ES2364254T3 - PIPERIDINILCARBONIL PIRROLIDINAS AND ITS USE AS MELANOCORTINE AGONISTS. - Google Patents

Abstract

A compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, genometric isomer or tautomer thereof, wherein R1 is selected from: -C1-C6 alkyl, C2-C6 alkenyl , -C (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C5-C8) cycloalkenyl, -C1-C2-alkyl-(C3-C8) cycloalkyl, aryl, -C1-C2 alkylaryl, heterocyclic or -C1-C2 alkyl groups in which each of the above R1 groups is optionally substituted with one or more groups selected from -C1-C4 alkyl, - (CH2) m, C3-C5 cycloalkyl , halogen, - (CH2) mOR6, -CN, -C (O) OR6, - (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which m = 0.1 or 2; R2 is H, OH or OCH3; R3 is selected from: H, - (C1-C6) alkyl, - (C2 - C6) alkenyl, - (C2 - C3) alkynyl - (C3 - C8) alkyl, (C5 - C8) cycloalkenyl, - ( C1C2) cycloalkyl (C3-C8), aryl, -alkylaryl (C1-C2), heterocyclic or -alkylheterocyclic groups (C1-C2) in which each of the last ten R3 groups is optionally substituted with one or more groups selected from : -OH, -C1-C4 alkyl, - (CH2) n -cycloalkyl (C3-C6), halogen, -CN, - (CH2) nOR6 or - (CH2) nNR7R6, in which n = 0, 1 or 2 ; R4 is selected from: -H, -C1-C4 alkyl, -C2-C4-alkenyl, -C2-C4-alkynyl, - (CH2) cyclo-C3-C5 alkyl groups, - (CH2) p ( C5) cycloalkenyl, halogen, - (CH2) pOR6, (CH2) pNR7R8, -CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3 , OCF3 or OCH2CF3 in which p = 0, 1 or 2; R5 is selected from: -alkyl (C1-C4), -alkenyl (C2-C4), -alkynyl (C2-C4), - (CH2) cycloalkyl (C3-C5), - (CH2) cycloalkenyl (C5) groups, halogen, - (CH2) pOR6, - (CH2) pNR7R8, -CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 u OCH2CF3 in which p = 0, 1 or 2; or R4 and R5 can together form a saturated or unsaturated condensed ring of 5 to 7 members; each of R6, R7 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 member ring systems containing up to 4 heteroatoms independently selected from O, N or S.

Description

The present invention relates to a new class of melanocortin MCR4 agonist compounds and especially selective MCR4 agonist compounds, for use in medicine, compositions containing them, preparation processes and intermediates used in such procedures. In particular, the present invention relates to a class of MCR4 agonist compounds useful for the treatment of sexual dysfunctions and / or obesity. Such agonists are known from WO 02/068387.

The compounds of the present invention are useful in the treatment of male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and / or sexual pain disorder in women, erectile dysfunction in men as well as obesity (reducing appetite, increasing the metabolic rate, reducing fat intake or reducing carbohydrate appetite) and diabetes mellitus (boosting glucose tolerance and / or reducing insulin resistance). The compounds of the invention are useful in the treatment of additional diseases, disorders or conditions including, but not limited to, hypertension, hyperlipidemia, osteoarthritis, cancer, gallbladder disease, sleep apnea, depression, anxiety, compulsion, neurosis, insomnia. / sleep disorder, substance abuse, pain, fever, inflammation, immunomodulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective, cognitive and memory improvement including the treatment of Alzheimer's disease.

The compounds of the present invention are particularly suitable for the treatment of female sexual dysfunction, male erectile dysfunction, obesity and diabetes.

Desirable properties for MCR4 agonist compounds of the present invention include: desirable MCR4 powers as detailed hereafter; selectivity for MCR4 versus MCR1, MCR5 and / or MCR3 as detailed hereinafter; both desirable power of MC4R and selectivity for MCR4 versus MCR1, MCR5 and / or MCR3; good biopharmaceutical properties such as physical stability; solubility; appropriate metabolic stability.

GENERAL FORMULA

The present invention provides compounds of formula (I)

image 1

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, geometric isomer or tautomer of R1

same, in which it is selected from: -alkyl (C1-C6), -alkenyl (C2-C6), -alkynyl (C2-C6) groups, -C3-C8-cycloalkyl, -C5-C8-cycloalkenyl, -C1-C2-alkyl-(C3-C8) -alkyl, aryl, -C1-C2-alkyl, heterocyclic or - (C1-C2) alkylheterocyclics, in which each of the above R1 groups is optionally substituted with one or more groups selected from: -C1-C4 alkyl, - (CH2) m-C3-C5 cycloalkyl, halogen, - (CH2) mOR6, CN, -C (O) OR6, - (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3, in which m = 0, 1 or 2; R2 is H, OH or OCH3;

R3

is selected from: H, - (C1-C6) alkyl, - (C2 - C6) alkenyl, - (C2 - C6) alkynyl, - (C3 - C8) cycloalkyl, (C6 - C8) cycloalkenyl, - (C1) alkyl -C2) cycloalkyl (C3-C8), aryl, -alkylaryl (C1-C2), heterocyclic or -alkylheterocyclic (C1-C2) groups in which each of the last ten R3 groups is optionally substituted with one

or more groups selected from: OH, (C1-C4) alkyl, - (CH2) n (C3-C5) cycloalkyl, halogen, CN, - (CH2) nOR6 or

(CH2) nNR7R8, in which n = 0, 1 or 2; R4

is selected from: groups of H, -alkyl (C1-C4), -alkenyl (C2-C4), -alkynyl (C2-C4), - (CH2) cycloalkyl (C3-C5), - (CH2) cycloalkenyl (C5 ), halogen, - (CH2) pOR6, - (CH2) pNR7R8, CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3, in which p = 0, 1 or 2; R5 is selected from: -alkyl (C1-C4), -alkenyl (C2-C4), -alkynyl (C2-C4), - (CH2) cycloalkyl (C3-C5), - (CH2) cycloalkenyl (C5) groups , halogen, - (CH2) pOR6, - (CH2) pNR7R8, CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 u OCH2CF3, in which p = 0, 1 or 2;

or R4 and R5 can together form a saturated or unsaturated condensed ring of 5 to 7 members; each R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; and in which the heterocyclic groups of R1 and R3 are independently selected from a 4 to 10-membered ring system containing up to 4 heteroatoms independently selected from O, N or S.

Suitable heterocyclic groups for use herein are mono or bicyclic heteroaryl ring of 4 to 10 members containing one to three heteroatoms of the N, S and O list and combinations thereof and in which said bicyclic heteroaryl ring they are 9 or 10 member ring systems that can be two heteroaryl rings fused together or a heteroaryl ring fused to an aryl ring.

Suitable bicyclic heteroaryl groups for use herein include: benzoimidazolyl, benzotriazolyl, benzothiazolyl, indazolyl, indolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, and naphthyridylidene.

Preferred for use herein are monocyclic heteroaryl rings of 5 to 6 heteroaryl members containing one or three heteroatoms of the N and O list and combinations thereof.

The 5-membered monocyclic ring heteroaryl groups suitable for use herein include: triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and pyrrolyl and imidazolyl groups.

The 6-membered monocyclic ring heteroaryl groups suitable for use herein include: pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl groups.

They are R1 heterocyclic rings, 5- to 6-membered monocyclic heteroaryl rings containing one or two N and O heteroatoms and combinations thereof. They are more preferred R1 heterocyclic rings, 5 to 6 membered monocyclic heteroaryl rings containing one or two N heteroatoms. They are highly preferred R1 heterocyclic rings herein, 6 membered monocyclic heteroaryl rings containing one or two N heteroatoms, such as pyridinyl and pyrimidinyl.

An especially preferred heteroaryl group R 1 is the pyridyl group.

Preferred are R 3 heterocyclic rings, 5 to 6 membered monocyclic heteroaryl rings containing one or two N and O heteroatoms and combinations thereof, such as tetrahydropyranyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups. They are more preferred R3 heterocyclic rings, 5 to 6 membered monocyclic heteroaryl rings containing one or two N heteroatoms. Even more preferred as R3 heterocyclic rings, 6 member monocyclic heteroaryl rings containing one or two N heteroatoms, such as pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups.

Particularly preferred 6-membered R3 monocyclic ring heteroaryl groups for use herein, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl and pyrimidin-2 groups -ilo. 6-membered R3 monocyclic ring heteroaryl groups especially preferred for use herein include pyridin-2-yl, pyridin-3-yl and pyridazin-3-yl groups. Of these groups, the most preferred is pyridazin-3-yl.

They may be suitable condensed ring systems formed by R4 and R5 together, carbocyclic ring systems or heterocyclic ring systems containing up to two heteroatoms selected from O, N or S. Including the

R4 R5

phenyl ring to which they are attached, are preferred ring systems that can form and: indane, 1,2,3,4-tetrahydronaphthalene, indolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzoimidazolyl, benzo [1,3] dioxolane, 2 , 3-dihydrobenzo [1,4] dioxin, 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, can be straight chain or branched chain. For example, a C4 alkyl substituent may be in the form of normal butyl (n-butyl), iso-butyl (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) may not be optionally substituted by an additional (unsubstituted) alkyl group. In addition, when R3 is substituted with an alkenyl group or an alkynyl group, the carbon atom (of said unsaturated group), which is directly linked with the N atom, may not be unsaturated by itself.

The term halogen includes Cl, Br, F and I.

The term "aryl", when used herein, includes six to ten membered carbocyclic aromatic groups, such as phenyl and naphthyl.

The present invention further provides compounds of the formulas (IA) to (IF) as well as mixtures thereof that are detailed later herein. For the avoidance of doubt, all references to compounds of the general formula (I) hereinafter, such as, for example, salts, polymorphs, prodrugs or optical, geometric and tautomeric isomers thereof are intended to encompass compounds having the general formulas (IA) to (IF) unless specifically provided otherwise.

Pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition salts and the base addition salts thereof.

A pharmaceutically acceptable salt of a compound of the formula (I) can be easily prepared by mixing together solutions of a compound of the formula (I) and the base or acid, as appropriate. The salt can be precipitated from the solution and collected by filtration, or they can be recovered by evaporation of the solvent.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisilate, silate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hibenzate / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate / dihydrogen , sucrate, stearate, succinate, tanate, tartrate, tosylate, trifluoroacetate and xinofoate.

Suitable base addition salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.

Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemichalcic salts.

For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

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 an acid or base labile protecting group from a suitable precursor of the compound of formula I or reopening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) converting one salt of the compound of formula I into another by reaction with a suitable acid or base or by means of a suitable ion exchange column.

All three reactions are typically performed in solution. The resulting salt can be removed by precipitate and collected by filtration, or it can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.

The compounds of the invention may exist in the form of a continuous state of solid states that varies from totally amorphous to totally crystalline. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and, depending on the temperature, can show the physical properties of a solid or a liquid. Typically such materials do not give characteristic X-ray diffraction patterns and, even showing the properties of a solid, they are more formally described as a liquid. After heating, a change of properties of solid to a liquid occurs that is characterized by a change of state, typically of a second order ("glass 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 fine peaks. Such materials, when heated sufficiently, will also show the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically of the first order ("melting point").

The compounds of the invention may also exist in solvated or solvated 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, ethanol. The term "hydrate" is used when said solvent is water.

A classification system currently accepted for organic hydrates is one that defines isolated, channel or coordinate hydrates with metal ion - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones that water molecules are isolated from direct contact with others by the intervention of organic molecules. In channel hydrates, water molecules rest in network channels in which they are close to the other water molecules. In hydrates coordinated with metal ion, the water molecules bind to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry regardless of moisture. When, however, the solvent or water binds weakly, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on the humidity and drying conditions. In such cases, the absence of stoichiometry will be the norm.

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 will be 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 bind to each other through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals can be prepared by melt crystallization, by recrystallization from solvents or by or by physically grinding the compounds together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component compounds, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when the conditions are subjected. The mesomorphic state is intermediate between the authentic crystalline state and the authentic liquid state (both molten and in solution). The mesomorphism obtained as a result of a change in temperature is described as "thermotropic" and that resulting from the addition of a second component, such as water or other solvent, is described as "liotropic." Compounds are described that have the potential to form liotropic mesophases as "amphiphilic" and consist of molecules that possess a major ionic polar group (such as -COO -Na +, -COO -K + or -SO3-Na +) or non-ionic ( such as -N -N + (CH3) 3). For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970). Hereinafter all references to compounds of formula 1 include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

The compounds of the invention include compounds of formula (I) as defined hereinbefore, polymorphic and crystalline habits thereof and optical, geometric and tautomeric isomers as defined hereinbelow and compounds of formula ( I) isotopically marked.

"Prodrugs" of the compounds of formula (I) may be formed. Therefore, certain derivatives of compounds of formula (I), which may have little or no pharmacological activity by themselves, may, when administered in or on the body, may become compounds of formula (I) that have the activity desired, for example, by hydrolytic cleavage. Such derivatives are called "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 Drug Design, Pergamon Press, 1987 (Ed. EB Roche, American Pharmaceutical Association).

Prodrugs can be produced, for example, by replacing the appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985).

Some examples of prodrugs 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 functionality of the compound of formula (I) is replaced by -alkyl (C1-C8);

(ii)

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 -alkanoyloxymethyl (C1-C6), such as for example when R2 = OH, or when the R3 group is substituted with a -OH group, a preferred prodrug herein is an ether; Y

(iii) when the compound of formula I contains a primary or secondary amino functionality (-NH2 or -NHR in which R * H), such as for example, in which R3 = H, a preferred prodrug thereof is an amide thereof, for example, a compound in which, as may be the case, one or both hydrogens of the amino functionality of the compound of formula I is replaced / replaced by -alkanoyl (C1-C10), preferably -alkanoyl (C1- C6), more preferably methyl, ethyl or propylalkanoyl.

Particularly preferred prodrugs herein are esters, (C1-C4) alkyl and (C1-C4) alkyl esters of the compounds of general formula (I), with esters being particularly preferred. Ester prodrugs are described in detail in "Design of esther prodrugs to enhance oral absorption of poorly permeable compounds: Challenges to the discovery scientist", Current Drug Metabolism, (2003), 4 (6), 461-485.

Additional examples of replacement groups can be found according to the above examples and examples of other types of prodrugs can be found in the references already cited.

Finally, certain compounds of formula (I) can act by themselves as prodrugs of other compounds of formula (I).

They are metabolites of compounds of formula I, compounds formed in vivo after drug administration. Some examples of metabolites include

(i)

when the compound of formula I contains a methyl group, a hydroxymethyl derivative thereof (-CH3 → -CH2OH):

(ii)

when the compound of formula I contains an alkoxy group, a hydroxy derivative thereof (-OR → -OH);

(iii) when the compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR7R8 → -NHR7 or -NHR8 in which R8 and R8 are different groups);

(iv)

when the compounds of formula I contain a secondary amino group, a primary derivative thereof (-NHR7 → -NH2);

(v)

when the compound of formula I contains a phenyl moiety, a phenol derivative thereof (-Ph → -PhOH); Y

(saw)

when the compound of formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 → -COOH).

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, cis / trans (or Z / E) geometric isomers are possible. When structural isomers can be interconverted by a low energy barrier, tautomeric isomerisms ("tautomerisms") may occur. This may take the form of protonic tautomerisms in compounds of formula (I) that contain, for example, an imino, keto or oxime group, or the so-called valence tautomerisms in compounds that contain an aromatic moiety. It follows that a simple compound can show more than one type of isomerism.

Within the scope of the present invention all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included, including compounds that show more than one type of isomerism and mixtures of one or more thereof. Also included are acid or base addition salts in which the counterion is optically active, for example, d-lactate or I-lysine, or racemic, for example, dl-tartrate or dl-arginine.

Specifically within the scope of the present invention are stereoisomeric mixtures of compounds having formula (I) or a diastereomerically pure or diastereomerically enriched isomer of a compound of formula (I) or an enantiomerically pure or enantiomerically enriched isomer of a compound of formula (I).

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 optically pure precursor or resolution of the racemate (or the racemate or a salt or derivative) using, for example, high pressure chiral liquid chromatography (HPLC) .

Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case in the compound of formula (I) contains an acidic 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 become the corresponding enantiomers by means well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained enantiomerically enriched using chromatography, typically HPLC, on an asymmetric resin as a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50 % by volume of isopropanol, typically 2 to 20% and may contain 0 to 5% by volume of an alkylamine. The concentration of the eluate provides the enriched mixture. The absolute composition of the mobile phase will depend on the chiral stationary phase (asymmetric resin) selected. Preparation 2 as detailed hereinafter provides an example of said separation technique.

When any racemate crystallizes, if possible crystals of two different types. The first type is the racemic compound (authentic racemate) mentioned above, in which a homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic or conglomerate mixture in which two forms of the crystal are produced in equimolar amounts each comprising a single enantiomer.

Although both crystalline forms are presented in a racemic mixture, they have identical physical properties, they can have different physical properties compared to the authentic racemate. Racemic forms 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).

Therefore, the present invention further provides compounds of the general formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG) and (IH).

image 1

5 in which R1, R2, R3, R4 and R5 are as defined hereinbefore. Also included are compounds having the general formulas (IB) and (ID), in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are cis in mutual relation.

Preferably, the present invention provides compounds of the general formula (IA), more preferably compounds of the general formula (IC), even more preferably compounds of the general formula (IE) and

10 especially compounds of the general formula (IF).

The present invention includes all compounds labeled with pharmaceutically acceptable isotopes of

5

fifteen

25

35

Four. Five

formula (I), in which one or more atoms are replaced by atoms that have the same atomic number, but an atomic mass or mass number other than the atomic mass or mass number normally found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P and sulfur, such as 35S.

Some isotope-labeled compounds of formula (I), for example, those that incorporate a radioactive isotope, are useful in studies of drug distribution and / or tissue substrates. Tritium radioactive isotopes, i.e. 3H and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and simple detection means.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, greater in vivo half-life or less dosage requirements, and, therefore, may be preferred in some circumstances. .

Substitution with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, may be useful in Positron Emission Tomography (PET) studies to examine the occupation of the receptor in the substrate.

Isotopically labeled compounds of formula (I) can be prepared generally by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples and Preparations attached using an isotopically labeled reagent in place of the unlabeled reagent used above. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

In accordance with a preferred embodiment of the present invention the present invention provides a group of compounds having the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more preferably the formula (IE) and especially the formula (IF), in which R 1 is selected from: -C1-C6 alkyl, -C3-C8-alkyl, -C1-C2-alkyl-(C3-C8) alkyl, phenyl, - alkylaryl (C1-C2), heterocyclic groups

R1

or - (C1-C2) alkylheterocyclics and wherein each is optionally substituted with one or more groups selected from - (C1-C4) alkyl, - (CH2) mOR6, - (CH2) cycloalkyl (C3-C5), halogen, OCH3, OCH2CH3, CN, CF3, CH2CF3, OCF3 or OCH2CF3, in which m = 1 or 2 and in which when R1 is a heterocyclic or -alkyl heterocyclic (C1-C2) groups, said heterocyclic groups are independently selected from systems of 5 to 6 member monocyclic ring 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 having the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more

R1

preferably the formula (IE) and especially the formula (IF), in which it is selected from: -C1-C6-alkyl, -C3-C8-alkyl, -C1-C2-alkyl-C3-C8-alkyl ), phenyl, (C1-C2) alkyl, heterocyclic or (C1-C2) alkyl groups, in which each of the above R1 groups is optionally substituted with one or more groups selected from: - (C1-C4 alkyl) ), halogen, - (CH2) mOR6, CN, CF3, OCF3, in which m = 1 or 2;

R2 is OH;

R3

is selected from: H, - (C1-C6) alkyl, - (C3 - C8) cycloalkyl, - (C1 - C2) - (C3 - C8) cycloalkyl, aryl, - (C1 - C2) alkyl, heterocyclic groups or -alkyl heterocyclic (C1-C2) in which each of the last seven R3 groups

it is optionally substituted with one or more groups selected from: OH, -C1-C4 alkyl, - (CH2) n -cycloalkyl (C3-C5), halogen, CN, - (CH2) nOR6 or - (CH2) nNR7R8, in the that n = 0, 1 or 2;

R4 is selected from: groups H, -C1-C4 alkyl, - (CH2) cycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) pNR7R8, CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0.1 or 2;

R5 is selected from: -C1-C4 alkyl, - (CH2) cycloalkyl (C3-C5), halogen, - (CH2) pOR6, - (CH2) pNR7R8, CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0.1 or 2; R6, R7 and R8 are each independently selected from H, CH3 or CH2CH3;

wherein the heterocyclic group of R3 is selected from 5 to 6 membered monocyclic ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof;

and in which the heterocyclic group of R1 is selected from 5 to 6 membered monocyclic ring systems containing 1 heteroatom of N.

Preferred herein are groups of compounds having the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more preferably the formula (IE) and especially the formula (IF), as defined hereinbefore in which R3 is H, -C1-C6 alkyl, -C3-C8-alkyl, -C1-C2-alkyl-(C3-C8) alkyl, -alkylaryl ( C1-C2) or a heterocyclic group and in which each of its last five R3 groups is optionally substituted with one or more groups selected from -OH, -C1-C4 alkyl, - (CH2) n -cycloalkyl (C3-C5) ), halogen, -CN or - (CH2) nOR6 in which n = 0 or 1, in which R6 is H, CH3

or CH2CH3 and in which when R3 is a heterocyclic group said heterocyclic group is selected from 5- to 6-membered heterocyclic ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof.

According to a further preferred embodiment, the present invention provides a group of compounds of the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more preferably

R1

the formula (IE) and especially the formula (IF), in which it is selected from -C1-C6-alkyl, -C3-C8-cycloalkyl, phenyl or heterocyclic groups and in which and in which each of the above R1 groups are optionally substituted with one or more groups selected from: -C1-C4 alkyl, halogen, -OR6 or -CN;

R2 is OH;

R3

is selected from H, - (C2-C6) alkyl, - (C3-C8) cycloalkyl, - (C1-C2) - (C3-C8) alkyl or heterocyclic groups and in which each of the last four R3 groups it is optionally substituted with one or more groups selected from: -OH, -C1-C4 alkyl, - (CH2) n-C3-C5 cycloalkyl, halogen, -CN, -OR6 or - (CH2) nNR7R8 in which n = 0.1 or 2;

R4 is selected from: H, F or Cl;

R5 is selected from: F or Cl;

each R6, R7 and R8 is independently selected from H, CH3 or CH2CH3;

wherein the heterocyclic group of R3 is selected from 5- to 6-membered heterocyclic ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof;

and in which the heterocyclic group of R1 is selected from 5- to 6-membered heterocyclic ring systems containing 1 N heteroatom.

Preferred herein are groups of compounds having the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more preferably the formula (IE) and especially the formula (IF), as defined hereinbefore in which the heterocyclic group of R1 when present, is a 6-membered monocyclic ring system containing up to 1 heteroatom of N.

Preferred herein are groups of compounds having the general formula (I), preferably the formula (IA), more preferably the formula (IC), even more preferably the formula (IE) and especially the formula (IF), as defined hereinbefore, in which the heterocyclic group of R3, when present, is a 6-membered monocyclic ring system containing up to 2 N heteroatoms.

R1

Preferred groups for use herein are selected from - (C1-C4) alkyl, - (C3-C6) alkyl, phenyl, pyridyl or pyrimidinyl, in which R1 is optionally substituted with one or more groups selected from CH3 , CH2CH3, halogen, OCH3, OCH2CH3, CN, CF3 or OCF3.

The most preferred R1 groups for use herein are selected from n-propyl, i-propyl, n-butyl, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4- groups methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl or pyridin-3-yl.

Highly preferred R1 groups for use herein are selected from pyridin-2-yl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl groups, 2,4-difluorophenyl or 3,4-difluorophenyl.

Preferred R3 groups for use herein are selected from -H, -C (C2-C6) alkyl, -C3-C8 cycloalkyl, -C1-C2 alkyl (C3-C8) or heterocyclic alkyl and in which each of the last four R3 groups is optionally substituted with one or more groups selected from -OH, -alkyl (C1-C4) or -OR6 and in which R6 is -H, CH3 or CH2CH3 and in which when R3 is a heterocyclic group, said heterocyclic group is a 6-membered monocyclic ring system containing up to 2 N heteroatoms.

Preferred R3 groups for use herein are selected from: hydrogen, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methoxyethyl, cyclopentyl, cyclobutyl, cyclopentylmethyl groups, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl or tetrahydropyran-4-yl.

Preferred R4 groups for use herein are selected from H, F or Cl and preferred R5 groups for use herein are selected from F or Cl.

Preferred phenyl groups having R4 and R5 substituents for use herein are: a 2,4-substituted phenyl group, in each of the groups R4 and R5 is independently selected from F or Cl; or, a 4-monosubstituted phenyl group, wherein R4 is H and R5 is F or Cl.

The most preferred phenyl groups for use herein to which R4 and R5 bind are 4-chlorophenyl or 2,4-difluorophenyl groups.

When R3 is H, in a preferred group of compounds herein of the general formula (IC), more preferably (IE) and especially (IF), R1 is a phenyl, 3-fluorophenyl, 4-fluorophenyl group, 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.

Preferred compounds herein are R3 being H, 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 hereinbelow, in a preferred group of compounds of the general formula (IC), more preferably (IE) and especially (IF) herein, R1 is a phenyl group or pyridin-2-yl; R2 is -OH; R3 is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4 groups -ilo; and R4 and R5 are

F.

Preferred compounds herein, wherein R3 is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4- groups ilo, pyrimidin-2-yl or tetrahydropyran-4-yl, are the compounds of examples number 31, 34, 35, 42 and 47, and pharmaceutically acceptable salts, solvates and hydrates thereof.

When R3 is Et, i-Pr or t-Bu, in preferred group of compounds herein of the general formula R1

(IC), more preferably (IE) and especially (IF), 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.

Preferred compounds herein, wherein 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, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl- hydrochloride 4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine hydrochloride -4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride} -4- (3,4 -difluorophenyl) -3,5-dimethylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) hydrochloride ) -3,5dimethyl-piperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride} -4- (4-fluorophenyl) -3 , 5-dimethyl-piperidi n-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5- hydrochloride dimethylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-chlorophenyl) hydrochloride ) -3,5-dimethylpiperidin4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride} -4- (2,4 -difluorophenyl) -3,5-dimethylpiper idin-4-ol;

(3R, 4R, 5S) -4- (2,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl) hydrochloride -3, 5-dimethylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl) -3,5-dimethyl- hydrochloride 4-pyridin-2-ilpiperidin-4

ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine-4- hydrochloride ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyridin-2-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl hydrochloride -4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyridin-3-yl-pyrrolidin-3-yl] carbonyl} -3,5-dimethyl hydrochloride -4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyridazin-3-yl-pyrrolidin-3-yl] carbonyl} -3,5-dimethyl hydrochloride -4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl- hydrochloride 4-propylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-4-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl hydrochloride -4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyridazin-3-yl-pyrrolidin-3-yl] carbonyl} -3,5-dimethyl hydrochloride -4-pyridin-2-yl-piperidi n-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol hydrochloride;

(3R, 4R, 5S) -4- (4-chlorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3 hydrochloride , 5-dimethylpiperidin-4-ol;

(3R, 4R, 5S) -4- (3,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride} -3,5-dimethylpiper idin-4-ol;

(3R, 4R, 5S) -4- (2,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride} -3,5-dimethylpiper idin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-ethylpyrrolidin-3-yl] carbonyl hydrochloride} -4- (3-fluorophenyl) -3 , 5-dimethylpiperidin-4-ol

and pharmaceutically acceptable salts of acids, solvates and hydrates thereof.

Preferred compounds according to the present invention are independently selected from the group consisting of:

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl- hydrochloride 4-phenylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride} -4- (3,4 -difluorophenyl) -3,5-dimethylpipe ridin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) hydrochloride ) -3,5-dimethyl-piperidi n-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5- hydrochloride dimethylpiperidin-4-ol;

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-chlorophenyl) hydrochloride ) -3,5-dimethylpiperidin4-ol;

(3R, 4R, 5S) -4- (4-chlorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3 hydrochloride , 5-dimethylpiperidin4-ol

5

10

fifteen

twenty

25

30

35

40

and pharmaceutically acceptable salts, solvates and hydrates thereof.

Very preferred here:

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- phenylpiperidin-4-ol, also known as [1-tert-Butyl-4- (2,4-difluorophenyl) -pyrrolidin-3-yl] - (4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1- il) -methanone (the compound of Example 1) and / or pharmaceutically acceptable acid salts thereof, such as (3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl hydrochloride -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-difluorophenyl) -pyrrolidin-3-yl] - (4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl) -methanone (the compound of Example 5).

In accordance with a further embodiment, the present invention provides compounds of the general formula

(I)

image 1

or a stereoisomeric mixture thereof, or a diastereomerically enriched or diastereomerically pure isomer thereof, or an enantiomerically enriched or enantiomerically pure isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture or isomer thereof

wherein R1 is selected from: (C1-C6) alkyl, (C2-C6) alkenyl, C2-C6 alkynyl, cycloalkyl (C3-C8), cycloalkenyl (C5-C8), alkyl (C1-C2) groups cycloalkyl (C3-C8), aryl, alkylaryl (C1-C2), heterocyclic or alkylheterocyclic (C1-C2) in which each of the above R1 groups is optionally substituted with one or more groups selected from: (C1-C4 alkyl) ), (CH2) mcycloalkyl (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, in which m = 0, 1 or 2;

R2 is H, OH or OMe;

R3

is selected from: groups H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl (C5-C8) cycloalkenyl, (C1-C2) alkyl (cyclo-alkyl) C3-C8), aryl, alkylaryl (C1-C2), heterocyclic or alkylheterocyclic (C1-C2), in which each of the last ten groups of R3 is optionally substituted with one or more groups selected from: OH, alkyl ( C1-C4), (CH2) n-cycloalkyl (C3-C5), halogen, CN, (CH2) nOR6, (CH2) nN (R7) 2, SMe or SEt in which n = 0, 1 or 2;

R4 R5

each and is independently selected from: (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (CH2) cycloalkyl (C3-C5), (CH2) cycloalkenyl (C5), 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 can together form a saturated or unsaturated condensed ring of 5 to 7 members;

each R6, R7 and R8 of is independently selected from H, Me or Et;

wherein the heterocyclic groups R1 and R3, when present, are optionally condensed with 4 to 10 member ring systems containing up to 4 heteroatoms selected from O, N or S.

A further preferred group of compounds according to this further embodiment are compounds in which R 1 is selected from: (C 1 -C 6) alkyl, C 3 -C 8 cycloalkyl, (C 1 -C 2) alkyl (C 3 -C 8) alkyl groups , aryl, alkylaryl (C1-C2), heterocyclic or alkylheterocyclic (C1-C2) and in which R1 is optionally substituted with one or more groups selected from (C1-C4) alkyl, (CH2) cycloalkyl (C3-C5), halogen, OMe, OEt, CN, halogen, CF3, CH2CF3, OCF3, OCH2CF3, SMe or SEt, in which m = 0, 1 or 2 and in which said heterocyclic group is selected from: pyridinyl, pyrimidinyl, triazinyl groups, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, benzoimidazoloyl, benzothiazolyl, indazolyl, quinolyl or isoquinolyl; R2 is H or OH; R3 is H, (C1-C6) alkyl, cycloalkyl (C3-C8), alkyl (C1-C2) cycloalkyl (C3-C8), alkylaryl (C1-C2) and in which each of the last four

R3

groups are optionally substituted with one or more groups selected from OH, (C1-C4) alkyl, (CH2) n-cycloalkyl (C3-C5), halogen, CN, (CH2) nOR6, SMe or SEt, where n = 0 or one; 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 in which R6 is as defined hereinbefore.

In an even more preferred group of compounds according to this further additional embodiment, R1 is a (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C2) alkyl (C3-C5) cycloalkyl, phenyl group, pyridyl or pyrimidinyl, wherein 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 (C1-C6) alkyl group optionally substituted with one of the following groups OH, OR6, CF3; each R4 and R5 are independently (C1-C4) alkyl, halogen, OR6, CN, CF3, CH2CF3, OCF3, OCH2CF3; R6 is

10 HoMe.

In a particularly preferred group of compounds according to this further additional 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 R4 and R5 are independently F.

They are highly preferred compounds according to this additional embodiment further, compounds of the formula

In general, IG, while more preferred compounds according to this additional embodiment, are compounds of the general formula IH.

image 1

in which R1, R2, R3, R4 and R5 as defined hereinbefore.

More preferred compounds according to this additional embodiment are more compounds of the formula (IG) or

20 (IH), more preferably (IH) in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are trans in relation to each other.

The routes below illustrate methods of synthesizing compounds of the formula (I).

Scheme 1 illustrates the preparation of compounds of the formula (I) by coupling peptides of intermediates (II) and (III), adding, if necessary, a suitable base and / or additive (such as carbohydrate).

1-hydroxybenzotriazole or 4-dimethylaminopyridine). Scheme 1a illustrates the preparation of compounds of formula (IA) by coupling peptides of intermediates of (II) and (IIIA). Similarly, Schemes 1b to 1e illustrate the preparation of the compounds of the formulas (IC), (ID), (IE) and (IF) by coupling peptides of intermediates: (IIA) and (IIIA); (IIB) and (III); (IIB) and (IIIA); and (IIB) and (IIIB) respectively. The compounds of the formulas (IB), (IG) and (IH) can be manufactured in a similar manner from the relevant intermediates.

image 1

image 1

With respect to compounds (I), (II), (III) in Scheme 1 and 1a to 1e, the definitions of R1, R2, R3, R4 and R5 are as defined hereinbefore for compounds of formula (I) unless otherwise indicated.

The alternative conditions used involve stirring a solution of piperidine (amine) of the general formula

(II) and pyrrolidine (acid) of the general formula (III) together with 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI), triethylamine or N-methylmorpholine and 1-hydroxybenzotriazole hydrate (HOBt) in dimethylformamide (DMF) or tetrahydrofuran (THF) or ethyl acetate at room temperature. A suitable alternative method is to stir a solution of the intermediate compounds of the general formula (II) and the general formula (III) together with O-benzotriazol-1-yl-N hexafluorophosphate, N, N ', N'-tetramethyluronium ( HBTU) or 1-propylphosphonic acid cyclic anhydride in CH2Cl2 or EtOAc. Any suitable inert solvent may be used in place of those mentioned above, in which inert solvent refers to a solvent, which does not contain a primary or secondary carboxylic acid or amine. At least one equivalent of each of the coupling reagents should be used and an excess of both one and both may be used if desired.

Therefore, according to a further embodiment, the present invention provides a process for the preparation of compounds of the general formula (I) comprising the peptide coupling of a piperidine (amine) of the 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 the general formula (IA) comprising the peptide coupling of a piperidine (amine) of the general formula (II) with a pyrrolidine (acid) of the general formula (IIIA). According to a more preferred embodiment, the present invention provides a process for the preparation of compounds of the general formula (ID) comprising peptide coupling of a piperidine (amine) of the general formula (IIB) with a pyrrolidine (acid) of the general formula (III). In accordance with an even more preferred embodiment, the present invention provides a process for the preparation of compounds of the general formula (IC) comprising peptide coupling of a piperidine (amine) of the general formula (IIA) with a pyrrolidine (acid) of the general formula (IIIA). In accordance with a further preferred embodiment, the present invention provides a process for the preparation of compounds of the general formula (IE) comprising peptide coupling of a piperidine (amine) of the general formula (IIB) with a pyrrolidine (acid) of the general formula (IIIA). According to one embodiment

5

10

fifteen

25

30

35

Especially preferred, the present invention provides a process for the preparation of compounds of the general formula (IF) comprising the peptide coupling of a piperidine (amine) of the general formula (IIB) with a pyrrolidine (acid) of the general formula ( IIIB).

According to a further embodiment, the present invention provides intermediate compounds of the general formulas (II), (IIA) and (IIB)

image 1

in which R1 and R2 are as defined hereinbefore. Preferred herein are formula (II), more preferably formula (IIA) and especially formula (IIB) in which R2 = OH and R1 = substituted mono phenyl, or 2,6- or 3-phenyl, 4-or 2,4-disubstituted, or a pyridinyl group, in which the phenyl substituent groups are selected from F, Cl and OCH3.

A highly preferred group of intermediates herein are compounds of the formula (II), more preferably the formula (IIA) and especially the formula (IIB) in which R2 = -OH and R1 is phenyl, 4-fluorophenyl, 3,4-Difluorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl.

Therefore, according to a preferred embodiment, the present invention provides intermediates of the general formula (IIB), wherein 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 pyridin-2-yl.

According to a further embodiment, the present invention provides intermediate compounds of the general formulas (III), (IIIA) and (IIIB)

image2

in which R3, R4 and R5 are as defined hereinbefore. Intermediates of the formula (II) are preferred herein, more preferably the formula (IIA), most preferably the formula (IIB) in which R4 is H or F or Cl and in which R5 is F or Cl and wherein R3 is H or -C (C2-C4) alkyl, -C3-C8 cycloalkyl, (C1-C2) alkyl (C3-C8) cycloalkyl or heterocyclic. A preferred group of intermediates herein are compounds of the formula (III), more preferably the formula (IIIA) and especially the formula (IIIB) in which R3 is -H, i-Pr, Et or a heterocyclic group selected between pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydraopyran-4-yl groups.

Therefore, according to another embodiment, the present invention provides a process for the preparation of compounds of the general formula (I), more preferably general formula (IC), even more preferably the general formula (IE) and especially the formula general (IF) by peptide coupling of intermediates (II) and (III), preferably (IIA) and (IIIA), more preferably (IIB) and (IIIA), especially (IIB) and (IIIB) in which: R2 is -OH; R1 is phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 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-5-yl, pyrimidin-4 groups -yl, pyrimidin-2-yl or tetrahydraopyran-4-yl; R4 is H, Cl or F and R5 is Cl or F.

According to a preferred method herein, the compounds of the general formula (IF) are prepared by peptide coupling of intermediates (IIA) and (IIIA), in which: R2 is -OH; R1 is phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 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 groups

5 pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydraopyran-4-yl; R4 is H, Clo F and R5 is Clo F.

In accordance with a further preferred method herein, the compounds of the general formula (IF) are prepared by peptide coupling of intermediates (IIA) and (IIIA) in which: 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

10 Et, and R4 and R5 are both F.

Scheme 2 illustrates an alternative route for the preparation of compounds of the general formula (I) having a selection of R3 groups through the use of a protective group strategy. The compounds of the general formulas (IA) to (IF) can also be prepared according to the route illustrated in Scheme 2 by using the appropriate intermediates (II), (IIA) or (IIB) with the protected amine appropriate formula (IV), (VAT) or

15 (IVB) as needed.

image 1

With respect to the compounds (I), (II), (IV) and (V) in Scheme 2 or (VAT) or (IVB), as illustrated hereinafter, the definitions of R1, R2, R3 , R4 and R5 are as defined hereinbefore for the compounds of the formula (I) unless otherwise indicated. PG is a group

20 nitrogen protector.

image 1

In scheme 2, the amine intermediates of the general formula (II) and the protected pyrrolidine acid intermediates of the general formula (IV) are coupled using conventional peptide coupling procedures as described above.

10

fifteen

twenty

25

30

previously described in scheme 1 to provide a coupled and protected intermediate of the general formula

(V) from which the nitrogen protecting group can be removed using conventional deprotection strategies to form a compound of the general formula (I) in which R3 = H. Any of the nitrogen protecting groups can be used (as described in " Protecting Groups in Organic Synthesis "3rd Edition TW Greene and PG Wuts, Wiley-Interscience, 1999). A common nitrogen protecting group (PG) suitable for use herein is tert-butoxy carbonyl, which is easily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent, such as dichloromethane or 1, 4-dioxane.

R3

Alternative groups (a H) can be introduced into using conventional alkylation techniques. Suitable procedures for 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 a properly activated alkyl halide or alcohol derivative (for example, as a sulfonate ester) in the presence of a base (such as triethylamine) in an inert solvent;

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 transition metal catalysts (for example, palladium, copper) or optionally together with a phosphine ligand, such as 1,1'-binaphthalene-2,2'-diylbisdiphenylphosphine, may be needed to achieve the preferred coupling products .

Scheme 3a illustrates the route for the preparation of the pyrrolidine acid intermediates of the general formula (III) from the unsaturated ester intermediates of the general formula (VI).

image 1

With respect to the compounds (III), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) in Scheme 3a the definitions of R1, R2 , R3, R4 and R5 are as defined hereinbefore for compounds of formula

(I) unless otherwise indicated. PG2 is a suitable carboxylic acid protecting group.

The compounds of the general formula (VI) can be manufactured by Wittig or similar olefination of an aldehyde intermediate of the general formula (X) with a suitable ilide for example (triphenylphosphoranilidene) methyl acetate or a phosphate anion, for example obtained from deprotonation of trimethyl phosphonoacetate, predominantly in the form of the trans isomer.

There are many alternative procedures in the literature for the production of unsaturated ester intermediates of the general formula (VI), including the esterification of a precursor cinnamic acid derivative (VII) using conventional esterification procedures or Heck reaction of an aromatic halide ( VIII) with conventional 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 the general formula (VI) will undergo a cycloaddition of [3 + 2] -azometin ilide by reaction with a compound of the general formula (XI), to provide a pyrrolidine with almost exclusively the trans stereochemistry. This reaction requires an inert solvent, such as dichloromethane, toluene.

or tetrahydrofuran and activation by one or more of: (1) an acid catalyst, such as TFA; (2) a distillation agent, such as silver fluoride; (3) heating.

Alternatively, a pyrrolidine is provided with almost exclusively cis stereochemistry, reacting a compound of the general formula (XI) with an ester or unsaturated acid of Z-olefin configuration. Said Z-olefins can be prepared by reducing Lindlar of an alkylene or by olefining Still-Gennari.

The compound of the general formula (XII) obtained from the cycloaddition reaction is a racemate and may need resolution in its enantiomeric constituents, which can be achieved by preparative HPLC using a chiral stationary phase. Alternatively, the acid intermediate of the general formula (III) can be resolved by conventional procedures (for example, formation of diastereomeric derivatives by reaction with an enantiomerically pure reagent, separation of the resulting diastereomers by physical procedures and cleavage to give an acid (III ).

Intermediate compounds of the general formula (XII) can be converted into compounds of the general formula (III) by ester hydrolysis. Many procedures are available to achieve this transformation (see Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition. March, Jerry, 1992, pp. 378-383 published by Wiley, New York, N. Y. United States). In particular, treating a compound of the general formula (XII) with an aqueous solution of alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable organic solvent will provide the corresponding compounds of the general formula ( III). Preferably, water-miscible organic co-solvents (such as 1,4-dioxane or tetrahydrofuran) are also used in said reactions. A preferred process herein for said ester hydrolysis involves treating the potassium trimethylsilanolate ester in an inert solvent, such as diethyl ether at room temperature. If needed, the reaction can be heated to aid hydrolysis. Ester hydrolysis can also be achieved using acidic conditions, for example, by heating the ester in an aqueous acid, such as hydrochloric acid. Certain esters are more conveniently hydrolyzed under acidic conditions, for example, tert-butyl or benzhydryl esters. Such esters can be cleaved by treatment with anhydrous acids, such as trifluoroacetic acid or hydrogen chloride in an inert organic solvent, such as.

Scheme 3b illustrates an alternative route for the preparation of a single enantiomer of the pyrrolidine acid intermediate of the general formula (III) from unsaturated ester intermediates of the general formula (VI), using an oxazolidinone as a chiral auxiliary. The acid of the formula (XVIII) can be obtained by hydrolysis of the unsaturated ester (VI) and an oxazolidinone can be used as a chiral auxiliary (wherein R is preferably phenyl, tertiary butyl or iso-propyl) to provide the intermediate of the 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 (for example, THF), can also provide a compound of formula (XVIII ).

The compound of the formula (XVIII) will undergo a cycloaddition of [3 + 2] -azometin by reaction with the compound of the general formula (XI), to provide the diastereomers (XX) and (XVIX) that can be separated by chromatography or crystallization and hydrolyzed to give a pyrrolidine of the formula (III).

image 1

Scheme 4 illustrates that the synthesis of protected pyrrolidine acid intermediate of the general formula (IV) can be achieved using a procedure similar to the procedure described hereinbefore for the intermediate of the general formula (III) with the exception that the intermediate of the general formula (XIIA)

5 contains a nitrogen protecting group that can be subsequently removed in the synthetic scheme. Once the protective group is removed, using any of the appropriate conventional techniques, alternative R3 groups can be introduced by the procedures described in Scheme 2.

The pyrrolidines of the general formula IV carrying a nitrogen protecting group can also be obtained enantioselectively by the use of an oxazolidinone chiral auxiliary, in a manner similar to that described.

10 in Scheme 3b.

image 1

With respect to compounds (VI), (XIA), (XIIA), (XII) and (IV) in Scheme 4, the definitions of R1, R2, R3, R4 and R5 are as defined hereinbefore. document for the compounds of the formula (I) unless otherwise indicated. In formulas (XIA), (XIIA) and (IV), PG is selected from protective groups of

5 suitable nitrogen. In formulas (VI), (XIIA) and (VII), PG2 is selected from suitable carboxylic acid protecting groups.

The synthesis of azometin ilium precursor compounds of the formula general (XI) can be achieved as illustrated in scheme 5. Therefore, a primary amine of the general formula (XIII) can be rented by treatment with chloromethyltrimethylsilane, optionally pure or in an inert solvent, heating the reaction if necessary.

Then, the resulting intermediates (XIV) can be reacted with formaldehyde in methanol and in the presence of a suitable base, such as potassium carbonate or tert-butylamine, to provide the intermediates (XI). To produce similar intermediates (XIA) containing a nitrogen protecting group a similar reaction sequence can be followed.

image 1

With respect to compounds (XIII), (XIIIA), (XIV), (XIVA), (XIA) and (XI) in Scheme 5, the definitions of R3 are as defined hereinbefore for compounds of formula (I) unless otherwise indicated. In formulas (XIIIA), (XIVA) and (XIA), PG is selected from the appropriate nitrogen protecting groups.

As illustrated in Scheme 6, piperidine intermediates of the general formula (II) can be prepared, in which

R2 = OH, by the addition of organometallic nucleophiles to ketones of the general formula (XV) containing a suitable nitrogen protecting group to form intermediates of the general formula (XVI). Said nucleophilic addition

It is generally performed at low temperature in a non-polar or anhydrous ether solvent, using Grignard, organolithium or other suitable organometallic reagent. These organometallic reagents can be manufactured by halogen-metal exchange, using a suitable halide precursor, Y-Br or Y-I and n-butyllithium or t-butyllithium. Suitable protecting groups include Bn, which can be removed by hydrogenation or Boc, which can be removed by treatment with an acid, such as TFA or PMB, which can be removed by treatment with DDQ, CAN or chloroethyl chloroformate, to provide the intermediate of Suitable piperidine of the general formula (II). With certain protecting groups and under certain conditions, the protecting group can be labile for treatment with the organometallic reagent and therefore the reactions can be completed in one step. For example, when PG = Boc the protecting group can sometimes be cleaved when intermediates of formula VII are treated with a reagent

10 organometallic.

image 1

With respect to compounds (XV), (XVI) and (II) in Scheme 6, the definitions of R1 are as defined hereinbefore for the compounds of formula (I), unless indicated otherwise. In formulas (XV), (XVI), PG is selected from suitable nitrogen protecting groups.

15 As illustrated by scheme 7, when (3R, 5S) -1-benzyl-3,5-dimethyl-piperidin-4-one is used, the stereochemistry of the addition thereby favors the hydroxyl group in the product is cis for the two methyl groups. Controlled addition to carbonyl systems such as this have been described in the literature (Journal of Medicinal Chemistry (1964), 7 (6), pp. 726-8).

image 1

With respect to compounds (XV), (XXI) and (II) in Scheme 7, the definitions of R1 are as defined hereinbefore for the compounds of formula (I) unless indicated. contrary. In formulas (XV), (XXI), PG is selected from suitable nitrogen protecting groups.

In addition, Scheme 8 illustrates under certain forced reduction conditions, such as hydrogenation at high pressure and / or temperature, or strong acid plus triethylsilane, intermediate compounds of the general formula formula (II),

In which R2 = OH may be converted into additional intermediate compounds of the general formula (II), in which R2 = H. In certain cases, the protection of the piperidine nitrogen atom may be needed to facilitate this transformation. Therefore, the intermediates of the general formula (XVI) can be converted into additional intermediate compounds of the general formula (XXII), wherein R2 = H and then subsequently protected to provide compounds of the general formula (II) in which R2 = H.

image 1

With respect to compounds (XVI) and (II) in Scheme 8, the definitions of R1 are as defined hereinbefore 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 the general formula (II), in which R2 = OH can R2

become additional intermediate compounds of the general formula (II), in which = OMe. This transformation can be achieved by conventional Williamson ether synthesis. That is, the alcohol group in the compounds of the general formula formula (II), in which 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 to be made

10 react with iodomethane, heating the reaction if necessary. The protection of the piperidine nitrogen atom may be needed to facilitate this transformation, therefore the intermediates of the general formula (XVI) in which R2 = OH can be converted into additional intermediate compounds of the general formula (XXV), in which R2 = OMe, and then optionally deprotected to provide compound of the general formula (II) in which R2 = Ome, as illustrated in Scheme 9.

image3

With respect to the compounds (XVI) and (II) in Scheme 9 the definitions of R1 are as defined hereinbefore 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 discussed above, at various times during the synthesis of the compounds of formula I, it may be necessary to protect more groups, such as, for example, hydroxy groups, with a suitable protective group and then remove the protective group. The procedures for deprotection of any particular group will depend on the protective group. For examples of protection / deprotection methodology see "Protective groups in Organic synthesis", TW Greene and PGM Wutz. For example, when a hydroxy group is protected as methyl ether, the deprotection conditions comprise refluxing in 48% aqueous HBr, or by stirring with borane tribromide 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.

In accordance with a preferred embodiment, the present invention provides processes for the preparation of compounds of the general formula (I) using methods analogous to those provided for the preparation of the compounds of Example 1 by preparations 1 to 5 and 12 to 16 and more preferably Example 5 by preparations 1, 21, 22b, 4, 5 and 12 to 16 having the stereochemistry defined therein.

In accordance with a further embodiment, the present invention independently provides: 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 the preparation

16.

The general reaction mechanisms described above herein for the preparation of new materials used in the above procedures are conventional reagents and reaction conditions and suitable for operation or preparation, as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to bibliographic precedents and the Examples and Preparations present.

MCR4 activity

The compounds of the present invention have utility as MCR4 agonists in the treatment of various pathologies.

Preferably said MCR4 agonists show a functional potency in the MCR4 receptor expressed as an EC50, less than about 1,000 nM, more preferably less than 150 nM, even more preferably less than about 100 nM, more preferably even less than about 50 nM and especially less than about 10 nM in which said EC50 measurement of functional power of MCR4 can be carried out using the C or E protocols as described hereafter. 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 powers of less than about 150 nM at the MC4 receptor. Therefore in accordance with a further embodiment the present invention provides compounds of formula I having a functional potency in the MC4R receptor of less than about 150 nM. A preferred group of compounds according to the present invention, 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 have been tested and found to demonstrate functional potencies of less than about 50 nM in the MC4 receptor. A further preferred group of compounds according to the present invention, 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 have been tested and found to demonstrate functional potencies of less than about 10 nM at the MC4 receptor.

Preferred compounds herein show functional potency in the MCR4 receptor as defined hereinbefore and are selective for MCR4 versus MCR1. Preferably said MCR4 agonists have a selectivity for MCR4 versus MCR1 in which said MCR4 receptor agonists are at least about 10 times, preferably at least about 20 times, more preferably at least about 30 times, even more preferably at least about 100 times, more preferably even at least about 300 times, even more preferably even at least about 500 times and especially at least about 1,000 times more functionally selective for an MCR4 receiver compared to the MCR1 receiver based on said relative selectivity assessments in the measurement of the functional powers of MCR1 and MCR4 that can be carried out using protocols A and C, or E as described herein below. 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 in the MCR4 receptor and have been tested and tested. He has found that they show selectivity for MCR4 versus MCR1 more than about 10 times. Therefore according to a further embodiment, the present provides compounds of formula I that show functional potency at the MCR4 receptor and show selectivity for MCR4 versus MCR1 more than about 10 times. Preferred groups of compound according to the present invention, including the compounds of Examples 1, 5, 13, 14, 17, 31 and 35, show functional potency in the MCR4 receptor have been tested and found to exhibit selectivity for MCR4 vs. MCR1 more than about 30 times. A further 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 have selectivity for MCR4 versus MCR1 more than about 100 times.

Preferably said MCR4 agonists have a selectivity for MCR4 versus MCR3 in which said MCR4 receptor agonists are at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times, even more preferably even at least about 500 times and especially at least about 1,000 times more functionally selective for an MCR4 receiver compared to the MCR3 receiver based on said relative selectivity assessments in measuring the functional powers of MCR3 and MCR4 that can be carried out using protocols A and B or E as described hereinafter. The compounds of Examples 1, 2 and 3 show functional potency at the MCR4 receptor and have been tested and found to show selectivity for MCR4 versus MCR3 more than about 30 times.

Preferred compounds herein show functional potency in the MCR4 receptor as defined hereinbefore and are selective for MCR4 versus MCR5. Preferably said MCR4 agonists have a selectivity for MCR4 versus MCR5 said MCR4 receptor agonists being at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably even at least about 300 times, even more preferably even at least about 500 times and especially about

1,000 times more functionally selective for an MCR4 receiver compared to the MCR5 receiver based on said relative selectivity assessments on the measurement of the functional powers of MCR5 and MCR4 that can be carried out using the D and E protocols as described herein. later. Compounds according to the present invention, including 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 in the MCR4 receptor and have been tested and found to show selectivity for MCR4 versus MCR5 more than about 10 times. Therefore 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 versus MCR5 more than about 10 times. 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, they show functional potency in the MCR4 receptor and have been tested and found to have selectivity for MCR4 versus MCR5 more than about 100 times. A further 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 in the MCR4 receptor and have been tested and found to demonstrate which exhibit selectivity for MCR4 versus MCR5 more than about 300 times.

Preferably said MCR4 agonists have a selectivity for MCR4 versus MCR1 and MCR3 said MCR4 receptor agonists being at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times , even more preferably even at least about 1,000 times more functionally selective for an MCR4 receptor compared to the MCR1 and MCR3 receptors.

Preferred compounds herein show functional potency in the MCR4 receptor as defined hereinbefore and are selective for MCR4 versus MCR1 and MCR5. Preferably said MCR4 agonists have a selectivity for MCR4 against MCR1 and MCR5 said MCR4 receptor agonists being at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times , even more preferably even at least about 500 times and especially at least about 1,000 times more functionally selective for 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 in the MCR4 receptor and have been tested and tested. He has found that they show selectivity for the MCR4 receptor compared to the MCR1 and MCR5 receptors more than about 10 times. Therefore in accordance with a further embodiment the present invention provides compounds of Formula I that show functional potency in the MCR4 receptor and show selectivity for the MCR4 receptor compared to the MCR1 and MCR5 receptors more than about 10 times. 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 have selectivity for the MCR4 receptor compared to the MCR1 and MCR5 receivers more than about 100 times.

Preferably said MCR4 agonists have a selectivity for MCR4 against MCR3 and MCR5 said MCR4 receptor agonists being at least about 10 times, preferably at least about 30 times, more preferably at least about 100 times, more preferably at least about 300 times , more preferably at least about 1,000 times more functionally selective for an MCR4 receptor compared to the MCR3 and MCR5 receptors.

In addition to their role in the treatment of sexual dysfunction the compounds of the present invention are probably effective in several additional indications as described hereinafter. The terms "treating", "treating" or "treatment" as used herein are intended to encompass both prevention and control, that is, 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, treating male and female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder and / or sexual pain disorder in women, male erectile dysfunction, obesity (reducing appetite, increasing metabolic rate, reducing fat consumption

or reducing carbohydrate appetite), diabetes mellitus (boosting glucose tolerance, reducing insulin resistance), hypertension, hyperlipidemia, osteoarthritis, cancer, gallbladder disease, sleep apnea, depression, anxiety, compulsion, neurosis , insomnia / sleep disorder, substance abuse, pain, fever, inflammation, immunomodulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective, cognitive and memory improvement including the treatment of Alzheimer's disease.

Some compounds of formula I show highly specific activity towards the melanocortin-4 receptor that make 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 (unable to reach orgasm).

Male sexual dysfunction includes male erectile dysfunction (MED) and ejaculation disorders such as anorgasmia (inability to reach orgasm) or desire disorders such as hypoactive sexual desire disorder (lack of interest in sex).

The compounds of the present invention are particularly useful in the treatment of female sexual dysfunctions including hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorder, 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), otherwise known as male erectile disorder, is defined as:

“The inability to achieve and / or maintain an erection of the penis for satisfactory sexual activity” (NIH Consensus Development Panel on Impotence, 1993) ”

It has been estimated that the prevalence of erectile dysfunction (ED) of all grades (minimum, moderate and complete impotence) is 52% in men 40 to 70 years of age, with higher rates in those over 70 (Melman et al. 1999, J. Urology, 161, p. 5-11). The condition has a significant negative impact on the quality of life of the individual and their partner, often resulting in increased anxiety and tension that can lead to depression and low self-esteem. Although MED two decades ago was considered primarily a psychological disorder (Benet et al 1994 Comp. Ther., 20: 669-673), it is now known that for the majority of individuals there is an underlying organic cause. As a result, great progress has been made in the identification of the mechanism of the erection of the normal penis and the pathophysiology of the MED.

Penile erection is a hemodynamic event dependent on the balance of contraction and relaxation of the smooth muscle and vasculature of the cavernous body of the penis (Lerner et al 1993, J. Urology, 149, 1256-1255). The smooth muscle of the corpora cavernosa is also referred to herein as "smooth muscle of the body" or in the plural sense "corpora cavernosa". The relaxation of the smooth muscle of the cavernous body leads to an increase in blood flow in the trabecular spaces of the cavernous body, causing them to expand against the surrounding tunic and compress the drainage veins. This results in a wide rise in blood pressure, which results in an erection (Naylor, 1998, J. Urology, 81, 424-431).

The changes that occur during the erectile process are complex and require a high degree of coordinated control that involves the central and peripheral nervous systems and the endocrine system (Naylor, 1998, J. Urology, 81, 424-431). Body smooth muscle contraction is modulated by sympathetic noradrenergic innervation by activating postsynaptic α1 adrenoceptors. MED may be associated with an increase in the tone of the endogenous smooth muscle of the corpora cavernosa. However, the body smooth muscle relaxation process is partially mediated by non-adrenergic, non-cholinergic neurotransmission (NANC). There are several other NANC neurotransmitters found in the penis, other than NO, such as calcitonin-related peptide (CGRP) and vasoactive intestinal peptide (VIP). The main relaxing factor responsible for mediating this relaxation is nitric oxide (NO), which is synthesized from L-arginine by nitric oxide synthase (NOS) (Taub et al 1993 Urology, 42, 698-704). It is believed that reducing the tone of the body smooth muscle can help NOT induce the relaxation of the corpora cavernosa. During sexual arousal in man, NO is released from neurons and endothelium and binds to, and activates, soluble guanylate cyclase (sGC) located in smooth muscle cells and the endothelium, which leads to an elevation of intracellular 3 ', 5'-cyclic monophosphate (cGMP) guanosine levels. This increase in cGMP leads to a relaxation of the corpora cavernosa due to a reduction in the intracellular concentration of calcium ([Ca2 +] i), through unknown mechanisms that are believed to involve the activation of protein kinase G (possibly due to the activation of bombs from Ca2 + and K + channels activated by Ca2 +).

Multiple potential sites have been identified within the central nervous system for the modulation of sexual behavior. It is believed that the key neurotransmitters are serotonin, norepinephrine, oxytocin, nitric oxide, dopamine and melanocortin, for example alpha-melanocyte stimulating hormone. By mimicking the actions of one of these key neurotransmitters, sexual function can be adjusted.

Melanocortins are peptides derived from pro-opiomelanocortins (POMC) that bind to and activate G-protein coupled receptors (GPCRs) of the melanocortin receptor family. Melanocortins regulate a diverse variety of physiological processes including sexual function and sexual behavior, food consumption and metabolism.

There are five melanocortin receptors that have been cloned, MCR1, MCR2, MCR3, MCR4, MCR5, and are expressed in various tissues. MRC1 is specifically expressed in melanocytes and melanoma cells, MCR2 is the ACTH receptor and is expressed in adrenal tissue, MCR3 is predominantly expressed in the brain and limbic system, MCR4 is widely expressed in the brain and spinal cord and MCR5 is Expresses in the brain and many peripheral tissues including skin, adipose tissue, skeletal muscle and lymphoid tissue. MCR3 may be involved in the control of sexual function, food consumption and thermogenesis. Activation of MCR4 has been shown to induce penile erection in rodents and it has been shown 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). Wessela et al describe the effects of Melanotan II (MT II), a non-selective melanocortin receptor agonist, in human subjects with erectile dysfunction (ED). MT II was administered to 20 organic and psychogenic ED men using a double-blind, placebo-controlled cross design. The stiffness of the penis was controlled for 6 hours using RigiScan. The level of sexual desire and side effects were indicated with a questionnaire. In the absence of sexual stimulation, Melanotan II led to penile erection in 17 of 20 men. The subjects experienced a mean rigidity of the RigiScan end of 41 minutes> 80%. An increase in sexual desire was indicated after 13/19 (68%) of MT II doses versus 4/21 (19%) of placebo (P <0.01). Nausea and yawning were frequently indicated as side effects due to MT II; At a dose of 0.025 mg / kg, 12.9% of the subjects had severe nausea. The 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.

It is proposed herein that a selective MCR4 agonist can be administered orally (including oral or sublingual administration) and will be effective in the treatment of female sexual dysfunction or male erectile dysfunction but will be devoid of significant adverse side effects such as those observed. by Wessels et al, that is, a selective agent will be better tolerated.

Palatin PT-141 is another synthetic peptide analog of alpha-MSH. It is an agonist in melanocortin receptors including MC3R and MC4R. Molinoff et al (Ann N.Y. Acad. Sci. (2003), 994, 96-102) describe as “the administration of PT-141 to non-human rats and primates results in penile erections. Systemic administration of PT-141 to rats activates neurons in the hypothalamus as shown by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system pick up pseudorabies virus injected into the cavernous body of the rat's penis. The administration of PT-141 (intranasally and subcutaneously) to normal men and to 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. documents. 5,576,290, U.S. 6,579,968 and U.S. 2002 / 0107.182A1. In addition, peptides such as MT-II or PT-141 are extensively metabolized in the intestine and as such are more efficiently administered parenterally, such as subcutaneously, intravenously, intranasally or intramuscularly, since it is not absorbed into the systemic circulation. when supplied orally.

Therefore, it would be desirable to develop MCR4 agonist compounds for the treatment of female and male sexual dysfunctions suitable for oral delivery (including oral or sublingual administration) and to reduce or overcome undesirable side effects such as nausea.

It is proposed herein that selective MCR4 agonists in accordance with the present invention will present oral bioavailability and as such may be additionally administered orally (including oral or sublingual administration).

There have been several reports illustrating that selective MCR4 agonists increase erectile activity in rats (Martin et al, 2002, Eur J Pharmacol., 454 (1), 71-79; Van Der Ploeg et al, 2002, Proc. Natl Acad. Sci. USA., 99 (17), 11381-11386). An example of an MCR4 agonist used in these studies is N - [(3R) -1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl] - (1R) -1- (4-chlorobenzyl) -2- [4 -cyclohexyl-4- (1H-1,2,4-triazol1-ylmethyl) piperidin-1-yl] -2-oxoethylamine (1), which is a selective potent melanocortin subtype 4 receptor agonist (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 behavior of lordosis in female rats after their injection into the ventromedial nucleus of the brain. In addition, they showed that HS014 (a potential MCR4 antagonist, Vergoni 1998, Eur. J. Pharmacol. 362 (2-3), 95-101) dose-dependently blocks the prosexual effect of alpha-MSH in lordosis in female rats . Procedures for stimulating the sexual response in females using various melanotropic peptides (similar to MT II) have been disclosed in U.S. document. 6,051,555.

In essence, MCR4 is an initiator of male and female sexual behavior. Accordingly, the present invention enables 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 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 PDE5 inhibitor / selective MCR4 agonist. Soft, moderate and severe MED will be terms known to the person skilled in the art, but guidelines can be found in The Journal of Urology, vol. 151, 54-61 (Jan 1994).

Early research suggests that the groups of patients with MED mentioned below would benefit from treatment with a selective MCR4 agonist and / or a PDE5i (or other combination set forth below in this document). These patient groups, which are described in more detail in Clinical Andrology vol. 23, number 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 as follows: psychogenic, organic, vascular, endocrinological, neurogenic, arteriogenic sexual dysfunction , drug-induced (lactogenic) and sexual dysfunction related to cavernous factors, particularly venogenic causes.

Accordingly, the present invention provides the use of a compound of formula I in the preparation of a medicament in combination with PDE5 inhibitor for the treatment of male erectile dysfunction.

Suitable PDE5 inhibitors are described herein 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 her sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, SR (1998) - Definition and classification of female sexual disorders. Int. J. Impotence Res., 10, S104-S106; Berman, JR, Berman, L. & Goldstein, I. (1999) - Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options (Urology, 54, 385-391). The woman may have a lack of desire, difficulty with arousal or orgasm, relationship pain or a combination of these problems. Various types of illnesses, medications, injuries or psychological problems can cause FSD. Developing treatments are aimed at treating specific subtypes of FSD, predominantly disorders of desire and excitement.

The categories of FSD 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. Impotence Res., 10, S104-S106). Desire or libido is the impulse of sexual expression. Its manifestations often include sexual thoughts when in the company of an interested couple or when exposed to other erotic stimuli. Arousal is the vascular response to sexual stimulation, an important component of which is genital dilation and includes increased vaginal lubrication, elongation of the vagina and increased genital sensation / sensitivity. Orgasm is the release of sexual tension that has culminated during arousal.

Therefore, FSD occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, excitement or orgasm. The categories of FSD include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders. Although the compounds of the invention can improve the genital response to sexual stimulation (as in the disorder of female sexual arousal), doing so can also improve the associated pain, distress and discomfort associated with the relationship and thus treat other sexual disorders. Feminine

Hypoactive sexual desire disorder occurs if a woman has little or no sexual desire and has few or no sexual thoughts or fantasies. This type of FSD may be caused by low testosterone levels due to natural menopause or surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterized by an inappropriate 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 the relationship is painful. Orgasms can be prevented. The excitation disorder can be caused by a reduction in estrogen in menopause or after childbirth and during breastfeeding, as well as diseases, with vascular components such as diabetes and atherosclerosis. Other causes result 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 pain resulting from penetration and can be caused by medications that reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and urinary tract problems.

As discussed above, MCR4 is believed to be an initiator of sexual behavior. The clitoris is considered to be a homolog of the penis (Levin, R.J. (1991), Exp. Clin. Endocrinol., 98, 61-69); The same mechanism that provides an erectile response in men causes an increase in genital blood flow in women with an associated effect after FSD. In addition there are changes in proceptivity and receptivity (lordosis).

Therefore, according to a preferred aspect of the invention, the use of a compound of formula is provided

(I) in the preparation of a medicament for the treatment or prophylaxis of female sexual dysfunction, more particularly hypoactive sexual desire disorder, 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 female sexual arousal disorder and joint hypoactive sexual desire disorder.

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines female sexual arousal disorder (FSAD) as:

"... a persistent or recurring inability to obtain or maintain until the completion of sexual activity an adequate lubrication-swelling response to sexual arousal. The disturbance should cause a significant interpersonal distress or difficulty ....".

The excitation response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disturbance causes significant distress and / or interpersonal difficulty.

FSAD is a highly prevalent sexual disorder that affects pre, peri and post menopausal women (± hormone replacement therapy (HRT)). It is associated with joint disorders such as depression, cardiovascular diseases, diabetes and urogenital disorders (UG).

The main consequences of FSAD are lack of dilation / swelling, lack of lubrication and lack of pleasant genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during the relationship and difficulty in achieving an orgasm.

The hypothesis has recently been presented that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein et al, Int J. Impot. Res., 10, S84-S90, 1998) with data on animals that support this vision (Park et al., Int J. Impot. Res., 9, 27-37, 1997).

R.J. Levin teaches us that because "... the male and female genitals develop embryologically from the common tissue principle, [that] male and female genital structures are considered homologous to each other. Therefore the clitoris is the homologue of the penis and homologous lips of the scrotal sac .... "(Levin, RJ (1991), Exp. Clin. Endocrinol., 98, 61-69).

The drug candidates for FSAD treatment, which are under investigation regarding efficacy, are primarily erectile dysfunction therapies that promote circulation to the male genitals.

The compounds of the present invention are advantageous by providing a means for restoring a normal sexual arousal response, namely increased genital blood flow that leads to vaginal, clitoral and labial dilation. This will result in increased vaginal lubrication through plasma transudation, increased vaginal compliance and increased genital sensitivity. Therefore, the present invention provides a means to restore or enhance the normal sexual arousal response.

Therefore, according to a preferred aspect of the invention, the use of a compound of formula is provided

(I) in the preparation of a medicament for the treatment or prophylaxis of female sexual arousal disorder.

By female genitals herein the authors of the invention understand: "the genital organs consist of an internal and external group. The internal organs are located inside the pelvis and consist of ovaries, uterine tubes, uterus and vagina. The external organs are superficial to the urogenital diaphragm and are below the pelvic arch. They include the pubic mount, the major and minor lips, the clitoris, the vestibule, the vestibular bulb and the major vestibular glands ”(Gray’s Anatomy, C.D. Clemente, 13th American Edition). The compounds of the invention have their application in the following subpopulations of patients with FSD: young, elderly, premenopausal, perimenopausal, postmenopausal women with or without hormone replacement therapy.

The compounds of the invention have their application in patients with FSD arising from:

i) vasculogenic etiologies for example cardiovascular or atherosclerotic diseases, hypercholesterolemia, smoking, diabetes, hypertension, radiation and perineal trauma, traumatic injury to the iliohypogastric pudendal vascular system; ii) neurogenic etiologies such as spinal cord injuries or diseases of the central nervous system including multiple sclerosis, diabetes, Parkinson's disease, strokes, peripheral neuropathies, trauma or radical pelvic surgery; iii) hormonal / endocrine etiologies such as hypothalamic / pituitary / gonadal axis dysfunction or ovarian dysfunction, pancreas dysfunction, surgical or medical castration, androgen deficiency, high levels of prolactin circulation, for example, hyperprolactinemia, natural menopause, premature ovarian insufficiency, hyper and hypothyroidism; iv) psychogenic etiologies such as depression, obsessive compulsive disorder, anxiety disorder, postpartum depression / "maternity melancholy", emotional and relational problems, performance anxiety, marital discord, dysfunctional attitudes, sexual phobias, religious inhibition or past traumatic experiences ; and / or v) drug-induced sexual dysfunction resulting from therapy with selective serotonin reuptake inhibitors (SSRi) and other antidepressant therapies (tricyclics and major tranquilizers), antihypertensive therapies, sympatholytic drugs, chronic oral contraceptive pill therapy.

The compounds of the present invention can be supplied 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 natruretic factors in particular atrial natruretic factor (also known as atrial natruretic peptide), type B and type C natruretic factors such as neutral endopeptidase inhibitors 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 02/079143, acid (2S) -2 {[1- {3-4 (-chlorophenyl) propyl] amino} carbonyl) -cyclopentyl] methyl} -4-methoxybutanoic; 2) Compounds that inhibit angiotensin converting enzyme such as enapril and combined angiotensin converting enzyme and neutral endopeptidase inhibitors such as omapatrilat; 3) Substrates for NO-synthase, such as L-arginine; 4) Cholesterol reducing agents such as statins (for example, atorvastatin / Lipitor-registered trademark) and fibrates; 5) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene, (-) - cis-6-phenyl-5- [4- (2-pyrrolidin-1-yl-ethoxy ) -phenyl] -5,6,7,8-tetrahydronaphthalene-2-ol and pharmaceutically acceptable salts thereof, the preparation of which is detailed in WO 96/21656; 6) A PDE inhibitor, more particularly a PDE 2, 3, 4, 5, 7 or 8 inhibitor, preferably PDE2 or PDE5 inhibitor and more preferably a PDE5 inhibitor (see later herein), said inhibitors having preferably an IC50 against the respective enzyme of less than 100 nM (provided that the PDE3 and PDE4 inhibitors are administered only topically or by injection into the penis); 7) Vasoactive intestinal protein (VIP), VIP mimetic, VIP analogue, more particularly mediated by one

or more of the VIP receptor subtypes, VPAC1, VPAC or PACAP (pituitary adenylate cyclase activating peptide), one or more of a VIP receptor agonist or a VIP analog (for example, Ro-125-1553) or a

VIP fragment, one or more of an α adrenoceptor antagonist with VIP combination (for example, Invicorp, Aviptadil); 8) An agonist, antagonist, or serotonin receptor modulator, more particularly agonists, antagonists or modulators for 5HT1A (including VML 670 (WO02 / 074288) and flibanserin [US2003 / 0104980]), 5HT2A, 5HT2C, 5HT3 and / or 5HT6 receivers, including those described in WO-09902159, WO-00002550 and / or WO-00028993; 9) A testosterone replacement agent (including dehydroandrostenedione), testosterone (for example, Tostrelle, LibiGel), dihydrotestosterone or a testosterone implant; 10) Selective androgen receptor modulators for example LGD-2226; 11) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and methyl testosterone hormone replacement therapy agent (for example, HRT especially Premarin, Cenestin, Oestrofeminal, Equin, Estrace, Estrofem, Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestrilo, Premphase, Preempro, Prempak, Premique, Estratest, Estratest HS, Tibolone); 12) A transport modulator for norepinephrine, dopamine and / or serotonin, such as bupropion, GW-320659; 13) An agonist or modulator for oxytocin / vasopressin receptors, preferably a modulating agonist of selective oxytocin; Y 14) An agonist or modulator for dopamine receptors, preferably an agonist or selective modulator of D3 or D4 for example apomorphine.

Combinations of the compounds of the present invention and one or more additional therapeutic agents selected from: PDE5 inhibitors are preferred herein; NEP inhibitors; selective agonists or modulators of D3 or D4; estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists; testosterone replacement agents, testosterone or a testosterone implant; estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) or estrogen and hormone testosterone replacement therapy agent.

Combinations of the compounds of the present invention and one or more PDE5 inhibitors and / or NEP inhibitors are preferred combinations for the treatment of MED.

Preferred combinations for the treatment of FSD are combinations of the compounds of the present invention and PDE5 inhibitors and / or NEP inhibitors and / or selective D3 or Dr4 agonists or modulators and / or estrogen receptor modulators, estrogen agonists, estrogen antagonists and / or testosterone, testosterone, testosterone and / or estrogen, estrogen and medroxyprogesterone implants

or medroxyprogesterone acetate (MPA), estrogen and methyl testosterone hormone replacement therapy agent.

Particularly preferred PDE5 inhibitors are for such combined products for the treatment of MED or FSD sildenafil, tadalafil, vardenafil and 5- [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.

Particularly preferred NEP inhibitors for such combination products for the treatment of MED or FSD are the compounds exemplified in WO 02/079143.

Preferred combination products herein are for the treatment of MED or FSD: a combination of sildenafil, tadalafil, vardenafil or 5- [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 herein; and / or a combination of any of the compounds exemplified in WO 02/079143 with the compound of Example 1 herein.

By cross-reference herein to compounds contained in patents and patent applications that can be used in accordance with the invention, the inventors understand therapeutically active compounds as defined in the claims (in particular of claim 1) and specific examples (all of which are incorporated herein by reference).

If a combination of active agents is administered, then these can be administered simultaneously, separately or sequentially.

Auxiliary Agents - PDE5 Inhibitors

Particularly preferred herein are auxiliary active agents PDE5 inhibitors.

The suitability of any particular cGMP PDE5 inhibitor can easily be determined by evaluation of its potency and selectivity using literature procedures followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with conventional pharmaceutical practice.

IC50 values for cGMP PDE5 inhibitors can be determined using the PDE5 assay (see later here).

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 against PDE3, more preferably against PDE3 and PDE4. Preferably (when they are oral), the cGMP PDE5 inhibitors of the invention have a selectivity ratio greater than 100, more preferably greater than 300, against PDE3 and more preferably against PDE3 and PDE4.

The selectivity ratios can be easily determined by the person skilled in the art. The IC50 values for the PDE3 and PDE4 enzyme can be determined using methodology established in the literature, see S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171 and as detailed later in this document.

PDE5 inhibitors of cGMP suitable for use in accordance with the present invention include:

(i)

5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-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-methylpiperazine (see EP-A-0463756);

(ii)

5- (2-Ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see EP-A -0526004);

(iii) 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenyl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one (see WO98 / 49166);

(iv)

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro- 7H-pyre zolo [4,3-d] pyrimidin-7-one (see WO99 / 54333);

(v)

(+) - 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) 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 - ([(1R) - 2-methoxy-1-methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazol or [4,3-d] pyrimidin-7-one (see WO99 / 54333 );

(saw)

5- [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, 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-ethylpiper azine (see WO 01/27113, Example 8);

(vii) 5- [2-iso-Butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1 methylpiperidin-4-yl) -2,6-dihydro -7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15);

(viii) 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7one (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-d] 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] pyrido [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 compound of 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-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] -as -triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine, ie the compound of examples 20, 19, 337 and 336 of published international application WO99 / 24433;

(xiii) the pyrazolo [4,3-d] pyrimidin-4-ones disclosed in WO00 / 27848, in particular N - [[3- (4,7-dihydro-1-methyl-7-oxo-3- propyl-1H-pyrazolo [4,3-d] -pyrimidin-5-yl) -4propoxyphenyl] sulfonyl] -1-methyl2-pyrrolidi npropanamide [DA-8159 (Example 68 of WO00 / 27848)];

(xiv) the compound of example 11 of published international application WO93 / 07124;

(xv) 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline; Y

(xvi) 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H-imidazo [4,5-g] quinazoline;

(xvii) 1- [3- [1 - [(4-fluorophenyl) methyl] -7,8-dihydro-8-oxo-1H-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-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one; Y

(xix) 1- {6-ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3d] pyrimidin-5-yl] - 3-pyridylsulfonyl} -4-ethylpiperazine; and pharmaceutically acceptable salts and solvates thereof.

The suitability of any particular PDE5 inhibitor can easily be determined by evaluation of its potency and selectivity using literature procedures followed by the evaluation of its toxicity, absorption, metabolism, pharmacokinetics, etc. in accordance with conventional pharmaceutical practice.

Preferably PDE5 inhibitors have an IC50 at less than 100 nmolar, more preferably, less than 50 nmolar, even more preferably less than 10 nmolar.

Preferably the PDE5 inhibitors used in the pharmaceutical combinations according to the present invention are selective for the PDE5 enzyme. They preferably have a selectivity of PDE5 against PDE3 of more than 100, more preferably more than 300. More preferably the PDE5 inhibitor has a selectivity against both PDE3 and PDE4 of more than 100, more preferably greater than 300. The selectivity ratios. they can be easily determined by the person skilled in the art from the relevant IC50 values. The IC50 values for the PDE3 and PDE4 enzyme can be determined using methodology established in the literature, such as the procedure described in S A Ballard et al, Journal of Urology, 1998, vol. 159, pages 2164-2171. The IC50 values for the PDE5 enzyme can be determined using methodology established in the literature and as described in WO 01/27113.

Pro Sexual Data in vivo

The in vivo MCR4 data for the compound of Example 1 was evaluated by selective activation of MCR4 melanocortin receptors using the methodology that evaluates the erection of the spontaneous penis in the conscious rat.

Erectile responses were recorded by measuring intracavernous pressure using a surgically implanted telemetric device (TA11 PA-C40, 8mm catheter, modified 3mm tip, available from Data Sciences International Inc.). An increase in intracavernous pressure is indicative of penile erection, since an increase in intracavernous pressure is an essential hemodynamic event during the onset and maintenance of penile erection. Specific details of the surgical procedures, data acquisition and analysis used herein to measure increases in intracavernous pressure can be found in detail in Bernabe J., Rampin O., Sachs BD, Giuliano F., "Intracavernous pressure during erection in 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 measurement of erectile function. Prior to administration of the test agent the baseline erectile activity (B) was evaluated for the vehicle for 10 minutes using intracavernous pressure telemetric recording. After subcutaneous administration of the compound of Example 1 (in the same vehicle), penile erections (using telemetric intracavernous pressure recording) were evaluated for periods of 10 minutes, at intervals of 30, 60 and 90 minutes after dosing .

The compound of Example 1 produced a dose-dependent increase in the number of penile erections when dosed at a level of 1-100 µg / kg subcutaneously (s.c.). (See Figures 1 and 2). Animals treated with vehicle / baseline measure showed minimal erectile activity (see Figure 1). Figure 1 illustrates the results of preliminary studies and compares the number of erections observed over a period of 10 minutes beginning at 60 minutes after dosing for animals dosed with 1, 10 and 100 µg / kg s.c. of the compound of Example 1 with the basal erectile activity (B). The data in Figure 1 illustrates that at all doses tested the compound of Example 1 increases erectile activity versus basal erectile activity (B). Additionally, Figure 1 illustrates that the compound of Example 1 dose-dependently increased the number of spontaneous erections in the conscious rat. The maximum effective dose observed in this preliminary study was 1 µg / kg s.c.

Figure 2 illustrates the results of an additional, more detailed study, and compares the number of erections observed over a period of 10 minutes beginning at 30 minutes after dosing for animals dosed with 1, 10 and 100 µg / kg s.c. of the compound of Example 1 with the basal erectile activity (treatment vehicle). The data in Figure 2 illustrates that at all doses tested the compound of Example 1 increases erectile activity versus basal erectile activity (treatment vehicle). In addition, Figure 2 illustrates that the compound of Example 1 dose-dependently increased the number of spontaneous erections in the conscious rat. The maximum effective dose observed in this additional, more detailed 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 additional, more detailed 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 dose levels. The same conclusion, that the compound of Example 1 increased in a dose-dependent manner the number of spontaneous erections in the conscious rat, can be concluded independently from both of these studies. It is proposed in this document that the difference observed between the preliminary and more detailed study with respect to the dose at which the maximum effect was 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 herein that selective MCR4 agonists in accordance with the present invention can provide opportunity to treat male erectile dysfunction.

Test

Stimulation of adenylate cyclase after receptor activation is a widely used measure of functional activity for various receptor systems. The functional assay to measure 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 that is measured using AlphaScreenTM (PerkinElmer) assay kits.

The AlphaScreenTM cAMP test kit consists of "donor beads", "acceptor beads" and biotinylated cAMP that binds the different beads together. The excitation of this complex bound at 680 nm in the FusionTM-α microplate analyzer results in light emission between 520 and 620 nm.

The cAMP generated in the assay competes with the biotinylated cAMP for binding sites in the acceptor beads, preventing the binding of the "donor" and "acceptor" beads and thereby reducing the emission of light.

Conventional functional test methodology of MCR1, MCR3 and MCR4 [TEST PROTOCOL A, B AND C RESPECTIVELY]

TEST CONCEPT

The activity against the human receptor subtypes MCR1, MCR3 and MCR4 was determined for compounds according to the present invention using three immortalized human embryonic kidney (HEK) cell lines that had been genetically engineered to express the subtypes of human melacortin receptors MCR1, MCR3 and MCR4. These cell lines were obtained by genetic engineering 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 and MCR4 receptors leads to stimulation of the cellular enzyme adenylate cyclase, which in turn leads to cell generation and intracellular accumulation of cyclic adenosine monophosphate (cAMP). It was found that the magnitude of these increases in intracellular cAMP was proportional to the degree to which the test compound activated the MCR1, MCR3 or MCR4 receptors present in these cell lines. Intracellular cAMP levels were quantified using commercially available test kits AlphaScreenTM from PerkinElmer. A detailed test protocol and an explanation of the concept underlying this kit are available through the PerkinElmer website (www.perkinelmer.com). The protocol listed below provides a summary of this information.

The amount of intracellular cAMP produced by compound-induced activation of the MCR1, MCR3 and MCR4 receptors in these three cell lines was measured using a FusionTM-α microplate analyzer adjusted to stimulate a wavelength of 680 nm and to measure energy emitted at wavelengths between 520 and 620 nm. Increases induced by compound in activation of MCR1, MCR3 or MCR4 receptor were subsequently quantified as a reduction in the amount of light emitted at wavelengths between 520 and 620 nm. Data analysis was subsequently performed using a curve fit program and the apparent potency of the test compound (expressed as an EC50 and defined as the concentration of effective compound that induced 50% of the maximum compound-induced response) was extrapolated to from the adjusted curve.

MATERIALS

From PerkinElmer: AlphaScreenTM cAMP test kit, Cat No. 6760600M, FusionTM-α microplate analyzer (adjusted to stimulate a wavelength of 680 nm and to record emitted light at wavelengths between 520 and 620 nm).

From Invitrogen: Phosphate buffered saline (PBS) (without Ca2 + or Mg2 +), Cat No. 14190-094; Dulbecco-modified Eagle's medium (DMEM) high in glucose, Cat No. 21969-035; Hank's balanced salt solution (HBSS), Cat No. 14065-049; Geneticina, Cat Nº 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; Cellular dissociation solution fluid, Cat No. C5914; Dimethyl sulfoxide (DMSO), Cat No. D8418; Adenosine monophosphate cyclic (cAMP), Cat No. A9501; 3-Isobutyl-1-methylxanthine (IBMX), Cat No. I5879; 1M magnesium chloride (MgCl2) solution, Cat No. M1028; Trypan blue, Cat No. T-8154, Chamber cell count (Bright-line 35,962-9).

From PAA laboratories GmbH: fetal calf serum (FCS), Cat No. A15-043.

From Gilson: pipettes that vary from 10 µl to 1,000 µl.

From Hereaus; CO2 Cell incubator Hera Cell.

From Medical Air Technology; BioMat2 class II microbiological safety cabinet.

From Bachem: αα-MSH Melanocyte Stimulating Hormone, Cat No. H1075, used as a positive control.

STAMPS

Stimulation buffer (according to the AlphaSreenTM protocol): HBSS supplemented with 0.5 mM IBMS, 5 mM HEPES, 0.1% BSA (w / v) and 10 mM MgCl2.

Lysis buffer (according to the AlphaSreenTM protocol): 5 mM HEPES solution supplemented with 0.1% BSA (w / v) and 0.3% Tween-20 (v / v).

Detection mixture (according to the AlphaSreenTM protocol): lysis buffer supplemented with biotinylated cAMP (10 nM) and Donor beads (10 µg / ml) as provided in the AlphaSreenTM cAMP test kit.

CONSUMABLES

From Fisher: 384-well surface plates without joint, Cat No. DPS-172.020Q.

Cost: Sterile pipettes of volumes from 2 to 50 ml, sterile tips from P10 to P1,000; Sterile deposits, Cat No. 4878; T225 flask opening lid, Cat No. 3001.

COMPOUND PREPARATION

For the Conventional functional test methodologies of MCR1, MCR3 and MCR4 the compounds were initially dissolved in DMSO to provide a concentration of 4 mM compound and then further diluted for stimulation buffer testing to provide real concentrations twice as large as the desired as the final test concentration.

DAILY CELL CULTURE

The three HEK cell lines, as detailed above herein, expressing the subtypes of human receptor MCR1, MCR3 or MCR4 were grown in stopper flasks with T225 opening containing 50 ml of growth medium (DMEM supplemented with FCS 10% (v / v), 2 mM L-Glutamine, 25 mM HEPES and 1.0 mg / ml Geneticin) and were kept in a cell incubator at a temperature of 37 ° C and in an environment containing 5% CO2. The cells were collected when they reached 80-90% confluence by first removing the existing growth medium and then washing with PBS that had been preheated to a temperature of 37 ° C. This PBS was then 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 environment containing 5% CO2 to separate the cells. The cells were dislodged 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 resuspended and mixed gently to achieve a simple cell suspension by pipetting. This cell suspension was then counted using a cell count chamber and used for experimentation or transferred to a new T225 flask to perpetuate cell culture.

TEST PROCEDURE

The test procedure used was essentially as described in the AlphaSreenTM kit methodology (www.perkinelmer.com), however, to facilitate liquid handling all test volumes were doubled.

First, 10 µl of the test compound solutions were transferred to the test plate 384 surface wells without binding.

Second, the test cells were collected as described above.

(i)

For the conventional functional test methodology of MCR1, a cell suspension at 3x105 cells / ml was prepared in stimulation buffer (supplemented with 10 µl / ml of the solution of anti-cAMP acceptor beads provided in the AlphaSreenTM cAMP test kit) ;

(ii)

For the conventional functional test methodology of MCR3, a cell suspension was prepared at 5x104 cells / ml in stimulation buffer (supplemented with 10 µl / ml of the solution of anti-cAMP acceptor beads provided in the AlphaSreenTM cAMP test kit) ; Y

(iii) For the conventional functional test methodology of MCR4, a cell suspension at 1x105 cells / ml was prepared in stimulation buffer (supplemented with 10 µl / ml of the solution of anti-cAMP acceptor beads provided in the test kit CAMP AlphaSreenTM).

Subsequently, 10 µl of the cell suspensions were transferred to each well of the 384-well surface plate without binding. The test plates were then incubated in the dark at room temperature for 30 minutes.

Third, the test reaction was terminated by the addition of 30 µl per well of detection mixture. The palcas were incubated overnight in the dark at room temperature before transferring them to the FusionTM-α microplate analyzer for quantification.

(ii) MCR5 CONVENTIONAL FUNCTIONAL TEST METHODOLOGY AND MCR4 IMPROVED FUNCTIONAL TEST METHODOLOGY [TEST PROTOCOL D AND E RESPECTIVELY]

TEST CONCEPT

The determination of compound activity against the subtype of the human MCR5 receptor was carried out using an immortalized Chimo hamster ovary cell line (CHO-K1) that had been engineered to stably express both the recombinant human MCR5 receptor as a β-lactamase reporter gene (CHO-K1-MCR5-CRE-β-lactamase). Similarly, using an improved assay methodology, the activity of the compounds against the human MCR4 receptor subtype was also determined using an immortalized CHO-K1 cell line that had been engineered to stably express both the human MCR4 receptor recombinant as a gene indicator of β-lactamase (CHO-K1-MC4R-CRE-β-lactamase). These cell lines were genetically engineered using protocols similar to those described by Zaccolo et al (Zaccolo, M., (2000) Nature, 2 (1); 25-29).

Compound-induced activation of the MCR5 or MCR4 receptors in these two cell lines stimulated intracellular production and 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 commercially available from Invitrogen Life Technologies. An in-depth description of this technology and test protocols is available from the Invitrogen website (www.invitrogen.com). The protocol listed below provides a summary of that test methodology.

The amount of β-lactamase enzyme produced by compound-induced activation of the MCR4 or MCR5 receptors expressed in these cell lines was quantified using an Ljl Biosystems AnalystTM HT plate reader.

96,384 adjusted to excite a wavelength of 405 nm and measure the energy emitted at wavelengths of 450 nm and 530 nm. 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. Data analysis was subsequently performed using a curve fit program and the apparent potency of the test compound (expressed as an EC50 and defined as the concentration of effective compound that induced 50% of the response induced by maximum compound) was extrapolated from the tight curve.

MATERIALS

From Invitrogen: Dulbecco's Modified Eagle Medium (DMEM) with Glutamax-1, Cat No. 32430-027; Non-essential amino acids, Cat No. 1140-0.35; Geneticina (G418), Cat Nº 10131-027; Cellular dissociation buffer (based on PBS without enzymes), Cat No. 13151-014; Phosphate buffered saline (PBS) (without Ca2 + or Mg2 +), Cat No. 14190-094; CCF4-AM, Cat No. K 1028; Pluronic Solution F 127s (Solution B), Cat No. K 1026N; 24% PEG solution and 18% TR40 (Solution C), Cat No. K1026N; Zeocina, Cat No. R250-05.

From Sigma: Fetal Calf Serum (FCS), Cat No. F7524; sodium pyruvate, Cat No. S8636; N- (2-Hydroxyethyl) piperazin-N ’- (2-ethanesulfonic acid) (HEPES), Cat No. H0887; Dimethyl sulfoxide (DMSO), Cat No. D-8418; Cyclohexamide, Cat No. C-7698; Trypan 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 that vary from 10 µl to 1,000 µl.

From Hereaus; Hera Cell CO2 cell incubator.

From Medical Air Technology; BioMat2 Class II Microbiological safety cabinet.

From Ljl Biosystems; AnalysTM HT 96.384 plate reader set to excite at a wavelength of 405 nm and measure the energy emitted at wavelengths of 450 nm and 530 nm.

From Bachem: αα-MSH Melanocyte Stimulating Hormone, Cat No. H1075, used as a positive control compound.

STAMPS

CCF4-AM was dissolved in 100% DMSO to provide a final solution concentration of 1 mM. This solution was called Solution A.

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

Probenecid was dissolved in 200 mM NaOH to provide a final solution concentration of 200 mM. This solution was called Solution D.

Composition of the β-lactamase test dye solution: for 1,072 µl of test dye solution combine: 12 µl of Solution A, 60 µl of Solution B, 925 µl of Solution C and 75 µl of Solution D.

CONSUMABLES

De Greiner: 384-well black transparent bottom microplate test plates, Cat No. 781091.

From Coster Sterile Pipettes from 2 to 50 ml volume, sterile tips from P10 to P1,000; Sterile deposits, Cat No. 4878; T225 flask opening caps, Cat No. 3001.

COMPOUND PREPARATION

For the methodology of the conventional functional test of MCR5 all test compounds were initially dissolved in DMSO to provide a concentration of 4 mM compound and then further diluted for testing in PBS, which contained 1.25% v / v DMSO and BSA 0.1% w / v, to provide real concentrations 5 times higher than desired as the final test concentration.

For the methodology of the enhanced functional test of MCR4 all test compounds were initially dissolved in DMSO to provide a concentration of 4 mM compound and then further diluted for testing in PBS, containing 2.5% v / v and pluronic DMSO F-127 0.05% w / v, to provide real concentrations 5 times greater than desired as the final test concentration.

DAILY CELL CULTURE

The cells were grown in T225 opening flask flasks containing 50 ml of growth medium and kept in a cell incubator at a temperature of 37 ° C and in an environment containing 5% CO2. The composition of the growth medium for CHO-K1-MC5R-CRE-β-lactamase was 90% v / v 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-K1-MC4R-CRE-β-lactamase this growth medium was further supplemented with Zeocin 200 µg / ml. The cells were collected when they reached 80-90% confluence by first removing the existing growth medium and then washing with PBS that had been preheated to a temperature of 37 ° C. This PBS was then removed and 5 ml of cell dissociation fluid 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 environment containing 5% CO2 to separate the cells. When the cells were separated, preheated growth medium was added, the cells were resuspended and mixed gently to achieve a simple cell suspension by pipetting. This cell suspension was then used for experimentation or transferred to a new T225 flask to perpetuate cell culture.

TEST PROCEDURE

On the first day of the test the cells were collected as described above. For the conventional functional assay methodology of MCR5, a cell suspension was prepared at 3.33x105 cells / ml in modified growth medium, containing 1% FCS instead of 10%, and 30 µl of this cell suspension was added to each well of a 384-well black transparent bottom microplate test plate of Greiner.

For the improved functional assay methodology of MCR4 a cell suspension was prepared at 2x105 cells / ml in modified growth medium, containing 5% FCS instead of 10%, and 40 µl of that cell suspension was added to each well of a 384 well Greiner black transparent bottom microplate test plate.

For each test the cell plates were then returned to a cell incubator maintained at a temperature of 37 ° C and in an environment containing 5% CO2 overnight before performing the test on the second day of the test.

On the second day of the test for the conventional functional test methodology of MCR5 the cell plate was removed from the cell incubator and 10 µl of a 5 µM cyclohexamine solution (prepared in PBS with 5% v / v DMSO) was added to each well of The test plate. For the improved functional assay methodology of MCR4 the cyclohexamide solution was not added. Subsequently, 10 µl of the test compound solution was transferred to the test plate. The test plate was then transferred to a cell incubator, set at 37 ° C and in an environment containing 5% CO2 and left for 4 hours for the improved MCR4 test methodology or 5 hours for the conventional test methodology. MCR5. After this incubation period the plate was removed from the incubator, 10 µl of the β-lactamase test dye 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 MCR4 assay methodology or 90 minutes for the conventional MCR5 assay methodology the plates were removed from the incubator and transferred to the Ljl Biosystems Analyst ™ H T 96,384 plate reader

for quantification

OBESITY

The compounds of the present invention can also be used together with pharmaceutical agents for the treatment of diseases, conditions and / or disorders related to obesity. Therefore, compositions (or medicaments) are also provided for use in the treatment of obesity that include compounds of the present invention in combination with anti-obesity agents. Suitable anti-obesity agents include cannabinoid 1 (CB-1) receptor antagonists (such as rimonabant), microsomal triglyceride transfer protein inhibitors / apoliprotein B secretion (apo-B / MTP) (in particular, MTP inhibitors selective bowel, such as edipatapide or dirlotapide), 11β-hydroxysteroid dehydrogenase-1 (11β-HSD type 1) inhibitors, YY3-36 peptide and analogues thereof, cholecystokinin-A agonists (CCK-A), inhibitors of monoamine reuptake (such as sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte stimulating hormone receptor analogs, 5HT2c receptor agonists, concentrating hormone antagonists of melanin, leptin (OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, 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 receptor antagonists of glucocorticoids, orexin receptor antagonists, glucagon 1 peptide receptor agonists, ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), inhibitors of human agouti-related protein (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like. Other anti-obesity agents, including the preferred agents set forth hereinbelow, are well known or will be readily apparent in light of the present disclosure, to a person skilled 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 commonly referred to as nutraceuticals and include, for example, garlic extract, Hoodia plant extracts and niacin.

Especially preferred are anti-obesity agents selected from the group consisting of CB-1 antagonists, selective MTP inhibitors of intestine, orlistat, sibutramine, 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 sensible diet.

Preferred CB-1 antagonists include Rimonabant (SR141716A also known by the trade name AcompliaTM available from Sanofi-Synthelabo) described in US Patent No. 5,624,941; and compounds described in U.S. Patent Nos. 5,747,524, 6,432,984 and 6,518,264; United States Patent Publications No. US2004 / 0092520, US2004 / 0157839, US2004 / 0214855 and US2004 / 0214838; U.S. Patent Application Serial 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 bowel MTP inhibitors include dirlotapide described in US 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-triazol-3 (4H) -one (R103757) described in US Pat. United States 5,521,186 and 5,929,075; and implitapide (BAY 13-9952) described in US 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 a person skilled in the art, for example; Sibutramine can be prepared as described in US Patent No. 4,929,629; Bromocriptine can be prepared as described in US Pat. Nos. 3,752,814 and 3,752,888; Orlistat can be prepared as described in US Pat. Nos. 5,274,143; 5,420,305;

5,540,917 and 5,643,874 and PYY3-36 (including analogs) can be prepared as described in US Publication No. 2002/0141985 and WO 03/027637.

Food consumption

The following scan can be used to evaluate the efficacy of test compounds to inhibit food consumption in Sprague-Dawley rats after an overnight fast.

Sprague-Dawley male rats can be obtained from Charles River Laboratories, Inc. (Wilmington, MA). The rats are housed individually and fed with powdered feed. They stay in a 12-hour light / dark cycle and receive food and water at will. The animals acclimatize to the vivarium for a period of one week before the test is carried out. The test is completed during the light part of the cycle.

To perform the efficacy scan of food consumption, the rats are transferred to individual test cages without food the evening before the test and the rats are fasted overnight. After the overnight fast, the rats are dosed the next morning with vehicle or test compounds. A known antagonist (3 mg / kg) is dosed as a positive control and a control group receives only vehicle (without compound). The test compounds are dosed at intervals 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 accommodate various compounds when required. Rats are fed 30 minutes after dosing and the Oxymax automatic food consumption system (Columbus Instruments, Columbus, Ohio) is started. Food consumption of individual rats is recorded continuously at 10 minute intervals over a period of two hours. When required, food consumption is recorded manually using an electronic scale; the food is weighed every 30 minutes after the food is provided up to four hours after the food is provided. The efficacy of the compound is determined by comparing the food consumption pattern of rats treated with compound with the vehicle and the conventional positive control.

Administration and Dosage Intervals

The compounds of formula (I) should be evaluated with respect to their biopharmaceutical properties, such as, for example, solubility, solution stability (over a pH range), probable dose level and permeability, to select dosage forms more appropriate and routes of administration considered appropriate for the treatment of the desired indication. Preliminary biopharmaceutical evaluations have indicated that some compounds according to the present invention may be especially suited for administration by the oral (including buccal and sublingual) or intranasal route. For example, the sublingual or intranasal oral route may be suitable for the compound of Examples 1 and 5, with 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.

Therefore according to a further embodiment the present invention provides a pharmaceutical composition comprising a compound of the general formula I as defined hereinbefore, preferably the compound of Examples 1 and 5, formulated for sublingual delivery.

The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. These can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporation drying. Microwave or radiofrequency drying can be used for this purpose.

They can be administered alone or in combination with one or more additional compounds of the invention or in combination with one or more additional drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound or compounds of the invention. The selection of excipient will depend largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability and the nature of the pharmaceutical form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and procedures for their preparation can be found, for example, in Remington’s Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995).

Any suitable route of administration can be employed to provide an effective dosage of a compound of the present invention to a mammal, especially a human being. For example, they can be used orally (including oral and sublingual administration), rectal, topical, parenteral, ocular, pulmonary, nasal and the like. Pharmaceutical forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably compounds of formula (I) are administered orally or intranasally.

The effective dosage of active ingredient used may vary depending on the particular compound employed, the mode of administration, the condition to be treated and the severity of the condition being treated. Said dosage can easily be determined by one skilled in the art.

Compounds of the present invention are provided for the treatment of sexual dysfunction in a dose range of from about 0.001 milligrams (mg) to about 1000 mg, preferably from about 0.001 mg to about 500 mg, more preferably from 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 mg per kilogram of body weight, preferably as 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 single or divided doses and may, at the discretion of the physician, be outside the typical range provided herein.

When treating obesity, together with diabetes and / or hyperglycemia, or only, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of about 0.0001 mg to about 1000 mg, preferably about 0.001 mg to about 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 body weight of the animal, preferably provided in a single dose or in divided doses two to six times at day or in the form of prolonged release. In the case of a 70 kg human adult, 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 it comes to 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 approximately 0.001 mg. up to about 100 mg per kilogram of the animal's body weight, preferably provided in a single dose or in divided doses two to six times a day or in a prolonged release form. In the case of a 70 kg human adult, the total daily dose will generally be from 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 that has a weight of approximately 65 kg to 70 kg. The doctor will be able to easily determine the doses for subjects whose weight falls outside this range, such as children and the elderly.

ORAL ADMINISTRATION

The compounds of the invention can be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract and / or oral, lingual or sublingual administration 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 filled with liquid); chewable tablets; gels; rapid dispersion pharmaceutical forms; films; ovules; sprays; and buccal / mucoadhesive patches.

Liquid formulations include suspensions, solutions, syrups and elixirs; such formulations can be used as fillers in soft or hard capsules (prepared, for example, from gelatin or hydroxypropyl methylcellulose) and typically comprise a vehicle, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid, for example, from a sachet, they can also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention can also be used in rapid dissolution, rapid disintegration pharmaceutical forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For pharmaceutical forms of tablets, depending on the dose, the drug may comprise from 1% by weight to 80% by weight of the pharmaceutical form, more typically from 5% by weight to 60% by weight of the pharmaceutical 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, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch starch and sodium starch. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the pharmaceutical form.

Binders are generally used to transmit cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydride and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

The tablets may also optionally comprise surfactants, such as sodium lauryl sulfate and polysorbate 80 and emollients such as silicon dioxide and talc. When present, the surfactants may comprise from 0.2% by weight to 5% by weight of the tablet and the emollients may comprise from 0.2% by weight to 1% by weight 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. Lubricants generally comprise 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 antioxidants, dyes, flavoring agents, preservatives and taste masking agents.

Exemplary tablets contain up to about 80% of 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 of disintegrant and from about 0.25% by weight to about 10% by weight of lubricant.

Tablet blends can be compressed directly or by roller to form tablets. The mixtures of tablets or portions of mixtures may alternatively be wet, dry or melt granulated, melt frozen or extruded before being compressed. The final formulation may comprise one or more layers and may be coated or uncoated; It may even be encapsulated.

The tablet formulation is analyzed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Consumable oral films for human or veterinary use are typically water soluble or water swellable thin film pharmaceutical forms that can dissolve rapidly or be 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, a viscosity modifying agent and a solvent. Some components of the formulation can perform more than one function.

The compound of formula I can be water soluble or insoluble. A water soluble compound typically comprises from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88% by weight of solutes. Alternatively, the compound of formula I may 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 antioxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, volume-forming agents, anti-foaming agents, surfactants and taste masking agents.

The films according to the invention are typically prepared by evaporation drying of thin aqueous films that are coated with a fractured support or paper. This can be done in a drying oven or tunnel, typically a combined coated dryer or by lyophilization or vacuum.

Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, pulse, controlled, directed and programmed release.

Modified release formulations suitable for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are found in Pharmaceutical Technology Online, 25 (2), 1-14 by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

PARENTERAL ADMINISTRATION

The compounds of the invention can also be administered directly into the bloodstream, into the muscle.

or in an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dry form for use in conjunction 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 compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as the incorporation of solubility enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, pulse, controlled, directed and programmed release. Therefore 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 modified release of the active compound. Examples of such formulations include drug-coated and semi-solid vascular stents and suspensions comprising drug-laden poly (dl-lactic-coglycolic acid) (PGLA) microspheres.

TOPICAL ADMINISTRATION

The compounds of the invention can also be administered topically, (intra) dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders for external use, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene 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 delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needleless injection (eg, Powderject ™, Bioject ™, etc.).

Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, pulse, 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, as a mixture, for example, in a dry mixture with lactose or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized reservoir, pump, sprayer, atomizer (preferably an atomizer that uses electrodynamics to produce a fine mist) or nebulizer, with or without use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane 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 reservoir, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound or compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or prolonging the release of the active ingredient. , a propellant or propellants as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for inhalation delivery (typically less than 5 micrometers). This can be achieved by any appropriate shredding process, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (prepared, for example, from gelatin or hydroxypropyl methylcellulose, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol or magnesium stearate The lactose may be anhydrous or in the form of the monohydrate, preferably the latter.Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and Trehalose

A solution formulation suitable for use in an atomizer that uses electrodynamics to produce a fine mist may contain from 1 µg to 20 mg of the compound of the invention per drive and the drive 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. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable saporifers, such as menthol and levomenthol or sweeteners, such as saccharin or sodium saccharin, may be added to the formulations of the invention intended for inhaled / intranasal administration.

Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, PGLA. Modified release formulations include delayed, prolonged, pulse, controlled, directed and programmed release.

In the case of dry powder inhalers and aerosols, the dosing unit is determined by means of a valve that supplies a measured quantity. The units according to the invention are typically arranged to administer a measured dose or "discharge" containing from 0.001 mg to 10 mg of the compound of formula (I). The overall 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 commonly, as divided doses throughout the day.

RECTAL / INTRAVAGINAL ADMINISTRATION

The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, pulse, controlled, directed and programmed release.

OCULAR / ETHICAL ADMINISTRATION

The compounds of the invention can also be administered directly to the eye or the ear, typically in the form of drops of a micronized suspension or solution in sterile saline solution, with adjusted, isotonic pH. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone), wafers, lenses and particle or vesicle systems, such as niosomes or liposomes A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methyl cellulose or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative, such as benzalkonium chloride . Such formulations can also be supplied by iontophoresis.

Formulations for ocular / otic administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, pulsed, controlled, directed or programmed release.

OTHER TECHNOLOGIES

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

It has been found that cyclodextrin-drug complexes, for example, are generally useful for most pharmaceutical forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an auxiliary additive, that is as a vehicle, diluent or solubilizer. Alpha, beta and gamma-cyclodextrins are more commonly used for these purposes, examples of which can be found in international patent applications No. WO 91/11172, WO 94/02518 and WO 98/55148.

TOOL EQUIPMENT

To the extent that it may be 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 present invention that two or more pharmaceutical compositions, at least one of which Containing a compound according to the invention, they can be conveniently combined in the form of a kit suitable for co-administration of the compositions.

Therefore the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention and means for separately keeping said compositions, such as a reservoir, Divided jar or divided aluminum foil package. An example of such a kit is the family blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different pharmaceutical forms, for example, orally and parenterally, for administering the separate compositions at different dosage intervals or for titrating the compositions separated from each other. To aid compliance, the kit typically comprises instructions for administration and can be provided with a so-called reminder.

For the avoidance of doubt, references in this document to "treatment" include references to curative, palliative and prophylactic treatment.

The invention is illustrated by the following non-limiting examples in which the following abbreviations are used and

definitions:

Abbreviations

APCI

chemical ionization mass spectrum at atmospheric pressure

[α] D

specific rotation at 587 nm.

Arbocel®

filter agent

δ

chemical shift

d

Doublet

dd

double double

CG-EM

gas chromatography-mass spectrometry

HPLC

high performance liquid chromatography

HRMS

high resolution mass spectrum

CL-MS

liquid chromatography-mass spectrometry

LRMS

low resolution mass spectrometry

m

Multiplete

min

Minutes

m / z

peak mass spectrum

NMR

nuclear magnetic resonance

MPa (psi)

Megapascals (pounds per square inch)

that

Quartet

s

Singlet

t

Triplet

For synthetic convenience although in many cases compounds have been initially isolated in their free-base forms, they have often become their corresponding hydrochloride salts for analytical identification purposes. For the avoidance of doubt, both forms of free base and HCl salt are considered to be provided herein.

X-ray crystallographic data

Crystalline materials were obtained for four compounds as follows: (1) The compound of Example 5 was dissolved under reflux in i-PrOH / MeCN / AcOH 90: 5: 5 and then the solution was allowed to cool to room temperature to form a crystalline material that can be isolated for further analysis; (2) the compound of Preparation 16 was dissolved at reflux in MeCN / THF 95: 5 and then the solution was allowed to cool to room temperature to form a crystalline material that can be isolated for further analysis; (3) the compound of Preparation 22b was dissolved in hot EtOAc, then pentane was added to the point of turbidity and then the solution was allowed to cool to room temperature to form a crystalline material that can be isolated for further analysis; and (4) for (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide hydrochloride, crystalline material was obtained from EtOH / i -Pr2O by steam diffusion methodology.

The stereochemistry of the crystalline material obtained for these four compounds was determined using X-ray crystallography. Representations of the 3D structures of these compounds are illustrated in Figures 3, 4, 5 and 6 later in the present document.

Figure 3 illustrates a graphic representation of ORTEP with thermal ellipsoids plotted at the 50% confidence level for the asymmetric unit of the crystalline structure of the compound of Example 5.

Figure 4 illustrates a graphical representation of ORTEP with thermal ellipsoids plotted at the 50% confidence level for the asymmetric unit of the crystalline structure of the compound of Preparation 16.

Figure 5 illustrates a graphic representation of ORTEP with thermal ellipsoids plotted at the 50% confidence level for the asymmetric unit of the crystalline structure of the compound of Preparation 22b.

Figure 6 illustrates a graphic representation of ORTEP with thermal ellipsoids plotted at the 50% confidence level for the asymmetric unit of the crystalline hydrochloride structure of (3S, 4R) -4, - (2,4-difluorophenyl) -N- [ (1R) -1-phenylethyl] pyrrolidin-3-carboxamide. The disorder of the difluorophenyl ring and the phenyl ring have been omitted for reasons of clarity.

X-ray crystallographic data for the compound of Example 5 (wherein R1 = phenyl, R2 = OH, R3 = But and R4 and R5 = F) illustrate: the relative cis ratio of the methyl substituents on the piperidine ring; the cis structure of R2 for the methyl substituents on the piperidine ring; the relative trans structure for the groups at positions C3 and C4 of the pyrrolidine ring; and the absolute configuration in C3 and C4 of the pyrrolidine ring.

Crystallographic X-ray data for the intermediate compound of Preparation 16 (wherein R1 = phenyl and R2 = OH) illustrates: the relative cis ratio of the methyl substituents on the piperidine ring and the cis structure of R2 for the substituents methyl in the piperidine ring. The compound of Preparation 16 is a direct precursor to the compound of Example 5. The X-ray data confirms that there is no stereochemical interconversion in the piperidine ring in the subsequent reaction of the compound of Preparation 16 and the compound of Preparation 1 to form the compound of Example 5.

Crystallographic X-ray data for the intermediate compound of Preparation 22b (wherein R3 = But and R4 and R5 = F) illustrate: the relative trans structure for the groups at positions C3 and C4 of the pyrrolidine ring; and (by virtue of the known absolute configuration of the benzyloxazolidinone moiety) the absolute configuration in C3 and C4. The intermediate compound of Preparation 22b is hydrolyzed to provide the intermediate compound of Preparation 1 which is a direct precursor to the final compound of Example 5. The X-ray data confirms that there is no stereochemical interconversion in the pyrrolidine ring in synthetic process for the conversion of the intermediate of Preparation 22b into the intermediate of Preparation 16 and its subsequent reaction with the intermediate of Preparation 1 to form the final compound of Example 5.

The absolute and relative configuration of the compound of Preparation 53 was determined by conversion to (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3- hydrochloride carboxamide This conversion was achieved by:

(i)

Reaction of the compound of Preparation 53 with (R) - (+) - α-methylbenzylamine in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in tetrahydrofuran at room temperature to form ( 3R, 4S) -3- (2,4-Difluorophenyl) -4 - ({[(1R) -1-phenylethyl] amino} carbonyl) pyrrolidin-1-carboxylic acid tert-butyl ester;

(ii)

Deprotection of Boc by treating a solution of (3R, 4S) -3- (2,4-difluorophenyl) -4 - ({[(1R) -1-phenylethyl] amino} carbonyl) pyrrolidine-1-carboxylate tertiary butyl in dichloromethane with a solution of 4M hydrogen chloride in dioxane at room temperature to form (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidine- hydrochloride 3-carboxamide. X-ray crystallographic data for (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide hydrochloride demonstrated both the relative trans ratio of the substituents C3 and C4 of the pyrrolidine ring as well as the absolute configuration in C3 and C4 of the pyrrolidine ring. The representation of its 3D structure is illustrated in Figure 6 later in this document.

The stereochemicals illustrated for the remaining compounds in the Examples and Preparations have been assigned based on the stereochemical precedents set forth in the synthesis of the compounds of the Example, Preparation 22b, Preparation 16 and Preparation 53 as described hereinbefore. The exception to this is the compound of Example 7 that has a cis structure at positions 3 and 4 of the pyrrolidine ring.

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 Bruker AXS SMART-APEX CCD (Radiation Mo Kα) area diffractometer. The intensities were integrated from several series of exposures using the methodology described in SMART v5.622 (control) and SAINT v6.02 (integration) software, Bruker AXS Inc., Madison, WI 1994. Each exhibition covered 0.3º in ω , with an exposure time of 60 s (Example 5), 10 s (Preparation 16) or 120 s (Preparation 22b) and the total data settings were: more than one sphere (Example 5); hemisphere (Preparations 16 and 22b). The data settings were corrected for absorption, using the multibarrido procedure, as described in SADABS, program for adjustment and correction of area detector data, GM Sheldrick, University of Göttingen, 1997 (based on the RH Blessing procedure, Acta Cryst. 1995, A51, 33-38).

X-ray diffraction data for the (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidine-3-carboxamide hydrochloride crystal was recorded at 100K using an area detector diffractometer (Bruker AXS SMART-APEX CCD) (Mo Kα Radiation) equipped with a 700 C Series Liquid Nitrogen Cryptocurrent from Oxford Cryosystems. The intensities were integrated from various series of exposures (as described earlier in this document). Each exposure covered 0.3 ° in ω, with an exposure time of 60 s and the total data set was more than one sphere. The data set was corrected for absorption using the multibarrido procedure (as detailed above in this document).

The crystalline structures were successfully dissolved by direct procedures using SHELXS-97, (as described in SHELXS-97. Program for crystalline structure solution. GM Sheldrick, University of Göttingen, Germany, 1997, publication 97-2) in: Space Group P21 (Example 5); Pna21 Space Group (Preparation 16); Space Group P212121 (Preparation 22b and (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] -pyrrolidin-3-carboxamide hydrochloride) and all other hydrogen atoms in the asymmetric units they were located from the resulting electronic density maps. From these subsequent structural refinements and maps it was discovered that: there was a cation and a chloride ion in the asymmetric unit for the compound of Example 5 (as illustrated in Figure 3); there was a molecule of the compound of Preparation 16 in the asymmetric unit (as illustrated in Figure 4); there was a molecule of the compound of Preparation 22b in the asymmetric unit (as illustrated in Figure 5); and that there was a cation hydrochloride of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide and a chloride anion in the asymmetric unit (as is illustrated in Figure 6).

For the four crystals evaluated, the coordinates of the atoms other than hydrogen were refined against the diffraction data by the least squares procedure using SHELXL-97 (as described in SHELXL-97. Program for crystal structure refinement. GM Sheldrick , University of Göttingen, Germany, 1997, publication 97-2) each with anisotropic displacement parameters.

For the crystal of Example 5, the positions of the hydroxyl and hydrogen atoms N-H + were located from the Fourier difference map and their coordinates were refined with restrictions located at the respective OH and NH link angles and distances, so that the remaining groups maintained an idealized geometry. The remaining hydrogen atoms were placed in calculated positions and refined with a directional model and all hydrogen atoms were refined with isotropic displacement parameters. The absolute configuration for the stereochemistry of the cation for 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 depicted in Figure 3.

For the crystal of Preparation 16, the position of the hydroxyl and amine hydrogen atoms were located from a Fourier difference map and their coordinates were refined with restrictions located at the distances and angles of the respective NH and OH bonds , so that the remaining group maintained an idealized geometry. The remaining hydrogen atoms were located in calculated positions and were refined with a directional 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 directional 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 one of a pair of enantiomers (both the one shown in Figure 5 or its mirror image with all chiral centers reversed). If it is assumed that the configuration of the C4 center of the oxazolidnone ring was the same as in the starting material, ie "S", by deduction the other two centers can be assigned as in Figure 5.

For the (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] -pyrrolidine-3-carboxamide hydrochloride crystal, large thermal ellipsoids associated with both phenyl rings suggest strongly that the two groups were messy. The difluorophenyl ring was modeled in two orientations related by a double rotation around the axes C14, .... C17 with a relative occupancy of 80:20. The unsubstituted phenyl ring was finally modeled in two overlapping orientations with equal occupations. The hydrogen atoms were placed in the calculated positions and refined with a directional model and all with isotropic displacement parameters. The position of the amine and amide N-H hydrogen atoms were located from a Fourier difference map with isotropic displacement parameters. The remaining hydrogen atoms were placed in the calculated positions and refined with a directional model and all with isotropic displacement parameters. The absolute configuration of the stereochemistry of the cation hydrochloride of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide was determined directly from the data X-ray diffraction by Flack's procedure (as detailed earlier in this document). The final refined Flack parameter was -0.01 (7) for the diastereomer represented in Figure 6.

The% of final refined factor R [For data I> 2σ] are: for Example 5, 4.15%; Preparation 16, 4.07%; Preparation 22b, 4.62%; and for (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidine-3-carboxamide hydrochloride, 5.00%.

Simulated Dust X-Ray Diffraction Data

(i) Compound of Example 5

The 2-theta angles, the inter-planar 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 Å (Cu Kα); Polarization Factor = 0.5; Pseudo-Voigt Profile (U = 0.01, V = -0.001, W = 0.002).

The monocrystalline structure data obtained from the methodology described earlier in this document were used in these calculations. Table 1 shows the highest intensity peaks of the Simulated Dust Pattern of Example 5 from the Collection of Monocrystalline Data (as illustrated in Figure 7).

TABLE 1

Angle (º 2-theta)

Intensity (%)  Angle (º 2-theta) Intensity (%)

8.6

17.4 24.7 12

10.9

42.3 25.3 29.5

11.3

86 25.8 11.8

11.7

53.6 28.1 10.3

13.9

100

16.1

61.5

18.2

13.6

18.9

51.4

19.7

72.5

20.3

32.2

23.5

33.5

24.1

22.2

Therefore, according to a further aspect, the present invention provides the compound of Example 5 having the simulated PXRD pattern illustrated in Figure 7 with the highest intensity peaks as illustrated in Table 1 when said pattern Simulated PXRD is generated by the procedure indicated above in this document.

(ii) Compound of Preparation 16

The 2-theta angles, the inter-planar distances d and the relative intensities were calculated from the monocrystalline structure of Preparation 16 using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ 10 [version 3.0]. The relevant simulation parameters were in each case: Wavelength = 1,540562 Å (Cu Kα); Polarization Factor = 0.5; Pseudo-Voigt Profile (U = 0.01, V = -0.001, W = 0.002).

The monocrystalline structure data obtained from the methodology described earlier in this document were used in these calculations. Table 2 shows the highest intensity peaks of the

Simulated Dust Pattern of Preparation 16 from the Monocrystalline Data Collection (as illustrated in Figure 8).

TABLE 2 (cont.)

Angle (º 2-theta)

Intensity (%)

9.2

65.5

11.6

14.4

14.3

100

15.5

41.6

16.6

78.9

18.1

85.7

20.8

13.5

Angle (º 2-theta)

Intensity (%)

22.6

16

24.6

17.1

25.7

12.5

26.4

14.9

27.2

15.5

Therefore, according to a further aspect, the present invention provides the compound of Preparation 16 having the simulated PXRD pattern illustrated in Figure 8 with higher intensity peaks as illustrated in Table 2 when said pattern Simulated PXRD is generated by the procedure indicated above in this document.

(iii) Compound of Preparation 22b

2-theta angles, inter-planar distances d and relative intensities were calculated from the monocrystalline structure of Preparation 22b using the "Reflex Powder Diffraction" module of Accelrys Materials Studios ™

10 [version 3.0]. The relevant simulation parameters were in each case: Wavelength = 1,540562 Å (Cu Kα); Polarization Factor = 0.5; Pseudo-Voigt Profile (U = 0.01, V = -0.001, W = 0.002).

The monocrystalline structure data obtained from the methodology described earlier in this document were used in these calculations. Table 3 shows the highest intensity peaks of the Simulated Dust Pattern of Preparation 22b from the Collection of Monocrystalline Data (as illustrated in Figure 9).

15 TABLE 3

Angle (º 2-theta)

Intensity (%)  Angle (º 2-theta) Intensity (%)

6.5

20.7 20.1 23.7

9.1

34.3 20.3 17.3

9.4

60.1 20.6 28.2

10.5

17.4 21.9 16.2

14.9

35.2 23.4 27.3

16.9

100 23.7 11.3

17.1

19.8 24.1 24.1

17.5

43.6 25.4 12.5

18.3

24.5 27.4 19.2

18.9

73.1 29.2 16.2

19.4

28.3

19.7

13.3

Therefore, in accordance with a further aspect, the present invention provides the compound of Preparation 22b having the simulated PXRD pattern illustrated in Figure 9 with higher intensity peaks as illustrated in Table 2 when said PXRD pattern simulated is generated by the procedure indicated above in

20 this document.

(iv) (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide hydrochloride

The 2-theta angles, the inter-planar distances d and the relative intensities were calculated from the monocrystalline hydrochloride structure of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl ] pyrrolidin-3-carboxamide using the "Reflex Powder Diffraction" module of Accelrys Materials Studio ™ [version 3.0]. The relevant simulation parameters were in each case: Wavelength = 1,540562 Å (Cu Kα); Polarization factor = 0.5; Pseudo-Voigt Profile (U = 0.01, V = -0.001, W = 0.002).

The monocrystalline structure data obtained from the methodology described earlier in this document were used in these calculations. Table 4 shows the highest intensity peaks of the Simulated Dust Patterns of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidine-3-carboxamide hydrochloride from the Collection of Monocrystalline Data (as illustrated in Figure 10).

TABLE 4

Angle (º 2-theta)

Intensity (%)

4.4

100

8.8

17.1

11.4

20.1

18.1

17.4

18.7

12.7

19.0

14.6

20.0

11.7

20.6

11.2

22.8

11.8

23.9

24

25.2

10.8

Example 1 (3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl- 4-phenylpiperidin-4-ol

image 1

To a stirred suspension of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride salt

15 of preparation 1, (57 mg, 0.2 mmol) in dichloromethane (1 ml) at room temperature under a dry nitrogen atmosphere, O-benzotriazol-1-yl-N, N, N, hexafluorophosphate was added. N'-tetramethyluronium (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), all in single portions. The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 18 hours, quenched by the addition of water (10 ml),

20 it was then extracted with dichloromethane (2 x 10 ml). The combined organic phases 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 (APCI) 471 (100%) [MH +], 298 (40%), 220 (20%); HRMS C28H37F2O2 [MH +] requires 471.2818, found 471.2815.

25 Example 2

(3R, 4R, 5S) -4-Cyclohexyl-1 - {[(3S *, 4R *) - 4- (2,4-difluorophenyl) -1-ethylpyrrolidin-3-yl] carbonyl) -3,5-dimethylpiperidine -4-ol 5

image 1

10

fifteen

twenty

25

30

35

40

To a stirred suspension of acid hydrochloride salt (3S *, 4R *) -4- (2,4-difluorophenyl) -1-ethylpyrrolidine-3-carboxylic acid of preparation 17 (161 mg, 0.6 mmol) in N, N-dimethylformamide (10 ml) at room temperature under a dry nitrogen atmosphere, triethylamine (0.2 ml, 1.4 mmol) was added, then 1-hydroxybenzotriazole hydrate (77 mg, 0.6 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (109 mg, 0.6 mmol) and (3R, 4s, 5S) -4-cyclohexyl-3,5-dimethylpiperidin-4-ol (of preparation 7) (100 mg, 0.5 mmol), all in simple portions. The resulting mixture was stirred at 30 ° C under a dry nitrogen atmosphere for 25 hours. The reaction was stopped by the addition of 2M solution of sodium hydroxide (75 ml), then extracted with diethyl ether (80 ml). The organic phase was washed with brine (50 ml), separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a clear oil (209 mg, 99%). LRMS (APCI) 449 (100%) [MH +], 298 (40%), 220 (20%); HRMS C26H39F2O2 [MH +] requires 449.2974, found 449.2970.

Example 3

(3R, 4R, 5S) -4-Butyl-1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5- dimethylpiperidin-4-ol

image 1

To a stirred suspension of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid hydrochloride salt of preparation 1, (71 mg, 0.3 mmol) in N, N-dimethylformamide (10 ml) at room temperature in a dry nitrogen atmosphere, O-benzotriazoyl-1-yl-N, N, N ', N'-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 preparation 9) (50 mg, 0 , 3 mmol), all in simple portions. The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 2.5 days, then quenched by the addition of water (5 ml) and extracted with diethyl ether (10 ml). The organic phase was separated, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by HPLC using a Phenomenex Luna C18 column (2) 150 x 15mm (particle size 10 micrometers, porosity 100 Å), using an eluent of 2 acetonitrile solvents: water: trifluoroacetic acid (5: 95: 0, 1) [solvent A] and acetonitrile [solvent B]. A solvent gradient ran at a flow rate of 20 ml / min as follows: Time 0 min -B 5%; 0.6 min -5% B; 9.5 min -95% B; 10.5 min -B 95%. This gave the title compound, retention time 6.05 min, in the form of an oil (18 mg, 13%). LRMS (APCI) 451 (100%) [MH +]; HRMS C26H40F2O2 requires 451.3131, found 451.3114.

Example 4

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophen) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- (4-methyl) phenyl) piperidin-4-ol

image 1

To a stirred suspension of the hydrochloride salt of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid of preparation 1, (172 mg, 0.6 mmol) in N, N-dimethylformamide (10 ml) at room temperature, in a dry nitrogen atmosphere, O-benzotriazol-1-yl-N, N, N ', N'-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), all in single portions. The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 2.5 days, quenched by the addition of water (5 ml) and then extracted with diethyl ether (10 ml). The organic phase was separated and then dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by HPLC using a C18 column (1) Phenomenex Luna 150 x 15 mm (particle size 10 micrometers, porosity 100 Å), using an eluent of 2 acetonitrile solvents: water: trifluoroacetic acid (5: 95: 0, 1) [solvent A] and acetonitrile [solvent B]. A solvent gradient was run at a flow rate of 20 ml / min as follows: Time 0 min -B 5%; 0.6 min -5% B; 9.5 min -95% B; 10.5 min -B 95%.

5

10

fifteen

twenty

25

30

35

40

This gave the title compound, retention time 6.15 min, in the form of an oil (24 mg, 9%). LRMS (APCI) 485 (100%) [MH +]; HRMS C29H39F2O2 requires 485.2974, found 485.2959.

Example 5

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl- hydrochloride 4-phenylpiperidin-4-ol

image 1

(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid of 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 cyclic anhydride (50% in ethyl acetate) (54.5 ml, 92 mmol) was added dropwise, keeping the temperature below 5 ° C. Then, the mixture was allowed to warm to room temperature with continuous stirring. 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 was stirred for a further four hours at room temperature. A 10% solution of potassium carbonate (500 ml) was added and the mixture was stirred vigorously at room temperature for 2 hours. The organic phase was separated and then stirred with a 10% solution of potassium carbonate (500 ml) for 1 hour. Then, the dichloromethane phase was separated, washed with water (3 x 300 ml), dried over sodium sulfate and filtered. Then, a solution of 4M 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. Acetone (500 ml) was added to the crude hydrochloride, the mixture boiled for 30 minutes and then allowed to cool to room temperature. The hydrochloride salt was filtered off and washed with acetone (5 x 100 ml). Recrystallization of the product from isopropyl alcohol gave an analytically pure hydrochloride (39.5 g). MS (APCl +) 471 (M + H)

1H NMR (400 MHz, CD3OD δ (Rotamers), 0.35 (d, 2H), 0.50 (m, 3.60H), 0.95 (m, 0.6H), 1.22 (s, 9H ), 1.65 (m, 0.75H), 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, 1H), 7.05 (m, 0.5H), 7.20 (m, 1.5H), 7.25 (m , 3.5H), 7.45 (m, 0.5H), 7.60 (m, 1H). [Α] 25 D = -51.9 (c = 0.3, MeOH).

Example 6

Hydrochloride (3R, 4R, 5S) -1-H {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- phenylpiperidin-4-ol

image 1

To a stirred solution of (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylic acid, of preparation 33 (160 mg, 0.58 mmol) and (3R, 4s, 5S ) -3,5-dimethyl-4-phenylpiperidin-4-ol, of preparation 16 (100 mg, 0.48 mmol) in ethyl acetate (2 ml), triethylamine (140 µl, 0.97 mmol) was added and 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (290 µl, 0.48 mmol) at 0 ° C. The reaction mixture was stirred for 30 minutes, then heated to room temperature and the solvent removed in vacuo. The residue was partitioned between dichloromethane (20 ml) and a saturated solution of potassium carbonate (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 the product in form of a colorless oil. The oil was dissolved in 1,4-dioxane (3 ml) and 4M hydrogen chloride in dioxane (6 ml) was added slowly. Then, the solvent was removed in vacuo. Recrystallization from acetone provided the desired product, 110.8 mg.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.27-0.56 (m, 6H), 1.45 (m, 7H), 1.69 -2.02 (m, 1H), 2.75 (m, 2H), 3.14 (m, 2H), 3.40 (m, 1H), 3.61 (m, 1H), 3.77 (m, 1H), 3.92 (m, 2H) , 4.01-4.17 (m, 1H), 4.32 (dd, 1H), 7.05-7.24 (m, 4H), 7.34 (m, 3H), 7.62-7 , 72 (m, 1 H). LRMS (APCI) 457 [MH +]. [α] 25 D = -53.5 (c = 0.26, MeOH).

5

10

fifteen

twenty

25

30

35

40

Example 7 (3R, 4S, 5S) -1 - {[(3R *, 4R *) 1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl -4-phenylpiperidin-4-ol

image 1

To a cooled solution of (R *, R *) - 1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid, of preparation 36 (500 mg, 1.76 mmol) in dichloromethane (20 ml), a catalytic amount of N, N-dimethylformamide was added 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 azeotropically distilled with dichloromethane (2 x 10 ml). The white powder was dissolved again 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 saturated sodium hydrogen carbonate solution (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 1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.43-0.55 (m, 6H), 0.75-0.79 (m, 1H), 1.25 (s, 9H), 1.87 -1.97 (m, 1H), 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, 1H). LCMS (APCI) = 471 [MH +].

Example 8

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride} -4- (3,4 -difluorophenyl) -3,5-dimethylpiperidin4-ol

image 1

A solution of (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid of Preparation 1 (159 mg, 0.49 mmol), (3R, 4s, 5S ) -4- (3,4-Difluorophenyl) -3,5-dimethylpiperidin-4-ol (100 mg, 0.41 mmol) of Preparation 39, 1-propylphosphonic acid cyclic anhydride (50% in 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. The reaction was then diluted with dichloromethane (20 ml) and partitioned with a 10% solution of potassium carbonate (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 column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (99: 1: 0.1-96: 4: 0.4) as eluent gave the free base as a colorless oil 117 mg . The oil was dissolved in dichloromethane (1 ml) and treated with 2M hydrogen chloride in diethyl ether (3 ml). Then, the solvent was removed in vacuo and the residue was azeotropically distilled with diethyl ether to give the title compound as a white solid, 108 mg.

1H NMR (400 MHz, CD3OD) (Rotamers) □ 0.30-0.56 (m, 6H), 1.48 (s, 9H), 1.62-1.94 (m, 1H), 2.64 -2.75 (m, 1H), 3.12 (t, 2H), 3.40-3.54 (m, 2H), 3.70-3.96 (m, 2H), 4.00 (m , 1H), 4.2 (dd, 1H), 7.02-7.21 (m, 4H), 7.52 (m, 1H), 7.65 (m, 1H). LRMS (APCl) 507 [MH +]. [□] 25 D = -34.89 (c = 0.23, MeOH).

Example 9

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) hydrochloride ) -3,5-dimethyl-piperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

35

1-Propylphosphonic acid cyclic anhydride (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), acid (3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) ) pyrrolidin-3-carboxylic of 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. When the addition was completed, the resulting homogeneous solution was stirred for 6 hours at room temperature. The solution was washed with a 10% aqueous solution of potassium carbonate (3 x 20 ml), then dried over sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was purified by column chromatography (C-18 reverse phase, 40g Redisep® cartridge), 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%. Then, the product was 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, again dissolved in a solution of 4M hydrogen chloride in dioxane (100 ml) and evaporated to dryness once more. Then, the residue was dried under vacuum at 50 ° C, giving the product hydrochloride (391 mg) as a white amorphous solid. 1H NMR (CD3OD 400 MHz): (Rotamers), 0.31-0.57 (3 xd, 6H), 0.83-2.08 (3 xm, 2H), 1.55 (s, 9H), 1 , 60-2.07 (3 xm, 2H), 2.68-3.20 (2 xm, 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 (APCI) = 489 [MH +] [□] 25 D = -42.7 (c = 0, 31, MeOH)

Example 10

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropyrrolidin-3-yl] carbonyl hydrochloride} -4- (4-fluorophenyl) -3 , 5-dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 33 and 41 by a procedure similar to that described for Example 9.

1H NMR (400 MHz, CD3OD) δ (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, 1H), 3.11-4.18 (m, 7H), 4.35 (m, 1, H), 6.95-7, 19 (m, 5H), 7.38-7.85 (m, 2H) LRMS (APCI) 475 [MH +] [α] 25 D = -39.6 (c = 0.3, MeOH)

Example 11

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidin-3-yl] carbonyl hydrochloride} -4- (4-fluorophenyl) -3 , 5-dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 62 and 41 by a procedure

similar to that described for Example 9. 1H NMR (400 MHz, CD3OD) δ (Rotamers), 0.23-0.60 (m, 6H) 1.03-1.98 (m, 2H), 2.65 (m, 1H), 3.11 -4.18 (m, 11H), 4.35 (m, 1H), 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H)

LRMS (APCI) 448 [MH +] [α] 25

D = +49.7 (c = 0.3, MeOH)

5

10

fifteen

twenty

25

30

35

Example 12

(3R, 4R, 5S) - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidine- hydrochloride 4-ol

image 1

1-Propylphosphonic acid cyclic anhydride (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 (265 mg, 1.2 mmol), acid (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4- Difluorophenyl) pyrrolidine-3-carboxylic of Preparation 53 (0.75 mg, 1.4mol) and triethylamine (0.48 ml, 3.6 mmol) in dichloromethane (25 ml) at 0 ° C under a nitrogen atmosphere. When the addition was completed, the resulting homogeneous solution was stirred for 6 hours at room temperature. The solution was washed with a 10% aqueous solution of potassium carbonate (3 x 20 ml), 3% aqueous citric acid (3 x 50 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 Boc protected product as a solid of white color (529 mg). A portion 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. 1H NMR (400 MHz, CD3OD) δ (Rotamers), 0.36-0.66 (m, 6H) 0.81-1.97 (m, 2H), 2.70 (m, 1H), 3.19 -4.05 (m, 8H), 4.31 (m, 1H), 6.85-7.31 (m, 6H), 7.28-7.80 (m, 2H) LRMS (APCI) 433 [ MH +] [α] 25 D = -62.2 (c = 0.3, MeOH)

Example 13

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (4-chlorophenyl) hydrochloride ) -3,5-dimethyl-piperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 43 by a procedure similar to that described for Example 9.

1H NMR (400 MHz, CD3OD) 8 (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, 1H), 7.05-7 , 29 (m, 5H), 7.40-7.75 (m, 2H)

LRMS (APCI) 505 [MH] + [α] 25 D = -37.6 (c = 0.3, MeOH) Example 14 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-ethylpyrrolidin-3-yl] carbonyl} -4- (4-methoxyphenyl) -3.5 -dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 48 and 75 by a procedure similar to that described for Example 9.

1H NMR (400 MHz, CD3OD) δ (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, 1H), 6.81-7.29 (m , 5H), 7.60-7.74 (m, 2H)

LRMS (APCI) 472 [MH +] [α] 25

D = -42.7 (c = 0.3, MeOH)

Example 15

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride} -4- (2,4 -difluorophenyl) -3,5-dimethyl-piperidin4-ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 49 by a procedure

10 similar to that described for Example 9. 1H NMR (400 MHz, CD3OD) 8 (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, 1H), 7.04-7.28 (m, 4H), 7.55-7.72 (m, 2H)

LRMS (APCI) 507 [MH +] [α] 25

D = -79.7 (c = 0.3, MeOH) Example 16 (3R, 4R, 5S) Hydrochloride -4- (2,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) pyrrolidin-3-yl] carbonyl) -3,5-dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 49 and 53 by a procedure

20 similar to that described for Example 12. 1H NMR (400 MHz, CD3OD) δ (Rotamers), 0.36-0.66 (m, 6H), 0.81-1.97 (m, 2H) , 2.70 (m, 1H), 3.19-4.05 (m, 8H), 4.31 (m, 1H), 7.05-7.35 (m, 4H), 7.45-7 , 65 (m, 2H)

LRMS (APCI) 451 [MH +] [a] 25 D = -42.7 (c = 0.3, MeOH) 25 Example 17 Hydrochloride (3R, 4R, 5S) -1 - {[(3S, 4R) - 1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (2,6-difluorophenyl) -3,5-dimethyl-piperidin4-ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 44 by a procedure

similar to that described for Example 9.

1H NMR (400 MHz, CD3OD) δ (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 (APCI) 507 [MH +]

[α] 25

D = -77.7 (c = 0.3, MeOH) Example 18 Hydrochloride

(3R, 4R, 5S) -4- (2,6-difluorophenyl) -1 - {[((3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3.5 -dimethylpiperidin-4-ol

image 1

10 The title compound was prepared from the compounds of Preparations 44 and 53 by a procedure

similar to that used for Example 12. 1H NMR (400 MHz, CD3OD) δ (Rotamers), 0.36-0.57 (m, 6H), 0.81-1.97 (m, 2H), 2.70 (m, 1H), 3, 15-4.05 (m, 8H), 4.31 (m, 1H), 7.05-7.35 (m, 4H), 7.50-7.63 (m, 2H).

LRMS (APCI) 451 [MH +]

[α] 25

15 D = -22.7 (c = 0.3, MeOH)

Example 19

(3R, 4R, 5S) -1-4 {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl hydrochloride] -4- (3- fluorophenyl) -3,5-dimethyl-piperidin-4ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 46 by a procedure similar to that described for Example 9. 1H NMR (400 MHz, CD3OD) δ (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, 1H ), 7.38-7.85 (m, 2H)) 25 LRMS (APCI) 489 [MH +] [α] 25

D = -81.3 (c = 0.3, MeOH) Example 20 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4- (3-fluorophenyl) -3,5-dimethylpiperidine- 4-ol

image 1

The title compound was prepared from the compounds of Preparations 46 and 53 by a procedure

5

10

fifteen

twenty

25

30

35

similar to that described for Example 12.

1H NMR (CD3OD, 400 MHz) (Rotamers), 0.36-0.60, (m, 6H) 0.81-2.01 (m, 2H), 2.70 (m, 1H), 3.19 -4.05 (m, 8H), 4.31 (m, 1H), 6.95-7.15 (m, 4H), 7.32 (m, 1H), 7.28-7.80 (m, 2H) LRMS (APCI) 433 [MH +]

[α] 25

D = -72.7 (c = 0.3, MeOH) Example 21 Hydrochloride

(3R, 4R, 5S) -4- (4-chlorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidin-3-yl] carbonyl-3,5- dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 43 and 62 by a procedure

similar to that described for Example 9. 1H NMR (CD3OD, 400 MHz) (Rotamers), 0.20-0.62 (m, 6H) 1.03-1.98 (m, 2H), 2.67 (m, 1H), 3.0, 9-4.16 (m, 10H), 4.31 (m, 1H), 6.95-7.19 (m, 5H), 7.38-7.85 (m, 2H)

LRMS (APCI) 463 [MH +] [α] 25

D = -39.3 (c = 0.3, MeOH) Example 22 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- pyridin-2-ilpiperidin-4-ol

image 1

A solution of (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperidin-4, -ol, of preparation 74 (260 mg, 1.26 mmol), acid (3R, 4S) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylic acid, of preparation 1 (267 mg, 0.94 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 181 mg, 0.95 mmol) 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 dried over magnesium sulfate, filtered and concentrated in vacuo for the crude residue. Purification by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 -99: 1 -97: 3 -94: 6 -92: 8) and then dichloromethane: methanol: 0.88 ammonia (95: 5 : 0.5) provided the desired product as a colorless oil, 11 mg. This was converted into the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 7.00-7.26 (m, 2H), 7.97 (m, 1H), 7.53-8 , 66 (m, 3H), 8.71 (d, 1H)

LRMS (APCI) 472 [MH +]

[α] D25 = -42.46 (c = 0.35, MeOH)

Example 23

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-pyridin-2- hydrochloride ilpiperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

To a stirred solution of (3R, 4R, 5S) -3- (2,4-difluorophenyl) -4 - {[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-pyridin-2ylpiperidine -1-yl] carbonyl} pyrrolidin-1-carboxylic acid tert-butyl ester of preparation 54 (250 mg, 0.48 mmol) in dichloromethane (2 ml) was added a 4M solution of 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 that was triturated with diethyl ether to give the desired product in quantitative yield.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 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, 1H)

LRMS (APCI) 472 [MH +]

[α] D25 = -44.00 (c = 0.37, MeOH)

Example 24

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine-4- hydrochloride ol

image 1

The title compound was prepared from the compound of Preparation 55 by a procedure similar to that described for Example 23.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.98-7.39 (m, 7H), 7.46-7.64 (2 xc, 1H)

LRMS (APCI) 415 [MH +]

[α] D25 = -51.81 (c = 0.47, MeOH) Example 25 (3R, 4R, 5S) Hydrochloride -1 - {[(3S, 4R) -1-butyl-4- (2.4 -difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol

image 1

To a stirred solution of hydrochloride of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} 3,5-dimethyl-4- Phenylpiperidin-4-ol, from 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 butyraldehyde (54 µl, 0.61 mmol) was added 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 hydrogen carbonate 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 in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol (100: 0-97: 3) as eluent gave the pure product, 45 mg. This was converted into the hydrochloride salt by dissolution in dichloromethane, treatment with 2M hydrogen chloride hydrogen in diethyl ether and then evaporation of the solvent.

5

10

fifteen

twenty

25

30

35

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.20-0.58 (m, 6H), 0.65-2.06 (m, 2H), 1.02 (t, 3H), 1.47 (m, 2H), 1.77 (m, 2H), 2.67-3.20 (m, 2H), 3.32-4.22 (m, 9H), 4.32 (m, 1H), 7.00-7.40 (m, 7H), 7.54-7.74 (m, 1H)

LRMS (APCI +) = 471 [MH +]

[α] D25 = -60.39 (c = 0.32, MeOH) Example 26 Hydrochloride

(3R, 4R, 5S) -1 - {(3S, 4R) -4- (2,4-Difluorophenyl) -1-isobutylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4- ol

image 1

The title compound was prepared from the compound of Example 24 and isobutyraldehyde by a procedure similar to that described for Example 25.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.19-0.79 (m, 6H), 1.10 (t, 6H), 0.93-2.07 (m, 2H), 2.16 (m, 1H), 2.68-4.22 (m, 11H), 4.32 (m, 1H), 6.60-7.43 (m, 7H), 7.56-7.76 (m , 1 HOUR)

LRMS (APCI) 471 [MH +]

[α] D25 = -71.94 (c = 0.31, MeOH) Example 27 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-propylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4 -ol

image 1

To a hydrochloride solution of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl4-phenylpiperidine- 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 mmol) 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 removed in vacuo. The residue was partitioned between water (40 ml) and ethyl acetate (40 ml). The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo for the crude residue. Purification by column chromatography on silica gel using dichloromethane: methanol (100: 0 -99: 1-98: 2-97: 3-96: 4) provided the desired product as a colorless oil, 193 mg (70 %). This was converted into the hydrochloride salt by treatment with 4M hydrochloride in dioxane followed by evaporation of the solvent to give a white solid.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.94-7.38 ( m, 7H), 7.51-7.70 (m, 1H)

LRMS (APCI) 457 [MH +]

[α] D25 = -62.57 (c = 0.33, MeOH)

Example 28

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-methylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-pyridine trifluoroacetate -3-ilpiperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

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-dimethyl-4-pyridin-3-ylpiperidin-4-ol, of preparation 51 (200 mg, 0.96 mmol) in ethyl acetate (5 ml) was added triethylamine (400 µl, 2, 88 mmol) followed by 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (570 µl, 0.96 mmol) at room temperature. The reaction mixture was stirred for 24 hours, treated with a saturated solution of potassium carbonate (10 ml) and diluted with ethyl acetate (5 ml). The phases were separated and the organic phase was washed with a saturated solution of potassium carbonate (2 x 30 ml) and 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: 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 white solid 44 mg.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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 , 1H), 7.89 (m, 1H), 8.05-8.81 (m, 3H) LRMS (APCI) 430 (MH +]

Example 29

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyrimidin-2-yl] pyrrolidin-3-yl] carbonyl hydrochloride} -3.5 hydrochloride -dimethyl-4-phenylpiperidin-4-ol

image 1

A hydrochloride solution of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine-4 -ol, from 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 under reflux for 24 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (5 ml) and water (5 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 -99: 1-98: 2-97: 3) gave the desired product as a white foam, 220 mg (74%) . This was converted into the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane, followed by evaporation of the solvent.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.36-0.60 (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, 1H), 8.64 (d, 2H)

LRMS (ESI +) = 493 [MH +]

[α] D25 = -52.10 (c = 0.44, MeOH)

Example 30

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-cyclobutyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- hydrochloride phenylpiperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

35

The title compound was prepared from the compound of Example 24 and cyclobutanone by a procedure similar to that described for Example 25, with the exception that ethanol was used as the solvent.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H)

LRMS (APCI) 469 [MH +]

[α] D25 = -61.50 (c = 0.45, MeOH) Example 31 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyridin-2-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4 -phenylpiperidin-4-ol

image 1

To a hydrochloride solution of (3R, 4R, 5S) - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine-4- ol of Example 24 (200 mg, 0.44 mmol) in toluene (4 ml) was added sodium 2-methylpropan-2-olate (97 mg, 1.31 mmol) and the reaction was stirred for 10 minutes at room temperature. 2-Bromopyridine (63 µl, 0.66 mmol) was added followed by tris (dibenzylideneacetone) dipaladium (0) (40 mg, 0.04 mmol), (+/-) 1,1'-binaphthalene-2,2 ' -diylbis (diphenylphosphine) (55 mg, 0.09 mmol) and the reaction mixture was heated at reflux for 24 hours. The solvent was removed in vacuo and the residue was 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 g using dichloromethane: methanol (100: 0-96: 4) as eluent gave the desired product as a foam, 160 mg (67%). This was converted into the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.58-6.68 (m, 2H), 6.93-7.62 (m, 9H), 8 , 02 (m, 1H)

LRMS (APCI) 492 [MH +] [α] D25 = -44.46 (c = 0.37, MeOH)

Example 32

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1- (2-methoxyethyl) pyrrolidin-3-yl] carbonyl} -3,5- hydrochloride dimethyl-4-phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and 1-bromo-2-methoxyethane by a procedure similar to that used for Example 27.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.98-7.38 (m, 7H), 7.50-7 , 71 (m, 1 H)

LRMS (APCI) 473 [MH +]

[α] D25 = -62.03 (c = 0.32, MeOH) Example 33

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyrazin-2-yl] pyrrolidin-3-yl] carbonyl hydrochloride} -3.5 hydrochloride -dimethyl-4-phenylpiperidin-4-ol

image 1

A hydrochloride solution of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4

5 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 N, N-dimethylformamide (4 ml) was heated at 100 ° C for 24 hours. The solvent was removed in vacuo and the crude residue was partitioned between water (4 ml) and ethyl acetate (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 ethyl acetate: pentane (10:90 -100: 0) as eluent

10 provided the desired product in the form of a foam, 121 mg (55%). This was converted into the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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 (APCI) 493 [MH +]

15 [α] D25 = -46.98 (c = 0.31, MeOH)

Example 34

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyridin-3-yl-pyrrolidin-3-ylcarbonyl} -3,5-dimethyl-4 hydrochloride -phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and 3-bromopyridine by a procedure similar to that described for Example 31.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.94-7.62 (m, 8H), 7.70-7.83 (m, 2H), 7 , 98-8.10 (m, 2H)

LRMS (APCI) 492 [MH +]

25 [α] D25 = -33.26 (c = 0.36, MeOH). Example 35 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4 -phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and 3-chloropyridazine (J. Med. Chem. 30 (2),

239, 1987) by a procedure similar to that described for Example 31.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.97-8.11 (m, 10H), 8.50-9.30 (2 x d, 1H) LRMS (APCI) 493 [MH +]

[α] D25 = -36.61 (c = 0.31, MeOH) Example 36 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-5-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4 -phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and 5-bromopyrimidine by a procedure similar to that described for Example 31.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.37-0.60 (m, 6H), 0.85-2.12 (m, 2H), 2.70-3.26 (m, 2H) , 3.60-4.22 (m, 7H), 4.35 (m, 1H), 6.93-7.43 (m, 7H), 7.43-7.64 (m, 1H), 8 , 52 (m, 2H), 8.71-9.26 (m, 1H)

LRMS (APCI) 493 [MH +]

15 [α] D25 = -37.45 (c = 0.25, MeOH) Example 37 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4-isopropyl-3,5- dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 57 by a procedure similar to that described for Example 8.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.37-0.97 (m, 12H), 1.46 (s, 9H), 1.33-2.07 (m, 3H), 2.55 -3.05 (m, 2H), 3.07-4.06 (m, 8H), 7.05 (m, 2H), 7.60 (m, 1H)

LRMS (APCI) 437 [MH +]

[Α] D25 = -26.07 (c = 0.60, MeOH) Example 38 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -1- (Cyclopropylmethyl) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and (bromomethyl) cyclopropane by a procedure similar to that described for Example 27.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.20-0.80 (m, 10H), 1.19 (m, 1H), 0.83-2.02 (m, 2H), 2.68 -3.18 (m, 2H), 5 3.19-4.18 (m, 9H), 4.31 (m, 1H), 7.00-7.38 (m, 7H), 7.52- 7.71 (m, 1 H)

LRMS (APCI +) = 469 [MH +]

[α] D25 = -66.40 (c = 0.28, MeOH)

Example 39

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1- (tetrahydro-2H-pyran-4-yl) pyrrolidin-3-yl] carbonyl hydrochloride }

10 3,5-dimethyl-4-phenylpiperidin-4-ol

image 1

The title compound was prepared from the compound of Example 24 and tetrahydro-4H-pyran-4-one by a procedure similar to that described for Example 25, with the exception that ethanol was used as the solvent.

1 H NMR (400 MHz, CD3OD) (Rotamers) δ 0.18-0.55 (m, 6H), 0.78-2.20 (m, 6H), 2.67-3.18 (m, 2H ), 3.30-4.18 (m, 12H), 4.30 (m, 1H), 7.00-7.35 (m, 7H), 7.53-7.71 (m, 1H)

LRMS (APCI) 499 [MH +]

[α] D25 = -51.40 (c = 0.37, MeOH) Example 40 20 (3R, 4R, 5S) Hydrochloride -1 - ([(3S, 4R) -1-tert-butyl-4- ( 2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} 3,5-dimethyl-4-propylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 1 and 59 by a procedure similar to that described for Example 8.

1 H NMR (400 MHz, CD3OD) (Rotamers) δ 1.45 (s, 9H), 0.19-1.66 (m, 15H), 2.49-304 (m, 2H), 3.17- 4.05 (m, 7H), 4.11 (m, 1H), 7.05 (m, 2H), 7.59 (m, 1H).

LRMS (APCI) 437 [MH +],

[α] D25 = -28.03 (c = 0.38, MeOH) Example 41

5

10

fifteen

twenty

25

30

35

40

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-cyclopropyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- hydrochloride phenylpiperidin-4-ol

image 1

To a 1M solution of sodium hydroxide (15 ml) was added a hydrochloride of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl) -3,5-dimethyl-4-phenylpiperidin-4-ol, from Example 24 (200 mg, 0.48 mmol). The suspension was stirred and extracted with ethyl acetate (2 x 30 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The residual oil was dissolved in methanol (5 ml) and acetic acid (275 µl, 4.8 mmol), [(1-ethoxycyclopropyl) oxy] (trimethyl) silane (580 µl, 2.88 mmol) and sodium triacetoxyborohydride were added (90 mg, 0.96 mmol) at room temperature. The reaction mixture was heated at reflux for 2 hours, cooled to room temperature and methanol (5 ml) was added. The mixture was filtered and the filtrate was concentrated in vacuo. The recovered solid was partitioned between a 1M solution of sodium hydroxide (10 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. Purification by column chromatography on silica gel using dichloromethane: methanol (100: 0 -97: 3) as eluent gave the desired product as a colorless oil 131 mg. This was converted into the hydrochloride salt by treatment with 4M hydrogen chloride in dioxane followed by evaporation of the solvent to give a white solid. 1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 6.99-7.37 (m, 7H), 7.54-7 , 71 (m, 1 H)

LRMS (ESI +) = 455 [MH +]

[α] D25 = -64.04 (c = 0.26, MeOH)

Example 42

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyrimidin-4-yl] pyrrolidin-3-yl] carbonyl hydrochloride} -3.5 hydrochloride -dimethyl-4-phenylpiperidin-4-ol

image 1

A hydrochloride solution of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidine-4 -ol, from 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 1M solution of 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 into 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 a solidified product that was then isolated by filtration. 1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 8.71 (m, 1H)

LRMS (ESI +) = 493 [MH +]

[α] D25 = -54.71 (c = 0.35, MeOH)

Example 43

(3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4-cyclopropyl-3 hydrochloride, 5-dimethylpiperidin-4-ol The title compound was prepared from the compounds of Preparations 1 and 61 by a procedure similar to that described for Example 8.

image 1

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.19-0.53 (m, 4H), 0.65-0.99 (m, 6H), 1.27-1.74 (m, 2H) , 1.47 (s, 9H), 5 2.50-3.01 (m, 2H), 3.15-4.04 (m, 8H), 4.12 (m, 1H), 7.08 ( m, 2H), 7.49-7.64 (m, 1H)

LRMS (ESI +) = 435 [MH +]

[α] D25 = -21.74 (c = 0.33, MeOH) Example 44 Hydrochloride

10 (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-pyrimidin-4-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl- 4-pyridin-2-yl-piperidin-4-ol

image 1

The title compound was prepared from the compounds of Example 23 and 4-chloropyrimidine (Biorg. Chem. 30 (3), 188, 2002) by a procedure similar to that described for Example 42.

1H NMR (400 MHz, CD3OD) Rotamers δ 0.45-0.65 (m, 6H), 1.07-2.50 (m, 2H), 2.66-3.28 (m, 2H), 3 , 79-4.52 (m, 8H), 15 6.90-8.26 (m, 7H), 7.96 (m, 1H), 8.56 (m, 1H), 8.73 (m, 2H)

LRMS (APCI +) = 494 [MH +]

[α] D25 = -30.35 (c = 0.30, MeOH) Example 45 Hydrochloride

20 (3R, 4R, 5S) -4- (3,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -3.5 -dimethylpiperidin-4-ol

image 1

To a solution of (3R, 4S) -3- (2,4-difluorophenyl) -4 - {[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3,5-dimethylpiperidine- 1-yl] carbonyl} pyrrolidin-1-carboxylic acid tert-butyl ester of Preparation 63 (176 mg, 0.32 mmol) in dichloromethane (2 ml) was added a 4M solution of hydrogen chloride in dioxane ( 2 ml) at temperature

25 environment. The reaction mixture was stirred overnight at room temperature. Then, the solvent was evaporated and the solid residue 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. 1H NMR (400 MHz, CD3OD) (Rotamers) � 0.31-0.76 (m, 7 H), 1.81-2.00 (m, 1H), 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, 1H), 4.03 ( m, 1H), 4.34 (d, 1H), 7.04-7.27 (m, 4H), 7.46-7.60 (m, 2H).

30 LRMS (APCI) 451 [MH +] [�] 25

D = -65.29 (c = 0.17, MeOH). Example 46 Hydrochloride

(3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4- [4- (trifluoromethyl) phenyl] piperidin-4-ol

image 1

The title compound was prepared from the compound of Preparation 66 by a procedure similar to that described for Example 45.

1H NMR (400 MHz, CD3OD): (rotamers) □□ 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, 1H), 4 , 05 (m, 1H), 4.34 (d, 1H), 7.02-7.23 (m, 3H), 7.51-7.69 (m, 10 3H).

LRMS (APCI) = 483 [MH +] [□] 25

D = -55.67 (c = 0.26, MeOH). Example 47 Hydrochloride

15 (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-Difluorophenyl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -3,5-dimethyl- 4-pyridin-2-yl-piperidin-4-ol

image 1

The title compound was prepared from the compound of Example 23 and 3-chloropyridazine (J. Med. Chem. 30 (2), 239, 1987) by a procedure similar to that described for Example 31.

1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.46-0.66 (m, 6H), 1.02-2.49 (m, 2H), 2.65-3.28 (3 xm, 2H ), 3.78-4.27 20 (m, 7H), 4.48 (m, 1H), 6.98-7.22 (m, 2H), 7.49-8.29 (m, 5H) , 8.55 (d, 1H), 8.65 (t, 1H), 8.73 (d, 1H)

LRMS (APCI) 494 [MH +]

[α] D25 = -21.45 (c = 0.27, MeOH)

Example 48

(3R, 4R, 5S) -1 - {[(3S, R) -4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-phenylpiperidin-4-ol hydrochloride

image 1

The title compound was prepared from the compound of Preparation 69 by a procedure similar to that described for Example 45. 1H NMR (400 MHz, CD3OD) (Rotamers) δ 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, 1H), 4.20 (m, 1H), 7.07-7.42 (m, 9H). 30 LRMS (APCI) 413 [MH +]

[α] D25 = -122.15 (c = 0.36, MeOH) Example 49 4 - ((3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- ( 2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -4-hydroxy-3,5

dimethylpiperidin-4-yl) benzonitrile

image 1

5 The title compound was prepared from the compounds of Preparations 1 and 72 by a procedure similar to that described for Example 9. 1H NMR (400 MHz, CD3OD) δ (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, 1, H), 7.05-7.15 (m, 3H), 7.62-7.73 (m, 2H), 8.10-8.20 (m, 2H) 10 LRMS (APCI) = 496 [MH +] [α] 25

D = -97.7 (c = 0.30, MeOH) Example 50 Hydrochloride

(3R, 4R, 5S) -4- (4-chlorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl} -3.5 -dimethyl-piperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 33 and 43 by a procedure similar to that described for Example 9. 1H NMR (CD3OD, 400 MHz): (Rotamers), 0.30-0 , 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 , 1H), 3.11-4.18 (m, 7H), 4.31 (m, 1, H), 6.80-7.05 (m, 5H), 7.30-7.65 (m , 2H) 20 LRMS (APCI) = 492 [MH +] [�] 25

D = -43.8 (c = 0.35, MeOH)

Example 51

(3R, 4R, 5S) -4- (3,4-difluorophenyl) -1 {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride} - 3,5-dimethyl-piperidin-4 25 -ol

image 1

The title compound was prepared from the compounds of Preparations 39 and 33 by a procedure similar to that described for Example 8.

1H NMR (400 MHz, CD3OD): (rotamers) image4 = 0.30-0.59 (4 xd, 6H), 1.36-1.41 (m, 6H), 1.66-1.98 (m, 1H), 2.66-2.81 30 ( m, 2H), 3.12 (t, 1H), 3.38-3.49 (m, 3H), 3.61-3.70 (m, 1H), 3.71-3.83 (m, 2H), 3.90-4.05 (m, 2H), 4.35 (dd, 1H), 7.02

-7.31 (m, 5H), 7.57-7.68 (m, 1H). LRMS (APCI) = 493 [MH +]. [�] 25

D = -49.77 (c = 0.21, MeOH).

Example 52

(3R, 4R, 5S) -4, - (2,4-difluorophenyl) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidin-3-yl] carbonyl hydrochloride ) -3,5-dimethylpiperidin4-ol

image 1

The title compound was prepared from the compounds of Preparations 33 and 49 by a procedure

10 similar to that described for Example 9. 1H NMR (CD3OD, 400 MHz): (Rotamers), 0.34-0.52 (3 xd, 6H) 0.79 -1.20 (3 xm, 2H ), 1.39 (m, 6H), 1.49-2.30 (3 xm, 2H), 2.65 (m, 1H), 3.19 -4.21 (m, 7H), 4.35 (m, 1, H), 6.80-7.18 (m, 4H), 7.28-7.75 (m, 2H)

LRMS (APCI) = 493 [MH +] [�] 25

D = -49.8 (c = 0.33, MeOH) Example 53 Hydrochloride of (3R, 4R, 5S) -1 - {[(3S, 4R) -4- (2,4-difluorophenyl) -1- ethylpyrrolidin-3-ylcarbonyl} -4- (3-fluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

The title compound was prepared from the compounds of Preparations 46 and 75 by a procedure similar to that described for Example 9.

1H NMR (CD3OD, 400 MHz): (Rotamers), 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, 1H), 3.11 -4.20 (m, 7H), 4.31 (m, 1, H), 6.85- 7.20 (m, 5H), 7.35 (m, 1H), 7.55-7.95 (m, 1H)

LRMS (APCI) = 461 [MH +] [□] 25

D = -57.3 (c = 0.35, MeOH) Preparation 1 Acid hydrochloride (3S, 4R) -1-tert-butyl-4- (2A-difluorophenyl) pyrrolidine-3-carboxylic acid

image 1

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 in a dry nitrogen atmosphere was added potassium trimethylsilanolate (3.5 g, 24.6 mmol) in a single portion. The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 24 hours. Then, 4M hydrogen chloride was added in

5

10

fifteen

twenty

25

30

35

40

Four. Five

dioxane (60 ml) and the resulting mixture was stirred under a dry nitrogen atmosphere at room temperature for 30 minutes, then concentrated in vacuo, providing the hydrochloride salt of the title compound as a white solid containing potassium chloride. (8.4 g, approx. 100%).

1H NMR (400 MHz, CDCl3) δH 1.40 (9H, s), 3.45 (2H, m), 3.90 (4H, m), 7.00 (2H, m), 7.60 (1H , m);

LRMS (APCl) 284 (100%) [MH +].

Alternative procedure (isolation as zwitterion)

A solution of lithium hydroxide (0.93 g, 39 mmol) in water (15 ml) was added dropwise to a stirred suspension of (4S) -4-benzyl-3 - ([(3S, 4R) -1 -terc-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl) -1,3-oxazolidin-2-one, of preparation 22b (8.63 g, 19.5 mmol) in tetrahydrofuran (50 ml). Then, the resulting reaction mixture was stirred at room temperature for 1.5 hours, diluted with water (50 ml) and extracted with ethyl acetate (4 x 150 ml). The aqueous phase was separated, treated with 2M aqueous solution of hydrogen chloride (19.5 ml), concentrated to dryness and azeotroped with toluene (5 x 50 ml). The residual white solid was triturated in dichloromethane (40 ml) and the resulting lithium chloride was filtered off. Then, the residue was evaporated, providing the product as a white foam, 5.05 g. MS m / z (APCl +): 284 [MH +]; 1H NMR (CD3OD, 400 MHz) δ 1.44 (s, 9H), 3.36 (m, 2H), 3.64 (t, 1H), 3.25 (dd, 1H), 3.88 (m , 3H), 6.98 (t, 2H), 7.55 (c, 1H).

Preparation 2

(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) methyl pyrrolidine-3-carboxylate

image 1

To a stirred solution of methyl (2E) -3- (2,4-difluorophenyl) acrylate of preparation 3 (10 g, 50.5 mmol) and N- (methoxymethyl) -2-methyl-N - [(trimethylsilyl) ) methyl] propan-2-amine (preparation 4) (10.3 g, 50.5 mmol) in dichloromethane (200 ml) at room temperature in a dry nitrogen atmosphere was added trifluoroacetic acid (0.39 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] propan-2-amine (from preparation 4) (3.9 g, 19) was added to the reaction mixture , 2 mmol) and trifluoroacetic acid (0.39 ml, 5.1 mmol). The resulting mixture was stirred at room temperature in a dry nitrogen atmosphere for 18 hours, then quenched by the addition of a saturated solution of sodium bicarbonate (200 ml) and extracted with ethyl acetate (3 x 75 ml). The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by an automated ultrasound column chromatography system (CombiFlash® Separation System Sg 100c from Isco) using a pre-filled column (Redisep ™ Disposable Column for Isco Ultrafast Chromatography, 40 g column) eluting with 5-ethyl acetate % in pentane increasing polarity with a linear gradient to 100% ethyl acetate over the course of 1 hour. Then, the residue was subjected to chiral HPLC (eluting with 95: 5 hexane: isopropyl alcohol at 80 ml / min at room temperature on a Chirapak AD500 * 80 mm column) to provide the desired enantiomer of the title compound, which is designated herein as Enantiomer 1 and which was obtained as the most operating enantiomer (retention time 8 minutes) in the form of a transparent oil (6.1 g, 80%) with enantiomeric excess> 99% as determined by HPLC with reference to racemic patterns. The unwanted enantiomer was obtained in the form of the slowest elution component (Enantiomer 2, retention time 8.7 min). 1H NMR (400 MHz, CDCl3) δH 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 (APCI) 298 (100%) [MH +].

Preparation 3

(2E) -3- (2,4-Difluorophenyl) methyl acrylate

image 1

To a solution of 2,4-difluorocynamic acid (20 g, 135 mmol) in N, N-dimethylformamide (500 ml) at room temperature under a dry nitrogen atmosphere, potassium carbonate (90 g, 675 mmol) was added and then iodomethane (21 ml, 337.5 mmol). The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere for 7 hours before it was quenched by the addition of water (1 L) and extracted with diethyl ether (3 x 200 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by an automated flash column chromatography system.

5

10

fifteen

twenty

25

30

35

40

(Isco CombiFlash® Separation System Sg 100c) using a pre-filled column (Redisep ™ Disposable Columns for Ultrafast Chromatography of lsco, 120 g column) eluting with 2% ethyl acetate in pentane increasing polarity in a linear gradient of acetate 10% ethyl in pentane for 1 hour to provide the title compound as a white solid (20.5 g, 77%). 1H NMR (400 MHz, CDCl3) δH 3.80 (3H, s), 6.50 (1H, d), 6.85 (1H, m), 7.50 (1H, m), 7.75 (1H , d); LRMS (APCI) 216 [MNH4 +], 199 [MH +].

Preparation 4

N- (Methoxymethyl) -2-methyl-N - [(trimethylsilyl) methyl] propan-2-amine

image 1

2-Methyl-N - [(trimethylsilyl) methyl] propan-2-amine (from preparation 5) (4.31 g, 27 mmol) was added to an ice-cold methanol mixture (1.29 ml, 31, 8 mmol) and aqueous formaldehyde (37% w / v, 2.49 ml, 33 mmol) for 45 minutes. The heterogeneous mixture was stirred at 0 ° C for 2 hours and then solid potassium carbonate (325 mesh) (1.08 g, 13 mmol) was added and the mixture was stirred for 30 minutes at 0 ° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic phases 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 as a colorless oil (5 , 09 g). The mixture was used directly without further purification in preparation 2. 1H NMR (400 MHz, CD3OD) δH 0.04 (s, 9H), 1.11 (s, 9H), 2.27 (s, 2H), 3 , 34 (s, 3H), 4.17 (s, 2H).

Preparation 5

2-Methyl-N - [(trimethylsilyl) methyl] propan-2-amine

image 1

A procedure is given in J. Org. Chem. 53 (1), 194, 1988 for the preparation of this intermediate. Alternative procedures are given below:

A solution of chloromethyltrimethyl silane (50 g, 408 mmol) and tert-butylamine (130 ml) in a dry nitrogen atmosphere was heated at 200 ° C in a tightly sealed tube for 18 hours before inactivating it by adding a 2 M solution of sodium hydroxide (700 ml). The resulting mixture was extracted with diethyl ether (3 x 100 ml) and the combined organic phases were distilled under a dry nitrogen atmosphere at 1 atmosphere to provide the title compound as a clear oil (62 g, 96%). 1H NMR (400 MHz, CDCl3) δH 0.05 (9H, s), 1.05 (9H, s), 1.95 (2H, s).

Alternative Preparation:

Chloromethyltrimethylsilane (100 ml, 730 mmol) and tert-butylamine (250 ml, 2400 mmol) were placed in a tightly sealed pump and heated with vigorous stirring for 18 hours. With cooling to room temperature, the suspension of the hydrochloride salts produced and residual excesses of tert-butylamine were poured into a 4M solution of sodium hydroxide (500 ml) and stirred vigorously for 1 hour. The aqueous phase was separated and the organic phase was vigorously stirred with water (3 x 500 ml) (the excess of tert-butylamine is very soluble in water, the tert-butyl-trimethylsilanylmethylamine product is only slightly soluble in water). The residual organic phase was dried over sodium sulfate to give essentially pure tert-butyl-trimethylsilylmethylamine (105.4 g), which was used directly in preparation 23 without further purification. 1H NMR (400 MHz, CD3OD) 0.05 (s, 9H), 1.05 (s, 9H), 1.95 (s, 2H).

Preparation 6

(3R, 4s, 5S) -1-Benzyl-4-cyclohexyl-3,5-dimethylpiperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

35

40

(3R, 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 in a dry nitrogen atmosphere. The solution was cooled to -78 ° C and cyclohexylmagnesium chloride (2M solution in tetrahydrofuran) (2.42 ml, 4.84 mmol) was added dropwise over 2 hours. The reaction mixture was allowed to reach room temperature slowly for 18 hours. The reaction was stopped by careful addition of water (1 L) and diluted with ethyl acetate (1 L). The organic phase was separated and washed with water (2 x 1 L) and then brine. After drying over anhydrous sodium sulfate and filtration, the solution was evaporated to give a yellow oily residue (approx. 50 g). This material was purified by flash chromatography on silica gel in two batches eluting with 10% acetone in hexane. This provided the N-benzyl piperidinol intermediate containing approx. 8% residual 1-benzyl-3,5-dimethyl-piperidin-4-one, as estimated by 1 H NMR.

Preparation 7

(3R, 4s, 5S) -4-Cyclohexyl-3,5-dimethylpiperidin-4-ol

image 1

To a solution of (3R, 4s, 5S) -1-benzyl-4-cyclohexyl-3,5-dimethylpiperidin-4-ol, of preparation 6 (23 g, 76 mmol) in methanol (762 ml) was added ammonium 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 made basic with a 5M solution of sodium hydroxide and extracted with ethyl acetate (ca. 600 ml). The organic phase was washed four times with a 5M solution of sodium hydroxide and (the resulting organic phase) dried over anhydrous sodium sulfate. After filtration, evaporation of the aqueous phase gave the title compound as a white powder (11 g, 68%). LC-MS 212 [MH +]; 1H NMR (400 MHz, CDCl3) δ 0.84 (6H, d), 0.83-0.85 [1H, m (darkened)], 1.16 (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 indicated in the literature for (3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol [J. Med. Chem. 1964, 7, 726]

Preparation 8

(3R, 4s, 5S) -1-Benzyl-4-butyl-3,5-dimethylpiperidin-4-ol

image 1

(3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one [prepared according to preparation 14; also described in J. Med. Chem. 1964, 7, 726] (500 mg, 2.3 mmol) in anhydrous tetrahydrofuran (15 ml) and placed in a flame-dried round bottom flask in a nitrogen atmosphere. The solution was cooled to -78 ° C and n-butylmagnesium chloride (2M solution in tetrahydrofuran) (2.42 ml, 4.84 mmol) was added dropwise by syringe and then the solution was allowed to reach temperature ambient. The reaction mixture was cooled again to 0 ° C, quenched by the addition of water and diluted with ethyl acetate. The organic phase was separated and washed twice with water before drying 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 in a gradient to 30% acetone in dichloromethane, providing the title compound (300 mg, 47%) . 1H NMR (400 MHz, CD2Cl2) δ 0.78 (6H, d), 0.91 (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

image 1

5

10

fifteen

twenty

25

30

35

(3R, 4s, 5S) -1-benzyl-4-butyl-3,5-dimethylpiperidin-4-ol (from preparation 8) (300 mg, 1.1 mmol) was dissolved in methanol (10 ml). Palladium hydroxide on carbon (525 mg) was added followed by ammonium formate (237 mg, 5.5 mmol) and 2M hydrochloric acid solution (1.1 ml, 2.2 mmol). The reaction mixture was heated at 60 ° C overnight before cooling to room temperature. Then, the mixture was filtered through Celite®, washing the cake with methanol (500 ml). The filtrate was evaporated and the residue was diluted with water, the pH was adjusted to approx. 12 by the addition of saturated sodium carbonate solution and extracted with ethyl acetate. The organic phase was washed with water, then dried over sodium sulfate and evaporated to provide the title compound (75 mg, 37%). 1H NMR (400 MHz, CD2Cl2) δ 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

image 1

To a solution of 4-bromotoluene (0.80 ml, 6.5 mmol) in cyclohexane (2 ml) at 0 ° C in a dry nitrogen atmosphere was added n-butyllithium (2.5 M in hexanes) ( 2.5 ml, 6.25 mmol). The resulting mixture was stirred at 0 ° C under a nitrogen atmosphere dried for 2 hours. Then, (3R, 5S) -3,5-dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (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, then quenched at 0 ° C with water (10 ml). A 2M hydrochloric acid solution (10 ml) was added, the mixture was extracted with ethyl acetate (20 ml) and the organic phase was discarded. The aqueous phase was basified to pH 11 with a 2M solution of sodium hydroxide and extracted with ethyl acetate (2 x 15 ml). The combined organic phases (from the extraction of only the basic aqueous phase) were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (136 mg, 47%). .

1H NMR (400 MHz, CDCl3) δH 0.55 (6H, m), 2.00 (3H, m), 2.35 (3H, s), 5.80 (5H, m), 7.10 (4H , m); LRMS (APCI) 220 (100%) [MH +]; HRMS C14H22O [MH +] requires 220.1695, found 220.1693.

Preparation 11

(3R, 5S) -3,5-Dimethyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester

image 1

(3R, 5S) -1-Benzyl-3,5-dimethyl-piperidin-4-one (from preparation 14) was dissolved in ethanol (200 ml) and di-tert-butyl dicarbonate (5.08 g) was added , 23 mmol), followed by palladium on carbon hydroxide (20% on carbon, 200 mg) and the reaction mixture at a hydrogen pressure of 40 atmospheres and stirred overnight at room temperature. Then, the reaction mixture was filtered through a layer of Celite® and Arbocel® was concentrated in vacuo, providing a yellow oil crystallized after a rest period, providing the title compound (5.2 g, 90%) of sufficient purity to be used directly in the next step (preparation 10). 1H NMR (400 MHz, CDCl3) δ 1.03 (6H, d), 1.49 and 1.52 [9H, 2 xs (Rotamers)], 2.48-2.76 (4H, m), 4, 24-4.53 (2H, m).

Preparation 12

Dimethyl 2,4-Dimethyl-3-oxopentanedioate

image 1

5

10

fifteen

twenty

25

30

35

40

Potassium carbonate (325 mesh) (298.8 g, 2160 mmol) was added to a solution of dimethyl 3-oxopentanedioate (150.62 g, 865 mmol) in tetrahydrofuran (1.33 L). The suspension was heated at 45 ° C. Iodomethane (107.7 ml, 1.73mol) was added slowly at a rate such that the temperature was maintained below 60 ° C. The suspension was stirred between 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 quantitatively. 1 H NMR indicated that the material was a tautomeric mixture of enol and keto and was used in preparation 13 without further purification. MS (APCl-): 201 (M + H); 1H NMR (400 MHz, CDOD) 1.25 (s, 6H), 3.65 (s, 6H).

Preparation 13

Dimethyl 1-Benzyl-3,5-dimethyl-4-oxopiperidin-3,5-dicarboxylate

image 1

A 1M solution of hydrochloric acid (69 ml, 68.8 mmol) was added to a cooled solution (9 ° C) of dimethyl 2,4-dimethyl-3-oxopentanedioate [of preparation 12] (69.6 g, 344 mmol) and benzylamine (37.6 ml, 344 mmol) in methanol (1.8L). Formaldehyde, 37% solution in water (56.8 ml, 760 mmol) was added, the solution was stirred for 3 days at room temperature and then concentrated to dryness. The crude dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidin-3,5-dicarboxylate (125.7 g) was obtained as a bright brown oil. GC-MS analysis indicated that the material was 91% pure and was used in preparation 14 without further purification.

GC-MS: 333 (M +); 1H NMR (400 MHz, CDCl3) δ 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

image 1

A mixture of the crude dimethyl 1-benzyl-3,5-dimethyl-4-oxopiperidin-3,5-dicarboxylate (786.0 g, approx. 2.3mol) and 1 M solution of hydrochloric acid (11.5 l ) heated at reflux for 24 hours. The reaction mixture was cooled to 10 ° C and a 25% by weight solution of aqueous sodium hydroxide (1.92 kg) was added slowly. The mixture was extracted with dichloromethane (4 x 4 L) and the combined organic extracts were concentrated to dryness, giving the crude (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one (475 g) in Shape of a bright brown oil. 1 H NMR indicated that it was a 6: 1 mixture of desired diastereomers: 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), providing 94.8 g of the pure (3R, 5S) -1-benzyl-3,5-dimethyl-piperidin-4-one (diastereomeric ratio> 19: 1) and 44, 8 g of the least 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 +); 1H NMR (400 MHz, CDCl3) δ 7.27-7.38 (m, 5H), 3.60 (s, 2H), 3.15 (m, 2H), 2.70 (m, 2H), 2 , 04 (t, J = 11.6 Hz, 2H) 0.93 (d, J = 6.6 Hz, 6H).

Alternative procedure:

A mixture of crude 1-benzyl-3,5-dimethyl-4-oxo-piperidindicarboxylic acid methyl ester of preparation 13 (786.0 g, approx. -2300 mmol) and 1 M aqueous hydrochloric acid (11.5 l) heated at reflux for 24 hours. The reaction mixture was cooled to 10 ° C and 25% by weight aqueous sodium hydroxide (1.92 kg) was added slowly. The mixture was extracted with dichloromethane (4 x 4 L). The combined organic extracts were concentrated to dryness, giving 1-benzyl-3,5-dimethyl-piperidin-4-one (475 g) as a light brown oil. 1 H NMR indicated a 6: 1 diastereomeric mixture of cis: trans. A portion of the crude diastereomeric mixture (15 g) was purified using a chromatographic purification system using a normal phase Redisep silica cartridge column (330

5

10

fifteen

twenty

25

30

35

40

Four. Five

g), a solvent flow rate of 100 ml / min, with circumvention of cyclohexane / ethyl acetate, linear gradient of 2-3% ethyl acetate for 25 minutes, linear gradient of 3-14% ethyl acetate for 10 minutes, completing the elution with 14% ethyl acetate. This produced pure (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one (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-dimethylpiperidin-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 dissolved again in dichloromethane (500 ml). insoluble solids were removed by filtration and then the solvent was evaporated to give a 96: 4 enriched mixture of cis: trans by 1 H NMR (quantitative mass recovery). Longer reaction times did not produce any additional enrichment. If needed, the pure cis product could then be obtained by chromatographic purification as described above.

Preparation 15

(3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol

image 1

(3R, 5S) -1-Benzyl-3,5-dimethylpiperidin-4-one (prepared as in preparation 14; also presented in J. Med. Chem. 7, 726, 1964) (5 g, 23 mmol) ) in anhydrous tetrahydrofuran (77 ml) in a flame-dried flask in a dry nitrogen atmosphere. The solution was cooled to -78 ° C and phenyl lithium (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 was quenched by the careful addition of water (50 ml). The resulting mixture was diluted with ethyl acetate and the organic phase was separated and then washed three times with water and once with brine. Then, the organic phase was dried (sodium sulfate), filtered and evaporated. The resulting residue was purified by flash chromatography on silica gel eluting with 10% to 50% ethyl acetate in hexanes (1 L) to provide (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4 -phenylpiperidin-4-ol of purity> 90%.

LRMS: 296 (MH +); 1H NMR (400 MHz, CD2Cl2) δ 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 Procedure:

Phenyl lithium in diisopropyl ether (2M, 34.5 ml, 690 mmol) was added dropwise to a stirred solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one, of the Preparation 14 (10.0 g, 46 mmol) in anhydrous diethyl ether (150 ml) at -78 ° 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 phase was separated, washed with water (3 x 200 ml), 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 colored solid White. The crude compound was> 95% pure by 1 H NMR and was used directly in preparation 21.

LC-MS (ESI +): 296 (M + H); 11H NMR (400 MHz, CD3OD) δ 0.51 (d, 6H), 2.18 (m, 2H), 2.30 (m, 2H), 2.42 (m, 2H), 3.6 (s , 2H), 7.15 (m, 1H), 7.35 (m, 9H).

Preparation 16

(3R, 4s, 5S) -3,5-Dimethyl-4-phenylpiperidin-4-ol

image 1

(3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol of preparation 15 was dissolved in methanol (156 ml) and ammonium formate (4.9 g, 78 mmol) was added ), then palladium hydroxide on carbon (8 g) followed by 2M solution of hydrochloric acid in diethyl ether (11 ml, 22 mmol). A water condenser was equipped in the flask and the reaction was heated at 60 ° C overnight. After cooling to room temperature, the reaction mixture was filtered through Celite® by washing the cake with an additional 1 L of methanol. The combined filtrates evaporated and the

5

10

fifteen

twenty

25

30

35

The residue was dissolved in a minimum amount of water, which was then made basic (at 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 give the title compound (3.23 g, 68%). 1H NMR (400 MHz, CD2Cl2) δ 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 procedure:

(3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-phenylpiperidin-4-ol, of preparation 15 (15 g, 51 mmol) was dissolved in methanol and Pd (OH) 2 / (C) in water at 20% by weight (1.5 g). The mixture was hydrogenated at 50 ° C / 0.34 MPa (50 psi) 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 solid of White color. Recrystallization of the crude material from acetonitrile gave analytically pure (3R, 4s, 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol as white needles (9.6 g).

Preparation 17

(3S *, 4R *) Hydrochloride - 4- (2,4-difluorophenyl) -1-ethylpyrrolidine-3-carboxylic acid

image 1

To a stirred solution of (3S, 4R) -4- (2,4-difluorophenyl) -1-ethylpyrrolidine-3-carboxylate of preparation 18 (5.9 g, 22 mmol) in diethyl ether (59 ml ) at room temperature, in a dry nitrogen atmosphere, potassium trimethylsilanolate (2.36 g, 26 mmol) was added in a single portion. The resulting mixture was stirred at room temperature under an atmosphere of N2 for 3 hours. Then, a solution of 4M hydrogen chloride in dioxane (20 ml) was added and the resulting mixture was stirred under a dry nitrogen atmosphere at room temperature for 18 hours, and then concentrated in vacuo to provide the title compound in form of a white solid containing potassium chloride residues (7.0 g).

1H NMR (400 MHz, CDCl3) δH 1.25 (3H, m), 3.25 (5H, m), 3.8 (2H, m), 4.10 (1H, m), 7.20 (2H , m), 7.80 (1H, m); LRMS (APCI) 256 (100%) [MH +]; HRMS C13H15F2O2 [MH +] requires 256,1144, found 256,1142.

Preparation 18

(3S *, 4R *) - 4- (2,4-Difluorophenyl) -1-methylpyrrolidin-3-carboxylate methyl

image 1

To a stirred solution of (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate, of preparation 19 (10.5 g, 43 mmol) in tetrahydrofuran (215 ml) at room temperature in a dry nitrogen atmosphere, iodoethane (3.8 ml, 48 mmol) and N, N-diisopropylethylamine (8.3 ml, 48 mmol) were added in single portions. The resulting mixture was stirred at room temperature under a dry nitrogen atmosphere 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 pentane: ethyl acetate, increasing the polarity to 1: 1. This gave the title compound as a clear oil (7.9 g, 68%).

1H NMR (400 MHz, CDCl3) δH 1.15 (3H, m), 2.45 (1H, m), 2.55 (1H, m), 2.65 (1H, m), 2.95 (3H , m), 3.15 (1H, m), 3.65 (3H, s), 3.85 (1H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 270 (100%) [MH +].

Preparation 19

(3S *, 4R *) - 4- (2,4-Difluorophenyl) methyl pyrrolidin-3-carboxylate

image 1

5

10

fifteen

twenty

25

30

35

40

To a suspension of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate, of preparation 20 (15 g, 45 mmol) in ethanol (225 ml), a room temperature in a dry nitrogen atmosphere, 10% palladium on carbon (Degussa type) (1.5 g) was added, the reaction mixture was placed at a pressure of 0.34 MPa (50 psi) of hydrogen and It was heated at 40 ° C overnight. After cooling to room temperature, the reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound as an orange oil (10.8 g, 98%).

1H NMR (400 MHz, CDCl3) δH 2.85 (1H, m), 3.15 (1H, m), 3.30 (2H, m), 3.45 (1H, m), 3.65 (4H , m), 6.80 (2H, m), 7.20 (1H, m); LRMS (APCI) 242 (100%) [MH +]; HRMS C12H14F2O2 [MH +] requires 242.0987, found 242.0986.

Preparation 20

(3S *, 4R *) - 1-Benzyl-4- (2,4-difluorophenyl) methyl pyrrolidine-3-carboxylate

image 1

A solution of trifluoroacetic acid (2.42 ml, 31.5 mmol) in dichloromethane (5 ml) was added to a stirred solution at 0-5 ° C of N-benzyl-N- (methoxymethyl) trimethylsilylamine (45.1 g, 190 mmol) and (2E) -3- (2,4-difluorophenyl) acrylate methyl (from preparation 3) (25.1 g, 126 mmol) in dichloromethane (100 ml). After stirring overnight at room temperature, the organic solution was washed with a saturated sodium bicarbonate solution and then 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.

1H NMR (400 MHz, CDCl3) δH 2.80 (1H, m), 3.05 (3H, m), (3.25 (1H, m), 3.62 (3H, s), 3.85 ( 1H, m), 4.20 (2H, s), 6.55 (5H, m), 6.80 (2H, m), 7.40 (1H, m); LRMS (APCI) 332 (100%) [MH +].

Preparation 21

(4S) -4-Benzyl-3 - [(2E) -3- (2-4-difluorophenyl) prop-2-enoyl] -1,3-oxazolidin-2-one

image 1

Oxalyl chloride (19 ml, 216 mmol) in dichloromethane (50 ml) was added dropwise to an ice-cold stirred 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 hour (the residual gases from the reaction were cleaned with a concentrated sodium hydroxide solution). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred at room temperature under a nitrogen atmosphere for 18 hours. Then, the reaction mixture was concentrated and azeotroped with dichloromethane (2 x 50 ml). The resulting acid chloride was dissolved again in dichloromethane (50 ml) and this solution was added dropwise under a nitrogen atmosphere to a vigorously stirred suspension of lithium chloride (23.0 g, 540 mmol), triethylamine (76 ml , 540mol) and (S) - (-) - 4-benzyl-2-oxazolidinone (18.3 g, 103 mmol) in dichloromethane (400 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% solution of citric acid (500 ml). Then, the organic phase was separated and dried over magnesium sulfate. Filtration and evaporation of dichloromethane gave the crude product as an orange oil. The crude material was dissolved again in dichloromethane (100 ml) and the resulting solution was passed through a bed of silica, eluting with dichloromethane. Finally, the filtrate (1 L) was concentrated to provide 30.8 g of the

5

10

fifteen

twenty

25

30

35

40

product in the form of a white solid.

MS m / z (APCl +): 344 [MH +]; 1H NMR (CDCl3, 400 MHz) δ 2.85 (dd, 1H), 3.36 (dd, 1H), 4.22 (m, 2H), 4.80 (m, 1H), 6.90 (m, 2H), 7.68 (m, 5H), 7.68 (dd, 1H), 7.91 (d, 1H), 8.01 (dd, 1H). Preparation 22a (4S) -4-Benzyl-3 - {(3R, 4S) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidin-2-one and Preparation 22b

(4S) -4-Benzyl-3 - {(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidin-2-one

image 1

A stirred solution of (S) -4-benzyl-3- [3- (2,4-difluorophenyl) -acryloyl] -oxazolidin-2-one, of preparation 21 (1.70 g, 4.95 mmol) and N- (methoxymethyl) -2-methyl-N - [(trimethylsilyl) 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 solution of sodium hydrogen carbonate (50 ml). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 ml). The organic fractions were combined and dried over magnesium sulfate. Filtration and evaporation of dichloromethane gave the mixture of crude diastereomers.

Separation by column chromatography on silica gel with gradient elution pentane: ethyl acetate 80/20 at 10/90 v / v gave first 0.74 g (1.67 mmol) 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) pyrrolidine- 3-yl] carbonyl} -1,3-oxazolidin-2-one in the form of 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 -EM m / z (APCl +): 443 [MH +]; 1H NMR (CDCl3, 400 MHz) 8 1.12 (s, 9H), 2.77 (dd, 1H), 2.85 (m, 1H), 3.25 (dd, 1H), 3.17-3 , 47 (m, 1H), 4.15 (m, 3H), 4.65 (m, 1H), 6.74 (t, 1H), 6.82 (t, 1H), 7.17-7, 42 (m, 6H).

(4S) -4-benzyl-3 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidin-2- one -EM m / z (APCl +): 443 [MH +]; 1H NMR (CDCl3, 400 MHz) 1.12 (s, 9H), 2.72 (dd, 1H), 2.83 (m, 2H), 3.20 (m, 2H), 3.36 (t, 1H), 4.14 (m, 3H), 4.29 (m, 1H), 4.67 (m, 1H), 6.77 (t, 1H), 6.85 (t, 1H), 7, 08 (m, 2H), 7.24 (m, 3H), 7.43 (m, 1H). The

carbonyl stereochemistry} -1,3-oxazetyl / pentane.

relative olidin-2-one Y absolute determined of ino (4S) -4-benzyl-3 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] by X-ray analysis of crystals obtained from acetate

Preparation 23

(4S) -4-Benzyl-3 - [(2) -3- (4-chlorophenyl) prop-2-enoyl] -1,3-oxazolidin-2-one

image 1

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 N, N-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 heated to room temperature, stirred for 2 hours and then water (50 ml) was added. The mixture was diluted with dichloromethane (100 ml) and a 5% solution of 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

5

10

fifteen

twenty

25

30

column chromatography on silica gel using dichloromethane as eluent provided the desired product

in the form of a white solid, 14.6 g (74%). 1H NMR (400 MHz, CDCl3) δ 2.86 (dd, 1H), 3.37 (dd, 1H), 4.23 (m, 2H), 4.81 (m, 1H), 7.21-7 , 41 (m, 7H), 7.57 (d, 2H), 7.87 (2xd, 2H) LRMS (APCI) 342 [MH +]

Preparation 24 (4S) -4-Benzyl-3 - {(3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidin-2-one

image 1

To a cooled solution of (4S) -4-benzyl-3 - [(2E) -3- (4-chlorophenyl) prop-2-enoyl] -1,3-oxazolidin-2-one, of preparation 23 (5 g, 14.62 mmol) and N-benzyl-1-methoxy-N - [(trimethylsilyl) methyl] methanamine (5.24 ml, 20.47 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (60 µl , 0.73 mmol). The reaction mixture was stirred at 0 ° C for 20 minutes and then heated to room temperature and stirred for 24 hours. A solution of sodium hydrogen carbonate (80 ml) was added and the reaction mixture was stirred for 10 minutes. The phases were separated, 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 provided the desired product (which is the second eluting diastereomer) as a white crystalline solid, 733 mg (11%).

1H NMR (400 MHz, CDCl3) δ 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, 1H), 7.03 (m, 2H), 7.17-7.39 (m, 12H) LRMS (APCI) 475 [MH +]

Preparation 25

(3S, 4R) -1-Benzyl-4- (4-chlorophenyl) methyl pyrrolidine-3-carboxylate

image 1

To a stirred solution of (4S) -4-benzyl-3 - {[(3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin3-yl] carbonyl} -1,3-oxazolidin-2-one of preparation 24 (2.51 g, 5.28 mmol) and dimethyl carbonate (2.22 ml, 26.4 mmol) in dichloromethane (40 ml), sodium methoxide (1.42 g, 26, was added). 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 provide the desired product as a colorless oil, 1.61 g (79% ).

1H NMR (400 MHz, CDCl3) δ 2.67-3.17 (m, 5H), 3.65 (s, 3H), 3.53-3.75 (m, 3H), 7.20-7, 40 (m, 9H) LRMS (APCI) 330 [MH +]

Preparation 26

Methyl (3S, 4R) -4- (4-chlorophenyl) pyrrolidine-3-carboxylate hydrochloride

image 1

To a solution of methyl (3S, 4R) -1-benzyl-4- (4-chlorophenyl) pyrrolidin-3-carboxylate, of preparation 25 (0.93 g, 2.8 5

10

fifteen

twenty

25

30

35

mmol) in dichloromethane (9 ml) cooled with an ice bath was added 1-chloroethyl chloroformate (0.46 ml). The reaction mixture was allowed to warm to room temperature and 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 it was diluted with dichloromethane, washed with water (20 ml), 5% aqueous citric acid (20 ml) and then Dry over magnesium sulfate and filter. The solvent was removed in vacuo and the residual oil was refluxed 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.

1H NMR (400 MHz, CD3OD) δ 3.64 (s, 3H), 3.31-3.83 (m, 6H), 7.36 (s, 4H) LRMS (APCI) 240 [MH +]

Preparation 27

(2E) -3- (2,4-Difluorophenyl) prop-2-enoyl tert-butyl carbonate

image 1

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. Thin layer chromatography analysis indicated that the desired product had formed and this was used directly in the next step.

Preparation 28

(4S) -4-Benzyl-3 - [(2E) -3- (2,4-difluorophenyl) prop-2-enoyl] -1,3-oxazolidin-2-one

image 1

N-Butyllithium (2.5 M 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 anhydrous tetrahydrofuran (350 ml) at 0 ° C. The resulting solution was cooled to -78 ° C for 30 minutes and added dropwise to a stirring solution of tert-butyl (2E) -3- (2,4-difluorophenyl) prop-2-enoyl 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. Cyclohexane (178.5 ml) and tert-butyl methyl ether (126 ml) were added to the suspension 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%). 1H NMR (400 MHz, CDCl3) � 2.82 (dd, 1H), 3.34 (dd, 1H), 4.20 (m, 2H), 4.77 (m, 1H), 6.84 (m , 1H), 6.91 (t, 1H), 7.20-7.33 (m, 3H), 7.65 (m, 2H), 7.96 (m, 3H).

Preparation 29

(4S) -4-Benzyl-3 - {[(3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidin-2-one

image 1

To a stirred solution of (4S) -4-benzyl-3 - [(2E) -3- (2,4-difiuorophenyl) prop-2-enoyl] -1,3-oxazolidin-2-one, of preparation 28 (46.83 g, 140 mmol) in dichloromethane (300 ml) was added N-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. Mix

5

10

fifteen

twenty

25

30

35

The reaction was heated to room temperature and stirred for 24 hours and a saturated sodium hydrogen carbonate solution (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 provide 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 gave the title compound (which is the second diastereomer to be eluted), 63.0 g (49%). 1H NMR (400 MHz, CDCl3) � 2.75 (m, 3H), 3.12 (t, 1H), 3.24 (m, 2H), 3.70 (c, 2H) 4.13 (m, 2H), 4.27 (c, 1H), 4.33 (m, 1H), 4.67 (m, 1H), 6.57 (m, 1H), 6.84 (t, 1H), 7, 13 (m, 2H), 7.16 (m, 1H), 7.24-7.41 (m, 8H).

Preparation 30

(3S, 4R) -1-Benzyl-4- (2,4-difluorophenyl) methyl pyrrolidin-3-carboxylate

image 1

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 saturated sodium hydrogen carbonate solution (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 under vacuum to give the crude residue. The residue was suspended in hot cyclohexane (300 ml) and stirred until a solid formed. 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 give the desired compound, 38 g (87%).

1H NMR (400 MHz, CDCl3) � 2.67 (t, 1H), 2.86 (m, 1H), 2.93 (t, 1H), 3.04 (m, 2H), 3.64 (s , 3H), 3.65 (t, 1H), 3.84 (m, 1H), 6.72 (m, 1H), 6.80 (t, 1H), 7.23 (m, 2H), 7 , 29-7.38 (m, 5H). [�] 25 D = -38 (c = 0.5, MeOH)

Preparation 31

(35,4R) -4- (2,4-Difluorophenyl) methyl pyrrolidin-3-carboxylate

image 1

Palladium hydroxide (20% on carbon, 1 g) was added to a solution of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate, of the Preparation 30 (10 g, 30 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was hydrogenated at 0.34 MPa (50 psi) 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%). 1H NMR (400 MHz, CD3OD) image4 2.60 (s, 1H), 2.91 (t, 1H), 3.08 (c, 1H), 3.31-3.44 (m, 1H), 3.50 (t, 1H), 3 , 63 (m, 1H), 3.66 (s, 3H), 6.76 (m, 1H), 6.84 (m, 1H), 7.20 (m, 1H). LRMS (EI) 242 [MH +].

Preparation 32

(3S, 4R) -4- (2,4-Difluorophenyl) -1-methyl isopropylpyrrolidine-3-carboxylate

image 1

5

10

fifteen

twenty

25

30

35

Sodium triacetoxyborohydride (1.32 g, 6.22 mmol) and acetic acid (235 µl, 4.14 mmol) were added to a solution of acetone (304 µl, 4.14 mmol) and (3S, 4R) -4- (2,4-Difluorophenyl) methyl pyrrolidine-3-carboxylate, of preparation 31 (1 g, 4.14 mmol) in dichloromethane (20 ml) at room temperature. The resulting mixture was stirred for 2 hours and diluted with dichloromethane (10 ml). An aqueous solution of sodium hydrogen carbonate (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 removed in vacuo to give the crude residue. Purification of the residue by column chromatography using dichloromethane: methanol (99: 1-98: 2) as eluent gave the desired product, 1.01 g (86%).

1H NMR (400 MHz, CDCl3) image4 1.10-1.13 (m, 6H), 2.48 (m, 1H), 2.72 (t, 1H), 3.00 (c, 1H), 3.05-3.12 (m, 3H), 3.65 (s, 3H), 3.83 (c, 1H), 6.73 (m, 1H), 6.82 (t, 1H), 7.37 (c, 1H). LRMS (APCI) 284 [MH +].

Preparation 33

(3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylic acid

image 1

Lithium hydroxide (171 mg, 7.14 mmol) was added to a solution of (3S, 4R) -4- (2,4-difluorophenyl) -1-isopropylpyrrolidine-3-carboxylate of preparation 32 (1 , 01 g, 3.59 mmol) 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 2M aqueous solution of hydrochloric acid (3.59 ml) and extracted with ethyl acetate (20 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to provide the desired product as a foam, 686 mg (71%).

1H NMR (400 MHz, CD3OD) � 1.42 (m, 6H), 3.31 (m, 3H), 3.32 (m, 1H), 3.57 (m, 2H), 3.91 (m , 1H), 7.03 (t, 2H), 7.55 (m, 1H). LRMS (EI) 270 [MH +].

Preparation 34

(2Z) -3- (2,4-Difluorophenyl) methyl acrylate

image 1

To a solution of 18-crown-6 (30 g, 110 mmol), bis (2,2,2-trifluororethyl) (6 ml, 28 mmol) bis-methoxycarbonylmethyl phosphonate in tetrahydrofuran at -78 ° C, hexamethyldisilazide was added potassium (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 heated 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 gave the desired product as a colorless oil, 5.1 g (91%). 1H NMR (400 MHz, CDCl3) � 3.70 (s, 3H), 6.05 (d, 1H), 6.80 (m, 1H), 6.86 (m, 1H), 6.97 (d , 1H), 7.69 (c, 1H). LRMS (APCI) 199 [MH +]

Preparation 35

(2Z) -3- (2,4-Difluorophenyl) acrylic acid A solution of methyl (2Z) -3- (2,4-difluorophenyl) acrylate, of preparation 34 (1.3 g, 6.56 mmol) and 1M lithium hydroxide (314 mg, 13.1 mmol) in tetrahydrofuran (51 ml) was 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 are

image 1

5 separated and the aqueous phase was acidified to pH 2 using a 2M solution of hydrochloric acid (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%). 1H NMR (400 MHz, CD3OD): � 6.09 (d, 1H), 6.93 (m, 2H), 6.97 (d, 1H), 7.66 (c, 1H).

Preparation 36

10 (3R *, 4R *) - 1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid

image 1

To a stirred solution of (2Z) -3- (2,4-difluorophenyl) acrylic acid, of preparation 35 (400 mg, 2.17 mmol) and trifluoroacetic acid (17 µl, 0.2 mmol) in dichloromethane (1 ml) N- (methoxymethyl) -2-methyl-N - [(trimethylsilyl) methyl] propan-2-amine, of preparation 23 (882 mg, 4.35 mmol) was added over 30

15 minutes at 0 ° C. The reaction mixture was heated to room temperature and stirred for 24 hours. The solvent was removed in vacuo, the white residue formed was triturated with diethyl ether (5 ml) and the solid was filtered off to give the desired product, 400 mg (65%). 1H NMR (400 MHz, CD3OD) � 1.46 (s, 9H), 3.31 (s, 1H), 3.59 (m, 1H), 3.69 (m, 1H), 3.78 (d , 1H), 3.89 (t, 1H), 3.97 (m, 1H), 6.93 (m, 2H), 7.41 (m, 1H). LCMS (APCI) = 284 [MH +].

Preparation 37

Methyl 20 (3S, 4R) -4- (2,4-Difluorophenyl) -1-methylpyrrolidin-3-carboxylate

image 1

To a solution of (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate, of preparation 31 (500 mg, 2.07 mmol) and formaldehyde (155 µl, 2.07 mmol ) in dichloromethane (20 ml) acetic acid (188 µl, 2.07 mmol) was added followed by sodium triacetoxyborohydride (659 mg, 3.11 mmol) at room temperature. The reaction mixture is

The mixture was stirred for 2 hours, diluted with dichloromethane (10 ml) and partitioned with a saturated sodium hydrogen carbonate solution (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%). 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.68 (t, 1H), 3.00 (m, 2H), 3.01 (c, 1H), 3.11 (m , 1H), 3.65 (s, 3H), 3.88 (m, 1H), 6.78 (m, 1H), 6.82 (t, 1H), 7.37 (m, 1H). LRMS: m / z APCI + 256 [MH +].

30 Preparation 38

(3R, 4S) -3- (2,4-Difluorophenyl) -4 - {[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] tert-butyl carbonyl} pyrrolidine-1 carboxylate

image 1

5

10

fifteen

twenty

25

30

35

(3R, 4s, 5S) -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol, of preparation 41 (265 mg, 1.2 mmol), acid (3S, 4R) -1 were added - (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid, of preparation 53 (0.75 mg, 1.4 mmol) and triethylamine (0.48 ml, 3.6 mmol) to dichloromethane (25 ml). The stirred suspension was cooled under a nitrogen atmosphere and 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (0.67 ml, 2 mmol) was added dropwise. When the addition was complete, the resulting homogeneous solution was stirred for a further 6 hours at room temperature. The solution was washed with a 10% aqueous solution of potassium carbonate (3 x 20 ml), 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), gradient eluting 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).

1H 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, 1H), 6.90-7.29 ( m, 5H), 7.38-7.85 (m, 2H) [a] 25 D = -82.7 (c = 0.3, MeOH)

Preparation 39

(3R, 4s, 5S) -4- (3,4-Difluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

A solution of 3,4-difluorobromobenzene (4.45 g, 21 mmol) in diethyl ether (25 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-Butyllithium (2.5 M in hexanes) (8.10 ml, 20 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-3,5-dimethylpiperidin-4-one, from preparation 14 (5.90 g, 20 mmol) in diethyl ether (25 ml) was added dropwise, maintaining 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 phase 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 0.34 MPa (50 psi) 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 product from the crude product in acetonitrile provided the desired product as a solid, 1.58 g (24%).

1H NMR (400 MHz, CD3OD) δ 0.60 (d, 6 H), 2.21 (m, 2 H), 3.10 (m, 4H), 7.38 (d, 2H), 7.05 -7.20 (m, 1H), 7.25 (m, 1H), 7.30-7.50 (m, 1H) LRMS: m / z APCI + 242 [MH +]

Preparation 40

(3R, 4s, 5S) -1-Benzyl-4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

A solution of 4-fluorobromobenzene (4.51 g, 0.024 mol) in diethyl ether (20 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-Butyllithium (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. Then, the resulting 4-fluorophenyl lithium solution was added dropwise to a solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one [of preparation 14] (6 g, 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

5

10

fifteen

twenty

25

30

35

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. 1H NMR (400 MHz, CD3OD) δ 0.51 (d, 6H), 2.18 (m, 2H), 2.39 (m, 2H), 2.71 (m, 1H), 3.58 (s , 1H), 3.65 (s, 2H), 7.12 (m, 2H), 7.35 (m, 7H) LRMS (APCI) 314 [MH +]

Preparation 41 (3R, 4s, 5S) -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

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 0.34 MPa (50psi) 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 in acetonitrile provided the desired product as a solid, (3.81 g)

1H NMR (400 MHz, CD3OD) δ 0.54 (d, 6H), 2.18 (m, 2H), 2.85 (m, 4H), 7.05 (m, 2H), 7.20-7 , 45 (m, 2H), LRMS (APCI) 224 [MH +]

Preparation 42

(3R, 5S) -1- (4-Methoxybenzyl) -3,5-dimethylpiperidin-4-one

image 1

A 1M solution of hydrochloric acid (69 ml) was added to a solution of dimethyl 2,4-dimethyl-3-oxopentanedioate, of preparation 12 (69.6 g, 344 mmol) and 4-methoxybenzylamine (44.81 ml, 344 mmol) in methanol (1.8 l). Formaldehyde, 37% aqueous solution (56.8 ml, 760 mmol) was added. The solution was stirred for 72 hours at room temperature and then evaporated to dryness. The crude 1- (4-methoxybenzyl) -3,5-dimethyl-4-oxo-piperidine-dicarboxylic acid dimethyl ester (126.2 g) was added to a 1M solution of hydrochloric acid (1735 ml) and The mixture was heated at reflux for 24 hours. The reaction mixture was cooled to 10 ° C and a 20% by weight aqueous solution of sodium hydroxide (400 ml, 2.0mol) was added slowly. 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 bright brown oil. 1 H NMR of the crude material indicated a 6: 1 mixture of cis: trans. A portion of the crude diastereomeric mixture (15 g) was purified using an automated chromatographic purification system using a normal phase Redisep® silica cartridge column (330 g), a solvent flow rate of 100 ml / min, with elution of cyclohexane / ethyl acetate, linear gradient of 2-3% ethyl acetate for 35 minutes, linear gradient of 3-14% ethyl acetate for 10 minutes, 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 rest period (10.2 g, 99% + by LCMS).

1H NMR (400 MHz, CD3OD) δ 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 (APCI) 248 [MH +]

Preparation 43

(3R, 4s, 5S) -4- (4-Chlorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

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

10

fifteen

twenty

25

30

35

40

Four. Five

temperature below -65 ° C. The mixture was stirred at -78 ° C for 2 hours and allowed to warm to room temperature. Then, the 4-chlorophenyl lithium 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 crude 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. 1-Chloroethyl chloroformate (3.21 ml, 30 mmol) was added dropwise to the stirred solution and, when the addition was complete, the mixture was stirred for a further 3 hours at room temperature.

Then, the mixture was washed with a 10% aqueous solution of potassium carbonate (3 x 25 ml), dried over sodium sulfate and evaporated to dryness. The crude residue was heated under 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 filtered off and the filtrate was evaporated to dryness. Then, the crude product was crystallized from acetonitrile to give the desired product as fine white needles (3.90 g).

1H NMR (400 MHz, CD3OD) δ 0.60 (m, 6H), 2.25 (m, 2H), 3.10 (m, 4H) 7.38 (d, 2H), 7.55 (m, 4H) LRMS (APCI) 240 [MH +]

Preparation 44

(3R, 4s, 5S) -4- (2,6-Difluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

Tert-butyllithium (1.7 M 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, maintaining the temperature below -65 ° C. The mixture was stirred at -78 ° C for 1 hour, then allowed to warm to room temperature overnight. A saturated solution of 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 (0.34 MPa (50psi) 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 provide the desired product (1.78 g) as fine white needles. 1H NMR (400 MHz, CD3OD) (Rotamers) δ 0.60 (d, 6H), 2.21 (m, 2H), 3.10 (m, 4H), 7.38 (d, 2H), 7, 05-7.20 (m, 1H), 7.25 (m, 1H), 7.31-7.50 (m, 1.20H) LRMS (APCI) 242 [MH +]

Preparation 45

(3R, 4s, 5S) -4- (3-Fluorophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol

image 1

N-BuLi (2.5 M in hexanes) (7.2 ml, 18 mmol) was added dropwise to a stirred solution of 3-fluoroiodobenzene (1.91 g, 8.0 mmol) in anhydrous diethyl ether (10 ml) at -78 ° C. The mixture was stirred at -78 ° C for 3 hours and then added (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 saturated solution of ammonium chloride (25 ml) was added, the mixture was stirred for 30 minutes and the organic phase separated. The organic phase was washed with water (3 x 50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo. Recrystallization from ethyl acetate: cyclohexane provided the desired product (2.88 g). 1H NMR (400 MHz, CD3OD) δ 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 (APCI) 344 [MH +]

Preparation 46

5

10

fifteen

twenty

25

30

35

(3R, 4s, 5S) -4- (3-Fluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

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 (0.34 MPa (50psi) 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 in acetonitrile gave the title compound (1.52 g).

1H NMR (400 MHz, CD3OD) 8 0.59 (d, 6H), 2.10 (m, 2H), 2.85 (m, 5H), 6.95 (m, 1H), 7.35 (m , 2H) LRMS (APCI) 224 [MH +]

Preparation 47

(3R, 4s, 5S) -1-Benzyl-4- (4-methoxyphenyl) -3,5-dimethylpiperidin-4-ol

image 1

Tert-butyllithium (1.7 M in pentane) (33.0 ml, 56 mmol) was added to an anhydrous diethyl ether (20 ml) under a nitrogen atmosphere and cooled to -78 ° C. A solution of 4-methoxy-iodobenzene (6.89 g, 29 mmol) in anhydrous diethyl ether (25 ml) was added dropwise to the tert-butyllithium solution, keeping the temperature between -78 ° C and -60 ºC. When the addition was complete, the mixture was stirred for an additional 30 minutes at -78 ° C and then allowed to warm to room temperature. Then, the resulting 4-methoxyphenyl lithium 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 anhydrous diethyl ether (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 phase was separated, washed with water (3 x 100 ml), dried over sodium sulfate and evaporated to dryness to give the crude product, which was recrystallized from cyclohexane / ethyl acetate to give the pure product (7 , 1 g)

1H NMR (400 MHz, CD3OD) δ 0.51 (d, 6H), 2.12 (m, 2H), 2.25 (m, 2H), 2.61 (m, 2H), 3.58 (s , 2H), 3.78 (s, 3H), 6.85 (m, 3H), 7.25 (m, 6H) LRMS (APCI) 326 [MH +]

Preparation 48

(3R, 4s, 5S) -4- (4-Methoxyphenyl) -3,5-dimethylpiperidin-4-ol

image 1

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) was hydrogenated on palladium on carbon (1.0 g) (0.34 MPa (50 psi) 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 provided the desired compound (3.1 g) that was used directly without further purification. 1H NMR (400 MHz, CD3OD) δ 0.52 (d, 6H), 2.00 (m, 2H), 2.68 (m, 4H), 3.78 (s, 3H), 6.82 (d , 2H), 7.20-7.60 (m, 2H). LRMS (APCI) 235 [MH +]

Preparation 49

(3R, 4s, 5S) -4- (2,4-Difluorophenyl) -3,5-dimethylpiperidin-4-ol

image 1

A solution of 2,4-difluorobromobenzene (4.51 g, 22 mmol) in diethyl ether (20 ml) was cooled to -78 ° C in a solution.

10

fifteen

twenty

25

30

35

nitrogen atmosphere N-Butyllithium (2.5 M 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-3,5-dimethylpiperidin-4-one, from preparation 14 (6.00 g, 19 mmol) in diethyl ether (25 ml) was added dropwise, maintaining 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 phase 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 hydrogenated (0.34 MPa (50 psi) 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 in acetonitrile provided the desired product (1.78 g) as fine white needles.

1H NMR (400 MHz, CD3OD) δ 0.60 (d, 6H), 2.21 (m, 2H), 3.10 (m, 4H), 7.38 (d, 2H), 7.05-7 , 20 (a, 1.00H), 7.25 (m, 1H), 7.31-7.50 (m, 1.20H) LRMS (APCI) 242 [MH +]

Preparation 50

(3R, 4s, 55) -1-Benzyl-3,5-dimethyl-4-pyridin-3-ylpiperidin-4-ol

image 1

A cooled solution of 3-bromopyridine (2.4 ml, 25 mmol) in dry diethyl ether (2 ml) was added to a solution of n-butyllithium (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, of preparation 14 (5.42 mg, 25 mmol) in tetrahydrofuran (2 ml) was added at -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 dissolved again 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 give the desired product, 4.35 g (61%). 1H NMR (400 MHz, CDCl3): δ = 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, 1H), 7.84 (a, 1H), 8.47 (d, 1H), 8.68 (a, 1H) LRMS (APCI +) = 297 [MH +]

Preparation 51

(3R, 4s, 5S) -3,5-Dimethyl-4-pyridin-3-ylpiperidin-4-ol

image 1

A mixture of (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-pyridin-3-ylpiperidin-4-ol of preparation 50 (3.0 g, 10.12 mmol) and hydroxide of 20% palladium by weight on carbon (0.45 g) in ethanol (50 ml) was hydrogenated at 40 ° C and 0.28 MPa (40 psi) for 14 hours. Then, the reaction mixture was filtered through Arbocel® and the filtrate was concentrated in vacuo to give the desired product as an off-white foam, 2.05 g

1H NMR (400 MHz, CDCl3): δ = 0.57 (d, 6H), 2.12 (m, 2H), 2.81 (t, 2H), 2.94 (m, 2H), 7.27 (m, 1H), 7.51-7.99 (a, 1H), 8.48 (d, 1H), 8.67 (a, 1H) LRMS (APCI +) = 207 [MH +]

Preparation 52

1-tert-Butyl 3-methyl- (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidin-1,3-dicarboxylate

image 1

5

10

fifteen

twenty

25

30

35

40

To a solution of methyl (3S, 4R) -1-benzyl-4- (2,4-difluorophenyl) pyrrolidin-3-carboxylate, of preparation 30 (1.0 g, 3.01 mmol), 1-methylcyclohexa -1,4-diene (1.25 ml, 11.12 mmol) and di-tert-butyl dicarbonate (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 heated at reflux for 4 hours, cooled to room temperature and filtered through Arbocel®. The filtrate was concentrated in vacuo to give the crude residue that was partitioned between ethyl acetate (80 ml) and a 10% solution of citric acid (5 ml). The phases were separated and the organic phase 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.

1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 3.14-3.25 (m, 1H), 3.25-3.40 (m, 1H), 3.48-3, 59 (m, 4H), 3.68-3.89 (m, 3H), 6.71-6.82 (m, 2H), 7.15 (m, 1H) LRMS (APCI) 242 [MH + -BOC +1]

Preparation 53

(3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid

image 1

Lithium hydroxide (130 mg, 23.5 mmol) was added dropwise to a stirred solution of 3-methyl- (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-1,3-dicarboxylate of 1 -terc-butyl, 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 phase was acidified with a 2M solution of hydrochloric acid (2.7 ml) and was further extracted with ethyl acetate (2 x 40 ml). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo and azeotroped with dichloromethane to give the desired product, 775 mg (87%).

1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 3.23-3.46 (m, 2H), 3.56-3.65 (m, 1H), 3.74-3, 93 (m, 3H), 6.75-6.87 (m, 2H), 7.20 (m, 1H)

LRMS (APCI) 228 [MH + -BOC +1]

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

Preparation 54

(3R, 4S) -3- (2,4-difluorophenyl) -4 - {[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-pyridin-2-ylpiperidin-1-yl] tert-butyl carbonyl} pyrrolidine-1 carboxylate

image 1

A solution of (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperidin-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 a saturated sodium hydrogen carbonate solution (15 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 eluent gave the desired product as a white foam, 380 mg (43%). 1H NMR (400 MHz, CDCl3) (Rotamers) δ 0.27-0.52 (m, 6H), 1.46 (s, 9H), 0.81-1.97 (m, 2H), 2.68 (m, 1H), 2.93-3.24 (m, 2H), 3.38-4.14 (m, 7H), 4.41 (m, 1H), 5.50 (m, 1H), 6.82 (m, 1H), 6.87-7.36 (m, 3H), 7.71 (m, 1H), 8.47 (m, 1H). LRMS (APCI) 516 [MH +].

Preparation 55

5

10

fifteen

twenty

25

30

35

40

(3R, 4S) -3- (2,4-Difluorophenyl) -4 - {[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl] carbonyl} pyrrolidine- Tert-butyl 1-carboxylate

image 1

To a solution of (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid, of preparation 53 (1000 mg, 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 ml) 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (1.5 ml, 2.54 mmol) was added 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 solution of potassium carbonate (2 x 50 ml) was added followed by a 10% solution of 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 eluent gave the desired product as a white foam, 560 mg (43%).

1H NMR (400 MHz, CDCl3) (Rotamers) δ 0.41-0.62 (m, 6H), 0.94-1.24 (m, 1H), 1.47 (s, 9H), 1.65 -2.07 (m, 1H), 2.59-3.02 (m, 1H), 3.15 (m, 1H), 3.40-4.15 (m, 7H), 4.42 (d , 1H), 6.76-6.85 (m, 2H), 7.16-7.41 (m, 6H) LRMS (APCI) 515 [MH +].

Preparation 56

(3R, 4s, 5S) -1-Benzyl-4-isopropyl-3,5-dimethylpiperidin-4-ol

image 1

To a solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidin-4-one of preparation 14 (500 mg, 2.3 mmol) was added isopropyl lithium (0.7 M in pentane) ( 3.6 ml, 2.53 mmol). The reaction mixture was stirred at -78 ° C for 1 hour, then slowly heated 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%).

1H NMR (400 MHz, CDCl3) δ 0.82 (d, 6H), 0.99 (d, 6H), 1.88-2.03 (m, 4H), 2.08 (m, 1H), 2 , 48 (m, 2H), 3.45 (m, 2H), 7.19-7.34 (m, 5H)

LRMS (APCI) 262 [MH +], 244 [MH + -H2O]

Preparation 57

(3R, 4s, 55) -4-Isopropyl-3,5-dimethylpiperidin-4-ol

image 1

A solution of (3R, 4s, 5S) -1-benzyl-4-isopropyl-3,5-dimethylpiperidin-4-ol, of preparation 56 (1.42 g, 5.44 mmol) and palladium hydroxide on carbon (210 mg) in ethanol (25 ml) was hydrogenated for 40 ° C and 0.28 MPa (40 psi) 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 that was recrystallized from acetonitrile to provide the desired product as brown needles, 390 mg (42%).

1H NMR (400 MHz, CDCl3) δ 0.83 (d, 6H), 0.99 (d, 6H), 1.74 (m, 2H), 2.08 (m, 1H), 2.64 (m , 4H) LRMS (APCI) 172 [MH +].

5

10

fifteen

twenty

25

30

35

Preparation 58 (3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-propylpiperidin-4-ol

image 1

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 chloride of propylmagnesium (2 M in 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 slowly heated to room temperature. The reaction mixture was diluted with ethyl acetate (40 ml) and the phases 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: 0.88 ammonia (98: 2: 0-95: 5: 0.5) as eluent gave the desired product, 790 mg (66%).

1H NMR (400 MHz, CDCl3) δ 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 (APCI) 262 [MH +], 244 [MH + -H2O].

Preparation 59

(3R, 4s, 5S) -3,5-Dimethyl-4-propylpiperidin-4-ol

image 1

A solution of (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-propylpiperidin-4-ol, of preparation 58 (780 mg, 3 mmol) and palladium hydroxide (20% carbon, 130 mg) in ethanol (10 ml) was hydrogenated at 40 ° C and 0.28 MPa (40 psi) for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (10 ml). The filtrate was concentrated in vacuo to give the desired product, 504 mg (98%).

1H NMR (400 MHz, CDCl3): δ 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 (APCI) 172 [MH +].

Preparation 60

(3R, 4s, 5S) -1-Benzyl-4-cyclopropyl-3,5-dimethylpiperidin-4-ol

image 1

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 (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 slowly heated to room temperature. The reaction mixture was diluted with water (40 ml) and the phases 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 residue as a result. Purification of the residue by column chromatography using dichloromethane: methanol (100: 0-96: 4) as eluent, provided the desired product as a colorless liquid, 780 mg (65%).

1H NMR (400 MHz, CDCl3) δ 0.35 (m, 4H), 0.52 (m, 1H), 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-dimethylpiperidin-4-ol

image 1

5

10

fifteen

twenty

25

30

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% carbon) (140 mg) in ethanol (10 ml) was hydrogenated at 40 ° C and 0.28 MPa (40 psi) for 24 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (10 ml). The filtrate was concentrated in vacuo to provide the desired product, 480 mg (94%).

1H NMR (400 MHz, CDCl3) δ 0.35 (m, 4H), 0.55 (m, 1H), 0.92 (d, 6H), 1.72 (m, 2H), 1.84 (m , 1H), 2.65 (m, 4H) LRMS (APCI +) = 170 [MH +], 152 [MH + -H2O]

Preparation 62

(3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidine-3-carboxylic acid

image 1

To a solution of methyl (3S, 4R) -4- (2,4-difluorophenyl) -1-methylpyrrolidine-3-carboxylate, of preparation 37 (800 mg, 3.13 mmol) in tetrahydrofuran (10 ml) Lithium hydroxide (150 mg, 6.27 mmol) was added 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 2M hydrochloric acid solution (3.13 ml). The aqueous phase was evaporated and the residue was azeotropically distilled with toluene (6 x 20 ml) to provide an oily residue (1000 mg) that was used without further purification in the subsequent step.

1H NMR (400 MHz, CD3OD) δ 3.05 (s, 3H), 3.41 (m, 1H), 3.50-3.81 (m, 3H), 3.91 (m, 3H), 7 , 06 (m, 2H), 7.62 (m, 1H). LRMS (APCI +): 242 [MH +] LRMS (APCI-): 240 (M-1)

Preparation 63

(3R, 4S) -3- (2,4-difluorophenyl) -4 - {[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1- il] carbonyl} pyrrolidin-1-c tert-butyl arboxylate

image 1

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-dimethylpiperidin-4-ol, of preparation 39 (100 mg, 0.42 mmol), 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (244 µl, 0.41 mmol) and triethyl amine (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 of potassium carbonate (2 x 20 ml) was added. The phases were separated and the organic phase was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to provide the desired product as a white foam, 257 mg (77% ).

1H NMR (400 MHz, CDCl3) (Rotamers) D0.44-0.61 (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, 1H), 7.07-7.15 ( m, 3H). LRMS (APCI +): 551 (MH +)

Preparation 64

(3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4- [4- (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, with the exception that the compound was purified

image 1

5 additionally by column chromatography using pentane: ethyl acetate (4: 1) as eluent.

1H NMR (400 MHz, CDCl3) D0.54 (d, 6H), 1.58 (s, 1H), 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 (APCI) 364 [MH +]

Preparation 65

(3R, 4s, 5S) -3,5-Dimethyl-4- [4- (trifluoromethyl) phenyl] piperidin-4-ol

10

image 1

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) , 20% palladium on carbon (65 mg) and dihydrotoluene (570 µl, 5.4 mmol) in ethanol (10 ml) was heated at reflux for 3 hours. The reaction mixture was filtered through Arbocel® and washed with ethanol (100 ml). The solvent was removed in vacuo to provide the desired compound as a brown foam, 501 mg.

15 (87%). 1H NMR (400 MHz, CDCl3) � 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- (2,4-difluorophenyl) -4 - ({(3R, 4r, 5S) -4-hydroxy-3,5-dimethyl-4- [4- (trifluoromethyl) phenyl] piperidine- Tert-butyl 1-yl} carbonyl) pyrrolidine -1-carboxylate

image 1

twenty

The title compound was prepared in 94% yield from (3S, 4R) -1- (tert-butoxycarbonyl) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylic acid, of preparation 53 and (3R, 4s, 5S) -3,5-dimethyl-4- [4- (trifluoromethyl) phenyl] piperidin-4-ol, of preparation 65 following a procedure similar to that described in preparation 38.

1 H NMR (400 MHz, CDCl3) (Rotamers) � 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), 6.86 (m, 1H), 7.16-7.32 (m, 2H), 7.58 (m, 2H). LRMS (EI) 583 [MH +]

Preparation 67

1-tert-Butyl 3-methyl- (3S, 4R) -4- (4-chlorophenyl) pyrrolidin-1,3-dicarboxylate

image 1

5

10

fifteen

twenty

25

30

35

To a solution of methyl (3S, 4R) -4- (4-chlorophenyl) pyrrolidine-3-carboxylate hydrochloride, of preparation 26 (870 mg, 2.8 mmol) and triethylamine (780 µl, 5.6 mmol ) in dichloromethane (5 ml), di-tert-butyl dicarbonate (610 mg, 2.8 mmol) in dichloromethane (5 ml) was added. 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 a 5% solution of 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 provide the desired product as a colorless oil with quantitative yield.

1H NMR (400 MHz, CDCl3) 8 1.45 (s, 9H), 3.07-3.25 (m, 2H), 3.36 (m, 1H), 3.58 (m, 1H), 3 , 63 (s, 3H), 3.85 (m, 2H), 7.17 (d, 2H), 7.29 (d, 1H)

LRMS (APCI) 340 [MH +], 240 [MH + -BOC + 1]

Preparation 68

(3S, 4R) -1- (tert-butoxycarbonyl) -4- (4-chlorophenyl) pyrrolidine-3-carboxylic acid

image 1

To a solution of 1-tert-butyl 3-methyl (3S, 4R) -4- (4-chlorophenyl) pyrrolidin-1,3-dicarboxylate, of preparation 67 (0.98 g, 2.88 mmol) 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 1M solution of hydrochloric acid (8.65 ml) was added. 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 give the desired product as a white solid, 705 mg (75%). .

1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 3.17 (m, 1H), 3.36 (m, 1H), 3.61 (m, 2H), 3.88 (m , 2H), 7.18 (d, 2H), 7.29 (d, 2H) LRMS (APCI) 226 [MH + -BOC + 1] LRMS (APCI-) = 324 [M-1]

Preparation 69

(3R, 4S) -3- (4-chlorophenyl) -4 - {[(3R, 4r, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl] carbonyl] pyrrolidin-1- tert-butyl carboxylate

image 1

To a solution of (3S, 4R) -1- (tert-butoxycarbonyl) -4- (4-chlorophenyl) pyrrolidine-3-carboxylic acid, of preparation 68 (250 mg, 0.76 mmol), (3R, 4s , 5S) -3,5-dimethyl-4-phenylpiperidin-4-ol, of preparation 16 (190 mg, 0.91 mmol) and triethylamine (320 µl, 2.28 mmol) in ethyl acetate (5 ml) , 1-propylphosphonic acid cyclic anhydride (50% in ethyl acetate) (540 µl, 1.10 mmol) was added at room temperature. The reaction mixture was stirred for 24 hours, a 1M solution of 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 1M solution of 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 provide the desired product as a white foam, 370 mg (95%).

1H NMR (400 MHz, CDCl3) (Rotamers) δ 0.32-0.59 (m, 6H), 1.46 (s, 9H), 0.64-2.05 (m, 2H), 2.63 (m, 1H), 2.79-3.15 (2 xc, 1H), 3.30-4.01 (m, 7H), 4.42 (m, 1H), 7.16-7.40 ( m, 9H) LRMS (APCI) 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

image 1

5

10

fifteen

twenty

25

30

35

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-Methoxybenzyl) -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 About 2 more hours. The mixture was quenched with saturated ammonium chloride (50 ml) and the phases separated. The organic phase was washed with water (3 x 50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo to give (3R, 4s, 5S) -4- (4-bromophenyl) -1- Crude (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol (7.9 g), which was used directly without further purification.

1H NMR (400 MHz, CD3OD) δ 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 (APCI) = 404 [MH +]

Preparation 71

4 - [(3R, 4s, 5S) -4-hydroxy-1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-yl] benzonitrile

image 1

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, 16 mmol), tris (triphenylphosphonium) paladate (1-) (0.462 g, 0.4 mmol) and copper iodide (1.52 g, 8 mmol) in acetonitrile (30 ml) It was heated at 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 that was purified by column chromatography on silica gel using ethyl acetate: hexane (3: 97-15: 85) as eluent to provide the title compound as a colored solid. yellow (2.51 g).

1H NMR (400 MHz, CD3OD) δ 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 (APCI) 351 [MH +]

Preparation 72

4 - [(3R, 4s, 5S) -4-hydroxy-3,5-dimethylpiperidin-4-yl] benzonitrile

image 1

To a solution of (3R, 4s, 5S) -4- (4-isocyanophenyl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol, of preparation 71 (2.50 g, 7, 1 mmol) in dichloromethane (50 ml) triethylamine (2.0 ml, 14 mmol) was added at -15 ° C. 1-Chloroethyl chloroformate (1.50 ml, 14 mmol) was added dropwise to the stirred solution, 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 that was heated under 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 give the pure compound as fine white needles (1.23 g). 1H NMR (400 MHz, CD3OD) δ 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

5

10

fifteen

twenty

25

30

35

(3R, 4s, 5S) -1-Benzyl-3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol

image 1

A solution of 2-bromopyridine (4.10 ml, 0.024mol) in diethyl ether (50 ml) was cooled to -78 ° C under a nitrogen atmosphere. N-BuLi (2.5 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. Then, a solution of (3R, 5S) -1-benzyl-3,5-dimethylpiperidinone from preparation 14 (6.10 g, 28.0 mmol) (50 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 phase was separated, washed with water (3 x 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the desired product as an orange oil 7.31 g

1H NMR (400 MHz, CDCl3): δ = 0.43 (d, 6H), 2.09-2.30 (m, 4H), 2.71 (d, 2H), 3.59 (s, 2H) , 5.48 (s, 1H), 7.19 (m, 1H), 7.22-7.42 (m, 6H), 7.71 (t, 1H), 8.48 (d, 1H) LRMS (APCI +) = 297 [MH +]

Preparation 74

(3R, 4s, 5S) -3,5-Dimethyl-4-pyridin-2-ylpiperidin-4-ol

image 1

A mixture of (3R, 4s, 5S) -1-benzyl-3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol, of preparation 73 (3.0 g, 10.12 mmol) and hydroxide Palladium (20% carbon) (0.45 g) in ethanol (50 ml) was hydrogenated at 40 ° C and 0.28 MPa (40 psi) for 14 hours. The reaction mixture was allowed to cool to room temperature and stirred at 0.28 MPa (40 psi) 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 gave the desired product, 2.05 g ( 99%)

1H NMR (400 MHz, CDCl3) δ 0.43 (d, 6H), 2.00 (m, 2H), 2.84 (m, 4H), 5.50 (a, 1H), 7.20 (m , 1H), 7.33 (d, 1H), 7.72 (t, 1H), 8.49 (d, 1H)

LRMS (ESI +) = 207 [MH +], 413 [2MH +]

Preparation 75

(3S, 4R) -4- (2,4-Difluorophenyl) -1-ethylpyrrolidine-3-carboxylic acid hydrochloride

image 1

Concentrated aqueous hydrochloric acid (10 ml) was added to (3S, 4R) -4- (2,4-difluorophenyl) -1-ethyl-pyrrolidine-3-carboxylate of 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 was azeotropically distilled with toluene (2 x 50 ml). This gave the title compound as an off-white foam, 500 mg.

1H NMR (400 MHz, CD3OD): �� 1.10 (t, 3H), 2.51-2.62 (m, 2H), 2.69 (t, 1H), 2.86 (t, 1H) , 3.05 (t, 1H), 3.10-3.13 (m, 2H), 3.92 (c, 1H), 6.80-6.86 (m, 2H), 7.45 (c , 1 HOUR). LRMS (APCI) = 256 [MH +]

Preparation 76

(3S, 4R) -4- (2,4-Difluorophenyl) -1-ethylpyrrolidin-3-carboxylate A mixture of (3S, 4R) -4- (2,4-difluorophenyl) pyrrolidine-3-carboxylate methyl of Preparation 31 (500 mg, 2.07 mmol), ethyl tosylate (519 mg, 2.59 mmol) and potassium carbonate (573 mg, 4.15 mmol) were heated in acetonitrile at 70 ° C for 16 hours in 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 phase was washed with brine (20 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The above procedure was performed in duplicate. Then, 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.

image 1

1H NMR (400 MHz, CDCl3): �� 1.14 (t, 3H), 2.55-2.62 (m, 1H), 2.63-2.68 (m, 1H), 2.70- 2.73 (m, 1H), 2.95-3.05 (m, 2H), 3.11 (t, 1H), 3.69 (s, 3H), 3.89 (c, 1H), 6 , 76 (t, 1H), 6.83 (t, 1H), 7.37 (c, 1H). LRMS (EI) = 270 [MH +]

In accordance with a preferred embodiment, compounds and intermediates according to the present invention and especially the compounds and intermediates illustrated above herein are made available in a pure isolated manner. As defined herein, pure isolated form means that said compounds and / or intermediates are substantially free of compounds that have alternative stereospecific characteristics. As defined herein, substantially free 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 It is present in the desired stereospecific form.

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 demonstrate functional potencies of less than about 150 nM at the MC4 receptor when tested using the test procedure described in Protocol E.

The EC50 data of MCR1, MCR3, MCR4 and MCR5 for compounds of the invention generated using the test procedures described in protocols A, B, C and D, as well as their relative selectivity for MCR4 versus MCR3, MCR1 and MCR5 are illustrated in Table 5.

Table 5

Nº of Ex.

M504 CE50 (nM) M503 CE50 (nM) M501 CE50 (nM) M505 CE50 (nM) Selectivity MCR3 / MCR4 Selectivity MCR1 / MCR4 Selectivity MCR5 / MCR4

one

25 1389 8100 6710 56 324 268

2

68 8380 - - 123 - -

3

44 2620 - - 60 - -

4

Four. Five - - - - - -

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

Table 6 5

Nº of Ex.

M504 CE50 (nM) M501 CE50 (nM) M505 CE50 (nM) Selectivity MCR1 / MCR4 Selectivity MCR5 / MCR4

one

9.6 1197 2738 125 285

6

19 541 1586 28 83

22

2. 3 - 17754 - 772

13

27 8403 16861 311 624

31

3.6 10687 956 2969 266

3. 4

4 - - - -

12

75 667 20000 9 267

35

1.5 1270 20000 847 13,333

fifteen

6.3 - 3505 - 556

16

54 - - - -

5

9.6 1197 2738 125 285

10

fifteen

twenty

25

30

35

40

Four. Five

Claims (41)

1. A compound of general formula (I) image 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, genometric isomer or tautomer of the same, in which R 1 is selected from: -C1-C6 alkyl, -C2-C6-alkenyl, -C2-C6-alkynyl, -C3-C8-cycloalkyl, -C5-C8-cycloalkenyl, -C1-C2-alkyl-C3-C8-cycloalkyl, aryl, -C1-C2-alkylaryl, heterocyclic groups or - (C1-C2) alkylheterocyclics in which each of the above R1 groups is optionally substituted with one or more groups selected from -C1-C4 alkyl, - (CH2) m, cycloalkyl (C3-C5), halogen, - (CH2) mOR6, -CN, -C (O) OR6, - (CH2) mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which m = 0.1 or 2; R2 is H, OH or OCH3; R3 is selected from: H, - (C1-C6) alkyl, - (C2 - C6) alkenyl, - (C2 - C3) alkynyl, - (C3 - C8) cycloalkyl, (C5 - C8) cycloalkenyl, - (C1C2) alkyl ) cycloalkyl (C3-C8), aryl, -alkylaryl (C1-C2), heterocyclic or -alkyl-heterocyclic (C1-C2) groups in which each of the last ten R3 groups is optionally substituted with one or more groups selected from: -OH, -C1-C4 alkyl, - (CH2) n -cycloalkyl (C3-C6), halogen, -CN, - (CH2) nOR6 or - (CH2) nNR7R6, where n = 0, 1 or 2; R4 is selected from: groups -H, -alkyl (C1-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) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0, 1 or 2; R5 is selected from: -C1-C4 alkyl, -C2-C4-alkenyl, -C2-C4-alkynyl, - (CH2) cycloalkyl (C3-C5), - (CH2) cycloalkenyl (C5), halogen groups , - (CH2) pOR6, - (CH2) pNR7R8, -CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0, 1 or 2; or R4 and R5 can together form a saturated or unsaturated condensed ring of 5 to 7 members; each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; and 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 O, N or S.

2.

A compound according to claim 1, wherein R1 is selected from: -C1-C6 alkyl, -C3-C8-cycloalkyl, -C1-C2-alkyl (C3-C8) -cycloalkyl, phenyl, -C1-C2-alkylaryl, heterocyclic groups or -alkyl heterocyclic (C1-C2) and in which R1 is optionally substituted with one or more groups selected from - (C1-C4) alkyl, - (CH2) mOR6, - (CH2) cycloalkyl (C3-C5), halogen, OCH3, OCH2CH3, CN, CF3, CH2CF3, OCF3 or OCH2CF3 in quem = 1 or 2 and wherein when R1 is a heterocyclic group or a (C1-C2) alkylheterocyclic, said heterocyclic groups are independently selected from 5 to 6 member monocyclic ring systems containing up to 3 heteroatoms independently selected from O, N or S and combinations thereof.

3.

A compound according to claim 1 or 2, wherein R1 is selected from: -C1-C6 alkyl, -C3-C8-cycloalkyl, -C1-C2-alkyl (C3-C8) -cycloalkyl, phenyl, -C1-C2-alkylaryl, heterocyclic groups or -alkyl heterocyclic (C1-C2) wherein each of the above R1 groups is optionally substituted with one or more selected groups between: -C1-C4 alkyl, halogen, - (CH2) mOR6, CN, CF3 or OCF3, in which m = 1 or 2; R2 is OH;

R3 is selected from: -H, -C1-C6 alkyl, cycloalkyl (C3-C8), alkyl (C1-C2) -cycloalkyl (C3-C8), aryl, -alkylaryl (C1-C2), heterocyclic groups or -C1-C2 alkylheterocyclics R3 in which each of the last seven groups is optionally substituted with one or more groups selected from: -OH, -C1-C4 alkyl, - (CH2) n-cycloalkyl (C3-C5), halogen, CN, - (CH2) nOR6 or - (CH2) nNR7R8 in the quen = 0, 1 or 2; R4 is selected from: -H, -C1-C4 alkyl, - (CH2) cycloalkyl (C3-C5), halogen, - (CH2) pOR6 groups, - (CH2) pNR7R8, -CN, -C (O) R6, -C (O) OR6, -C (O) NR7R8, - (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0.1 or 2; R5 is selected from: -C1-C4 alkyl, - (CH2) cycloalkyl (C3-C5), halogen, - (CH2) pOR6, (CH2) pNR7R8 groups, CN, C (O) R6, C (O) OR6, CONR7R8, (CH2) pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 in which p = 0, 1 or 2; 5 10 fifteen twenty 25 30 35 each of R6, R7 and R8 is independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3 is selected from 5 to 6 membered monocyclic ring systems containing up to 2 heteroatoms 2 independently selected from O or N and combinations of the same. and wherein the heterocyclic group of R1 is selected from 5 to 6 membered monocyclic ring systems containing up to 1 heteroatom independently selected from O or N.

Four.

A compound according to any of the preceding claims wherein R3 is -H, -C1-C6 alkyl, -C3-C8-cycloalkyl, -C1-C2-alkyl (C3-C8) -alkyl, -C1-C2-alkyl or a heterocyclic group and in which each of the last five groups R3 is optionally substituted with one or more groups selected from -OH, -alkyl (C1-C4), - (CH2) n -cycloalkyl (C3-C5), halogen, -CN or - (CH2) nOR6, in which n = 0 or 1 and in which R6 is H, CH3 or CH2CH3 and wherein when R3 is a heterocyclic group, said heterocyclic group is selected from systems of 5- to 6-membered heterocyclic ring containing up to 2 independently selected heteroatoms between O or N and combinations thereof.

5.

A compound according to any of the preceding claims, wherein R1 is selected from -C1-C6 alkyl, cycloalkyl (C3-C8), phenyl or heterocyclic groups and in which each of the above R1 groups it is optionally substituted with one or more groups selected from: -C1-C4 alkyl, halogen, -OR6 or CN; R2 is -OH;

R3 is selected from -H, -C2-C6 alkyl, cycloalkyl (C3-C8), alkyl (C1-C2) -cycloalkyl (C3-C8) or heterocyclic groups and in which each of the last four groups R3 is optionally substituted with one or more groups selected from: -OH, -C1-C4 alkyl, - (CH2) n -cycloalkyl (C3-C5), halogen, -CN, -OR6 or - (CH2) nNR7R8, in that 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 6-membered monocyclic ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof and in which the heterocyclic group of R1 is selected from monocyclic ring systems of 6 members containing up to 1 heteroatom independently selected from O or N.

6.

A compound according to any of the preceding claims, wherein the heterocyclic group of R1, when present, is a 6-membered monocyclic ring system containing 1 heteroatom of N.

7.

A compound according to any of the preceding claims, wherein the R3 heterocyclic groups, when present, are a 6-membered monocyclic ring system containing up to 2 N heteroatoms.

8.

A compound according to any of the preceding claims having the general formula (1A)

image 1 in which R1, R2, R3, R4 and R5 are as defined above and in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are trans in relation to each other.

9.

A compound according to any of the preceding claims having the general formula (1B)

in which R1 R2, R3, R4 and R5 are as defined above and in which the stereochemistry of the methyl groups at positions 3 and 5 of the piperidine ring are cis in mutual relation.

10.

A compound according to any of the preceding claims having the general formula (1 B) in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are trans in relation to each other.

eleven.

A compound according to any of the preceding claims having the general formula (1C)

image 1 image 1 wherein R1, R2, R3, R4 and R5 are as defined above in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring are trans in relation to each other and in which the stereochemistry of the groups 10 methyl in positions 3 and 5 of the piperidine ring are cis in mutual relation. 12. A compound according to any of the preceding claims having the general formula (1 D) image 1 in which R1, R2, R3, R4 and R5 are as defined above and in which the stereochemistry of the methyl groups at positions 3 and 5 of the piperidine ring is cis in mutual relation and in which the group R1 in position 4 15 is trans with respect to the methyl groups at positions 3 and 5 of the piperidine ring and the group R2 is cis with respect to the methyl groups.

13.

A compound according to any of the preceding claims having the general formula (1D) in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is trans in relation to each other.

14.

A compound according to any of the preceding claims having the general formula (1 E)

image 1 5 in which R1, R2, R3, R4 and R5 are as defined hereinbefore and in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is trans in relation to each other and in the that the stereochemistry of the methyl groups in positions 3 and 5 of the piperidine ring is cis in mutual relation and in which the group R1 in position 4 is trans with respect to the methyl groups in positions 3 and 5 of the piperidine ring and the R2 group is cis with respect to the methyl groups. 15. A compound according to any of the preceding claims having the general formula (1F) image 1 in which R1, R2, R3, R4 and R5 are as defined above and in which the stereochemistry of the groups at positions 3 and 4 of the pyrrolidine ring is trans in relation to each other and in which the stereochemistry of the methyl groups in positions 3 and 5 of the piperidine ring are cis in mutual relation and in which the group R1 in position 4 15 is trans with respect to the methyl groups in positions 3 and 5 of the piperidine ring and the group R2 is cis with respect to the methyl groups and in which R4 and R5 are in positions 2 and 4 of the phenyl ring. 16. A compound according to any of the preceding claims, wherein R1 is selected from - (C1-C4) alkyl, - (C3-C6) alkyl, 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. A compound according to any of the preceding claims, wherein R1 is selected from n-propyl, i-propyl, n-butyl, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3-fluorophenyl, 4-fluorophenyl groups, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl or pyridin-3-yl. 18. A compound according to any of the preceding claims, wherein R1 is selected Between pyridin-2-yl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl or 3,4-difluorophenyl groups. 19. A compound according to any one of the preceding claims, wherein R3 is -H, -C2-C6 alkyl, -C3-C8-cycloalkyl, (C1-C2) alkyl (C3-C8) cycloalkyl or heterocyclic in which each of the last four R3 groups is optionally substituted with one or more groups selected from -OH, -C1-C4 alkyl or -OR6, in which R6 is -H, CH3 or CH2CH3 and wherein when R3 is a heterocyclic group, said heterocyclic group is a 6-membered monocyclic ring system containing up to 2 N. heteroatoms.

twenty.

A compound according to any of the preceding claims, wherein R3 is selected from: hydrogen, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methoxyethyl, cyclopentyl groups, 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.

twenty-one.

A compound according to any of the preceding claims, wherein R4 is selected from H, F or Cl and R5 is selected from F or Cl.

22

A compound according to any of the preceding claims, wherein the phenyl group having R4 and R5 substituents 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-monosubstituted phenyl group, wherein R4 is H and R5 is F or Cl.

2. 3.

A compound according to any of the preceding claims, wherein the phenyl group having substituents R4 and R5 is selected from 4-chlorophenyl or 2,4-difluorophenyl groups.

24.

A compound according to any one of claims 16 to 23 having the general formula (IF).

25.

A compound according to any of the preceding claims of general formula (IC) in which:

R1 it is a phenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl group; R2 is OH; R3 is H; R4 is selected from: H or F and R5 is selected from: F or Cl.

26.

A 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.

A compound according to any one of claims 1 to 24 of the general formula (IC) wherein:

R1 is a phenyl or pyridin-2-yl group; R2 is OH; R3 it is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahydropyran-4- groups ilo; R4 and R5 are F.

28.

A 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.

A compound according to any one of claims 1 to 24 of the 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; R4 and R5 are F.

30

A 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.

31.

A 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 and 53 and pharmaceutically acceptable salts, solvates or hydrates thereof.

32

A compound according to any of the preceding claims selected from: the compounds of examples number 1, 5, 9, 12, 13 and pharmaceutically acceptable salts, solvates or hydrates thereof.

33.

A compound according to claim 1 selected from (3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl } -3,5-dimethyl-4-phenylpiperidin-4-ol also known as [1-tert-butyl-4- (2,4-difluorophenyl) -pyrrolidin-3-yl] - (4-hydroxy-3,5 -dimethyl-4-phenylpiperidin-1-yl) -methanone and salts of pharmaceutically acceptable acids, hydrates or solvates thereof.

3. 4.

A compound according to claim 1 selected from (3R, 4R, 5S) -1 - {[(3S, 4R) -1-tert-Butyl-4- (2,4-difluorophenyl) pyrrolidin-3-yl hydrochloride ] carbonyl} -3,5-dimethyl-4-172-phenylpiperldin-4-ol and HCl salt of [1-tert-butyl-4- (2,4-difluorophenyl) -pyrrolidin-3-yl] - (4- hydroxy-3,5-dimethyl-4-phenylpiperidin-1-yl) -methanone.

35

A process for the preparation of a compound of the formula I as defined above in

any one of claims 1 to 34 by a coupling reaction of compounds (II) and (III) image 1 in which R1, R2, R3, R4 and R5 are as defined above.

36.

A pharmaceutical composition that includes a compound of the formula (I), (IA), (IB), (IC), (ID), (IE) or (IF) or a salt, hydrate, solvate, stereoisomer, geometric isomer or Pharmaceutically acceptable tautomer thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.

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 additional therapeutic agent is one or more agents selected from: PDE5 inhibitors; NEP inhibitors; selective agonists or modulators of D3 or D4; estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists; testosterone replacement agents, testosterone or a testosterone implant; estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) or estrogen and hormone testosterone replacement therapy agent.

39.

A pharmaceutical composition according to claim 36, wherein the additional therapeutic agent is a PDE5 inhibitor or an NEP inhibitor.

40

A compound of the formula (I), (IA), (IB), (IC), (ID), (IE) or (IF), or a pharmaceutically acceptable salt, stereoisomer solvate, geometric isomer or tautomer thereof, or a pharmaceutical composition according to any of claims 37 to 39, for use as a medicament.

41.

A compound of the formula (I), (IA), (IB), (IC), (ID), (IE) or (IF) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, geometric isomer or tautomer of the themselves, or a pharmaceutical composition according to any of claims 37 to 39, for use in the treatment of female sexual dysfunction, male erectile dysfunction, obesity or diabetes.

42

The use of a compound of the formula (I), (IA), (IB), (IC), (ID), (IE) or (IF), or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or tautomer thereof, or a pharmaceutical composition according to any of claims 37 to 39, for the preparation of a medicament for use in the treatment of female sexual dysfunction, male erectile dysfunction, obesity or diabetes.

43

A compound of the formula (V)

image 1 wherein Rt, R2, R4 and R5 are as described in claim 1 and R3 is a t-butoxycarbonyl group. image 1 image 1 Figure 3 Representation of ORTEP for the crystalline structure of the compound of Example 5. image 1 Figure 4 ORTEP representation for the crystalline structure of the compound of preparation 16 image 1 Figure 5 ORTEP representation for the crystalline structure of the compound of preparation 22B image 1 Figure 6 ORTEP representation for the asymmetric unit of the crystalline hydrochloride structure of (3S, 4R) -4- (2,4-difluorophenyl) -N - [(1R) -1-phenylethyl] pyrrolidin-3-carboxamide