MXPA06008934A - Piperidinylcarbonyl-pyrrolidines and their use as melanocortin agonists - Google Patents

Abstract

The present invention relates to a class of melanocortin MCR4 agonists of general formula (I) wherein R', R2, R3, R4 and R5 are as defined herein and especially to selective MCR4 agonist compounds, tot heir use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.

Description

PIPERIDINILCARBONIL-PIRROLIDINAS AND ITS USE AS AGELISTS OF MELANOCORTINA DESCRIPTIVE MEMORY The present invention relates to a new class of melanocortin agonist compounds MCR4 and, especially, to selective MCR4 agonist compounds, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. In particular, the present invention relates to a class of MCR4 agonist compounds useful for the treatment of sexual dysfunction and / or obesity. The compounds of the present invention are useful for treating male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and / or female sexual pain disorder, male erectile dysfunction, as well as obesity (reducing appetite, increasing the metabolic rate, reducing fat intake or reducing the craving for carbohydrates) and diabetes mellitus (enhancing glucose tolerance and / or reducing insulin resistance). The compounds of the invention are useful for treating other diseases, disorders or conditions including, but not limited to, hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neurosis, insomnia / disorders. of sleep, substance abuse, pain, fever, inflammation, immune modulation, rheumatoid arthritis, darkening of the skin, acne and other skin disorders, and neuroprotective, cognitive and memory enhancement including the treatment of Alzheimer's disease. The compounds of the present invention are particularly suitable for treating female sexual dysfunction, male erectile dysfunction, obesity and diabetes. The desirable properties of the MCR4 agonist compounds of the present invention include: desirable MCR4 potencies as detailed hereinafter; selectivity for MCR4 against MCR1 and / or MCR5 and / or MCR3 as detailed later in this document; desirable MCR4 potency and selectivity for MCR4 against MCR1 and / or MCR5 and / or MCR3; good biopharmaceutical properties such as physical stability; solubility; and appropriate metabolic stability.

General Formula The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. where R1 is selected from: -alkyl (C -? - C6), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C6), -cycloalkenyl (C5-C8), -alkyl (C -? - C2) - (C3-Ce) cycloalkyl, aryl, -arylalkyl (CrC2), heterocyclyl or alkylheterocyclic groups (CrC2) where each of the above R1 groups are optionally substituted with one or more groups selected from: -alkyl (C C4), - (CH2) mCycloalkyl (C3-C5), halogen, - (CH2) mOR6, CN, -C (O) OR6, - (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2 where m = 0, 1 or 2; R2 is H, OH or OCH3; R3 is selected from: H, -alkyl (C-pCß), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C6), -cycloalkenyl (C5-C8), -alkyl ( C C2) -cycloalkyl (OrCß), aryl, -alkylaryl (C C2), heterocyclyl, or alkylheterocyclic groups (CrC2) where each of the last ten R3 groups is optionally substituted with one or more groups selected from: OH, -alkyl (C C4), - (CH2) nCycloalkyl (C3-C5), halogen, CN, - (CH2) nOR6 or - (CH2) nOR6 or - (CH2) nNR7R8, where n = 0, 1 or 2; R4 is selected from: H, -alkyl (CC), -alkenyl (C2-C4), -alkynyl (C2-C4), - (CH2) pccycloalkyl (C3-C5), - (CH2) p (C5) c; clo-alkenyl, halogen, - (CH2) PNR7R8, CN, -C (O) R6, -C (0) OR6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or groups OCH2CF3 where p = 0, 1 or 2; R5 is selected from: -alkyl (C4), -alkenyl (C2-C4), -alkynyl (C2-C4) '"(CH2) pccycloalkyl (C3-C5), - (CH2) p (C5) cycloalkenyl , halogen, - (CH2) pOR6, - (CH2) PNR7R8, CN-C (O) R6, -C (O) NR7R8, (CH2) pNR7SO2R8, CF3, CH2CF3, OCF or groups OCH2CF3, where p = 0.1 or 2; or R4 and R5 can together form a 5 to 7 membered ring, saturated or unsaturated and condensed; each of R6, and R8 is independently selected from H, CH3 or CH2CH3; and wherein the heterocyclic groups of R1 and R3 are independently selected from 4- to 10-membered ring systems containing up to 4 heteroatoms independently selected from 0, N, or S. Suitable heterocyclic groups for use herein are mono or bicyclic heteroaryl rings from 4 to 10 members containing one to three heteoatoms selected from N, S and O and combinations thereof and wherein said bicyclic heteroaryl rings are 9 to 10 membered ring systems which may be two fused heteroaryl rings or a heteroaryl ring condensed with an aryl ring. Bicyclic heteroaryl groups suitable for use in this document include; benzimidazolyl, benzotriazolyl, benzothiazolyl, indazolyl, indolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl and pyridopiimidinyl groups.

Preferred for use herein are 5 to 6 monocyclic heteroaryl rings containing one or three heteroatoms selected from N and O and combinations thereof. The monocyclic 5-membered ring heteroaryl groups for use herein include: triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, and pyrrolyl and imidazolyl groups. Monocyclic heteroaryl groups with 6-membered ring for use herein include: pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl groups. Preferred heterocyclic rings R1 are the heteroaryl rings of to 6 members containing one to two heteroatoms selected from N and O and combinations thereof. More preferred heterocyclic rings R are heteroaryl rings of 5 to 6 monocyclic members containing one or two heteroatoms N. Heterocyclic rings R are most preferred heteroaryl rings of 6 monocyclic members containing one or two N heteroatoms such as pyridinyl and pyrimidinyl. A heteroaryl group R1 especially preferred herein is the pyridinyl group. Preferred heterocyclic rings R3 are the 5- to 6-membered monocyclic heteroaryl rings containing one or two heteroatoms selected from N and O and combinations thereof, such as tetrahydropyranyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidihyl groups. More preferred heterocyclic rings R3 are 5-6 membered heterocyclic monocyclic rings containing one or two heteroatoms N. More heterocyclic rings R3 are more preferred 6-membered heterocyclic monocyclic rings containing one or two N heteroatoms such as pyridinyl, pyridazinyl groups , pyrazinyl and pyrimidinyl. Particular monocyclic heteroaryl groups with 6-membered ring R3 are particularly preferred pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl and pyrimidin-2-yl groups. Particularly preferred 6-ring ring heteroaryl groups R3 for use herein include the pyridin-2-yl, pyridin-3-yl and pyridazin-3-yl groups. Of these groups, pyridazin-3-yl is most preferred. Suitable fused ring systems formed together by R 4 and R 5 can be carbocyclic ring systems or heterocyclic ring systems containing up to two heteroatoms selected from 0, N or S. Including the phenyl ring to which they are attached, the preferred ring systems which can form R4 and R5 are: indane, 1, 2,3,4-tetrahydronaphthalene, ndolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzimidazolyl, benzo [1,3] dioxolane, 2,3-dihydrobenzo [1, 4] doxin, 2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene and 1,3-dihydroisobenzofuran. In the above definitions, unless otherwise indicated, alkyl, alkenyl and alkynyl groups having three or more carbon atoms and alkanoyl groups having four or more carbon atoms may be straight chain or branched chain. For example, a C4 alkyl substituent may be in the form of normal butyl (n-butyl), isobutyl (i-butyl), secondary butyl (sec-butyl) or tertiary butyl (t-butyl). For the avoidance of doubt, when R1 and / or R3 is an optionally substituted alkyl group, said alkyl group (s) can not be further substituted with another (unsubstituted) alkyl group. Further, when R3 is substituted with an alkenyl or alkynyl group, the carbon atom (of said unsaturated group), which is directly attached to the N atom, can not be unsaturated. The term halogen includes Cl, Br, F and I. The term "aryl", when used herein, includes carbocyclic aromatic groups of six to ten members, such as phenyl and naphthyl. The present invention also provides compounds of general formulas (IA) to (IF) as well as mixtures thereof as detailed later in this document. For the avoidance of doubt, it is intended that all references to compounds of the general formula (I) in this document, such as, for example, salts, polymorphs, prodrugs or optical, geometric and tautomeric isomers thereof include the compounds of the general formulas (IA) to (IF) unless specifically indicated otherwise. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and the base addition salts thereof. A pharmaceutically acceptable salt of a compound of formula (I) can be prepared easily by mixing solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from the solution and be collected by filtration or recovered by evaporation of the solvent. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate salt, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, id royod uro / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylisulfate, naphthylate, 2, napsylate, nicotinate, oratate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate , pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Hemisal acids and bases may also be formed, for example, hemisulfate and hemicálcic salts. For a review of suitable salts, see Handbook or Pharmacuetical Salts; Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002).

The pharmaceutically acceptable salts of compounds of formula I can be prepared by one or more of three methods: (i) by reacting the compound of formula I with the desired acid or base; (ii) removing a protecting group from the labile acid or base of a suitable precursor of the compound of formula I or opening the ring with a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) transforming one salt of the compound of formula I into another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. The three reactions are typically performed in solution. The resulting salt can be removed by precipitation and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from completely ionized to almost un-ionized. The compounds of the invention can exist in a variety of solid states ranging from completely amorphous to fully crystalline. The term "amorphous" refers to a state in which the material lacks ordering at the molecular level and, depending on the temperature, can show the physical properties of a solid or a liquid. Typically such materials did not provide different X-ray diffraction patterns and, although they show the properties of a solid, they are more formally described as a liquid. Upon heating, a change from solid to liquid state occurs which is characterized by a change of state, typically of second order ('vitreous transition'). The term "crystalline" refers to a solid phase in which the material has an internal structure ordered at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. When sufficiently heated such materials also show properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of first order ('melting point'). The compounds of the invention can also exist in solvated and unsolvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethane. The term "hydrate" is used when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or coordinated metal hydrates - see Polymorphism in Pharmacuetical Solids by K.R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are those in which water molecules are isolated from direct contact with each other by the intervention of organic molecules. In channel hydrates, water molecules are in the channels of the crystallographic network where they are close to other water molecules. In hydrates coordinated by metal ion, the water molecules are bound to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of moisture. However, when the solvent or water is weakly bound, as in channel solvates and in hygroscopic compounds, the water / solvent content will depend on the humidity and the drying conditions. In such cases, the norm will be the lack of stoichiometry. Also included within the scope of the invention are multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents that are bound together by non-covalent interactions, but they could also be a complex of a neutral molecule with a salt. The co-crystals can be prepared by melt crystallization, by recrystallization from solvents or by physical trituration of the components - see Chem Common, 17, 1889-1896, by O. Almarsson and M. J. Zawarotko (2004). As a general reference for multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975). The compounds of the invention can also exist in a mesomophic state (mesophase or liquid crystal) when subjected to the appropriate conditions. The mesomorphic state is intermediate between the actual crystalline state and the actual liquid state (molten or in solution). The mesomorphism that arises as a result of a change in temperature is described as "thermotropic" and that which results from the addition of a second component, such as water or other solvent, is described as "lyotropic". Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and are composed of molecules that have an ionic polar head group (such as -COO "Na +, -COO" K +, or - SO3-Na +) or not ions (such as -N "N + (CH3) 3) For more information, see Crvstals and the Polarizinq Microscope by NH Hartshorne and A. Stuart, 4th Edition (Edgard Arnold, 1970). Henceforth, all references to Compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof The compounds of the invention include compounds of formula (I) as defined hereinbefore, polymorphs and crystalline habits. of them, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinbelow and compounds of formula (I) labeled with isotopes. "of the compounds of formula (I) are also within the scope of the invention. In this way, certain derivatives of compounds of formula (I), which may have little or no pharmacological activity by themselves, may, when administered in the body, be transformed into compounds of formula (I) with the desired activity, for example , by hydrolytic cleavage. Reference is made to such derivatives as "prodrugs". Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Druq Design, Pergamon Press, 1987 (Ed. EB Roche, American Pharmacuetical Association). Prodrugs according to the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) with certain residues known to those skilled in the art as "pro-residues" as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the invention include: (i) when the compound of formula I contains a carboxylic acid functionality (-COOH) or an ester thereof, for example, a compound in which the hydrogen of the carboxylic acid of the compound of formula (I) is replaced by -alkyl (C-tC8); (I) when the compound of formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound in which the hydrogen of the alcohol functionality of the compound of formula I is replaced by -alkyloxymethyl (Ci) -Ce), such as for example when R2 = OH, or when the group R3 is substituted with an -OH group, a preferred prodrug in this document is an ether; and (iii) when the compound of formula I contains a primary or secondary amino functionality (-NH2 or -NHR where R? H), such as for example when R3 = H, a preferred prodrug is an amide thereof, for example, a compound in which, as the case may be, one or both of the hydrogens of the amino functionality of the compound of formula I are replaced by (C1-C10) alkanoyl, preferably alkanoyl (CrC6), more preferably methyl, ethyl or propylalkanoyl . Particularly preferred prodrugs herein are ethers, alkyl ethers, etc. (C C) and alkyl esters (CrC 4) of the compounds of general formula (I), with esters being particularly preferred.

The ester prodrugs are described in detail in "Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: Challenges to the discovery scientist" Current Drug Metabolism, (2003), 4 (6), 461-485. Other examples of replacement groups can be found according to the above examples and examples of other types of prodrugs in the references mentioned above. Finally, certain compounds of formula (I) can act by themselves as prodrugs of other compounds of formula (I). Also included within the scope of the invention are metabolites of compounds of formula I, i.e., compounds formed in vivo after drug administration. Some metabolite temples according to the invention include: (i) when the compound of formula I contains a methyl group, a hydroxymethyl derivative thereof (-CH3-> -CH2OH): (ii) when the compound of formula 1 contains an alkoxy group, a hydroxy derivative thereof (-O- > -OH); (iii) when the compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR7R8-> -NHR7R8-> -NHR7 or -NHR8 where R7 and R8 are different groups); (iv) when the compound of formula I contains a secondary amino group, a primary derivative thereof (-NR7"> -NH2); (v) when the compound of formula I contains a phenyl residue, a phenol derivative thereof ( -Ph-> -PhOH) and (vi) when the compound of formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> -COOH) The compounds of formula (I) containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers.When a compound of formula (I) contains an alkenyl or alkenylene group, the cis / trans (or ZJ / E) geometric isomers are possible. are convertible to each other through a low energy barrier, tautomeric isomerism ("tautomería") can take place. This can take the form of proton tautomerism in compounds of formula (I) which contain, for example, an imino, keto or oxime group, or the so-called valence tautomerism in an aromatic moiety. From this it follows that a single compound can show more than one type of soma. Within the scope of the present invention are included all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds that show more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition salts or bases in which the counterion is optimally active, for example, -lactate or / -lysine, I or racemic, for example, aV-tartrate or a7-arginine. Specifically included within the scope of the present invention are stereoisomeric mixtures of compounds of formula (I), or a diastereomerically enriched or diastereomerically pure isomer of a compound of formula (I), or an enantiomerically enriched or enantiomerically pure isomer of a compound of formula (I). The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optimally pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, high pressure chiral liquid chromatography (HPLC). .

Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optimally active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acid or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers can be transformed into the corresponding pure enantiomer or enantiomers by means well known to those skilled in the art. The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, in an asymmetric resin with a mobile phrase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isoproanol, typically from 2 to 20%, and may contain from 0 to 5% in volume of an alkylamine. The concentration of the eluate produces the enriched mixture. The absolute composition of the mobile phase will depend on the selected chiral stationary phase (asymmetric resin). Preparation 2 as described in detail below in this document provides an example of such separation technique. When a racemate crystallizes, there are two types of crystals possible. The first type is the racemic compound (real racemate) referred to above when a homogeneous crystal form is produced which contains both enantiomers in equimolar amounts. The second type is the racemic or conglomerate mixture in which two crystal forms are produced in equimolar amounts each comprising a single enantiomer. Although both crystalline forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the actual racemate. The racemic mixtures can be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S.H. Wilen (Wiley, 1994). In this way, the present invention additionally provides compounds of the general formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG) and (IH). where R1, R2, R3, R4 and R5 are as previously defined herein. Also included are compounds of the general formulas (IB) and (ID) in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are in the cis configuration with each other. Preferably the present invention provides compounds of general formula (IA), more preferably compounds of general formula (IC), even more preferably compounds of general formula (IE) and especially compounds of general formula (IF). The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms are replaced with atoms having the same atomic number but having an atomic mass or mass number other than the atomic mass or number Mass that is normally found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen isotopes, such as 2H and 3H, carbon, such as 11C, 13C and 14C, of chlorine, such as 36CI, of fluorine, such as 18F, of iodine, such as 123l and 125l, of nitrogen, such as 13N and 15N, of oxygen, such as 15O, 17O and 18O, of phosphorus, such as 32P, and of sulfur, such as 35S. Certain compounds labeled with isotopes of formula (I), for example, those that incorporate a radioactive isotope, are useful in studies of drug distribution and tissue substrates. The radioactive tritium, ie, 3H, and carbon-14, i.e., 14C, radioactive sotopes are particularly useful for this purpose in view of their ease of incorporation and detection means. Substitution with heavier isotopes such as deuterium, i.e., 2h, may produce certain therapeutic advantages as a result of increased metabolic stability, for example, a longer half-life in vivo or lower dosing requirements and therefore may be preferred in some circumstances. Substitution of positron emission isotopes, such as 11C, 18F, 15 ° and | 3N, may be useful in Positron Emission Topography (PET) studies to examine receptor occupancy in the substrate. The isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples and adjunct preparations using an isotope-labeled reagent instead of unlabelled reagent previously employed . The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with isotopes, for example, D2O-acetone and d6-DMSO. According to a preferred embodiment, the present invention provides a group of compounds of formula (I), preferably formula (IA), more preferably formula (IC), even more preferably formula (IE) and especially of formula (IF), where R1 is selected from alkyl (C -? - C6), - C3 - C8 - cycloalkyl), - CrC2 - alkyl - cycloalkyl OrCß), phenyl, - C -? - C2 - alkylaryl), heterocyclyl or - CrC2 - alkyl --heterocyclic groups and - wherein R1 is optionally substituted with one or more groups selected from -C1-alkyl), - (CH2) n, OR6, - (CH2) -C3-C5-cycloalkyl), halogen, OCH3, OCH2CH3, CN, CF3, CH2CF3, OCF3 or OCH2CF3 , where m = 1 or 2. and where when R1 is a heterocyclyl, or an -alkyl (Ci- C2) -heterocyclic group said heterocyclic groups are independently selected from a 5-6 membered monocyclic ring system containing up to 3 heteroatoms independently selected from O, N or S and combinations thereof. According to a more preferred embodiment, the present invention provides a group of compounds of general formula (I), preferably of formula (IA), more preferably of formula (IC), even more preferably of formula (IE) and especially of formula (IF), wherein R1 is selected from: -alkyl (CrC6), -cycloalkyl (C3-C8), -alkyl (C2) -cycloalkyl (C3-C8), phenyl, -alkylaryl (CrC2), heterocyclyl, or groups -alkyl (Ct C2) -heterocyclic. wherein each of the above R1 groups is optionally substituted with one or more groups selected from: -alkyl (C-1-C4), halogen, - (CH2) mOR6, CN, CF3, OCF3, where m = 1 or 2; R2 is OH; R3 is selected from: H, -alkyl (C-pCß), -cycloalkyl (C3-C8), -alkyl (C -? - C2) -cycloalkyl (C3-C6), aryl, -alkylaryl (C C2), heterocyclyl, or heterocyclic (C1-C2) alkyl groups. wherein each of the last seven R3 groups is optionally substituted with one or more groups selected from: OH, -alkyl (C4), - (CH2) n-cycloalkyl (C3-C5), halogen, CN, - (CH2) nOR6 or - (CH2) nNR7R8, where n = 0, 1 or 2; R4 is selected from: H, -alkyl (CC), - (CH2) pccycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) PNR7R8, CN, -C (O) R6-, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 where p = 0, 1 or 2; R5 is selected from: alkyl (C4), - (CH2) pccycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) pNR7R8, CN, -C (O) R6-, -C (O ) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 where p = 0, 1 or 2; each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3 is selected from 5-6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof; and wherein the heterocyclic group of R1 is selected from monocyclic ring systems of 5 to 6 members containing 1 heteroatom N. Preferred in this document are groups of compounds of general formula (I), preferably of formula (IA), more preferably of formula (IC), even more preferably of formula (IE) and especially of formula (1E) as defined above in this document, wherein R3 is H, -alkyl (C6), -cycloalkyl (C3-C8), -alkyl (C2) -cycloalkyl (C3-C8), -alkyl (CrC2) aryl or a heterocyclic group and where each of the latter five groups R3 is optionally substituted with one or more groups selected from -OH, -alkyl (C -? - C4), - (CH2) pccycloalkyl (C3-C5), halogen, CN or - (CH2) pOR6, where n = 0 or 1 and where R6 is H, CH3 or CH2CH3 and where when R3 is a heterocyclic group, said heterocyclic group is selected from 5-6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from 0 or N and combinations thereof.

According to another preferred embodiment, the present invention provides a group of compounds of general formula (I), preferably of formula (IA), more preferably of formula (IC), even more preferably of formula (IE) and especially of formula (IF), wherein R1 is selected from -alkyl (C -? - C6), -cycloalkyl (C3-C8), phenyl or heterocyclic groups and wherein each of the groups R1 above is optionally substituted with one or more groups selected from : alkyl (CC), halogen, -OR6 or-CN; R2 is OH; R3 is selected from H groups, -alkyl (C2-C6), -cycloalkyl (C3-C8), -alkyl (C1-C2) -cycloalkyl (C3-C8) or heterocyclic and where each of the last four groups R3 is optionally substituted with one or more groups selected from: -OH, -alkyl (d-C4), - (CH2) pCycloalkyl (C3-C5), halogen, -CN, -OR6 or - (CH2) nNR7R8, where n = 0, 1 or 2; R4 is selected from: H, F or Cl; R5 is selected from: F or Cl; Each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3 is selected from 5-6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from 0 or N and combinations thereof; and wherein the heterocyclic group of R1 is selected from 5-6 membered monocyclic ring systems containing 1 heteroatom N. Preferred in this document are groups of compounds of general formula (I), preferably of formula (IA), more preferably of formula (IC), even more preferably of formula (IE) and especially of formula (IF), as defined hereinabove, where the heterocyclic group of R1 when present, is a monocyclic ring system of 6 members containing up to 1 hetero atom of N. In this document, groups of compounds of general formula (I), preferably of formula (IA), more preferably of formula (IC), even more preferably of formula (IE), are preferred. and especially of formula (IF), as defined earlier herein, wherein the heterocyclic group of R3, when present, is a 6-membered monocyclic ring system containing up to 2 hours. Theatoms N. The preferred R1 groups for use herein are selected from alkyl (CC), -cycloalkyl (C3-C6), phenyl, pyridyl or pyrimidinyl, wherein R1 is optionally substituted with one or more groups selected from CH3, CH2CH3, Halogen, OCH3, OCH2, CH3, CN, CF3 or OCF3. The most preferred R1 groups for use herein are selected from n-propyl, i-propyl, n-butyl groups, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3-fluorophenyl, 4-fluoroenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridine- 2-yl or pyridin-3-yl. The R1 groups even more preferred for use herein are selected from pyridin-2-yl groups, phenyl, 3-fluorophenyl, 4-fluoroenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, , 4-diflurophenylol or 3,4-difluorophenyl. Preferred R3 groups for use herein are selected from -H, -alkyl (C2-C6), -cycloalkyl (C3-C8), alkyl (CrC2) c -cloalkyl (C3-C8) or heterocyclyl and wherein each of the last four groups R3 is optionally substituted with one or more groups selected from -OH, -alkyl (C4) or -OR6 and where R6 is -H, CH3 or CH2CH3 and where when R3 is a heterocyclic group, said heterocyclic group is a 6-membered monocyclic ring system containing up to 2 N heteroatoms. Most preferred R3 groups for use herein are selected from: hydrogen, ethyl, i-propyl, n-propyl, n-butyl, t-butyl groups , -butyl, 2-methoxyethyl, cyclopentyl, cyclobutyl, cyclopentylmethyl, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4- ilo or tetrahydroiran-4-yl. Preferred R4 groups for use herein are selected from H, F or Cl and the preferred R5 groups for use herein are selected from F p Cl. Preferred phenyl groups with substituents R4 and R5 for use herein are: a 2,4-substituted phenyl group in which each of the groups R 4 and R 5 is independently selected from F or Cl; or, a 4-mono-substituted group in which R 4 is H and R 5 is F or Cl. The most preferred phenyl groups for use herein to which R 4 and R 5 are attached are 4-chlorophenyl or 2,4-difluorophenyl groups . When R3 is H, in a preferred group of compounds in this document of general formula (IC), more preferably (IE) and especially (IF), R1 is a phenyl group, 3-fluorophenyl, 4-fluorophenyl, 2.6- difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl; R2 is OH; and R4 is selected from: H or F and R5 is selected from: F or Cl. The preferred compounds herein in which R3 is H are the compounds of examples 12, 16, 24 and 48 or pharmaceutically acceptable salts, solvates or hydrates thereof. When R3 is a heterocyclic group as defined hereinafter, in a preferred group of compounds of general formula (IC), more preferably (IE) and especially (IF) herein, R1 is a phenyl or pyridin-2 group -ilo; R2 is -OH; R3 is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyrazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4- ilo; and both R 4 and R 5 are F. The preferred compounds herein in which R 3 is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-groups ilo, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4-yl are the compounds of examples numbers 31, 34, 35, 42 and 47 and pharmaceutically acceptable salts, solvates and hydrates thereof. When R3 is et, i-Pr or t-Bu, in a preferred group of compounds in this document of general formula (IC), more preferably (IE) and especially (IF), R1 is phenyl, 4-fluorophenyl, 4- chlorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl; R2 is OH; and R4 and R5 are F. The preferred compounds herein in which R3 is Et, i-Pr or t-Bu are the compounds of examples 1, 5, 6, 8, 9, 10, 13, 15, 22, 40, 50, 51, 52 and 53 and pharmaceutically acceptable salts, solvates and hydrates thereof. Preferred compounds according to the present invention include: (3R, 4R, 5S) -1-. { [(3S, 4 /?; - 1-e? C-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -3,5-dimethyl-4-phenylpiperidin-4 -ol; (3R, 4 5S) -1- { [(3S, 4 /? J-1-ferc-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbon hydrochloride. L.) .3,5-dimethyl-4-phenylpiperidine-4-ol; (3 4 5S) -1- { [(3S, 4R> 4- (2) hydrochloride. , 4-Difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol; Hydrochloride of (SR R.dSJ-l-iKSS ^ Rj -l-ferc-Butyl ^ a -d¡fluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (3,4-difluorophenyl) -3,5-dimethylpiperidin-4-ol; (3R, 4 5S) -1- { [(3S, 4 /? J-1-te / 'c-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride .}. -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol; Hydrochloride of (3, 4R, 5S) -1-. { [(3S, 4- 4- (2,4-d? -fluorophenyl) -1- isopropylpyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol; Hydrochloride (3ft, 4fi, 5S) -1- { [(3S, 4 /? J-4- (2,4-d? Fluorourenyl) pyrrolidin-3-yl] carbonyl.} -4- (4 -fluorophenyl) -3,5-dimethylpiperidine-4-ol; (3R, 4?, 5S) -1- { [(3S, 4f? J-1-ferc-butyl-4- (2-hydrochloride , 4- difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-chlorophenyl) -3,5-dimethylpiperidin-4-ol; (3R, 4R, 5S) -1- Hydrochloride { [(3S, 4RJ-1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidn-3-yl] carbonyl] -4- (2,4- difluorophenyl) -3,5-dimethylpiperidin-4-ol; (3 4R5S) -4- (2,4-D-fluoro-phenyl) -1- hydrochloride. { [(3S, 4RJ-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -3,5-dimethylpiperidin-4-ol; (3R, 4f?, 5S) -1 Hydrochloride - { [(3S, 4R -1-tert -butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] - 3,5-dimethylpiperidin-2-ylpiperidin-4-ol; (3R, 4R, 5S) -1- { [(3S, 4? -4- (2,4-D? -fluorophenyl) pyrrolidn-3-yl] carbonyl] hydrochloride. 3,5-dimethyl-4-phenylpiperidin-4-ol; (3R, 4R, 5S) -1- { [(3S, 4RJ-4- (2,4-Difluorophenyl) -1-p Hydrochloride Ridin-2-ylpyrrolidin-3-yl] carbonyl] -3,5-d-methyl-4-phenylpiperidin-4-ol; Hydrochloride of (3ft, 4ft, 5S) -1- { [(3S, 4ftj-4- (2,4-D? -fluorophen ??) -1-pyridin-3-ylpyrrolidin-3-yl] carbonyl. -3,5-dimethyl-4-phenylpiperidin-4-ol; (3R, 4 /? 5S) -1- { [(3S, 4R) -4- (2,4-Difluorophenyl) -1-hydrochloride pyridazin-3-yl-pyrrolidin-3-yl] carbonyl] -3,5-dimethyl-4-phenylpiperidin-4-ol; (3R, 4 5S) -1-. [(3S, 4Rj-1-ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -3,5-dimethyl-4-propylpiperidin-4-ol; Hydrochloride of (3R, 4, 5S) -1-. { [(3S, 4R) -4- (2,4-D? -fluorophenyl) -1- pyrimidin-4-pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol; Hydrochloride of (3R, 4R, 5S) -1-. { [(3S, 4RJ-4- (2,4-D-fluoro-phenyl) -1-pyridazin-3-yl-pyrrolidin-3-yl] -carbonyl] -3,5-dimethyl-4 -pyridin-2-ylpperidin-4-ol; (3R, 4R, 5S) -1-. {[[(3S, 4R> 4- (4-Chlorophenyl) pyrrolidin-3-yl] carbonylhydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol; (3R, 4R, 5S) -4- (4-chlorophenyl) -1- { [(3S, 4RJ-4- (2) hydrochloride , 4-difluorophenyl-phenyl] -1-isopropyl-pyrrolidin-3-yl] -carbonyl} -3,5-dimethylpiperidin-4-ol; (3R, 4R, 5S) -4- (3,4-difluorophenyl) hydrochloride ) -1- { [(3S, 4RJ-4- (2,4-D-fluoro-phenyl) -1-isopropyl-pyrrolidin-3-ylcarbonyl} -3,5-dimethylpiperidin-4-ol; (3R4R5S) Hydrochloride ) -4- (2,4-difluorophenyl) -1- { [(3S, 4 J-4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-alkylcarbonyl} -3.5 -dimethylpiperidin-4-ol; (3R, 4R, 5S) -1- { [(3S, 4Rj-4- (2,4-difluorophenyl) -1-ethylpyrrolidin-3-yl] carbonyl hydrochloride} -4- (3-fluorophenyl) -3,5-dimethylpiperidin-4-ol and pharmaceutically acceptable salts, solvates and hydrates thereof Preferred compounds according to the present invention The invention is independently selected from the groups consisting of: (3R, 4R, 5S) -1-. { [(3S, 4 -1-tert-butyl-4- (2,4-difluorophenyl) -pyrrolidin-3-ylcarbonyl] -3,5-dimethyl-4-phenylpiperidin-4-ol; Hydrochloride ( 3R, 4R, 5S) -1- { [(3S, 4RM-ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -3,5-dimethyl- 4-phenylpiperidin-4-ol; Hydrochloride of (3R, 4R, 5S) -1-. { [(3S, 4R; -1-Yerc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -4- (3,4-difluorophenyl) -3,5-dimethylpiperidin-4 -ol; (3R, 4R, 5S) -1- { [(3S, 4RJ-1-ferc-butyl-4- (2,4- d? fluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride. .}. -4- (4-fluorophenyl) -3,5-d-methylpiperidin-4-ol; (3R, 4R, 5S) -1- { [(3S, 4RJ-4- ( 2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol; (3R, 4R, 5S) -hydrochloride - 1- { [(3S, 4R; -1-tert-Butyl-4- (2,4-d.fluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-chlorophenyl) -3, 5-dimethylpiperidin-4-ol; (3R, 4R, 5S) -4- (4-chlorophenyl) -1 - { [(3S, 4R 4- (2,4-difluorophenyl) -1 - hydrochloride Sodropylpyrrolidin-3-yl] carbonyl] -3,5-dimethylpyridin-4-ol and pharmaceutically acceptable salts of acids, solvates and hydrates thereof The most preferred compounds herein are: (3R, 4R, 5S) -1- { [(3S, 4R 1 -tert -butyl-4- (2,4-difluorophenyl) -pyrrolidin-3-ylcarbonyl.] - 3,5-dimethyl-4- phenylpiperid-4-o l also known as [1-tert-butyl-4- (2,4-d-fluoro-phenyl) pyrrolidin-3-yl] - (4-hydroxy-3,5-dimethyl-4-phenylpiperidine) -1-yl) -metanone (the compound of Example 1) and / or pharmaceutically acceptable acid salts thereof such as (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R 1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl] -3,5-dimethyl-4-phenylpiperidin-4-ol also known as HCl salt of [1-tert-butyl-4- (2,4-difluoro-pheny] pyrrolidin-3-yl] - (4-hydroxy-3,5-d-methyl-4) phenyl-piperidin-1-ylo) -methanone (the compound of example 5).

According to another additional embodiment, the present invention provides compounds of general formula (I) or a stereoisomeric mixture thereof, or a diastereomerically enriched or diastereomerically pure isomer thereof, or a prodrug of said compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug thereof. where R1 is selected from: (C -? - C6) alkyl, (C2 - C6) alkenyl, (C2 - C6) alkynyl, (C3 - C8) cycloalkyl, (C5 - C8) cycloalkenyl, (C -? - C2) ) -cycloalkyl (C3-C8), aryl, alkylaryl (CrC2), heterocyclyl or alkyl groups (Cr C2) heterocyclics wherein each of the above R1 groups is optionally substituted with one or more groups selected from: alkyl (d-C4), (CH2) m-cycloalkyl (C3-C5), halogen, - (CH2) mOR6, (CH2) mNR7R8, CN, C (O) R6, C (O) OR6, CON (R7) 2, (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3, OCH2CF3, SMe or Set, where m = 0, 1 or 2; R2 is H, OH or OMe; R3 is selected from: H, -alkyl (C-pCß), -alkenyl (C2-C6), alkynyl (C2-C6), -cycloalkyl (C-CB), -cycloalkenyl (C5-C8), alkyl (C-C2) ) - (C3-C8) cycloalkyl, aryl, alkylaryl (C2), heterocyclyl, or heterocyclic (dC2) alkyl groups wherein each of the last ten R3 groups is optionally substituted with one or more groups selected from: OH, alkyl (C C4), (CH2) n-cycloalkyl (C3-C5), halogen, CN, (CH2) nOR6, (CH2) nN (R7) 2, SMe or Set, where n = 0, 1 or 2; each of R4 and R5 is independently selected from: - (C -? - C4) alkyl, (C2 - C4) alkenyl, - (C2 - C4) alkynyl, - (CH2) pccycloalkyl (C3 - C5), (CH2) p (C5) cycloalkenyl, halogen, (CH2) pOR6, (CH2) pNR7R8, CN, C (O) R6, C (O) OR6, CON (R7) 2, (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3, OCH2CF3, SME or Set, where p = 0, 1 or 2 or R4 and R5 may together form a saturated or unsaturated condensed ring of 5 to 7 members; each of R6, R7 and R8 is independently selected from H, Me or Et; where the heterocyclic groups R1 and R3, when present, are optionally 4- to 10-membered ring systems containing up to 4 heteroatoms selected from 0, N or S. A preferred group of compounds according to this additional embodiment are the compounds in wherein R1 is selected from: alkyl (C-? -C6), cycloalkyl (C3-C8), alkyl (C2) -cycloalkyl (C3-C8), aryl, alkylaryl (C-? - C2), heterocyclyl, or (C -? - C2) heterocyclic alkyl groups, and wherein R1 is optionally substituted with one or more groups selected from (C1-C4) alkyl, - (CH2) mCycloalkyl (C3-C5), halogen, OMe, OEt, CN, halogen, CF3, CH2CF3, OCF3, OCH2CF3, SMe or Set, where m = 0, 1 or 2 and wherein said heterocyclic group is selected from: pyridinyl, pyrimidinyl, triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl group, benzothiazolyl, indazolyl, quinolyl or isoquinolyl; R2 is H or OH; R3 is H, alkyl (C Ce), cycloalkyl (C3-C8), alkyl (C? -C2) -cycloalkyl (C3-C8), alkylaryl (C? -C2) and where each of the last four groups R3 is optionally substituted with one or more groups selected from OH, (C 4) alkyl, (CH 2) n (C 3 -C 5) cycloalkyl, halogen, CN, (CH 2) nOR 6, SMe or Set, where n = 0 or 1; R4 and R5 are independently selected from (C1-C4) alkyl, cyclopropyl, halogen, OR6, CN, CF3, CH2CF3, OCF3, OCH2CF3, SMe, Set, or R4 and R5 together form a saturated or unsaturated condensed ring of 5 to 6 members; and where R6 is as defined earlier in this document. In an even more preferred group of compounds according to this additional embodiment R1 is an alkyl (CC), (C3-C6) cycloalkyl, alkyl (CrC2) -cycloalkyl (C3-C5), phenyl, pyridyl or pyrimidinyl group, where R1 is optionally substituted with one or more groups selected from Me, Et, halogen, OMe, OEt, CN, CF3. OCF3 and SMe; R2 is OH; R3 is a (C -? - C6) alkyl group optionally substituted with one of the following groups OH, OR6, CF3; each of R4 and R5 is independently alkyl (CrC4), halogen, OR6, CN, CF3, CH2CF3, OCF3, OCH2CF3; R6 is H or Me. It is an especially preferred group of compounds according to this further embodiment, R1 is an n-butyl group, a cyclohexyl group, a phenyl group, or a 4-methyl phenyl group; R2 is OH; R3 is an ethyl group or a t-butyl group; and each of R4 and R5 is independently F. Even more preferred compounds according to this further embodiment are compounds of general formula IG whereas especially preferred compounds according to this further embodiment are compounds of general formula IH. wherein R1, R2, R3, R4 and R5 are as defined above in this document. More preferred compounds are according to this further embodiment the compounds of formula (IG) or (IH), more preferably (IH) in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are in trans position with each other .

Shown below are routes illustrating methods for synthesizing compounds of formula (I). Scheme 1 illustrates the preparation of compounds of formula (I) by linking peptides of intermediates (II) and (III) by adding if necessary a suitable base and / or an additive (such as 1-hydroxybenzotriazole hydrate or 4-dimethylaminopyridine) ). The scheme illustrates the preparation of compounds of formula (IA) by linking peptides of intermediates (II) and (Illa). Similarly, Schemes Ib illustrate the preparation of compounds of formulas (IC), (ID), (IE) and (IF) by peptide binding of intermediates: (HA) and (IIIA); (IIB) and (III); (IIB) and (IIIA); and (IIB) and (IIIB) respectively. The compounds of formulas (IB), (IG) and (IH) can be prepared in a similar manner from the relevant intermediates.

Scheme 1 IIIA Scheme 1a IIIA Scheme 1 b Scheme 1c II1A Scheme 1d IIIB Scheme 1e SCHEME 1E With respect to the compounds (I), (II), (III) of Scheme 1 and a, the definitions of R1, R2, R3, R4 and R5 are as defined hereinabove for the compounds of formula (I) unless otherwise indicated. Alternative conditions involve stirring a solution of the piperidine (amine) of the general formula (II) and the pyrrolidine (acid) of the general formula (III) together with 1- (3-dimethylaminopropyl) -3-ethyl-carbodumide hydrochloride (EDC) ), triethylamine or? / - methylmorpholine and 1-hydroxybenzotriazole hydrate (HOBt) in dimethylformamide (DMF) or tetrahydrofuran (THF) or ethyl acetate at room temperature. A suitable alternative procedure is to stir a solution of the intermediates of general formula (II) and general formula (III) together with O-benzotriazol-1-yl-N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) or anhydride cyclic 1-propylphosphonic acid in CH2Cl2 or EtOAc. Any suitable inert solvent can be used in place of those mentioned above, where inert solvent refers to a solvent that does not contain a primary or secondary carboxylic acid or amine. At least one equivalent of each of the binding reagents must be used and an excess of one or both may be used if desired. Thus, according to another embodiment, the present invention provides a process for the preparation of compound of general formula (I) comprising the peptide bonding of a piperidine (amine) of general formula (II) with a pyrrolidine (acid) of general formula (III). According to a preferred embodiment, the present invention provides a process for the preparation of compounds of general formula (IA) comprising the peptide linkage of a piperidine (amine) of general formula (II) with a pyrrolidine (acid) of formula general (HIA). According to a more preferred embodiment, the present invention provides a process for the preparation of compounds of general formula (ID) comprising the peptide linkage of a piperidine (amine) of general formula (IIB) with a pyrrolidine (acid) of general formula (III). According to an even more preferred embodiment, the present invention provides a process for the preparation of compounds of general formula (IC) comprising the peptide bonding of a piperidine (amine) of the general formula (HA) with a pyrrolidine (acid) of general formula (IIIA). According to an even more preferred embodiment, the present invention provides a process for the preparation of compounds of general formula (IE) which comprises the peptide linkage of a piperidine (amine) of general formula (IIB) with a pyrrolidine (acid) of general formula (IIIA). According to an especially preferred embodiment, the present invention provides a process for the preparation of compounds of general formula (IF) comprising the peptide bonding of a piperidine (amine) of general formula (IIB) with a pyrrolidine (acid) of formula general (IIIB). According to yet another embodiment, the present invention provides intermediate compounds of general formula (II) (HA) and (IIIB) IIA IB where R1 and R2 are as defined above in this document.

Preferred in this document are intermediates of formula (II), more preferably of formula (HA) and especially of formula (IIB) in which R2 = OH and R1 = mono-substituted phenyl, or phenyl 2,6- or 3, 4- or 2,4-di-substituted, or a pyridinyl group wherein the phenyl substituent groups are selected from F, Cl and OCH3. A still more preferred group of intermediates herein are the compounds of formula (III), more preferably of formula (HA) and especially of formula (IIB) wherein R 2 = -OH and R 1 is phenyl, 4-fluorophenyl, , 4-difluorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl. Thus, according to a preferred embodiment, the present invention provides intermediates of general formula (IIB) in which R2 = -OH and R1 is phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridine -2-ilo.

According to an even more preferred embodiment, the present invention provides intermediates of general formulas (III), (IIIA) and (IIIB) IIIA IIIB wherein R3, R4 and R5 are as defined above in this document. Preferred herein are intermediates of formula (II), more preferably of formula (HA), most preferably of formula (IIIB), wherein R4 is H, or F or Cl and where R5 is F or Cl and where R3 is H or (C2-C4) alkyl; -cycloalkyl (C3-C8), alkyl (C? -C2) cycloalkyl (C3-C8) or heterocyclyl. A preferred group of intermediates herein are the compounds of formula (III), more preferably of formula (IIIA) and especially of formula (IIIB) wherein R3 is -H, i-PR, Et or a heterocyclic group selected from pyridin groups 3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4-yl. Thus, according to another embodiment, the present invention provides a process for the preparation of compounds of general formula (I) more preferably of general formula (IC), even more preferably of general formula (IE) and especially of general formula (IF) by the peptide linkage of intermediates (II) and (III), preferably (HA) and (IIIA), more preferably (IIB) and (IIIA) especially (IIB) and (IIIB) where: R2 is -OH:; R1 is phenyl, 4-fluorophenyl, 3,4-difluoroenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl; R3 is -H, t-Bu, i-Pr, ET or a heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyridin-5-yl, pyrimid groups N-4-yl, pyrimidin-2-yl, tetrahydropyran-4-yl; R4 is H, Cl or F and R5 is Cl or F. According to a preferred process of this document, compounds of general formula IF are prepared by peptidic binding of intermediates (HA) and (IIIA) where: R2 is - OH; R is phenyl, 4-fluorophenyl, 3,4-diflurophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl; R3 is -H, t-Bu, i-Pr, Et or a heterocyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-4-yl, pyrimidin-2 groups -yl or tetrahydropyran-4-yl; R4 is H, Cl or F and R5 is Cl or F. According to a more preferred process, in this document the compounds of general formula (IF) are prepared by the peptide binding of intermediates (HA) and (IIIA) in the that: R2 is -OH; R1 is phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-fluorophenyl, 2,4-difluorophenyl or 3,4-difluorophenyl or pyridin-2-yl; R3 is t-Bu, i-Pr or Et and R5 are F.

Scheme 2 illustrates an alternative route for the preparation of compounds of general formula (I) with a range of R3 groups by the utility of a protecting group strategy. Compounds of general formulas (IA) to (IF) can also be prepared according to the route illustrated in Scheme 2 by the utility of appropriate intermediates (II), (HA) or (IIB) with the appropriate protected amine of formula (IV), (VAT) or (IVB) as necessary.

IV checkout Scheme 2 With respect to the compounds (I), (II), (IV) and (V) in Scheme 2 or (IVA) or (IVB), as illustrated below in this document, the definitions of R1, R2, R3, R4 and R5 are as defined hereinabove for the compounds of formula (I) unless otherwise indicated. PG is a nitrogen protecting group.

VAT GVB In scheme 2, the amine intermediates of general formulas (II) and the protected pyrrolidine acid intermediates of general formula (IV) are coupled using conventional peptide binding methods as previously described in scheme 1 to provide a coupled and protected intermediate of general formula (V) from which the nitrogen protecting group can be removed using conventional deprotection strategies to produce a compound of general formula (I) in which R3 = H. Any suitable nitrogen protecting group (as described in US Pat. "Protecting Groups n Organics Synthesis" 3rd Edition TW Greene and PG Wuts, Wiley-lnterscience, 1999). A conventional nitrogen protecting group (PG) suitable for use herein is tert-butoxycarbonyl, which is easily removed by treatment with an acid such as trifluoroacetic acid or nitrogen chloride in an organic solvent such as dichloromethane or 1, 4- dioxane Alternative groups (a H) in R3 can be introduced using conventional alkylation techniques. Suitable methods for the alkylation of secondary amines include: (i) reaction with an aldehyde and a hydride reducing agent such as sodium triacetoxyborohydride, optionally in the presence of acetic acid in an inert solvent such as dichloromethane or acetonitrile. (ii) reaction with an alkyl halide or an appropriately activated alcohol derivative (eg, in the form of a sulfonate ester) in the presence of a base (such as triethylamine) in an inert solvent; The aryl and heteroaryl groups can be introduced as R3 by displacement of a suitable leaving group from a heteroaromatic precursor. Suitable leaving groups include halogens. In certain cases, catalysis with transition metals (eg palladium, copper) or optionally in combination with a phosphine ligand such as 1,1'-binaphthalen-2,2'-diisobisdiphenylphosphine may be required to achieve the desired binding partners. Scheme 3a illustrates the route for the preparation of the acid pyrrolidine intermediates of the general formula (III) from the unsaturated ester intermediates of the general formula (VI). resolution SCHEME 3A With respect to the compounds (III), (VI), (VII), (VIll), (IX), (X), (XI), (XII), (Xlll) of Scheme 3a, the definitions of R1, R2 , R3, R4 and R5 are as defined hereinabove for the compounds of formula (I) unless otherwise indicated. PG2 is a suitable carboxylic acid protecting group. The compounds of general formula (VI) can be prepared by olefining Wittig or the like of an intermediate aldehyde of general formula (X) with a suitable delusional, for example methyl (triphenylphosphoranylidene) acetate, or a phosphonate anion, for example, the derivative of the deprotonation of trimethyl phosphoacetate, mainly in the form of the trans isomer. There are many alternative methods in the literature for the production of unsaturated ester intermediates of general formula (VI), including the esterification of a precursor derivative of cinnamic acid (Vil) using conventional esterification methods, or the Heck reaction of an aromatic halide (Vlll) with a suitable acrylate ester such as t-butyl acrylate (IX) in the presence of a palladium catalyst and a suitable base such as triethylamine. The resulting E-olefin intermediate of general formula (VI) will undergo a cycloaddition of [3 + 2] azetine by reaction with a compound of general formula (XI), to provide a pyrrolidine with almost exclusively trans stereochemistry. This reaction requires an inert solvent such as dichloromethane or toluene or tetrahydrofuran and activation by one or more of: (1) an acid catalyst, such as TFA; (2) a desilylation agent such as silver fluoride; (3) heat. Alternatively, a pyrrolidine is provided with almost exclusively cis stereochemistry by reaction of a compound of general formula (XI) with an unsaturated ester or acid of Z-olefin configuration. Such Z-olefins can be prepared by means of Lindlar reduction of an alkyne or by Still-Gennari olefination. The compound of general formula (XII) obtained from the cycloaddition reaction is a racemate and may require resolution in its constituent enantiomers, which can be achieved by preparative HPLC using a chiral stationary phase. Alternatively, the acid intermediate of general formula (III) can be resolved by conventional methods (for example formation of diastereomeric derivatives by reaction with an enantiomerically pure reagent, separation of the resulting diastereomers by physical methods and acid cleavage (III). general formula (XII) can be transformed into compounds of general formula (III) by hydrolysis of the ester.There are many methods to achieve this transformation (see Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition, March, Jerry, 1992, p 378-383 published by Wiley, New York, N.Y. USES). In particular, treatment of a compound of general formula (XII) with an aqueous solution of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable organic solvent will provide the corresponding compounds of general formula (III ): Preferably, organic miscible water co-solvents (such as 1,4-diosazo or tetrahydrofuran) are also used in such reactions. A preferred method herein for said ester hydrolysis involves treating the ester with potassium trimethylsilanolate in an inert solvent such as diethyl ether at room temperature. If required, the reaction can be heated to enhance hydrolysis. The hydrolysis of the ester can also be carried out using acidic conditions, for example, by heating the ester in an aqueous acid such as hydrochloric acid. Certain esters are hydrolyzed more conveniently under acidic conditions, for example, tere-butyl esters or benzhydryl. Such esters can be cleaved by treatment with anhydrous acids such as trifluoroacetic acid or hydrogen chloride in an inert organic solvent such as dichloromethane. Scheme 3b illustrates an alternative route for the preparation of a single enantiomer of the pyrrolidine acid intermediate of general formula (III) from unsaturated ester intermediates of general formula (IV), using an oxazolidinone as a chiral auxiliary. The acid of formula (XVIII) can be obtained by hydrolysis of the unsaturated ester (VI) and an oxazolidinone can be used as a chiral auxiliary (where R is preferably phenyl, butyl, tertiary or iso-propyl) to provide the intermediate of formula (XVIII). Alternatively, the reaction of a compound of formula (VI) (when R = Cot-Bu) with the lithium salt of an oxazolidinone, in a suitable solvent (eg, THF), may also provide a compound of formula (XVIII ). The compound of formula (XVIII) will undergo a cycloaddition of ylide of "3 + 2C-azometrine by reaction with the compound of general formula (XI), to provide the diastereomers (XX) and (XVIV) which can be separated by chromatography or crystallization and hydrolyzed to give a pyrroline of formula (III). separation R = alkyl 0, -Cg XX SCHEME 3B Scheme 4 illustrates that the synthesis of protected pyrrolidine acid intermediates of general formula (IV) can be achieved using a method similar to the process described hereinabfor the intermediate of general formula (III), with the exception that the intermediate of General formula (XI IA) contains a nitrogen protecting group that can later be rem in the synthetic scheme. Once the protecting group has been rem using any suitable conventional technique, alternative R3 groups can be introduced by the methods described in scheme 2.

The pyrrolidines of general formula IV with a nitrogen protecting group can also be obtained enantioselectively using a chiral auxiliary of oxazolidinone, similar to that described in Scheme 3b.

IV XIIA XII SCHEME 4 With respect to the compounds (VI), (XIA), (XIIA), (XII) and (IV) in scheme 4, the definitions of R1, R2, R3, R4 and R5 are as defined abin this document for compounds of formula (I) unless otherwise indicated. In the formulas (XIA), (XIIA) and (IV), PG is selected from suitable nitrogen protecting groups. In the formulas (VI), (XIIA), and (Vil) PG2 is selected from suitable carboxylic acid protecting groups.

The synthesis of azomethine illusion precursor compounds of general formula (XI) can be achieved as illustrated in scheme 5. In this way, a primary amine of general formula (Xlll) can be alkylated by treatment with chloromethyltrimethylsilane, optionally pure or in a inert solvent, heating the reaction if necessary. Subsequently, the resulting intermediates (XIV) can be reacted with formaldehyde in methanol and in the presence of a suitable base such as carbonate, potassium or tert-butylamine, to produce the intermediates (XI). To produce similar intermediates (XIA) containing a nitrogen protecting group, a similar reaction sequence can then be carried out NH2 • HN ^ Si (CH3) 3 »- CH30 ^ N ^ Si (CH3) 3 l < -Y -Y; / U \ formaldehyde A R3 c S, (CH3) 3 R3 K2C03, methanol R 'Xlll X "XI NH2 ». HN Si (CH3) 3 +. CH O / VN ^ Yes (CHo) And \ ".,,, Or formaldehyde I PG Cr ^ S. (CH3) 3 PG K2C03, methanol G XIIIA XIVA XIA SCHEME 5 With respect to the compounds (Xlll), (XI HA), (XIV), (XIVA), (XIA), and (XI) in Scheme 5, the definitions of R3 are as defined abin this document for the compounds of formula (I) unless otherwise indicated. In the formulas (XHIA), (XIVA), (XIA), PG is selected from suitable nitrogen protecting groups. As illustrated in Scheme 6, the piperidine intermediates of general formula (II), wherein R2 = OH, can be prepared by addition of organometallic nucleophiles to ketones of general formula (XV) containing a suitable nitrogen protecting group for producing intermediates of general formula (XVI). Such nucleophilic addition is generally carried out at a low temperature in an ethereal or non-polar solvent, using Grignard reagent, organolithium or other organometallic reagent. These organometallic reagents can be manufactured by halogen-metal exchange using a suitable halide precursor, Y-Br or Y-1 and n-butyl lithium. Suitable protecting groups include Bn, which can be rem by hydrogenation, or Boc, which can be rem by treatment with an acid such as TFA, or PMB that can be rem by treatment with DDQ, CAN or chloroacetyl chloroformate, to produce the piperidine intermediate. desired of general formula (II). With certain protecting groups and under certain conditions, the protecting group can be labile to treatment with the organometallic reagent and thus both transformations can be carried out in one step, for example, when PG = Boc, the protecting group can sometimes be cleaved when the intermediates of formula VII are treated with an organometallic reagent XV XVI SCHEME 6 With respect to the compounds ((XV), (XVI) and (II) in the scheme 6, the definitions of R1 are as described hereinabove for the compounds of formula (I) unless otherwise indicated. In the formulas (XV), (XVI), PG is selected from suitable nitrogen protecting groups. As illustrated in Scheme 7, when (3R, 5S) -1- benzyl-3,5-dimethylpiperidin-4-one is used, the stereochemistry of the addition is favored such that the hydroxyl group in the product is cis position with respect to the two methyl groups. The controlled addition to carbonyl systems such as this has been described in the literature (Journal of Medicinal Chemistry (1964), 7 (6), p 726-8).

XV XXI SCHEME 7 With respect to the compounds (XV), (XXI) and (II) in Scheme 7, the definitions of R are as defined above in this document for the compounds of formula (I) unless otherwise indicated. In the formulas (XV), (XXI), PG is selected from suitable nitrogen protecting groups. In addition, Scheme 8 illustrates that, under conditions of forced reduction, such as hydrogenation at high pressure and / or temperature, or strong acid plus triethylsilane, intermediate compounds of general formula (II), wherein R2 = OH, can be transformed with intermediate compounds of general formula (II) in which R2 = H. In certain cases the protection of the piperidine nitrogen atom may be necessary to facilitate this transformation. In this way, the intermediates of the general formula (XVI) can be transformed into other compounds of intermediates of the general formula (XXII) in which R2 = H, and subsequently deprotected to provide compounds of the general formula (II) in which R2 = H .

XXII XVI XXII XXII SCHEME 8 With respect to the compounds (XVI) and (II) in Scheme 8, the definitions of R1 are as defined above in this document for the compounds of formula (I) unless otherwise indicated. In formulas (II) and (XXIII), PG is selected from suitable nitrogen protecting groups. In addition, scheme 9 illustrates that intermediate compounds of general formula (II), wherein R2 = OH can be transformed into other intermediate compounds of general formula (II) wherein R2 = OMe. This transformation can be carried out by conventional synthesis of Williamson's ether. That is, the alcohol group in the compounds of general formula (II), wherein R2 = OH can be deprotonated with a strong base such as sodium hydride, in an anhydrous solvent, such as tetrahydrofuran or dimethylformamide, and the resulting anion reacted with iodomethane, heating the reaction if necessary. The protection of the piperidine nitrogen atom may be necessary to facilitate this transformation, and in this way, the intermediates of the general formula (XVI) in which R2 = OH can be transformed into other intermediates of general formula (XXV) in which R2 = OMe, and subsequently deprotected to provide compounds of general formula (II) wherein R2 = OMe, as illustrated in Scheme 9.

R > 1 '- = Me Ph ?? V XXIV SCHEME 9 With respect to the compounds (XVI), and (II) in Scheme 9, the definitions of R1 are as defined above in this document for the compounds of formula (I) unless otherwise indicated. In formulas (II), and (XVI), PG is selected from suitable nitrogen protecting groups. Those skilled in the art will appreciate that, in addition to nitrogen protecting groups, as described hereinabove, at various times during the synthesis of the compounds of formula I, it may be necessary to protect other groups, such as, for example, hydroxy groups, with a suitable protecting group and then remove the protecting group. The methods for deprotection of any particular group will depend on the protecting group. As a reference for the protection / deprotection methodology see "Protective groups in Organic Synthesis", TW Greene and PGM Wutz. For example, when a hydroxy group is protected as a methyl ether, the deprotection conditions comprise heating to reflux in 48% aqueous HBr or stirring with tribromide or borane in dichloromethane. Alternatively, when a hydroxy group is protected as a benzyl ether, the deprotection conditions comprise hydrogenation with a palladium catalyst in a hydrogen atmosphere. According to a preferred embodiment, the present invention provides processes for the preparation of compounds of general formula (I) using methods analogous to those provided for the preparation of the compounds of Example 1 by means of preparations 1 to 5 and 12 to 16 and, more preferably, those of Example 5 by the preparations 1, 21, 22b, 4, 5 and 12 to 16 with the stereochemistry defined therein. According to a further embodiment, the present invention provides independently: the intermediate compound of preparation 1; and / or the intermediate compound of preparation 2; and / or the intermediate compound of preparation 3; and / or the intermediate compound of preparation 4; and / or the intermediate compound of preparation 5; and / or the intermediate compound of preparation 21; and / or the intermediate compound of preparation 22b; and / or the intermediate compound of preparation 12; and / or the intermediate compound of preparation 13; and / or the intermediate compound of preparation 14; and / or the intermediate compound of preparation 15; and / or the intermediate compound of preparation 16.

The general reaction mechanisms described hereinabove for the preparation of new starting materials used in the above methods are conventional and the appropriate reagents and the reaction conditions for their preparation or preparation, as well as the procedures for the isolation of the products. desired, are well known to those skilled in the art with reference to bibliographic precedents and to the Examples and Preparations herein.

Mcr4 activity The compounds of the present invention have utility as MCR4 agonists in the treatment of various disease states. Preferably, said MCR4 agonists show functional potency at the MC4 receptor expressed as an EC50 less than about 1000 nM, more preferably less than 150 nM, even more preferably less than about 100 nM, even more preferably less than about 50 nM and especially less than about 10 nM, where said MCR4 functional power EC50 measurement can be performed using Protocols C or E as described later in this document. Compounds according to the present invention have been tested, including the compounds of Examples 12, 20, 16, 48, 1, 5, 6, 22, 13, 9, 10, 50, 14, 17, 19, 53, 40 , 15, 52, 51, 8, 33, 31, 34, 35, 36, 42, 44 and 47, and have been found to exhibit functional potencies less than about 150 nM in the MC4 receptor. Thus, according to a further embodiment, the present invention provides compounds of formula I with a functional potency at the MC4R receptor of less than about 150 nM. A preferred group of compounds according to the present invention has been tested, including the compounds of Examples 1, 5, 6, 22, 13, 9, 17, 19, 53, 15, 52, 51, 8, 31, 34 , 35, 42, 44 and 47 and have been found to exhibit functional potencies of less than about 50 nM in the MC4 receptor. Another preferred group of compounds according to the present invention has been tested, including the compounds of Examples 1, 5, 9, 19, 8, 31, 34, 35, 42 and 47, and it has been found that they show functional potencies of less than about 10 nM in the MC4 receptor. Preferred compounds herein show functional potency at the MCR4 receptor as defined herein above and are selective for MCR4 with respect to MCR1. Preferably, said MCR4 agonists with respect to MCR1. Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR1, said MCR4 receptor agonists having a functional selectivity at least about 10 times, preferably at least about 20 times, more preferably at least about 30 times, even more preferably at less than about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times and especially at least about 1,000 times greater at the MCR4 receptor compared to the MCR1 receptor, based on such evaluations of realistic selectivity in the measurement of functional powers of MCR1 and MCR4 that can be made using Protocols A and C, or E as described later in this document. The compounds according to the present invention, including the compounds of Examples 1, 5, 6, 13, 10, 50, 14, 17, 33, 31, 35, show a functional potency at the MCR4 receptor and have been tested and checked that they show a selectivity for MCR4 with respect to MCR1 greater than about 10 times. Thus, according to a further embodiment, the present invention provides compounds of formula I that show functional potency at the MCR4 receptor and show selectivity for MCR4 with respect to MCR1 greater than about 10 fold. A preferred group of compounds according to the present invention, including the compounds of Examples 1, 5, 13, 14, 17, 31, and 35, which show functional potency at the MCR4 receptor have been tested and found to show selectivity for MCR4 with respect to MCR1 greater than about 30. times. A more preferred group of compounds according to the present invention, including the compounds of Examples 13, 14, 31 and 35, show functional potency at the MCR4 receptor and have been tested and found to exhibit a selectivity for MCR4 with respect to to MCR1 greater than about 100 times. Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR3, said MCR4 receptor agonists having a functional selectivity at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, still more preferably at less than about 300 times, even more preferably at least about 500 times, and especially at least about 10,000 times greater than an MCR4 receptor compared to the MCR3 receptor, said selectivity evaluations being based on a measurement of functional potencies of MCR3 and MCR4 that can be performed using Protocols A and B, or E as described later in this document. The compounds of Examples 1, 2 and 3 show functional potency at the MCR4 receptor and have been tested and found to exhibit an MCR4 selectivity to MCR3 greater than about 30 fold. Preferred compounds herein show functional potency at the MCR4 receptor as defined hereinabove and are selective for MCR4 with respect to MCR5. Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR5, said MCR4 receptor agonists having a functional selectivity at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, still more preferably at less than about 300 times, even more preferably at least about 500 times and especially about 1000 times through an MCR4 receptor compared to the MCR5 receptor, said relative selectivity evaluations being based on the measurement of functional powers of MCR5 and MCR4 which can be performed using Protocols D and E as described later in this document. The compounds according to the present invention include the compounds of Examples 1, 5, 6, 22, 13, 9, 10, 50, 14, 17, 19, 53, 15, 52, 51, 33, 31, 35, 42 and 44, show functional potency at the MCR4 receptor and have been tested and found to show a selectivity for MCR4 over MCR5 greater than about 10 fold. Thus, according to a further embodiment, the present invention provides compounds of formula I that show functional potency at the MCR4 receptor and show a selectivity for MCR4 over MCR5 greater than about 10 fold. A preferred group of compounds according to the present invention, including the compounds of Examples 1, 5, 22, 13, 9, 50, 17, 19, 53, 15, 52, 31, 33, 35, 42 and 44, show functional potency at the MCR4 receptor and have been tested and found to show a selectivity for MCR4 over MCR5 greater than about 100 fold. A more preferred group of compounds according to the present invention, including the compounds of Examples 22, 13, 19, 15, 35, 42 and 44, show functional potency at the MCR4 receptor and have been tested and found to be show a selectivity for MCR4 with respect to MCR5 greater than about 300 fold.

Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR1 and MCR3, said MCR4 receptor agonists having a functional selectivity at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 1000 times greater than an MCR4 receptor compared to the MCR1 and MCR3 receptors. Preferred compounds herein show functional potency at the MCR4 receptor as defined hereinabove and are selective for MCR4 with respect to MCR1 and MCR5. Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR1 and MCR5, said MCR4 receptor agonists having a functional selectivity at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times and especially at least about 1000 times higher at an MCR4 receptor compared to the MCR1 and MCR5 receptors. The compounds according to the present invention, including the compounds of Examples 1, 5, 6, 13, 10, 50, 14, 17, 33, 31 and 35, show functional potency at the MCR4 receptor and have been tested and tested. discovered to show a selectivity for the MCR4 receptor compared to the MCR1 and MCR5 receptors greater than about 10 fold. Thus, according to a further embodiment, the present intervention provides compounds of formula I that show functional potency at the MCR4 receptor and show a selectivity for the MCR4 receptor compared to MCR1 and MCR5 receptors greater than about 10 fold. A preferred group of compounds according to the present invention, including the compounds of Examples 1, 5, 13, 31 and 35, show functional potency at the MCR4 receptor and have been tested and found to show selectivity for the receptor MCR4 compared to MCR1 and MCR5 receptors greater than approximately 00 fold. Preferably, said MCR4 agonists have a selectivity for MCR4 with respect to MCR3 and MCR5, said MCR4 receptor agonists having a functional selectivity of at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, yet more preferably at least about 300 times, and still more preferably at least about 1000 times higher by an MCR4 receptor compared to the MCR3 and MCR5 receptors. In addition to their role in the treatment of sexual dysfunction, it is likely that the compounds of the present invention are effective in several additional indications as described later herein. The terms "treat" or "treatment", as used herein, are intended to include both prevention and control, that is, the prophylactic and palliative treatment of the indicated conditions. The compounds of the invention are useful in the treatment of diseases, disorders or conditions including, but not limited to, the treatment of male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and / or sexual dysfunction. female sexual pain, male erectile dysfunction, obesity (reducing appetite, increasing the metabolic rate, reducing fat intake or reducing the craving for carbohydrates) and diabetes mellitus (enhancing glucose tolerance and / or reducing resistance to insulin), hypertension, hyperllpidemia, osteoarthritis, cancer, gallbladder disease, sleep apnea, depression, anxiety, compulsion, neurosis, insomnia / sleep disorder, substance abuse, pain, fever, inflammation, immune modulation, rheumatoid arthritis, darkening of the skin, acne and other skin disorders, neuroprotective, cognitive and memory enhancement including the treatment of Alzheimer's disease. Some compounds of formula I show a highly spec activity toward the melanocortin-4 receptor, which makes them especially useful in the treatment of male and female sexual dysfunctions, as well as obesity.

The compounds of the present invention are useful in the treatment of male and female sexual dysfunction, particularly male erectile dysfunction. Female sexual dysfunction (FSD) includes female sexual arousal disorder (FSAD), desire disorders such as hypoactive sexual desire disorder (lack of interest in sex) and orgasmic disorders such as anorgasmia (inability to achieve orgasm). Male sexual dysfunction includes male erectile dysfunction (ED) and ejaculatory disorders such as anorgasmia (inability to achieve orgasm) or desire disorders such as hypoactive sexual desire disorders (lack of interest in sex). The compounds of the present invention are particularly useful for treating female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders, sexual pain disorder and male erectile dysfunction. The compounds of the present invention are particularly suitable for treating female sexual dysfunctions, male erectile dysfunction, obesity and diabetes.

Male erectile dysfunction (MED) The compounds of the present invention are useful in the treatment of male sexual dysfunction, particularly male erectile dysfunction. Male Erectile Dysfunction (MED), also known as male erectile disorder, is defined as: "The inability to achieve and / or maintain a penile erection for satisfactory sexual performance" (NIH Consensus Development Panel on Impotent, 1993). has estimated that the frequency of erectile dysfunction (ED) in all grades (minimal, moderate and complete impotence) is 52% in men aged 40 to 70 years, with the highest rates in men older than 70 years (Melman et al. to 1999, J. Urology, 161, p 5-11) The condition has a significant negative impact on the quality of life of the individual and his partner, often resulting in increased anxiety and tension that can lead to depression and fall Self-esteem Although two decades ago, MED was considered primarily a psychological disorder (Benet et al 1994 Comp.Ther., 20: 669-673), it is known that most individuals have an underlying organic cause. , s e has made great progress in identifying the mechanism of normal penile erection and the pathophysiology of MED. The erection of the penis is a hemodynamic event that depends on the balance between the contraction and relaxation of the smooth muscle of the corpora cavernosa and the vasculature of the penis (Lerner et al 1993, J. Urology, 149, 1256-1255). The smooth muscle of the corpus cavernosum is also referred to herein as body smooth muscle or in the plural sense corpora cavernosa. Relaxation of the smooth muscle of the corpora cavernosa leads to an increased flow of blood in the trabecular spaces of the corpora cavernosa, causing them to expand against the surrounding tunica and compress the drainage veins. This produces a wide elevation in blood pressure, which results in an erection (Nailoor, 1998, J. Urology, 81, 424-431). The changes that occur during the erectile process are complex and require a high degree of coordinated control involving the central and peripheral nervous system and the endocrine system (Nailoor, 1998, J. Urology, 81, 424-431). The contraction of the corporal smooth muscle is modulated by sympathetic noradrenergic innervation by the activation of postsynaptic arenoreceptor ai. The MED may be associated with an increase in the tone of the endogenous smooth muscle of the corpora cavernosa. However, the process of relaxation of the corporal smooth muscle is partially mediated by non-adrenergic and non-cholinergic neurotransmission (NANC). There are several NANC neurotransmitters found in the penis, other than NO, such as the peptide related to the calcitonin gene (CGRP) and the vasoactive intestinal peptide (VIP). The main relaxation factor responsible for mediating this relaxation is nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthase (NOS) (Taub ei al 1993 Urology, 42, 698-704). It is believed that the reduction of the tone of the corporal smooth muscle can help the NO to induce the relaxation of the corpora cavernosa. During sexual excitement in the male sex, NO is released from neurons and endothelium and binds and activates soluble guanylate cyclase (sGC) located in smooth muscle cells and in the endothelium, leading to an increase in the levels of guanosine 3 ', 5'-cyclic monophosphate (cGMP) intracellular. This increase in cGMP causes a relaxation of the corpora cavernosa due to a reduction in the concentration of intracellular calcium ([Ca2 +];), by unknown mechanisms that are believed to involve the activation of the Kinase G protein (possibly due to the activation of Ca2 + pumps and K + channels activated with Ca2 +). Multiple potential sites within the central nervous system have been identified for the modulation of sexual behavior. It is believed that the key nurotransmitters are serotonin, norepinephrine, oxytocin, nitric oxide, dopamine and melanocortins, for example, stimulation hormone of alpha-melanocytes. Sexual function can be adjusted by mimicking the actions of one of these key neurotransmitters. Melanocortins are peptides derived from proopiomelanocortins (POMC) that bind to and activate receptors coupled to the G protein (GPCR) of the malanocortin receptor family. Malanocortins regulate a wide range of physiological processes including sexual function and sexual behavior, food intake and metabolism. There are five malanocortin receptors that have been cloned, MCR1, MCR2, MCR3, MCR4, MCR5, and are expressed in various tissues. MCR1 is expressed specifically in melanocytes and melanoma cells, MCR2 is the ACTH receptor and is expressed in adrenal tissue, MCR3 are expressed mainly in the brain and in the limbic system, MCR4 is widely expressed in the brain and in the spinal cord and MCR5 is widely expressed in the brain and in many peripheral tissues including the skin, adipose tissue, skeletal muscle and lymphoid tissue. MCR3 may be involved in the control of sexual function, food intake and thermogenesis. It has been shown that activation of MCR4 induces penile erection in rodents and that inactivation of MCR4 causes obesity (reviewed in Hadley, 1999, Ann NY Acad Sci., 885: 1-21, Wikberg et al 2000, Pharmacol Res. , 42 (5), 393-420). It has been found that synthetic melanocortin receptor agonists initiate erections in men with psychogenic erectile dysfunction (Wessells et al, Int J Impot Res. 2000 Oct; 12 Suppl 4: S74-9). Wessels et al describe the effects of Melanotan II (MT II), a non-selective agonist of the malanocortin receptor, in human subjects with erectile dysfunction (ED). MT II was administered to 20 men with psychogenic ED using a double-blind placebo-controlled crossover design. The stiffness of the penis was observed for 6 hours using RigiScan. The level of sexual desire and side effects were obtained with a questionnaire. In the absence of sexual stimulation, Melanotan II caused penile erection in 17 of 20 men. The subjects experienced an average of 41 minutes with a rigidity Rigiscan > 80% A higher sexual desire was reported in 13/19 (68%) dose of MT II versus 4/21 (19%) of placebo (P <0.01). Nausea and yawning were side effects presented frequently due to MT II; with a dose of 0.025 mg / kg, 12.9% of the subjects had severe nausea. Adverse reactions observed with MT-II may be the result of the activation of MC-1 R, MC-2R, MC-3R and / or MC 5R. In this document it is proposed that a selective MCR4 agonist can be administered orally (including buccal or sublingual administration) and will be effective in the treatment of female sexual dysfunction or male erectile dysfunction, but will be free of significant side effects such as those observed by Wessels et al, that is, it will be a selective agent that will be better tolerated. PT-141 of Palatin is another synthetic peptide analogue of alpha-MSH. It is a melanocortin receptor agonist including MC3R and MCR4R. Molinoff et al (Ann NY Acad. Sci (2003), 994, 96-102) describe how "the administration of PT-141 to rats and non-human primates results in penile erections." Systemic administration of PT-141 to rats activates the neurons of the hypothalamus as demonstrated by an increase in c-Fos immunoreactivity.Some neurons in the same region of the central nervous system absorb the pseudorabies virus by injecting into the corpora cavernosa of the penis of the rat. -141 (by intranasal or subcutaneous route) to normal men and patients with erectile dysfunction resulted in a rapid dose-dependent increase in erectile activity. " The use of PT-141 for sexual dysfunction is described in U.S. 5,576,290, U.S. 6,579,968 and U.S. 2002 / 0107,182 A1.

In addition, peptides such as MT-II or PT-141 are extensively metabolized in the intestine and, as such, are more effectively administered parenterally, such as subcutaneously, intravenously, intranasally or intramuscularly, since they are not They absorb into the systemic circulation when administered orally. Thus, it would be desirable to create MCR4 agonist compounds for the treatment of male and female sexual dysfunctions suitable for oral administration (including buccal or sublingual administration) and which reduce or avoid undesirable side effects such as nausea. It is proposed in this document that selective MCR4 agonists according to the present invention will present oral bioavailability and, as such, may be further administered orally (including buccal or sublingual administration). There have been numerous reports showing that selective MCR4 agonists increase erectile activity in rats (Martin et al, 2002, Eur J Pharmacol., 4 54 (1), 71-79; Van Der Ploeg et al, 2002, Proc. Nati Acad. Sci. USA., 99 (17), 11381-11386). An example of an MCR4 agonist used in these studies is / V - [(3R) -1, 2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl] - ((1 R)) - 1- (4-chlorobenzyl) - 2- [4-cyclohexyl-4- (1 H-1, 2,4-triazol-1-ylmethyl) p -peridin-1-yl] -2-oxoethylamine (1), which is a potent selective receptor agonist of melanocortin subtype-4 (Sebhat et al, 2002, J. Med. Chem., 45 (21), 4589-4593).

Cragnolini et al (Neuropeptides, 34 (3-4), 211-5) have shown that alpha-MSH significantly increases the sexual lordosis behavior in female rats after injection into the ventromedial nucleus of the brain. In addition, they demonstrated that HS014 (a putative MCR4 antagonist, Vergoni 1998, Eur. J. Pharmacol 362 (2-3), 95-101) blocks the prosexual effect of alpha-MSH on lordosis in a dose-dependent manner in female rats. In the U.S. 6,051, 555 methods for stimulating sexual response in females have been described using various melanotropic peptides (similar to MT II). In essence MCR4 is an initiator of male and female sexual behavior. Accordingly, the present invention provides the use of a compound of formula (I) in the preparation of a medicament for the treatment of male and female sexual dysfunction and, in particular, of male erectile dysfunction. Patients with mild to severe MED would benefit from treatment with the compounds according to the present invention. However, early research suggests that the response rate of patients with mild, moderate and severe MED may be higher with a combination of selective MCR4 agonist / PDE5 inhibitor. The mild, moderate and severe MED are terms known to the person skilled in the art, but guidelines can be found in The Journal of Urology, vol. 151, 54-61 (January 1994).

Initial investigations suggest that the groups mentioned further in MED patients would benefit from treatment with a selective MCR4 agonist and / or a PDE5i (or another combination described later in this document). These patient groups, which are described in more detail in Clinical Andrology vol. 23, no.4, p. 773-782 and chapter 3 of the book by I. Eardley and K. Sethia "Erectile Dysfunction-Current Investigation and Management, published by Mosby-Wolfe, are the following: psychogenic, organic, vascular, endocrinological, neurogenic, arteriogenic, sexual dysfunction induced by drugs (lactogenic) and sexual dysfunction related to cavernous factors, particularly venogenic causes.Therefore, the present invention provides the use of a compound of formula (I) in the preparation of a medicament in combination with a PDE5 inhibitor for the Treatment of male erectile dysfunction Further suitable PDE5 inhibitors are described below.

Female sexual dysfunction (FSD) The compounds of the present invention are useful in the treatment of female sexual dysfunction (FSD), particularly FSAD. According to the invention, FSD can be defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several female sexual disorders (Leiblum, SR (1998) - Definition and classification of female sexual disorders, Int.J. Impotent Res., 10, S104-S106; Berman, JR, Berman, L. &; Goldstein, I. (1999) - Female sexual dysfunction: lncidence, pathophysiology, evaluations and treatment options, Urology, 54, 385-391.). The woman may have a lack of desire, difficulty with excitement or orgasm, pain in intercourse or a combination of these problems. Various types of illnesses, medications, injuries or psychological problems can cause FSD. The treatments under development are aimed at the treatment of specific subtypes of FSD, mainly disorders of desire and arousal. The FSD categories are best defined by contrast with the phases of the normal female sexual response: desire, arousal and orgasm (Leiblum, SR (1998) - Definition and classification of female sexual disorders, Int. J. Impotent Res., 10, S104-S106). Desire or libido is the appetite for sexual expression. Their manifestations often include sexual thoughts in the company of an interested partner or on exposure to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital dilation and includes greater vaginal lubrication, lengthening of the vagina and greater sensation / genital sensitivity. Orgasm is the release of sexual tension that culminates during excitement. Therefore, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, excitement or orgasm. The FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders, and sexual pain disorders. Although the compounds of the invention will improve the genital response to sexual stimulation (as in female sexual arousal disorder), by doing this they can also improve the associated pain, discomfort and discomfort associated with intercourse and thus treat others. female sexual disorders. Hypoactive sexual desire disorder is present if a woman has little or no desire for sexual expression and has little or no sexual thought or fantasy. This type of FSD may be caused by low levels of testosterone due to a natural menopause or a surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety. Female sexual arousal disorder (FSAD) is characterized by an inadequate genital response to sexual stimulation. The genitals do not experience the dilation that characterizes normal sexual arousal. The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded. Arousal disorder may be caused by low estrogen levels in menopause or after delivery and during breastfeeding, as well as by disease, with vascular components such as diabetes and atherosclerosis. Other causes may arise from treatment with diuretics, antihistamines, antidepressants, for example, selective serotonin reuptake inhibitors (SSRIs) or antihypertensive agents. Sexual pain disorders (including dyspareunia and vaginismus) are characterized by the presence of pain as a result of penetration and may be due to medications that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems. As discussed above, it is believed that MCR4 is an initiator of sexual behavior. The clitoris is considered a penis homologue (Levin, R.J. (1991), Exp. Clin. Endocrino /., 98, 61-69); The same mechanism that provides an erectile response in the male produces an increase in the genital blood flow in the female with the associated effect on FSD. In addition, there are changes in the proceptivity and receptivity (lordosis). Thus, according to a preferred aspect of the invention, there is provided the use of a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, more particularly of sexual desire disorder hypoactive, sexual arousal disorder, orgasmic disorder and sexual pain disorder. Preferably, the compounds of formula (I) are useful in the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder and hypoactive sexual desire disorder, and more preferably in the treatment or prophylaxis of sexual arousal disorder. In a preferred embodiment, the compounds of formula (I) are useful in the treatment of a subject with a female sexual arousal disorder and concurrent hypoactive concurrent sexual desire disorder. The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines the Female Sexual Arousal Disorder (FSAD) as: "... a persistent or recurrent inability to achieve or maintain until the end of sexual activity a lubrication-swelling response suitable for sexual arousal, the alteration must cause a notable discomfort or interpersonal difficulties .... "The arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The alteration causes a considerable discomfort and / or interpersonal difficulties. FSAD is a sexual disorder with a high frequency that affects pre-, peri- and post-menopausal women (± women in hormone replacement therapy (HRT)). It is associated with concurrent disorders such as depression, cardiovascular diseases, diabetes and urogenital disorders (UG). The primary consequences of FSAD are lack of dilation / swelling, lack of lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm. Recently it has been hypothesized that there is a vascular basis for at least part of the patients with symptoms of FSAD (Goldstein et al., Int. J. Impot. Res., 10, S84-S90, 1998) with data in animals that support this hypothesis (Park et al., Int. J. Impot. Res., 9, 27-37, 1997). R.J. Levin reports that because "... the male and female genitalia develop embryologically from common tissue, [that] it is argued that the male and female genital structures are homologous to each other." Thus, the clitoris is the homologous of the penis and the homologous lips of the scrotal pouch ... "(Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69). The candidate drugs to treat FSAD, whose efficacy is being investigated, are mainly erectile dysfunction therapies that promote circulation in the male genitalia. The compounds of the present invention are advantageous in providing a means of recovering a normal sexual arousal response - namely, increased blood flow in the genitals leading to vaginal, clitoral, and labial dilation. This will cause greater vaginal lubrication by transudation of plasma, greater vaginal acceptance and greater genital sensitivity. Therefore, the present invention provides means to recover or enhance the normal response to sexual arousal.

Thus, in accordance with a preferred aspect of the invention, there is provided the use of a compound of formula (I) in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder. The term female genitalia in this document means: "The genital organs that consist of an internal group and an external group The internal organs are located inside the pelvis and consist of the ovaries, the uterine ducts, the uterus and the vagina The external organs are on the surface of the urogenital diaphragm and below the pelvic arch, comprising the pubis, the labia majora and the labia minora, the clitoris, the vestibule, the vestibular bulb and the main vestibular glands "(Gray's Anatomoy, CD Clemente, 13th American Edition). The compounds of the invention find application in the following sub-populations of patients with FSD: the young, the elderly, pre-menopausal, peri-menopausal, post-menopausal women with or without hormone replacement therapy. The compounds of the invention find application in patients with FSD due to: i) Vasculogenic etiologies, for example, cardiovascular or atherosclerotic diseases, hypercholesterolemia, cigarette smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury in the pudendal iliohypogastric vascular system; ii) Neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system, including multiple sclerosis, diabetes, Parkinson's, cerebrovascular accidents, peripheral neuropathies, trauma or radical pelvic surgery; Ii) Hormonal / endocrine aetiologies such as hypothalamic / pituitary / gonadal axis dysfunction, or ovarian dysfunction, pancreatic dysfunction, medical or surgical castration, androgen deficiency, high circulating prolactin levels, eg, hyperprolactinemia, natural menopause , premature ovarian insufficiency, hyper and hypothyroidism; iv) Psychogenic etiologies such as depression, obsessive-compulsive disorder, anxiety disorder, postnatal depression / "Baby Blues", emotional and relationship problems, secondary anxiety from apprehension to sexual failure, conjugal problems, dysfunctional attitudes, sexual phobias, religious inhibition or past traumatic experiences; and / ov) Drug-induced sexual dysfunction as a result of selective serotonin reuptake inhibitor therapy (SSRi) and other antidepressant therapies (tricyclics and major tranquillizers), antihypertensive therapies, sympatholytic drugs, oral contraceptive pill therapy chronicle. The compounds of the present invention can be administered in combination with an auxiliary active agent for the treatment of sexual dysfunction, obesity or diabetes. Auxiliary active agents suitable for use in the combinations of the present invention include: 1) Compounds that modulate the action of natriuretic factors, in particular, atrial natriuretic factor (also known as atrial natriuretic peptide), type B natriuretric factors and type C such as inhibitors or neutral endopeptidase and, in particular, the compounds described and claimed in WO 02/02513, WO 02/03995, WO 02/079143 and EP-A-1258474 and especially the compound of Example 22 of WO document 02/079143, acid (2S) -2. { [1-. { 3-4 (-chlorophenyl) propyl] amino} carbonyl) - cyclopentyl] methyl} -4-methoxybutanoic. 2) Compounds that inhibit the enzyme angiotensin convertidot such as enapril, and combined inhibitors of the enzyme angiotensin convertid and neutral endopeptidase such as omapatrilat; 3) Substrates for NO-synthase, such as L-arginine; 4) Cholesterol reduction agent such as statins (eg, atorvastatin / Lipitor-registered trademark) and fibrates; 5) Modulators of estrogen receptors and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene, (-) - c / s-6-phenyl-5- [4- (2-pyrrolidin-1) -yl-ethoxy) -phenyl] -5,6,7,8-tetrahydro naphthalen-2-or I and pharmaceutically acceptable salts thereof, the preparation of which is detailed in WO 96/21656; 6) A PDE inhibitor, more particularly a PDE inhibitor 2, 3, 4, 5, 7 or 8, preferably a PDE2 or PDE5 inhibitor and even more preferably a PDE5 inhibitor (see below), said inhibitors preferably having an IC50 against the respective enzyme of less than 100. nM (with the proviso that PDE 3 and 4 inhibitors are only administered topically or by injection into the penis); 7) Vasoactive intestinal protein (VIP), VIP mimic, VIP analogue, more particularly mediated by one or more of the VIP receptor subtypes VPAC1, VPAC or PACAP (adenylate cyclase activation peptide of the pituitary), one or more than one VIP receptor agonist or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more of an adrenoceptor antagonist with VIP combination (eg, Invicorp, Avlptadil); 8) An agonist, antagonist or modulator of serotonin receptors, more particularly agonists, antagonists or modulators of 5HT1A receptors (including VML 670 [WO02 / 074288] and flibanserin [US2003 / 0104980]), 5HT2A, 5H5T2C, 5HT3 and / or 5HT6 , including those described in WO-09902159, WO-00002550 and / or WO-00028993. 9) A testosterone replacement agent (including dehydroandrostenedione), testosterone (eg, Tostrelle, LibiGel), dihydrotestosterone or a testosterone implant; 10) Selective androgen receptor modulators, for example LGD-2226; 11) Estrogens, estrogens and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie, in combination form), or estrogen and a hormone replacement therapy agent demethyl testosterone (eg, HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Be, Estrofem, Ellese Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, P "remphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone); 12) A modulator of noradrenaline, dopamine and / or serotonin transporters, such as bupropion, GW-320659; 13) An oxytocin receptor agonist or modulator / vasopressin, preferably a selective oxytocin agonist or modulator, and 14) A dopamine receptor agonist or modulator, preferably a selective D3 agonist or modulator. or D4, for example apomorphine, combinations of the compounds of the present invention and one or more additional therapeutic agents selected among: PDE5 inhibitors; NEP inhibitors; Selective D3 or D4 agonists or modulators; estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists; testosterone, testosterone replacement agents or a testosterone implant; estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA), or estrogen and hormone replacement therapy agent for methyl testosterone.

Preferred combinations for the treatment of MED are combinations of the compounds of the present invention and one or more PDE5 inhibitors and / or NEP inhibitors. Preferred combinations for the treatment of FSD are combinations of the compounds of the present invention and inhibitors of PDE5 and / or NEP inhibitors and / or selective D3 or D4 agonists or modulators and / or estrogen receptor modulators, estrogen agonists, estrogen antagonists and / or testosterone replacement agents, testosterone, testosterone and / or estrogen implants, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA), estrogen and hormone replacement therapy agent of methyl testosterone. Particularly preferred PDE5 inhibitors for such combined products for the treatment of MED or FSD are sildenafil, tadalafil, vardenafil and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3 -eti-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one. Particularly preferred NEP inhibitors for such combined products for the treatment of MED or FSD are the compounds exemplified in WO 02/079143. Preferred combination products are herein for the treatment of MED or FS: a combination of sildenafil, tadalafil, vardenafil or - [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H- pyrazolo [4,3-d] pyrimidin-7-one with the compound of Example 1 of this document; and / or a combination of any of the compounds exemplified in WO 02/079143 with the compound of Example 1 herein. By cross-referencing in this document to compounds contained in patents and patent applications that may be used in accordance with the invention, reference is made to therapeutically active compounds as defined in the claims (in particular of claim 1) and to the specific examples (all of which are incorporated herein by reference). If a combination of active agents is administered, then they can be administered simultaneously, separately or sequentially.

Auxiliary agents - PDE5 inhibitors PDE5 inhibitors are particularly preferred as active agents. The suitability of any particular cGMP PDE5 inhibitor can be easily determined by evaluating its potency and selectivity using literature methods followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with conventional pharmaceutical practice. The IC 50 values for the cGMP PDE5 inhibitors can be determined using the PDE5 assay (see below in this document).

Preferably, the cGMP PDE5 inhibitors used in the pharmaceutical combinations according to the present invention are selective for the PDE5 enzyme. Preferably (when used orally) they are selective with respect to PDE3, more preferably with respect to PDE3 and PDE4. Preferably (when administered orally, the GMPC PDE5 inhibitors of the invention have a selectivity ratio greater than 100, more particularly greater than 300 with respect to PDE3 and more preferably with respect to PDE3 and PDE4. can easily be determined by the specialist IC50 values for PDE3 and PDE4 enzymes can be determined using methodology established in the literature, see SA Ballard et al, Jornal or Urology, 1998, Vol 159, pages 2164-2171 and as detailed subsequently, in this document, cGMP PDE5 inhibitors suitable for use in accordance with the present invention include: (i) 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) fenii] -1-methyl -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidn-7-one (sildenafil), also known as 1 [[3- (6,7-dihydro)] -1-Methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methy1p perazine (see document or EP-A-0463756); (i) 5- (2-ethoxy-5-morpnoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3- d] pyrimidin-7-one (see EP-A-0526004); (ii) 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (piperidin-2-yl) methyl-2,6-dihydro-7H- pyrazolo [4,3-d] pyrimidin-7-one (see WO98 / 49166; (iv) 3-ethyl-5- [5- (4-etl-piperazin-1-ylsulfonyl) -2- (2- methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333 ); (v) (+) - 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methlethoxy) pyridin -3-yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4-3-d] pyrimidin-7-one, also known as 3-ethyl-5-. {5- [4-ethylpiperazin -1-ylsulfonyl] -2 - ([(1)) - 2-methoxy-1-methylethyl] oxy] pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333); (vi) 5- [2-ethoxy-5- (4-ethy1-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethanol] -2 , 6-dihydro-7H-pyrrazolo [4,3-d] pyrimidin-7-one, also known as 1-. { 6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl] -3-pyridylsulfonyl} -4-ethylpiperazine (see WO document) 01/27113, Example 8); (vii) 5- [2-iso-Butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2- (1-methylpiperidin-4-yl) - 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, (see WO 01/2713, Example 15); (viii) 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, (see WO 01/27113, Example 66); (ix) (5- (5-Acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4.3- d] pyrimidin-7-one (see WO 01/27112, Example 124); (x) 5- (5-Acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl) 3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-] -pyrimidin-7-one (see WO 01/27112, Example 132); (xi) (6R, 12aR) - 2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) -pyrazino [2 ', 1': 6,1] pyrid [ 3,4-b] indole-1,4-dione (tadalafil, IC-351, Cialis®), ie the compound of Examples 78 and 95 of published international application WO95 / 19978, as well as the compounds of the Examples 1, 3, 7 and 8; (xii) 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H- imidazo [5,1-f] [1, 2,4] triazin-4-one (vardenafil) also known as 1 - [[3- (3,4-dydro-5-methyl-4-oxo -7-propylimidazo [5,1-f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperzine, ie, the compound of examples 20, 19, 337, 336 of the application published international issue WO99 / 24433; (xi) the pyrazolo [4,3-d] pyrimidin-4-ones described in WO00 / 27848, in particular? / - [[3- (4,7-dihydro-1-methyl- 7-Oxo-3-propyl-1 H-pyrazolo [4,3-d] -pyrimidin-5-yl) -4-propoxyphenol] sulfonyl] -1-methyl-2-pyrrolidinepropanamide [DA-8159 (Example 68 of WO 00/27848)]; (xiv) the compound of example 11 of the publication of the international application WO93 / 07124; (xv) 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline; and (xvi) 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1 H-imidazo [4,5- g] quinazoline. (xvii) 1 - [3- [1 - [(4-fluorophenyl) methyl] -7,8-dihydro-8-oxo-1 H- imidazo [4,5-g] quinazolin-6-yl] -4- propoxyphenyl] carboxamide; (xviii) 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dih Dro-7H-pyrrazolo [4,3.c /] pyrimid-7-one; and (xix) 1-. { 6-ethoxy-5- [3-ethylyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl]. 3. pyridylsulfonyl} -4-ethylpipeprazine; and pharmaceutically acceptable salts and solvates thereof. The suitability of any particular PDE5 inhibitor can be easily determined by evaluating its potency and selectivity using methods of the literature followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with conventional pharmaceutical practice. Preferably, the PDE5 inhibitors have an IC50 of less than 100 nanomolar, more preferably less than 50 nanomolar, and even more preferably less than 10 nanomolar. Preferably, the PDE5 inhibitors used in the pharmaceutical combinations according to the present invention are selective for the PDES enzyme. Preferably, they have a selectivity of PDE5 with respect to PDE3 greater than 100, more preferably greater than 300. More preferably, and PDE5 inhibitor has a selectivity with respect to PDE3 and PDE4 greater than 100, more preferably greater than 300.

The person skilled in the art can easily determine the selectivity ratios from the relevant IC50 values. The IC50 values for the PDE3 and PDE4 enzymes can be determined using the methodology established in the literature, such as the method described in S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171. The IC5o values for the PDE5 enzyme can be determined using the methodology established in the literature and as described in WO 01/27113.

Sexual in vivo data The in vivo data of MCR4 for the compound of Example 1 were evaluated by selective activation of the melanocortin MCR4 receptors using the methodology that evaluates the spontaneous erection of the penis in the conscious rat. Erectile responses were recorded by measuring intracavernous pressure using a telemetry device surgically implanted (TA11 PA-C40, 8 mm catheter, modified 3 mm tip, available from Data Sciences International Inc.). An increase in ncacavernosal pressure is indicative of an erection in the penis, since an increase in ncacavernosal pressure is an essential hemodynamic event during the initiation and maintenance of penile erection. The specific details of the surgical procedures, data acquisition and analysis used in this document to measure increases in intracavernous pressure can be found in detail in Bernabé, J., Rampin O., Sachs BD, Giuliano F., "Intracavernous pressure during erection rats: an integrative approach based on telemetric recording ", Am. J. Physiol. 1999 Feb; 276 (2 Pt 2): R441-9. The test animals (rats) (during the dark cycle) were habituated for 18 hours before the baseline evaluation of erectile function. Before administration of the test agent, the baseline erectile activity (B) was evaluated for the vehicle for 10 minutes using a telemetric record of the intracavernous pressure. After subcutaneous administration of the compound of Example 1 (in the same vehicle), penile erections were evaluated (using a telemetric record of intracavitary pressure) for periods of 10 minutes, at intervals of 30, 60 and 90 minutes after the dosage The compound of Example 1 produced a dose-dependent increase in the amount of penile erections when dosed at a level of 1-100 μg / kg subcutaneously (s.s.). (See Figs 1 and 2). The basal / vehicle-treated animals showed minimal erectile activity (see Fig. 1). Figure 1 illustrates the results of preliminary studies and compares the number of erections observed during a 10 minute period beginning 60 minutes after dosing for animals dosed with 1, 10 and 100 μg / kg s.c. of the compound of Example 1 with basal erectile activity (B). The data of Figure 1 illustrate that at all doses tested, the compound of Example 1 increases erectile activity against basal erectile activity (B). In addition, Figure 1 illustrates that the compound of Example 1 increased the amount of spontaneous erections in the conscious rat in a dose-dependent manner. The maximum effective dose observed in this preliminary study was 1 μg / kg s.c. Figure 2 illustrates the results of a more detailed additional study and compares the number of erections observed during a 10-minute period beginning 30 minutes after dosing for animals dosed at 1, 10 and 100 pg / kg s.c. of the compound of Example 1 with basal erectile activity (vehicle treatment). The data in Figure 2 illustrate that at all doses tested, the compound of Example 1 increases erectile activity against baseline erectile activity (vehicle treatment). In addition, Figure 2 illustrates that the compound of Example 1 increased the amount of spontaneous erections in the conscious rat in a dose-dependent manner. The maximum effective dose observed in this more detailed additional study was 10 μg / kg s.c. For the compound of Example 1, in the preliminary study the maximum effective dose observed in this preliminary study was 1 μg / kg s.c., and in the more detailed additional study, the maximum effective dose observed was 10 μg / kg s.c. The number of erections observed was not significantly different between these two studies and at these dosage levels. The same conclusion that the compound of Example 1 increased in a dose-dependent manner the amount of spontaneous erections in the conscious rat can be obtained independently of both studies. In this document it is proposed that the difference observed between the preliminary study and the more detailed study in relation to the dose at which the maximum effect is observed is a reflection of the anticipated biological variation associated with this type of animal model. The data illustrated by Figures 1 and 2 strongly suggest that MCR4 receptors are involved in the induction and maintenance of penile erection and it is proposed in this document that the agonists of Selective MCR4 according to the present invention can provide an opportunity to treat male erectile dysfunction.

Assay The stimulation of adenylate cyclase after receptor activation is a widely used measure of functional activity for several receptor systems. The functional assay for measuring cyclic AMP (cAMP) uses human embryonic kidney (HEK) cells that stably express the human melanocortin receptor MCR1, MCR3 or MCR4. Activation of the MCR1, MCR3 or MCR4 receptors stimulates adenylate cyclase, generating cAMP, which is measured using AlphaScreen ™ assay kits (PerkinElmer). The AlphaScreen ™ cAMP assay kit is composed of "donor beads", "acceptor beads" and biotinylated cAMP that bind the different beads together. The excitation of this complex bound at 680 nm in the Fusion ™ -a microplate analyzer results in light emission between 520-620 nm.

The cAMP generated in the assay competes with the biotinylated cAMP for the binding sites in the acceptor beads, avoiding the binding of "donor" and "acceptor" beads and therefore reducing the emission of light. (i) Conventional functional test methodology with MCR1, MCR3 and MCR4 [PROTOCOL OF ESSAY A.B and C RESPECTIVELY! Assay Concept The determination of activity against human MCR1, MCR3 and MCR4 receptor subtypes for compounds according to the present invention was performed using three immortalized human embryonic kidney (HEK) cell lines that had been biologically designed to express the subtypes of MCR1, MCR3 or MCR4 receptors of human melanocortin. These cell lines were designed using protocols similar to those described by Gouarderes et al (Gouarderes, C. (2002) Neuroscience, 115 (2); 349-361). Such compound-induced activation of these MCR1, MCR3 or MCR4 receptors led to the stimulation of the cellular enzyme adenylate cyclase, which in turn led to cell generation and intracellular accumulation of cyclic adenosine monophosphate (cAMP). of these increases in intracellular AMPc was proportional to the degree to which the test compound activated the MCR1, MCR3 or MCR4 receptors present in these cell lines. The intracellular levels of cAMP were quantified using the test kits available on the market AlphaScreen ™ from PerkinElmer. A detailed test protocol and explanation of the concept underlying this kit is available on the PerkinElmer website (www.perkinelmer.com). The protocol listed below provides a summary of this information. The amount of intracellular cAMP produced by the compound-induced activation of the MCR1, MCR3 and MCR4 receptors in these three cell lines was measured using a Fusion ™ -a microplate analyzer programmed to stimulate at a wavelength of 680 nm and to measure the energy emitted at wavelengths between 520-620 nm. The increases induced by the compound in the activation of the MCR1, MCR3 or MCR4 receptors were subsequently quantified as a reduction in the amount of light emitted at wavelengths between 520-620 nm. The analysis of the data was subsequently performed using a curve fitting program and the apparent power of the test compound was extrapolated (expressed as an EC5o and defined as the effective concentration of compound that caused 50% of the maximum response induced by the compound ) from the adjusted curve.

PerkinElmer Materials: AMPc AlphaScreen ™ Test Kit, Cat No. 6760600M, Fusion ™ -a microplate analyzer (programmed to stimulate at a wavelength of 680 nm and to record light emitted at wavelengths of between 520- 620 nm). From Invitrogen: Phosphate-buffered saline solution (PBS) (with / without Ca2 + and Mg2 +), Cat. No. 14190-094; Dulbecco modified Tagle Medium (DMEM) high in glucose, Cat No. 21969-035; Hank's balanced salt solution (HBSS), Cat. No. 14065-049; Geneticin, Cat # 10131 -. 10131 -027. From Sigma: Bovine serum albumin (BSA), Cat. No. A7030; L- Glutamine, Cat No. G7513; (N- (2-Hydroxyethyl) piperazin-N '- (2-ethanesulfonic acid) (HEPES), Cat No. H0887; Liquid in solution for cellular dissociation, Cat No. C5914; Dimethylsulfoxide (DMSO), N Cat D8418, Cyclic adenosine monophosphate (cAMP), Cat No. A9501, 3-lsobutyl-1-methylxanthine (IBMX), Cat No. 15879, Magnesium chloride solution (MgCl 2) 1 M, Cat No. M1028, Bluetripane, Cat No. T-8154, cell counting chamber (Bright-line 35,962-9) From PAA laboratories GmbH: Fetal calf serum (FCS), Cat # A15-043. From Gilson: pipettes from 10 μl to 1000 μl. From Hereaus; Incubator of cells with CO2 Hera Cell. From Medical Air Technology; microbiological safety cabinet class II BioMat2. De Bachem: Melanocyte Stimulation Hormone a, MSH-a, Cat No. 1075, used as a positive control.

Tampons Stimulation buffer (according to AlphaScreen ™ protocol): HBSS supplemented with 0.5 mM IBMX, 5 mM HEPES, 0.1% BSA (w / v) and 10 mM MgCl2. Lysis buffer (according to the AlphaScreen ™ protocol): solution mM HEPES supplemented with 0.1% BSA (w / v) and 0.3% (v / v) -20% Tween-20. Detection mixture (according to AlphaScreen ™ protocol): Lysis buffer supplemented with biotinylated cAMP (10 nM) and donor beads (10 μg / kg) such as those provided in the cAMP AlphaScreen ™ assay kit.

Fisher Consumables: 384-well assay plates with nonadherent surface, Cat No. DPS-172-020Q. Costar: Sterile pipettes with volumes from 2 to 50 ml, sterile tips from P10 to P1000; Sterile reservoirs, Cat No. 4878; T225 flasks with purge cap, Cat No. 3001.

Composition Preparation For the functional assay methodologies of MCR1, MCR3 and MCR4, the compounds were initially dissolved in DMSO giving a compound concentration of 4 mM and then further diluted for the stimulation buffer assay giving real concentrations 2 times higher than those desired as the final test concentration.

Cell culture day by day The three HEK cell lines, as detailed earlier in this document, expressing the human receptor subtypes MCR1, MCR3 or MCR4 were cultured in T225 flasks with purge cap containing 50 ml of growth medium ( DMEM supplemented with 10% FCS (v / v), 2 mM L-Glutamine, 25 mM HEPES and 1.0 mg / ml Geneticin) and kept in a cell incubator at a temperature of 37 ° C and in an atmosphere containing 5 ml. % of CO2. The cells were harvested when they reached a confluence of 80-90% by first removing the existing growth medium and then washing with PBS which had been preheated to a temperature of 37 ° C. Then, this PBS was removed and 5 ml of cell dissociation fluid was added to the flask. The flasks were incubated for 5 minutes in a cell incubator set at a temperature of 37 ° C and in an atmosphere containing 5% CO2 to separate the cells. The cells were separated from the bottom of the flask by administering a dry blow to the flask. When the cells were separated, preheated growth medium was added at a temperature of 37 ° C, the cells were re-suspended and gently mixed to obtain a single cell suspension by pipetting. This cell suspension was subsequently counted using a cell counting chamber and used for experimentation or transferred to a new T225 flask to perpetuate the cell culture.

Test procedure The test procedure used was essentially as described in the methodology of the AlphaScreen ™ kit (www.perkinelmer.com) however, to facilitate handling of the liquids all volumes were doubled. First, 10 μl of the test compound solutions were transferred to 384-well assay plates with a non-stick surface. Second, the test cells were harvested as described above. (i) For the functional assay methodology with MCR1, a cell suspension was prepared at a concentration of 3x105 cells / ml in stimulation buffer (supplemented with 10 μl / ml of the AMPc acceptor antiperipher solution supplied in the assay kit of cAMP AlphaScreen ™); (I) For the conventional functional assay methodology with MCR3, a cell suspension was prepared at a concentration of 5 × 10 4 cells / ml in stimulation buffer (supplement with 10 μl / ml of the anti-cAMP acceptor bead solution supplied in the test kit AlphaScreen ™); and (iii) For the conventional functional test methodology with MCR4, a cell suspension was prepared at a concentration of 1 × 10 5 cells / ml in stimulation buffer (supplemented with 10 μl / ml of the anti-cAMP acceptor bead solution supplied in the AMPc AlphaScreen ™ assay kit). Subsequently, 10 μl of the cell suspensions were transferred to each well of the 384-well assay plate with nonadherent surface. Then, the test plates were incubated in the dark at room temperature for 30 minutes. | Third, the assay reaction was stopped by addition of 30 μl per well of detection mixture. The plates were incubated overnight in the dark at room temperature before being transferred to a Fusion ™ -a microplate analyzer for quantification. (ii) Conventional functional test methodology of MCR5 and improved functional test methodology with MCR4 TEST PROTOCOL D and E RESPECTIVELY Assay Concept Determination of the activity of the compound against the human receptor subtype MCR5 was performed using an immortalized Chinese hamster ovary cell line (CHO-K1) that was designed to stably express the recombinant human MCR5 receptor and an indicator of the ß-lactamase gene (CHO-K1-MC5R-CRE-ß-lactamase). Similarly, using an improved assay methodology, the activity of the compounds against the human MCR4 receptor subtype was also determined using a modified CHO-K1 cell line that was designed to stably express the recombinant human MCR4 receptor and a indicator of the ß-lactamase gene (CHO-K1-MC4R-CRE- ß-lactamase). These cell lines were designed using protocols similar to those described by Zaceólo et al (Zaceólo, M., (2000) Nature, 2 (1); 25-29). The activation induced by the compound of the MCR5 or MCR4 receptors in these two cell lines stimulated the production and intracellular accumulation of the β-lactamase enzyme. The amount of β-lactamase enzyme produced was directly proportional to the degree to which the test compound activated the MCR5 or MCR4 receptors present in these cells and was quantified using the β-lactamase gene indicator analysis kit that is available on the market in In vitro Life Technologies. An in-depth description of this technology and test protocols is available on the Invitrogen website (www.invitrogen.com). The protocol described below provides a summary of this test methodology. The amount of β-lactamase enzyme produced by compound-induced activation of the MCR5 or MCR4 receptors expressed in these cell lines was quantified using a Ljl Biosystems Analyst ™ HT 96,384 plate reader set to excite at a wavelength of 405 nm and to measure the energy emitted at wavelengths of 450 nm and 530 nm. The cellular responses were quantified by dividing the measured energy emitted at a wavelength of 450 nm by the measured energy emitted at a wavelength of 530 nm. Subsequently, the data analyzes were performed using a curve fitting program and the apparent power of the test compound was extrapolated (expressed as an EC50 and defined as the effective concentration of the compound that caused 50% of the maximum response induced by the compound) from adjusted curve.

Invitrogen Materials: Dulbecco Modified Tagle Medium (DMEM) with Glutamax-1, Cat No. 32430-027; Non-essential amino acids, Cat. No. 1140-0.35; Geneticin (G418), Cat No. 10131-027; Cell diaziption buffer (based on PBS, without enzymes), cat no. 13151-014; Phosphate buffered saline (PBS) (with / without Ca2 + and Mg2 +), Cat. No. 14190-094; CCF4-AM, Cat. No. K 1028; Pluronic solution F 127s (Solution B), Cat. No. 1026N K 1026N; 24% PEG and 18% TR40 solution (Solution C), Cat No. K1026N, Zeocin, Cat No. R250-05. Sigma: Fetal calf serum (FCS), Cat No. F7524; Sodium pyruvate, Cat. No. S8636; ? / - (2-Hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid) (HEPES), Cat No. H0887; Dimethylsulfoxide (DMSO), Cat. No. D-8418 Cyclohexamide, Cat. No. C-7698; Tripane Blue Solution, Cat. No. T-4424 Probenecid, Cat. No. P8761; Bovine serum albumin (BSA), Cat. No. A2153 Pluronic F-127, Cat. No. 9003-11-6. From Gilson: pipettes ranging from 10 μl to 1000 μl.

From Hereaus; Incubator of cells with CO Hera Cell. From Medial Air Technology; Class II microbiological safety cabinet BioMat2 from Ljl Biosystems; Analyst ™ HT 96,384 Plate Reader prepared to excite at a wavelength of 405 nm, and to measure the energy emitted at wavelengths of 450 nm and 530 nm. De Bachem: Melanocyte Stimulation Hormone a, MSH-a, Cat No. H1075, used as a positive control compound.

Buffers CCF4-AM was dissolved in 100% DMSO giving a final solution concentration of 1 mM. This solution was named Solution A. Probenecid was dissolved in 200 mM NaOH giving a final solution concentration of 200 mM. This solution was named Solution D. Composition of the pigmentation solution of the β-lactamase assay: for 1072 μl of test pigment solution, combine: 12 μl of Solution A, 60 μl of Solution B, 925 μl of Solution C and 75 μl of Solution D.

Greiner consumables: Microplate assay plates with 384-well transparent black bottom, Cat No. 781091. From Costar: Sterile pipettes with volumes from 2 to 50 ml, sterile tips from P10 to P1000; Sterile reservoirs, Cat. No. 4878; T225 flasks of purge plug, Cat. No. 3001.

Preparation of compounds For the functional assay methodology with MCR5, all test compounds were initially dissolved in DMSO giving a compound concentration of 4 mM and then further diluted for the PBS assay, which contained 1.25% v / vy DMSO. BSA at 0.1% w / v, to give real concentrations 5 times higher than desired as the final test concentration. For the improved functional assay methodology with MCR4, all test compounds were initially dissolved in DMSO giving a compound concentration of 4 mM and then further diluted for the PBS assay, containing 2.5% v / v DMSO and Pluronic F -127 AL 0.05% p / v, giving real concentrations 5 times higher than desired as the final test concentration.

Day-to-day cell culture Cells were cultured in T225 purge stopper flasks containing 50 ml of growth medium and kept in a cell incubator at a temperature of 37 ° C and in an atmosphere containing 5% CO2. The composition of the growth medium for CHO-K1-MC5R-CRE-ß-lactamase was 90% v / v of DMEM supplemented with: Glutamax-1, 25 mM HEPES, 10% v / v fetal calf serum (FCS ), 1 mM sodium pyruvate, 0.1 mM non-essential amino acids and 800 μg / ml geneticin. For CHO-Kl -MC4R-CRE-ß-lactamase, this growth medium is additionally supplemented with 200 μg / ml Zeocin. The cells were harvested when they reached an 80-90% confluence by first removing the existing growth medium and then washing with PBS which had been preheated to a temperature of 37 ° C. This PBS was then removed and 5 ml of cell dissolution liquid was added to the flask. These cells were incubated for 5 minutes in a cell incubator set at a temperature of 37 ° C and in an atmosphere containing 5% CO2 to separate the cells. When the cells were separated, the preheated medium was added, the cells were resuspended and gently mixed to achieve a single cell suspension with the aid of a pipette. This cell suspension was subsequently used for experimentation, or was transferred to a new T225 flask to perpetuate the cell culture.

Assay procedure The first day of the assay the cells were harvested as described above. For the conventional functional assay methodology with MCR5, a cell suspension was prepared at a concentration of 3.33x10 5 cells / ml in modified growth medium, containing 1% FCS instead of 10% FCS and 30 μl of this cell suspension to each well of a 384-well clear black bottom Microplate assay plate Greiner. For the improved functional assay methodology with MCR4, a cell suspension was prepared at a concentration of 2x105 cells / ml in modified growth medium, containing 5% FCS instead of 10% FCS, and 40 μl of this cell suspension was added to each well of a 384-well clear black bottom Microplate assay plate Greiner. For each assay, the cell plates were returned to a cell incubator maintained at a temperature of 37 ° C and in an atmosphere containing 5% CO2 overnight before performing the assay on the second day of testing. On the second day of testing the conventional functional assay methodology for MCR5, the cell plate was removed from the cell incubator and 10 μl of a 5 μM solution of cyclohexamine (prepared in PBS with 5% v / v DMSO) was added to each well of the test plate. For the improved functional assay methodology for MCR4, the cyclohexamide solution was not added. Subsequently, 10 μl of test compound solution was transferred to the test plate. The assay plate was subsequently transferred to a cell incubator, set at 37 ° C and in an atmosphere containing 5% CO2 and left for 4 hours for the improved assay methodology with MCR4, or 5 hours for the assay methodology conventional with MCR5. After this incubation period, the plate was removed from the incubator, 10 μl of the β-lactamase test pigment solution was added to each well and then the plate was returned to the cell incubator. After an additional incubation period of 60 minutes for the improved assay methodology with MCR4 or 90 minutes for the conventional assay methodology with MCR5, the plates were removed from the incubator and transferred to the plate reader Ljl Biosystems Analyst ™ HT 96,384 for the quantification.

Obesity The compounds of this invention may also be used in conjunction with pharmaceutical agents for the treatment of diseases, conditions and / or disorders related to obesity. Therefore, compositions (or medicaments) for use in the treatment of obesity are also provided which include compounds of the present invention in combination with anti-obesity agents. Suitable anti-obesity agents include cannabinoid receptor antagonists 1 (CB-1) (such as rimonabant), inhibitors of microsomal triglyceride transfer apolipoprotein (apo-B / MTP) secretion (in particular, selective MTP inhibitors). of the intestine, such as edipatapide or dirlotapide), inhibitors of 11β-hydroxy steroid dehydrogenase-1 (11β-HSD type 1), peptide YY3-36 and analogs thereof, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetics, ß3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte stimulation hormone receptor analogues, 5HT2c receptor agonists, beta-blockers, the melanin concentration hormone, leptin (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydride) rolipstatin, ie, orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists (in particular, NPY-5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone or an analogue thereof, agonists or antagonists of glucocorticoid receptors, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, filial neurotrophic factors (such as Axokine ™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), inhibitors of the human agouti-related protein (AGRP), ghrelin receptor antagonists, antagonists or inverse agonists of the histamine 3 receptor, neuromedine U receptor agonists and the like. Other anti-obesity agents, including the preferred agents described hereinafter, are well known or will be apparent in view of the present invention to one of ordinary skill in the art. The compounds of the present invention can also be administered in combination with a naturally occurring compound that acts to reduce plasma cholesterol levels. Such naturally occurring compounds are usually referred to as nutraceuticals and include, for example, garlic extract, Hoodia plant extract and niacin. Especially preferred anti-obesity agents are those selected from the group consisting of CB-1 antagonists, selective intestine MTP inhibitors, orlistat, sibutramine, bromocriptine, bromocriptine, ephedrine, leptin, peptide YY3-36 and analogs thereof and pseudoephedrine. . Preferably, the compounds of the present invention and combination therapies for the treatment of obesity and related conditions are administered together with exercise and a reasonable diet. Preferred CB-1 antagonists include Rimonabant (SR141716A also known under the trade name Acomplia ™ available from Sanofi-Synthelabo) described in U.S. Patent No. 5,624,941; and the compounds described in U.S. Patent Nos. 5,747,524, 6,432,984 and 6,518,264; U.S. Patent Publications No. US2004 / 0092520, US2004 / 0157839, US2004 / 0214855, and US2004 / 0214838; U.S. Patent Applications No. 10/971599 filed October 22, 2004; and PCT Patent Publications No.

WO 02/076949, WO 03/075660, WO04 / 048317, WO04 / 013120, and WO 04/012671. Preferred selective gut MTP inhibitors include dirlotapide described in U.S. Patent No. 6,720,351; 4- (4- (4- (4 - ((2 - ((4-methyl-4H-1, 2,4-triazol-3-ylthio) methyl) -2- (4-chlorophenyl) -1, 3-dioxolan-4-yl) methoxy) phenyl) piperazin-1-yl) phenyl) -2-sec-butyl-2H-1, 2,4-triazole-3 (4H) -one (R103757) described in the Patents from United States No. 5,521, 186 and 5,929,075; and implitapide (BAY 13-9952) described in U.S. Patent No. 6,265,431. Other representative anti-obesity agents for use in the combinations, pharmaceutical compositions and methods of the invention can be prepared using methods known to those skilled in the art, for example: sibutramine can be prepared as described in U.S. Patent No. 4,929,629; Bromocriptine can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888; Orlistat can be prepared as described in U.S. Patent Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; and PYY3-36 (include analogs) can be prepared as described in U.S. Publication No. 2002/0141985 and in WO 03/027637.

Food Intake The following assay can be used to evaluate the efficacy of test compounds in inhibiting food intake in Sprague-Dawyley rats after an overnight fast. Male Sprague-Dawyley rats can be obtained from Charles River Laboratories, Inc. (Wilmington, MA). Rats are housed individually and powdered feed is provided. They are kept in a 12-hour light / dark cycle and receive food and water ad limitum. The animals are acclimated to the vivarium for a period of one week before performing the test. The test is completed during the light part of the cycle. To perform the efficacy test on food intake, the rats are transferred to individual test cages without food the evening before the test and they are fasted overnight. After fasting during the night, they are administered the next morning vehicle or test compounds. A known antagonist (3 mg / kg) is dosed as a positive control and a control group receives vehicle alone (without compound). The test compounds are dosed at intervals of between 0.1 and 100 mg / kg depending on the compound. The conventional vehicle is 0.5% (w / v) methylcellulose in water and the conventional route of administration is oral. However, different vehicles and routes of administration can be used to adjust to different compounds when necessary. Feed is provided to the rats 30 minutes after dosing and the Oximax automated feed intake system is started (Columbus Instruments, Columbus, Ohio). The individual feed intake of the rats is recorded continuously at 10 minute intervals for a period of two hours. If necessary, food intake is recorded manually using an electronic scale; the food is weighed every 30 minutes after providing the food for up to four hours after providing the food. The efficacy of the compound is determined by comparing the food intake pattern of compound treated rats with the vehicle treated rats and the conventional positive control.

Administration and dosage ranges The biopharmaceutical properties of the compounds of formula (I), such as, for example, solubility, solution stability (in a pH range), probable dosage level and permeability, should be evaluated to select the forms of more appropriate dosage and the routes of administration considered appropriate for the treatment of the desired condition. Preliminary biopharmaceutical evaluations have indicated that some compounds according to the present invention may be especially suitable for oral administration (including buccal and sublingual) or intranasal route. For example, the oral, sublingual or intranasal route may be suitable for the compounds of Examples 1 and 5, the sublingual oral route being preferred. Other compounds may be more suitable for any form of oral administration, such as for example the compound of Example 9.

Thus, according to a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of general formula I as defined hereinabove, preferably the compound of Examples 1 and 5, formulated for sublingual administration. The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. Microwave or radio frequency can be used for this purpose. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). Generally, they will be administered as a formulation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability and the nature of the dosage form. Pharmaceutical compositions suitable for the administration of compounds of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Reminqton's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Any suitable route of administration can be employed to provide a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, the oral route of administration (including buccal and sublingual administration), rectal, topical, parenteral, ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably, the compounds of Formula (I) are administered orally or intranasally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such a dosage can easily be ascertained by one skilled in the art. For the treatment of sexual dysfunction, the compounds of the present invention are administered in a dosage range of about 0.001 milligrams (mg) to about 1000 mg, preferably from about 0.001 mg to about 500 mg, more preferably about 0.001 mg to about 100 mg, even more preferably from about 0.001 mg to about 50 mg and especially from about 0.002 mg to about 25 per kilogram of body weight, preferably in the form of a single oral dose or as a nasal spray. For example, oral administration may require a total daily dose of about 0.1 mg to about 1000 mg, while an intravenous dose may only require about 0.001 mg to about 100 mg. The total daily dose may be administered in a single dose or in divided doses and may, in the judgment of the physician, be outside the typical range provided herein. When it comes to obesity, along with diabetes and / or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of about 0.0001 milligrams to about 1000 milligrams, preferably about 0.001. mg to 500 mg, more preferably from about 0.005 mg to about 100 mg and especially from about 0.005 mg to about 50 mg per kilogram of animal body weight, preferably administered in a single dose or in divided doses two to six times a day or in the form of sustained release. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.7 mg to about 3500 mg. This dosage regimen can be adjusted to provide the optimal therapeutic response. When treating diabetes mellitus and / or hyperglycemia, as well as other diseases or disorders for which the compounds of formula I are useful, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of about 0.001. mg to about 100 mg per kilogram of body weight of the animal, preferably administered in a single dose or divided doses of two to six times a day, or in a sustained release form. In the case of an adult human being 70 kg, the total daily dose will generally be about 0.07 mg to about 350 mg. This dosage regimen can be adjusted to provide the optimal therapeutic response. These dosages are based on an average human subject weighing approximately 65 kg to 70 kg. The doctor will easily determine the doses for subjects whose weight is not in this range, such as children and the elderly.

Oral administration The compounds of the invention can be administered orally. Oral administration may involve swallowing the compound, so that it enters the gastrointestinal tract, and / or buccal, lingual or sublingual administration may be employed, whereby the compound enters directly into the bloodstream from the mouth. Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; hard or soft capsules containing multi or nano-particles, liquids or powders; pills (including those filled with liquid); chewing gums; gels; rapid dispersion dosage forms; films; ovules nebulizers; and oral / mucoadhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in hard or soft capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more agents emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, in an envelope. The compounds of the invention can also be used in dissolution and rapid disintegration dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001). For the tablet dosage forms, the drug may be from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polvinylpyrrolione, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will constitute from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, the surfactants may be from 2 wt% to 5 wt% of the tablet and the glidants may be from 0.2 wt% to 1 wt% of the tablet. The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants are generally from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and flavor masking agents.

Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight. % by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant. The tablet mixtures can be compressed directly or by a roller to form tablets. The tablet mixtures or mixture portions, as an alternative, can be granulated wet, dry or in the molten state, can be coagulated in the molten state or can be exempted prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it can even be encapsulated. Tablet formulation is discussed in "Pharmaceutical Dosages Forms: Tablets, Vol. 1" by H. Lieberman and L. Lachman, Marcel Dekker, New York, 1980). Oral films consumable for human or veterinary use are typically dosage forms in water soluble or swellable thin films which can be fast dissolving or mucoadhesive and typically comprise a compound of formula I, a film forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier an agent that modifies the viscosity and a solvent. Some components of the formulation can perform more than one function. The compound of the formula I can be soluble or insoluble in water. A water soluble compound is typically from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight of the solutes. Less soluble compounds can constitute a greater proportion of the composition typically up to 88% by weight of the solutes.

Alternatively, the compound of formula I can be in the form of multiparticulate beads. The film forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include anti-oxidants, colorants, flavors and flavor enhancers, preservatives, salivary stimulating agents, refreshing agents, co-solvents (including oils), emollients, bulking agents, antifoaming agents, surfactants and flavor masking agents. The films according to the invention are typically prepared by evaporative drying of thin aqueous films applied as a coating on a releaseable carrier or on paper. This can be done in a drying oven or tunnel, typically a combined coater, or by lyophilization or vacuum.

Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable modified release technologies such as high energy dispersions, osmotic and coated particles can be found in Pharmaceutical Tehnology On-line, 25 (2), 1-14 of Verma et al (2201). In WO 00/35298 the use of chewing gums is described to achieve a controlled release.

Parental Administration The compounds of the invention can also be administered directly to the bloodstream, to the muscle, or to an internal organ. Suitable means for parenteral administration include intravenous, intraperitonal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration. Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors and infusion technique. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9) although, for some applications, they may be formulated more conveniently as a sterile non-aqueous solution or as a dry form to be used together with a suitable vehicle such as sterile pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily achieved using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased using appropriate formulation techniques, such as the incorporation of agents that enhance solubility. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this manner, the compounds of the invention can be formulated as a suspension, or as a solid, semi-solid or thixotropic liquid for administration as an implanted reservoir that provides a modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising microspheres of poly-lactactic-coglycolic acid (PGLA) loaded with drug.

Topical administration The compounds of the invention can also be administered topically, (intra) dermally or transdermally in the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10) 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, ontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Inhaled / intranasal administration The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone or as a mixture, for example, in a dry mixture with lactose or in the form of a particle of mixed components, example, mixed with phospholipids such as phosphatidylcholine) in a dry powder inhaler or as an aerosol spray with a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1, 1, 1, 2-tetraf luoroethane or 1, 1, 1, 2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersion, solubilization or extension of the release of the ingredient. active, one or more propellants as solvents and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid. Before use in a dry powder or suspension formulation, the product drug is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding method such as jet grinding in spiral, fluid bed jet grinding, processed with supercritical fluid to take nanoparticles, high pressure homogenization or spray drying.

Capsules (made, for example, of gelatin or hydroxypropylmethylcellulose, blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a modifier of the yield such as magnesium / -leucine, mannitol or stearate.Lactose may be anhydrous or in the monohydrate form, preferably the latter.Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitrol, fructose, sucrose and trehalose. Solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other alternative solvents that e can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin can be added to the formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled and directed and programmed release. In the case of inhalers and dry powder aerosols, the dosage unit is determined by means of a valve that delivers a measured amount. The units according to the invention are typically arranged to deliver a metered dose or "pulse" containing from 0.001 mg to 10 mg of the compound of formula (I). The total daily dose will typically be in the range of 0.001 mg to 40 mg that can be administered in a single dose or, more usually, in divided doses throughout the day.

Rectal / Vaginal Administration The compounds of the invention can be administered rectally or vaginally, for example, in the form of suppositories, vaginal suppositories or enemas. Cocoa butter is a traditional suppository base, but other alternatives may be used as appropriate. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulse, controlled controlled and programmed release.

Ocular / aural administration The compounds of the invention can also be administered directly to the eye or ear, typically in the form of droplets of a suspension or micronized solution in sterile saline with adjusted pH. Other formulations suitable for ocular and aural administration include ointment, gels, biodegradable implants (e.g., sponges with absorbable gel, collagen) and non-biodegradable (e.g., silicone), wafers, lenses and systems of particles or vesicles such as niosomes or liposomes A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylceloulosa, or a heteropolysaccharide polymer, for example, galane gum, together with a preservative such as chloride may be incorporated. of benzalkonium. Such formulations can also be administered by iontophoresis. Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release.

Other technologies The compounds of the invention can be combined with soluble macromolecular entities such as cyclodextrin or suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the modes of administration mentioned above.

Drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148.

Kit of parts Whenever it is desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the invention that two or more pharmaceutical compositions can conveniently be combined, at least one of the which contains a compound according to the invention, in the form of a kit suitable for the co-administration of the compositions. In this way, the kit of the invention comprises two or more different pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention and means for separately maintaining said compositions, such as a container , divided bottle or divided laminated package. An example of such a kit is the known blister pack used for the packaging of tablets, capsules and the like. The kilt of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the different compositions in different dosage ranges, or for assessing the different compositions among themselves. To improve acceptance, the kit typically comprises illustrations for administration and can be provided with a reminder. For the avoidance of doubt, the references in this document to "treatment" include references to curative, palliative and prophylactic treatment. The invention is illustrated by means of the following non-limiting examples in which the following abbreviations and definitions are used: APCl abbreviations mass spectral by chemical ionization at atmospheric pressure [a] D specific rotation at 587 nm. Arbocel® filter agent? chemical shift d doublet doublet doubles GC-MS mass spectrometry by HPLC gas chromatography high performance liquid chromatography HRMS high resolution mass spectrum LC-MS mass spectrometry by liquid chromatography LRMS low resolution mass spectrum M multiplote Min minutes m / z peak mass spectrum NMR nuclear magnetic resonance psi pounds per square inch c quadruplet s singlet t triplet For convenience for synthesis, although in many cases the compounds have been initially isolated in their free base form, they have often been so formed in their corresponding hydrochloride salts for analytical identification purposes. For the avoidance of doubt, this document considers that both the free base and the HCl salt are provided.

X-Ray Crystallography Data Crystalline material of four compounds was obtained as follows: (1) The compound of Example 5 was dissolved in 90: 5: 5 i- PrOH / MeCN / AcOH at reflux and the solution allowed to cool then at room temperature to produce crystalline material that was isolated for further analysis; (2) the compound of Preparation 16 was dissolved in 95: 5 MeCN / THF under reflux, and the solution was then allowed to cool to room temperature to produce crystalline material which was isolated for further analysis; (3) the compound of Preparation 22b was dissolved in hot EtOAc, then pentane was added to the cloud point and then the solution was allowed to cool to room temperature to produce crystalline material which can be isolated for further analysis; and (4) for (3S, 4RJ-4- (2,4-difluorophenyl) -N - [((1R)) - -phenylethyl] pyrrolidin-3-carboxamide hydrochloride, material was obtained from EtOH / i- Pr2O by vapor diffusion methodology The stereochemistry of the crystalline material obtained for these four compounds was determined using X-ray crystallography. The representations of the 3D structures of these compounds are illustrated below in Formulas A, B, C, and D of This document The X-ray crystal data for the compound of Example (wherein R 1 = phenyl, R 2 = OH, R 3 = But 7 and R 4 and R 5 = F) illustrates: the relative cis relation of the methyl substituents on the piperidine ring; the cis-arrangement of R2 in relation to the methyl substituents on the piperidine ring; the trans relative arrangement for the groups at positions C3 and C4 of the pyrrolidine ring; and the absolute configuration at C3 and C4 of the pyrrolidine ring. X-ray crystal data for the intermediate compound of Preparation 16 (wherein R 1 = phenyl and R 2 = OH) illustrates: the relative cis relation of the methyl substituents on the piperidylne ring and the cis disposition of R 2 in relation with the methyl substituents in the piperidine ring. The compound of Preparation 16 is a direct precursor of the compound of Example 5. The X-ray data confirm that there was no stereochemical inteconversion to the piperidine ring in the subsequent reaction of the compound of Preparation 16 and the compound of Preparation 1 to produce the compound of Example 5. The X-ray crystal data for the intermediate compound of Preparation 22b (wherein R3 = Bu. {and R4 and r5 = F) illustrates: the relative trans arrangement of the groups in the C3 and C4 positions of the pyrrolidine ring; and (by means of the known absolute configuration of the benzyloxazolidinone moiety) the absolute configuration in C3 and C4. The intermediate of preparation 22b is hydrolyzed to provide the intermediate compound of Preparation 1 which is a direct precursor for the final compound of Example 5. The X-ray data confirm that there was no stereochemical interconversion in the pyrrolidine ring in the process of the intermediate of Preparation 22b in the intermediate of preparation 16 and its subsequent reaction with the intermediate of Preparation 1 to produce the final compound of Example 5. The relative and absolute configuration of the compound of Preparation 53 was determined by its conversion to (3S hydrochloride, 4RJ) -4- (2,4-difluorophenyl) -N - [((7R)) - 1 -phenylethyl] pyrrolidine-3-carboxamide. This conversion was achieved by: (i) reacting the compound of Preparation 53 with (R) - (+) - a-methylbenzylamine in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in tetrahydrofuran at room temperature to form (3R, 4SJ-3- (2,4-difluorophenyl) -4- ( { [(7R)) - 1-phenylethyl] amino.} Carbonyl) pyrrolidine -1-tert-butyl carboxylate; (ii) Deprotection Boc by treatment of a solution (3R, 4SJ-3- (2,4-difluorophenyl) -4- ( { [(R)) - 1-phenylethyl] amino} carbonyl) p Rutidin-1-tert-butylcarboxylate in dichloromethane with a solution of 4M hydrogen chloride in dioxane at room temperature to form (3S, 4R,) - 4- (2,4-difluorophenium) -N- [-] hydrochloride ((7R)) - 1-phenolletyl] pyrrolidine-3-carboxamide. The X-ray crystal data for (3S, 4R4- (2,4-difluorophenyl) -N - [(7R) -1-phenylethyl] pyrrolidine-3-carboxamide hydrochloride demonstrated the relative relationship of the substituents on C3 and C4 of the rolidine ring, and also the absolute configuration on C3 and C4 of the rolidine ring The representation of the 3D structure of this is illustrated in Formula D of this document. The remaining compounds in the Examples and Preparation have been assigned on the basis of the stereochemical precedents established in the synthesis of the compounds of Example 5, Preparation 22b, Preparation 16 and Preparation 53 as described hereinabove. compound of Example 7, which has a cis arrangement at positions 3 and 4 of the pyrrolidine ring.

The X-ray diffraction data for the monocrystals of the compounds of Example 5 and Preparations 16 and 22b were recorded at room temperature using a difframeometer with Bruker AXS SMART-APEX CCD area detector (Mo Ka radiation). The intensities were integrated from several series of exposures using the methodology described in the software SMART v5.622 (control) and SAINT v6.02m (integration), Bruker AXS Inc., Madison, Wl 1994. Each exposure covered 0.3 ° in ?, with an exposure time of 60s (Example 5), 10s (Preparation 16) or 120s (Preparation 22b) and the total data sets were: more than one sphere (Example 5); hemiefesfera (Preparations 16 and 22b). The absorption of the data sets was corrected using the multibarrido method, as described in SADABS, a program to change the scale and correct the detector data, GM Sheldrick, University of Gottingen, 1997 (based on the RH Blessing method). , Acta Cryst, 1995, A57, 33-38). The X-ray diffraction data for the hydrochloride crystal of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1 R) -1-phenylethyl] pyrrolidine-3-carboxamide was recorded at 100 K using a diffractometer with Bruker AXS SMART-APEX CCD area detector (Mo Ka radiation equipped with an Oxford Cryosystems Series 700 Liquid Nitrogen Cryostream.) The facilities were integrated from different exposure sites (as described earlier in this document). Each exposure covered, 0.3 in co with an exposure time of 60 s and the total data set was greater than one sphere, the absorption of the data sets was corrected using the multibarridos method (as detailed earlier in this document). The crystalline structures were satisfactorily resolved by direct methods using SHELXS-97, (as described in SHELXS-97, Program for crystal structure solution, GM Sheldrick, University of Gottingen, Germany, 1997, version 97-2) in: Space Group P2 ? (Example 5); Spatial group Pna2 (preparation 16); Spatial Group R? X? ^ (Preparation 22b and (3S, 4R) -4- (2,4-difluorophenyl-N - [(1 R) -1-phenylethyl] -pyrrolidin-3-hydrochloride carboxamide) and all the atoms other than hydrogen in the asymmetric units are located from the resulting electron density maps.With these maps and the later refined maps it was discovered that there was a cation and a chloride ion in the asymmetric unit for the compound of Example 5 (as shown in Formula A), there was one molecule of the compound of Preparation 16 is the asymmetric unit (as illustrated in Formula B), there was one molecule of the compound of Preparation 22b in the asymmetric unit (as illustrated in Formula C), and there was a hydrochloride cation of (3S, 4R) -4 (2,4-difluorophenyl) -N - [(1 R) -1-phenylethyl) pyrrolidin-3 -carboxamide and a chloride anion in the asymmetric unit (as illustrated in Formula D).

FORMULA A ORTEP graph of the crystal structure of the compound of Example 5 Formula A illustrates an ORTEP graph with thermal ellipses drawn with a confidence level of 50% for the asymmetric unit of the crystal structure of the compound of Example 5.

FORMULA B ORTEP graph of the crystal structure of the compound of preparation 16 Formula B illustrates an ORTEP graph with thermal ellipses drawn with a confidence level of 50% for the asymmetric unit of the crystal structure of the compound of Preparation 16.

FORMULA C ORTEP graph of the crystal structure of the compound of preparation 22b Formula C illustrates an ORTEP graph with thermal ellipses drawn with a confidence level of 50% for the asymmetric unit of the crystal structure of the compound of Preparation 22b.

FORMULA D ORTEP graph of the asymmetric unit of the crystalline structure of (3S.4? -4- (2,4-difluorophenyl) -N-rf (Y?)) - 1-phenylepyrrolidine-3-carboxamide hydrochloride Formula D illustrates an ORTEP graph with thermal ellipses drawn with a confidence level of 50% for the asymmetric unit of the hydrochloride crystal structure of (3SJ4RJ-4- (2, 4-difluorophenyl) -N - [((7R)) - 1-phenylethyl] pyrrolidine-3-carboxamide. The disorder of the difluorophenyl ring and the phenyl ring have been omitted for clarity. For the four crystals evaluated, the coordinates of the atoms other than hydrogen were refined against the diffraction data obtained by the least squares method using SHELXL-97 (as described in SHELXL-97, Program for crystal struture refinement.) GM Sheldrick, University of Gottingen, Germany, 1997, version 97-2), each with anisotropic displacement parameters.

For the crystal of Example 5, the positions of the hydrogen atoms of hydroxyl and N-H + were located from a map of Fourier differences and their coordinates were refined with limitations imposed on the respective and angles of the OH and NH bonds so that the groups retained an idealized geometry. The remaining hydrogen atoms were located in calculated positions and refined with a "riding" model and all hydrogen atoms were refined with isotropic displacement parameters. The absolute configuration of the stereochemistry of the cation of the compound of Example 5 was determined directly from the X-ray diffraction data by the Flack method (as detailed in HD Flack, Acta Cryst, 1983, A39, 876-881) . The final refined Flack parameter was 0.00 (5) for the enantiomer shown in Formula A. For the crystal of Preparation 16, the positions of the amine and hydroxyl hydrogen atoms were located from a difference map Fourier and its coordinates were refined with limitations imposed on the respective distances and angles of the NH and OH bonds so that the group maintained an idealized geometry. The remaining hydrogen atoms were located in calculated positions and refined with a "riding" model and all hydrogen atoms were refined with isotropic displacement parameters. For the crystal of Preparation 22b, the hydrogen atoms were placed in calculated positions and refined with a riding model and all with isotropic displacement parameters. The absolute stereochemistry of the compound of Preparation 22b could not be determined directly from the diffraction data. However, this crystalline structure established that the configuration could only be with a pair of enantiomers (the one shown in Formula C or its image with all the inverted chiral centers). If it is assumed that the configuration of the C4 center of the oxazolidinone ring was the same as in the starting material, ie "S", by deduction, the other two centers can be assigned that of Formula C. For the crystal of (3S, 4R) -4- (2,4-difluorophenyl) -N- [(1 R) -1-phenylethyl] -pyrrolidine-3-carboxamide hydrochloride, the large thermal eclipses associated with both phenyl rings suggested firmly that the two groups were disordered. The difluorophenyl ring was modeled on two orientations related by a double rotation around the C14 C17 axis with a relative occupation of 80:20. The unsubstituted phenyl ring was finally patterned on two blown orientations with equal occupations. The hydrogen atoms were placed in calculated positions and refined with a riding model and all with sotropic displacement parameters. The positions of the amide and amine N-H hydrogen atoms were located from a refined Fourier difference map with isotropic displacement parameters. The remaining hydrogen atoms were placed in calculated positions and refined with a "riding" model and all with isotopic displacement parameters. The absolute configuration of the stereochemistry of the hydrochloride cation of (3S, 4R) -4- (2,4-difluorophenyl) -N - [((1 R)) - 1 -phenylethyl] pyrrolidine-3-carboxamide was determined directly at from the X-ray diffraction data by the Flack method (as detailed earlier in this document). The final refined Flack parameter was -0.01 (7) for the diastereomer shown in Formula D. The final refined R factor (%) [for data | > 2D |] is: for Example 5 it is 4.15%; Preparation 16 is 4.07%; Preparation 22b is 4.62%; and for (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1 R) -1-phenylethyl] pyrrolidin-3-carboxamide hydrochloride is 5.00%.

Simulated Powder X-ray Diffraction Data (i) - Compounds of Example 5 The 2-theta angles, the interplane distances d and the relative intensities were calculated from the monocrystalline structure of the compound of Example 5 using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ [version 3.0 ] The relevant simulation parameters in each case were: Wavelength = 1.540562 A (Cu Ka); Polarization Factor = 0.5; Pseudo-Voigt profile (U = 0.01, V = 0.001, W = 0.002). In these calculations the data of the monocrystalline structure obtained by means of the methodology described previously in this document were used. Table 1 indicates the most intense peaks of the Simulated Powder Pattern of Example 5 from the Single Crystal Data Collection (as illustrated in Figure 3).

TABLE 1 Thus, in accordance with a further aspect, the present invention provides the compound of Example 5 with the simulated PXRD pattern illustrated in Figure 3 with the most intense peaks as illustrated in Table 1 when said simulated PXRD pattern is generated by the method described earlier in this document. (ii) Compound of Preparation 16 The 2-theta angles, the interplanar spaces d and the relative intensities were calculated from the monocrystalline structure of Preparation 16 using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ [version 3.0] . The relevant simulation parameters in each case were: Wavelength = 1.540562 A (CU Ka); Polarization Factor = 0.5; Pseudo-Voigt profile (U = 0.01, V = 0.001, W = 0.002). The data of the monocrystalline structure obtained by the methodology described earlier in this document were used in these calculations: Table 2 shows the most intense peaks of the Dust Pattern Simulation of Preparation 16 from the Collection of Data of a Single crystal (as illustrated in Figure 4) TABLE 2 Thus, according to a further agreement, the present invention provides the compound of Preparation 16 with the simulated PXRD pattern illustrated in Figure 4 with the most intense peaks illustrated in FIG.

Table 2 when said simulated PXRD pattern is generated by the method described earlier in this document.

(Ii) Compound of Preparation 22b The 2-theta angles, interplanar distances d and relative intensities were calculated from the monocrystalline structure of Preparation 22b using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ [version 3.0 ] The relevant simulation parameters in each case were: Wavelength = 1.540562 A (Cu Ka); Polarization Factor = 0.5; Pseudo-Voigt profile (U = 0.01 V = -0.001, W = 0.002). In this calculations the data of the monocrystal structure obtained by the methodology described above in this document were used. Table 3 indicates the most intense peaks of the Simulated Powder Pattern of Preparation 22b from the Monochrist Data Collection (as illustrated in Figure 5).

TABLE 3 Thus, according to a further aspect, the present invention provides the compound of Preparation 22b with the Standard Simulated PXRD illustrated in Figure 5 with the most intense peaks illustrated in Table 2 when said simulated PXRD pattern is generated by the method described earlier in this document.

(V) (3S, 4R) -4- (2,4-difluorophennNr (1R) -1-phenylethypyrrolidine-3-carboxamide hydrochloride. The 2-theta angles, the interplanetary distances d and the relative intensities were calculated. Starting from the monocrystalline structure of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1 R) -1-phenylethyl] pyrrolidine-3-carboxamide hydrochloride using the "Reflex Powder Diffraction" module "from Accelrys Materials Studio ™ [version 3.0] .The relevant simulation parameters in each case were: Wavelength = 1.540562 A (Cu Ka); Polarization Factor = 0.5; Pseudo-Voigt Profile (U = 0.01, V = - 0.001, W = 0.002) The data of the simple crystal structure obtained by the mythology described earlier in this document were used in these calculations Table 4 indicates the most intense peaks of the Simulated Powder Pattern of hydrochloride of 3S, 4R) - 4- (2,4-difluorophenyl) -N - [(1 R) -1-phenylethyl] pyrrolidine-3-carboxamide from the Data Collection of a Single Crystal (as illustrated in Figure 6).

TABLE 4 (3R, 4R, 5S) -1- (f (3S.4MR-ferc-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3'-pcarbonyl} - 3,5-dimethyl-4-phenylpiperidine -4-ol To a stirred suspension of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride salt of preparation 1, (57 mg, 0.2 mmol) in dichloromethane ( 1 ml) at room temperature under an atmosphere of dry nitrogen was added O-benzotriazol-1-yl hexafluorophosphate.,? /, A /, / V ',? /' - tetramethyluronyl (76 mg, 0.2 mmol), followed by N-methylmorpholine (132 μl, 0.4 mmol) and then (3R, 4s, 5S) -3, 5-dimethyl-4-phenylpiperidin-4-ol, of preparation 16 (45 mg, 0.2 mmol) in individual portions. The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 18 hours, quenched by the addition of water (10 ml) and then extracted with dichloromethane (2 x 20). The combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in dichloromethane to give the title compound as a white foam (72 mg, 77%) LRMS (APCl) 471 (100%) [ MH +], 298 (40%), 220 (20%); HRMS C28H37F2O2 [MH +] requires 471.2818 found 471.2815.

EXAMPLE 2 (3R, 4R 5S) -4-Cyclohexyl-1 -ff (3S *, 4R *) - 4- (2,4-difluorophenylH-ethylpyrrolidin-3-incarbonyl.) - 3,5-dimethylpiperidin- 4-ol To a stirred suspension of (3S *, 4R *) - 4- (2,4-difluorophenyl) -1-ethylpyrrolidine-3-carboxylic acid hydrochloride salt of preparation 17 (161 mg, 0.6 mmol) in? /, [0159] 10 ml) at room temperature under a dry nitrogen atmosphere was added triethylamine (0.2 ml, 1.4 mmol), then 1-hydroxybenzotriazole hydrate (77 mg, 0.6 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (109 mg, 0.6 mmol) y, (3R, 4s, 5S) -4-cyclohexyl-3,5-dimethylpiperidin-4-ol (from preparation 7) (100 mg , 0.5 mmole) in individual portions. The resulting mixture was stirred at 30 ° C under an atmosphere of dry nitrogen for 25 hours. The reaction was quenched by the addition of a 2 M sodium hydroxide solution (75 ml) and then extracted with diethyl ether (80 ml). The organic layer was washed with brine (50 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a clear oil (209 mg, 99%). LRMS (APCl) 449 (100%) [MH +], 298 (40%), 220 (20%); HRMS C28H39F2O2 [MH +] requires 449.2974 found 449.2970.

EXAMPLE 3 (3R, 4R, 5SJ-4"Butyl-1- (r (3S.4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-pcarboni» -3.5- dimethyl-4-ol To a stirred suspension of (3S, 4R) -erc-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride salt of preparation 1, (71 g, 0J3 mmole) in?; / V-dimethylformamide (10 ml) at room temperature under an atmosphere of dry nitrogen was added O-benzotriazol-1-yl- / V,? /,? /, A / ', A /' - tetramethyluronium hexafluorophosphate ( 95 mg, 0.3 mmol), N-methylmorpholine (83 μl, 0.8 mmol), and then (3R, 4s, 5S) -4-butyl-3,5-dimethylpiperidin-4-ol, (from? A preparation 9) ( 50 mg, 0.3 mmol) in individual portions. The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 2.5 days and then quenched by the addition of water (5 ml) and then extracted with diethyl ether (10 ml). The organic layer was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by HPLC using a Phenomenex Luna C18 (2) column of 150 x 15 mm (particle size 10 microns, porosity 100A), using an eluent of two solvents of acetonitrile: water: trifluoroacetic acid (5.95: 0.1) [solvent A] and acetonitrile [solvent B]. A solvent gradient with a flow rate of 20 ml / min was used as follows: time 0 min - 5% B; 0.6 min - 5% B; 9.5 min - 95% B; 10.5 min - 95% B. This yielded the title compound, retention time 6.05 min, as an oil (18 mg, 13%) LRMS (APCl) 451 (100%) [MH +], HRMS C26H40F2O2 requires 451.3131 found 451.3114.

EXAMPLE 4 (3R, 4R, 5S) -1-fr (3S, 4R) -1-ferc-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl > -3,5-dimethyl-4- (4-methylphenyl) piperidin-4-ol To a stirred suspension of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride salt of preparation 1, (172 mg, 0.6 mmol) in? / V-dimethylformamide (10 ml) at room temperature under an atmosphere of dry nitrogen was added O-benzotriazole-1-yl-N, N, / V ',? /' - tetramethyluronium hexafluorophosphate (231). mg, 0.6 mmol), N-methylmorpholine (201 μl, 1.8 mmol), and then (3R, 4s, 5S) -3,5-dimethyl-4- (4-methylphenyl) piperidin-4-ol, (from Preparation 10) (136 mg, 0.6 mmol) in individual portions. The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 2.5 days and then quenched by the addition of water (5 ml) and then extracted with diethyl ether (10 ml). The organic layer was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by HPLC using a column Phenomenex Luna C18 (1) of 150 x 15 mm (particle size of 10 microns, porosity 100A), using an eluent of 2 acetonitrile solvents [solvent B]. A solvent gradient with a flow rate of 20 ml / min was used as follows: time 0 min - 5% B; 0.6 min - 5% B; 9.5 min - 95% B; 10.5 min - 95% B. This yielded the title compound, retention time 6.15 min, as an oil (24 mg, 9%) LRMS (APCl) 485 (100%) [MH +], HRMS C29H39F2O2 requires 485.2974 found 485.2959.

EXAMPLE 5 (3R, 4R, 5SM-fl (3S, 4R) -1-tert-Butyl-4, 2,4-difluorophenyl) pyrrolidin-3-incarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol The (3S, 4R) -1-tert-butyl-4- (2,4-d-fluoro-phenyl) -pyrrolidine-3-carboxylic acid from preparation 1 (26.0 g, 92 mmol) and (3R, 4s, 5s) were suspended. ) -3,5-dimethyl-4-phenylpiperidin-4-ol of preparation 16, (17.4 g, 85 mmol) in dichloromethane (1000 ml). Triethylamine (14.2 ml, 102 mmol) was added and the mixture was cooled to 0 ° C with stirring under a nitrogen atmosphere. 1-Propylphosphonic acid anhydride (50% in ethyl acetate) (54.5 ml, 92 mmol) was added dropwise, keeping the temperature below 5 ° C. Subsequently, the mixture was allowed to warm to room temperature with continuous agitation. After stirring for 1 hour at room temperature, acetic acid (5 ml) was added to remove the last traces of (3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol, The reaction mixture it was stirred for an additional hour at room temperature. A 10% potassium carbonate solution (500 ml) was added and the mixture was stirred vigorously at room temperature for 2 hours. The organic layer was separated, and then stirred with a 10% potassium carbonate solution (500 ml) for 1 hour. Subsequently, the dichloromethane layer was separated, washed with water (3 x 300 ml), dried on sodium sulfate and filtered. Then, a solution of 4 M hydrogen chloride in dioxane (50 ml) was added to the dichloromethane solution. Then, the solvent was evaporated to give the crude hydrochloride as a white powder. To the crude hydrochloride was added acetone (50 ml) and the mixture was heated to boiling for 30 minutes then allowed to cool to room temperature. The hydrochloride salt was removed by filtration and washed with acetone (5 x 100 ml). Recrystallization of the product from isopropyl alcohol gave the analytically pure hydrochloride (39.5 g). MS (APCI +) 471 (M + H) 1 H NMR (400 MHz, CD 3 OD) d (Rotamers), 0.35 (d, 2 H), 0.50 (m, 3.60 H), 0.95 (m, 0.6 H), 1.22 (s, 9H), 1.65 (m, 0.75), 1.97 (m, 0.48H), 2.70 (m, 1.02H), 2.87 (m, 0.54H), 3.2 (m, 0.66H), 3.70 (m, 0.8H), 3.20-3.40 (m, H), 3.57 (m, 0.66H), 3.65 (m, 0.24H), 3.80 (m, 1.5H), 4.30 (m, 1 H), 7.05 (m, 0.5H) , 7.20 (m, 1.5 H), 7.25 (m, 3.5H), 7.45 (m, 0.5H), 7.60 (m, 1 H). [α] 25 D = -51.9 (c = 0.3, MeOH).

EXAMPLE 6 Hydrochloride of f3 4 5SJ-1-. { r (3S, 4R) -4- (2,4-difluorophenyl) -1- isopropylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol To a stirred solution of (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylic acid from Preparation 33, (160 mg, 0.58 mmol) (3R, 4s, 5S) -3 , 5-dimethyl-4-phenylpiperidin-4-ol, of preparation 16 (100 mg, 0.48 mmol) in ethyl acetate (2 ml) was added triethylamine (140 μl, 0.97 mmol) and cyclic anhydride. of 1-propylphosphonic acid (50% in ethyl acetate) (290 μl, 0.48 mmol) at 0 ° C. The reaction mixture was stirred for 30 minutes, then warmed to room temperature and the solvent removed in vacuo. The residue was dissolved between dichloromethane (20 ml) and a saturated potassium carbonate solution (2 x 20 ml). The phases were separated and the organic phase was washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography using dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1-98: 2: 0.2-97: 3: 0.3) as eluent gave 170 mg of product as a colorless oil. The oil was dissolved in 1,4-dioxane (3 ml) and 4M hydrogen chloride in dioxane (6 ml) was slowly added. Then, the solvent was removed in vacuo. Recrystallization from acetone yielded the desired product, 110.8 mg. 1 H NMR (400 MHz, CD3OD) (Rotamers), d 0.27-0.56 (m, 6H), 1.45 (m, 7H), 1.69-2.02 (m, 1 H), 2.75 (m, 2H), 3.14 (m, 2H), 3.40 (m, 1 H), 3.61 (m, 1 H), 3.77 (m, 1 H), 3.92 (m, 2H), 4.01-4.17 (m, 1 H), 4.32 (dd, 1 H) ), 7.05-7.24 (m, 4H), 7.34 (m, 3H), 7.62-7.72 (m, 1H). LRMS (APACI) 457 [MH +]. [α] 25 D = -53.5 (c = 0.26, MeOH).

EXAMPLE 7 (3 4S, 5SM-p (3 /? *, 4 /? *) 1-ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl> -3,5-dimethyl-4 -phenylpiperidin-4-oi To a cooled solution of (R *, R *) - 1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid from preparation 36 (500 mg, 1.76 mmol) in dichloromethane (20 ml ) was added a catalytic amount of N, N-dimethylformamide followed by oxalyl chloride (309 μL, 3.53 mmol). The reaction mixture was stirred for 2 hours and then the solvent was removed in vacuo. The residual white powder obtained was distilled azeotropically with dichloromethane (2 x 10 ml). The white powder was redissolved in dichloromethane (10 ml) and added dropwise to a solution of (3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol [prepared as in preparation 16] (362 mg, 1.76 mmol) and triethylamine (246 μl, 1.76 mmol) in dichloromethane (10 ml) for 10 minutes at room temperature. The resulting mixture was stirred for 24 hours, diluted with dichloromethane (10 ml) and partitioned with a saturated solution of sodium hydrogen carbonate (2 x 30 ml). The phases were separated and the organic phase was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1-98: 2: 0.2) gave the desired product as a white foam, 497 mg. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.43-0.55 (m, 6H), 0.75-0.79 (m, 1 H), 1.25 (s, 9H), 1.87-1.97 (m, 1 H), 2.16- 2.66 (m, 2H), 3.09 (t, 2H), 3.18-3.30 (m, 2H), 3.41-3.61 (m, 2H), 3.80-4.17 (m, 3H), 6.91-7.09 (m, 3H), 7.28-7.35 (m, 3H), 7.47 (c, 1 H). LCMS (APACI) = 471 [MH +].

EXAMPLE 8 Hydrochloride of (3R4 5S) -1- (r (3S, 4R) -1-fer-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl-carbonyl > -4- (3,4 -difluorophenyl) -3,5- dimethylpiperidin-4-ol A solution of (3S, 4R) -1-ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylic acid of Preparation 1, (159 mg, 0.49 mmol), (3R, 4s, 5SJ-4- (3,4-difluorophenyl) -3,5-dimethylpiperidin-4-ol (100 mg, 0.41 mmol) of preparation 39, 1-propylphosphonic acid cyclic anhydride (50% strength) ethyl acetate) (244 μl, 0.41 mmol) and triethylamine (120 μl, 0.41 mmol) in dichloromethane (2.5 ml) was stirred for 3 days at room temperature, then the reaction was diluted with dichloromethane (20 ml) and partitioned with a 10% potassium carbonate solution (20 ml) The phases were separated and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo Purification by gel column chromatography silica gel using dichloromethane: methanol: ammonia 0.88 (99: 1: 0.1-96: 4: 0.4) as the eluent gave the free base as a colorless oil, 177 mg.The oil was dissolved in dichloromethane (1 ml) and dealt with c 2 M hydrogen loride in diethyl ether (3 ml). Then, the solvent was removed in vacuo and the reside was azeotropically distilled with diethyl ether to yield the title compound as a white solid, 108 mg. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.30-056 (m, 6H), 1.48 (s, 9H), 1.62-1.94 (m, 1H), 2.64-2.75 (m, 1 H), 3.12 (t , 2H), 3.40-3.54 (m, 2H), 3.70-3.96 (m, 2H), 4.00 (m, 1 H), 4.2 (dd, 1 H), 7.02-7.21 (m, 4H), 7.52 (m , 1 H), 7.65 (, 1 H). LRMS (APCl) 507 [MH +]. [a] 25 D = -34.89 (c = 0.23, MeOH).

EXAMPLE 9 Hydrochloride of (3 /? 4 5SM- (r3S, 4R) -1-tert-butyl-4- (2,4-d »fluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4 -fluorophenyl) -3,5-dimethylpiperidin-4-ol Cyclic anhydride of 1-propylphosphonic acid (50% by weight solution in ethyl acetate) (0.67 ml, 2.0 mmol) was added dropwise to a mixture of (3R, 4s, 5S) -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol of preparation 41 (267 mg, 1.2 mmol) (3S, 4R 1 -ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3) -carboxylic acid from preparation 1 (450 mg, 1.4 mmol) and triethylamine (0.48 ml, 3.6 mmol) in dichloromethane (25 ml) at 0 ° C under a nitrogen atmosphere., the resulting homogeneous solution was stirred for 6 hours at room temperature. The solution was washed with a 10% aqueous solution of potassium carbonate (3x 20 ml), then dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by column chromatography (reverse phase C-18, Redisep® cartridge 40 g) using an ISCO Companion® self-purification system. Mobile phase gradient for 20 minutes: MeCN / H2O / TFA (5% / 95% / 0.1%) 95%: MeCN (100%) 5% eluting at: MeCN / H2O / TFA (5% / 95% / 0.1% ) 5%: MeCN (100%) 95%. The purified product was then dissolved in 1,4-dioxane (100 ml) and a 4M solution of hydrogen chloride in dioxane (20 ml) was added. Then, the solution was evaporated to dryness, redissolved in a solution of 4 M hydrogen chloride in dioxane (100 ml) and evaporated to dryness once more. Then, the residue was dried under vacuum at 50 ° C to give the hydrochloride product (391 mg) as a white amorphous solid. 1 H NMR (CD3OD 400MHz,) (Rotamers) d 0.31 - 0.57 (3xd, 6H), 0. 83-2.08 (3xm, 2H), 1.55 (s, 9H), 1.60-2.07 (3xm, 2H), 2.68-3.20 (2xm, 2H), 3.20-4.12 (m, 5H), 4.29 (m, 1 H) , 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H). LRMS (APACI) = 489 [MH +]. [a? 25 ° D _ = -42.7 (c = 0.31, MeOH).

EXAMPLE 10 Hydrochloride of (3?, 4 5S) -1-. { r (3S, 4R) -4- (2,4-difluorophenyl) -1- isopropylpyrrolidin-3-incarbonyl > -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 33 and 41 by a method similar to that described for example 9. 1 H NMR (400MHz, CD3OD) d (Rotamers), 0.31-0.57 (m, 6H), 0. 83-2.08 (m, 2H), 1.42 (m, 6H), 1.64-2.35 (m, 2H), 2.65 (m, 1 H), 3.11-4.18 (m, 7H), 4.35 (m, 1 H), 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H). LRMS (APACI) 475 [MH +]. [α] 25 D = -39.6 (c = 0.3, MeOH).

EXAMPLE 11 Hydrochloride of (3 4?, 5SM-fr (3S.4R) -4- (2,4-difluorophenin-1-methylpyrrolidin-3-incarbonyl > -4- (4-fluorophenyl) -3,5-dimethylpiperidin -4-ol The title compound was prepared from the compounds of Preparations 62 and 41 by a method similar to that described for example 9. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.23-0.60 (m, 6H) 1.03 -1.98 (m, 2H), 2.65 (m, 1 H), 3.11-4.18 (m, 11 H), 4.35 (m, 1 H), 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H) ) LRMS (APCl) 448 [MH +] [a] 25D = +49.7 (c = 0.3, MeOH) EXAMPLE 12 (3R, 4R, 5S) -1 - Hydrochloride. { r3S, 4R) -4- (2,4-difluorophenyl) pyrroHdin-3-ylcarbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol Cyclic anhydride of 1-propylphosphonic acid (50% by weight solution in ethyl acetate) (0.67 ml, 2.0 mmol) was added dropwise to a mixture of (3R, 4s, 5S) -4- (4-fluorophen l) -3,5-dimethylpiperidin-4-ol of preparation 41 (265mg, 1.2mmol), (3S, 4R) -1- (te / -butoxycarbonyl) -4- (2,4- difluorophenol) pyrrolidine-3-carboxylic acid of preparation 53 (0.75 mg, 1.4 mmol) and triethylamine (0.48 ml, 3.6 mmol) in dichloromethane (25 ml) at 0 ° C under a nitrogen atmosphere. After the addition was complete, the resulting homogeneous solution was stirred for 6 hours at room temperature. The solution was washed with a 10% aqueous potassium carbon solution (3x 20 mL), 3% aqueous citric acid (3x50 mL), then dried over sodium sulfate and filtered. Then, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ethyl acetate: pentane (gradient from 1: 9 to 4: 6) to give the product protected with Boc as a white solid. (529 mg). A part of this product (300 mg, 5.6 mmol) was dissolved in 1.4 dioxane (20 ml) and then a solution of 4M hydrogen chloride in dioxane (80 ml) was added. The solution was stirred for a further 8 hours and then the solvent was removed in vacuo. Then, the residue was dried under vacuum at 50 ° C to give the title compound (311 mg) as a white solid. 1 H NMR (400 MHz, CD 3 OD) d (Rotamers), 0.36-0.66 (m, 6H) 0. 81-1.97 (m, 2H), 2.70 (m, 1 H), 3.19-4.05 (m, 8H), 4.31 (m, 1 H), 6.85-7.31 (m, 6H), 7.28-7.80 (m, 2H) ) LRMS (APCl) 433 [MH +] [a] 25D = -62.2 (c = 0.3, MeOH) EXAMPLE 13 Hydrochloride of (3 /? 4 5S) -1- (r (3S.4 /?) - 1- ferc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-ipcarbonyl.} -4- (4-chlorophenyl) -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 1 and 43 by a method similar to that described for Example 9. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.31.0-57 (m, 6H), 0.79-1.99 (m, 2H), 1.45 (s, 9H), 1.60-2.07 (m 2H), 2.68-3.20 (m, 2H), 3.20-4.12 (m, 5H), 4.29 (m, 1 H), 7.05-7.29 (m, 5H), 7.40-7.75 (m, 2H) LRMS (APCl) 505 [MH +] [a] 25D = -37.6 (c = 0.3, MeOH) EXAMPLE 14 (3 4 5S) -1- (r (3S, 4?) -4- (2,4-difluorophenin-1-ethylpyrrolidin-3-carboncarbonyl) -4- (4-methoxypheni) hydrochloride - 3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 48 and 75 by a method similar to that described for Example 9. 1 H NMR (400 MHz, CD3OD). d (Rotamers), 0.20-0.57 (m, 6H) 1. 05 (t, 3H), 1.81 (c, 2H), 0.79-1.99 (m, 4H), 1.60-2.07 (m, 3H), 2.68-3.20 (m, 2H), 3.20-4.12 (m, 5H), 4.29 (m, 1 H), 6.81-7.29 (m, 5H), 7.60-7.74 (m, 2H LRMS (APCl) 472 [MH +] [a] 25 D = -42.7 (c = 0.3, MeOH) EXAMPLE 15 (3 4 5S) -1- ((3S, 4R) -1-Fer-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl} -4- (2,4- hydrochloride. difluorophenyl) -3,5- dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparation 1 and 49 by a method similar to that described for Example 9. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.31-0.55 (m, 6H) 0.83 -1.95 (m, 2H), 1.50 (s, 9H), 1.57-2.01 (m, 2H) 2.68-3.20 (m, 2H), 3.12-4.17 (m, 5H), 4.29 (m, 1 H), 7.04 -7.28 (m, 4H), 7.55-7.72 (m, 2H) LRMS (APCl) 507 [MH +] [a] 25D = -79.7 (c = 0.3, MeOH) EXAMPLE 16 (3?, 4 5S) -4- (2,4-difluorophenyl) -1- (r (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl-1-carbonyl} -3 hydrochloride. 5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 49 and 53 by a method similar to that described for Example 12. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.36-0.66 (m, 6H), 0. 81-1.97 (m, 2H), 2.70 (m, 1 H), 3.19-4.05 (m, 8H), 4.31 (m, 1 H), 7.05-7.35 (m, 4H), 7.45-7.65 (m, 2H) ) LRMS (APCl) 451 [MH +] [a] 25D = -42.7 (c = 0.3, MeOH) EXAMPLE 17 Hydrochloride of (3R4 5S) -1-. { f (3S.4R i-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl.} carbonyl} -4- (2,6-difluorophenyl) -3,5-dimethylpiperidin-4 -ol The title compound was prepared from the compounds of Preparations 1 and 44 by a method similar to that described for Example 9. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.31-0.59 (m, 6H), 0.83-2.08 (m, 2H), 1.55 (s, 9H), 1.60-2.07 (m, 2H), 2.68-3.20 (m, 2H), 3.20-4.12 (m, 5H), 4.29 (m, 1H), 7.05-7.15 (m, 4H), 7.45-7.65 (m, 2H) LRMS (APCl) 507 [MH +] [a] 25D = -77.7 (c = 0.3, MeOH) EXAMPLE 18 (3R4R5S) -4- (2,6-dif luo-phenyl) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-ipcarbonyl > -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 44 and 53 by a method similar to that used for Example 12. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.36-0.57 (m, 6H), 0.81-1.97 (m, 2H), 2.70 (m, 1 H), 3.15-4.05 (m, 8H), 4.31 (m, 1 H), 7.05-7.35 (m, 4H), 7.50-7.63 (m , 2H). LRMS (APCl) 451 [MH +] [a] 25D = -22.7 (c = 0.3 MeOH) EXAMPLE 19 (3R4R5S) -1-fr (3S, 4R) -1-Fer-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl-1-carbonyl hydrochloride} -4- (3-fluorophenyl) -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 1 and 46 by a method similar to that described for Example 9. 1 H NMR (400 MHz, CD3OD) d (Rotamers), 0.31-0.54 (m, 6H), 0.83-2.08 (m, 2H), 1.55 (s, 9H), 1.58-2.09 (m, 2H), 2.68-3.20 (m, 2H), 3.25-4.15 (m, 5H), 4.29 (m, 1.H ), 6.95-7.19 (m, 4H), 7.33 (m, 1 H), 7.38-7.85 (m, 2H)) LRMS (APCl) 489 [MH +] [a] 25D = -81.3 (c = 0.3 MeOH) EXAMPLE 20 (3R4R5S) -1- (r (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-halocarbonyl} -4- (3-fluorophenyl) -3,5-dimethylpiperidinyl hydrochloride 4-ol The title compound was prepared from the compounds of Preparations 46 and 53 by a method similar to that described for Example 12. 1 H NMR (CD3OD, 400 MHz) d (Rotamers), 0.36-0.60, (m, 6H) 0.81-2.01 (m, 2H), 2.70 (m, 1 H), 3.19-4.05 (m, 8H), 4.31 (m, 1 H), 6.95-7.15 (m, 4H), 7.32 (m, 1 H) , 7.28-7.80 (m, 2H) LRMS (APCl) 433 [MH +] [a] 25D = -72.7 (c = 0.3 MeOH) EXAMPLE 21 (3R4R5Sl-4- (4-chlorophenyl) -1- (r (3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrroHdin-3-incarbonyl-3,5-dimethylpiperidin-4-ol hydrochloride The title compound was prepared from the compounds of Preparations 43 and 62 by a method similar to that described for Example 9. 1 H NMR (CD3OD, 400MHz) d (Rotamers), 0.20-0.62 (m, 6H) 1.03- 1.98 (m, 2H), 2.67 (m, 1 H), 3.09-4.16 (m, 10H), 4.31 (m, 1 H), 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H) LRMS (APCl) 463 [MH +] [a] 25D = -39.3 (c = 0.3 MeOH) EXAMPLE 22 (3R4R5S) -1- (r (3S, 4R) -1-Fer-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl} -3,5-dimethyl-4-pyridine hydrochloride. 2-ilpiperidin-4-ol A solution of (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol of preparation 74 (260 mg, 1.26 mmol), (3R, 4S) -1-ferc acid -butyl-4- (2,4-difluorophenyl) pyrroidine-33-carboxylic acid from preparation 1 (267 mg, 0.94 mmol), 1- (3-dithylammonopropyl) -3-ethylcarbodimidyl hydrochloride (181 mg, 0. 95 mmoles) and 1-hydroxybenzotriazole hydrate (9 mg, 0.07 mmol) in tetrahydrofuran (5 ml) was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between water (5 ml) and ethyl acetate (5 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 5 ml). The combined organic extracts were brought up over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica eluting with dichloromethane: methanol (100: 0-99: 1-97: 3-94: 6-92: 8) and then with dichloromethane: methanol: ammonia 0.88 (95: 5: 0.5 produced The desired product in the form of a colorless oil, 11 mg, This was converted to the hydrochloride salt by treatment with 4 M hydrogen chlorine in dioxane followed by evaporation of the solvent: 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.32. -0.64 (m, 6H), 0.69-2.42 (m, 5H), 2.60-3.22 (m, 5H), 3.47-4.17 (m, 10H), 4.46 (m, 1 H), 7.00-7.26 (m, 2H) ), 7.97 (m, 1 H), 7.53-8.66 (m, 3H), 8.71 (d, 1 H) LRMS (APCl) 472 [MH +] • [a] 25D = -42.46 (c = 0.35 MeOH) EXAMPLE 23 Hydrochloride of (3R4R5SH - { R (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-n-carbonyl} - 3,5-dimethyl-4-pyridin-2-ylpiper din-4-ol To a stirred solution of (3R, 4R, 5S) -3- (2,4-difluorophenyl) -4-. { [(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-pyridin-2-ylpperidin-1-yl] carbonyl} 1-Butyl-butyl carboxylate of Preparation 54 (250 mg, 0.48 mmol) in dichloromethane (2 mL) was added a solution of 4M hydrochloric acid in dioxane (3.9 mL) at room temperature. The reaction mixture was stirred for 27 hours and the solvent was removed in vacuo to give a white solid which was triturated with diethyl ether to give the desired product in quantitative yield. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.36-0.66 (m, 6H), 1.08-2.41 (m, 2H), 2.66-3.23 (m, 2H), 3.45-4.10 (m, 7H), 4.47 ( m, 1 H), 7.01- 7.24 (m, 2H), 7.53-7.72 (2 xc, 1H), 7.74-8.22 (m, 2H), 8.63 (m, 1H), 8.72 (d, 1 H) LRMS ( APCl) 472 [MH +] [a] D25 = -44.00 (c = 0.37 MeOH) EXAMPLE 24 Hydrochloride of (3R4R5SM - { R (3S, 4R) -4- (2,4-difluoropheninpyrrolidin-3-ylcarbonyl.} - 3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Preparation 55 by a method similar to that described for Example 23. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.27-0.56 (m, 6H), 0.77-2.06 (m, 2H), 2.68-3.19 (m, 2H ), 3.40-4.08 (m, 7H), 4.30 (m, 1 H), 6.98-7.39 (m, 7H), 7.46-7.64 (2 xc, 1 H), LRMS (APCl) 415 [MH +] [a] D25 = 51.81 (c = 0.47, MeOH) EXAMPLE 25 (3R4R5S) -1-fr (3S, 4R) -1-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl > hydrochloride; -3,5-dimethyl-4-phenylpiperidin-4-ol To a stirred solution of (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4RJ -4- (2,4-difluorophenyl) pyrrolidn-3-yl] carbonyl] -3,5-d, methyl-4-phenylpiperidyl-4 -ol of Example 24 (135 mg, 0.3 mmol) in dichloromethane (2 ml) was added triethylamine (85 μl, 0.61 mmol) at room temperature, the reaction mixture was stirred for 10 minutes and butyric aldehyde (54 μl, 0.61 mmol) and the solution was stirred for a further 20 minutes, then sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added and the reaction mixture was stirred for 24 hours at room temperature.The reaction mixture was diluted with dichloromethane (3 x. 2 ml) and a saturated sodium hydrogencarbonate solution (6 ml) was added The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 2 ml) The combined organic fractions were dried over magnesium sulfate and concentrated to the vacuum to give the crude residue The purification by column chromatography on silica gel using dichloromethane: methanol (100: 0-97: 3) as The eluent produced the pure product, 45 mg. This was converted to the hydrochloride salt by dissolution in dichloromethane, treatment with 2 M hydrogen chloride in diethyl ether and then evaporation of the solvent. 1 H NMR (400 MHz, CD 3 OD) (Rotamers) d 0.20-0.58 (m, 6 H), 0.65-2.06 (m, 2 H), 1.02 (t, 3 H), 1.47 (m, 2 H), 1.77 (m, 2 H) , 2.67-3.20 (m, 2H), 3.32-4.22 (m, 9H), 4.32 (m, 1 H), 7.00-7.40 (m, 7H), 7.54-7.74 (m, 1 H) LRMS (APCl) = 471 [MH j [a] D25 = -60.39 (c = 0.32 MeOH) EXAMPLE 26 (3R, 4R5S) -1-r (3S, 4R) -4- (2,4-difluorophenin-1-isobutylpyrrolidin-3-incarbonyl) -3,5-dimethyl-4-hydrochloride -phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and isobutyraldehyde by a method similar to the development for Example 25. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.19-0.79 (m, 6H), 1. 10 (t, 6H), 0.93-2.07 (m, 2H), 2.16 (m, 1 H), 2.68-4.22 (m, 11 H), 4. 32 (m, 1 H), 6.60-7.43 (m, 7H), 7.56-7.76 (m 1 H) LRMS (APCl) 471 [MH +] [a] D¿0 = -71.94 (c = 0.31, MeOH).

EXAMPLE 27 (3R4R5S) -1-fr (3S, 4R) -4- (2,4-difluorophenyl) -1- propylpyrrolidin-3-incarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol To a solution of (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-Dimethyl-4-phenylpiperidin-4-ol from Example 24 (250 mg, 0.55 mmol) in acetonitrile (3 ml) was added triethylamine (115 μl, 0.83 mmol), potassium carbonate (151 mg, 1.11 mmoles) and 1-bromopropane (55 μl, 0.61 mmol) at room temperature. The reaction mixture was heated at 40 ° C for 90 minutes. The mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (40 ml) and ethyl acetate (40 ml). The phases were separated and the organic layer to give the crude residue. Purification by silica gel column chromatography using dichloromethane: methanol (100: 99: 1-98: 2-97: 3-96: 4) yielded the desired product as a colorless oil with 193 mg (70%) . This was converted to the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent to give a white solid. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.20-0.57 (m, 6H), 1.05 (t, 3H), 1.81 (c, 2H), 0.83-2.04 (m, 2H, 2.69-3.18 (2 xm, 2H ), 3.20-4.18 (m, 9H), 4.31 (m, 1 H), 6-94-7.38 (m, 7H), 7.51-7.70 (m, 1 H) LRMS (APCl) 457 [MH +] [a] D25 = -62.57 (c = 0.33, MeOH).

EXAMPLE 28 (3R4R5S) -1-f r (3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidin-3-incarbonyl trifluoroacetate} -3,5-dimethyl-4-pyridin-3-ylpiperidin-4-ol To a solution of (3R, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidine-3-carboxylic acid of preparation 62 (323 mg, 1.16 mmol), (3R, 4s, 5S) -3, 5-d.methyl-4-pyridin-3-ylpiperidin-3-ol of preparation 51 (200 mg, 0.96 mmol) in ethyl acetate (5 ml) was added triethylamine (400 μl, 2.88 mmol) followed by cyclic acid anhydride. 1-propyphosphonic (50% ethyl acetate) (570 μl, 0.96 mmol) at room temperature. The reaction mixture was stirred for 24 hours, treated with a saturated potassium carbonate solution (10 ml) and diluted with ethyl acetate (5 ml). The phases were separated and the organic layer was washed with a saturated solution of potassium carbonate (2 x 30 ml) and with brine (1 x 30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give the crude residue. Purification by reverse phase chromatography on silica gel using acetonitrile: water: trifluoroacetic acid (5: 95: 0.1-100: 0) as eluent gave a colorless oil, which was azeotropically distilled with toluene, then triturated with diethyl ether and finally evaporated to dryness to give a soft solid, 44-mg. 1 H NMR (400 MHz, CD3OD) (Rotamers) d 0.23-0.60 (m, 6H), 1.03-2.13 (m, 2H), 3.06 (s, 3H), 2.67-3.18 (m, 2H), 3.30-4, 15 (m, 7H), 4.38 (m, 1H), 7.10 (m, 2H), 7.48-7.67 (m, 7.89 (m, 1 H), 8.05-8.81 (m, 3H) LRMS (APCl) 430 [MH +] EXAMPLE 29 (3R4R5S) -1- (r (3S, 4R) -4- 2,4-Difluorophenyl) -1-pyrimidin-2-ylpyrrolidin-3-ipcarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol A solution of (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol, of Example 24 (250 mg, 0.55 mmol), 2-bromopyrimidine (123 mg, 0.79 mmol) and triethylamine (230 μl, 1.65 mmol) in ethanol (5 ml. ) was heated to reflux for 24 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (5ml) and water (5ml). The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol (100: 0-99: 1-98: 2-97: 3) gave the desired product as a white foam, 220 mg, (74%). This was converted to the hydrochloride salt by treatment of 4 M hydrogen chloride in dioxane followed by evaporation of the solvent. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.36-60 (m, 6H), 0.76-2.10 (m, 2H), 2.70-3.25 (m, 2H), 3.63-4.37 (m, 9H) , 6.98-7.44 (m, 8H), 7.46-7.68 (m, 1 H), 8.64 (d, 2H) LRMS (ESI +) = 493 [MH +] [a] 025 = -52.10 (c = 0.44, MeOH ) EXAMPLE 30 Hydrochloride of (3R4R5S) -1- (r (3S.4RH-Cyclobutyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl) -3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and cyclobutanone by a method similar to that described for Example 25, with the exception that ethanol was used as the solvent. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.15-0.51 (3 xm, 6H), 0.58-2.01 (m, 4H), 2.15-3.13 (m, 6H), 3.25-4.17 (m, 8H), 4.25 ( m, 1H), 6.93-7.35 (m, 7H), 7.47-7.66 (M, 1 H). LRMS (APCl) 469 [MH +] [a] D25 = -61.50 (c = 0.45, MeOH) EXAMPLE 31 (3R4R5S) -1-fr (3, 4R) -4- (2,4-Difluorophenyl) -1-pyridin-2-ylpyrrolidin-3-incarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol To a solution of 3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5 dimethyl-4-phenylpiperidin-4-ol of Example 24 (200 mg, 0.44 mmol) in toluene (4 ml) was added 2-methylpropan-2-sodiumlatelate (97 mg, 1.31 mmol) and the reaction it was stirred for 10 minutes at room temperature. 2-Bromopyridine (63 μl, 0.66 mmol) was added followed by tris (dibenzylideneacetone) dipalladium (0) (40 mg, 0.04 mmol) and (+/-) 1.1'- binaphthalen-2,2'-diylbis (diphenylphosphine) ( 55 mg, 0.09 mmol) and the reaction mixture was heated to reflux for 24 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (4 ml) and water (4 ml). The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol (100: 0-96: 4) as the eluent afforded the desired product as a foam, 160 mg (67%). This was converted to the hydrochloride salt by treatment with 4 M hydrogen chloride in dioxane followed by evaporation of the solvent. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.38-0.62 (m, 6H), 0. 87-2.14 (m, 2H), 2.70-3.24 (m, 2H), 3.51-4.20 (m, 7H), 4.33 (m, 1 H), 6.58-6.68 (m, 2H), 6.93-7.62 (m, 9H), 8.02 (m, 1 H) LRMS (APCl) 492 [MH +] [a] D25 = -44.46 (c = 0.37, MeOH) EXAMPLE 32 (3R4R5S) -1-ffl3S, 4R) -4- (2,4-difluorophenyl) -1 - (2-methoxyethyl) pyrrolidin-3-incarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and 1-bromo-2-methoxyethane by a method similar to that used for Example 27. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.20-0.58 (m, 6H ), 0.77-2.05 (m, 2H), 2.68-3.19 (m, 2H), 3.43 (s, 3H), 3.30-4.20 (m, 11H), 4.31 (m, 1 H), 6.98-7.38 (m, 7H), 7.50-7.71 (m, 1 H) LRMS (APCl) 473 [MH +] [a] D25 = -62.03 (c = 0.32, MeOH) EXAMPLE 33 Hydrochloride of (3R4R5S) -1-fr 3S, 4R) -4- (2,4-difluorophenyl) -1-pyrazin-2-ylpyrrolidin-3-illcarbonyl-3, 5-dimethyl-4-phenylpiperidin-4 ol A solution of 3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5 dimethyl-4-phenylpiperidin-4-ol of Example 24 (200 mg, 0.44 mmol), 2-chloropyrazine (75 mg, 0.84 mmol) and triethylamine (122 μl, 0.88 mmol) in? /,? / - dimethylformamide (4 ml) was heated at 100 ° C for 24 hours. The solvent was drawn under vacuum and the crude residue was partitioned between water (4 ml) and ethyl acetate (4 ml). The phases were separated and the organic was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using ethyl acetate.-pentane (10: 90-100: 0) as eluent afforded the desired product as a foam, 121 mg (55%). This was converted to the hydrochloride salt by treatment of 4M hydrogen chloride in dioxane followed by evaporation of the solvent. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.37-0.60 (m, 6H), 0.82-2.10 (m, 2H), 2.70-3.26 (m, 2H), 3.64-4.21 (m, 7H), 4.34 (m , 1H), 6.94-7.43 (m, 7H), 7.43-7.64 (m, 1H), 7.90 (d, 1H), 8.26 (m, 2H) LRMS (APCl) 493 [MH +] [a] D25 = -46.98 (c = 0.31, MeOH) EXAMPLE 34 Hydrochloride of (3R4R5S) -1-. { r (3S, 4R) -4- (2,4-difluorophenyl) -1-pyridin-3-ylpyrrolidin-3-carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and 3-bromopyridine by a method similar to that described for Example 31. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.36-0.57 (m, 6H), 0.83- 2.08 (m, 2H), 2.69-3.24 (m, 2H), 3.56-4.23 (m, 7H), 4.33 (m, 1 H), 6.94-7.62 (m, 8H), 7.70-7.83 (m, 2H) 7.98-8.10 (m, 2H) LRMS (APCl) 492 [MH +] [a] D25 = -33.26 (c = 0.36, MeOH).

EXAMPLE 35 (3R4R5SH-M3S, 4R) -4- (2,4-difluorophenyl-pyridazin-3-ylpyrrolidin-3-yl-1-carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol hydrochloride.

The title compound was prepared from the compound of Example 24 and 3-chloropyridazine (J. Med. Chem. 30 (2), 239, 1987) by a method similar to that described for Example 31. 1 H NMR (400MHz, CD3OD ) (Rotamers) d 0.35-0.58 (m, 6H), 0.73-2.08 (m, 2H), 2.68-3.24 (m, 2H), 3.60-4.27 (m, 7H), 4.30 (m, 1 H), 6.97 -8.11 (m, 10H), 8.50-9.30 (2 xd, 1 H) LRMS (APCl) 493 [MH +] [a] D25 = -36.61 (c = 0.31, MeOH) EXAMPLE 36 (3R4R5S) -1-f r (3S, 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-5-ylpyrrolidin-3-illcarbonyl hydrochloride} -3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and 5-bromopyrimidine by a method similar to that described for Example 31. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.37-0.69 (m, 6H), 0.85- 2.12 (m, 2H), 2.70-3.26 (m, 3.60-4.22 (m, 7H), 4.35 (m, 1 H), 6.93-7.43 (m, 7H), 7.43-64 (m, 1 H) , 8.52 (m, 2H), 8.71-9.26 (m, 1 H) LRMS (APCl) 493 [MH +] [a] D25 = -37.45 (c = 0.25, MeOH) EXAMPLE 37 Hydrochloride of f3R4R5S) -1-p (3S.4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-ipcarbonyl > -4-isopropyl-3,5-dimethylpiperidin-1-ol The title compound was prepared from the compounds of Preparations 1 and 57 by a method similar to that described for Example 8. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.37-0.97 (m, 12H), 1.46 (s, 9H), 1.33.07 (m, 3H), 2.55-3.05 (m, 2H), 3.07-4.06 (m, H), 7.05 (m, 2H), 7.60 (m, 1 H) LRMS (APCl ) 437 [MH +] [a] D25 = -26.07 (c = 0.60, MeOH) EXAMPLE 38 (3R4R5SH-M3S, 4R) -1 - (cyclopropylmethyl) -4- (2,4-difluorophenyl) pyrrolidin-3-hydrochloride incarbonil > -3,5-dimethyl-4-phenylpiperidin-4-ol The title compound was prepared from the compound of Example 24 and (bromomethyl) cyclopropane by a method similar to that described for Example 27. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.20-0.80 (m, 10H). 1.19 (m, 1 H), 0.83-2.02 (m, 2H), 2.68-3.18 (m, 2H), 3.19-4.18 (m, 9H), 4.31 (m, 1 H), 7.00-7.38 (m, 7H) ), 7.52-7.71 (m, 1 H) LRMS (APCl) 469 [MH +] [a] D25 = -66.40 (c = 0.28, MeOH) EXAMPLE 39 (3R4R5S) -1- Hydrochloride. { r (3S, 4R) -4- (2,4-difluorophenyl-1- (tetrahydro-2H-pyran-4-yl) pyrrolidin-3-yl-1-carbonyl} -3,5-dimethyl-4-phenylpiperidin-4- ol The title compound was prepared from the compound of Example 24 and tetrahydrate-4H-pyran-4-one by a method similar to that described for Example 25, with the exception that ethanol was used as the solvent. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.18-0.55 (m, 6H), 0.78-2.20 (m, 6H), 2.67-3.18 (m, 2H), 3.40-4.18 (m, 12H), 4.30 (m , 1 H9, 7.00-7.35 ((m, 7H), 7.53-7.71 (m, 1 H) LRMS (APCl) 469 [MH +] [a] D25 = -51.40 (c = 0.37, MeOH) EXAMPLE 40 (3R4R5S) -1- (I (3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboncarbonyl} -3,5-dimethyl-4 hydrochloride -propylpiperidin-4-ol The title compound from the compounds of Preaparicions 1 and 59 by a method similar to that described for Example 8. 1 H NMR (400MHz, CD3OD) (Rotamers) d 1.45 (s, 9H), 0.19-1.66 ( m, 15H), 2.49-304 (m, 2H9, 3.17-4.05 (m, 7H) 4.11 8m, 1 H), 7.05 (m, H), 7.59 (m, 1 H). LRMS (APCl) 437 [MH +] [a] D25 = -28.03 (c = 0.38, MeOH) EXAMPLE 41 (3R4R5S) -1- Hydrochloride. { r (3S, 4R) -1-Cyclopropyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl} 3,5-dimethyl-4-phenylpiperidin-4-ol A solution of 1 M sodium hydroxide (15 m) was added to (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} 3,5-dimethyl-4-phenylpiperidin-4-ol of Example 24 (200 mg, 0.48 mmole). The suspension was stirred and extracted with ethyl acetate (2 x 30 ml) The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo.The residual oil was dissolved in methanol (5 ml) and added acetic acid (275 μl, 4.8 mmol), [(1-ethoxy-xlpropyl) oxy] (trimethyl) silane (580 μl, 2.88 mmol) and sodium triacetoxyborohydride (90 mg, 0.96 mmol) at room temperature The reaction mixture was added methanol ( 5ml) The mixture was filtered and the filtrate was concentrated in vacuo The recovered solid was partitioned between a solution of 1 M sodium hydroxide 810 ml) and ethyl acetate (10 ml) The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 5 ml) The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue, purified by column chromatography on silica gel using dichloromethane: methanol (100: 0-97: 3) as eluent produced the desired product as a colorless oil, 131 mg. This was converted to the hydrocarbon salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent to give a white solid. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.20-0.55 (m, 6H), 1.03 (m, 4H), 0.76-2.05 (m, 2H), 2.67-3.18 (m, 2H), 3.29-4.24 (m , 8H), 4.30 (m, 1 H), 6.99-7.37 (m, 7H), 7.54-7.71 (m, 1 H) LRMS (ESI +) = 455 [MH +] [a] D 25 ° _ = -64.04 ( c = 0.26, MeOH) EXAMPLE 42 (3R4R5S) -1-ffl3S, 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-4-ylpyrrolidin-3-carbonyl hydrochloride} 3,5-dimethyl-4-phenylpiperidin-4-ol A solution of (3R, 4R, 5S) -1- hydrochloride. { [(3S, 4R) -4- (2,4-d.fluorophenyl) pyrrolidin-3-yl] carbonyl} 3,5-Dimethyl-4-phenylimper-4-ol of Example 24 (200 mg, 0.44 mmol), 4-chloropyrimidine (Biorg, Chem. 30 (3), 188, 2002) (140 mg , 0.88 mmol) and triethylamine (250 μL, 1.80 mmol) in N, N-dimethylformamide (3 mL) was heated at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude residue was partitioned between ethyl acetate (5 ml) and water (5 ml). The phases were separated and the organic phase was washed with a solution of 1 M sodium hydroxide (2 x 20 ml) and brine (1 x 20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the compound desired in the form of a yellow foam, 192 mg (81%). This was converted to the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent to give a yellow oil. The oil was triturated with diethyl ether to produce the solidified product which was then isolated by filtration. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.32-0.58 (m, 6H), 0.75-2-08 (m, 2H), 2.67-3.23 (m, 2H), 3.60-4.47 (m, 9H), 6.84 -7.40 (m, 8H), 8.19 (t, 1 H), 8.71 (m, 1 H) LRMS (ESI +) = 493 [MH +] [a] p25 = -54.71 (c = 0.35, MeOH) EXAMPLE 43 (3R4R5S) -1- (f (3S.4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl} -4-cyclopropyl-3-5- hydrochloride dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 1 and 61 by a method similar to that described for Example 8. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.19-0.53 (m, 4H), 0.65- 0.99 (m, 6H), 1.27-1.74 (m, 2H), 1.47 (s, 9H), 2.50-3.01 (m, 2H), 3.15-4.04 (m, 8H), 4.12 (m, 1 H), 7.08 (m, 2H), 7.49-7.64 (m, 1 H) LRMS (ESI +) = 435 [MH +] [a] D25 = -21.74 (c = 0.33, MeOH) EXAMPLE 44 Hydrochloride of (3R4R5S) -1- (3S , 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-4-yl-pyrrolidin-3-incarbonyl > -3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol The title compound was prepared from the compound of Example 23 and 4-chloropyrimidine (Biorg, Chem. 30 (3), 188, 2002) by a method similar to that described for Example 42. H NMR (400MHz, CD3OD) Rotamers of 0.45-0.65 (m, 6H), 1.07 -2.50 (m, 2H), 2.66-3.28 (m, 2H), 3.79-4.52 (m, 8H), 6.90-8.26 (m, 7H), 7.96 (m, 1 H), 8.56 (m, 1 H) , 8.73 (m, 2H) LRMS (APCI +) = 494 [MH +] [a] D25 = -30.35 (c = 0.30, MeOH) EXAMPLE 45 (3R4R5S) -4- (3,4-difluorophenyl) -1-M3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl-1-carbonyl hydrochloride} -3,5-dimethylpiperidin-4-ol To a solution of (3R, 4S) -3- (2,4-difluorophenyl) -4-. { [(3R, 4R, 5S) -4- (3,4-d-fluoro-phenyl) -4-hydroxy-3,5-dimethyl-pyridin-1-yl] -carbonyl} Tert-butyl pyrrolidin-1-carboxylate of Preparation 63 (176 mg, 0.32 mmol) in dichloromethane (2 ml) was added a solution of 4 M hydrogen chloride in dioxane (2 ml) at room temperature. Then, the solvent was evaporated and the residual solid was triturated with diethyl ether (10 ml), filtered and dried in a vacuum oven to give the title compound as a white solid, 116 mg. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.31-0.76 (m, 7H), 1.81-2.00 (m, 1 H), 2.65-2.81 (m, 1.5H), 3.14 (t, 0.5H), 3.48 ( m, 2H), 3.66-3.81 (m, 3H), 3.89 (m, 1 H), 4.03 (m, 1 H), 4.34 (d, 1 H), 7.04-7.27 (m, 4H), 7.46-7.60 (m, 2H). LRMS (APCl) 451 [MH +] [a] 25 D = -65.29 (c = 0.17, MeOH).

EXAMPLE 46 Hydrochloride of f 3R4R5S) -1-p (3S, 4R) -4- (2,4-d? -fluorophenyl) pyrrolidin-3-incarbonyl > -3,5-dimethyl-4- [4- (trifluoromethyl) phenypiperidin-4-ol The title compound was prepared from the compound of Preparation 66 by a method similar to that described for Example 45. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.31-0.56 (4 xd, 7H), 0.83-2.06 ( 4 xma, 2H), 2.69-2.90 (m, 1.5H), 3.16 (t, 0.5H), 3.50 (m, 2H), 3.56-3.82 (m, 3H), 3.91 (m, 1 H), 4.05 ( m, 1 H), 4.34 (d, 1H), 7.02-7.23 (m, 3H), 7.51-7.69 (m, 3H). LRMS (APCl) = 483 [MH +] [a] 25D = -55.67 (c = 0.26, MeOH).

EXAMPLE 47 Hydrochloride of (3R4R5S) -1- (r (3S, 4R) -4- (2,4-difluorophenyl) -1-pyridazin-3-ylpyrrolidin-3-carbonyl} -3.5- dimethyl-4-pyridin-2-ylpiperidin-4-ol The title compound was prepared from the compound of Example 23 and 3-chloropyridazine (J. Med. Chem. 30 (2), 239, 1987) by a method similar to that described for Example 31. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.46-0.66 (m, 6H), 1.02-2.49 (m, 2H), 2.65-3.28 (3 xm, 2H), 3.78-4.27 (m, 7H), 4.48 (m, 1 H), 6.98-7.22 (m, 2H), 7.49- 8.29 (m, 5H), 8.55 (d, 1 H), 8.65 (t, 1 H), 8.73 (d, 1 H) LRMS (APCl) 494 [MH +] [a] D25 = -21.45 (c = 0.27, MeOH).

EXAMPLE 48 (3R4R5S) -1- (r (3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-ylcarbonyl) -3,5-dimethyl-4-phenylpiperidin-4-ol hydrochloride The title compound was prepared from the compound of Preparation 69 by a procedure similar to that described for Example 45. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.14-0.46 (m, 6H), 0. 42-1.93 (m, 2H), 2.57-3.03 (m, 2H), 3.25-3.72 (m, 6H), 3.76-3.91 (m, 1 H), 4.20 (m, 1 H), 7.07-7.42 (m , 9H). LRMS (APCl) 413 [MH +] [a] D25 = -122.15 (c = 0.36, MeOH) EXAMPLE 49 4- (3R.4R.5S) -1- (r3S.4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-incarbonyl > -4-hydroxy-3-5-dimethylpiperidin-4-yl) benzonitrile The title compound was prepared from the compounds of Preparations 1 and 72 by a method similar to that described for Example 9. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.31-0.59 (m, 6H), 0.83-2.08 (m, 2H), 1.55 (s, 9H), 1.60-2.07 (m, 2H), 2.68-3.20 (m, 2H), 3.20-4.12 (m, 5H), 4.29 (m, 1H) ), 7.05-7.15 (m, 3H), 7.62-7.73 (m, 2H) 8.10-8.20 (m, 2H) LRMS (APCl) 496 [MH +] [a] D25 = -97.7 (c = 0.30, MeOH) EXAMPLE 50 (3R4R5S) -4- (Chlorophenyl) -1 - (r (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride. -3.5 -dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 33 and 43 by a method similar to that described for Example 9. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.30-5.54 (3 xd, 6H), 0.81 -2.18 (3 xm, 2H), 1.37 (m, 6H), 1.55-2.28 (3 xm, 2H) 2.65 (m, 1 H), 11-4.18 (m, 7H), 4.31 (m, 1 H), 6.80-7.05 (m, 5H), 7.30-7.65 (m, 2H) LRMS (APCl) 492 [MH +] [a] D25 = -43.8 (c = 0.35, MeOH) EXAMPLE 51 3R4R5S Hydrochloride) -4- (3.4 -difluorophenyl) -1-fr (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-incarbonyl} -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 39 and 33 by a method similar to that described for Example 8 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.30-0.59 (4 xd, 6H), 1.36- 1.41 (M, 6H), 1, 66-1.98 (m, 1 H), 2.66-2.81 (m, 2H), 3.12 (t, 1 H), 3.38-3.49 (m, 3H), 3.61-3.70 8m, 1 H), 3.71-3.83 (m, 2H), 3.90-4.05 (m, 2H), 4.35 (dd, 1 H), 7.02-7.31 (m, 5H), 7.57-7.68 (m, 1 H). LRMS (APCl) 493 [MH +] [a] D25 = -49.77 (c = 0.21, MeOH).

EXAMPLE 52 (3R4R5S) -4- (2,4-difluorophenyl) -1-fr (3S.4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-illcarbonyl hydrochloride > -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 23 and 49 by a method similar to that described for Example 9. 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.34-0.52 (3 x d.6H) 0.79 -1, 20 (3 xm, 2H), 1.39 (m, 6H), 1.49-2.30 (3 xm, 2H), 2.65 (m, 1 H), 3.19-4.21 (m, 7H), 4.35 (m, 1 H), 6.80-7.18 (m, 4H), 7.28-7.75 (m, 2H) LRMS (APCl) 493 [MH +] [a] D25 = -49.8 (c = 0.33, MeOH) EXAMPLE 53 Hydrochloride of (3R4R5S) -1-. { r (3S, 4R) -4- (2,4-difluorophenyl) -1-ethylpyrrolidin-3-ipcarbonyl} -4- (3-fluorophenyl) -3,5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 46 and 75 by a method similar to that described for Example 9 1 H NMR (400MHz, CD3OD) (Rotamers) d 0.28-0.56 (3 xd, 6H) 0.85-1.98 (3 xm, 2H), 1.47 (m, 4H), 1.55-2.05 (3 xm, 2H), 2.55 (m , 1 H), 3.11-4.20 (m, 7H), 4.31 (m, 1 H), 6.85-7.20 (m, 5H), 7.35 (m, 1 H), 7.55-7.95 (m, 1 H) LRMS ( APCl) = 461 [MH +] [a] D25 = -57.3 (c = 0.35, MeOH) PREPARATION 1 (3S, 4R) -1-Fer-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride To a stirred solution of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate of preparation 2, (6.1 g, 20.5 mmol) in diethyl ether (60 ml) at room temperature under a dry nitrogen atmosphere, potassium trimethylsilanolate (3.5 g, 24.6 mmol) was added in a single portion. The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 24 hours. Then 4M hydrogen chloride in dioxane (60 ml) was added and the resulting mixture was stirred under an atmosphere of dry nitrogen at room temperature for 30 minutes and then concentrated in vacuo to yield the hydrochloride salt of the title compound in the form of a white solid containing potassium chloride (8.4 g, approx 100%). 1 H NMR (400 MHz, CDCl 3) d 1.40 (9H, s), 3.45 (2H, m), 3.90 (4H, m), 7.00 (2H, m), 7.60 (1 H, m): LRMS (APCl) = 284 (100% [MH < (] [a] D25 = -60.39 (c = 0.32 MeOH) Alternative method (isolation in the form of zwitterion) A solution of lithium hydroxide (3.93 mmol) in water (115 ml) was added dropwise to a stirred suspension of (4S9-4 benzyl-3 { [3S, 4R) - tert -butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl) -1,3-oxazoliin-2-one from preparation 22b (8.63 g, 19.5 mmol) in tetrahydrofuran (50 ml) . The resulting reaction mixture was then stirred at room temperature for 1.5 hours, diluted with water (50 ml) and extracted with ethyl acetate (4 x 150 ml) The aqueous layer was separated, treated with a solution of hydrogen chloride aqueous 2 M (19.5 ml), concentrated to dryness and azeotropically distilled with toluene (5 x 50 ml.) The residual soft solid was triturated in 840 ml diclomethane) and the insoluble lithium chloride was removed by filtration. evaporated to produce the product in the form of a soft foam, 5.05 g.

MS m / z (APCI +); 284 [MH +]; 1 H NMR (CD3OD, 400MHz) d 1.44 (s, 9H), 3.36 (m, 2H), 3.64 (t, 1 H), 3.25 (dd, 1 H9, 3.88 (m, 3H), 6.98 (t, 2H) 7.55 (c, 1 H).

PREPARATION 2 (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid methyl To a stirred solution of methyl (2E) -3-2 (2,4-difluorophenyl) acrylonitrile from preparation 3 (10 g, 50.5 mmol) and? / - (methoxymethyl9-2-methyl- / V- [trimethylsilyl]) methanol] propan-2-amino (preparation 4 ((10.3 g, 50.5 mmol) in dichloromethane (200 ml) at room temperature under an atmosphere of dry nitrogen was added trifluoroacetic acid 80.39 ml, 5.1 mmol), The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 17 hours, then an additional portion of N- (methoxymethyl) -2-methyl-N - [(trimethylsilyl) methyl) was added to the reaction mixture} propan-2-amine (from preparation 4) (3.9 g, 19.2 mmol) and trifluoroacetic acid (0.39 ml, 5.1 mmol) The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 18 hours, then was quenched by the addition of a saturated solution of sodium bicarbonate (200 ml) and extracted with ethyl acetate (3x 75 ml) The combined organic phases dried (magnesium sulfate?), filtered and concentrated in vacuo. The residue was purified by an automatic flash column chromatography (Isco CombiFlash ® Separation System Sg 100c) using a pre-filled column (Rediseo ™ Disposable Columns for Isco Flash Chromatography, 40 g column) eluting with 5% ethyl acetate. % in pentane, increasing the polarity with a linear gradient to 100% ethyl acetate for 1 hour. After, the residue was subjected to chiral HPLC (flowing with 95: 5 hexane-isopropyl alcohol at 80 ml / min at room temperature on a Chiralpak AD500 * 80 mm column to produce the desired enantiomer of the title compound, which has been designated in this document as Enantiomer 1, and which was obtained as the fastest eluting enantiomer (resistance time 8 minutes) in the form of a transparent oil (6.1 g, 80%) with an enantiomeric excess of> 99% determined by chiral HPLC in reference to a RACEMIC pattern The unwanted enantiomer was obtained as the slowest elution component (Enantiomer2, retention time 8.7 min) 1 H NMR (400 MHz, CDCl 3) d 1.10 (9H, s), 2.80 ( 1H, m), 3.00 (1H, m), 3.15 (3H, m), 3.60 (3H, s) 3.80 (1H, m) 6.80 (2H, m), 7.40 (1H, m); LRMS ( APCl 298 (100%) [MH +].

PREPARATION 3 (2E) -3- (2,4-Difluorophenyl) methyl acrylate To a solution of 2,4-difluorocynamic acid (20 g., 1 35 mmol) in? /,? / - dimethylformamide (500 ml) at room temperature under an atmosphere of dry nitrogen was added potassium carbon (90 g). , 675 mmoles) and then iodomethane (21 ml, 337.5 mmoles). The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 7 hours before being quenched by the addition of water (1 L) and extracted with diethyl ether (3 x 200 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by an atmospheric flash column chromatography system (CombiFlash ® Separation System Sg 100c from Isco) using a pre-filled column (Rediseo ™ Disposable Columns for Isco Flash Chromatography, 40 g column) flowing with 2% ethyl acetate. % in pentane, increasing the polarity with a linear gradient to 10% ethyl acetate in pentane for 1 hour to yield the title compound as a soft solid (20.4 g, 77%). 1 H NMR (400 MHz, CDCl 3) d 3.80 (3H, s), 6.50 (1 H, d), 6.85 (1 H, m), 7.50 (1 H, m), 7.75 (1 H, d); LRMS (APCl 216 [MNH4 +], 199 [MH +].

PREPARATION 4? - (Methoxymethyl) -2-methylene- / V- (trimethylsilyl) 1methane-2-amine 2-Methyl-γ / - [(trimethyldilyl) methyl] propan-2-amine (from preparation 5) (4.31 g, 27 mmol) was added to an ice-cooled mixture of methanol (1.29 ml, 31.8 mmol) and formaldehyde aqueous (37% w / v 2.49 ml, 33 mmol) for 45 minutes. The heterogeneous mixture was stirred at 0 ° C for 2 hours and potassium carbonate (mala 325) (1.08 g, 13 mmol) was added and the mixture was stirred for 30 minutes at 0 ° C. The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to give an 80:20 mixture of the title compound and unreacted tert-butyl [(trimethylsilyl) methyl] amine in the form of a colorless oil (5.09 g). The mixture was used directly without further purification in preparation 2. 1 H NMR (400 MHz, CDCl 3) dH 0.04 (s, 9H), 1.11 (s, 9H), 2.27 (s, 2H), 3.34 (s, 3H), 4.17 (s, 2H).

PREPARATION 5 2-Methyl-A / - (trimethylsilyl) 1metinpropan-2-amine In J. Org. Chem. 53 (1), 194, 1988 a method for the preparation of this intermediate is provided. Alternative procedures are given below: A solution of chloromethyl silane (50 g, 408 mmol) and tert-butyl amine (130 ml) in a dry nitrogen atmosphere was heated to 200 ° C in a sealed tube for 18 hours before being inactivated by the addition of a 2 M sodium hydroxide solution (700 ml). The resulting mixture was extracted with diethyl ether (3 x 100 ml) and the combined organic layers were distilled under an atmosphere of dry nitrogen at 1 atmosphere to yield the title compound as a clear oil (62 g, 96%). 1 H NMR (400 MHz, CDCl 3) dH 0.05 (9H, s), 1.05 (9H, s), 1.95 (2H, s).

Alternative preparation: Chloromethyltrimethyisilane (100 ml, 730 mmol) and tere-butylamine (250 ml, 2400 mmol) were introduced into a sealed bomb and heated with vigorous stirring for 18 hours. After cooling to room temperature, the suspension of the hydrochloride salts produced and the residual excess of tert-butylamine were poured into a 4 m sodium hydroxide solution (500 ml) and stirred vigorously for 1 hour. The aqueous layer was separated and the organic layer was stirred vigorously with water (3 x 500 ml) (the excess of tert-butylamine is very soluble in water, the product tert-butyl trimethylsilylmethyl-amine is only slightly soluble). The residual organic layer was dried over sodium sulfate to give essentially pure tert-butyltrimethylsilanylmethylamine (105.4 g), which was used directly in the further preparation. 1 H NMR (400 MHz, CD 3 OD) 0.05 (s, 9 H), 1.05 (s, 9 H), 1.95 (2 H, s).

PREPARATION 6 (3R4S, 5S) -1-Benzyl-4-cyclohexyl-3,5-dylmethylperidin-4-ol It was dissolved (3R, 4S, 5S -1-benzyl-3,5-dimethylpiperidin-4-one [prepared according to preparation 14; also described in J. Med.

Chem. 7, 726, 1964] (36 g, 166 mmol) in anhydrous tetrahydrofuran (331 ml) in a flame-dried flask under an atmosphere of dry nitrogen. The solution was cooled to -78 ° C and cyclohexylmagnesium chloride (2 M solution in tetrahydrofucane) 2.42 mL, 4.84 mmol) was added dropwise over 2 h. The reaction mixture was allowed to slowly reach room temperature for 18 hours. The reaction was quenched by the careful addition of water (1 L) and diluted with ethyl acetate (1 L). The organic layer was separated and washed with water (2 x 1 L) and then with brine. After drying over anhydrous sodium sulfate and filtration, the solution was evaporated to a yellow oily residue (approximately 50 mg). This material was purified by flash chromatography on silica gel in two batches, flowing with 10% acetone in hexane. This produced the desired N-benzyl piperidinol intermediate containing about 8% residual 1-benzyl-3,5-dimethypiperidin-4-one, estimated by 1 H NMR.

PREPARATION 7 (3R, 4s, 5S) -4-Cyclohexyl-3,5-dimethylpiperidin-4-ol To a solution of (3R, 4S, 5S) -1-benz \\ - 4, cyclohexyl-.3,5-dimethylpiperldin-4-one of preparation 6 (23 g, 76 mmol) in methanol (762 ml) was he added harmonic formate (24.07 g, 381 mmol) and palladium hydroxide (35%, 40.25 g) followed by 5 M hydrogen chloride in methanol (20 ml). The reaction flask was equipped with a condenser and heated in an oil bath at 60 ° C for 2 hours. Then, the mixture was filtered through Celite®, washing the filter cake with ethyl acetate. The filtrate was concentrated in vacuo and then basified with a 5M sodium hydroxide solution and extracted with ethyl acetate (ca 600 ml). The organic layer was washed four times with a 5 M sodium hydroxide solution and (the resulting organic layer) was dried over anhydrous sodium sulfate. After filtration, evaporation of the aqueous layer afforded the title compound as a white powder (11 g, 68%). LC-MS 212 [MH +]; 1 H NMR (400 MHz, CDCl 3) d 0.84 (6H, d), 0.83-0.85 [1 H, m (darkened)], 1.16 (6H, m), 1.63-183 (6H, m), 1.63-1.83 (6H , m), 2.62-2.29 (4H, m). The relative stereochemistry of the product was established by X-ray crystallography and is in accordance with the stereochemistry presented in the literature for (3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol [J. Med. Chem. 1964, 7, 726] PREPARATION 8? F3R, 4s, 5SH-Benzyl-4-butyl-3,5-dimethylpiperidin-4-ol It was dissolved (3R, 5S) -1-benzyl-3,5-dimetripiperidin-4-one [preparations according to preparation 14; also described in J. Med.

Chem. 7, 726] (500 mg, 2.3 mmol) in anhydrous tetrahydrofuran (15 ml) and a round-bottomed flask was introduced to the flame under a nitrogen atmosphere. The solution was cooled to -78 ° C and n-butyl magnesium chloride (2M solution in tetrahydrofuran) (2.42 ml, 4.84 mmol) was added dropwise via syringe and then the solution was allowed to reach room temperature. The reaction mixture was again cooled to 0 ° C and quenched by the addition of water and diluted with ethyl acetate. The organic layer was separated and washed twice with water before being dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel eluting with 15% acetone in dichloromethane increasing the polarity of the solvent with a gradient of up to 30% acetone in dichloromethane, to yield the title compound (300 mg, 47%. 1 H NMR (400 MHz, CD 2 Cl 2) d 0.78 (6H, d), 09.1 (3H, t), 1.00-1.20 (2H, m), 1.26-1.33 (2H, m), 1.47-1.52 (2H, m ), 1.80-1.85 (2H, m), 1.98-2.03 (2H, m), 2.48-2.51 (2H, m), 3.43 (2H, s), 7.21-7.30 (5H, m).

PREPARATION 9 (3R, 4s, 5S) -4-butyl-3,5-dimethylpiperidin-4-ol (3R, 4s, 5S) -1-benzyl-4-butyl-3,5-dimethylpiperidin-4-ol (from preparation 8) (300 mg, 1.1 mmol) in methanol (10 ml) was dissolved. . Palladium hydroxide on carbon (525 mg) was added followed by ammonium formate (237 mg, 5.5 mmol) and a 2 M hydrochloric acid solution (1.1 ml, 2.2 mmol). The reaction mixture was heated to 60 ° C overnight before cooling to room temperature. Then, the mixture was filtered through Celite® by washing the cake with methanol (500 ml). The filtrate was evaporated and the residue was diluted with water, the pH adjusted to ca. 12 by the addition of a saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, then dried over sodium sulfate and evaporated to give the title compound (75 mg, 37%). 1 H NMR (400 MHz, CD 2 Cl 2) d 0.77 (6H, d), 0.79-0.81 (2H, m), 0.91 (3H, t), 1.11-1.96 (8H, m), 2.57-2.64 (2H, m).

PREPARATION 10 (3R, 4s, 5S) -3,5-dimethyl-4- (4-methylphenyl) piperidin-4-ol To a solution of 4-bromotoluene (0.80 ml, 6.5 mmol) in cyclohexane (2 ml) at 0 ° C under an atmosphere of dry nitrogen was added n-butyllithium (2.5 M in hexanes) (2.5 ml, 5.25 mmol). The resulting mixture was stirred at 0 ° C under an atmosphere of dry nitrogen for 2 hours. Then (3R, 5S) -3,5-dimethyl-4-oxopiperidin-1-tert-butylcarboxylate (from preparation 11) 300 mg, 1.3 mmol) in toluene (4.5 ml) was added and the resulting mixture was stirred at 0 ° C in a dry nitrogen atmosphere for 2.5 hours and then quenched at 0 ° C with water (10 ml). A solution of 2 M hydrochloric acid (10 ml) was added, the mixture was extracted with ethyl acetate (20 ml) and the organic layer was discarded. The aqueous layer was basified to pH 11 with a 2M solution of sodium hydroxide and extracted with ethyl acetate (2 x 15 ml). The combined organic layers (from extraction of the aqueous phase only) were dried over magnesium sulfate, filtered and concentrated in vacuo to yield the title compound as a white solid (136 mg, 47%). 1 H NMR (400 MHz, CDCl 3) d 0.55 (6H, m), 2.00 (3H, m), 2.35 (3H, s), 5.80 (5H, m), 7.10 (4H, m); LRMS (APCl) 220 (100%) [MH +]; HRMS Ci4H22O [MH +] requires 220, 1695 found 220, 1693.

PREPARATION Fert-Butyl 11 (3R, 5S) -3,5-dimethyl-4-oxopiperidin-1-carboxylate (3R, 5S) -1-benzyl-3,5-dimethyl-piperidin-4-one (from preparation 14) was dissolved in ethanol (200 ml) and di-tert-butyl bicarbonate (5.08 g) was added. , 23 mmol), followed by palladium hydroxide on carbonate (20% on carbon, 200 mg) and the reaction mixture was placed under a pressure of 40 atmospheres of hydrogen and stirred overnight at room temperature. Then, the reaction mixture was filtered through a pad of Celite® and Arbocel® and concentrated in vacuo to yield a yellow oil which crystallized after a standing period to yield the title compound (5.2 g, 90%) with a sufficient purity to be used directly in the next step (preparation 10). H NMR (400 MHz, CDCl 3) d 1.03 (6H, d), 1.49 and 1.52 [9H, 2 x s (Rotamers)], 2.48-2.76 (4H, m), 4.24-4.53 (2H, m).

PREPARATION 12 Dimethyl 2,4-dimethyl-3-oxopentanedioate Potassium carbonate (325 mesh) (298.8 g, 2160 mmol) was added to a solution of dimethyl 3-oxopentanedione (150.62 g, 865 mmol) in tetrahydrofuran (1.33 L). The suspension was heated to 45 ° C. Iodomethane (107.7 ml, 1.73 moles) was slowly added at a rate such as to maintain the temperature below 60 ° C. The suspension was stirred at 50-60 ° C for 1 hour before cooling to 20 ° C and then filtered. The filter cake was washed with tetrahydrofuran (500 ml) and the combined filtrates were concentrated to dryness in vacuo. The crude dimethyl 2,4-dimethyl-3-oxopentanedioate (179 g) was obtained as a light yellow viscous oil with a quantitative yield. 1 H NMR indicated that the material was a tautomeric enol and keto mixture and was used in preparation 13 without further purification. MS (APCL): 201 (M + H); 1 H NMR (400 MHz, CDOD) 1.25 (s, 6H), 3.65 (s, 6H).

PREPARATION 13 Dimethyl 1-Benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate A solution of 1 M hydrochloric acid (69 ml, 68.8 mmol) was added to a refrigerated (9 ° C) solution of dimethyl 2,4-dimethyl-3-oxopentanedioate [from preparation 12] (69.6 g, 344 mmol) and benzylamine (37.6 ml, 344 mmol) in methanol (1.8 L). Formaldehyde, 37% solution in water (56.8 ml, 760 mmol) was added and the solution was stirred for 3 days at room temperature and then concentrated to dryness. The crude dimephile 1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate (125.7 g) was obtained as a light brown oil. The GC-MS indicated that the material had a purity of 91% and was used in preparation 14 without further purification. GC-MS: 333 (M +); 1 H NMR (400 MHz, CDCl 3) d 7.27-7.38 (m, 5H), 3.64 (s, 6H), 3.62 (s, 2H), 3.48 (d, 2H), 2.21 (d, 2H), 1.26 (s, 6H).

PREPARATION 14 (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one A mixture of crude dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidin-3,5-dicarboxylate (786.0 g, approximately 2.3 mol) and a 1 M hydrochloric acid solution (11.5 I) ) was heated to reflux for 24 hours. The reaction mixture was cooled to 10 ° C and a solution was added slowly with dichloromethane (4 x 41) and the combined organic extracts were concentrated to dryness to give (3R, 5S) -1-benzyl-3,5-dimethylpiperidin. -4- crude Ona (475 g) in the form of a light brown oil. 1 H NMR indicated that it was a diastereomeric mixture 6: 1 of desired diastereomer: unwanted. 205 g of the above crude product was purified on silica gel (4.7 kg) eluting with hexane / ethyl acetate (20: 1 to 7: 1) to yield 94.8 g of a (3R, 5S) -1-benzyl-3, Pure 5-dimethy1-piperidin-4-one (diastereomeric ratio> 19: 1) and 44.8 g of the less pure material (diastereomeric ratio-8: 1). Both materials were colorless oils. Analytical data for (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one: GC-MS: 217 (M +); 1 H NMR (400 MHz, CDCl 3) d 7.27-7.38 (m, 5H), 3.60 (s, 2H), 33.15 (m, 2H), 2.70 (m, 2H), 2.04 (t, J = 11.6Hz, 2H) 0.93 (d, J = 6.6Hz, 6H).

Alternative method: A mixture of 1-benzyl-3,5-dimethyl-4-oxo-piperidine dicarboxylic acid methyl ester of preparation 13 (786.0 g, approx -2300 mmol) and 1 M aqueous hydrochloric acid (11.5 L) ) was heated to reflux for 24 hours. The reaction mixture was cooled to 10 ° C and 25% by weight aqueous sodium hydroxide was slowly added. The mixture was extracted with dichloromethane (4 x 41). The combined organic extracts were concentrated to dryness to give 1-benzyl-3,5-dimethyl-piperidin-4-one (475 g) as a light brown oil. 1 H NMR indicated a 6: 1 cis: trans distereomeric mixture. A portion of the crude diastereomeric mixture (15 g) was purified using an automatic purification system which employed a normal phase Redissep silica cartridge (330 g), solvent flow rate of 100 ml / min, with circumference of the cyclohexane linear gradient ethyl acetate - 2-3% ethyl acetate for 25 minutes, linear gradient of effetyl acetate at 314% for 10 minutes, completing the elution with 14% ethyl acetate. This was produced (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one pure (10.2 g, 99% + by LC-MS). LC-MS (ESI +): 218 (M + H); Alternatively, the crude cis / trans mixture could be enriched in the desired cis component before purification by the following procedure: The crude cis / trans mixture of 1-benzyl-3,5-dimethylpiperid-4 One (typically 6: 1 cis / trans) (45 g) was added to a 5% solution of sodium methoxide in methanol (500 ml) and stirred at room temperature for 6 hours. Saturated aqueous ammonium chloride (30 ml) was added and the mixture was stirred for a further 30 minutes at room temperature. The mixture was evaporated to dryness and then redissolved in dichloromethane (500 ml). The insoluble solids were removed by filtration and the solvent was subsequently evaporated to give an enriched 96: 4 mixture of cis / trans as showed by 1 H NMR analysis (quantitative mass recovery). A longer reaction time did not provide additional enrichment. If required, the pure cis product can be subsequently recovered by chromatographic purification as described above.

PREPARATION 15 (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-phenylpiperdin-4-ol (3R, 5S) -1-benzyl-3,5-dimethylpiperidn-4-one (prepared as preparation 14, also described in J. Med. Chem. 7, was dissolved. 726, 1964) (5 g, 23 mmol) in anhydrous tetrahydrofuran (77 ml) in a flame-dried flask under an atmosphere of dry nitrogen. The solution cooled to -78 ° C and phenyllithium (2M solution in cyclohexane-ether) (34.6 ml, 69 mmol) was added dropwise. The reaction mixture was allowed to slowly reach room temperature overnight and then quenched by the careful addition of water (50 ml). The resulting mixture was diluted with ethyl acetate and the organic layer was separated and then washed three times with water and once with brine. Then, the organic layer was dried (sodium sulfate), filtered and evaporated. The resulting residue was purified by flash chromatography on silica gel eluting with 10% -50% ethyl acetate in hexanes (11) to yield (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4- phenyl-pylpperidin-4-ol with a purity > 90% LRMS: 296 (MH +); 1 H NMR (400 MHz, CD 2 Cl 2) d 0.52 (6H, d), 2.09-2.24 (4H, m), 2.67-2.71 (2H, m), 3.54 (2H, s), 7.22-7.38.

Alternative method: Phenyl nitro in diisopropyl ether (2 M, 34.5 mL, 690 mmoles) to a stirred solution of (3R, 5S) -1-benzyl-3,5-dimetiipiperidin-4-one of preparation 14 (10.0 g, 46 mmol) in anhydrous diethyl ether (150 ml) at -78 ° C. C. The mixture was stirred for a further 30 minutes at -78 ° C, before adding a solution of saturated aqueous ammonium chloride (10 ml) and the mixture was allowed to warm to room temperature. The organic layer was separated, washed with water (3 x 200 ml) and dried over sodium sulfate and then filtered. Then, the solvent was evaporated to give the crude (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol (12.8 g) as a bench solid. The crude compound was > 95% pure by 1 H NMR and used directly in preparation 21. LC-MS (ESI "): 269 (M + H); 1 H NMR (400 MHz, CD 3 OD) d 0.51 (d, 6 H), 2.18 (m, 2H), 2.30 (m, 2H), 2.42 (m, 2H), 3.6 (s, 2H), 7.15 (m, 1 H), 7.35 (m, 9H).

PREPARATION 16 (3R, 4s, 5S) -3,5-Dimethyl-4-phenylpiperidin-4-ol (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol was dissolved from preparation 15 in methanol (156 ml) and ammonium formate (4.9 g, 78 mmol) and then palladium hydroxide on carbon (8g) was added followed by a solution of 2M hydrochloric acid in diethyl ether (11 ml, 22 mmol). The flask was equipped with a water condenser and the reaction was heated at 60 ° C overnight. After cooling to room temperature, the reaction mixture was filtered through Celite® washing the cake with 1 L more methanol. The combined filtrates were evaporated and the residue was dissolved in a minimum amount of water, which was made basic (to pH 11) by the addition of a saturated sodium carbonate solution. The resulting mixture was extracted twice with ethyl acetate and the combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated to yield the title compound (3.23 g, 68%). 1 H NMR (400 MHz, CD 2 Cl 2) d 0.52 (6H, d), 2.03-2.10 (2H, m), 2.71-2.77 (2H, m), 2.83-2.88 (2H, dd), 7.22-7.38 (5H, m ).

Alternative method: (3R, 4s, 5S) -1-benzyl-3,5-d, methyl-4-phenylpiperidin-4-ol was dissolved from preparation 15 (15 g, 51 mmol) in methanol and 20% Pd (OH) 2 / (C) in water (1.5 g) was added. The mixture was hydrogenated at 50 ° C / 50 psi (344.73 kPa) for 18 hours. Then, the mixture was filtered through an Arbocel filtration agent and the methanol was evaporated to give crude ((3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol as a white solid. Recrystallization of the crude material from acetonitrile gave analytically pure (3R, 4S, 5S) -3,5-dimethyl-4-phenylpiperdin-4-ol in the form of white needles (9.6 g).

PREPARATION 17 3S *, 4R *) - 4- (2,4-Difiuorophenol) -ethylpyrrolidin-3-carboxylic acid hydrochloride To a stirred solution of (3S *, 4R *) - Methyl 4- (2,4-difluorophenyl) -ethylpyrrolidine-3-carboxylate from Preparation 18 (5.9 g, 22 mol) in diethyl ether (59 ml) at room temperature under a dry nitrogen atmosphere added potassium trimethylsilanolate (2.36 g, 26 mmol) in a single portion. The resulting mixture was stirred at room temperature under a N2 atmosphere for 3 hours. Then a solution of 4M hydrogen chloride in dioxane (20 ml) was added and the resulting mixture was stirred under an atmosphere of dry nitrogen at room temperature for 18 hours and then concentrated in vacuo to yield the title compound as a solid. a white solid containing potassium chloride residues (7.0 g). 1 H NMR (400 MHz, CDCl 3) d H 1.25 (3 H, m), 3.25 (5 H, m), 3.8 (2 H, m), 4.10 (1 H, m), 7.20 (2 H, m), 7.80 (1 H, m); LRMS (APCl) 256 (100%) [MH +]; HRMS C13H15F2O2 [MH +] requires 256.1144 found 256.1142.

PREPARATION 18 (3S *, 4R *) - Methyl 4- (2,4-difluorophenyl) -1-ethyl-3-carboxylic acid To a stirred solution of methyl (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate from preparation 19 (10.5 g, 43 mmol) and tetrahydrofuran (215 ml) at room temperature In an atmosphere of dry nitrogen, iodoethane (3.8 ml, 48 mmol) and NN-diisopropylethylamine (8.3 ml, 48 mmol) were added in single portions. The resulting mixture was stirred at room temperature under an atmosphere of dry nitrogen for 72 hours, then quenched by the addition of water (200 ml) and extracted with ethyl acetate (2 x 250 ml). The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a 2: 1 mixture of penta no: ethyl acetate increasing the polarity to 1: 1. This produced the title compound as a clear oil (7.9 g, 68%). 1 H NMR (400 MHz, CDCl 3) dH 1.15 (3H, m), 2.45 (1 H, m), 2.55 (1 H, m), 2.65 (1 H, m), 2.95 (3 H, m), 3.15 (1 H, m), 3.65 (3 H, s), 3.85 (1 H, m), 6.80 (2 H, m ), 7.40 (1H, m); LRMS (APCl) 270 (100%) [MH *].

PREPARATION 19 (3S *, 4R *) - methyl 4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate . To a suspension of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate from preparation 20 (15 g, 45 mmol) in ethanol (225 ml) at room temperature in an atmosphere of dry nitrogen, 10% palladium on carbon (Degusta type) (1.5 g) was added and the reaction mixture was placed under a pressure of 50 psi (344.73 kPa) of hydrogen and heated to 40 ° C during one night. After cooling to room temperature, the reaction mixture was filtered through Celite® and concentrated in vacuo to yield the title compound as an orange oil (10.8 g, 98%). H NMR (400 MHz, CDCl 3) dH 2.85 (1H, m), 3.15 (1 H, m), 3.30 (2H, m), 3.45 (1 H, m), 3.65 (4H, m), 6.80 (2H, m), 7.20 (1 H, m); LRMS (APCl) 242 (100%) [MH +]; HRMS C12H14F2O2 [MH +] requires 242.0987 found 242.0986.

PREPARATION 20 (3S *, 4R *) - 1 -benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate methyl A solution of trifluoroacetic acid (2.42 mL, 31.5 mmol) in dichloromethane (5 mL) was added at 0-5 ° C to a stirred solution of / V-benzyl-? / - (methoxymethyl) trimethylsilylamine (45.1 g). , 190 mmol) and (2E) -3- (2,4-dichlorophenyl) methyl acrylate (e preparation 3) (25.1 g, 126 mmol) in dichloromethane (10 ml). After stirring overnight at room temperature, the organic solution was washed with a saturated solution of sodium bicarbonate and then with brine. The resulting organic solution was dried over anhydrous sodium sulfate, filtered and then evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of toluene: tetrahydrofuran (11: 1) to give the title compound (31.6 ml, 71%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3) dH 2.80 (1 H, m), 3.05 (3 H, m), (3.25 (1 H, m), 3.62 (3 H, s), 3.85 (1 H, m), 4.20 ( 2H, s), 6.55 (5H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCl) 332 (100%) [MH +].

PREPARATION 21 (4S) -4-Benzyl-3-r (2E) -3- (2,4-difluorophenyl) prop-2-ene-1,3-oxazolidin-2-one Oxalyl chloride (19 ml, 216 mmol) in dichloromethane (50 ml) was added dropwise to a stirred and ice-cooled suspension of 2,4-difluorocynamic acid (20.0 g, 108 mmol) in dichloromethane (400 ml) and N, N-dimethylformamide (0.4 ml) for 0.5 hours (the residual gases from the reaction were removed with a concentrated sodium hydroxide solution.) After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at room temperature. The reaction mixture was concentrated and azeotropically distilled with dichloromethane (2 x 50 ml) The resulting acid chloride was dissolved in dichloromethane (50 ml) and this solution was added dropwise. dropwise under a nitrogen atmosphere to a vigorously stirred suspension of halium chloride (23.0 g, 240 mmole), triethylamine (76 m, 540 mol), (S) - (-) - 4-benzyl-2-oxazolidinone (1.83 g, 103 mmol) in dichloromethane 8400 ml) for 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was diluted with dichloromethane (200 ml) and treated with a 5% citric acid solution (500 ml). Then, the organic layer was separated and dried over magnesium sulfate. Filtration and evaporation of dichloromethane gave the crude product as an orange oil. The crude material was redissolved in dichloromethane (100 ml) and the resulting solution passed through a layer of silica, eluting with dichloromethane. Finally, the filtrate (1 I) was concentrated to yield 30.8 g of the product as a white solid. MS m / z (APCI +): 344 [MH +]; 1 H NMR (400 MHz, CDCl 3) dH 2.85 (dd, 1 H), 3.36 (dd, 1 H, 4.22 (m, 2 H), 4.80 (m, 1 H), 6.90 (m, 2 H), 7.68 (m, 5 H). , 7.68 (dd, 1 H), 7.91 (d, 1 H), 8.01 (dd, 1 H).

PREPARATION 22a f4S) -4-Benzyl-3-fr (3R4S) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-pcarbonyl} -1,3-oxazolidin-2-one and PREPARATION 22b (4S) -4-Benzyl-3-. { r (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-ylcarbonyl} -1,3-oxazolidin-2-one A stirred solution of (S) -4-benzyl-3- [3- (2,4-difluoro-phenyl) -acyloyl] -oxazolidin-2-one from Preparation 21 (1.70 g, 4.95 mmol) and N- ( methoxymethyl) -2-methylal / - [(triamethylsilyl) methyl] propan-2-amine of preparation 4 (1.60 g, 5.94 mmol) in dichloromethane (15 ml) was treated with trifluoroacetic acid ( 0.075 ml, 1 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4.5 hours. The reaction mixture was diluted with dichloromethane (50 ml) and treated with a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 ml). The organic fractions were combined and dried over magnesium sulfate.

Filtration and evaporation of dichloromethane gave the crude mixture of diastereoisomers. Separation by column chromatography on silica gel with pentane: ethyl acetate 80/20 at 10/90 to 10/90 v / v, gradient elution, produced first 0.74 g (1.67 mmoles) of (4S) - 4-benzyl-3-. { [(3R, 4S) -1- tert -butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one in the form of a colorless oil, and then 0.82 g (1.85 mmol) of (4S) -4-benzyl-3-. { [(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one as a white solid. (4S) -4-benzyl-3-. { [(3R, 4S) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one-MS m / z (APCI +): 443 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 1.12 (s, 9 H), 2.77 (dd, 1 H), 2.85 (m, 1 H), 3.25 (dd, 1 H), 3.17-3.47 (m, 1 H), 4.15 (m, 3H), 4.65 (m, 1 H), 6.74 (t, 1 H), 6.82 (t, 1 H), 7.17-7.42 (m, 6H). (4S) -4-benzl-3-. { [(3R, 4S) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one-MS m / z (APCI +): 443 [MH +]; 1 H NMR (CDCl 3, 400 MHz) 1.12 (s, 9 H), 2.72 (dd, 1 H), 2.83 (m, 2 H), 3.20 (m, 2 H), 3.36 (t, 1 H), 4.14 (m, 3 H) ), 4.29 (m, 1 H), 4.67 (m, 1 H), 6.67 (t, 1 H), 6.85 (t, 1 H), 7.08 (m 2 H), 7.24 (m, 3 H), 7.43 (m. m, 1 H). the absolute and relative stereochemistry of (4S) -4-benzyl-3-. { [(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one was determined by X-ray analysis obtaining in ethyl acetate / pentane PREPARATION 23 (4S) -4-Benzyl-3-r (2E) -3- (4-chlorophenyl) propionate. 2-ene-1,3-oxazolidin-2-one A solution of oxalyl chloride (10.82 ml, 124 mmol) in dichloromethane (50 ml) was added dropwise to a cooled solution of (2E) -3- (4-chlorophenyl) acrylic acid (11.33 g, 62.0 mmol) in dichloromethane (110 ml) and? /,? / - dimethylformamide (0.4 μl, 0.01 mmol). After stirring the reaction mixture for 24 hours, the solution was added dropwise to a cooled solution of (4S) -4-benzyl-1,3-oxazolidin-2-one (9.49 g, 53.6 mmol), triethylamine ( 39.2 mL, 282 mmol) and lithium chloride (11.95 g, 282 mmol) in dichloromethane (110 mL). The reaction mixture was slowly warmed to room temperature, stirred for 2 hours and then water (50 ml) was added. The mixture was diluted with dichloromethane (100 ml) and a solution of 5% citric acid (2 x 150 ml) was added. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel using dichloromethane as eluent afforded the desired product as a white solid, 14.6 g (74%). 1 H NMR (400MHz, CDCl 3) d 2.86 (dd, 1 H), 3.37 (dd, 1 H), 3.37 (dd, 1 H), 4.23 (m, 2H), 4.81 (m, 1 H), 7.21-7.41 (m, 7H), 7.57 (d, 2H), 7.87 (2 xd, 2H) LRMS (APCl) 342 [MH +] PREPARATION 24 (4S) -4-benzyl-3 (r (3S-4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-carbonyl) - 1,3-oxazolidin-2-one To a cooled solution of (4S) -4-benzyl-3 [(2E) -3- (4-chlorophenyl) proa-2-enoyl] -1, 3-oxazolidin-2-one from Preparation 23 (5 g, 14.62 mmol) and? / - benzyl-1-methoxy -? / - [(trimethylsilyl) methyl] methanamine (5.24 mL, 20.47 mmol) in dichloromethane (50 mg). ml) was added trifluoroacetic acid (60 μl, 0.73 mmol). The reaction mixture was stirred at 0 ° C for 20 minutes and then warmed to room temperature and stirred for 24 hours. A solution of sodium hydrogencarbonate (80 ml) was added and the reaction mixture was stirred for 10 minutes. The phases were separated and the organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel using ethyl acetate: pentane (10: 50-50: 50) as eluent yielded the desired product (which is the diastereomer eluting second) as a white crystalline solid, 733 mg (11%). 1 H NMR (400MHz, CDCl 3) d 2.63-2.82 (m, 3H), 3.09-3.25 (m, 3H), 3.67 (dd, 2H), 3.98-4.28 (m, 4H), 4.65 (m, 1 H), 7.03 (m, 2H), 7.17-7.39 (m, 12H) LRMS (APCl) 475 [MH +] PREPARATION 25 (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-carboxylate methyl To a stirred solution of (4S) -4-benzyl-3-. { [3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidyl-3-yl] carbonyl} -1, 3-oxazolidin-2-one from Preparation 24 (2.51 g, 5 J28 mmol) and dimethyl carbonate (2.22 mL, 26.4 mmol) in dichloromethane (40 mL) was added with sodium methoxide (1.42 g, 26.4 mmol) at room temperature. The reaction mixture was stirred for 24 hours and diluted with dichloromethane (50 ml). The phases were separated and the organic phase was washed with water (2 x 40 ml), dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using ethyl acetate: pentane (5: 95-20: 80) as eluent to yield the desired product as a colorless oil, 1.61 g (79%). 1 H NMR (400 MHz, CDCl 3) d 2.67-3.17 (m, 5 H), 3.65 (s, 3 H), 3.53-3.75 (, 3 H), 7.20-7.40 (m, 9 H), LRMS (APCl) 330 [MH +] PREPARATION 26 Methyl (3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-carboxylate hydrochloride To a solution of methyl (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidine-3-carboxylate from preparation 25 (0.93 g, 2.8 mmol) in dichloromethane (9 ml) cooled in a water bath. to ice was added 1-chloroethyl chloroformate (0.46 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. Then, the reaction mixture was cooled to 0 ° C and triethylamine (0.43 ml, 3.1 mmol) was added followed by more 1-chloroethyl chloroformate (0.31 ml, 2.8 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours before being diluted with dichloromethane, washed with water (20 ml) and 5% aqueous citric acid (20 ml) and then dried over sulfate of magnesium and filtered.

The solvent was removed in vacuo and the residual oil was heated to reflux in methanol (20 ml) for 1 hour. Then, the solvent was removed in vacuo and the residue was triturated with diethyl ether and filtered to give the desired product as a white solid, 0.874 g. 1 H NMR (400 MHz, CD 3 OD) d 3.64 (s, 3 H), 3.31-3.83 (m, 6 H), 7. 36 (s, 4H). LRMS (APCl) 240 [MH +] PREPARATION 27 (2 £) -3- (2,4-difluorophenyl) proa-2-enoyl tert-butyl carbonate To a stirred solution of (2E) -3- (2,4-difluorophenyl) acrylic acid (42.0 g, 230 mmol) in anhydrous tetrahydrofuran (400 ml) was added triethylamine (37.5 ml 270 mmol) and the reaction mixture was cooled to -70 ° C. Trimethyl acetyl chloride (30 ml, 250 mmol) was added dropwise over 20 minutes and the solution was allowed to warm to room temperature for 1 hour. Analysis by thin layer chromatography indicated that the desired product had been formed and used directly in the next step.

PREPARATION 28 (4S) .4-benzyl-3r (2 £) -3- (2,4-difluorophenyl) proa-2-enein-1,3-oxazolidin-2-one N-Butyllithium (2.5M in hexanes) (100 mL, 250 mmol) was added dropwise to a stirred solution of (S) - (-) - 4-benzyl-2-oxazolidinone (43.55 g, 250 mmol) in tetrahydrofuran anhydrous (350 ml) at 0 ° C. The resulting solution was cooled to -78 ° C for 30 minutes and added dropwise to a stirring solution of (2E) -3- (2,4-difluorophenyl) proa-2-enei-tere-butyl carbonate of the preparation 27 by means of a cannula at -78 ° C. The resulting suspension was allowed to warm to 0 ° C and a saturated solution of ammonium chloride (75 ml) was added, followed by water (50 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give a suspension. To the suspension were added cyclohexane (178.5 ml) and tert-butyl methyl ether (126 ml) and the mixture was stirred for 2 hours at room temperature. The resulting white solid was collected by filtration and dried in a vacuum oven at 40 ° C to give the desired product, 45.48 g (61%). 1 H NMR (400MHz, CDCl 3) d 2.82 (dd, 1 H), 3.34 (dd, 1 H), 4.20 (m, 2H), 4.77 (m, 1 H), 6.84 (m, 1 H), 6.91 (t , 1 H), 7.20-7.33 (m, 3H), 7.65 (m, 2H), 7.96 (m, 3H).

PREPARATION 29 (4S) -4-benzyl-3-fr3S.4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-ylcarbonyl} -1,3-oxazolidin-2-one To a stirred solution of (4S) -4-benzyl-3 - [(2E) -3- (2,4-difluorophenyl) proa-2-enoyl] -1,3-oxazolidin-2-one of preparation 28 ( 46.83 g, 140 mmol) in dichloromethane (300 ml) was added / V-methoxymethyl-N- (trimethylsilylmethyl) benzylamine (50.2 ml, 210 mmol) at room temperature. The solution was cooled to -12 ° C and a solution of trifluoroacetic acid (1.05 ml) in dichloromethane (10 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 24 hours and a saturated solution of sodium hydrogencarbonate (180 ml) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (180 ml). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude residue. Purification of the residue by column chromatography using toluene: methyl tert-butyl ether (12: 1) followed by dichloromethane: methyl tert.butyl ether (19: 1) as eluent yielded the title compound (which is the diastereomer eluting at second place), 63.0 g (49%). 1 H NMR (400MHz, CDCl 3) d 2.75 (m, 3H), 3.12 (t, 1 H), 3.24 (m, 2H), 3.70 (c, 2H), 4.13 (m, 2H), 4.27 (c, 1 H) ), 4.33 (m, 1 H), 4.67 (m, 1 H), 6.57 (m, 1 H), 6.84 (t, 1 H), 7.13 (m, 2 H), 7.16 (m, 1 H), 7.24 -7.41 (m, 8H).

PREPARATION 30 (3S, 4R) "methyl 1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate) Samarium triflate (6.32 g, 10 mmol) was added to a stirred solution of (4R) -4-benzyl-3-. { [(3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1, 3-oxazolidin-2-one of preparation 29 (63 g, 130 mmol) in methanol (350 ml) at room temperature. The reaction mixture was stirred for 24 hours and the solvent was removed in vacuo. Dichloromethane (290 ml) was added followed by a saturated solution of sodium hydrogencarbonate (140 ml) and the mixture was stirred for 15 minutes. The resulting precipitate was filtered and washed with dichloromethane (250 ml) and water (25 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 40 ml). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. The residue was suspended in hot cyclohexane (300 ml) and stirred until the formation of a solid took place. The mixture was allowed to stand at room temperature for 24 hours. The solid was filtered and washed with cold cyclohexane (150 ml). The filtrate was concentrated in vacuo to yield the desired compound, 38 g (87%). 1 H NMR (400 MHz, CDCl 3) d 2.67 (t, 1 H), 2.86 (m, 1 H), 2.93 (t, 1 H), 3.04 (m, 2 H), 3.64 (s, 3 H), 3.65 (t, 1 H), 3.84 (m, 1 H), 6.72 (m, 1 H), 6.80 (t, 1 H), 7.23 (m, 2H), 7.29-7.38 (m, 5H). [a] 25D = -38 (c = 0.5, MeOH) PREPARATION 31 (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-carboxylic acid methyl Palladium hydroxide (20% on carbon, 1 g) was added to a solution of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate preparation (10). g, 30 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was hydrogenated at 50 psi (344.76 kPa) for 24 hours and then filtered through Arbocel® washing with ethanol (50 ml). The solvent was removed in vacuo to give the desired compound as a colorless oil, 7.19 g (98%). 1 H NMR (400MHz, CD3OD) d 2.60 (s, 1 H), 2.91 (t, 1 H), 3.08 (c, 1 H), 3.31-3.44 (m, 1 H), 3.50 (t, 1 H), 3.63 (m, 1 H), 3.66 (s, 3 H), 6.76 (m, 1 H), 6.84 (m, 1 H), 7.20 (m, 1 H). LRMS (El) 242 [MH +] PREPARATION 32 (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylic acid methyl Sodium triacetoxyborohydride (1.32 g, 6.22 mmol) and acetic acid (235 μl, 4.14 mmol) were added to an acetone solution (3.4 μl)., 4.14 mmol) and methyl (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate from Preparation 31 (1 g, 4.14 mmol) in dichloromethane (20 mL) at room temperature. The resulting mezcal was stirred for 2 hours and diluted with dichloromethane (10 ml). An aqueous solution of sodium hydrogencarbonate (2 x 20 ml) was added followed by brine (20 ml). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane: methanol (99: 1-98: 2) as the eluent afforded the desired product, 1.01 g (86%). 1 H NMR (400 MHz, CDCl 3) d 1.10-1.13 (m, 6H), 2.48 (m, 1 H), 2. 72 (t, 1 H), 3.00 (c, 1 H), 3.05-3.12 (m, 3H), 3.65 (s, 3H), 3.83 (c, 1 H), 6.73 (m, 1 H), 6.82 ( t, 1 H), 7.37 (c, 1 H). LRMS (APCl) 284 [MH +].

PREPARATION 33 Acid (3S, 4R) -4- (2,4-D-fluorophenyl) -1-isopropylpyrrolidine-3-carboxylic acid Lithium hydroxide (171 mg, 7.14 mmol) was added to a solution of methyl (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylate from Preparation 32 (1.01 g, 3.59 mmoles) in tetrahydrofuran (10 ml) at room temperature. The reaction mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was dissolved in water (20 ml) and washed with ethyl acetate (2 x 20 ml). The phases were separated and the aqueous phase was acidified with a 2 M aqueous hydrochloric acid solution (3.59 ml) and extracted with ethyl acetate (20 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield the desired product as a foam, 686 mg (71%). 1 H NMR (400 MHz, CDCl 3) d 1.42 (m, 6 H), 3.31 (m, 3 H), 3.32 (m, 1 H), 3.57 (m, 2 H), 3.91 (m, 1 H), 7.03 (t, 2H), 7.55 (m, 1 H). LRMS (El) 270 [MH +].

PREPARATION 34 (2Z) -3- (2,4-difluorophenyl) methyl acrylate To a solution of 18-crown-6 (30 g, 110 mmol), bis (2,2,2-trifluororethyl) (methoxycarbonylmethane) phosphonate (6 mL, 28 mmol) in tetrahydrofuran at -78 ° C was added. He added potassium hexamethyldisilazide (0.5 M in toluene) (50 mL, 25 mmol) followed by 2,4-difluorobenzaldehyde (4 g, 28 mmol). The reaction mixture was stirred at this temperature for 8 hours and slowly warmed to room temperature for 24 hours, then, the reaction mixture was poured into a saturated solution of ammonium chloride (200 ml). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using pentane: ethyl acetate (99: 1-98: 2) as eluent afforded the desired product as a colorless oil, 5.1 g (91%). 1 H NMR (400 MHz, CDCl 3) d 3.70 (s, 3 H), 6.05 (d, 1 H), 6.80 (m, 1 H), 6.86 (m, 1 H), 6.97 (d, 1 H), 7.69 (c , 1 HOUR). LRMS (APCl) 199 [MH +].

PREPARATION 35 Acid (2Z) -3- (2,4-difluorophenyl) acrylic A solution of methyl (2Z) -3- (2,4-difluorophenyl) acrylate from preparation 34 (1.3 g, 6.56 mmol) and 1 M lithium hydroxide (314 mg, 13.1 mmol) in tetrahydrofuran (51 ml) were added. stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 ml) and ethyl acetate (20 ml) was added. The phases were separated and the aqueous phase was acidified to pH 2 using a 2M hydrochloric acid solution (3 ml). The aqueous phase was extracted with diethyl ether (2 x 30 ml). These organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a white solid, 1.03 g (86%). 1 H NMR (400 MHz, CDCl 3) d 6.09 (d, 1 H), 6.93 (m, 2 H), 6.97 (d, 1 H), 7.66 (c, 1 H).

PREPARATION 36 Acid (3R *, 4R *) - 1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid To a stirred solution of 2Z) -3- (2,4-difluorophenyl) acrylic acid from preparation 35 (400 mg, 2.17 mmol) and trifluoroacetic acid (17 μl, 0.2 mmol) in dichloromethane (1 ml) was added N - (methoxymethyl) -2-meth1 N - [(trimethylsilyl) methyl] propan-2-amine from Preparation 23 (882 mg, 4.35 mmol) for 30 minutes at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo and the white residue formed triturated with diethyl ether (5 ml) and the sodium was removed by filtration to give the desired product, 400 mg (65%). 1 H NMR (400 MHz, CDCl 3) d 1.46 (s, 9 H), 3.31 (s, 1 H), 3.59 (m, 1 H), 3.69 (m, 1 H), 3.78 (d, 1 H), 3.89 ( t, 1 H), 3.97 (m, 1 H), 6.93 (m, 2H), 7.41 (m, 1 H). LCMS (APCl) = 284 [MH +].

PREPARATION 37 3S, 4R) "methyl 4- (2,4-difluorophenyl) -1-methylpyrrolidin-3-carboxylate To a solution of (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid methyl ester of preparation 31 (500 mg, 2.07 mmol) and formaldehyde (155 μl, 2.07 mmol) in dichloromethane (20 ml) were added with acid acetic acid (188 μl, 2.07 mmol) followed by so triacetoxyborohydride (659 mg, 3.11 mmol) at room temperature. The reaction mixture was stirred for 2 hours, diluted with dichloromethane (10 ml) and partitioned with a saturated solution of so hydrogencarbonate (40 ml). The phases were separated and the organic phase was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colorless oil, 288 mg (54%). 1 H NMR (400 MHz, CDCl 3) d 2.41 (s, 3 H), 2.68 (t, 1 H), 3.00 (m, 2 H), 3.01 (c, 1 H), 3.11 (m, 1 H) m, 3.65 ( s, 3H), 3.88 (m, 1 H), 6.78 (m, 1 H), 6.82 (t, 1 H), 7.37 (m, 1 H). LRMS: m / z APCI + 256 [MH +].

PREPARATION 38 (3R, 4S) -3- (2,4-difluorophenyl) -4-frf3R < 4R, 5S) -4-f4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-ipcarbonyl} pyrrolidin-1-tert-butyl carboxylate (3R, 4s, 5S) -4- (4-fluorophenyl) -3,5-dylmethylpiperidin-4-ol of Preparation 41 (265 mg, 1.2 mmol), (3S, 4R) - 1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid from preparation 53 (0.75 mg, 1.4 mmol) and triethylamine (0.48 ml, 3.6 mmol) in dichloromethane (25 ml) . The stirred suspension was cooled in a nitrogen atmosphere and 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (0.67 ml, 2 mmol) was added and added dropwise. After the addition was complete, the resulting homogeneous solution was stirred for a further 6 hours at room temperature. The solution was washed with an aqueous solution of 10% potassium carbonate (3 x 20 ml) and with 3% citric acid (3 x 50 ml), then dried over sodium sulfate and filtered. Then, the dichloromethane was removed in vacuo and the crude compound was purified by column chromatography (silica) with gradient elution with ethyl acetate: pentane (10:90) to ethyl acetate: pentane (40:80) to give the desired product in the form of a white solid (529 mg). 1 H NMR (CD3OD, 10 mg / ml, 400 MHz) (Rotamers), 0.21-0.58 (m, 6H), 1.46 (s, 9H), 0.81-1.97 (m, 2H), 2.68 (m, 1H), 4.35 (m, 1H), 2.93-3.91 (m, 7H), 4.31 (m, 1 H), 6.90-7.29 (m, 5H), 7.38-7.85 (m, 2H). [a] 250 = -82.7 (c = 0.3, MeOH).

PREPARATION 39 (3R, 4s, 5S) -4- (3,4-difluorophenyl) -3,5-dimethylpiperidin-4-ol A solution of 3,4-difluorobromobenzene (4.45 g, 21 mmol) in diethyl ether (25 ml) was cooled to -78 ° C in a nitrogen atmosphere. N-Butyllithium (2.5 M in hexanes) (8.10 mL, 20 mmol) was added dropwise as stirring, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 4 hours. (3R, 4s, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one from Preparation 14 (5.90 g, 20 mmol) in diethyl ether (25 ml) was added dropwise, keeping the temperature below -65 °. The mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. A solution of saturated ammonium chloride (40 ml) was added and the mixture was stirred for 30 minutes. The ether layer was separated, washed with water (3 x 50 ml), dried over sodium sulfate, filtered and then evaporated to dryness. The crude product was dissolved in methanol (100 ml) and the solution was hydrogenated at 50 psi (344.73 kPa) and 50 ° C on 20% palladium on carbon for 18 hours. The mixture was filtered using Celite® and the filtrate was evaporated to dryness. Recrystallization of the product from acetonitrile yielded the desired product as a solid, 1.58 g (24%). 1 H NMR (CD3OD) d 0.60 (d, 6H), 2.21 (m, 2H), 3.10 (m, 4H), 7.38 (d, 2H), 7.05-7.20 (m, 1 H), 7.25 (m, 1 H), 7.30-7.50 (m, 1 H). LRMS: m / z APCI + 242 [MH +] PREPARATION 40 (3R, 4s, 5S) -1-benzyl-4- (4-fluorophenyl) -3,5-dimetiipiperidin-4-ol A solution of 4-fluorobromobenzene (4.51 g, 0.024 mmol) in diethyl ether (20 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-Butyl (8.40 ml, 21 mmol) (2.5 M in hexanes) was added dropwise with stirring, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. The resulting solution of 4-fluorophenylthio was then added dropwise to a solution of (3R, 5S) -1-benzyl-3,5-dylmethylpiperidin-4-one [of preparation 14] (6g, 19 mmol) in diethyl ether (20 ml) at -78 ° C, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. A saturated solution of ammonium chloride (40 ml) was added and the mixture was stirred for 30 minutes. The organic phase was separated, washed with water (3 x 50 ml), dried over sodium sulfate, filtered and then evaporated to dryness. The crude product was used without further purification. 1 H NMR (CD3OD) d 0.51 (d, 6H), 2.18 (m, 2H), 2.39 (m, 2H), 2.71 (m, 1 H), 3.58 (s, 1 H), 3.65 (s, 2H), 7.12 (m, 2H), 7.35 (m, 7H) LRMS (APCl) 314 [MH +] PREPARATION 41 (3R, 4s, 5S) -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol A solution of (3R, 4s, 5S) -1-benzyl-4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol of Preparation 40 (5.0 g, 16 mmol) in methanol (100 mL) was hydrogenated at 50 psi (344.73 kPa) and 50 ° C on 20% palladium on carbon (1.1 g) for 18 hours, then, the mixture was filtered through Celite® and the filtrate was evaporated to dryness. Recrystallization of the crude product from acetonitrile yielded the desired product as a solid, (3.81 g) - 1 H NMR (CD3OD) d 0.54 (d, 6H), 2.18 (m, 2H), 2.85 (m, 4H), 7.05 (m, 2H), 7.20-7.45 (m, 2H), LRMS (APCl) 224 [MH +] PREPARATION 42 (3R, 5S) -1- (4-Methoxybenzyl) -3,5-dimethylpiperidin-4-one A solution of 1 M hydrochloric acid (69 ml) was added to a solution of dimethyl 2,4-dlmethyl-3-oxopentanedioate from preparation 12 (69.6 g, 344 mmol) and 4-methoxybenzylamine (44.81 ml, 344 mmol) in methanol (1.8L). A 37% aqueous solution of formaldehyde (56.8 ml, 760 mmol) was added. The solution was stirred for 72 hours at room temperature and then evaporated to dryness. Dimethyl ester of 1- (4-methoxybenzyl) -3,5-dimethyl-4-oxo-piperidine dicarboxylic acid (126.2 g) was added to a 1 M hydrochloric acid solution (1735 ml) and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to 10 ° C and a 20% by weight aqueous solution of sodium hydroxide (400 ml, 2.0 mol) was slowly added. The mixture was extracted with dichloromethane (4 x 400 ml). The combined organic extracts were evaporated to dryness to give the crude product as a light brown oil which, as indicated by the 1 H NMR of the crude material was a 6: 1 cis: trans mixture. A portion of the crude diastereomeric mixture (15 g) was purified using an automated chromatographic purification system using a column with a normal phase Redisep® silica cartridge (330 g), solvent flow rate of 100 ml / min, with elution linear gradient of cyclohexane / ethyl acetate 2-3% for 35 minutes, linear gradient of ethyl acetate at 3-14% for 10 minutes and completing the elution with 14% ethyl acetate. This produced the pure cis isomer in the form of a pale yellow oil that solidified after a period of rest (10.2 g, 99% + by LCMS). 1 H NMR (400 MHz, CD3OD) d 0.91 (d, 6H), 2.02 (m, 2H), 2.75 (m, 2H), 3.18 (m, 2H), 3.58 (s, 2H), 3.95 (s, 3H) ), 6.85 (d, 2H), 7.25 (d, 2H). LRMS (APCl) 248 [MH +] PREPARATION 43 (3R, 4s, 5S) -4- (4-Chlorophenyl) -3,5-dimethylpiperdin-4-ol A solution of 4-chloroiodobenzene (4.6 g, 25 mmol) in anhydrous diethyl ether (200 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-Butyllithium (2.5 M in hexanes) 15.2 mL, 20 mmol) was added dropwise maintaining the temperature below -65 ° C. The mixture was stirred at -78 ° C for 2 hours and allowed to warm to room temperature. Then, the 4-chlorophenyllithium solution was added dropwise to a solution of (3R, 5S) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-one of preparation 42 (5.0 g, 20 mmol ) in diethyl ether (25 ml) at -78 ° C. The mixture was stirred at -78 ° C for a further 2 hours and then allowed to warm to room temperature. The mixture was quenched with saturated ammonium chloride (50 ml). The organic phase was separated, washed with water (3 x 50 ml), dried over sodium sulfate, filtered and then evaporated to dryness to give the crude intermediate. This product was dissolved in dry dichloromethane (150 ml), triethylamine (4.0 ml, 29 mmol) was added and the solution was cooled to 0 ° C under a nitrogen atmosphere. To the stirred solution was added dropwise 1-chloroethyl chloroformate (3.21 ml, 30 mmol) and after completion of the addition, the mixture was stirred for a further 3 hours at room temperature. The mixture was then washed with an aqueous 10% potassium carbonate solution (3 x 25 ml), dried over sodium sulfate and evaporated to dryness. The crude residue was heated to reflux in methanol (150 ml) for 3 hours and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 ml), solid potassium carbonate (5 g) was added and the heterogeneous mixture was stirred for 1 hour. The solid potassium carbonate was removed by filtration and the filtrate was evaporated to dryness. Then, the crude product was recrystallized from acetonitrile to give the desired product as fine white needles (3.90 g). . 1 H NMR (400MHz, CD3OD) d 0.60 (m, 6H), 2.25 (m, 2H), 3.10 (m, 4H) 7.38 (d, 2H), 7.55 (m, 4H) LRMS (APCl) 240 [MH +] PREPARATION 44 (3R, 4s, 5S) -4- (2,6-Difluorophenyl) -3,5-dimethylpiperidin-4-ol Tert-butyllithium (1.7M in pentane) 9.62 ml, 16.4 mmol) was added dropwise to a stirred solution of 2,6-difluorobromobenzene (3.0 g, 15.5 mmol) at -78 ° C. The solution was stirred for a further 3 hours at -78 ° C. Then a solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one, preparation 14 (2.16 g, 12 mmol) in diethyl ether (30 ml) was added dropwise, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature overnight. A solution of saturated ammonium chloride (20 ml) was added and the mixture was stirred for 30 minutes. The organic phase was washed with water (3 x 50 ml) and dried over sodium sulfate. The solvent was removed in vacuo, the residue was dissolved in methanol (100 ml) and the solution was hydrogenated (50 psi (344.73 kPa) and 50 ° C on 20% palladium on carbon) for 18 hours. The mixture was filtered through Celite® and the filtrate was evaporated to dryness. The crude product was recrystallized from acetonitrile to produce the desired product (1.78 g) as fine white needles. 1 H NMR (400 MHz, CD 3 OD) (Rotamers) d 0.60 (d, 6 H), 2.21 (M, 2 H), 3.10 (m, 4 H), 7.38 (d, 2 H), 7.05-7.20 (m, 1 H), 7.25 (m, 1 H), 7.31-7.50 (m, 1.20H) LRMS (APCl) 242 [MH +] PREPARATION 45 (3R, 4s, 5S) -4- (3-Fluorophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol To a stirred solution of 3-fluoroiodobenzene (1.91 g, 8.0 mmol) in anhydrous diethyl ether (10 ml) at -78 ° C was added dropwise nB? Li (2.5 M in hexanes) (7.2 ml, 18 mmol) . The mixture was stirred at -78 ° C for 3 hours and then dropwise (3R, 5S) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-one from preparation 42 (1.85 g, 7.5 mmol) in diethyl ether (10 ml) keeping the temperature below -60 ° C. Then, the mixture was allowed to warm to room temperature. A solution of saturated ammonium chloride (25 ml) was added, the mixture was stirred for 30 minutes and the organic phase was separated. The organic phase was washed with water (3 x 50 ml) and dried over sodium sulfate, filtered and the solvent removed in vacuo. Recrystallization from ethyl acetate: cyclohexane gave the desired product (2.88 g). 1 H NMR (400MHz, CD3OD) d 0.51 (d, 6H), 2.18 (m, 2H), 2.35 (m, 2H), 2.71 (m, 2H), 3.58 (s, 2H), 3.65 (s, 3H), 7.12 (m, 3H), 7.35 (m, 5H) LRMS (APCl) 344 [MH +] PREPARATION 46 (3R, 4s, 5S) -4- (3-Fluorophenyl) -3,5-dimethylpiperidin-4-ol A solution of (3R, 4s, 5S) -4- (3-fluorophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol of preparation 45 (2.5 g, 7.3 mmol) in methanol (25 ml) was hydrogenated (50 psi (344.73 kPa) and 50 ° C over 20% palladium on carbon) for 18 hours. The mixture was filtered through Celite® and the filtrate was evaporated to dryness. Recrystallization of the crude product from acetonitrile afforded the title compound (1.52 g). 1 H NMR (400 MHz, CD 3 OD) d 0.59 (d, 6 H), 2.10 (m, 2 H), 2.85 (m, 5H), 6.95 (m, 1 H), 7.35 (m, 2H) LRMS (APCl) 224 [MH] PREPARATION 47 (3R, 4S, 5S) -1-benzyl-4- (4-methoxyphenip-3) , 5-dimethylpiperidin-4-ol Tert-butyllite (1.7 M in pentane) (33.0 ml, 56 mmol) was added to anhydrous diethyl ether (20 ml) under a nitrogen atmosphere and cooled to -78 ° C. A solution of 4-methoxyiodobenzene (6.89 g, 29 mmol) in anhydrous diethyl ether (25 ml) was added dropwise to the tert-butyl ether solution maintaining the temperature between -78 ° C and -60 ° C. After the addition was complete, the mixture was stirred for a further 30 minutes at -78 ° C and then allowed to warm to room temperature. Then, the resulting 4-methoxyphenyllithium solution was added dropwise to a solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one of preparation 14 (4.0 g, 18 mmol) in diethyl ether anhydrous (70 ml) at -78 ° C. The mixture was stirred at -78 ° C for 2 hours and then allowed to warm to room temperature. Saturated ammonium chloride (20 ml) was added dropwise and the mixture was stirred for 30 minutes. The organic layer was separated, washed with water (3 x 100 ml), dried over sodium sulfate and evaporated to dryness to give the crude product, which was pre-crystallized from cyclohexane / ethyl acetate to give the pure product 7.1 g) 1 H NMR (400 MHz , CD3OD) d 0.51 (d, 6H), 2.12 (m, 2H), 2.25 (m, 5H), 2.61 (m, 2H), 3.58 (s, 2H), 3.78 (s, 3H), 6.85 (m, 3H), 7.25 (m, 6H) LRMS (APCl) 326 [MH +] PREPARATION 48 (3R, 4S, 5S) -4- (4-methoxyphenyl) -3,5-dimethylpiperidin-4-ol A solution of (3R, 4s, 5S) -1-benzyl-4- (4-methoxyphenyl) -3,5-dimethylpiperidin-4-ol (7.1 g, 21 mmol), of preparation 47 in methanol (100 ml) it was hydrogenated in palladium on carbon (1.0 g) (50 psi (344.73 kPa) and 50 ° C) for 18 hours. The mixture was filtered through Celite® and the filtrate was evaporated to dryness to give the crude product. Recrystallization from acetonitrile yielded the desired compound (3.1 g) which was used directly without further purification. 1 H NMR (400 MHz, CD 3 OD) d 0.52 (d, 6 H), 2.00 (m, 2 H), 2.68 (m, 4 H), 3.78 (s, 3 H), 6.82 (d, 2 H), 7.20-7.60 (m, 2H) LRMS (APCl) 235 [MH +] PREPARATION 49 (3R, 4S, 5S) -4- (2,4-difluorophenyl) -3,5-dimethylpiperidin-4-ol A solution 2,4-difluorobromobenzene (4.51 g, 22 mmol) in diethyl ether (20 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-Butyllithium (2.5M in hexanes) (8.40 mL, 21 mmol) was added dropwise with stirring, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 4 hours. Then (3R, 5S) -1- benzyl-Sd-dimethylpiperidin-1 -one, from preparation 14 (6.00 g, 19 mmol) in diethyl ether (25 ml) was added dropwise, keeping the temperature below -65. ° C the mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature. A saturated solution of ammonium chloride (40 ml) was added and the mixture was stirred for 30 minutes. The ether layer was separated, washed with water (3 x 50 ml), dried over sodium sulfate, filtered and then evaporated to dryness. The product was dissolved in methanol (100 ml) and the solution was hydrogen (50 psi (344.73 kPa) and 50 ° C on 20% palladium on carbon) for 18 hours. The mixture was filtered through Celite® and the filtrate was evaporated to dryness. Recrystallization of the crude product from acetonitrile afforded the desired product (1.78 g) as fine white needles. 1 H NMR (400MHz, CD3OD) d 0.60 (D, 6h), 2.21 (m, 2H), 3.10 (m, 4H), 7.38 (d, 2H), 7.05-7.20 (a, 1 OOH), 7.25 (m, 1 H), 7.31-7.50 (m, 1.20H) LRMS (APCl) 242 [MH +] PREPARATION 50 (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-pyridin-3-ylpiperidin-4-ol A cold solution of 3-bromopyridine (2.4 mL, 25 mmol) in dry diethyl ether (2 mL) was added to a solution of n-butylithium (2.5 M in hexane) (10 mL, 25 mmol) at - 78 ° C. The reaction mixture was stirred for 1 hour. A solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one, from preparation 14 (5.42 mg, 25 mmol) in tetrahydrofuran (2 ml) was added to - 78 ° C and the reaction mixture was stirred for 1 hour. The reaction was allowed to warm to -20 ° C, a saturated solution of ammonium chloride (10 ml) was added and the resulting mixture was stirred for 24 hours at room temperature. The suspension was filtered and the solid was washed with diethyl ether (4 x 50 ml). The solid was redissolved in dichloromethane: methanol (90:10) and the solution was washed with brine. The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the desired product, 4.35 g (61%). 1 H-NMR (400MHz, CDCl 3): d = 0.56 (d, 6H), 2.07-2.43 (a, 4H), 2.79 (a, 2H), 3.63 (a, 2H), 7.25-7.46 (m, 5H), 7.65 (a, 1 H9, 7.84 (a, 1 H), 8.47 (d, 1 H), 8.68 (a, 1 H), LRMS (APCI +) = 297 [MH +].

PREPARATION 51 (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-3-ylpiperidin-4-ol A mixture of (3R, 4s, 5S) -1-benzyl-3,5-d-methyl-4-pyridin-3-ylpiperidin-4-ol of preparation 50 (3.0 g, 10.12 mmol) and 20% by weight palladium hydroxide on carbon (0.45 g) in ethanol (50 ml) was hydrogenated at 40 ° C and 40 psi (275.79 kPa) for 14 hours. Then, the reaction mixture was filtered through Arbocel® and the filtrate was concentrated in vacuo to give the desired product in signature of a whitish foam, 2.05 g. 1 H-NMR (400MHz, CDCl 3): d = 0.57 (d, 6H), 2.12 (m, 2H), 2.81 (t, 2H), 2.94 (m, 2H), 7.27 (m, 1 H), 7.51-7.99 (a, 1 H), 8.48 (d, 1 H), 8.67 (a, 1 H). LRMS (APCI +) = 207 [MH +].

PREPARATION 52 3-methyl- (3S, 4R) -4- (2,4-difluorophenifl) pyrrolidin-1,3-dicarboxylic acid-1-tert-butyl ester To a solution of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate from preparation 30 (1.0 g, 3.01 mmol), 1-methylcyclohexa-1, 4- diene (1.25 ml, 11.15 mmol) and di-tert-butyl bicarbonate (0.72 g, 3.31 mmol) in ethanol (10 ml) was added palladium hydroxide on carbon (0.1 g) at room temperature. The resulting mixture was refluxed for 4 hours, cooled to room temperature and filtered through Arbocel®. The filtrate was concentrated in vacuo to give the crude residue which was partitioned between ethyl acetate (80 ml) and a 10% citric acid solution (5 ml). The phases were separated and the organic layer was washed with brine (60 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product as a colorless oil, 940 mg. 1 H-NMR (400MHz, CDCl 3): d 1.40 (s, 9H), 3.14-3.25 (m, 1 H), 3. 25-3.40 (m, 1 H), 3.48-3.59 (m, 4H), 3.68-3.89 (m, 3H), 6.71-6.82 (m, 2H), 7.15 (m, 1 H). LRMS (APCl) 242 [MH + -BOC +1].

PREPARATION 53 Acid (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid Lithium hydroxide (130 mg, 23.5 mmol) was added dropwise to a stirred solution (3S, 4R) -4- (2,4-d-fluoro-phenyl) -pyrrolidin-1,3-dicarboxylate. - tert -butyl 3-methyl of preparation 52 (930 mg, 2.72 mmol) in tetrahydrofuran (10 ml) at room temperature. The reaction mixture was stirred for 48 hours, concentrated in vacuo and diluted with water (15 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (1 x 25 ml). The aqueous layer was acidified with a 2 M hydrochloric acid solution (2.7 ml) and then extracted with ethyl acetate (2 x 40 ml). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo and azeotropically distilled with dichloromethane to give the desired product, 775 mg (87%). 1 H-NMR (400MHz, CDCl 3): d 1.45 (s, 9H), 3.23-3.46 (m, 2H), 3.56-3.65 (m, 1 H), 3.74-3.93 (m, 3H), 6.75-6.87 (m , 2H), 7.20 (m, 1 H). LRMS (APCl) 228 [MH + -BOC +1].

LRMS (APCI-) = 326 [M-1].

PREPARATION 54 (3R4S) -3- (2,4-difluorophenyl) -4-rr (3R4R5S) -4-hydroxy-3,5-dimethyl-4-pyridin-2-ylpiperidin-1-incarbonyl} Ferric butyl pyrrolidin-1-carboxylate A solution of (3R, 4S, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperdin-4-ol of preparation 74 (835 mg, 4 mmol), acid (3S, 4R) -1- (tert-butoxycarbonyl) "4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid of preparation 53 (1.32 g, 4 mmol) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 776 mg, 4 mmol) and 1-hydroxybenzotriazole hydrate (62 mg, 0.4 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 20 hours.The solvent was removed in vacuo and the crude residue was partitioned between water (15 ml. ) and ethyl acetate (15 ml) The phases were separated and the organic phase was washed with saturated sodium hydrogen carbonate solution (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the residue The purification of the residue by column chromatography using ethyl acetate: pentane (10: 90-40-60) as eluent gave the desired product as a white foam, 380 mg (43%). 1 H-NMR (400MHz, CDCl 3) (Rotamers) d 0.27-0.52 (m, 6H), 1.46 (s, 9H), 0.81-1.97 (m, 2H), 2.68 (m, 1 H), 2.93-3.24 (m , 2H), 3.38-4.14 (m, 7H), 4.41 (m, 1 H), 5.50 (m, 1H), 6.82 (m, 1H), 6.87-7.36 (m, 3H), 7.71 (m, 1 H ), 8.47 (m, 1 H). LRMS (APCl) 516 [MH +].

PREPARATION 55 (3R4S) -3- (2,4-difluorophenyl) -4-. { r (3R4R5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-incarbonyl} ferric butyl pyrrolidin-1-carboxylate To a solution of (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-d-fluoro-phenyl) -pyrrolidin-3-carboxylic acid of preparation 53 (1000mg, 3 mmol), (3R, 4S, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol, of preparation 16 (522 mg, 2.54 mmol) and triethylamine (706 μl, 0.73 mmol) in ethyl acetate (10 mg). ml) was added 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (1.5 ml, 2.54 mmole) at 0 ° C and the resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (70 ml) and a saturated potassium carbonate solution (2 x 50 ml) was added followed by a solution of 10% citric acid (1 x 50 ml). The phases were separated and the organic phase was washed with brine (1 x 50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using ethyl acetate: pentane (10: 90-40: 60) as the eluent afforded the desired product as a white foam, 560 mg (43%). 1 H-NMR (400MHz, CDCl 3) (Rotamers) d 0.41-0.62 (m, 6H), 0.94-1.24 (m, 1 H), 1.47 (s, 9H), 1.65-2.07 (m, 1 H), 2.59 -3.02 (m, 1 H), 3.15 (m, 1 H), 3.40-4.15 (m, 7H), 4.42 (d, 1 H), 6.76-6.85 (m, 2H), 7.16-7.41 (m, 6H) ). LRMS (APCl) 515 [MH *].

PREPARATION 56 (3R4S, 5S) -1-benzyl-4-isopropyl-3,5-dimethylpiperidin-4-ol To a solution of (3R, 5S) -1-benzyl-3,5-di-methylpiperidin-4-one of preparation 14 (500 mg, 2.3 mmol) was added isopropyl lithium (0.7 M in pentane ) (3.6 ml, 2.53 mmoles). The reaction mixture was stirred at -78 ° C for 1 hour and then slowly warmed to 0 ° C and stirred at this temperature for an additional 30 minutes. Then a saturated solution of ammonium chloride (6 ml) was added at -10 ° C. The reaction mixture was partitioned between ethyl acetate (6 ml) and water (6 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (6 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane: methanol: 0.88 ammonia (100: 0-99: 1-96: 4: 0.4) as eluent gave the desired product, 244 mg (41%). 1 H-NMR (400MHz, CDCl 3) d 0.82 (d, 6H), 0.99 (d, 6H), 1.88-2.03 (m, 4H), 2.08 (m, 1 H), 2.48 (m, 2H), 3.45 (m , 2H), 7.19-7.34 (m, 5H). LRMS (APCl) 262 [MH +], 244 [MH + -H2O].

PREPARATION 57 (3R4S, 5S) -4-isopopropyl-3,5-dimethylpiperidin-4-ol A solution of (3R, 4S, 5S) -1-benzyl-4-isopropyl-3,5-dimethylpiperidin-4-ol from Preparation 56 (1.42 g, 5.44 mmol) and palladium hydroxide on carbon (210 mg) in Ethanol (25 ml) was hydrogenated at 40 ° C and 40 psi (275.79 kPa) for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (25 ml). The filtrate was concentrated in vacuo to give the crude residue which was recrystallized from acetonitrile to yield the desired product in the form of brown needles, 390 mg (42%). 1 H-NMR (400MHz, CDCl 3) d 0.83 (d, 6H), 0.99 (d, 6H), 1.74 (m, 2H), 2.08 (m, 1 H), 2.64 (m, 4H). LRMS (APCl) 172 [MH +].

PREPARATION 58 (3R4S, 5SÍ-1-benzyl-3,5-dimethyl-4-propylpiperidin-4-ol To a stirred solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one of preparation 19 (1.0 g, 4.6 mmol) in tetrahydrofuran (7 ml) was added propylmagnesium chloride (2M in US Pat. diethyl ether) (7.5 ml, 15 mmol) at -78 ° C. The reaction mixture was stirred for 1 hour, a saturated solution of ammonium chloride (20 ml) was added and the mixture was heated slowly to room temperature. The reaction mixture was diluted with ethyl acetate (40 ml) and the phases were separated. The aqueous phase was extracted with ethyl acetate (1 x 40 ml) and the organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane: methanol: ammonia 0.88 (98: 2: 0-95: 5: 0.5) as eluent yielded the desired product, 790 mg (66%). 1 H-NMR (400MHz, CDCl 3) d 0.80 (d, 6H), 0.90 (t, 3H), 1.20 (m, 2H), 1.51 (m, 2H), 1.87 (m, 2H), 2.04 (m, 2H) , 2.54 (m, 2H), 3.47 (m, 2H), 7.19-7.36 (m, 5H). LRMS (APCl) 262 [MH +], 244 [MH + -H2O].

PREPARATION 59 (3R4S, 5S) -3,5-dimethyl-4-propylpiperidin-4-ol A solution of (3R, 4S, 5S) -1-benzyl-3,5-dimethyl-4-propylpperidin-4-ol of Preparation 58 (780 mg, 3 mmol) and palladium hydroxide (20% strength) % on carbon, 130 mg) in ethanol (10 ml) was hydrogenated at 40 ° C and 40 psi (275.79 kPa) for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (10 ml). The filtrate was concentrated in vacuo to yield the desired product, 504 mg (98%). 1 H-NMR (400MHz, CDCl 3): d 0.80 (d, 6H), 0.91 (t, 3H), 1.21 (m, 2H), 1.50 (m, 2H), 1.70 (m, 2H), 2.70 (m, 5H) ). LRMS (APCl) 172 [MH +].

PREPARATION 60 (3R, 4s, 5S) -1-Benzyl-4-cyclopropyl-3,5-dimethylpiperidin-4-ol To a stirred solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one from Preparation 19 (1.0 g, 4.6 mmol) in tetrahydrofuran (8 ml) was added. bromine (cyclopropyl) magnesium (0.5 M in tetrahydrofuran) (28 mL, 14 mmol) at -78 ° C. The reaction mixture was stirred for 2 hours, a saturated solution of ammonium chloride (40 ml) was added and the mixture was heated slowly to room temperature. The reaction mixture was diluted with water (40 ml) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 60 ml) and the organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane: methanol (100: 0-96: 4) as eluent afforded the desired product as a colorless liquid, 780 mg (65%). 1 H NMR (400MHz, CDCl 3) d 0.35 (m, 4H), 0.52 (m, 1 H), 0.90 (d, 6H), 1.95 (m, 4H), 2.56 (d, 2H), 3.50 (s, 2H), 7.20-7.37 (m, 5H) LRMS (APCI +) = 260 [MH +], 242 [MH + -H2O] PREPARATION 61 (3R, 4s, 5S) -4-Cyclopropyl-3,5-dirnethylpperidin-4-ol A solution of (3R, 4s, 5S) -1-benzyl-4-cyclopropyl-3,5-dimethylpiperidin-4-ol of preparation 60 (780 mg, 3 mmol) and palladium hydroxide (20% on carbon) ) (140 mg) in ethanol (10 ml) was hydrogenated at 40 ° C and 40 psi (275.79 kPa) for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (10 ml). The filtrate was concentrated in vacuo to yield the desired product, 480 mg (94%). 1 H NMR (400MHz, CDCl 3) d 0.35 (m, 4 H), 0.55 (m, 1 H), 0.92 (d, 6 H), 1.72 (m, 2 H), 1.84 (m, 1 H), 2.65 (m, 4 H) ). LRMS (APCI +) = 170 [MH +], 152 [MH + -H2O] PREPARATION 62 Acid (3S, 4R) -4- (2,4-difluorophenyl-1-methylpyrrolidine-3-carboxylic acid To a solution of methyl (3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidine-3-carboxylate from preparation 37 (800 mg, 3.13 mmol) in tetrahydrofuran (10 ml) was added hydroxide. lithium (150 mg, 6.27 mmol) at room temperature. The reaction mixture was stirred for 2 hours and the solvent was concentrated in vacuo. The crude residue was dissolved in water (20 ml) and partitioned with ethyl acetate (2 x 20 ml). The phases were separated and the aqueous phase was acidified using a 2 M hydrochloric acid solution (3.13 ml). The aqueous phase was evaporated and the residue was azeotropically distilled with toluene (6 x 20 ml) to yield an oily residue (1000 mg) which was used without further purification in the next step. 1 H NMR (400MHz, CDCl 3) d 0.35 (s, 3 H), 3.41 (m, 1 H), 2.50-3.81 (m, 3 H), 3.91 (, 3 H), 7.06 (m, 2 H), 7.62 (m, 1 H). LRMS (APCI +): 242 [MH +], LRMS (APCI-): 240 (M-1).

PREPARATION 63 (3R, 4S) -3- (2,4-Difluorophenyl) -4-fr (3R, 4R, 5S) -4- (3-difluoropheni [4] -4-hydroxy-3,5-dimethylpiperidin-1-lcarbonyl} ferric butyl pyrrolidin-1-carboxylate A solution of (3S, 4R) -1- (tert-butoxycarbonyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid of preparation 53 (160 mg, 0.49 mmol) and (3R, 4s, 5S) -4- (3,4-difluorophenyl) -3,5-d-methylpiperidin-4-ol of preparation 39 (100 mg, 0.42 mmol), cyclic anhydride of 1-propylphosphonic acid (50% in ethyl acetate ) (244 μl, 0.41 mmol) and triethylamine (120 μl, 0.82 mmol) in dichloromethane (2 ml) was stirred at room temperature for 16 hours.The reaction mixture was diluted with dichloromethane (20 ml) and a saturated solution was added. of potassium carbonate (2 x 20 ml) The phases were separated and the organic phase was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to yield the desired product as a white foam, 257 mg (77%). 1 H NMR (400MHz, CDCl 3) (Rotamers) d 0.44-0.61 (4 xd, 6H), 1.47 (s, 9H), 2.59 (t, 2H), 3.10 (m, 2H ), 3.51-3.91 (m, 6H), 4.44 (d, 2H), 6.82 (m, 2H), 6.90 (m, 1 H), 7.07-7. 15 (m, 3H). LRMS (APCI +) = 551 (MH +).

PREPARATION 64 (3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-r4- (trifluoromethyl) phenyl] piperidin-4-ol The title compound was prepared in 33% yield from (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one, preparation 14 and 4-bromo-trifluoromethylbenzene following a procedure similar to that described in Preparation 40, except that the compound was further purified by column chromatography using pentane: ethyl acetate (4: 1) as eluent. 1 H NMR (400MHz, CDCl 3) d 0.35 (m, 4H), 0.54 (d, 6H), 1.58 (s, 1 H), 2.12 (t, 2H), 2.24 (m, 2H), 2.71 (dd, 2H), 3.55 (s, 2H), 7.27-7.36 (m, 7H), 7.59 (d, 2H). LRMS (APCl) 364 [MH +].

PREPARATION 65 (3R, 4s, 5S) -3,5-Dimethyl-4-r4- (trifluoromethyl) feninpiperidin-4-ol A mixture of (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4- [4- (trifluoromethyl) phenyl] piperidin-4-ol of preparation 64 (527 mg, 1.45 mmol), palladium al 20% on carbon (65 mg) and dihydrotoluene (570 μl, 5.4 mmol) in ethanol (10 ml) was heated to reflux for 3 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (100 ml). The solvent was removed in vacuo to yield the desired compound as a brown foam, 501 mg (87%). 1 H NMR (400MHz, CDCl 3) d 0.53 (d, 6H), 1.74 (s, 2H), 2.07 (m, 2H), 2.73 (t, 2H), 2.91 (dd, 2H), 7.26-7.70 (m, 4H ). LRMS (APCI +) 274 [MH +].

PREPARATION 66 (3R.4s) -3-82,4-Difluorophenyl) -4 - (((3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-r4- (trifluoromethyl) pheninpiperidin- 1-yl.} Carbonyl) ferr-butyl pyrrolidin-1-carboxylate The title compound was prepared in 94% yield from (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidin-3-carboxylic acid Preparation 53 and (3R, 4s, 5S) -3,5-dimethyl-4- [4- (trifluoromethyl) phenyl] piperidin 4-ol of preparation 64 following a procedure similar to that described in Preparation 38 1H NMR (400MHz , CDCI3) (Rotamers) d: 0.43-0.60 (m, 6H), 1.46 (s, 9H), 2.63 (m, 2H), 3.14 (m, 2H), 3.45-3.90 (m, 6H), 4.44 (d , 2H), 6.82 (m, 2H), 6.68 (m, 1 H), 7.16-7.32 (m, 2H), 7.58 (m, 2H). LRMS (El) 583 [MH +].

PREPARATION 67 (3S, 4R) -4- (4-Chlorophenyl) pyrrolidin-1,3-dicarboxylic acid 1-fer-butyl-3-methyl To a solution of methyl (3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-carboxylate hydrochloride of preparation 26 (870 mg, 2.8 mmol) and triethylamine (780 μl, 5.6 mmol) in dichloromethane (5 ml) was added di-tert-butyl bicarbonate (610 mg, 2.8 mmol) in dichloromethane (5 ml). The reaction mixture was stirred for 20 hours and diluted with ethyl acetate (50 ml). The phases were separated and the organic phase was washed with an acid solution. 5% citric acid (3 x 20 ml) and brine (1 x 20 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the desired product as a colorless oil with a quantitative yield. 1 H NMR (400MHz, CDCl 3) d 1.45 (s, 9H), 3.07-3.25 (m, 2H), 3.36 (m, 1 H), 3.58 (m, 1 H), 3.63 (s, 3 H), 3.85 (m, 2 H), 7.17 (d, 2 H), 7.29 (d, 1 H). LRMS (APCl) 340 [MH +], 240 [MH + -BOC + 1].

PREPARATION 68 Acid (3S.4R) -1- (ferc-butoxycarbonyl-4- (4-chlorophenyl-pyrrolidine-3-carboxylic acid To a solution of 3-methyl- (3S, 4R) -4- (4-chlorophenyl-pyrrolidin-1,3-dicarboxylic acid-1-tert-butyl ester of preparation 67 (0.98 g, 2.88 moles) in tetrahydrofuran (8 ml ), lithium hydroxide (0.21 g, 8.64 mmol) was added at room temperature, the reaction mixture was stirred for 24 hours and the solvent was removed in vacuo, the crude residue was dissolved in water (8 ml) and a 1 M hydrochloric acid solution (8.65 ml) The suspension was extracted with dichloromethane (2 x 40 ml) and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield the desired product as a solid. white, 705 mg (75%). 1 H NMR (400MHz, CDCl 3) d 1.45 (s, 9H), 3.17 (m, 1 H), 3.36 (m, 1 H), 3.61 (m, 2H), 3.88 (m , 2H), 7.18 (d, 2H), 7.29 (d, 2H), LRMS (APCl) 226 [MH + -BOC + 1] LRMS (APCI-) = 324 [M-1].

PREPARATION 69 (3R, 4S) -3- (4-Chlorophenyl-4-ffl3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl-1-carbonyl) pyrrolidin-1-carboxylate fer-butyl To a solution of (3S, 4R) -1- (tert-butoxycarbonyl) -4- (4-chlorophenyl) pyrrolidin-3-carboxylic acid of preparation 68 (250 mg, 0.76 mmol), (3R, 4s, 5S) -3,5-d, methyl-4-phenylpiperidin-4-ol, of preparation 16 (190 mg, 0.91 mmol) and triethylamine (320 μl, 2.28 mmol) in ethyl acetate (5 ml) was added 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (450 μl, 1.10 mmol) at room temperature. The reaction mixture was stirred for 24 hours, a solution of 1 M hydrochloric acid (20 ml) was added and the solution was stirred for 10 minutes. The phases were separated, the organic phase was diluted with ethyl acetate (3 ml) and a solution of 1 M sodium hydroxide (6 ml) was added. The organic phase was separated, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude residue was purified by column chromatography using pentane: ethyl acetate (90: 10-50: 50) as eluent to produce the desired product as a white foam, 370 mg (95%). 1 H NMR (400MHZ, CDCl 3 (Rotamers) d 0.32-0.59 (m, 6H), 1.46 (s, 9H), 0.64-2.05 (m, 2H), 2.63 (m, 1 H), 2.79-3.15 (2xq, 1H ), 3.30-4.01 (m, 7H), 4.42 (m, 1 H) 7.16-7.40 (m, 9H) LRMS (APCl) 513 [MH +], 457 [MH + -t-Bu + 1], 413 [MH + - BOC + 1] PREPARATION 70 (3R, 4s, 5S) -4- (4-Bromophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol N-BuLi (2.5 m in hexanes) (7.89 mL, 195 mmol) was added dropwise to a solution of 1,4-dibromobenzene (4.9 g 20 mmol) in diethyl ether (150 mL) at -78 ° C. The mixture was stirred for 3 hours and allowed to warm to room temperature. 1- (4-methoxy-benzyl) -trans-3,5-dimethyl-piperidin-4-one (5.0 g, 20 mmol) in diethyl ether (25 ml) was added dropwise and the reaction mixture was stirred for two hours. more hours The mixture was quenched with saturated ammonium chloride (50 ml) and the phases were separated. The organic phase was washed with water (3 x 50 ml), dried over sodium sulfate, filtered and the solvent was removed under vacuum to give (3R, 4s, 5S) -4- (4-bromophenyl) -1- ( 4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol (7.9 g), which was used directly without further purification. 1 H NMR (400 MHz, CD 3 OD) d 0.51 (d, 6 H), 218 (m, 2 H), 2.35 (m, 2 H), 2.71 (m, 2 H), 3.58 (s, 2 H), 3.65 (s, 3 H) , 7.12 (m, 3H) 7.35 (m, 5H) LRMS (APCI) = 404 [MH +] PREPARATION 71 4-r (3R, 4S, 5S) -4-hydroxy-1- (4-methoxybenzyl) -3,5-dimethylpieridin-4-illbenzonitrile A solution of (3R, 4s, 5S) -4- (4-bromophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol of preparation 70 (3.50 g, 8 mmol), potassium cyanide (1.05 g) g, 16 mmol), tris (triphenylphosphonino) paladate (1-) (0.462 g, 0.4 mmol) and copper iodide (1.52 g, 8 mmol) in acetonitrile (30 ml) was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (30 ml) and filtered through Celite®. The filtrate was washed with water and brine, dried over sodium sulfate and filtered. Concentration in vacuo gave the crude residue which was purified by column chromatography on silica gel using ethyl acetate: hexane (3: 97-15: 85) as eluent to produce a title compound in the yellow solid (2.51 g) format. ). 1 H NMR (400MHz, CD3OD) d 0.51 (d, 6H), 2.25 (m, 2H), 2.42 (m, 2H), 2.79 (m, 2H), 3.58 (s, 2H), 3.65 (s, 3H), 7.12 (m, 4H), 7.52 (d, 2H), 8.10 (m, 2H). LRMS (SPCI) 351 [MH +] PREPARATION 72 4-K3R, 4s, 5S) -4-hydroxy-1-3,5-dimethylpieridin-4-inbenzonitrile To a solution of (3R, 4s, 5S) -4- (4-isocyanophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol from Preparation 71 (2.50 g 7.1 mol) in dichloromethane (50 ml ) triethylamine (2.0 ml, 14 mmol) was added at -15 ° C. To the stirred solution was added 1-chloroethylchloroformate (1.50 ml, 14 mmol) keeping the temperature at -15 ° C and the mixture was stirred for 30 minutes. The solvent was removed in vacuo to give a crude residue which was heated to reflux in methanol (150 ml) for 3 hours. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 ml). Potassium carbonate (5 g) was added and the mixture was stirred for 1 hour, then filtered and the solvent removed in vacuo. The crude residue was recrystallized from acetonitrile to produce the pure compound in the form of fine white needles (1.23 g). 1 H NMR (400MHz, CD3OD) d 0.60 (d, 6H), 2.25 (m, 2H), 3.1 (m, 4H), 7.62 (d, 2H), 8.15 (d, 2H). LRMS (APCI) = 232 [MH +] PREPARATION 73 4-f (3R, 4s, 5S) -1-Benzyl-3,5-dimethyl 4-pieridin-2-ylpiperidin-4-ol A solution of 2-bromopyridine (4.10 ml, 0.024 mmol) in diethyl ether (50 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-BuLi (2.25 M / hexanes) (10.10 mL, 25.3 mmol) was added dropwise with stirring, keeping the temperature below -65 ° C. The mixture was stirred at -78 ° C for 3 hours. A solution of (3R, 5) -1-benzyl-3,5-dimethylpiperidinone from preparation 14 (6.10 g, 28.0 mmol) in diethyl ether (50 ml) was then stirred dropwise keeping the temperature below -65 ° C . The mixture was stirred at -78 ° C for 1 hour and then allowed to warm to room temperature, a solution of saturated ammonium chloride (40 ml) was added and the mixture was stirred for 30 minutes. The ester layer was separated, washed with water (3 x 50 ml), stirred over sodium sulfate, cooled and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the desired product as an orange oil, 7.31g. 1 H NMR (400MHz, CDCL 3) d 0.43 (d, 6H), 2.09-2.30 (m, 4H), 2. 71 (d, 4H), 3.59 (s, 2H), 5.48 (s, 1 H), 7.19 (m, 1 H), 7.22-7.42 (m, 6H), 7.71 IX, 1 H), 8.48 (d, 1 HOUR). LRMS (APCI +) = 297 [MH +] PREPARATION 74 4-f (3R, 4s, 5S) 3,5-Dimethyl 4-pieridin-2-ylpiperidin-4-ol A mixture of 4 - [(3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-pieridin-2-ylpiperidin-4-ol of preparation 73 (3.0 g, 10.12 mmol) and palladium hydroxy ( 20% on carbon) (0.45 g) in ethanol (50 ml) was hydrogenated at 40 ° C and 40 psi (275.79 kPa) for 14 hours. The reaction mixture was allowed to cool to room temperature and was stirred at a pressure of 40 psi (275.78 kPa) for 5 hours. The reaction mixture was filtered through Arbocel® and the filtrate was concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (97.5: 2.5: 0.25-90: 10: 1) as eluent yielded the desired product, 2.05 g (99%). 1 H NMR (400MHz, CDCl 3) d 0.43 (d, 6H), 2.00 (m, 2H), 2.84 (m, 4H), 5.50 (a, 1 H), 7.20 (m, 1 H), 7.33 (d, 1 H), 7.72 (t, 1 H), 8.49 (d, 1 H). LRMS (ESI +) = 207 [MH +], 413 [2MH +] PREPARATION 75 (3S, 4R) -4- (2,4-Difluorophenyl) -1-ethylpyrrolidin-3-carboxylic acid hydrochloride Concentrated aqueous hydrochloric acid (10 ml) was added to methyl (3S, 4R) -4- (2,4-d-fluoro-phenyl) -1-ethylpyrrolidin-3-carboxylate from preparation 76 (500 mg, 1.85 mmol) and The resulting solution was stirred at room temperature for 16 hours. Then the reaction mixture was evaporated to dryness in vacuo and the resulting residue slid azeotropically with toluene (2 x 50 ml). This gave the title compound as a whitish foam, -500 mg. 1 H NMR (400 MHz, CD 3 OD) d 1.10 (t, 3 H), 2.51-2.62 (m, 2 H), 2.69 (t, 1 H), 2.86 (t, 1 H), 3.05 (t, 1 H), 3.10- 3.13 (m, 2H), 3.92 (c, 1 H), 6.80-6.86 (m, 2H), 7.45 (c, 1 H).

LRMS (APCl) = 256 [MH +] PREPARATION 76 (3S, 4R) -4- (2,4-Difluorophenyl) -1-ethylpyrrolidin-3-methyl carboxylic acid A mixture of methyl (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate of preparation 31 (500 mg, 2.07 mmol), ethyl tosylate (519, 259 mmol) and potassium carbonate ( 573 mg, 4.15 mmol) was heated in acetonitrile at 70 ° C for 16 hours under a nitrogen atmosphere. Then, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (30 ml) and partitioned with saturated aqueous sodium bicarbonate (30 ml). Then, the organic layer was washed with brine (20 ml), dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The above procedure was carried out in duplicate The crude products of the two reactions were combined and purified by column chromatography on silica eluting with dichloromethane: methanol (99: 1) to give the title compound as a pale yellow oil, 968 mg . 1 H NMR (400MHz, CDCl 3) d 1.14 (t, 3H), 2.55-2.62 (m, 1 H), 2.63- 2.68 (m, 1 H), 2.70-2.73 (m, 1 H), 2.95-3.05 (m , 2H), 3.11-3 (t, 1H), 3.69 (s, 3H), 3.89 (c, 1 H), 6.76 (t, 1 H), 6.83 (t, 1 H), 7.37 (c, 1 H) ). LRMS (El) = 270 [MH +] According to a preferred embodiment, the compounds and intermediates according to the present invention and especially the compounds and intermediates exemplified hereinbefore provide in pure isolated form. As defined herein, "pure isolated form" means that such compounds and / or intermediates substantially lack compounds with alternative stereo-specific characteristics as defined herein. Substantially means that at least 90%, preferably at least 92, more preferably at least 95%, even more preferably at least 98% and especially at least 99% of the compound is present in the desired ester-specific formula.

Data The compounds according to the present invention, including the compounds of examples 12, 20, 16, 48, 1, 5, 6, 22, 13, 9, 10, 50, 14, 17, 19, 53, 40 , 15, 52, 51, 8, 33, 31, 34, 35, 36, 42, 44 and 47, have been tested and found to show functional potencies of less than about 150 nM in the MC4 receptor when they are tested using the test method described in Protocol E.

Table 5 illustrates the EC 0 data of MCR1, MCR3, MCR4 and MCR5 for the compounds of the invention generated using the test methods described in Protocols A, B, C and D, as well as their relative selectivity by MCR4. against MCR3, MCR1 and MCR5.

TABLE 5 The EC50 data of MCR1, MCR3, MCR4 and MCR5 for the compounds of the invention generated using the test methods described in Protocols A, B, D and E, as well as their relative selectivity for MCR4 against MCR3, MCR1 and MCR5 are illustrated in Table 6.

TABLE 6

Claims (40)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof; wherein R1 is selected from: -alkyl (CrC6), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C8), -cycloalkenyl (C5-C8), -alkyl ( C -? - C2) -cycloalkyl (C3-C8), aryl, -alkylaryl (CrC2), heterocyclic or (C -? - C2) -alkylheterocyclic groups; wherein each of the above R1 groups is optionally substituted with one or more groups selected from: -alkyl (C4), - (CH2) mclocloalkyl (C3-C5), halogen, - (CH2) mOR6, CN, -C ( O) OR6, - (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 where m = 0, 1 or 2; R2 is H, OH or OCH3; R3 is selected from: H groups, -alkyl (Ci-Cß), -alkenyl (C2-C6), -alkynyl (C2-C6), -cycloalkyl (C3-C6), -cycloalkenyl (C5-C8), -alkyl (C- | -C2) -cycloalkyl (C3-C8), aryl, -alkylaryl (d-C2), heterocyclic, or -alkyl (C -? - C2) heterocyclic groups; wherein each of the last ten R3 groups is optionally substituted with one or more groups selected from: OH, -alkyl (C4), - (CH2) n-cycloalkyl (C3-C5), halogen, CN, - (CH2) nOR6 or - (CH2) nNR7R6; where n = 0, 1 or 2; R4 is selected from: -H, -alkyl (C4), - (C2-C) alkenyl, -alkynyl (C2-C), - (CH2) -cycloalkyl (C3-C5), - (CH2) -cycloalkenyl (-) C5), halogen; - (CH2) P (O) R6, - (CH2) PNR7R8, -CN, -C (O) R6, - C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or groups OCH2CF3 where p = 0, 1 or 2; R5 is selected from: -alkyl (CrC4), -alkenyl (C2-C4), -alkynyl (C2-C4. '"(CH2) pccycloalkyl (C3-C5), - (CH2) pccycloalkenyl (C5 ), halogen, - (CH2) pOR6, - (CH2) PNR7R8, CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3, where p = 0, 1 or 2, or R4 and R5 can together form a saturated or unsaturated 5-7 membered condensed ring, each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; wherein the heterocyclic groups of R1 and R3 are independently selected from ring systems of 4 to 10 members containing up to 4 heteroatoms independently selected from 0, N or S.

2. The compound according to claim 1, further characterized in that R1 it is selected from: -alkyl (CrC6) -cycloalkyl (C3-C8), -alkyl (C -? - C2) -cycloalkyl (C3-C8), phenyl, alkylaryl (C2), heterocyclyl or -alkyl ( CrC2) heterocyclic and where R1 is optionally substituted with one or more groups selected from alkyl (C4), C4 alkyl), - (CH2) n, OR6, - (CH2) cycloalkyl (C3-C5), halogen, OCH3, OCH2CH3, CN, CF3, CH2CF3, OCF3 or OCH2CF3, where m = 1 or 2; and wherein when R1 is a heterocyclic or a (C -? - C2) -heterocyclic alkyl group said heterocyclic groups are independently selected from a 5-6 membered monocyclic ring system containing up to 3 heteroatoms independently selected from O, N or S and combinations thereof.

3. The compound according to claim 1 or 2; further characterized in that R1 is selected from: -alkyl (C-pCß), -cycloalkyl (C3-C8), -alkyl (CrC2) -cycloalkyl (C3-C8), phenyl, -alkylaryl (C C2), heterocyclyl or groups -alkyl (C C2) heterocyclic; wherein each of the above R groups is optionally substituted with one or more groups selected from: -alkyl (C -? - C4), halogen, - (CH2) mOR6, CN, CF3 or OCF3 where m = 1 or 2; R2 is OH, R3 is selected from: H groups, -alkyl (C -? - C6), -cycloalkyl (C3-C8), -alkyl (CrC2) -cycloalkullo (C3-C8), aryl, -alkylaryl (C C2) ), heterocyclyl, or heterocyclic (C? -C2) groups; wherein each of the last ten R3 groups is optionally substituted with one or more groups selected from: OH, -alkyl (C? .- C), - (CH2) n-cycloalkyl (C3-C5), halogen, CN, - (CH2 ) nOR6 or - (CH2) nNR7R8, where n = 0, 1 or 2; R4 is selected from: -H, -alkyl (CrC), - (CH) -cycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) PNR7R8, CN, -C (O) R6, -C (0) OR6, -C (0) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or -OCH2CF3 where p = 0, 1, or 2; R5 is selected from: -alkyl (C C4), "(CH2) pccycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) PNR7R8, CN, C (O) R6, C (O) groups OR6, CONR7R8, (CH2) pNR7SO2R8, CF3, CH2CF3, OCF or OCH2CF3, where p = 0, 1 or 2, each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3 is selected from 5-6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from 0 or N and combinations thereof; and wherein the heterocyclic group of R1 is selected from 5-6 membered ring systems containing up to 1 heteroatom independently selected from 0 or N.

4. The compound according to any of the preceding claims, further characterized in that R3 is a group H, - (C6) alkyl, (C3-C8) alkyl, -alkyl (CrC2) -cycloalkyl (C3-C8), -alkyl (CrC2) aryl or a heterocyclic group and where each of the last five groups R3 is optionally substituted with one or more groups selected from: -OH, -alkyl (CrC4), - (CH2) nCycloalkyl (C3-C5), halogen, CN or - (CH2) nOR6 where n = 0 or 1 and where R6 is H, CH3) or CH2CH3; and wherein when R3 is a heterocyclic group, said heterocyclic group is selected from 5-6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from 0 or N and combinations thereof.

5. The compound according to any of the preceding claims, further characterized in that R1 is selected from -alkyl (C? -C6), -cycloalkyl (C3-C8), phenyl or heterocyclic groups and where each of the groups where each of the above R1 groups is optionally substituted with one or more groups selected from: -alkyl (C4), halogen, -OR6 or CN; R2 is -OH; R3 is selected from H groups, -alkyl (C2-C6), -cycloalkyl (C3-C8), -alkyl (CrC ^ -cycloalkyl (C3-C8), or heterocyclic groups and where each of the last four R3 groups is optionally substituted with one or more groups selected from: OH, -alkyl (C C4), - (CH2) n-cycloalkyl (C3-C5), halogen, CN, -OR6 or - (CH2) nOR6 where n = 0, 1 or 2 R4 is selected from: H, F or CL, R5 is selected from: FO Cl, each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3, where the heterocyclic group of R3 is selected from ring systems of 6 members containing up to 2 heteroatoms independently selected from 0 or N and combinations thereof, and wherein the heterocyclic group of R is selected from 6-membered monocyclic ring systems containing up to 1 heteroatom independently selected from 0 or N.

6 The compound according to any of the preceding claims, further characterized s because the heterocyclic group of R1, when present, is a 6-membered monocyclic ring system containing 1 heteroatom N.

7. The compound according to any of the preceding claims, further characterized by the heterocyclic groups of R3, when present, they are a 6-membered monocyclic ring system containing up to 2 N. heteroatoms.

The compound according to any of the preceding claims having the general formula (1A) wherein R1, R2, R3, R4 and R5 are as defined hereinbefore and wherein the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is in trans configuration with each other.

9. The compound according to any of the preceding claims having the general formula (1 B) wherein R1, R2, R3, R4 and R5 are as defined above and where the stereochemistry of the methyl groups at positions 3 and 5 of the piperidine ring is in the cis configuration with each other.

10. The compound according to any of the preceding claims having the general formula (1B), wherein the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is in trans configuration with each other.

11. - The compound according to any of the preceding claims having the general formula (1 C) wherein R1, R2, R, R and R are as defined hereinbefore and wherein the stereochemistry of the groups at positions 3 and 4 of the plrrolidine ring is in the cis configuration with each other where the stereochemistry of the methyl groups in positions 3 and 5 of the piperidine ring is in cis configuration with each other.

12. The compound according to any of the preceding claims having the general formula (1 D) wherein R1, R2, R3, R4 and R5 are as defined above and wherein the stereochemistry of the methyl groups at positions 3 and 5 of the piperidine ring is in the cis configuration with each other and in that the Group R1 in the 4-position is in the trans position with respect to the methyl groups in positions 3 and 5 of the piperidine ring and the group R2 is in the cis position with respect to the methyl groups.

13. The compound according to any of the preceding claims having the general formula (1 D), wherein the stereochemistry of the groups in positions 3 and 4 of the pyrrolidine ring is in trans configuration with each other.

14. The compound according to any of the preceding claims having the general formula (1 E) wherein R1, R2, R3, R4 and R5 are as defined above in this document, and wherein the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is in trans configuration with each other and in which the stereochemist of the methyl groups at positions 3 and 5 of the piperidine ring is in the cis configuration with each other and where the group R at the 4-position is in the trans position with respect to the methyl groups at positions 3 and 5 of the piperidine ring and the Group R2 is in cis position with respect to the methyl groups.

15. The compound according to any of the preceding claims that has the general formula (1 F) wherein R1, R2, R3, R4 and R5 are as defined above and where the stereochemistry of the methyl groups at positions 3 and 4 of the piperidine ring is in the cis configuration with each other and where the stereochemistry of the methyl groups at positions 3 and 5 of the piperidine ring are cis to each other and where the group R1 at the 4-position is trans-position with respect to the methyl groups at positions 3 and 5 of the piperidine ring and the group R2 is in cis position with respect to methyl groups and where R 4 and R 5 are in positions 2 and 4 of the phenyl ring.

16. The compound according to any of the preceding claims, further characterized in that R1 is selected from -alkyl (CrC). -cycloalkyl (C3-C6), phenyl or pyridyl wherein R1 is optionally substituted with one or more groups selected from CH3. CH2CH3, halogen, OCH3, OCH2CH3, CN, CF3 or OCF3.

17. The compound according to any of the preceding claims, further characterized in that R1 is selected from n-propyl, -propyl, n-butyl, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3-fluorophenyl, 4-fluoroenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl or pyridin-3-yl.

18. The compound according to any of the preceding claims, further characterized in that R1 is selected from pyridin-2-yl groups, phenyl, 3-fluorophenyl, 4-fluoroenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-diflurophenylol or 3,4-difluorophenyl.

19. The compound according to any of the preceding claims, further characterized in that R3 is -H, -alkyl (C- | -C6), -cycloalkyl (C3-C8), -alkyl (CrC2) -cycloalkyl (C3-) C8) or heterocyclyl, wherein each of the last four R3 groups is optionally substituted with one or more groups selected from -OH, -alkyl (C? -C) or -OR6, where R6 is -H, CH3 or CH2CH3 and where when R3 is a heterocyclic group, said heterocyclic group is a 6-membered monocyclic ring system containing up to 2 N heteroatoms.

The compound according to any of the preceding claims, further characterized in that R3 is selected from: hydrogen groups , ethyl, i-propyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methoxyethyl, cyclopentyl, cyclobutyl, cyclopentylmethyl, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl or tetrahydropyran-4-yl.

21. The compound according to any of the preceding claims, further characterized in that R4 is selected from H, F or Cl and R5 is selected from F or Cl.

22. The compound according to any of the preceding claims, characterized in addition because the phenyl group having substituents R4 and R5 is: a 2,4-substituted phenyl group in which each of the groups R4 and R5 is independently selected from F or Cl; or a 4-mono-substituted phenyl group in which R4 is H and R5 is F or Cl.

23. The compound according to any of the preceding claims, further characterized in that the phenyl group having substituents R4 and R5 is selected between 4-chlorophenyl or 2,4-difloromethyl groups.

24. The compound according to any of claims 16 to 23, which has the general formula (IF).

25. The compound according to any of the preceding claims of general formula (IC), wherein: R1 is a phenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3 group , 4-difluorophenyl or pyridin-2-yl; R2 is OH; R3 is H; R4 is selected from: H or F and R5 is selected from: F or Cl.

26. The compound according to claim 25 selected from the compounds of examples 12, 16, 24 and 48 or pharmaceutically acceptable salts, solvates or hydrates thereof.

27. The compound according to any of claims 1 to 24 of general formula (IC), wherein: R1 is a phenyl or pyridin-2-yl group, R2 is OH; R3 is a heterocyclic group selected from: pyridin-2-ylo groups; pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl; pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4-yl; both R4 and R5 are F. The compound according to claim 27 selected from the compounds of examples number 31, 34, 35, 42 and 47 and pharmaceutically acceptable salts, solvates or hydrates thereof. 29. The compound according to any of claims 1 to 24 of general formula (IC), wherein: R1 is phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,4 -difluorophenyl, pyridin-2-yl; R2 is OH; R3 is t-Bu, i-Pr, Et; and R4 and R5 are F. 30. The compound according to claim 29 selected from the compounds of examples 1, 5, 6, 8, 9, 10, 13, 15, 22, 40, 50, 51, 52 , and 53 and pharmaceutically acceptable salts, solvates or hydrates thereof. The compound according to any of the preceding claims selected from: the compounds of examples number 1, 5, 6, 8, 9, 10, 12, 13, 15, 16, 22, 24, 31, 34, 35, 40, 42, 47, 48, 50, 51, 52, 53 and pharmaceutically acceptable salts, solvates or hydrates thereof. 32. The compound according to any of the preceding claims selected from: the compounds of examples number 1, 5, 9, 12 and 13 and pharmaceutically acceptable salts, solvates, or hydrates thereof. 33. The compound according to claim 1 selected from 3R, 4R, 5S) -1-. { [(3S, 4RJ-1-ferc-butyl-4- (2,4-difluorophenol) pyrrolidin-3-yl] carbonyl] -3,5-d-methyl-4-phenylp peridin-4-ol also known as [1-tert-butyl-4- (2,4-difluoro-phenyl) -pyrrolidin-3-yl] - (4-hydroxy-3,5-dimethyl-4-phenyl- piperidin-1-methanone and salts of pharmaceutically acceptable acids, hydrates or solvates thereof 34. The compound according to claim 1 selected from 3R, 4R, 5S) -1- { [(3S) hydrochloride , 4R) -1-tert-butyl-4- (2,4-d-fluoro-phenyl) -pyrrolidin-3-yl] -carbonyl} -3,5-dimethyl-4-phenylpiperidine- 4-ol; and [1-tert-butyl-4- (2,4-difluoro-phenyl) pyrroidin-3-yl] - (4-hydroxy-3,5-dimethyl-4-phenylpiperidine) -1-l) -metanone, HCl salt, 35.- A process for the preparation of a compound of formula I as defined hereinabove in any of the preceding claims 1 to 34 by a coupling reaction of the compounds (II) (III) where R1, R2, R3, R4 and R5 are as defined above in this document. 36. A pharmaceutical composition comprising a compound of formula (I), (IA) (B) (IC), (ID, (IE) or (IF) or a pharmaceutically acceptable salt hydrate, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or vehicles 37.- A pharmaceutical composition according to claim 36 which includes one or more additional therapeutic agents 38.- A pharmaceutical composition according to claim 36 wherein the agent The additional therapeutic is one or more agents selected from: PDE5 inhibitors, NEP inhibitors, selective D3 or D4 agonists or modulators, estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, testosterone replacement agents. , testosterone or a testosterone implant, estrogen, estrogen and medroxyprogesterone medroxyprogesterone acetate (MPA), or estrogen and hormone replacement therapy agent of methotrexate 39. The pharmaceutical composition according to claim 36, further characterized in that the additional therapeutic agent is an inhibitor of PDE5 or a NEP inhibitor. 40.- The use of a compound of formula (I), (IA), (B), (IC), (ID), (IE) or (IF) or a pharmaceutically acceptable salt, solvate or derivative thereof, or a pharmaceutical composition according to any of claims 37 to 39, for the manufacture of a medicament for the treatment of female sexual dysfunction, male erectile dysfunction, obesity or diabetes.