 g) were added. The mixture was stirred at room temperature for 40 minutes, then dry MeOH (10 mL) was added and the dark brown mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with DCM (200 mL) and washed with an aqueous solution of 5% sodium hydrogen carbonate (2 x 250 mL) and then with brine (250 mL); The organic phase was dried, concentrated in vacuo to provide the title compound (28.6 g) as a dark brown oil. T. I. c: CH / AcOEt 1: 1, Rf = 0.72 (detection with ninhydrin). MS (ES / +): m / z = 374 [M + Na] +.

INTERMEDIARY 27 4- (4-Fluorophenyl) -4-. { 1 - [(methyloxy) carbonn-3-buten-1-yl} -1- 1,1-dimethylethyl piperidinecarboxylate To a solution of the crude intermediate 26 (38.7 g) in dry THF (300 mL) at -60 ° C and under a nitrogen atmosphere, it was added dropwise lithium bis (trimethylsilyl) -amide (1 M solution in THF -120 mL). The resulting mixture was heated to -15 ° C and stirred at this temperature for 2 hours, then cooled again to -60 ° C for the addition of the allyl bromide (11 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was quenched at 5 ° C with water (25 ml), the THF was evaporated in vacuo and the oily residue was dissolved in Et20 (400 mL) and washed with a saturated aqueous solution of NH4CI (300 mL) and Then with brine (2 x 200 mL). The organic phase was dried, concentrated in vacuo and the dark brown residue (38.5 g) was purified by flash chromatography (Biotage Flash 75L, CH / AcOEt 9: 1). The title compound was obtained as a yellow oil (26 9) - T. I.c .: CH / AcOEt 8: 2, Rf = 0.39 (detection with ninhydrin). MS (ES / +): m / z = 414 [M + Na] + INTERMEDIARY 28 Acid 2-f1-. { f (1,1-Dimethylethyl) oxycarbonyl} -4- (4-fluorophenyl) -4-piperidinin-4- pentenoic Method A To a solution of intermediate 27 (38.7 g) in isopropanol (200 mL) was added an aqueous solution of lithium hydroxide (25 g in 200 mL). The resulting suspension was refluxed for 24 hours, added Additional lithium hydroxide (12.5 g in 100 mL of water) and the suspension was refluxed for an additional 48 hours. The isopropanol was evaporated in vacuo and the basic aqueous phase (pH = 14) was extracted with Et20 (2 x 300 mL). The aqueous phase was acidified at 0 ° C with an aqueous solution of 5N hydrochloric acid (230 mL) until pH = 4.5. The aqueous acid phase was then extracted with AcOEt (3 x 600 mL); The collected organic phases were dried and concentrated in vacuo to give the title compound (29 g) as a white solid. T. I. c: CH / AcOEt 8: 2, Rf = 0.06 (detection with ninhydrin). MS (ESI +): m / z = 400 [M + Na] +. MS (ES / -): m / z = 376 [M-Hj. " Method B Intermediate 64 (0.76 g) was taken with dry THF (4 ml) under N2. The solution was cooled to -20 ° C and a THF solution of lithium bis (trimethylsilyl) amide (2.41 ml) was added dropwise over 10 minutes, maintaining the temperature between -20 ° C and -15 ° C. The reaction was stirred for 15 minutes between -20 ° C and -15 ° C and Pd (PPh3) (0.23 g) was added in one portion.The reaction was allowed to reach room temperature and checked by HPLC. with 3 ml of ethyl ether, then 5 ml of a potassium carbonate solution was added. collected and concentrated to a foam to provide the title compound (0.624 g). NMR (DMSO): d (ppm) 12.1 (broad, 1 H), 7.40 (dd, 2H), 7.16 (t, 2H), 5.55 (m, 1 H), 4.90 (m, 2H), 3.78 (broad m , 2H), 2.8-2.4 (broad m, 2H), 2.42 (m, 2H), 2.24 (d, 1 H), 2.05 (m, 1 H), 1.91 (m, 2H), 1.63 (m, 1 H ), 1.35 (s, 9H).

INTERMEDIARY 29 4- [1 ( { F (3,5-dichlorophenyl) methyl-amino} -carbonyl) -3-buten-1-ip-4- (4-fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl To a solution of intermediate 28 (29 g) in dry DMF (280 mL), DIPEA (33 mL) and TBTU (27.1 g) were added, the solution turned dark and after 45 minutes of stirring at room temperature, he added 3,5-dichlorobenzylamine (14.2 g); the reaction mixture turned orange; it was stirred for 1 hour at room temperature under a nitrogen atmosphere, then diluted with AcOEt (800 mL) and washed with ice / water 1/1 (4 x 400 mL). The organic phase was dried and concentrated in vacuo to give the crude title compound (38.8 g) as a pale orange foam. This material was purified by flash chromatography (Biotage Flash 75L, CH / AcOEt 85:15) to obtain the title compound (38.6 g) as a white foam. T. I. c: CH / AcOEt 7: 3, Rf = 0.45 (detection with ninhydrin).

MS (ES / +): m / z = 557 [M + Na] +.

INTERMEDIARY 30 4-ri- (ri- (3,5-dichlorophenyl) etinamino carbonip-3-buten-1-in-4 (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Chain Enantiomer 1) DIPEA (0.7 mL) and TBTU (0.835 g) were added to a solution of intermediate 28 (0.77 g) in anhydrous DMF (12 mL) under a nitrogen atmosphere. After stirring for 45 minutes, intermediate 2 (0.44 g) was added. The mixture was stirred at room temperature for 14 hours, then diluted with AcOEt and washed with cold water. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3) to give the title compound (0.955 g) as a colorless oil. T. I. c: CH / AcOEt 8: 2, Rf = 0.35 (detection with ninhydrin). MS (ES / +): m / z = 571 [M + Na] +. Following the same procedure described for intermediary 30, intermediates 31 and 32 were obtained.

INTERMEDIARY 31 4-ri- (ip- (3,5-dichlorophenyl) etipamino > carbonyl) -3-buten-1-ip-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer of Chain 2) Beginning from Intermediary 28 (0.77 g) and using intermediary 3, 0.9 g of the title compound was obtained. T. I. c: CH / AcOEt 8: 2, Rf = 0.33 (detection with ninhydrin). MS (ES / +): m / z = 571 [M + Na] +.

INTERMEDIARY 32 4-p - ( {K1 R) -1 - (3-chloro-1 -naphthalenyl) etipamino > carbonyl) -3-buten-1-H-4- (4- fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl Beginning from intermediate 28 (313 mg) and using intermediate 5, 320 mg of the title compound was obtained. T. I. c: CH / AcOEt 7: 3, Rf = 0.45 (detection with ninhydrin). MS (ES / +): m / z = 587 [M + Na] +.

INTERMEDIARY 33 4-ri- ( { R (1S) -1- (3-chloro-1-naphthalenyl) ethylamino carbonyl) -3-buten-1-in-4- (4-fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl To a solution of intermediate 28 (320 mg) in dry DMF (6 mL), DIPEA (0.296 mL) and TBTU (354 mg) were added, the solution turned dark and after 1 hour of stirring at room temperature, dissolved intermediate 6 (0.192 mg) in DMF (1 mL); The reaction mixture was stirred for 4 hours at room temperature under a nitrogen atmosphere, then diluted with AcOEt (10 mL) and washed with ice / water 1/1. The organic phase was dried and concentrated in vacuo to provide the crude title compound, which was purified by flash chromatography (elution with CH / AcOEt 95: 5 to 8: 2) to obtain the title compound (0.451 g) as a white foam. T. I. c: CH / AcOEt 7: 3, Rf = 0.4 (detection with ninhydrin). MS (ES / +): m / z = 587 [M + Na] +.

INTERMEDIARY 34 4-f 1 - (H? 3-chloro-1 -naphthalenyl) metir | amino} carbonyl) -3-buten-1-j |] -4- (4- fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl To a solution of intermediate 28 (400 mg) in dry DMF (4 mL), DIPEA (0.46 mL) and TBTU (374 mg) were added, after 20 minutes of stirring at room temperature, 3-chloronaphthylamine (213 mg) was added; The reaction mixture was stirred for 14 hours at room temperature under a nitrogen atmosphere, then diluted with AcOEt (25 mL) and washed with ice / brine (3 x 30 mL). The organic phase was dried and concentrated in vacuo to provide the crude title compound, which was purified by flash chromatography (elution with CH to CH / AcOEt 8: 2), to obtain the title compound (500 mg) as a solid. White. T. I. c: CH / AcOEt 7: 3, Rf = 0.34 (detection with ninhydrin). MS (ES / +): m / z = 573 [M + Na] +.

INTERMEDIARY 35 4-ri- (rt (3-cyano-1-naphthalenyl) methylamino> carbopy-3-buten-1-in-4- (4- fluoropheniP-1-piperidinecarboxylate 1,1-dimethylethyl) To a solution of Intermediary 28 (269 mg) in dry DMF (3 mL), DIPEA (0.30 mL) and TBTU (230 mg) were added, after 20 minutes of stirring at room temperature, 3-cyano-naphthylamine was added (130 mg); The reaction mixture was stirred for 14 hours at room temperature under a nitrogen atmosphere, then diluted with AcOEt (25 mL) and washed with ice / brine (3 x 30 mL). The organic phase was dried and concentrated in vacuo to provide the crude title compound, which was purified by flash chromatography (elution with CH to CH / AcOEt 1: 1) to obtain the title compound (165 mg) as a white solid. T. I. c: CH / AcOEt 7: 3, Rf = 0.27 (detection with ninhydrin). MS (ES / +): m / z = 564 [M + Naf.

INTERMEDIARY 36 4- (4-Fluorophenyl) -4-. { 1-f (methyloxy) carbonin-3-oxopropyl} -1- 1,1-dimethylethyl piperidinecarboxylate To a suspension of intermediate 27 (2 g) in THF (9 mL) and water (3 mL) was added a solution of 4% by weight osmium tetraoxide in water (0.3 mL). The mixture was stirred at room temperature for 15 minutes, during which it became dark, then Nal04 (2.18 g) was added and the brown reaction mixture was stirred at room temperature for 2 hours. After this time, it was diluted with water and extracted with AcOEt. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt from 8: 2 to 1: 9). MS (ES / +): m / z = 416 [M + Naj +.

INTERMEDIARY 37 4-f1-r (3,5-dichlorophenyl) metin-2-oxo-3-pyrrolidinyl -4- (4-fluorophenyl) -1- piperidinecarboxylate 1,1-dimethylethyl 3,5-Dichlorobenzylamine (117 mg) was added to a solution of intermediate 36 (180 mg) in dry dichloroethane (5 mL) under a nitrogen atmosphere. After stirring for 1 hour at room temperature, NaBH (OAc) 3 (169 mg) was added, and the resulting mixture was stirred at room temperature overnight. It was then diluted with DCM, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried and concentrated in vacuo to give a crude oil, which was purified by flash chromatography (Biotage Flash 25M, CH / AcOEt 4: 1). The two fractions corresponding to the products with Rf = 0.36 and Rf = 0.50 (CH / AcOEt 1: 1, detection with ninhydrin), were collected to provide, after evaporation, an oil (40 mg), which was dissolved in Then, under a nitrogen atmosphere, in dry MeOH (5 mL) and to which sodium methoxide (4.5 mg) was added. The mixture was refluxed for 5 hours, then allowed to cool to room temperature and the solvent removed in vacuo. The residue was dissolved in AcOEt, washed with a saturated aqueous sodium hydrogen carbonate solution, dried and concentrated in vacuo. The crude product thus obtained was purified by flash chromatography (CH / AcOEt 9: 1), to give the title compound (35 mg) as a colorless oil.

T. I. c: CH / AcOEt 1: 1, Rf = 0.5 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.31 (dd, 2H); 7.2 (t, 1 H); 6.98 (t, 2H); 6. 83 (d, 2H); 4.25 (d, 1 H); 4.04 (d, 1 H); 3.76 (broad, 2H); 3.01 (td, 1 H); 2.88 (m, 1 H); 2.82 (broad m, 1 H); 2.63 (dd, 1 H); 2.41 (broad, 1 H); 2.18 (broad d, 1 H); 2.05-2.15 (m, 2H); 1.94 (broad, 1 H); 1.81 (broad, 1 H); 1.69 (m, 1 H); 1.4 (s, 9H). MS (ES / +): m / z = 543 [M + Na] +.

INTERMEDIARY 38 4-. { 3- (r (1 S) -1 - (3-chloro-1 -naphthalenyl) -aceipamino) -1-f (methyloxy) carbonypropyl} - 1,1-dimethyl-4- (4-fluorophenyl) -1-piperidinecarboxylate To a solution of intermediate 36 (45 mg) in dry CH3CN (7 mL), intermediate 6 (23.5 mg) was added, the resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) was added. 3 in portions (35 mg) (observed exothermic reaction). The reaction mixture was stirred at room temperature for 1 hour, then the CH3CN was evaporated in vacuo and the residue was dissolved in DCM (100 mL) and washed with water (80 L) and then with brine (2 x 100 mL). ). The organic phase was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 8: 2) to give the title compound (745 mg) as a white solid. HPLC (LC / MS -ES / +): tR = 4.9 minutes MS (ES / +): m / z = 583 [M + H] +.

INTERMEDIARY 39 4-. { 3-. { f1- (3,5-dichlorophenyl) etipamino > -1-f (methyloxy) carbonn-propyl} 1,1- Dimethylethyl 4- (4- fluorophenyl) -1-piperidinecarboxylate (Chain Enantiomer 1) To a solution of intermediate 36 (300 mg) in dry CH3CN (8 mL), intermediate 2 (144.3 mg) was added, the resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) was added. 3 in portions (241.7 mg) (observed exothermic reaction). The reaction mixture was stirred at room temperature for 1 hour, then the CH3CN was evaporated in vacuo and the residue was dissolved in DCM (100 mL) and washed with water (80 mL) and then with brine (2 x 100 mL). ). The organic phase was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 8: 2 to 1: 1), to give the title compound (351 mg) as a white foam. T. I. c: CH / AcOEt 1: 1, Rf = 0.48 (detection with ninhydrin) MS (ES / +): m / z = 567 [M + Hf.

INTERMEDIARY 40 4-. { 3-. { f1- (3,5-dichlorophenyl) ethylamino} -1-} '(methyloxy) carboninpropyl} -4- (4- fluoropheniD-1-piperidinecarboxylate 1,1-dimethylethyl ester (Chain Enantiomer 2) To a solution of intermediate 36 (300 mg) in dry CH3CN (8 mL), intermediate 3 (144.3 mg) was added, the resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) was added. 3 in portions (241.7 mg) (observed exothermic reaction). The reaction mixture was stirred at room temperature for 1 hour, then the CH3CN was evaporated in vacuo and the residue was dissolved in DCM (100 mL) and washed with water (80 mL) and then with brine (2 x 100 mL). ). The organic phase was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH / AcOEt from 8: 2 to 1: 1) to give the title compound (390 mg) as a white foam. T. I. c: CH / AcOEt 1: 1, Rf = 0.48 (detection with ninhydrin) MS (ES / +): m / z = 567 [M + H] +.

INTERMEDIARY 41 4- (4- fluorophenyl) -4-p- (methyloxy) carbonin-3-ffl1R) -1-r4- (methyloxy) phenylethyl amino) propin-1-piperidinecarboxylate 1,1-dimethylethyl To a solution of intermediate 36 (318 mg) in dry CH3CN (10 mL), (R) -1- (4-Methoxyphenyl) ethyl-amine (122 mg) was added, the resulting mixture was stirred at room temperature for 15 minutes. minutes, then NaBH (OAc) 3 was added in portions (257.6 mg) (observed exothermic reaction). The reaction mixture was stirred at room temperature for 1 hour, then the CH3CN was evaporated in vacuo and the residue was dissolved in DCM (150 mL) and washed with water (100 mL) and then with brine (2 x 100 mL). ). The organic phase was dried, concentrated in vacuo to give the title compound (461 mg) as a foam. MS (ES / +): m / z = 529 [M + H] +.

INTERMEDIARY 42 AND INTERMEDIARY 43 4 ^ 1-r 1S) -1- (1,1-dimethylethyl-3-chloro-1-naphthaleninetin-2-oxo-3-pyrrolidinyl-4-f4-fluorophenyl) -1-piperidinecarboxylate (Diastereoisomer 1), 4- (1-r (1S) -1- (3-chloro-1-naphthalenyl) etn-2-oxo-3-pyrrolidinyl-4- (4-fluorophenyl) - 1- 1,1-dimethylethyl piperidinecarboxylate (Diastereoisomer 2) A mixture of intermediate 38 (48 mg) and NaOMe (6.68 mg) in dry MeOH (5 mL) was processed by microwave irradiation at 150 ° C. (2 cycles of 12 minutes, one cycle of 15 minutes and 2 cycles of 30 minutes). The MeOH was then evaporated in vacuo and the residue was dissolved in AcOEt (100 mL) and washed with water (80 mL). The organic phase was dried and concentrated in vacuo to provide an oil. This material was dissolved in dry DCM (6 mL) and then di-tert-butyl bicarbonate (18.6 mg) was added to this mixture. After stirring for 1 hour at room temperature, the DCM was evaporated in vacuo. The crude product was purified by flash chromatography (CH / AcOEt from 9: 1 to 8: 2) to provide Intermediate 42 (21 mg) and intermediate 43 (19 mg).

INTERMEDIARY 42 T. I. c: CH / AcOEt 7: 3, Rf = 0.29 (detection with ninhydrin). HPLC (LC / MS -ES / +) tR = 6.9 minutes MS (ES / +): m / z = 495 [M-tButj +.

INTERMEDIARY 43 T. I. c: CH / AcOEt 7: 3, Rf = 0.21 (detection with ninhydrin). HPLC (LC / MS -ES / +) tR = 6.8 minutes MS (ES / +): m / z = 495 [M-tBut] +.

INTERMEDIARY 44 AND INTERMEDIARY 45 4- 1-ri- (3,5-dichlorophenyl) -etin-2-oxo-3-pyrrolidinyl -4- (4-fluorophenyl) -1- piperidinecarboxylate 1,1-dimethyl (Diastereomer 1, Enantiomer of Chain 1), 4-f1-ri- (3,5-dichlorophenyl) -etin-2-oxo-3-pyrrolidinyl-4- (4-fluorophenyl) -1- piperidinecarboxylate 1,1-dimethyl (Diastereomer 2 Chain Enantiomer 1) A mixture of intermediate 39 (351 mg) and NaOMe (67 mg) in dry MeOH (4 mL) was processed by microwave irradiation at 150 ° C. (3 cycles of 30 minutes and a cycle of 20 minutes). The MeOH was then evaporated in vacuo and the residue was dissolved in AcOEt (100 mL), and washed with water (80 mL). The organic phase was dried and concentrated in vacuo to provide an oil. This material was dissolved in dry DCM (6 mL) and then di-tert-butyl bicarbonate (135.2 mg) and TEA (0.13 mL) were added to this mixture. After stirring for 1 hour at room temperature, the DCM was evaporated in vacuo. The crude product was purified by flash chromatography (CH / AcOEt from 9: 1 to 1: 1) to provide intermediate 44 (125 mg). { the first spot to be elulda that has an MS (ES / +): m / z = 535 [M + H] +} and intermediate 45 (165 mg). { the second spot to be eluted that has an MS (ES / +): m / z = 535 [M + H] +} .

INTERMEDIARY 46 AND INTERMEDIARY 47 4- (1-ri- (3,5-dichlorophenyl) -etin-2-oxo-3-pyrrolidinyl-4- (4-fluorophenyl) -1- piperidinecarboxylic acid 1,1-dimethylethyl ester (diastereoisomer 1, Chain Enantiomer 2), 4-1-ri- (3,5-dichlorophenyl) -etin-2-oxo-3-pyrrolidinyl> -4- (4-fluorophenyl) -1- piperidinecarboxylic acid 1,1-dimethylethyl ester (Diastereoisomer 2, Chain Enantiomer 2) A mixture of intermediate 40 (390 mg) and NaOMe (74.4 mg) in dry MeOH (4 mL) was processed by microwave irradiation to 150 ° C (3 cycles of 30 minutes and one cycle of 20 minutes). Next, the MeOH was evaporated in vacuo and the residue was dissolved in AcOEt (100 mL) and washed with water (80 mL). The organic phase was dried and concentrated in vacuo to provide an oil. This material was dissolved in dry DCM (6 mL) and then di-tert-butyl bicarbonate (150.4 mg) and TEA (0.14 mL) were added to this mixture. After stirring for 1 hour at room temperature, the DCM was evaporated in vacuo The crude product was purified by flash chromatography (CH / AcOEt from 9: 1 to 1: 1) to provide intermediate 46 (125 mg). the first spot to be eluted that has an MS (ES / +): m / z = 535 [M + H] +.}. and the intermediate 47 (165 mg). {the second spot to be eluted that has an MS (ES / +): m / z = 535 [M + H] +.}.

INTERMEDIARY 48 AND INTERMEDIARY 49 4- (4-Fluorophenyl) -4- (1 - ((1R) -1-r4- (methyloxy) phenylethyl-2-oxo-3-pyrrolidinyl) -1- piperidinecarboxylate 1.1 -dimethylethyl (diastereoisomer 1), 4- (4-fluorophenyl) -4- (1 - ((1R) -1-r4- (methyloxy) phenylethyl < -2-oxo-3-pyrrolidinin-1-piperidinecarboxylate of 1,1-dimethylethyl (Diastereomer 2) To a solution of intermediate 41 (740 mg) in dry toluene (10 mL), pyridine (1.13 mL) was added, the mixture was heated to 130 ° C and stirred at this temperature During the weekend, the toluene was evaporated in vacuo and the residue was dissolved in AcOEt (150 mL) and washed with water (100 mL), the organic phase was dried, concentrated in vacuo to give an oil The crude product was purified by flash chromatography (CH / AcOEt from 9: 1 to 8: 2) to provide intermediate 48 (201.5 mg) and intermediate 49 (218.5 mg).

INTERMEDIARY 48 HPLC (LC / MS -ES / +) tR = 6.3 minutes MS (ES / +): m / z = 442 [M-tButf.

INTERMEDIARY 49 HPLC (LC / MS -ES / +) tR = 6.6 minutes MS (ES / +): m / z = 442 [M-tBut] +.

INTERMEDIARY 50 4- (1-R (3,5-Dichlorophenyl) metin-5-hydroxy-2-oxo-3-pyrrolidinyl> 4- (4-fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl To a suspension of intermediate 29 (0.72 g) in THF (37.5 mL) and water (12.5 mL), a solution of 4% by weight osmium tetraoxide in water (0.8 mL) was added. The mixture was stirred for 20 minutes, during which it turned dark, then Nal04 (1.15 g) was added in portions in 10 minutes, and the brown reaction mixture was stirred at room temperature for 12 hours, thus becoming a suspension. Milky The reaction mixture was diluted with AcOEt (250 mL) and washed with water (4 x 50 mL) and then with brine (40 mL). The organic phase was dried and concentrated in vacuo to give a brown-gray foam (0.635 g). This material was purified by flash chromatography (Biotage Flash 40S, CH / AcOEt 6: 4 to 1: 1) to provide the title compound (0. 335 g) as a white foam. T. I. c: CH / AcOEt 1: 1, Rf = 0.33 (detection with ninhydrine) NMR (CDCl 3): d (ppm) 7.32 (dd, 2H); 7.21 (s, 1 H); 6.98 (t, 2H); 6.78 (s, 2H); 4.61 (d, 1 H); 4.45 (broad t, 1 H); 3.91 (d, 1H); 3.85-3.68 (broad m, 2H); 3.05 (t, 1 H); 2.95-2.78 (broad m, 2H); 2.25-2.15 (m, 3H); 2.11-1.60 (m, 3H); 1.39 (s, 9H). MS (ES / +): m / z = 559 [M + Naf.

INTERMEDIARY 51 4-RI-1 R (3,5-Dichlorophenyl) methylamino > carbonyl) -3-oxopropin-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Chain Enantiomer 1) To a suspension of intermediate 30 (0.07 g) in THF (2 mL) and water (0.5 mL), a suspension of 4% by weight osmium tetraoxide in water (3.2 mL) was added. The mixture was stirred at room temperature for 1 hour, during which it became dark, then Nal0 (0.082 g) was added in portions and the brown reaction mixture was stirred at room temperature for 1 hour. After this time, it was diluted with water and extracted with AcOEt. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3) to give the title compound as a yellow oil (0.047 g). T. I. c: CH / AcOEt 6: 4, Rf = 0.37 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 9.70 (s, 1 H); 7.24 (s, 2H); 7.13 (dd, 2H); 6. 96 (s, 1 H); 6.93 (t, 2H); 5.40 (broad c, 1 H); 3.96-3.82 (m, 2H); 3.02 (dd, 1 H); 2.71-2.35 (m, 4H); 2.11-1.85 (m, 2H); 1.74-1.57 (m, 2H); 1.39 (s, 9H); 1.33 (d, 3H). MS (ES / +): m / z = 573 [M + Na] +.

INTERMEDIARY 52 4-Ri - ((rt1S) -1- (3-Chloro-1-naphthalenyl-amino) -carbonyl) -3-oxopropin-4- (4-fluorophenyl) -1-p8peridinecarboxylate 1,1-dimethylethyl To a suspension of intermediate 33 (0.45 g) in THF (4 mL) and water (1 mL) was added a solution of 4% by weight osmium tetraoxide in water (0.05 mL). The mixture was stirred at room temperature for 40 minutes, during which it turned dark, then Nal04 (0.35 g) was added portionwise and the brown reaction mixture was stirred at room temperature for 1.15 hours. After this time, it was diluted with AcOEt and extracted with water. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 6: 4) to give the title compound as a yellow oil (0.128 g). MS (ES / +): m / z = 589 [M + Naf.

INTERMEDIARY 53 4-f1- ( { [(3-Chloro-1-naphthalenyl) methyl] [amino > carbonyl) -3-oxopropin-4- (4-fluorophenyl) -1-piperidinecarboxylate 1,1-dimethylethyl To a suspension of intermediate 34 (500 mg) in THF (3.75 mL) and water (1.25 mL), a solution of 4% by weight osmium tetraoxide in water (0.057 mL) was added. The mixture was stirred at room temperature for 15 minutes, during which it became dark, then Nal04 was added in portions (388 mg) and the brown reaction mixture was diluted with water (2.5 mL) and THF (2.5 mL), and stirred at room temperature for 1.5 hours. After this time, it was diluted with AcOEt (30 mL) and washed with water (30 mL), then with brine (30 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (elution of CH to CH / AcOEt 1: 1) to give the title compound as a white solid (210 mg). T. I. c: CH / AcOEt 6: 4, Rf = 0.16 (detection with ninhydrin). MS (ES / +): m / z = 575 [M + Na] +.

INTERMEDIARY 54 4-ri- ( { | - (3-cyano-1-naphthalenyl) methylamino}. Carbonyl) -3-oxopropyl-1-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester To a suspension of intermediate 35 (165 mg) in THF (3 mL) and water (1 mL) was added a solution of 4% by weight osmium tetraoxide in water (0.020 mL). The mixture was stirred at room temperature for 15 minutes, during which it turned dark, then Nal04 was added in portions (130 mg) and the brown reaction mixture was stirred at room temperature for 1.5 hours. After this time, it was diluted with AcOEt (30 mL) and washed with water (30 mL), then with brine (30 mL). The organic layer was dried and concentrated in vacuo. The residue is purified by flash chromatography (elution of CH / AcOEt 7: 3 to CH / AcOEt 1: 1) to give the title compound as a white solid (120 mg). T. I. c: CH / AcOEt 6: 4, Rf = 0.08 (detection with ninhydrin). MS (ES / +): m / z = 566 [M + Na] +.

INTERMEDIARY 55 4- (4-Fluorophenyl) -4- (2-oxo-3-pyrrolidinyl) -1-piperidinecarboxylate 1,1-dimethylethyl ester (Enantiomer 1) A suspension of intermediate 48 (30 mg), cerium (IV) ammonium nitrate (99.4 mg), silica gel (142 mg) and a 3: 1 mixture of CH3CN / water (1.2 mL) was stirred for 10 minutes under a nitrogen atmosphere at room temperature and then quenched with a saturated aqueous solution of sodium sulfite (1 mL) and a saturated aqueous solution of sodium carbonate (1 mL). The liquid was decanted from the insoluble cerium carbonate salts, and the aqueous phase was washed with DCM (3 x 5 mL). The combined organic extracts were dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 8: 2 to 0:10), to give the title compound (21 mg) as a white foam. HPLC (LC / MS -ES / +) tR = 5.7 minutes MS (ES / +): m / z = 307 [M-tBut] +.

INTERMEDIARY 56 4- (4-Fluorophenyl) -4- (2-oxo-3-pyrrolidinyl) -1-piperidinecarboxylate 1,1-dimethylethyl ester (Enantiomer 2) A suspension of intermediate 49 (192 mg), cerium (IV) ammonium nitrate (641.2 mg), silica gel (923 mg) and a 3: 1 mixture of CH3CN / water (8 mL) was stirred for 10 minutes under a nitrogen atmosphere at room temperature and then quenched with a saturated aqueous solution of sodium sulfite (2 mL) and a saturated aqueous solution of sodium carbonate (2 mL). The liquid was decanted from the insoluble cerium carbonate salts, and the aqueous phase was washed with DCM (3 x 10 mL). The combined organic extracts were dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 8: 2 to 1: 1) to give the title compound (105 mg) as a white foam. HPLC (LC / MS -ES / +): tR = 5.5 minutes MS (ES / +): m / z = 307 [M-tBut] +.

INTERMEDIARY 57 4-. { 1-F (3-Cyano-1-naphthalenyl) metip-2-oxo-3-pyrrolidinyl- (4-fluorophenyl) -1- piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer 1) NaH (12.6 mg) was added to a solution of intermediate 55 (57 mg) in dry DMF (3.0 mL) at 0 ° C under a nitrogen atmosphere. Mix The resultant was stirred at 0 ° C for 30 minutes; then intermediate 9 (43 mg) was added. The reaction mixture was stirred at 0 ° C for 35 minutes and then quenched with water and brine; the aqueous phase was washed with AcOEt (3 x mL). The combined organic extracts were dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 8: 2 to 6: 4) to give the title compound (41 mg) as a white foam. TI c: CH / AcOEt 1: 1, Rf = 0.39 (detection with ninhydrine) HPLC (LC / MS -ES / +) tR = 6.6 minutes MS (ES / +): m / z = 428 [M-BOC] + .

INTERMEDIARY 58 4-f 1 -K3-cyano-1-naphthalenyl) metSp-2-oxo-3-pyrrolidin-p-4- (4-f-lorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer 2) NaH (11.5 mg) was added to a solution of intermediate 56 (52 mg) in dry DMF (3.0 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 30 minutes; then intermediate 9 (39 mg) was added. The reaction mixture was stirred at 0 ° C for 35 minutes and then quenched with water and brine; the aqueous phase was washed with AcOEt (3 x 30 mL). The combined organic extracts were dried, concentrated in vacuo, and purified by flash chromatography.

(CH / AcOEt from 8: 2 to 6: 4), to provide the title compound (41 mg) as a white foam. T. I. c: CH / AcOEt 1: 1, Rf = 0.39 (detection with ninhydrin) MS (ES / +): m / z = 528 [M + H] +.

INTERMEDIARY 59 4-. { 1-f (3-cyano-6-fluoro-1-naphthalenyl) metip-2-oxo-3-pyrrolidinyl-1-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer 2) NaH (11 mg) was added to a solution of intermediate 22 (49 mg) in dry DMF (3.0 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 30 minutes; then intermediate 21 (39 mg) was added. The reaction mixture was heated at 40 ° C for 1/2 hour and then quenched with ice; the aqueous phase was washed with AcOEt (3 x 30 mL), the collected organic extracts were washed with brine and dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 9: 1 to 8: 2) to provide the title compound (28 mg) as a white foam. HPLC (LC / MS -ES / +) tR = 6.41 minutes MS (ES / +): m / z = 468 [M + Na] +.

INTERMEDIARY 60 4-f1-r (3-cyano-7-fluoro-1-naphthalenyl) methan-2-oxo-3-pyrrolidinin-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer 2 ) NaH (11 mg) was added to a solution of intermediate 56 (49 mg) in dry DMF (3.0 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 30 minutes; then intermediate 22 (39 mg) was added. The reaction mixture was heated at 40 ° C for 1/2 hour and then quenched with ice; the aqueous phase was washed with AcOEt (3 x 30 mL), the collected organic extracts were washed with brine and dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 9: 1 to 8: 2) to provide the title compound (19 mg) as a white foam. HPLC (LC / MS -ES / +) tR = 6.31 minutes MS (ES / +): m / z = 568 [M + Na] +.

INTERMEDIARY 61 4-f1-r (3-cyano-6-fluoro-1-naphthalenyl) metip-2-oxo-3-pyrrolidin-p-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester ( Enantiomer 1) NaH (9 mg) was added to a solution of intermediate 55 (41 mg) in dry DMF (5.0 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 30 minutes; then the intermediary 21 (30 mg). The reaction mixture was heated at 40 ° C for 2 hours and then quenched with ice; the aqueous phase was washed with AcOEt (3 x 30 mL), the collected organic extracts were washed with brine and dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3) to provide the title compound (52 mg) as a white foam. HPLC (LC / MS -ES / +) tR = 6.43 minutes MS (ES / +): m / z = 568 [M + Na] +.

INTERMEDIARY 62 4-. { 1-r (3-cyano-7-fluoro-1-naphthalenyl) methyl-1-oxo-3-pyrrolidinyl-4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (Enantiomer 1) NaH (9 mg) was added to a solution of intermediate 55 (41 mg) in dry DMF (5.0 mL) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 30 minutes; then intermediate 22 (30 mg) was added. The reaction mixture was heated at 40 ° C for 2 hours and then quenched with ice; the aqueous phase was washed with AcOEt (3 x 30 mL), the collected organic extracts were washed with brine and dried, concentrated in vacuo, and purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3) to give the title compound (21 mg) as a white foam. HPLC (LC / MS -ES / +) tR = 6.41 minutes MS (ES / +): m / z = 568 [M + Naf.

INTERMEDIARY 63 1'-r (3,5-Dichlorophenyl) metip-4- (4-fluorophenyl) -2-, 5? -espyror-azab.c8chlor2.2.nheptan-7,3'-pyrrolidin-2 ', '-diona Nal04 (29 g) was dissolved in water (200 mL). The mixture was allowed to stir overnight and was filtered the next morning. Intermediate 29 (29 g) was charged to the reactor, then THF (150 mL) and K2Os? 4 (261 mg) in water (43 mL) were added. The mixture was heated to 40 ° C (internal temperature), and the solution was stirred for 30 minutes. Then, the Nal04 solution was added dropwise in water for 5 hours. The reaction was cooled to room temperature. Then saturated aqueous Na2SO3 (100 mL) was added, and the solution was stirred under these conditions for 1 hour. Then AcOEt (300 mL) was added and the phases separated. The organic phase was concentrated to a volume of 130 mL, then 14 mL of a 5M HCl solution in AcOEt was added. The mixture was refluxed for 2 hours. It was then cooled to room temperature and 2.5M aqueous NaOH (348 mL) was added. The phases were separated, and the organic phase was concentrated in vacuo to provide a crude oil. The oil was then diluted with AcOEt (160 mL) and acetonitrile was added at 0 degrees. A solid was precipitated to provide 6 g of the title compound.

NMR (DMSO): d (ppm) 7.53 (broad s, 1 H), 7.26 (dd, 2H), 7.05 (d, 2H), 6.93 (t, 2H), 4.47 (d + d, 2H), 3.66 ( m, 1 H), 3.02 (m, 1 H), 2.98 (d, 1 H), 2.68 (d, 1H), 2.65 (m, 2H), 2.58 (m, 1 H), 2.36 (m, 1H) , 1.69 (m, 1H), 1.59 (m, 1H).

INTERMEDIARY 64 4- (4-fluorophenip-4-r2-oxo-2- (2-propene-1-yloxy) etin-1-piperidinecarboxylic acid 1,1-dimethylethyl ester To a solution of 1-piperidinecarboxylic acid, ester was added 4- (2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl) -4- (4-fluorophenyl) -1,1-dimethyl (0.288 g) in DMF (5 ml), allyl alcohol (0.15 ml) at room temperature. The reaction mixture was heated at 100-105 ° C for 16 hours. The reaction was cooled to room temperature and concentrated to provide the title compound as an oil (0.171 g). NMR (DMSO): d (ppm) -7.39 (dd, 2H), 7.12 (t, 2H), 5.65 (m, 1H), 5.06 (m, 2H), 4.28 (m, 2H), 3.49 (broad m, 2H), 3.12 (broad m, 2H), 2.67 (s, 2H), 2.07 (m, 2H), 1.88 (m, 2H), 1.38 (s, 9H).

INTERMEDIARY 65 N- (3,5-dichlorophenoxymethipglycinate hydrochloride salt To a solution of glycine ethyl ester hydrochloride (35.7 g) in acetonitrile (90 ml), in a 3-neck flask equipped with an air-operated mechanical stirrer, a thermometer and an addition funnel, was added , 5-dichlorobenzyl (5.0 g) and triethylamine (35.7 ml) at 20-25 ° C, maintaining good agitation. The reaction was then heated to reflux (82 ± 3 ° C) under stirring for 30-60 minutes. When the reaction was complete, after cooling to 20-25 ° C, the reaction mixture was filtered and the cake was rinsed with toluene. The filtrate and toluene rinses were combined and concentrated to 90 ml. This solution was washed with water and then cooled to approximately 5 ± 3 ° C in an ice-water bath. Then concentrated HCl (2.3 ml) was added dropwise for about 5 minutes at 5-10 ° C. The mixture was stirred at 5-10 ° C for about 30-90 minutes. The white precipitate was filtered, rinsed with toluene and tert-butyl methyl ether, and dried at 40-50 ° C under vacuum to obtain the title compound (6.62 g). 1 H NMR (DMSO-de): d (ppm) 10.17 (broad s, NH / NH 2 +); 7.71 (fine doublet, 2H); 7.68 (fine d, 1 H); 4.16-4.20 (m, 4H); 3.94 (broad s, 2H); 1.23 (t, 3H).

INTERMEDIARY 66 4-. { 2-M3,5-dichlorophenyl) metipr2- (ethyloxy) -2-oxoethamino > -1- r (methyloxy) carbonin-2-oxoethyl} -4- (4-fluorophenyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester Piperidinecarboxylic acid, 4- (2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl) -4- (4-fluorophenyl) -1,1-dimethyl ester (26.8 g) was added and Intermediate 65 (18.4 g) to dimethylformamide (148 ml) in a neck flask equipped with a mechanical air-operated stirrer, a thermometer and a condenser. The mixture was stirred at 20-25 ° C for about 15 minutes to obtain a well dispersed suspension and then heated at 55 ± 3 ° C for 15-30 minutes, and stirred at 55 ± 3 ° C for approximately 2- 3 hours. The reaction was cooled to 20 ± 5 ° C and then K2C03 (5.1 g) and Me2SO (11.7 g) were added under stirring at 20 ± 5 ° C. The reaction was then completed, the reaction mixture was filtered through celite and the celite was washed with tert-butyl methyl ether (TBME, 276 ml). The TBME was washed with 10% aqueous KHS04 (180 ml) and then with water (180 ml), and the TBME layer (containing 38.37 g of the title compound) was collected and concentrated to a minimum volume. Mass spectrometry (m + Na +) = 661.2.

INTERMEDIARY 67 Salt of 1-r (3,5-dichlorophenyl) metin-3-r4- (4-fluorophenopyr-4-piperidinyl-2,4-pyrrolidinedione hydrochloride A solution of intermediate 66 (85.46 g) in tert-butyl methyl ether (TBME, 310 ml) was concentrated to a minimum volume by stirring under reduced pressure at < 30 ° C and then ethanol (510 ml) was added. After further concentration at 475 mL, the mixture was cooled (0 ° C) and a solution of sodium ethoxide in ethanol (21% by weight in EtOH, 23 mL) was added for 10 minutes under nitrogen, while maintaining the temperature at 0-5 ° C. The mixture was stirred for an additional 10-20 minutes at 0-5 ° C. When the cyclization was complete, the mixture was acidified with 1 N HCl (160 ml) to a pH of 1-3 while keeping the temperature below 25 ° C. The mixture was then concentrated to ca. 250 mL at ca. 25-43 ° C under reduced pressure. After adding water (350 mL), the mixture was again concentrated to ca. 350 mL under reduced pressure. 350 ml of concentrated HCl were added keeping the temperature below 35 ° C. The mixture was heated to 58-63 ° C for about 30 minutes and stirred for an additional 30-45 minutes, and then refluxed for 30-45 minutes and stirred for 1-1.5 hours at 100-106 ° C. When the detoxification carbonylation was completed, the mixture was cooled to about 60 ° C for about 30 minutes and THF (80 ml) was added at 57-60 ° C until the mixture became a clear solution. After cooling to 51-53 ° C during about 15 minutes, the seeds of the title compound were added. The mixture was stirred at 51-53 ° C for approximately 50 minutes and then cooled to 20 ° C and stirred at 20 ° C overnight. The resulting suspension was filtered and the filter cake was washed with water (85 ml). After drying the wet cake under vacuum for 4-6 hours at about 50 ° C, the title compound (54 g) was obtained as a white off-white solid. 1 H NMR (DMSO-de): d (ppm) 11.62 (s, 1 H, enol form O-H); 8.86 (s, 2H, NH2); 7.47 (t, 1 H), 7.34 (m, 2 H); 7.15 (d, 2H), 7.11 (m, 2H); 4. 42 (s, 2H); 3.84 (s, 2H); 3.25 (m, 2H); 3.11 (m, 2H); 2.90 (m, 2H); 1.91 (m, 2H). MS (ES / +): m / z = 437, 435 [M + 1] +.

INTERMEDIARY 68 1-r (3,5-dichlorophenyl) metin-3-r4- (4-fluorophenyl) -4-piperidinin-4-hydroxy-2-pyrrolidinone Sodium borohydride (794 mg) was added to a stirred solution of intermediate 67 (3.30 g) in 50 mL of 2-propanol at room temperature. After 5 minutes at room temperature, the mixture was cooled to 5 ° C and then water (10 mL) was slowly added over a period of 10 minutes, while keeping the temperature below 20 ° C. The mixture was stirred for 15 hours at room temperature and then sodium borohydride (265 mg) was added. The mixture was stirred for 4.5 hours at room temperature. Sodium borohydride (133 mg) and water (10 mL) were added, and the mixture was stirred for 3 hours at room temperature. The mixture was acidified with 6N HCl to pH = 1 and stirred for 30 minutes. Ethyl acetate (50 mL) was added and the mixture basified with NaOH (25% by weight) at pH = 13. The organic layer was separated and then washed with 17 mL of brine. The organic layer was concentrated under reduced pressure to leave an oily solid. Ethyl acetate (50 mL) was added and the mixture was again concentrated under reduced pressure to provide 3.24 g of the title compound as a white off-white solid. 1 H NMR (DMSO-de): d (ppm) 7.48 (m, 3 H); 7.25 (d, 2 H); 7.07 (t, 2 H); 4.86 (broad s, 1H, O-H); 4.42 (d, 1 H); 4.27 (d, 2 H); 3.70 (broad s, 1H); 3.18 (dd, 1 H); 2.70 (m, 4H); 2.53 (m, 2H); 2.28 (t, 1 H); 2.18 (broad t, 1 H); 2.04 (d, 1 H). MS (ES / +): m / z = 439, 437 [M + 1] +.

INTERMEDIARY 69 1 -r (3,5-dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidin-4-hydroxy-2-pyrrolidinone Intermediate 68 (2.01 g,) was placed in a flask equipped with a stir bar, a temperature probe and a condenser. Next, water (10 ml) and a 37% solution of formaldehyde (0.74 ml) were added, and it was stirred at room temperature for about 5 hours. minutes Slowly 88% formic acid (12 ml) was added to the reaction, which was heated to about 100 ° C for 4-12 hours. Once the reaction was complete, it was cooled to room temperature and 1 M NaOH was slowly added until the pH was 9, followed by ethyl acetate (20 ml). The organic layers were separated and after evaporation of the solvent, the title compound 1.1 g was obtained as a tan solid. Analytical: mass spectrometry (m + H) = 451.2 NMR: H1 DMSO-400MHz: 7.48 (m, 3H), 7.25 (m, 2H), 7.08 (t, 2H), 4.87 (d, 1 H), 4.42 (d, 1 H), 4.29 (d, 1 H), 3. 68 (s, 1 H), 3.19 (d, 1 H), 2.92 (t, 1 H), 2.73 (d, 1 H), 2.61 (m, 1 H), 2.58 (m, 1 H), 2.53 (m, 1 H), 2.47 (m, 1 H), 2.33 (t, 1 H), 2.10 (d, 1 H), 1.98 (s) , 3H), 1.92 (t, 1 H), 1.69 (t, 1 H).

EXAMPLE 1 1-r (3,5-Dichlorophenemethane-3-r4- (4-fluorophenyt) -4-piperidinin-1,5-dihydro-2H-pyrrol-2-one Method A To intermediate 50 (0.22 g), TFA (15 mL) was added, and the solution was heated to 60 ° C under a nitrogen atmosphere for 3 hours.

The reaction mixture was evaporated in vacuo, the residue was dissolved in DCM (30 mL), and slowly added to an aqueous solution of sodium hydroxide 2.5 M, previously cooled to 0 ° C. The organic phase was separated and the solution aqueous was extracted with DCM (40 mL); The collected organic phases were dried and concentrated in vacuo to give the crude compound (0.17 g) as a yellow oil, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 7: 3), to provide the title compound (104 mg) as a white solid. T. I. c: DCM / MeOH 9: 1, Rf = 0.15 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.34 (dd, 2H); 7.23 (t, 1 H); 6.99 (t, 2H); 6.97 (m, 2H); 6.68 (t, 1 H); 4.46 (s, 2H); 3.75 (dd, 2H); 2.89 (t, 4H); 2.53 (m, 2H); 2.23 (m, 2H). MS (ES / +): m / z = 419 [M + H] +.

Method B A mixture of Nal04 (15 Kg) in 108 L of water was stirred overnight and then filtered. Intermediate 29 (15 Kg) was charged to the reactor, then THF (75L), water (22.5 L) and K20s04 (0.001 equivalents, 10.35 g) were added. The mixture was heated to 40 ° C, and stirred for 30 minutes, and then of Nal0 (15 Kg) in water (108 L) was added dropwise during 5 hours. The reaction was cooled to room temperature and then 60 L of H20 was added, followed by the addition of 90 L of CH2Cl2. The mixture was stirred overnight. The phases separated. Then 0.255 Kg of functionalized silica gel (Tiol-3) was added, and the mixture was stirred for 2 hours under reflux. Once the mixture was cooled to room temperature, then the The solution was slowly filtered through a CUNO filter (R55S), and the filter was washed with 45 L of CH2Cl2. All the organics were collected and transferred to a clean reactor and concentrated to 67.5 L. Then water (7.5 L) was added and the reaction was stirred vigorously under N2, and TFA (30 L) was added in one portion. The reaction was stirred at 20 ° C for 30 minutes. Additional TFA (30 L) was added, and the solution was heated to 55 ° C (internal temperature) and verified via HPLC. After 5 hours, the reaction mixture was cooled to 10 ° C, DCM (150 L) and methanol (75 L) were successively added, and the reaction mixture was cooled to 10 ° C. An aqueous solution of 5M NaOH was added, keeping the temperature below 20 ° C, until pH 12-13. The phases were separated and the aqueous layer was extracted with DCM (45 L). The combined organic layers were washed with water (15 L), the collected organic layer was concentrated under vacuum (400 mm Hg, 27 ° C) at 60 L and PrOAc (120 L) was added. The solution was concentrated to 60 L under vacuum at 55 ° C, and then cooled to 10 ° C. Seeds were added and 2.25 L of water were added dropwise. The mixture was stirred overnight. The solid was filtered and placed in an oven at 40 ° C under vacuum to obtain 8,358 Kg of the title compound. NMR (DMSO): (ppm) 7.47 ppm (t, 1 H), 7.35 ppm (dd, 2H), 7.08 ppm (d, 5H), 4.46 ppm (s, 2H), 3.93 ppm (s, 2H), 2.75 -2.60 ppm (m, 4H), 2.5 ppm (broad m, 2H), 1.94 ppm (m, 2H).

EXAMPLE 2 1-r Hydrochloride (3,5-di-oropheniommet-p-3-r4- (4-fluorophenyl) -4-piperidinip-1,5-dihydro-2H-pyrrol-2-one To a suspension of Example 1 (15 mg) in dry Et 2 O (0.5 mL) a 0 ° C, hydrogen chloride (1 M solution in Et20-39 μL) was added dropwise, the resulting slurry was stirred at 0 ° C for 15 minutes, then the solvent was evaporated under a flow of nitrogen and the solid residue was triturated in pentane (3 x 1 mL), to obtain the title compound (16 mg) as a white solid. NMR (d6-DMSO): d (ppm) 8.52 (broad s, 2H); 7.52 (t, 1 H); 7.42 (dd, 2H); 7.2-7.16 (m, 5H); 4.51 (s, 2H); 3.97 (s, 2H); 3.12-3.0 (m, 4H); 2.78 (d, 2H); 2.3 (m, 2H). MS (ES / +): m / z = 419 [M-HCl + H] +.

EXAMPLE 3 1-r (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinyl-1,5-dihydro-2H-pyrrol-2-one Method A To a solution of Example 1 (16.1 g) in CH3CN (200 mL), 37% by weight formaldehyde in water (6.5 mL) was added, the resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) 3 (12.2 g) was added dropwise (exothermic reaction observed). The reaction mixture was stirred at room temperature for 1 hour, then quenched with an aqueous solution of 5% sodium hydrogen carbonate (40 ml), the CH3CN was evaporated and the residue was diluted with an aqueous solution of acidic carbonate of additional 5% sodium (200 mL), and extracted with DCM (3 x 200 mL). The collected organic phases were dried, concentrated in vacuo to give a crude white foam (16.5 g), which was purified by flash chromatography (Biotage Flash 75 L, DCM, then DCM / MeOH from 95: 5 to 8: 2 ). The title compound (12.7 g) was obtained as a white solid. T. I. c: DCM / MeOH 9: 1, Rf = 0.41 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.35 (dd, 2H); 7.23 (t, 1 H); 6.98 (t, 2H); 6.96 (m, 2H); 6.76 (broad t, 1 H); 4.46 (s, 2H); 3.76 (dd, 2H); 2.70-2.25 (broad m, 8H); 2.23 (s, 3H). MS (ES / +): m / z = 433 [M + H] +.

Method B nyl chloride (0.67 ml) was added to a cooled solution (approximately -5 ° C) of dichloromethane (10 ml) and pyridine (1.86 ml) at such a rate to maintain the temperature below 0 ° C. The resulting solution was stirred at about -5 ° C for 10 minutes, and a solution of intermediate 69 (2.0 g) in dichloromethane (10 ml) was slowly added keeping the temperature lower than 0 ° C. The resulting solution was stirred to Then it was warmed to room temperature in 30-40 minutes and then stirred at room temperature until complete for approximately 1.0 additional hours. The reaction was quenched with water (20 ml). The mixture sedimented and separated. A 25% potassium carbonate aqueous solution was added to the dichloromethane layer. The mixture was stirred for 30 minutes and then sedimented and separated. The organic phase was concentrated to dryness to provide the title compound as an oil (1.5 -1.7 g), 1 H NMR: 7.31-7.20 (m, 2H), 7.16 (s, 1 H), 6.93-6.89 (m, 4H ), 6.71 (s, 1 H), 4.39 (s, 2H), 3.71 (s, 2H), 2.52-2.28 (broad, m), 2.21 (s, 3H). 66 MS: M + 1 433.

EXAMPLE 4 1-R (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinyl-1,5-dihydro-2H-pyrrol-2 hydrochloride -one To a suspension of Example 3 (10.7 g) in dry Et20 (200 mL) at 0 ° C, hydrogen chloride (1 M solution in Et20 -26 mL) was added dropwise, the resulting slurry was stirred at 0 ° C. ° C for 1 hour, then filtered under a nitrogen atmosphere in a Gooch filter and washed with Et20 (2 x 100 mL) and with pentane (3 x 100 mL), then dried in vacuo at 40 ° C. for 3 hours and at room temperature for 14 hours. The title compound (11.2 g) was obtained as a white solid.

NMR (de-DMSO): d (ppm) 9.97 (broad, 1 H); 7.51 (broad s, 1H); 7.40 (s, 1 H); 7.36 (dd, 2H); 7.16 (d, 2H); 7.15 (t, 2H); 4.51 (s, 2H); 4.01 (s, 2H); 3.55-3.3 (m, 2H); 3.04 (broad d, 1 H); 2.96 (broad dd, 1 H); 2.76 (d, 3H); 2.55-2.3 (m, 2H); 2.13 (broad t, 2H). MS (ES / +): m / z = 433 [M-HCl + H] +.

EXAMPLE 5 1-ri- (3,5-Dichlorophenyl) -etin-3-r4- (4-fluorophenyl) -4-piperidin-1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1) TFA (0.8 mL) was added to intermediate 51 (0.019 g), and the mixture was allowed to stir at 60 ° C for 1 hour. After time, the mixture was cooled to room temperature and concentrated in vacuo. The crude product thus obtained was diluted with DCM and poured into a 2M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was then separated, dried and concentrated in vacuo to provide a residue, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 8: 2), to provide the title compound. title (0.014 g) as a white foam. T. I. c: DCM / MeOH 9: 1, Rf = 0.39 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.37 (dd, 2H); 7.27 (m, 1H); 7.06 (d, 2H); 7.04 (t, 2H); 6.72 (s, 1H); 5.40 (c, 1H); 3.88 (dd, 1 H); 3.60 (dd, 1H); 2.96 (m, 4H); 2.62 (m, 2H); 2.27 (m, 2H); 1.56 (d, 3H).

MS (ES / +): m / z = 433 [M + H] +.

EXAMPLE 6 1-r (1S) -1- (3-Chloro-1-naphthaleninetin-3-r4- (4-fluorophenin-4-piperidinin-1,5-dihydro-2H-pyrrol-2-one) TFA (4 mL) was added to intermediate 52 (0.128 g) and the mixture was allowed to stir at room temperature for 20 minutes. The TFA was evaporated, and TFA (2 mL) was added. The mixture was stirred at 60 ° C for 1.15 hours. After time, the mixture was cooled to room temperature and concentrated in vacuo. The crude product thus obtained was diluted with DCM and poured into a 2M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was then separated, dried and concentrated in vacuo to provide a residue, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 8: 2), to provide the title compound. title (0.048 g) as a white foam. NMR (CDCl 3): d (ppm) 7.89 (d, 1 H); 7.82 (d, 1 H); 7.77 (d, 1 H); 7.51 (t, 1H); 7.48 (d, 1 H); 7.37 (td, 1 H); 7.34 (dd, 2H); 7.02 (t, 2H); 6.59 (s, 1 H); 6.09 (c, 1 H); 3.8 (dd, 1 H); 3.06 (dd, 1 H); 3.05-2.85 (broad m, 4H); 2.68 (broad d, 1 H); 2.6 (broad d, 1 H); 2.24 (broad m, 2H); 1.69 (d, 3H). MS (ES / +): m / z = 449 [M + H] +.

EXAMPLE 7 1-r (3-Chloro-1-naphthalenyl) metin-3-r4- (4-fluorophenip-4-piperidinin-1,5-dihydro-2H-pyrrol-2-one) TFA (10 mL) was added to intermediate 53 (210 mg) at 0 ° C, and the mixture was allowed to stir at 0 ° C for 15 minutes. The TFA was evaporated and then added again to reach the original volume. The mixture was stirred at 60 ° C for 2 hours. After this time, the mixture was cooled to room temperature and concentrated in vacuo. The crude product thus obtained was diluted with DCM and poured into a 2.5 M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to provide a residue, which was purified by flash chromatography (elution: DCM, then DCM / MeOH from 95: 5 to 70:30), provide the title compound (140 mg) as a white solid. T. I. c: DCM / MeOH 8: 2, Rf = 0.08 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.9 (d, 1 H); 7.77 (s, 1 H); 7.74 (d, 1 H); 7.49 (t, 1 H); 7.38 (t, 1 H); 7.33 (dd, 2H); 7.25 (d, 1 H); 6.99 (t, 2H); 6.64 (s, 1 H); 4.92 (s, 2H); 3.63 (broad s, 2H); 2.95 (broad m, 4H); 2.62 (broad m, 2H); 2.29 (broad m, 2H). MS (ES / +): m / z = 435 [M + Hf.

EXAMPLE 8 4 - (^ 3-r4- (4-Fluorophenyl) -4-piperidinip-2-oxo-2,5-dihydro-1H-pyrrol-1-yl methylene-2-naphthalenecarbonitrile TFA (12 mL) was added to intermediate 54 (120 mg) at 0 ° C, and the mixture was allowed to stir at 0 ° C for 15 minutes. The TFA was evaporated and then added again to reach the original volume. The mixture was stirred at 60 ° C for 1.5 hours. After this time, the mixture was cooled to room temperature and concentrated in vacuo. The crude product thus obtained was diluted with DCM and poured into a 2.5 M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to provide a residue, which was purified by flash chromatography (elution: DCM, then DCM / MeOH from 9: 1 to 7: 3) to provide the title compound (70 mg) as a white solid. T. I. c: DCM / MeOH 8: 2, Rf = 0.06 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 8.18 (s, 1 H); 8.02 (d, 1 H); 7.89 (d, 1 H); 7.6 (td, 1 H); 7.55 (td, 1 H); 7.41 (s, 1 H); 7.33 (dd, 2H); 6.99 (td, 2H); 6.67 (s, 1 H); 4.96 (s, 2H); 3.64 (broad s, 2H); 2.92 (broad m, 4H); 2.59 (broad m, 2H); 2.27 (broad m, 2H). MS (ES / +): m / z = 426 [M + H] +.

EXAMPLE 9 1-ri- (3,5-Dichlorophenyl) etin-3-r4- (4-fluorophenin-4-piperidinyl-1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 2) To a suspension of intermediate 31 (0.9 g) in THF (20 mL) and water (5 mL) was added a solution of 4% by weight osmium tetraoxide in water (1.5 mL). The mixture was stirred at room temperature for 1 hour during which it turned dark, then Nal0 (1.4 g) was added, and the brown reaction mixture was stirred at room temperature for 14 hours. After this time, it was diluted with water and extracted with AcOEt. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3), and the fractions were collected with Rf = 0.37 (CH / AcOEt 6: 4, detection with ninhydrine) and MS (ES / +): m / z = 573 [M + Na] +, to provide an intermediate (0.4 g), to which TFA (0.8 mL) was added and the mixture allowed to stir at 60 ° C for 2 hours. After this time, the mixture was cooled to room temperature and concentrated in vacuo. The crude product thus obtained was diluted with DCM and poured into a 2M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was then separated, dried and concentrated in vacuo to provide a residue, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 8: 2), to provide the title compound. title (0.065 g) as a white foam.

T. I. c: DCM / MeOH 9: 1, Rf = 0.39 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.37 (dd, 2H); 7 27 (m, 1 H); 7.06 (d, 2H); 7.04 (t, 2H); 6.72 (s, 1 H); 5.40 (c, 1 H); 3.88 (dd, 1 H); 3.60 (dd, 1 H); 2.96 (m, 4H); 2.62 (m, 2H); 2.27 (m, 2H); 1.56 (d, 3H). MS (ES / +): m / z = 433 [M + H] +.

EXAMPLE 10 1-f (1 R) -1 - (3-Chloro-1 -naphthalenyl) etn-3-r4- (4-fluorophenyl) -4-piperidin-1, 5-dihydro-2H-pyrrole -2-one To a suspension of intermediate 32 (0.32 g) in THF (16 mL) and water (4 mL), a solution of 4% by weight osmium tetraoxide in water (1 mL) was added. The mixture was stirred at room temperature for 45 minutes, then Nal04 (0.5 g) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After this time, it was diluted with water and extracted with AcOEt. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (CH / AcOEt from 9: 1 to 7: 3), and the fractions were collected with Rf = 0.78 and Rf = 0.63 (CH / AcOEt 1: 1, detection with ninhydrin), and both had one MS (ES / +): m / z = 589 [M + Na] +, to provide a mixture of the intermediates (0.068 g), to which was added TFA (2 mL) and the mixture was allowed to stir at 60 ° C for 2 hours. After this time, the mixture was cooled to room temperature and concentrated in vacuo. The raw product as well obtained was diluted with DCM and poured into a 2M aqueous sodium hydroxide solution previously cooled to 0 ° C. The organic layer was then separated, dried and concentrated in vacuo to provide the title compound (0.05 g) as a white foam. T. I. c: DCM / MeOH 8: 2, Rf = 0.77 (detection with ninhydrin).

EXAMPLE 11 1-ri- (3,5-Dichlorophenyl) etin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1) To a solution of Example 5 (0.241 g) in CH3CN (14 mL), 37% by weight formaldehyde in water (0.130 mL) was added. The resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) 3 (0.235 g) was added. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water, the CH3CN was evaporated and the residue was diluted with water and extracted with DCM. The collected organic phases were dried, concentrated in vacuo to give a crude product, which was purified by flash chromatography (DCM, then DCM / MeOH from 98: 2 to 9: 1) to give the title compound (0.177 g) as a white solid. T. I. c: DCM / MeOH 85:15, Rf = 0.54 (detection with ninhydrin). MS (ES / +): m / z = 447 [M + H] +.

EXAMPLE 12 1 -f (1 S) -1 - (3-Chloro-1 -naphthalene-3-r4- (4-fluorophenyl) -1-methyl-4-piperidin-1,5-dihydro-2H -pyrrole-2-one To a solution of Example 6 (0.025 g) in CH3CN (2 mL), 37% by weight formaldehyde in water (0.013 mL) was added. The resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) 3 (0.024 g) was added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with water, the CH3CN was evaporated and the residue was diluted with water and extracted with DCM. The collected organic phases were washed with a saturated aqueous solution of NaHCO 3, dried, concentrated in vacuo to give a crude product, which was purified by flash chromatography (DCM, then DCM / MeOH from 98: 2 to 9: 1) , to provide the title compound (0.022 g) as a white foam. T. I. c: DCM / MeOH 9: 1, Rf = 0.6 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.85 (d, 1 H); 7.82 (d, 1 H); 7.77 (d, 1 H); 7.51 (t, 1 H); 7.47 (d, 1 H); 7.40-7.32 (m, 3H); 7.04 (t, 2H); 6.67 (broad s, 1 H); 6.08 (c, 1 H); 3.82 (d, 1 H); 3.09 (d, 1 H); 3.00-2.55 (broad m, 6H); 2.52 (broad s, 3H); 2.0-1.8 (broad m, 2H); 2.24 (broad m, 2H); 1.69 (d, 3H). MS (ES / +): m / z = 463 [M + H] +.

EXAMPLE 13 1-r (3-Chloro-1-naphthalenyl) metip-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinyl-1,5-dihydro-2H-pyrrol-2-one To a solution of Example 7 (50 mg) in CH3CN (2 mL), 37% by weight formaldehyde in water (0.020 mL) was added. The resulting mixture was stirred at room temperature for 10 minutes, then NaBH (OAc) 3 (37 mg) was added. The reaction mixture was stirred at room temperature for 1.5 hours, then quenched with water, the CH3CN was evaporated and the residue was diluted with a 5% aqueous solution of NaHCO3 and extracted with DCM (2 x 10 mL).; the organic layers were dried, concentrated in vacuo to give a crude product, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 70:30), to give the title compound (40 mg) as a white solid. T. I. c: DCM / MeOH 8: 2, Rf = 0.35 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.88 (d, 1 H); 7.76 (d, 1 H); 7.72 (d, 1 H); 7.48 (t, 1 H); 7.36 (tt, 1H); 7.33 (dd, 2H); 7.23 (d, 1H); 6.96 (t, 2H); 6.68 (s, 1 H); 4.91 (s, 2H); 3.62 (s, 2H); 2.56 (broad t, 4H); 2.36 (broad t, 4H); 2.22 (s, 3H). MS (ES / +): m / z = 449 [M + H] +. Following the same procedure described for example 13, examples 14, 15 and 16 were obtained.

EXAMPLE 14 January-ri- (3,5-Dichlorophenyl) ethyn-3-r4- (4-fluorofenii) -1-methyl-4-piperidin¡n-1,5- dihydro-2H-pyrrol-2-one (Enantiomer of Chain 2) Starting from Example 9 (0.10 g), 0.025 g of the title compound was obtained. T. I. c: DCM / MeOH 85:15, Rf = 0.5 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.39 (dd, 2H); 7.28 (m, 1 H); 7.08-7.06 (m, 4H); 6.82 (broad s, 1 H); 5.36 (c, 1 H); 3.89-3.62 (dd, 2H); 3.3-2.2 (broad m, 8H); 2.65 (s, 3H); 1.53 (d, 3H). MS (ES / +): m / z = 447 [M + H] +.

EXAMPLE 15 1-r (1R) -1- (3-Chloro-1-naphthalenyl) etn-3-r4- (4-fluorophenin-1-methyl-4-piperidinyl) -1,5-dihydro-2H- pyrrol-2-one Starting from example 10 (0.050 g), 0.024 g of the title compound was obtained. T. I. c: DCM / MeOH 85:15, Rf = 0.6 (detection with ninhydrin). MS (ES / +): m / z = 463 [M + H] +.

EXAMPLE 16 4- (3-r4- (4-Fluorophenyl) -1-methyl-4-piperidin-2-oxo-2,5-dihydro-1H-pyrrol-1-yl} methyl) -2- naphthalenecarbonitrile Beginning with example 8 (0.049 g), they were obtained 0. 039 g of the title compound. T. I. c: DCM / MeOH 8: 2 with the addition of 1% NH4OH, Rf = 0.56 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 8.2 (s, 1 H); 8.0 (d, 1 H); 7.89 (d, 1 H); 7.57 (m, 2H); 7.41 (d, 1 H); 7.33 (m, 2H); 6.99 (t, 2H); 6.72 (s, 1 H); 4.95 (s, 2H); 3.65 (m, 2H); 2.8-2.3 (broad m, 8H); 2.31 (s, 3H).

EXAMPLE 17 Hydrochloride of 1-ri- (3,5-dichlorophenyl) ethyn-3-r4- (4-fluorofenin-1-methyl-4- pineridinin-1,5-dihydro-2H-pyrrol-2-one (Enantiomer of Chain 1) Hydrogen chloride (1M solution in Et20- 0.43 mL) was added to a solution of Example 11 (0.176 g) in dry Et20 (4 mL) previously cooled to 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with pentane (3 x 1 mL), to give the title compound (0.180 g) as a white solid.

NMR (d6-DMSO): d (ppm) 10.11 / 9.94 (2 s broad, 1 H); 7.51-7.46 (m, 1H); 7.41 (broad s, 1H); 7.32 (dd, 2H); 7.2-7.1 (m, 4H); 5.11 (m, 1 H); 4.14-3.74 (dd, 2H); 3.3-2.13 (broad m, 8H); 2.77 (d, 3H); 1.52 (d, 3H). MS (ES / +): m / z = 447 [M-HCl + H] +.

EXAMPLE 18 1-r (1R) -1- (3-chloro-1-naphthalenyl) etp-3-r4- (4-fluorophenin-1-methyl-4-piperidini | - | -1 hydrochloride , 5-dihydro-2H-pyrrol-2-one Hydrogen chloride (1 M solution in Et 2 O - 57 μL) was added to a solution of Example 15 (0.024 g) in dry Et 2 O (1 mL), previously cooled to 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with pentane (3 x 1 mL), to give the title compound (0.024 g) as a white solid. NMR (de-DMSO): d (ppm) 9.57 (broad s, 1 H); 8.01 (s, 1 H); 7.92 (d, 1 H); 7.88 (broad d, 1 H); 7.55 (t, 1 H); 7.47 (s, 1 H); 7.40 (t, 1 H); 7.3-6.5 (broad m, 5H); 5.87 (c, 1 H); 4.1-3.9 (broad m, 1 H); 3.2-2.0 (broad m, 12H); 1.61 (broad s, 3H). MS (ES / +): m / z = 463 [M-HCl + H] +.

Example 19 1-rí1S) -1- (3-Cioro-1-naphthalenyl) eTIP-ri--3 (cyclopropylmethyl) -4- (4-fluorophenyl) - 4-piperidinin-1,5-dihydro-2H-pyrrole 2-one To a solution of Example 6 (0.018 g) in CH3CN (2 mL), cyclopropancarboxaldehyde (0.015 mL) was added. The resulting mixture was stirred at room temperature for 15 minutes, then NaBH (OAc) 3 (0.017 g) was added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with water, the CH3CN was evaporated and the residue was diluted with water and extracted with DCM. The collected organic phases were washed with saturated NaHC03 aqueous solution, dried, concentrated in vacuo to give a crude product which was purified by flash chromatography (DCM, then DCM / MeOH from 98: 2 to 9: 1) , to provide the title compound (0.017 g) as a white foam. T. I. c: DCM / MeOH 9: 1, Rf = 0.51 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.67 (d, 1 H); 7.63 (d, 1 H); 7.58 (d, 1 H); 7.33 (t, 1 H); 7.28 (d, 1H); 7.17 (m, 3H); 6.84 (t, 2H); 6.48 (s, 1 H); 5.89 (c, 1 H); 3.62 (d, 1 H); 2.89 (d, 1 H); 2.7-2.1 (broad m, 10H); 1.5 (d, 3H); 0.8 (broad m, 1 H); 0.4 (broad s, 2H); -0.01 (s broad, 2H). MS (ES / +): m / z = 503 [M + H] +.

EXAMPLE 20 1-f (3-Chloro-1-naphthalenyl) methyl] -3-p- (cyclopropylmethyl) -4- (4-fluorophen-8) -4-piperidinip-1,5-dihydro-2H-pyrrol-2-one To a solution of example 7 (50 mg) in CH3CN (2 mL), cyclopropancarboxaldehyde (0.043 mL) was added. The resulting mixture was stirred at room temperature for 10 minutes, then NaBH (OAc) 3 (37 mg) was added. The reaction mixture was stirred at room temperature for 1.5 hours, then quenched with water, the CH3CN was evaporated and the residue was diluted with a 5% aqueous solution of NaHCO3 and extracted with DCM (2 x 10 mL); the organic layers were dried, concentrated in vacuo to provide a crude product, which was purified by flash chromatography (DCM, then DCM / MeOH from 95: 5 to 80:20), to provide the title compound (22 mg) as a white solid. T. I. c: DCM / MeOH 8: 2, Rf = 0.5 (detection with ninhydrin). NMR (CDCl 3): d (ppm) 7.87 (d, 1 H); 7.75 (d, 1H); 7.72 (d, 1H); 7.47 (t, 1 H); 7.36 (t, 1 H); 7.33 (dd, 2H); 7.22 (d, 1 H); 6.96 (t, 2H); 6.68 (s, 1H); 4.91 (s, 2H); 3.61 (d, 2H); 2.62 (broad d, 4H); 2.38 (broad d, 4H); 2.22 (broad s, 2H); 0.84 (broad, 1 H); 0.47 (d, 2H); 0.05 (d, 2H). MS (ES / +): m / z = 489 [M + H] +.

EXAMPLE 21 1-r (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -4-piperidinin-2-pyrrolidinone TFA (200 μl) was added to a solution of intermediate 37 (35 mg) in dry DCM (1.8 mL), and the mixture was stirred for 3 hours at room temperature. It was then diluted with DCM, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried and concentrated in vacuo. The residue was purified by SCX to give the title compound (22 mg) as a colorless oil. T. I. c: DCM / MeOH 2: 8, Rf = 0.16 (detection with ninhydrin). NMR (de-DMSO): d (ppm) 7.43 (t, 1H); 7.36 (dd, 2H); 7.06 (t, 2H); 6.96 (d, 2H); 5.34 (broad s, 1 H); 4.27 (d, 1 H); 4.04 (d, 1 H); 2.94 (dd, 2H); 2.89 (m, 1H); 2.72 (t, 1H); 2.6 (, 1H); 2.58 (m, 1 H); 2.49 (m, 1 H); 2.41 (dd, 1H); 2.16 (broad d, 1 H); 1.95 (m, 2H); 1.82 (m, 1H); 1.56 (m, 1 H). MS (ES / +): m / z = 421 [M + H] +.

EXAMPLE 22 1-r (1S) -1- 3-Chloro-1-naphthalenyl) etin-3-r4- (4-fluorophenyl) -4-piperidin-2-pyrrolidinone (diastereoisomer 1) TFA (0.8 mL) was added to a solution of intermediate 42 (21 mg) in dry DCM (3.2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue is purified on an SCX cartridge (loaded with DCM, washed with MeOH, eluted with 2M NH3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (14.5 mg) as a white foam. NMR (CDCl 3): d (ppm) 7.95 (d, 1 H); 7.76 (s, 1 H); 7.75 (d, 1 H); 7.53 (m, 2H); 7.38 (m, 2H); 7.27 (s, 1 H); 7.11 (t, 2H); 5.93 (c, 1H); 3.32 (broad t, 2H), 2.93 (m, 1 H); 2.77 (broad t, 1 H); 2.62 (broad m, 1 H); 2.3-2.5 (m, 3H); 2.05-2.25 (m, 2H); 1.89 (broad d, 1 H); 1.5-1.75 (m, 2H); 1.25 (d, 3H).

EXAMPLE 23 1-r (1S) -1- (3-Chloro-1-naphthalenyl) etin-3-r4- (4-fluorophenyl) -4-piperidin-2-pyrrolidinone (diastereoisomer 2) TFA (0.8 mL) was added to a solution of intermediate 43 (19 mg) in dry DCM (3.2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (14.3 mg) as a white foam. NMR (CDCl 3): d (ppm) 7.84 (d, 1 H); 7.76 (s, 1 H); 7.75 (d, 1 H); 7.52 (t, 1 H); 7.4 (t, 1 H); 7.28 (s, 1 H); 7.23 (dd, 2H); 6.71 (t, 2H); 5.99 (c, 1 H), 3.02 (broad t, 1H), 3.01 (m, 1 H), 2.99 (m, 1 H); 2.84 (broad d, 1H); 2.6-2.75 (m, 3H); 2.22 (broad t, 1 H); 2.17 (broad d, 1 H); 2.0-2.15 (m, 2H), 1.79 (m, 1 H); 1.55 (d, 3H); 1.38 (m, 1 H).

EXAMPLE 24 1-ri- (3,5-Dichlorophenyl) -etin-3-r4- (4-fluorophenyl) -4-piperidinin-2-pyrrolidinone (Diastereoisomer 1, Chain Enantiomer 1) TFA (1.0 mL) was added to a solution of intermediate 44 (125 mg) in dry DCM (4.0 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (91 mg) as a white foam. HPLC (LC / MS -ES / +): tR = 4.6 minutes MS (ES / +): m / z = 435 [M + H] +. NMR (CDCl 3): d (ppm) 7.33 (dd, 2H); 7.21 (t, 1H); 7.03 (d, 2H); 7.02 (t, 2H); 5.24 (c, 1H); 3.03 (m, 1 H); 2.99 (m, 1 H); 2.81 (broad d, 1 H); 2.78 (t, 1 H), 2.66 (tm, 1H), 2.63 (m, 1 H), 2.56 (dd, 1 H); 2.15-2.35 (broad m, 3H); 1.94 (m, 1 H); 1.88 (m 1 H); 1.75 (m, 1 H); 1.11 (d, 3H). - EXAMPLE 25 1-ri- (3,5-Dichlorophenyl) -etin-3-f4- (4-fluorophenyl) -4-piperidin-2-pyrrolidinone (Diastereomer 2, Chain Enantiomer 1) TFA (1.5 mL) was added to a solution of intermediate 45 (165 mg) in dry DCM (6.0 mL) at 0 ° C under a nitrogen atmosphere. Mix of reaction was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (101 mg) as a white foam. HPLC (LC / MS-ES / +): tR = 4.6 minutes MS (ES / +): m / z = 435 [M + H] + NMR (CDCl 3): d (ppm) 7.34 (dd, 2H); 7.24 (t, 1 H); 6.99 (t, 2H); 6.82 (dd, 2H); 5.27 (c, 1 H); 3.1 (m, 1 H); 3.08 (m, 1 H); 3.04 (m, 1H); 2.84 (td, 1 H), 2.75 (t, 1 H), 2.68 (td, 1 H), 2.4 (td, 1 H); 2.10-2.4 (broad m, 3H); 1.99 (tm, 1 H); 1.67 (m, 1 H); 1.41 (dd, 3H).

EXAMPLE 26 1- [1- (3,5-Dichlorophenyl) ethyp-3- [4- (4-fluorophenyl) -4-piperidinin-2-pyrrolidinone (Diastereoisomer 1, Chain Enantiomer 2) TFA (1.0 mL) was added to a solution of intermediate 46 (133 mg) in dry DCM (4.0 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (97 mg) as a white foam. HPLC (LC / MS -ES / +): tR = 4.6 minutes MS (ES / +): m / z = 435 [M + H] + NMR (CDCl 3): d (ppm) 7.28 (dd, 2H); 7.17 (t, 1 H); 6.99 (t, 2H); 6.98 (d, 2H); 5.18 (c, 1 H); 3.04 (m, 1 H); 3.02 (m, 1 H); 2.86 (broad d, 1 H); 2.77 (t, 1 H), 2.59 (m, 1H), 2.56 (m, 1H), 2.52 (tm, 1 H); 2.0-2.4 (broad m, 3H); 1.94 (td, 1 H); 1.85 (m, 1 H); 1.69 (m, 1 H), 1.06 (d, 3H).

EXAMPLE 27 1-ri- (3,5-Dichlorophenol) etin-3-r4- (4-fluorophenyl) -4-p -peridinin-2-pyrrolidinone (Diastereoisomer 2, Chain Enantiomer 2) TFA (2.0 mL) was added to a solution of intermediate 47 (180 mg) in dry DCM (8.0 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (111 mg) as a white foam. HPLC (LC / MS-ES / +): tR = 4.6 minutes MS (ES / +): m / z = 435 [M + H] + NMR (CDCl 3): d (ppm) 7.34 (dd, 2H); 7.24 (t, 1 H); 6.99 (t, 2H); 6.82 (dd, 2H); 5.27 (c, 1 H); 3.1 (m, 1 H); 3.08 (m, 1 H); 3.04 (m, 1H); 2.84 (td, 1 H), 2.75 (t, 1 H), 2.68 (td, 1 H), 2.4 (td, 1 H); 2.10-2.4 (broad m, 3H); 1.99 (tm, 1 H); 1.67 (m, 1 H); 1.41 (dd, 3H).

EXAMPLE 28 4-I'3-R4- (4-Fluorophenyl) -4-piperidinin-2-oxo-1-pyrrolidinyl > methyl) -2- naphthalenecarbonitrile (Enantiomer 1) TFA (0.75 mL) was added to a solution of intermediate 57 (40 mg) in dry DCM (3 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (25 mg) as a white foam. NMR (CDCl 3): d (ppm) 8.15 (s, 1 H); 8.08 (d, 1 H); 7.89 (dd, 1 H); 7.66 (td, 1 H); 7.61 (td, 1 H); 7.27 (dd, 2H); 7.25 (s, 1 H); 6.84 (td, 2H); 4.66 (s, 2H); 3.05 (broad t, 2H); 2.92 (broad d, 1H), 2.6-2.85 (m, 4H); 2.18-2.35 (m, 3H); 2.02 (m, 1 H); 1.88 (m, 1 H); 1.63 (m, 1 H).

EXAMPLE 29 4 ( {3-r4- (4-Fluorophenyl) -4-piperidinin-2-oxo-1-pyrrolidinyl > methyl) -2- naphthalenecarbonitrile (Enantiomer 2) TFA (0.75 mL) was added to a solution of intermediate 58 (33 mg) in dry DCM (3 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (loaded with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (18.5 mg) as a white foam. NMR (CDCl 3): d (ppm) 8.15 (d, 1 H); 8.05 (d, 1H); 7.89 (dd, 1H); 7. 66 (td, 1 H); 7.61 (td, 1 H); 7.26 (dd, 2H); 7.24 (s, 1 H); 6.85 (td, 2H); 4.7 (d, 1H); 4.61 (d, 1H); 3.14 (broad t, 2H); 3.11 (broad d, 1H), 2.62-2.91 (m, 4H); 2.26-2.40 (m, 3H); 2.07 (m, 1 H); 1.89 (m, 1 H); 1.62 (m, 1 H).

EXAMPLE 30 7-Fluoro-4- (. {3-r4- (4-fluorophenyl) -4-piperidinip-2-oxo-1-pyrrolidinyl} methyl) -2- naphthalenecarbonitrile (Enantiomer 2) TFA (0.5 mL) was added to a solution of intermediate 59 (28 mg) in dry DCM (2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (19 mg) as a white foam. HPLC (LC / MS -ES / +): t R = 4.08 minutes MS (ES / +): m / z = 446 [M + H] + NMR (CDCl 3): d (ppm) 8.17 (dd, 1 H); 8.08 (s, 1 H); 7.5 (dd, 1 H); 7.43 (td, 1 H); 7.27 (dd, 2H); 7.22 (s, 1 H); 6.85 (td, 2H); 4.69 (d, 1 H); 4.55 (d, 1 H); 2.95 (broad t, 2H); 2.85-2.50 (m, 4H), .2.3-2.10 (m, 3H); 2.00-1.50 (m, 4H).

EXAMPLE 31 6-Fluoro-4- ( {3-f4- (4-fluorophenyl) -4-piperidinip-2-oxo-1-pyrrolidinyl} methyl) -2- naphthalenecarbonitrile (Enantiomer 2) TFA (0.5 mL) was added to a solution of intermediate 60 (19 mg) in dry DCM (2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (11 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 4.06 minutes MS (ES / +): m / z = 446 [M + H] + NMR (CDCl 3): d (ppm) 8.14 (s, 1 H); 7.91 (td, 1 H); 7.83 (broad d, 1 H); 7.41 (tt, 1 H); 7.29 (s, 1 H); 7.26 (dd, 2H); 6.85 (td, 2H); 4.65 (d, 1 H); 4.52 (d, 1 H); 2.99 (broad t, 2H); 2.90-2.55 (m, 4H), 2.4-2.1 (m, 3H); 2.00-1.50 (m, 4H).

EXAMPLE 32 7-Fluoro-4 - ((3-r4- (4-fluorophenyl) -4-piperidinip-2-oxo-1-pyrrolidinylmethyl) -2- naphthalenecarbonitrile (Enantiomer 1) TFA (0.5 mL) was added to a solution of intermediate 61 (52 mg) in dry DCM (2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (31 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 3.99 minutes MS (ES / +): m / z = 446 [M + H] + NMR (CDCl 3): d (ppm) 8.23 (dd, 1 H); 8.14 (s, 1 H); 7.55 (dd, 1 H); 7.48 (m, 1 H); 7.33 (dd, 2H); 7.28 (d, 1 H); 6.9 (t, 2H); 4.75 (d, 1 H); 4.6 (d, 1 H); 2.98 (m, 2H); 2.85-27 (m, 4H), 2.65 (td, 1 H); 2.35-2.15 (m, 3H); 2.00-1.75 (m, 2H); 1.72 (m, 1 H).

EXAMPLE 33 6-Fluoro-4 - ((3-r4- (4-fluorophenyl) -4-piperidinin-2-oxo-1-pyrrolidinyl > methyl) -2- naphthalenecarbonitrile (Enantiomer 1) TFA (0.5 mL) was added to a solution of intermediate 62 (21 mg) in dry DCM (2 mL) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred 1 hour before concentrating it in vacuo at 0 ° C. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (16 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 3.95 minutes MS (ES / +): m / z = 446 [M + H] + NMR (CDCl 3): d (ppm) 8.09 (s, 1 H); 7.86 (dd, 1 H); 7.79 (dd, 1 H); 7.36 (td, 1 H); 7.24 (dd, 2H); 7.24 (s, 1 H); 6.81 (t, 2H); 4.6 (d, 1 H); 4.48 (d, 1 H); 2.91 (m, 2H); 2.80-2.65 (m, 4H), 2.55 (td, 1 H); 2.27 (m, 1 H); 2.15 (broad d, 2H); 1.95-1.75 (m, 2H); 1.59 (m, 1 H).

EXAMPLE 34 1-r (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-pyrrolidinone Formaldehyde was added to 37% by weight in water (8 μL) and NaBH (OAc) 3 (16 mg) to a solution of Example 21 in CH 3 CN (3 mL). After stirring for 2 hours, the same amounts of 37% by weight formaldehyde in water and NaBH (OAc) 3 were added, and the mixture was stirred at room temperature overnight. It was then diluted with DCM (2 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and filtered in a phase separation cartridge. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography (DCM / MeOH 4: 6), to give the title compound (15 mg) as a colorless oil. T. I. c: DCM / MeOH 4: 6, Rf = 0.15 (detection with ninhydrin). NMR (d6-DMSO): d (ppm) 7.43 (t, 1 H); 7.34 (dd, 2H); 7.03 (t, 2H); 6.95 (s, 2H); 4.28 (d, 1H); 4.02 (d, 1 H); 2.9 (dd, 1 H); 2.69 (m, 1 H); 2.4-2.52 (m, 2H); 2.41 (dd, 1 H); 2.0-2.2 (m, 2H); 2.0 (s, 3H); 1.8-2.05 (m, 5H); 1.61 (m, 1 H). MS (ES / +): m / z = 435 [M + H] +.

EXAMPLE 35 1-r (1S) -1- (3-chloro-1-naphthalenyl) etin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-pyrrolidinone (diastereoisomer 2) A solution of formaldehyde in water (37% w / w; 8.5 μL) was added to a stirred solution of Example 23 (9.2 mg) in CH 3 CN (5 mL) under a nitrogen atmosphere at ambient temperature. After 15 minutes, NaBH (OAc) 3 (7 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Solvent evaporation gave the compound of the formula (2.4 mg) as a white foam. HPLC (LC / MS -ES / +): IR = 4.6 minutes MS (ES / +): m / z = 465 [M + H] +.

EXAMPLE 36 1-ri- (3,5-Dichlorophenyl) etin-3-r4- (4-fluorophenin-1-methyl-4-piperidinin-2-pyrrolidinone (Diastereomer 1, Chain Enantiomer 1) A solution of formaldehyde in water (37% w / w; 72 μL) was added to a stirred solution of Example 24 (78 mg) in CH 3 CN (6 mL) under a nitrogen atmosphere at ambient temperature. After 15 min., NaBH (OAc) 3 (57.2 mg) was added in portions. The mixture became agitated for an additional hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvenfe provided the compound of the extract (80 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 4.6 minutes MS (ES / +): m / z = 449 [M + H] + NMR (CDCl 3): d (ppm) 7.39 (dd, 2H); 7.26 (1, 1H); 7.09 (f, 2H); 7.07 (d, 2H); 5.26 (c, 1 H); 2.92 (broad, 2H); 2.67 (broad, 1 H); 2.63 (m, 1 H); 2.1-2.6 (broad m, 5H), 2.38 (s, 3H), 2.17 (broad 1, 1 H), 1.99 (m, 1 H); 1.79 (m, 1 H); 1.5-1.8 (broad, 1 H); 1.15 (d, 3H).

EXAMPLE 37 1-ri- (3,5-Dichlorophenyl) etin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinip-2-pyrrolidinone (Diastereomer 2, Chain Enantiomer 1) A solution of formaldehyde in water (37% w / w; 80 μL) was added to an agitated solution of Example 25 (86.5 mg) in CH3CN (8 mL) under a nihinogen atmosphere at ambient temperature. After 15 minutes, NaBH (OAc) 3 (63.6 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the compound of the extract (82 mg) as a white foam.

HPLC (LC / MS-ES / +): t R = 4.6 minutes MS (ES / +): m / z = 449 [M + H] + NMR (CDCl 3): d (ppm) 7.36 (dd, 2H); 7.24 (t, 1H); 7.01 (1, 2H); 6.78 (d, 2H); 5.25 (c, 1 H); 3.07 (dd, 1 H); 2.98 (broad, 1 H); 2.76 (broad, 1 H); 2.43 (dd, 1 H), 2.1-2.6 (broad m, .5H), 2.41 (s, 3H), 2.22 (broad d, 1 H), 2.05 (m, 1 H); 1.68 (m, 1 H); 1.62 (m, 1 H); 1.4 (d, 3H).

EXAMPLE 38 1-ri- (3,5-Dichlorophenyl) etp-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-pyrrolidinone (Diastereoisomer 1, Chain Enantiomer 2)A solution of formaldehyde in water (37% w / w; 72 μL) was added to a stirred solution of Example 26 (80 mg) in CH 3 CN (6 mL) under an atmosphere of nitrogen at ambient temperature. After 15 minutes, NaBH (OAc) 3 (57 mg) was added in portions. The mixture was stirred for a further 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Solvent evaporation gave the title compound (81 mg) as a white foam. HPLC (LC / MS -ES / +): tR = 4.6 min. MS (ES / +): m / z = 449 [M + H] + NMR (CDCl 3): d (ppm) 7.39 (dd, 2H); 7.26 (1, 1H); 7.08 (f, 2H); 7.07 (d, 2H); 5.27 (c, 1 H); 2.88 (broad, 2H); 2.71 (broad, 1 H); 2.62 (m, 1 H); 2. 2-2.6 (broad m, 6H); 2.36 (s, 3H); 2.14 (broad t, 1 H); 1.97 (m, 1 H); 1.8 (m, 1 H); 1.14 (d, 3H).

EXAMPLE 39 1-ri- (3,5-Dichlorophenyl) -etin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidin-2-pyrrolidinone (Diastereomer 2, Chain Enantiomer 2) A solution of formaldehyde in water (37% w / w; 90 μL) was added to a stirred solution of Example 27 (80 mg) in CH3CN (8 mL) under a nylogen atmosphere at ambient temperature. After 15 min., NaBH (OAc) 3 (73.1 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Solvent evaporation gave the compound (91 mg) as a white foam. HPLC (LC / MS -ES / +): R = 4.6 min. - MS (ES / +): m / z = 449 [M + H] + NMR (CDCl 3): d (ppm) 7.36 (dd, 2H); 7.24 (1, 1 H); 6.99 (1, 2H); 6.79 (d, 2H); 5.26 (c, 1 H); 3.05 (dd, 1 H); 2.83 (broad, 1 H); 2.75 (broad, 1 H); 2.39 (id, 1 H); 2.25-2.5 (broad m, .5H); 2.32 (s, 3H); 2.18 (broad, 1 H); 2.06 (m, 1 H); 1.7 (m, 1 H); 1.67 (m, 1 H); 1.4 (d, 3H).

EXAMPLE 40 and 41 1-r (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-pyrrolidinone (Enantiomer 1), 1 - [(3,5-Dichlorophenyl)) methyn-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-pyrrolidinone (Enantiomer 2) A solution of formaldehyde in water (37% w / w; 170 μL) was added to a watery solution of Example 21 (175 mg) in CH3CN (10 mL) under an atmospheric atmosphere of nihorogen at ambient temperature. After 15 min., NaBH (OAc) 3 (134 mg) was added in portions. The mixture was agitated for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent provided a white foam (167 mg), which was purified by preparative SFC chromatography (Gilson) [semi-preparative conditions: chiral column: CHIRALCEL OD, 25 x 2.1 cm; modifier: (n-Hexane / Eilanol + 0.1% isopropylamine) 90/10% volume / volume; -flow rate = 7.0 mL / minute; UV wavelength: 220 nm; injection: 20 mg each injection]; to obtain the compound of item 40 [analytical conditions: Chiral column: CHIRACEL OD, 26 x 0.46 cm; modifier: (n-Hexane / Efanol + 0.1% isopropylamine) 90/10% volume / volume; flow rate = 1.0 mL / minute; UV wavelength: 220 nm; time of residence = 9.5 minutes] (81 mg) and the compound 41 [analytical conditions: Chiral column: CHIRACEL OD, 26 x 0.46 cm; modifier: (n-Hexane / Eilanol + 0.1% of isopropylamine) 90/10% volume / volume; flow rate = 1.0 mL / minute; UV wavelength: 220 nm; Relation time = 11.4 min.] (81.5 mg).

EXAMPLE 40 NMR (CDCl 3): d (ppm) 7.38 (dd, 2H); 7.26 (1, 1H); 7.03 (1, 2H); 6.88 (dd, 2H); 4.29 (d, 1H); 4.1 (d, 1H); 2.92 (m, 1H); 2.7 (broad m, 2H); 2.43 (m, 1H); 2.3 (broad d, 1H); 2.23 (s, 3H); 2.06 (m, 1H); 1.96 (broad, 1H); 1.77 (m, 1H).

EXAMPLE 41 NMR (CDCl 3): d (ppm) 7.38 (dd, 2H); 7.26 (f, 1H); 7.03 (1, 2H); "6.88 (dd, 2H), 4.29 (d, 1H), 4.1 (d, 1H), 2.92 (m, 1H), 2.7 (broad m, 2H), 2.43 (m, 1H), 2.3 (broad d, 1H) ), 2.23 (s, 3H), 2.06 (m, 1H), 1.96 (broad 1, 1H), 1.77 (m, 1H).

EXAMPLE 42 4- (f3-r4- (4-Fluorophenyl) -1-methyl-4-piperidinip-2-oxo-1-pyrrolidinyl > methyl) -2- naphthalenecarbonitrile (Enantiomer 1) A solution of formaldehyde in water (37% w / w; 20 μL) was added to a stirred solution of Example 28 (20 mg) in CH 3 CN (3 mL) under a nitrogen atmosphere at ambient temperature. After 15 min., NaBH (OAc) 3 (15.9 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (19 mg) as a white foam. NMR (CDCl 3): d (ppm) 8.15 (d, 1 H); 8.09 (d, 1 H); 7.89 (dd, 1 H); 7.65 (id, 1 H); 7.61 (id, 1 H); 7.29 (dd, 2H); 7.25 (s, 1 H); 6.85 (id, 2H); 4.67 (d, 1 H); 4.61 (d, 1 H); 2.96 (broad, 1 H); 2.61-2.83 (broad m, 3H); 2.4 (broad, 1 H); 1.92-2.34 (broad m, 6H); 2.25 (s, 3H); 1.91 (m, 1 H); 1.67 (m, 1 H).

EXAMPLE 43 4 - ('f3-r4- (4-Fluorophenip-1-methyl-4-piperidinin-2-oxo-1-pyrrolidinyl methan-2-naphthalenecarbonitrile (Enantiomer 2) A solution of formaldehyde in water (37% w / w; 16 μL) was added to a stirred solution of Example 29 (15 mg) in CH 3 CN (3 mL) under an atmosphere of nitrogen at ambient temperature. After 15 min., NaBH (OAc) 3 (13 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (15 mg) as a white foam.

NMR (CDCl 3): d (ppm) 8.15 (d, 1 H); 8.05 (d, 1 H); 7.89 (dd, 1 H); 7. 65 (id, 1H); 7.61 (td, 1 H); 7.29 (dd, 2H); 7.22 (s, 1 H); 6.87 (td, 2H); 4.65 (d, 1 H); 2.92 (broad t, 2H); 2.81 (broad d, 1 H); 2.7 (m, 1 H); 2.20-2.60 (broad m, 7H); 2.36 (s, 3H); 1.92 (m, 1 H); 1.50-1.80 (m, 1 H).

EXAMPLE 44 7-Fluoro-4- (3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-oxo-1-pyrrolidinyl) methyl) -2-naphthalenecarbonitrile (Enantiomer 2) A solution of formaldehyde in water (37% w / w; 11 μL) was added to a stirred solution of Example 30 (12 mg) in CH 3 CN (2 mL) under an atmosphere of nitrogen at room temperature. After 15 minutes, NaBH (OAc) 3 (8.5 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (11 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 3.99 minutes MS (ES / +): m / z-460 [M + Hf NMR (CDCl 3): d (ppm) 8.22 (d, 1 H); 8.13 (s, 1 H); 7.55 (dd, 1 H); 7. 47 (ddd, 1 H); 7.33 (dd, 2H); 7.26 (d, 1 H); 6.9 (t, 2H); 4.75 (d, 1H); 4.57 (d, 1H); 2.81 (m, 1 H); 2.69 (broad, 3H); 2.45-2.15 (broad m, 5H); 2.22 (s, 3H); 2.15-1.9 (broad m, 3H); 1.71 (m, 1 H).

EXAMPLE 45 6-Fluoro-4 - ((3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 2) A solution of formaldehyde in water (37% w / w, 20 μL) was added to a stirred solution of Example 31 (8 mg) in CH CN (2 mL) under an atmosphere of nitrogen at room temperature. After 15 minutes, NaBH (OAc) 3 (6 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (7 mg) as a white foam. HPLC (LC / MS -ES / +): t R = 3.99 min. MS (ES / +): m / z = 460 [M + H] + NMR (CDCl 3): d (ppm) 8.18 (s, 1 H); 7.95 (dd, 1 H); 7.88 (dd, 1 H); 7. 45 (ddd, 1 H); 7.34 (dd, 2H); 7.31 (s, 1 H); 6.89 (1, 2H); 4.65 (d, 1 H); 4.58 (d, 1 H); 2.86 (m, 1 H); 2.8-2.6 (broad, 3H); 2.45-2.25 (m, 5H); 2.23 (s, 3H); 1.97 (m, 3H); 1.67 (m, 1H).

EXAMPLE 46 7-Fluoro-4- (f3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 1) A solution of formaldehyde in water (37% w / w; 22 μL) was added to an stirred solution of Example 32 (24 mg) in CH3CN (2.5 mL) under a niinogen atmosphere at ambient temperature. After 15 min., NaBH (OAc) 3 (17 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Solvent evaporation gave the title compound (21 mg) as a white foam. HPLC (LC / MS-ES / +): t R = 3.99 minutes MS (ES / +): m / z = 460 [M + H] + NMR (CDCl 3): d (ppm) 8.21 (dd, 1 H); 8.13 (s, 1 H); 7.55 (dd, 1 H); 7. 47 (m, 1 H); 733 (dd, 2H); 7.26 (d, 1 H); 6.9 (t, 2H); 4.-74 (d, 1 H); 4.57 (d, 1 H); 2.9 (broad, 1H); 2.81 (m, 1 H); 2.7 (broad, 4H); 2.45-2.2 (m, 3H); 2.23 (s, 3H); 2.1-1.9 (m, 3H); 1.72 (m, 1 H).

EXAMPLE 47 6-Fluoro-4- (3-r4- (4-fluorophenyl) -1-methyl-4-p -peridinin-2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarbonitrile (Enantiomer 1) A solution of formaldehyde in water (37% w / w; 15 μL) was added to a stirred solution of Example 33 (10 mg) in CH3CN (2.5 mL) under an atmosphere of nitrogen at ambient temperature. After 15 minutes, NaBH (OAc) 3 (8 mg) was added in portions. The mixture was stirred for an additional 1 hour and then concentrated in vacuo. The residue was purified on an SCX cartridge (charged with DCM, washed with MeOH, eluted with 2 M NH 3 in MeOH, followed by MeOH). Evaporation of the solvent afforded the title compound (8 mg) as a white foam. HPLC (LC / MS-ES / +) R = 3.96 minutes MS (ES / +): m / z = 460 [M + H] + NMR (CDCl 3): d (ppm) 8.19 (s, 1 H); 7.95 (dd, 1 H); 7.87 (dd, 1 H); 7. 45 (m, 1 H); 7.35 (dd, 2H); 7.32 (s, 1 H); 6.9 (1, 2H); 4.65 (d, 1 H); 4.58 (d, 1 H); 3.00-2.60 (broad, 3H); 2.5-2.15 (broad m, 5H); 2.24 (s, 3H); 2.09 (broad, 1 H); 1.98 (m, 2H); 1.69 (m, 2H).

EXAMPLE 48 ir (3,5-Dichlorophenyl) metin-3-r 4 - (4-fluorophenyl) -1-methyl-4-piperidinin-1H-pyrrole-2,5-dione Intermediate 63 (92g) was taken with MeOH (100 L). After the solution was complete, 37% aqueous formaldehyde (21 mL) was added, and the mixture was stirred for 10 minutes at 25 ° C. Sodium triacedoxyborohydride (60 g) was added in 10 portions for 30 minutes. After 40 minutes, the reaction mixture was concentrated in vacuo (P = 250 mBar, infernal imaging 37-40 ° C). Aqueous saturated NaHC03 (500 mL) was added to reach pH 8. AcOEi (500 mL) was added, and the phases were separated. The aqueous phase was extracted with AcOEi (500 mL). The combined organic phases were washed with saturated brine / water (1/1). The solution was concentrated to 300 mL, then 450 mL of MeOH was added and the solution was concentrated to obtain an acefe. A chromatographic column (DCM / MeOH 9/1) was necessary to isolate the 5 g of the compound from the ileum. NMR (DMSO): d (ppm) 7.46 (1, 1 H), 7.41 (dd, 2H), 7.11 (m, 4H), 6.93 (s, 1 H), 4.49 (s, 2H), 2.5-2.1 ( m broad, 8H), 2.10 (s, 3H).

EXAMPLE 49 1-r (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-5-methylidene-1,5-dihydro-2H-pyrrol-2-one Example 3 (5 g) was taken with CH 3 CN (50 mL) and added 1. 25 ml of 37% aqueous formaldehyde. After 10 min. At 25 ° C, a solution of 3M NaOH (10 mL) was added and the mixture was stirred at 40 ° C for 4 hours. The reaction was followed by HPLC. The reaction mixture was cooled and filtered to provide 0.6 g of the yolk compound. NMR (CDCl 3): d (ppm) 7.45 (1, 1 H), 7.37 (dd, 2H), 7.18 (broad s, 1H), 7. 09 (1, 2H), 7.02 (d, 2H), 5.03 (d, 1 H), 4.93 (d, 1H), 4.72 (s, 2H), 2.59 (broad m, 2H), 2.49 (broad m, 2H), 2.19 (broad m, 2H), 2.10 (broad m + s, 5H).

EXAMPLE 50 1-R (3,5-dichlorophenyl) metip-3-r4- (4-fluoropheni-1-methyl-4-piperidinip-1,5-dihydro-2H-pyrrol-2-one fumarate salt Example 3 (250 mg) was dissolved in MeOH (2.5 mL) at room temperature under a nitrogen atmosphere. The clear solution was seeded and fumaric acid (67 mg) was added. The crystallization of the solid was observed. The suspension was stirred 16 hours at ambient temperature. He The solid was filtered and dried at ambient temperature in vacuo to give the compound (227 mg). NMR: (d6-DMSO) d (ppm) 7.51 (t, 1 H); 7.41 (dd, 2H); 7.13 (f, 2H); 7.13 (m, 2H); 7.13 (m, 1 H); 6.55 (s, 2H); 4.50 (s, 2H); 3.96 (s, 2H); 2.78 (broad m, 2H); 2.70 (broad m, 2H); 2.62 (broad m, 2H); 2.24 (broad m, 2H); 2.38 (s, 3H). P. f. (mediated by DSC): 205.8 ° C.

TABLE 1 The X-ray powder diffraction pattern of the production of Example 50 in terms of spacing "d" is as follows EXAMPLE 51 1-R (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenyl) -1-methyl-4-piperidinin-1,5-dihydro-2H-pyrrole-2 citrate salt -one (crystalline form 1) Method A Example 3 (200 mg) was dissolved in teirahydrofuran (2 mL) at ambient temperature under a nimrogen atmosphere. The clear solution was seeded and a solution of citric acid (88 mg) in MeOH (0.5 mL) was added. The chilling of the solid was observed. The suspension was stirred for 16 hours at ambient temperature. The solid was filtered and dried at ambient temperature in vacuo to provide the compound of the extract (200 mg). NMR (de-DMSO) d (ppm) 11.6-10.4 (broad, 3H); 7.52 (f, 1 H); 7.42 (dd, 2H); 7.17 (f, 2H); 7.16 (m, 2H); 7.16 (m, 1 H); 4.51 (s, 2H); 3.96 (s, 2H); 3.06-2.97 (broad m, 4H); 2.82 (broad m, 2H); 2.29 (broad m, 2H); 2.65 (s, 3H); 2.60 (d, 2H); 2.52 (d, 2H), p. F. (mediated by DSC): 156.6 ° C.

Method B Example 1 (5 Kg) was taken with 100 mL of MeOH (25 L). After fermenting the solution, aqueous formaldehyde (1.15 L) was added, and the mixture was stirred for 10 minutes at 25 ° C. Sodium idozoxiborohydride (3.3 kg) was added in 10 portions during 30 minutes. After 40 min., The reaction was concentrated under vacuum (P = 250 mBar, infernal imaging 37-40 ° C) at 15 L. Aqueous saturated NaHCO 3 was added. (30 L) to reach a pH 8 (pH paper). AcOEf (25 L) was added and the phases separated. The aqueous phase was extracted with AcOEi (25 L). The combined organic phases were washed with salted brine / paraffin water (1/1, 10 L). The solution was concentrated to 15 L, then MeOH (25 L) was added, and the solution containing Example 3 was concentrated to 25 L and added with citric acid (2285 g) in one portion. The solution was stirred for 15 minutes (until the solid solution was completed), and Buhenone (50 L) was added in 1.5 hours. Some seeds were added and the solution stirred for 18 hours. The suspension was concentrated to 30 L and stirred for 4 hours. The solid was filtered and washed with MeOH / 2-Buyenone 1/1 (10 I) to obtain the compound of the filtrate (2.5 Kg). Melting point (by DSC): 161 ° C. NMR (de-DMSO) d (ppm) 11.6-11.4 ppm (broad, 3H), 7.49 ppm (t, 1 H), 7.40 ppm (m, 2H), 7.14 ppm (m, 5H), 4.49 ppm (s, 2H), 3.95 ppm (s, 2H), 3.1-2.9 ppm (broad m, 4H), 2.8 ppm (broad m, 2H), 2.65ppm (s, 3H), 2.58ppm (d, 2H), 2.52ppm ( d, 2H), 2.30 ppm (broad m, 2H).

TABLE 2 The X-ray powder diffraction pattern of the product of Example 51 in spacing "d" is as follows EXAMPLE 52 1-R (3,5-Dichlorophenyl) metin-3-r4- (4-fluorophenip-1-methyl-4-piperidinin-1,5-dihydro-2H-pyrrol-2-one citrate salt) Crystal shape 2) Example 3 (25 g) was dissolved in feirahydrofuran (200 ml) at room temperature under nitrogen. The clear solution was seeded and A solution of cyclic acid (11 g) was added to meianol (50 ml). 125 ml isocyanum was added to the mixture and the mixture was allowed to stir overnight. Then an additional 50 ml of isocyana was added and it was stirred for 2 hours. The solid was filtered very leniamenle and dried in an oven at 40 degrees to provide 30.5 g of the title compound. Melting point (by DSC): 137 ° C. NMR (de-DMSO) d (ppm) 11.6-11.4 ppm (broad, 3H), 7.49 ppm (t, 1H), 7.40 ppm (m, 2H), 7.14 ppm (m, 5H), 4.49 ppm (s, 2H) ), 3.95 ppm (s, 2H), 3.1-2.9 ppm (broad m, 4H), 2.8 ppm (broad m, 2H), 2.65 ppm (s, 3H), 2.58 ppm (d, 2H), 2.52 ppm (d) , 2H), 2.30 ppm (broad m, 2H).

TABLE 3 The X-ray powder diffraction paphron of the production of Example 52 in terms of spacing "d" is as follows EXAMPLE 53 Citrate salt of 1-r (3,5-dichlorophenyl) metip-3-r 4 - (4-fluorophenyl) -1-methyl-4-piperidinir) -1,5-dihydro-2H-pyrrole-2- ona (crystalline form of hydrate) Example 52 (0.200 g) was suspended and stirred in water (2 ml) at ambient temperature. The suspension was heated to 50 ° C. The solution was cooled to 20 ° C. Precipitation of the solid occurred. The suspension was stirred 16 hours at 20 ° C. The solid was filtered and dried at ambient temperature under vacuum to give the condensate of the filtrate (0.172 g). Melting point (mediated DSC): 100.29 ° C NMR (s2364): (DMSO) d (ppm) 11.8-10.2 (broad, 3H), 7.48 (m, 1H), 7.39 (m, 2H), 7.14 (m, 2H), 7.13 (m, 3H), 4.48 (s, 2H), 3.93 (s, 2H), 3.6-2.1 (broad m, 8H), 2.62 (s, 3H), 2.53 (d, 2H), 2.49 ( d, 2H).

TABLE 4 The X-ray powder diffraction pattern of the product of Example 53 in terms of spacing "d" is as follows

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I) where --- represented a single link or a double link; R represented a radical selected from: wherein R 1 is halogen, cyano, C 4 alkyl, C- alkoxy, trifluoromethyl or trifluoromethyloxy and p is zero or an ether of 1 to 3; R2"represented hydrogen or alkyl of C-; R3 represented hydrogen, hydroxy or C1-4 alkyl, R4 represents hydrogen or R4 june with R3 represents it = 0 or = CH2, R5 represents phenyl, naphthyl, a bicyclic heterocyclic group of 9 to 10 members or a 5- or 6-membered heteroaryl group, wherein the groups are optionally substituted with 1 to 3 groups independently selected from trifluoromethyl, C alquilo _ alkyl, hydroxy, cyano, C? -4 alkoxy, trifluoromethoxy, halogen or S (0) C1-6alkyl; R6 and R7 represent independently hydrogen, cyano, C 4 -alkyl; R8 is (CH2) rR? 0; Rg represents hydrogen, halogen, C3-7 cycloalkyl, hydroxy, nitro, cyano or C1.4 alkyl optionally substituted with one or two groups selected from halogen, cyano, hydroxy or C1-4 alkoxy; R10 represented hydrogen or C3-7 cycloalkyl; n represented 1 or 2; q is 0, 1 or 2; r is 0 or an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof. 2. The compound according to claim 1, further characterized, because n is

2.

3. The compound according to claim 1 or claim 2, further characterized because R represented: wherein R-i is halogen, C 1-4 alkyl, cyano, C-? - alkoxy, frifluoromethyl or trifluoromethyloxy, p is zero or an ether of 1 to 3;

4. The compound according to any of claims 1 to 3, further characterized in that R5 represents phenyl or optionally naphthyl optionally with one or two groups selected from trifluoromethyl, cyano, C ?- or halogen alkyl.

5. The compose of conformity with any of claims 1 to 4, further characterized in that R8 is (CH2) rR10 wherein R10 is hydrogen or C3-7 cycloalkyl (for example) and r is 0 or 1.

6. - The compound according to any of claims 1 to 5, further characterized in that Rg is hydrogen or optionally substituted C 1 - 4 alkyl with one or two groups selected from halogen.

7. The compound according to any of claims 1 to 6, further characterized in that R is phenyl which is suspended by a fluorine, R2, Rg and R4 are hydrogen, R3 is hydrogen, hydroxy or meiyl, or together with R4 form = 0 or = CH2, R6 and R7 are independently hydrogen or meityl, R5 is phenyl or naphthyl independently substituted with one or two groups independently selected from cyano, methyl, a chlorine atom, bromine, fluorine, R8 is hydrogen , meiloyl or cyclopropylmethyl and n is 2.

8. The compound according to claim 1, further characterized in that it is 1 - [(3,5-Dichlorophenol) meily] -3- [4- (4-fluorophenyl) - 4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-pperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 1- [1- (3,5-Dichlorophenyl) -yryl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1); 1 - [(1S) -1- (3-Chloro-1-naphthalenyl) eyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrole-2 -one; 1 - [(3-Chloro-1-naphthalenyl) -methyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; 4- ( { 3- [4- (4-Fluorophen-l) -4-p-peridinyl] -2-oxo-2,5-dihydro-1 H -pyrrol-1-yl} .methyl) - 2-naphthalenecarbonaryl; 1 - [1 - (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 2); 1 - [(1 R) -1- (3-Chloro-1-naphthalenyl) eyl] -3- [4- (4-fluorophenyl) -4-piperidin] -1,5-dihydro-2H- pyrrole-2-one; eleven - (3,5-Dichlorophenyl) -yryl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1); 1 - [(1S) -1- (3-Chloro-1-naphthalethylethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrole-2 -one; 1 - [(3-Chloro-1-naphthalenyl) meityl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidin] -1,5-dihydro-2H-pyrrole -2- ona; 1- [1- (3,5-Dichlorophenyl) eyl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Enantiomer of Chain 2); 1 - [(1 R) -1- (3-Chloro-1-naphthalene) eyl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -1, 5-dihydro-2H-pyrrol-2-one; 4- ( { 3- [4- (4-Fluorophenyl) -1-meityl-4-piperidinyl] -2-oxo-2,5-dihydro-1 H -pyrrol-1-yl} .methyl) - 2-naphthalenecarbonaryl; Chlorhydrate of 1- [1- (3,5-Dichlorophenyl) efyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one (Chain Enantiomer 1); 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidin] -1,5-dihydro-2H-pyrrole hydrochloride -2-ona (Chain Enantiomer 1); 1 - [(3-Chloro-1-naphthalene-1) -methyl] -3- [1- (cyclopropylmethyl) -4- (4-fluorophenyl) -4-piperidinyl] -1,5-dlhydro-2H -pyrrol-2-one; 1 - [(3,5-Dichlorophenyl) -methyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone 1 - [(1 S) -1 - (3-Chloro-1 -naphthalenyl ) -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (diastereoisomer 1) "; 1 - [(1S) -1- (3-chloro-1-naphthalenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone; 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) - 4-piperidinyl] -2-pyrrolidinone (diastereoisomer 1 chain enaniomer 1); 1- [1- (3,5-dichlorophenyl) eyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2- pyrrolidinone (Diasereoisomer 2 Chain Enaniomer 1): 1- [1- (3,5-Dichlorophenyl) etl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (diastereoisomer 1 enaniomer of Chain 2); 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -4-piperidinyl] -2-pyrrolidinone (Diasteroisomer 2 Chain Enantiomer 2); 4- ( { 3- [4- (4-Fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl}. MethyI) -2-naphthalenecarbonitrile (Enaniomer 1); 4- ( { 3- [4- (4-Fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2- naphthalenecarbonitrile (Enantiomer 2); 7-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl}. Mephyl) -2-naphthalenecarbonylphrite (Enantiomer 2); 6- Fluoro-4- ( { 3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2- naphthalenecarboniiryl (Enaniomer 2); 7-Fluoro-4- (. {3- [4- (fluorophenyl) -4-pperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2-naphthalenecarbonitrile (Enantiomer 1); 6- Fluoro-4- ( { 3- [4- (4-fluorophenyl) -4-piperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2- naphthalenecarboniiryl (Enaniomer 1); 1 - [(3,5-Dichlorophenyl) meily] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone; 1 - [1 - (3-Chloro-1 -naphthalenyl) eyl] -3- [4- (4-fluorofenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (diastereoisomer 2 chain enaniomer 1); 1- [1- (3,5-Dichlorophenyl) eyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-pyrrolidinone (Diasphereisomer 1 Chain Enantiomer 1); 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-mephyl-4-piperidinyl] -2-pyrrolidinone (diastereomer 2 chain enaniomer 1); 1- [1- (3,5-Dichlorophenyl) eyl] -3- [4- (4-fluorophenyl] -1-meityl-4-piperidinyl] -2-pyrrolidinone (Diastereoisomer 1 Chain Enantiomer 2); 1- [1- (3,5-Dichlorophenyl) ethyl] -3- [4- (4-fluorophenyl) -1-methyl-4-p-perldinyl] -2-pyrrolidinone (diastereoisomer 2 enantiomer of Chain 2); 1 - [(3,5-Dichlorophenyl) meily] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -2-pyrrolidinone (Enantiomer 1); 1 - [(3,5-Dichlorophenyl) meityl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -2-pyrrolidinone (Enaniomer 2); 4- ( { 3- [4- (4-Fluorophenol) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2- naphthalenecarbonifrile (enaniomer 1); 4- ( { 3- [4- (4-Fluorophenyl) -1-meityl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} methyl) -2-naphthalenecarboniiryl (Enantiomer 2); 7- Fluoro-4- ( { 3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2 - naphthalenecarboniiryl (enaniomer 2); 6-Fluoro-4- ( { 3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -2-oxo-1-pyrrolidinyl} -methyl) -2-naphthalenecarbonaryl; 7-Fluoro-4- (3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrroxy-pentyl} -methyl) -2-naphthalenecarbonitrile ( Enaniomer 1); 6-Fluoro-4- (. {3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -2-oxo-1-pyrrolidinyl] -methyl) -2-naphthalenecarbon Írilo (Enaníiómero 1); 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1 H -pyrrole-2,5-dione; 1 - [(3,5-Dichlorophenol) meily] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidin] -5-methylidene-1,5-dihydro-2H -pyrrole-2-one; or a pharmaceutically acceptable salt (for example, hydrochloride, fumarole or gallium) or a solvap or amorphous or chylaaline forms thereof.

9. The compound according to claim 1, further characterized in that it is 1 - [(3,5-Dichlorophenyl) methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; Chlorhydrate of. 1 - [(3,5-D'-chlorophenyl) -methyl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; Fumarum of 1 - [(3,5-Dichlorophenyl) -methyl] -3- [4- (4-fluorophenyl) -1-meityl-4-piperidinyl] -1,5-dihydro-2H-pyrrol-2-one; Crystallization of 1 - [(3,5-Dichlorophenyl) -methyl] -3- [4- (4-fluorophenyl) -1-methyl-4-pperidinyl] -1,5-dydro-2H-pyrrole -2-ona; or chrysalis forms thereof.

10. A process for the preparation of a compound according to claim 1, the method comprises: a) cyclization of a compound of formula (IV), wherein R 11 is C 1 - alkyl (eg methyl) or ethyl), R3 is hydrogen or C---4 alkyl and R8a has the meaning defined in formula (I) or is a nitrogen protecting group, and R, R2, R5, R6, R7, R9 and n are according to claim 1, to provide a compound of formula (I), wherein - is a single bond, R3 represents hydrogen or C? -4 alkyl and R4 represents hydrogen, or b) cyclization of a compound of formula (V) , where R8a has the (SAW) meaning defined in formula (I) or is a protecting group of niógeno, R, R2, R5. Re, R7, R9 and n are in accordance with claim 1, to provide a compound of formula (I), wherein - is a single bond, R3 is hydroxy and R4 is hydrogen, or c) cyclization of a compound of formula (VII) ), wherein R8a has the meaning defined in formula (I) or is a protecting group of nihologen, is a leaving group and R, R2, R5, Re, R7, R9 and n are in accordance with claim 1, to provide a compound of formula (I) wherein - is a single bond and R3 together with R4 represents = 0, or d) the reaction of a compound of formula (VIIA), wherein R, R2, R5, Re, R7, R9 and n are in accordance with claim 1, (VISA) with an aldehyde, CH (O) (CH2) mR? 0 (Villa), wherein m is an integer from 0 to 3 and R10 is in accordance with claim 1, to provide a compound of formula (I), wherein - is a single bond, R8 represents (CH2) rR? 0, where r is an integer from 1 to 4 and R3 june with R4 represented = 0, oe) cyclization in the presence of an acid of a compound of formula (Via), wherein R3 is hydrogen, R8a has the meaning defined in formula (I) or is a protecting group of nihorogen, R, R2, R5, Re, R, R9 and n are in accordance with claim 1, to provide compounds of formula (I ), where - is a double bond, R3 represented hydrogen or C1-4 alkyl and R4 is hydrogen; of) N-alkylation of a compound of formula (VIII) wherein R8a has the meaning defined in formula (I) or is a nitrogen protecting group and R, R2, R5, R6, R7, Rg and n are in accordance with Claim 1, with a compound of formula (IX) L-CÍRsKRßXRy) (IX) in which L is a leaving group, R_, Re and R7 are according to claim 1, to provide a compound of formula (I), wherein - is a simple bond, and optionally, optionally for any of steps (a) to (f): removing any protecting group and / or converting a compound of formula (I) into another compound of formula (I) and / or separation of a compound of formula (I) in or a derivative thereof in the enantiomers thereof, forming a pharmaceutically acceptable salt thereof.

11. The compound according to any of claims 1 to 9, for use in therapy.

12. The use of a compound according to any of claims 1 to 9 in the preparations of a medicament for use in the period of conditions mediated by the ayacicinins. (including substance P and other neurokinins) and / or selective inhibition of the protein of the serotonin reuptake transporter.

13. A pharmaceutical composition comprising a compound according to any of claims 1 to 9, in admixture with one or more pharmaceutically acceptable carriers or excipients. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I) where - represented a single link or a double link; R represents a radical selected from formulas i), ii), iii) and iv), in which Ri is halogen, cyano, C? -4 alquiloalkyl, C -? Alco alco alkoxy, írif lu lu o,,,,, or an integer from 1 to 3; R2 represented hydrogen or a C? -4 alkyl; R3 represented hydrogen, hydroxy or C1-4 alkyl; R4 represented hydrogen or R4 together with R3 represented = O or = CH2; R5 represented phenyl, naphthyl, a fused bicyclic heyerocyclic group of 9 to 10 members or a 5- or 6-membered heteroaryl group, wherein the groups were optionally substituted with 1 to 3 groups independently selected from C1-4 alkyl fluoride, hydroxy, cyano, C1.4 alkoxy, frifluoromethoxy, halogen or S (0) qalkyl of C? -4; R6 and R7 independently represented hydrogen, cyano, alkyl C ?.; R8 is (CH2) rR-? 0; Rg represented hydrogen, halogen, C3.7 cycloalkyl, hydroxy, nylro, cyano or optionally C-unsubstituted alkyl with one or two groups selected from halogen, cyano, hydroxy or C-alkoxy; R 0 represented hydrogen or C 3 - cycloalkyl; n represented 1 or 2; q is 0, 1 or 2; r is 0 or an integer from 1 to 4; or a pharmaceutically acceptable salt or solvation thereof, a procedure for its preparation and its use in the irradiation of conditions mediated by the ichquicinins and / or by the selective inhibition of the serotonin reuptake transporter protein. 28B P06 / 436F