MXPA00005520A - Hydroxamic acid derivatives as matrix metalloprotease (mmp) inhibitors - Google Patents

Abstract

Compounds of formula (I) or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity, wherein the broken line represents an optional bond;A is C or CH;B is CH2, O or absent;R 1 and R2 are each independently selected from hydrogen, C1 to C6 alkyl optionally substituted with C1 to C4 alkoxy or phenyl, and C1 to C6 alkenyl;or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group which optionally incorporates a heteroatom linkage selected from O, SO, SO2 and NR6 or which is optionally benzo-fused;R3 is hydrogen, halo, R7 or OR7;R4 is hydrogen, C1 to C4 alkyl, C1 to C4 alkoxy, trifluoromethyl or halo;R6 is hydrogen or C1 to C4 alkyl;R7 is an optionally substituted monocyclic or bicyclic ring system;m is 1 or 2;and n is 0, 1 or 2;with the proviso that B is not O when A is C;are MMP inhibitors useful in the treatment of, i(inter alia), tissue ulceration, wound repair and skin diseases.

Description

HYDROXAMIC ACID DERIVATIVES AS MATRIX METALOPROTEASE INHIBITORS (MMP) This invention relates to a series of substituted α-aminosulfonyl-acetohydroxamic acids, which are inhibitors of zinc-dependent metalloprotease enzymes. In particular, the compounds are inhibitors of certain members of the matrix metalloprotease family.

(MMP). Matrix metalloproteases (MMPs) constitute a family of structurally similar zinc-containing murine proteases that are involved in the remodeling and degradation of extracellular matrix proteins, both as part of normal physiological processes and pathological conditions. As they have a great destructive potential, MMPs are usually under precise regulation and failures in maintaining the regulation of MMPs can be a component of several diseases and pathological conditions, including the rupture of atherosclerotic plaques, heart failure, restenosis, periodontal disease, tissue ulceration, wound repair, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells. Another important function of certain MMPs is to activate various enzymes, including other MMPs, by cleaving the pro-domains of their protease domains. Thus, some MMPs act by regulating the activities of other MMPs, so that excessive production of one MMP can lead to excessive proteolysis of the extracellular matrix by another MMP. In addition, MMPs have different substrate preferences (shown in the following table for selected members of the family) and different functions within normal and pathological conditions. As recent reviews of MMP, see Current Pharmaceutical Design, 1996, 2, 624 and Exp. Opin. Ther. Patents, 1996, 6, 1305.

PICTURE It is believed that the excessive production of MMP-3 causes a pathological destruction of tissues that is the cause of various diseases and conditions. For example, MMP-3 has been found in the synovium and in the cartilage of patients with osteoarthritis and rheumatoid arthritis, thus implicating MMP-3 in tissue injuries caused by these diseases; see Biochemistry, 1989, 28, 8691 and Biochem. J., 1989, 258. 115. It is also believed that MMP-13 plays an important role in the pathology of osteoarthritis and rheumatoid arthritis: see Lab. Invest., 1997, 76, 717 and Arthritis Rheum., 1997 , 40, 1391. The compounds of the present invention inhibit both MMP-3 and MMP-13 and, therefore, may be useful in the treatment of these diseases. It is also believed that excessive expression of MMP-3 is responsible for much of the tissue damage and the chronicity of chronic wounds, such as venous ulcers, diabetic ulcers and pressure sores: see Brit. J. Dermatology, 1996, 135. 52. In addition, the production of MMP-3 can also cause tissue damage in conditions in which there is ulceration of the colon (as in ulcerative colitis and in Crohn's disease: see J. Immunol., 1997, 158, 1582 and J. Clin. Pathol., 1994, 47, 13) or the duodenum (see Am. J. Pathol., 1996, 148, 519). In addition, MMP-3 may also be involved in skin diseases, such as dystrophic vesicular epidermolysis (see Arch. Dermatol. Res., 1995, 287, 428) and dermatitis herpetiformis (see J. Invest. Dermatology, 1995, 105 , 184). Finally, rupture of atherosclerotic plaques by MMP-3 can cause cardiac or cerebral infarction: see Circulation, 1997, 96, 396. Thus, MMP-3 inhibitors may be useful in the prevention of heart attack and stroke. . Certain studies of human cancers have shown that MMP-2 is activated on the surfaces of invasive tumor cells (see J. Biol. Chem., 1993, 268, 14033) and it has been reported that BB-94, a non-selective MMP inhibitor of peptide hydroxamate, decreases the tumor mass and prolongs the survival of mice carrying xenografts of human ovarian carcinomas (see Cancer res., 1993, 53, 2087). Certain compounds of the present invention inhibit MMP-2 and, therefore, may be useful in the treatment of cancer metastasis and tumor angiogenesis. Various series of MMP inhibitors have appeared in the patent literature. For example, in EP-A-0606046, WO-A-9627583 and WO-A-9719068, substituted a-arylsulfonamido acetohydroxamic acids are described, while certain substituted hydroxamic substituted acids are described in EP-A-0780386. with sulfone. The compounds of the present invention are inhibitors of some members of the MMP family. In particular, they are potent inhibitors of MMP-3 and MMP-13, certain compounds presenting varying degrees of selectivity with respect to other MMPs, such as MMP-1, MMP-2 and MMP-9. Some of the compounds are potent inhibitors of MMP-2. Thus, according to the present invention, there is provided a compound of formula (I): a pharmaceutically or veterinarily acable salt thereof, or a pharmaceutically or veterinarily acable solvate (including the hydrate) of either of the two entities, in the that the dashed line represents an optional link; A is C or CH; B is CH2, O or is absent; each of R1 and R2 is independently selected from hydrogen, Ci to Ce alkyl optionally substituted with Ci to C alkoxy or phenyl, and Ci to Ce alkenyl, or, together with the carbon atom to which they are attached, form a group C3 to C6 cycloalkyl optionally incorporating a bond with a heteroatom selected from O, SO, SO2 and NR6 or which is optionally condensed with benzene; R3 is hydrogen, halo, R7 or OR7; R 4 is hydrogen, C 1 to C alkyl, C 1 to C 4 alkoxy, trifluoromethyl or halo; R is hydrogen or C 1 to C 4 alkyl; R7 is a monocyclic or bicyclic ring system, selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, wherein any of the ring systems is optionally substituted by one or two substituents selected from Ci to C alkyl optionally substituted by Ci to C4 alkoxy or hydroxy, C to C alkoxy optionally substituted by Ci to C4 aloxy or hydroxy, Ci alkylthio to C, trifluoromethyl, trifluoromethoxy, halo and cyano; m is 1 or 2; and n is 0, 1 or 2; with the proviso that B is not O when A is C. In the above definition, unless otherwise indicated, alkyl, alkoxy, alkylthio and alkenyl groups having three or more carbon atoms may be straight chain or branched. Halo means fluorine, chlorine, bromine or iodine. The ounds of formula (I) may contain one or more chiral centers and, therefore, may exist in the form of stereoisomers, that is, as enantiomers or diastereomers, as well as mixtures thereof. The invention includes the individual stereoisomers of the ounds of formula (I) and any mixture thereof. The separation of the diastereoisomers can be achieved by conventional techniques, for example, by fractional crystallization or chromatography (including HPLC) of a diastereomeric mixture of a ound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a ound of formula (I) can be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallization of the diastereoisomeric salts formed by reacting the racemate with a suitable and optically active base or acid. In addition, ounds of formula (I) containing alkenyl groups can exist as cis or trans stereoisomers. Again, the invention includes the separate individual stereoisomers as well as mixtures thereof. In the invention, radiolabeled derivatives of the ounds of formula (I) are also included, which are suitable for biological studies. The ounds of formula (I) can provide pharmaceutically or veterinarily acceptable base salts, in particular, non-toxic alkali metal salts with bases. Examples include the sodium and potassium salts. The pharmaceutically or veterinarily acceptable salts of the ounds of formula (I) containing a basic center are, for example, addition salts of non-toxic acids formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, with organic acids. -carboxylics, or with organosulfonic acids. A preferred group of ounds of formula (I) is that in which B is absent; R1 is hydrogen, C1 to C alkyl optionally substituted with methoxy or phenyl, or Ci to C5 alkenyl; R2 is hydrogen or Ci to C4 alkyl; or R1 and R2, together with the carbon atom to which they are attached, form a C4 to C5 cycloalkyl group which optionally incorporates a bond with a heteroatom selected from O and NR6 or which is optionally condensed with benzene; R3 is selected from 4-phenyl, 4-pyridinyl, 4- (indan-5-yl), 4- (2,3-dihydrobenzofuran-5-yl), 4- (quinolin-3-yl), 4- (benzodioxol) -5-yl) and 4- (benzoimidazol-5-yl), any of which being optionally substituted with one or two substituents selected from Ci to C3 alkyl optionally substituted by methoxy or hydroxy, C1 to C3 alkoxy optionally substituted by methoxy or hydroxy , methylthio, trifluoromethyl, trifluoromethoxy, fluorine, chlorine and cyano; R 4 is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine or chlorine; R6 is methyl; m is 2; and n is 1. A more preferred group of compounds of formula (I) is that in which R is hydrogen, methyl, ethyl, 2-methylprop-1-yl, but-1-yl, 2-methoxyethyl, benzyl, 3- phenylprop-1-yl, allyl, 2-methylallyl, 3,3-dimethylallyl; R2 is hydrogen, methyl or ethyl; or R1 and R2, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl, 1-methylpiperidin-4,4-diyl or ndan-2,2- group dülo; R3 is 4-phenyl, 4- (2-methylphenyl), 4- (3-methylphenyl), 4- (3-ethylphenyl), 4- [3- (prop-2-yl) phenyl], 4- (3, 5-dimethylphenyl), 4- (3-methoxymethylphenyl), 4- (3-hydroxymethylphenyl), 4- (2-methoxyphenyl), 4- (3-methoxyphenyl), 4- (3-ethoxyphenyl), 4- (4- ethoxyphenyl), 4- [3- (prop-1-oxy) phenyl], 4- [3- (prop-2-oxy) phenyl], 4- [4- (prop-2-oxy) phenyl], 4- (3,4-dimethoxyphenyl), 4- [3- (2-methoxyethoxy) phenyl], 4- [3- (2-hydroxyethoxy) phenyl], 4- (3-methylthiophenyl), 4- (3-trifluoromethylphenyl), 4- (3-trifluoromethoxy-phenyl), 4- (2-phlorophenyl), 4- (3-chloro-4-fluorophenyl), 4- (3-cyanophenyl), 4- (pyridin-2-yl), 4- (pyrid) N-3-yl), 4- (pyridin-4-yl), 4- (6-ethoxypyridin-2-yl), 4- (5-ethoxypyridin-3-yl), 4- (indan-5-yl) ), 4- (2,3-dihydrobenzofuran-5-yl), 4- (quinolin-3-yl), 4-benzodioxol-5-yl), 4- (2,2-dimethylbenzodioxol-5-yl) and - (1,2-dimethylbenzoimidazol-5-ylo); and R 4 is hydrogen, 2-methyl, 3-methyl, 3-ethyl, 3-methoxy, 3-trifluoromethyl, 3-fluoro or 3-chloro. A particularly preferred group of compounds of formula (I) is that in which both R1 and R2 are hydrogens or methyl groups or, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4, group. -diyl or 1-methylpiperidin-4,4-diyl; R3 is 4-phenyl, 4- (3-methoxyphenyl), 4- (3-ethoxyphenyl), 4- [3- (2-methoxyethoxy) phenyl], 4- [3- (2-hydroxyethoxy) phenyl] or 4- (6-ethoxypyridin-2-yl); and R 4 is 3-methyl or 3-methoxy. Particularly preferred individual compounds of the invention include N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methylphenyl] -1,2,3,6-tetrahydropyridin-1-ylsulfonyl} acetamide; N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methylphenyl] -1,2,3,6-tetrahydropyridin-1-ylsufonyl} -2-methylpropanamide; N-hydroxy-2-. { 4- [4- (3-ethoxy-phenyl) -3-methylphenyl] -piperidin-1-ylsulfonyl} -2-methylpropanamide; N-hydroxy-1-. { 4- [4- (3-methoxyphenyl) -3-methylphenyl] -piperidin-1-ylsulfonii} cyclopentanecarboxamide; N-hydroxy-1 -. { 4- [4- (3-methoxyphenyl) -3-methylphenyl] piperidin-1-ylsulfonyl} Cyclobutanecarboxamide; N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methoxyphenyl] -piperidin-1-ylsulfonyl} -2-methylpropanamide; N-hydroxy-2-. { 4- [4- (6-ethoxypyridin-2-yl) -3-methylphenyl] -piperidin-1-ylsulfonyl} -2-methylpropanamida; N-hydroxy-2-. { 4- [4- (3- [2-methoxyethoxy] phenyl) -3-methylphenyl] pyridin-1-ylsulfonyl} -2-methylpropanamide; and N-hydroxy-2-. { 4- [4- (3- [2-hydroxyethoxy] phenyl) -3-methylphenyl] piperidine-1-ylsulfonyl} -2-methylpropanamide. In a further aspect, the present invention provides processes for the preparation of a compound of formula (I), a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate thereof (including the hydrate) of either of the two entities, as indicated above. Those skilled in the art will appreciate that, within certain described processes, the order of the synthesis steps employed may be varied, and that this will depend, among other things, on factors such as the nature of other functional groups present on a particular substrate, the availability of key intermediates and the strategy of protective groups (if present) to be adopted. Obviously, such factors will also influence the choice of reagent to be used in said synthesis steps. Illustrative examples of protecting group strategies are the synthetic routes of Example 64, in which a protected O-benzyl hydroxamate is formed prior to the required Suzuki reaction step, and Example 66, wherein the protection is employed. of the alcohol using a t-butyldiphenylsilyl group. It will also be appreciated that various interconversions and transformations of conventional substituents or functional groups within certain compounds of formula (I) will provide other compounds of formula (I). An example is the conversion of the tetrahydropyridine derivative (example 28) in the piperidine derivative (example 29) by hydrogenation. The following processes are illustrative of the general synthetic procedures that can be adopted to obtain the compounds of the invention. A compound of the formula (I) can be prepared directly from an ester of the formula (II): wherein R5 is C1 to C3 alkyl, and the dashed line, A, B, R1, R2, R3, R4, and m are as previously defined for formula (I), or by use of the corresponding carboxylic acid of formula (II) as an intermediate in which R5 is hydrogen. When prepared directly from an ester of formula (II), the reaction can be carried out by treating the ester with an excess of up to three times of hydroxylamine in a suitable solvent, at a temperature from about room temperature to about 85 ° C. . The hydroxylamine is conveniently generated in situ from its hydrochloride salt, the reaction being conducted in the presence of a molar equivalent amount of a suitable base such as an alkali metal carbonate or bicarbonate, eg, potassium carbonate. Preferably, the solvent is methanol, optionally combined with tetrahydrofuran or dichloromethane cone co-d solvent, and the reaction temperature is about 65 to 70 ° C. Alternatively, the ester can be converted by conventional hydrolysis into the corresponding carboxylic acid, which is then transformed into the required hydroxamic acid of formula (I). Preferably, the hydrolysis is carried out under basic conditions using an up to 6-fold excess of an alkali metal hydroxide in aqueous solution, optionally in the presence of a co-solvent, at a temperature from about room temperature to about 85 ° C. Typically, the cosolvent is selected from methanol, 1,4-dioxane, a mixture of methanol and tetrahydrofuran and a mixture of methanol and 1,4-dioxane, and the reaction temperature is from about 40 to about 70 ° C. The subsequent coupling step can be performed using conventional techniques of amide bond formation, for example, by the acyl chloride derivative and the hydroxylamine hydrochloride, in the presence of an excess of a tertiary amine, such as triethylamine or pyridine, which acts as acid scavenger, optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at a temperature from about 0 ° C to about room temperature. For reasons of convenience, pyridine can also be used as a solvent. In particular, any of a number of amino acid coupling variations can be used. For example, the acid of formula (II) is that R5 is hydrogen, can be activated using a carbodiimide, such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminoprop-1-yl) carbodiimide, optionally in the presence of 1-hydroxybenzotriazole and / or a catalyst such as 4-dimethylaminopyridine, or by the use of a halotrisaminophosphonium salt such as bromotris (pyrrolidino) -phosphonium hexafluorophosphate. Any of these types of coupling is carried out in a suitable solvent, such as dichloromethane or dimethylformamide, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example, when the hydroxylamine or the activating reagent is present in the form of an acid addition salt), at a temperature from about 0 ° C to about room temperature. Typically, 1.1 to 2.0 molecular equivalents of the activating reagent and 1.0 to 4.0 molecular equivalents of any tertiary amine present are employed.

A preferred reagent for mediating the coupling reaction is O- (7-azabenzotriazol-1-yl) -1,1,3-tetramethyluronium hexafluorophosphate (HATU). Preferably, a solution of the acid and 1.0 to 1.2 molecular equivalents of N-ethyldiisopropylamine in a suitable solvent is treated., such as anhydrous dimethylformamide or anhydrous 1-methylpyrrolidin-1-one, under nitrogen, with an excess of up to 50% of HATU, at about room temperature, followed after about 15 to 30 minutes, with an excess of up to about 3. hydroxylamine hydrochloride and an excess of up to about 4 times of N-ethyldiisopropylamine, optionally in the same solvent, at the same temperature. From an amine of formula (III); wherein the dashed line, A, B, R3, R4, m and n are as previously defined for formula (II), an ester of formula (II) can be prepared by sulfonylation with a compound of formula (IV): wherein Z is halo, R5 is C 1 to C 3 alkyl, and R 1 and R 2 are as previously defined for formula (II). Preferably, Z is chlorine. When R6 is hydrogen, it will normally be advantageous to protect this secondary amino linkage with a conventional amine protecting group. The reaction may be carried out in the presence of an excess of up to 50% of an appropriate base, in a suitable solvent, at a temperature from about 0 ° C to about room temperature. For example, when both R1 and R2 are hydrogens, an appropriate base is 1,8-diazabicyclo [5.4.0] undec-7-ene and a suitable solvent is dichloromethane. Alternatively, the anion of (III) can be generated initially using an excess of up to 20% of a strong base in a suitable solvent, under nitrogen, and then sulfonylation performed with 1.0 to 1.2 molecular equivalents of (IV). Conveniently, such coupling can be carried out at room temperature with N, O-bis (trimethylsilyl) acetamide as the base and anhydrous tetrahydrofuran as the solvent. Other routes for the preparation of an ester of formula (II), wherein R3 is R7 are based on the exploitation of a Suzuki reaction or a Stille reaction with an ester of formula (II), wherein R3 (but not R4) is bromine and iodine. Thus, in the Suzuki reaction, the last ester is treated with 1.0 to 1.5 molecular equivalents of a boronic acid of formula R7B (OH) 2, in the presence of 2.0 to 3.0 molecular equivalents of an alkali metal fluoride, approximately 0.1 equivalents Molecules of a triarylphosphine and about 0.05 molecular equivalents of a palladium catalyst in a suitable solvent, under nitrogen, at a temperature of about 65 to about 100 ° C. Typically, the fluoride is cesium fluoride, the phosphine is tri-o-tolylphosphine, the catalyst is tris (dibenzylideneacetone) -dipaladium (0) and the solvent is degassed 1,2-dimethoxyethane, optionally with 1-methylpyrrolidin-2-one as a co-solvent. In the Stille reaction, the aforementioned ester starting material is treated with 1.0 to 2.0 molecular equivalents of a suitable trialkylstannane derivative of the formula R7Sn (alkyl) 3, wherein alkyl is, for example, n-butyl, presence of 2.0 to 3.0 molecular equivalents of a tertiary base, 0.3 to 0.6 molecular equivalents of a triarylphosphine, and 0.05 to 0.2 molecular equivalents of a palladium catalyst in a suitable solvent, under nitrogen, at a temperature of about 65 to about 100 ° C. Typically, the base is triethylamine, the phosphine is tri-o-tolylphosphine, the catalyst is palladium (II) acetate optionally in the presence of tetrakis (triphenylphosphine) palladium (O) and the solvent is anhydrous acetonitrile. Certain esters of formula (II), in which at least one of R1 and R2 is other than hydrogen, can conveniently be obtained from the α-carbanion of an ester of formula (II), wherein at least one of R1 and R2 is hydrogen, by conventional C-alkylation procedures, using an alkylating agent of formula (VA) or (VB) RX XWY (VA) (VB) where R is as previously defined for R or R2, but is not hydrogen, X and Y may be the same or different and are suitable leaving groups, and W is a C2 to C5 alkylene group optionally incorporating a bond with a heteroatom selected from O, SO, SO2 and NR6 or optionally condensed with benzene. When R6 is to be hydrogen in a compound of formula (I), then a conventional strategy of amine protecting groups during this alkylation process may be advantageous. A suitable leaving group may be selected from halo (eg, chlorine, bromine or iodine), C 1 -C 4 alkanesulfonyloxytrifluoromethanesulfonyloxy and arylsulfonyloxy (for example, benzenesulfonyloxy or p-toluenesulfonyloxy). Preferably, X and Y are selected from bromine, iodine and p-toluenesulfonyloxy. The carbanion can be generated using an appropriate base in an appropriate solvent. Typical base-solvent combinations may be selected from lithium, sodium or potassium hydride, lithium, sodium or potassium bis- (trimethylsilyl) amide, lithium diisopropylamide and butyllithium, together with toluene, ether, 1, 2 dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide, N, N-dimethylacetamide, 1-methylpyrrolidin-2-one and any mixture thereof.

Preferably, the base is sodium hydride and the solvent is anhydrous dimethylformamide, optionally with anhydrous tetrahydrofuran as a co-solvent or anhydrous 1-methylpyrrolidin-2-one. For monoalkylation, a base excess of up to about 10% is employed, while for dialkylation, from about 2 to about 3 molar equivalents are generally appropriate. Typically, carbanion is generated at about room temperature, under nitrogen, and then treated with an excess of up to 30% of the alkylating agent required at the same temperature. Obviously, when dialkylation is required and R1 and R2 are different, the substituents can be introduced in tandem in a "single vessel reaction" or in separate steps. An alternative alkylation process, particularly convenient, involves the treatment of the substrate with the required alkylating agent, in the presence of 3.0 to 3.5 molecular equivalents of anhydrous potassium carbonate in anhydrous dimethylsulfoxide or anhydrous 1,2-dimethoxyethane, under nitrogen, at about the temperature ambient. Clearly, an alternative variation to prepare a compound of formula (II) is to introduce R1 and / or R2 into a suitable brominated or iodinated intermediate before further processing by, for example, a Suzuki or Stille reaction. An amine of formula (III) can be obtained by conventional chemical methods. For example, when B is absent, m is 2 and n is 1, a conveniently N-protected piperidin-4-one of formula (VI): wherein P is a conventional amine protecting group, it is reacted with a carbanion derivative of a compound of formula (VII): wherein Z is as previously defined for formula (IV) and R3 and R4 are as previously defined for formula (III), to provide a compound of formula (VIII): Preferably, Z is chlorine, bromine or iodine. Conveniently, (VII) is converted to an aryl lithium or aryl Grignard derivative, while, of the plethora of available amine protecting groups, typically P is t-butoxycarbonyl (Boc) or benzyl. When P is Boc, (Vil) can be transformed directly into a compound of formula (III), where the dashed line represents a bond, A is C, B is absent, m is 2, n is 1 and R3 and R4 are like have been previously defined for formula (III), using trifluoroacetic acid, optionally in a suitable solvent such as dichloromethane, at about room temperature. Alternatively, when P is benzyl, (VIII) can be converted, in two stages, into the same compound of formula (III). For example, in the first step, a dehydration in refluxing toluene can be performed using p-toluenesulfonic acid and a Dean-Starck apparatus. N-deprotection of the resulting alkene (1, 2, 3, 6-tetrahydropyridine derivative) in the second step can be achieved using 1-chloroethyl chloroformate in refluxing toluene, followed by treatment of the reaction mixture, at room temperature , with methanol or ethanol. This unsaturated piperidine can be converted into a compound of formula (III), in which the dotted line does not represent a bond, A is CH, B is absent, m is 2, n is 1 and R3 and R4 are as defined previously for formula (III) under conventional catalytic, catalytic transfer or hydrogenation conditions. Alternatively, these hydrogenation conditions can be used to convert the previously described N-benzyl alkene (1, 2, 3, 6-tetrahydropyridine derivative) into the same piperidine derivative, directly in one step. In addition, this fully saturated piperidine can also be achieved in one step, starting from (VIII), when P is Boc, by conventional ionic hydrogenation, using, for example, triethylsilane and trifluoroacetic acid in dichloromethane. Other amines of formulas (III) can be obtained, when they can not be purchased on the market nor are they described below., by analogy with the process described in the preparations section or by conventional synthetic methods, according to conventional textbooks of organic chemistry or the above literature, from readily available starting materials, using appropriate reagents and reaction conditions. In addition, the persons skilled in the art will know the variations and alternatives to those procedures described later in the section of examples and preparations, which allow to obtain the compounds defined by the formula (I). The pharmaceutically and veterinarily acceptable base salts of the compounds of formula (I) can also be prepared in a conventional manner. For example, a solution of the hydroxamic acid is treated with the appropriate base, either neat or in a suitable solvent, and the resulting salt is isolated by filtration or by evaporation of the reaction solvent in vacuo. The pharmaceutically and veterinarily acceptable acid addition salts can be obtained in an analogous manner, by treating a solution of a basic compound of formula (I) with the appropriate acid. Both types of salts can be formed and interconverted using ion exchange resin techniques. The biological activities of the compounds of the present invention were determined by the following test methods, which are based on the ability of the compounds to inhibit the cleavage of various fluorogenic peptides by MMPs 1, 2, 3, 9, 13 and 14 .

The assays for MMPs 2, 3, 9 and 14 are based on the original protocol described in FEBS, 1992, 296, 263, with the minor modifications described below.

Inhibition of MMP-1 Enzymatic preparation The catalytic domain of MMP-1 was prepared in the Pfizer Central Research laboratories. A stock solution of MMP-1 (1 μM) was activated by the addition of aminophenylmercuric acetate (APMA), at a final concentration of 1 mM, for 20 minutes at 37 ° C. Then, MMP-1 was diluted in Tris-HCl assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl 2, 20 mM ZnSO and 0.05% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assay was 1 nM.

Substrate The fluorogenic substrate used in this assay was Dnp-Pro-β-cyclohexyl-Ala-Gly-Cys (Me) -His-Ala-Lys- (N-Me-Ala) -NH2 as originally described in Anal Biochem., 1993, 212, 58. The final substrate concentration used in the assay was 10 μM.

Determination of Enzyme Inhibition The test compound was dissolved in dimethyl sulfoxide and diluted with assay buffer so that no more than 1% dimethylsulfoxide was present. The test compound and the enzyme were added to each well of a 96-well plate and allowed to equilibrate for 15 minutes at 37 ° C on an orbital shaker before the addition of the substrate. The plates were then incubated for 1 hour at 37 ° C before the fluorescence determination (substrate cleavage) using a fluorimeter (Fluostar, BMG Lab Technologies, Aylesbury, UK) at an excitation wavelength of 355 nm and at a length emission wave of 440 nm. The inhibition potency was measured from the amount of cleaved substrate, obtained using a series of concentrations of test compound and, from the resulting dose-response curve, an IC50 value (the inhibitor concentration necessary for inhibit 50% of the enzymatic activity).

Inhibition of MMP-2, MMP-3 and MMP-9 Enzymatic preparation Catalytic domains of MMP-2, MMP-3 and MMP-9 were prepared in Pfizer Central Research laboratories. A stock solution of MMP-2, MMP-3 or MMP-9 (1 μM) was activated by the addition of APMA. For MMP-2 and MMP-9, a final APMA concentration of 1 mM was added, followed by incubation for 1 hour at 37 ° C. MMP-3 was activated by the addition of 2 mM APMA, followed by incubation for 3 hours at 37 ° C. The enzymes were then diluted in Tris-HCl assay buffer (100 mM Tris, 100 mM NaCl, 10 mM CaCl 2 and 0.16% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assays was 1nM.

Substrate The fluorogenic substrate used in this evaluation was Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys (Dnp) -NH2 (Bachem Ltd., Essex, UK) as originally described in J Biol. Chem., 1994, 269, 20952. This substrate was selected because it had a balanced hydrolysis rate against MMPs 2, 3 and 9 (kcat / km of 54,000, 59,400 and 55,300 s'1M'1, respectively). The final concentration of the substrate used in the test was 5 μm.

Determination of Enzyme Inhibition The test compound was dissolved in dimethyl sulfoxide and diluted with assay buffer so that no more than 1% dimethylsulfoxide was present. The test compound and the enzyme were added to each well of a 96-well plate and allowed to equilibrate for 15 minutes at 37 ° C on an orbital shaker before the addition of the substrate. The plates were then incubated for 1 hour at 37 ° C, before the fluorescence determination using a fluorimeter (Fluostar, BMG Lab Technologies, Aylesbury, UK), at an excitation wavelength of 328 nm and at a wavelength. of emission of 393 nm. The inhibition potency was measured from the amount of cleaved substrate, obtained using a series of concentrations of test compounds and, from the resulting dose-response curve, a Cl 0 value was calculated (the concentration of inhibitor required to inhibit 50% of the enzymatic activity).

Inhibition of MMP-13 Enzymatic preparation A recombinant human MMP-13 was prepared by PanVera Corporation (Madision, Wisconsin) and characterized in Pfizer Central Research laboratories. A 1.9 mg / ml stock solution was activated with 2 mM APMA for 2 hours at 37 ° C. Then, the MMP-13 was diluted in assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl 2, 20 μM ZnSO and 0.02% Brij 35, pH 7.5) to a concentration of 5.3 nM. The final concentration of enzyme used in the assay was 1.3 nM.

Substrate The fluorogenic substrate used in this evaluation was Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMa) -NH2. The final substrate concentration used in the assay was 10 μM.

Determination of Enzyme Inhibition The test compound was dissolved in dimethyl sulfoxide and diluted with assay buffer until no more than 1% dimethylsulfoxide was present. The test compound and the enzyme were added to each well of a 96-well plate. The addition of substrate to each well initiated the reaction. Fluorescence intensity was determined using a 96-well plate fluorimeter (Cytofluor II, PerSeptive Biosystems, Inc., Framingham, MA) at an excitation wavelength of 360 nm and at an emission wavelength of 460 nm. The inhibition potency was measured from the amount of cleaved substrate, obtained using a series of concentrations of test compounds and, from the resulting dose-response curve, an IC 50 value (the inhibitor concentration necessary for inhibit 50% of enzymatic activity).

Inhibition of MMP-14 Enzymatic preparation The catalytic domain of MMP-14 was prepared in the Pfizer Central Research laboratories. A 10 μM enzyme stock solution was activated for 20 minutes at 25 ° C, after the addition of 5 μg / ml trypsin (Sigma, Dorset, UK). Then, the trypsin activity was neutralized by the addition of 50 μg / ml of soybean trypsin inhibitor (Sigma, Dorset, UK) before dilution of this enzyme stock solution in TrisHCl assay buffer (100 mM Tris, NaCl 100 mM, 10 mM CaCl2, 0.16% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assays was 1 nM.

Substrate The fluorogenic substrate used in this evaluation was Mca-Pro-Leu-Gly-Leu-Dpa-Al-Arg-NH2 (Bachem Ltd., Essex, UK) as described in J. Biol. Chem., 1996, 271, 17119.

Determination of Enzyme Inhibition This was performed as described for MMPs 2, 3 and 9. In human therapy, the compounds of formula (I), their pharmaceutically acceptable salts and the pharmaceutically acceptable solvates of either of the two entities, can administered alone, but are generally administered in admixture with a pharmaceutical carrier selected in accordance with the desired route of administration and conventional pharmaceutical practice. They can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents. They can also be injected, for example, intravenously, intramuscularly or subcutaneously, and are best used in the form of a sterile aqueous solution which can contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with the blood. For other routes of parenteral administration, such as buccal or sublingual, they can be administered in the form of tablets or pills that can be formulated in a conventional manner. In addition, the compounds and their salts can be administered topically in the form of sterile creams, gels, suspensions, lotions, ointments, fine powders, sprays, bandages with incorporated drugs or by means of a skin patch. For example, they can be incorporated into a cream that consists of an aqueous or oily emulsion of polyethylene glycols or liquid paraffin., or they can be incorporated into an ointment consisting of a soft paraffin base of white wax, or as a hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers, or in the form of a dry powder, liquid spray or aerosol with butane / propane, HFA or CFC as propellants, or as a bandage with incorporated drug, either as a tulle bandage, gauze bandages impregnated with soft white paraffin or with polyethylene glycol or film bandages with hydrogel, hydrocolloids or alginates. In addition, the compounds and salts may be administered intraocularly as an eye drop with appropriate buffers, viscosity modifiers (e.g., cellulose derivatives), preservatives (e.g., benzalkonium chlorides (BZK)) and tonicity adjusting agents. (for example, sodium chloride). All such formulations may also contain stabilizers and preservatives.

Depending on the route of administration to human patients, the daily dosage level of the compounds of formula (I) and their salts may be from 0.001 to 20 mg / kg, in a single dose or in divided doses. Thus, for example, the tablets or capsules may contain from 0.02 to 500 mg of active compound for single administration or two or more times as appropriate. In any case, the doctor will determine the actual dose that is most appropriate for an individual patient and will vary with the age, weight and response of the particular patient. The above doses are exemplary of the average case; Of course, there may be individual cases in which higher or lower doses are necessary and such cases are within the scope of the invention. For veterinary use, a compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of the two entities, is administered in the form of a suitably acceptable formulation in accordance with normal veterinary practice and the veterinarian will determine the dosage regimen and the most appropriate route of administration for a particular animal. Thus, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either of the two entities, together with a pharmaceutically acceptable diluent or carrier.

In addition, it provides a veterinary formulation comprising a compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of the two entities, together with a veterinarily acceptable diluent or carrier. The invention also provides a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either of two entities, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament. In addition, it provides a compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of two entities, or a veterinary formulation containing any of the foregoing, for use as a medicament for an animal. In another aspect, the invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of either of two entities, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which an MMP inhibitor is indicated. It also provides the use of a compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of the two entities, for the manufacture of an animal medicament for the curative or prophylactic treatment of a medical condition for which is indicated an inhibitor of MMP. In addition, the invention provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of either of two entities, for the manufacture of a human medicament for the curative or prophylactic treatment of breakage of atherosclerotic plaques, myocardial infarction, heart failure, restenosis, apoplexy, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and Inflammatory diseases dependent on migratory inflammatory cells. It further provides the use of a compound of formula (I), a veterinarily acceptable salt thereof or a veterinarily acceptable solvate containing either of the two entities, for the manufacture of an animal medicament for the curative or prophylactic treatment of plaque rupture. atherosclerotic, myocardial infarction, heart failure, restenosis, apoplexy, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent migratory inflammatory cells.

In addition, the invention provides a method for treating or preventing a medical condition for which an MMP inhibitor is indicated, in a mammal (including a human), which comprises administering to said mammal a therapeutically effective amount of a compound of formula ( I), a pharmaceutically or veterinarily effective salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either of the two entities, or a pharmaceutical composition or veterinary formulation containing any of the foregoing. In addition, the invention provides a method for treating or preventing rupture of atherosclerotic plaques, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, macular degeneration. related to age, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells, in a mammal (including a human), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a pharmaceutically or veterinarily effective salt thereof or a pharmaceutically or veterinarily acceptable solvate of either of two entities, or a pharmaceutical composition or veterinary formulation containing any of the foregoing. The invention also includes any new intermediates described herein, for example, those of formula (II).

The synthesis of the compound of the invention and the intermediates for use herein is illustrated by the following examples and preparations. Ambient temperature means 20 to 25 ° C. Ultrafast chromatography refers to column chromatography on silica gel (Kiesegel 60, 230-400 mesh). The melting points are uncorrected. The 1H nuclear magnetic resonance (NMR) spectra were recorded using a Bruker AC300, Varian Unity lnova-300 or Varian Unity lnova-400 spectrometer and, in all cases, were consistent with the proposed structures. The characteristic chemical shifts (d) are provided in parts per million downfield of tetramethylsilane, using conventional abbreviations for the designation of principal peaks: e.g., s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; a, wide. Mass spectra were recorded using a Finnigan Mat mass spectrometer. TSQ 7000 or a Fisons Instruments Trio 1000. LRMS means low resolution mass spectrum and the calculated and observed ions mentioned refer to the lower mass isotopic composition.

EXAMPLE 1 N-Hydroxy-2-r4- (4-phenylphenyl) -1, 2,3.β-tetrahydropyridin-1-ylsulfoniipacetamide Potassium carbonate (207 mg, 1.5 mmol) was added to a stirred mixture of the title compound of Preparation 8 (186 mg, 0.5 mmol), hydroxylamine hydrochloride (104 mg, 1.5 mmol), tetrahydrofuran (2 mL) and methanol ( 3 ml). The reaction mixture was refluxed for 20 hours, allowed to cool, diluted with water (15 ml) and ethyl acetate (10 ml) and acidified with concentrated hydrochloric acid. This mixture was then heated briefly to 100 ° C, allowed to cool and filtered. The material thus obtained was washed sequentially with water and with ethyl acetate and then dried under vacuum to provide the title compound (125 mg, 67%) as a colorless solid, m.p. 216-218-C. Found: C, 61.05; H, 5.35; N, 7.41. C19H20N2O4S requires C, 61.27; H, 5.41; N, 7.52%. d (DMSOd6): 2.62 (m, 2H), 3.50 (m, 2H), 3.92 (s, 2H) 3. 98 (m, 2H), 6. 24 (sa, 1 H), 7. 35 (m, 1 H) 7.41-7. 48 (m, 2H), 7.52-7.58 (m, 2H), 7.62-7.73 (m, 4H) 9.22 (s, 1 H) 10.82 (s, 1 H). LRMS (APCl): 373 (M + H) +.

EXAMPLE 2 N-Hydroxy-2-r4- (3-methyl-4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-isulfonyl acetamide Obtained as a colorless solid (58%), m.p. 190-191 ° C, from the title compound of preparation 9, using the procedure of Example 1. Found: C, 62.05; H, 5.74; N, 7.12. C2oH22N2O4S requires C, 62.16; H, 5.74; N, 7.25%. d (DMSOd6): 2.23 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.90 (s, 2H), 3.95 (m, 2H), 6.20 (sa, 1 H), 7.17 ( d, 1 H), 7.30-7.48 (m, 7H), 9.20 (s, 1 H), 10.80 (s, 1 H). LRMS (Thermospray): 388 (M + H) +.

EXAMPLE 3 N-Hydroxy-2-r4- (4-phenylphenyl) piperidin-1-ylsulfonyl acetamide Obtained as a colorless solid (62%), m.p. 200-201 ° C, from the title compound of preparation 10, using the procedure of example 1. Found: C, 60.96; H, 5.86; N, 6.97. C19H22N2O4S requires C, 60.94; H, 5.92; N, 7.48%. d (DMSOd6): 1. 63 (m, 2 H), 1. 83 (m, 2H), 2.66 (m, 1 H), 2.98 (t, 2H), 3.70 (m, 2H), 3.83 (s, 2H), 7.30 (m, 3H), 7.40 (t, 2H), 7.54-7.60 (m, 4H), 9.18 (s, 1 H), 10.75 (s, 1 H). LRMS (Thermospray); 375 (M + H) +.

EXAMPLE 4 N-Hydroxy-2- (4-phenyl-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl) acetamidate Obtained as a colorless solid (76%), m.p. 175-176 ° C, from the title compound of preparation 11, using the procedure of Example 1. Found: C, 52.41; H, 5.39; N, 9.35. C 13 H 16 N 2 O 4 S requires C, 52.69; H, 5.44; N, 9.45%. d (DMSOd6): 2.58 (m, 2H), 3.46 (t, 2H), 3.90 (s, 2H), 3.95 (m, 2H), 6.18 (sa, 1 H), 7.23-7.48 (m, 5H), 9.20 (s, 1 H), 10.80 (s, 1 H).

EXAMPLE 5 N-Hydroxy-2- (4-phenylpiperidin-1-ylsulfonyl) acetamide Obtained as a colorless solid (44%), m.p. 185-187 ° C, from the title compound of preparation 12, using the procedure of example 1.

Found: C, 52.08; H, 6.04; N, 9.23. C? 3 H 18 N 2 O 4 S: requires C, 52.33; H, 6.08; N, 9.39%. d (DMSOd6): 1.62 (m, 2H), 1.82 (m, 2H), 2.62 (m, 1 H), 2.98 (t, 2H), 3.70 (m, 2H), 3.84 (s, 2H), 7.15- 7.33 (m, 5H), 9.20 (s, 1 H), 10.78 (s, IH).

EXAMPLE 6 N-Hydroxy-2- (4-benzylpiperidin-1-ylsulfonyl) acetamide Obtained as a colorless solid (35%), m.p. 132-135 ° C, from the title compound of preparation 13, using the procedure of example. Found: C, 53.66; H, 6.43; N, 8.82. C 14 H 20 N 2 O 4 S requires C, 53.83; H, 6.45; N, 8.97%. d (DMSOd6): 1.13 (m, 2H), 1.58 (m, 3H), 2.49 (d, 2H), 2.75 (t, 2H), 3.50 (d, 2H), 3.73 (s, 2H), 7.10 (m , 3H), 7.22 (m, 2H), 9.10 (s, 1 H), 10.70 (s, 1 H).

EXAMPLE 7 N-Hydroxy-2 (R.S) -r4-f4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-yl-sulfoninpent-4-enamide O- (7-azabenzotriazol-1-yl) -1,1,3-tetramethyluronium hexafluorophostat (100 mg, 0.26 mmol) was added to a stirred solution of the title compound of preparation 15 (70 mg, 0.18 mmol) ) and N-ethyldiisopropylamine (0.03 ml, 0.18 mmole) in anhydrous dimethylformamide (1 ml), under nitrogen, at room temperature. After 15 minutes, a solution of hydroxylamine hydrochloride (37 mg, 0.53 mmol) and N-ethyldiisopropylamine (0.12 ml, 0.7 mmol) in anhydrous dimethylformamide (0.5 ml) was added, the reaction mixture was stirred for 20 hours and then it was partitioned between ethyl acetate and aqueous phosphate buffer (pH 7). The organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure, and then the residue was purified by flash chromatography, using dichloromethane: methanol (97: 3) as eluent, to give the title compound. title (55 mg) as an amorphous colorless solid. d (DMSOd6): 2.50-2.80 (m, 4H), 3.50 (m, 2H), 3.80 (dd, 1 H), 4.00 (m, 2H), 5.03-5.18 (m, 2H), 5.62 (m, 1 H), 6.23 (sa, 1 H), 7.37 (m, 1 H), 7.45 (m, 2H), 7.53 (m, 2H), 7.67 (m, 4H), 9.22 (s, 1 H), 10.85 ( s, 1 H). LRMS (Thermonebulizer): 413 (M + H) +.

EXAMPLE 8 N-Hydroxy-2 (R.S) -r4- (3-methyl-4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfonylpent-4-enamide Obtained as a solid (13%) from the title compound of preparation 17, using the procedure of Example 7, but with an elution gradient of dichloromethane: methanol (100: 0 to 90:10) for the step of chromatographic purification. d (CDCl 3): 2.25 (s, 3H), 2.62 (m, 2H), 2.82 (m, 2H), 3.62 (m, 2H), 3.80 (dd, 1 H), 4.10 (m, 2H), 5.10- 5.22 (m, 2H), 5.75 (m, 1 H), 6.03 (sa, 1 H), 7.20-7.43 (m, 8H). LRMS (APCl): 427 (M + H) +.

EXAMPLE 9 N-Hydroxy-5-phenyl-2 (R, S) -r4-r4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfonylpentanamide Obtained as a colorless solid (35%), m.p. 150 ° C (decomp.), From the title compound of preparation 18, using the procedure of example 1. d (DMSOd6): 1.50 (m, 2H), 1.80 (m, 1 H), 2.00 (m, 1 H), 2.54 (m, 4H), 3.45 (m, 2H), 3.75 (dd, 1 H), 3.98 (m, 2H), 6.10 (sa, 1 H), 7.10-7.54 (m, 10H), 7.63 (m, 4H), 9.10 (s, 1 H), 10.88 (s, 1 H). LRMS (Thermospray): 492 (M + H) +.

EXAMPLE 10 N-Hydroxy-2-methyl-2-r4- (4-phenylfron-1, 2.3.6-tetrahydropyridin-1-Isulfonylpropanamide Obtained as an amorphous solid (41%) from the title compound of Preparation 19, using the procedure of Example 7. d (DMSOd6): 1.50 (s, 6H), 2.66 (m, 2H), 3.50 ( m, 2H), 4.00 (m, 2H), 6.10 (sa, 1 H), 7.30-7.70 (m, 9H), 9.00 (s, 1 H), 10.78 (s, 1 H).

EXAMPLE 11 N-Hydroxy-1-r4- (3-methyl-4-phenylfenin-1,2,3,6-tetrahydropyridin-1-ylsulfonylcyclopentanecarboxamide Obtained as a solid (44%) from the title compound of preparation 21, using the procedure of Example 7, but with dichloromethane: methanol (99: 1) as eluent for the chromatographic purification step. d (CDCl 3): 1.70 (m, 2H), 1.86 (m, 2H), 2.27 (s, 3H), 2.37 (m, 2H), 2.48 (m, 2H), 2.62 (m, 2H), 3.60 (t , 2H), 4.05 (m, 2H), 6.02 (sa, 1 H), 7.20-7.43 (m, 8H).

EXAMPLE 12 N-Hydroxy-2-ethyl-2-r4-.4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-sulfonylbutanamide Obtained as a solid (56%) from the title compound of preparation 23, using the procedure of Example 7. d (DMSOd6): 0.90 (m, 6H), 1.95-2.13 (m, 4H), 2.52 (m, 2H), 3.48 (m, 2H), 3.98 (m, 2H), 6.10 (sa, 1 H), 7.35 (m, 1 H), 7.44 (m, 2H), 7.52 (m, 2H), 7.64 (m, 4H), 9.03 (sa, 1 H), 10.70 (sa, 1 H).

EXAMPLE 13 N-Hydroxy-2 (R, S) -r4- (4-phenylphenyl) -1,2.3.6-tetrahydropyridin-1-ylsulfoninhexanamide Obtained as a colorless solid (72%), m.p. 186-189 ° C, from the title compound of preparation 25, using the procedure of Example 7, but with 1-methylpyrrolidin-2-one as the reaction solvent and with crystallization from diisopropyl ether: ethyl acetate, instead of ultra-fast chromatography, as a purification technique. Found: C, 63.03; H, 6.60; N, 6.43. C23H28N2O4S; 0.50 H2O requires C, 63.13; H 6.68; N, 6.40%. d (DMSOd6): 0.83 (t, 3H), 1.10-1.35 (m, 4H), 1.78 (m, 1 H), 1.98 (m, 1 H), 2.55 (m, 2H), 3.50 (m, 2H) , 3.70 (dd, 1 H), 3.98 (m, 2H), 6.12 (sa, 1H), 7.32 (m, 1H), 7.44 (m, 2H), 7.52 (m, 2H), 7.64 (m, 4H) , 9.20 (sa, 1H), 10.85 (sa, 1 H). LRMS (APCl): 429 (M + H) +.

EXAMPLE 14 N-Hydroxy-4-methyl-2 (R, S) -r4- (4-phenylphenyl) -1,2,3,6-tetrahydropyridine-1-lysulfoninpent-4-enamlda Obtained as a colorless solid (33%), m.p. 170-171 ° C, from the title compound of preparation 27, using the procedure of Example 7, but with an elution gradient of dichloromethane: methanol (100: 0 to 98: 2) for the chromatographic purification step. d (DMSOd6): 1.65 (s, 3H), 2.40-2.80 (m, 4H), 3.52 (m, 2H), 3.90 (dd, 1 H), 4.00 (m, 2H), 4.70 (s, 1 H) , 4.78 (s, 1 H), 6.23 (sa, 1 H), 7.35 (m, 1 H), 7.44 (m, 2H), 7.52 (d, 2H), 7.65 (m, 4H), 9.22 (s, 1 H), 10.85 (s, 1 H). LRMS (APCl): 427 (M + H) +.

EXAMPLE 15 N-Hydroxy-2 (R.sub.S) -methyl-2-r4- (3-methyl-4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfoninpent-4-enamide Obtained as a colorless gum (20%) from the title compound of Preparation 29, using the procedure of Example 7, but with an elution gradient of dichloromethane: methanol (100: 0 to 98: 2 to 95: 5) for the chromatographic purification step. d (CDCl 3): 1.60 (s, 3H), 2.28 (s, 3H), 2.64 (m, 3H), 3.00 (m, 1 H), 3.62 (m, 2H), 4.10 (m, 2H), 5.21 ( m, 2H), 5.70 (m, 1 H), 6.03 (s at, 1 H), 7.20-7.44 (m, 8H). LRMS (APCl): 441 (M + H) +.

EXAMPLE 16 N-Hydroxy-2-r3- (4-phenylphenoxy) azTtidin-1-ylsulfonyl acetamide Obtained as a colorless solid (66%) from the title compound of Preparation 32, using the procedure of Example 1. d (DMSOd6): 4.03 (s, 2H), 4.05 (dd, 2H), 5.09 ( m, 1 H), 6.94 (d, 2H), 7.30 (m, 1 H), 7.40 (m, 2H), 7.60 (m, 4H), 9.25 (s, 1 H), 10.80 (sa, 1 H) . LRMS (Thermospray): 364 (M + H) +.

EXAMPLE 17 N-Hydroxy-2-f4-r4- (3-ethoxy-phenyl) -3-methylphenin-1,2,3,6-tetrahydropyridin-1- Isulfonyl-D-tatamide Potassium carbonate (406 mg, 3 mmol) was added to a stirred mixture of the title compound of preparation 41 (429 mg, 1 mmol), hydroxylamine hydrochloride (212 mg, 3 mmol) and methanol (20 ml). The reaction mixture was heated to reflux for about 6 hours, allowed to cool and partitioned between ethyl acetate and 1 M hydrochloric acid. The separated organic phase was dried (MgSO), evaporated under reduced pressure, and then the residue was evaporated. triturated with diisopropyl ether and crystallized from ethyl acetate to yield the title compound (148 mg, 34%) as a colorless solid, mp 151-152 ° C. Found: C, 61.01; H, 6.04; N, 6.48. C 22 H 26 N 2 O 5 S requires C, 61.38; H, 6.09; N, 6.51%. d (DMSOd6): 1.33 (t, 3H), 2.23 (s, 3H), 2.60 (m, 2H), 3.46 (t, 2H), 3.91 (s, 2H), 3.96 (m, 2H), 4.03 (q , 2H), 6.10 (sa, 1 H), 6.80-6.95 (m, 3H), 7.17 (d, 1 H), 7.28-7.38 (m, 3H), 9.20 (sa, 1 H), 10.8 (sa, 1 HOUR). LRMS (APCl): 431 (M + H) +.

EXAMPLE 18 N-Hydroxy ^^ - O-methoxM-phenylpheniD-I .S ^ .β-tetrahydropyridin-l-ylsulfonyl acetamide Potassium carbonate (95 mg, 0.7 mmol) was added to a stirred mixture of the title compound of preparation 45 (170 mg, 0.4 mmol), hydroxylamine hydrochloride (49 mg, 0.7 mmol) and methanol (3 mL). The reaction mixture was heated to reflux for about 2 hours, allowed to cool, diluted with phosphate buffer (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were dried (MgSO) and evaporated under reduced pressure, and then the residue was triturated with ethyl acetate to give the title compound (50 mg, 30%) as a colorless solid, m.p. 175-177 ° C. Found: C, 58.84; H, 5.51; N, 6.70. C2oH2oN2? 5S; 0.10 CH2Cl2 requires C, 58.75; H, 5.45; N, 6.82%. d (DMSOd6): 2.63 (m, 2H), 3.50 (t, 2H), 3.80 (s, 3H), 3.93 (s, 2H), 3.99 (s, 2H), 6.27 (s, 1 H), 7.10 ( d, 1 H), 7.16 (s, 1 H), 7.27 (d, 1H), 7.31 (d, 1 H), 7.41 (t, 2H), 7.47 (d, 2H), 9.23 (sa, 1 H) , 10.80 (sa, 1 H). LRMS (Thermospray): 420 (M + NH 4) +.

EXAMPLE 19 N-Hydroxy-2-r4- (3-methoxy-4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfon-p-2-methylpropanamide O- (7-azabenzotriazol-1-yl) -1,1,3-tetramethylammonium hexafluorophosphate (274 mg, 0.72 mmol) was added to a stirred solution of the title compound of preparation 50 (200 mg, 0.48 mmol. ) and N-ethyldiisopropylamine (0.08 ml, 0.48 mmole) in anhydrous dimethylformamide (4 ml) under nitrogen, at room temperature. After 15 minutes, hydroxylamine hydrochloride (100 mg, 1.44 mmol) and N-ethyldiisopropylamine (0.33 ml, 1.9 mmol) were added, the mixture was stirred for about 3 hours, and then partitioned between ethyl acetate and aqueous phosphate buffer. (pH 7). The organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure, and then the residue was triturated with diisopropyl ether to give the title compound (71 mg, 36%) as a solid. amorphous colorless, pf 156-158 ° C. Found: C, 60.80; H, 6.17; N, 6.25. C22H26N2O5S; 0.10 H2O requires C, 61.12; H, 6.1 1; N, 6.48%. d (DMSOd6): 1.51 (s, 6H), 2.57 (m, 2H), 3.43 (t, 2H), 3.80 (s, 3H), 4.03 (m, 2H), 6.25 (sa, 1 H), 7.09 ( d, 1 H), 7.13 (s, 1 H), 7.26 (d, 1 H), 7.31 (d, 1 H), 7.39 (t, 2 H), 7.46 (d, 2 H), 9.24 (sa, 1 H) ), 10.79 (sa, 1 H). LRMS (APCl): 431 (M + H) +.

EXAMPLE 20 N-Hydroxy-2-r4- (3-fluoro-4-phenylfronyl) -1,2,3,6-tetrahydropyridin-1-isulfoninacetamide Obtained as a colorless solid (40%), m.p. 184-188 ° C, from the title compound of preparation 47, using the procedure of example 1. Found: C, 58.39; H, 4.90; N, 6.84. C19H19FN2O2S requires C, 58.45; H. 4.91; N, 7.17%. d (DMSOd6): 2.61 (m, 2H), 3.47 (t, 2H), 3.94 (s, 2H), 4.00 (s, 2H), 6.35 (sa, 1 H), 7.33-7.60 (m, 8H), 9.23 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermospray): 408 (M + NH4) +.

EXAMPLE 21 N-Hydroxy-2- ^ 4-r4- (3-ethoxyphenyl) phenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl} acetamide Obtained as a colorless solid (76%), m.p. 168-170 ° C, from the title compound of preparation 56, using the procedure of example 1. d (DMSOd6): 1.34 (t, 3H), 2.61 (m, 2H), 3.49 (t, 2H), 3.94 (s, 2H), 3.98 (s, 2H), 4.10 (q, 2H), 6.25 (s, 1 H), 6.91 (d, 1 H), 7.17 (s, 1 H), 7.22 (d, 1) H), 7.33 (t, 1 H), 7.52 (d, 2H), 7.66 (d, 2H), 9.22 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermonebuiization): 434 (M + NH4) +.

EXAMPLE 22 N-Hydroxy-2-f4-r4- (3-methoxyphenyl) -3-methylphenin-1.2.3.6-tetrahydropyridin-1-Isulfoni-D-tatamide Obtained as a colorless solid (76%), p.f.162-165 ° C, from the title compound of preparation 61, using the procedure of Example 1. Found. C, 60.26; H, 5.86; N, 6.43. C21H24N2O5S requires C, 60. 56; H, 5.81; N, 6.73%. d (DMSOd6): 2.23 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.77 (s, 3H), 3.93 (s, 2H), 3.97 (s, 2H), 6.20 (s) , 1 H), 6.83-6.94 (m, 3H), 7.18 (d, 1 H), 7.27- 7.39 (m, 3H), 9.22 (sa, 1 H), 10.80 (sa, 1 H). LRMS (APCl): 416 (M) +.

EXAMPLE 23 N-Hydroxy-2-f4-r4-3-ethylphenin-3-methylphenip-1, 2,3,6-tetrahydropyridin-1-isulfoni-D-tatamide Obtained as a colorless solid (58%), m.p. 151-154 ° C, from the title compound of preparation 63, using the procedure of Example 1. Found. C, 62.75; H, 6.24; N, 6.26. C22H26N2O4S; 0.50 H2O requires C, 62.39; H, 6.43; N, 6.61%. d (DMSOd6): 1.20 (t, 3H), 2.24 (s, 3H), 2.61 (m, 4H), 3.47 (t, 2H), 3.92 (s, 2H), 3.97 (s, 2H), 6.20 (s) , 1 H), 7.10-7.23 (m, 4H), 7.27-7.38 (m, 3H), 9.22 (sa, 1 H), 10.81 (sa, 1 H). LRMS (APCl): 414 (M) +.

EXAMPLE 24 N-Hydroxy ^ - (4-r4-f3-methoxyphenyl) -3-methylphenip-1, 2,3,6-tetrahydropyridin-1-lysulfonyl) tetrahydro-tetrahydran-4-carboxamide Obtained as a pale yellow solid (47%), m.p. 160-170 ° C, from the title compound of preparation 65, using the procedure of example 19. d (DMSOd6): 1.93 (m, 2H), 2.23 (s, 3H), 2.39 (m, 2H), 2.43 (m, 2H), 3.20 (t, 2H), 3.49 (m, 2H), 3.77 (s, 3H), 3.86 (m, 2H), 4.00 (m, 2H), 6.16 (sa, 1 H), 6.83-6.94 (m, 3H), 7.17 (d, 1 H), 7.36 (m, 3H), 9.21 (sa, 1 H), 1.0 (sa, 1 H). LRMS (APCl): 487 (M + H) +.

EXAMPLE 25 N-Hydroxy-4-f4-r4- (3-methoxyphenyl) -3-methylphenipp? Peridin-1-lsulfonintetrahydropyran-4-carboxamide Obtained as a white solid (82%), m.p. 200-202 ° C, from the title compound of preparation 67, using the procedure of Example 19, with the exception that the residue was crystallized from methanol. Found. C, 60.02; H, 6.78; N, 5.45. C25H32N2O6S; CH3OH requires C, 59.98; H, 6.97; N, 5.38%. d (DMSOd6): 1.60 (m, 2H), 1.78 (m, 2H), 1.90 (m, 2H), 2.20 (s, 3H), 2.38 (m, 2H), 2.64 (m, 1 H), 3.04 ( t, 2H), 3.20 (t, 2H), 3.70 (m, 2H), 3.77 (s, 3H), 3.86 (m, 2H), 6.87 (m, 3H), 7.13 (m, 3H), 7.33 (t , 1 H), 9.16 (sa, 1H), 10.97 (sa, 1 H). LRMS (APCl) 489 (M + H) +.

EXAMPLE 26 N-Hydroxy-2- (4-r3-methoxy-4- (3-methoxyphenyl) fenipiperidin-1-ylsulfonyl> -2- methylpropanamide Obtained as a white solid (47%), m.p. 161-163 ° C, from the title compound of preparation 74, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography using dichloromethane: methanol: concentrated aqueous ammonia solution (90:10 : 1) as eluent. Found: C, 59.39; H 6.58; N, 6.13. C23H30N2O6S requires C, 59. 72; H, 6.54; N, 6.06%. d (DMSOd6): 1.49 (s, 6H), 1.64 (m, 2H), 1.81 (m, 2H), 2.70 (m, 1 H), 3.06 (t, 2H), 3.75 (s, 8H), 6.87 ( m, 2H), 6.98 (m, 3H), 7.20 (d, 1 H), 7.27 (t, 1 H), 8.99 (ss, 1 H), 10.75 (ss, 1 H). LRMS (Thermospray): 480 (M + NH 4) +.

EXAMPLE 27 N-Hldroxy-2- ^ 4-r4- (3-ethoxyphenyl) -3-methoxy-phenone-p-perdin-1-ylsulfonyl > -2- methylpropanamide Obtained as a white solid (39%), m.p. 134-136 ° C, from the title compound of preparation 77, using the procedure of example 26.

Found: C, 60.60; H, 6.80; N, 5.82. C2 H32N2? 6S requires C, 60.48; H, 6.77; N, 5.88%. d (DMSOd6): 1.32 (t, 3H), 1.49 (s, 6H), 1.66 (m, 2H), 1.81 (m, 2H), 2.70 (m, 1 H), 3.07 (t, 2H), 3.76 ( s, 5H), 4.02 (q, 2H), 6.85 (m, 2H), 6.98 (m, 3H), 7.20 (d, 1 H), 7.27 (t, 1 H), 9.00 (sa, 1 H), 10.76 (sa, 1 H). LRMS (Thermospray): 494 (M + NH 4) +.

EXAMPLE 28 N-Hydroxy-4-f4-r4- (3-ethoxyphenyl) -3-methyphenin-1,2,3,6-tetrahydropyridin-1-ylsulfonyl} tetrahydropyran-4-carboxamide Obtained as a colorless solid (87%), m.p. 152-154 ° C, from the title compound of preparation 79, using the procedure of Example 19. Found: C, 61.99; H, 6.47; N, 5.54. C26H32N2O6S requires C, 62. 38; H, 6.44; N, 5.60%. d (DMSOd6): 1.33 (t, 3H), 1.93 (m, 2H). 2.24 (s, 3H), 2.40 (d, 2H), 2.52 (m, 2H), 3.21 (dd, 2H), 3.50 (m, 2H), 3.88 (m, 2H), 3.98-4.10 (m, 4H) , 6.18 (sa, 1 H), 6.80-6.95 (m, 3H), 7.18 (d, 1 H), 7.26-7.37 (m, 3H), 9.22 (sa, 1 H), 11.05 (sa, 1 H) . LRMS (APCl): 501 (M + H) +.

EXAMPLE 29 N-H -droxy-4- (4-r4- (3-ethoxy-phenyl) -3-methylphenyl-pyridin-1-ylsulfonyl-Utrahydropyran-4-carboxamide Palladium sulfate on barium (5%, 5 ml) was added to a stirred solution of the title compound of example 28 (50 mg, 0.1 mmol) in a mixture of 1,2-dimethoxyethane (1 ml) and methanol (3 ml). ), and then the reaction mixture was hydrogenated at a pressure of 345 kPa (50 psi) for about 20 hours. An additional portion of palladium sulfate was added to barium (5%, 5 mg) and the hydrogenation was continued for an additional 20 hours. The catalyst was removed by filtration, the solvent was evaporated under reduced pressure and the residue was crystallized from ether-hexane to yield the title compound (34 mg, 66%) as a colorless solid, m.p. 165-167 ° C. Found: C, 60.81; H, 6.76; N, 5.35. C26H3 N2O6S; 0.50 H2O requires C, 61.03; H, 6.89; N, 5.74%. d (DMSOdβ): 1.35 (t, 3H), 1.60 (m, 2H), 1.78 (m, 2H), 1.92 (m, 2H), 2.20 (s, 3H), 2.40 (d, 2H), 2.62 (m , 1 H), 3.03 (dd, 2H), 3.20 (dd, 2H), 3.73 (m, 2H), 3.86 (m, 2H), 4.04 (q, 2H), 6.80-6.92 (m, 3H), 7.07 -7.17 (m, 3H), 7.30 (t, 1 H), 9.18 (sa, 1 H), 11.0 (sa, 1 H). LRMS (Thermospray): 520 (M + NH4) +.

EXAMPLE 30 N-Hydroxy-4-.4-f4- (3-ethoxyphen-3-methylphenin-1.2.3.6-tetrahydro-dyridin-1-ylsulfonyl) -2-methylpropanamide Obtained as a colorless solid (33%), m.p. 116-118 ° C, from the title compound of Preparation 81, using the procedure of Example 19. Found: C, 62.52; H, 6.47; N, 6.00. C 24 H 3 o N 2 O 5 S requires C, 62.86; H, 6.59; N, 6.11%. d (DMSOd6): 1.34 (t, 3H), 1.52 (s, 6H), 2.23 (s, 3H), 2.53 (m, 2H), 3.50 (m, 2H), 4.00-4.10 (m, 4H), 6.18 (sa, 1 H), 6.80-6.95 (m, 3H), 7.18 (d, 1 H), 7.28-7.38 (m, 3H), 9.03 (sa, 1 H), 10.8 (sa, 1 H). LRMS (Thermospray): 459 (M + H) +.

EXAMPLE 31 N-Hydroxy-2-. { 4-r4- (3-ethoxyphenyl) -3-methylphenpipiperidin-1-ylsulfonyl > Acetamida Obtained as a colorless solid (48%), m.p. 179-180 ° C (crystallized from diisopropyl ether), from the title compound of preparation 82, using the procedure of example 17. Found: C, 60.72; H, 6.49; N, 6.36. C 22 H 28 N 2 O 5 S requires C, 61.09; H, 6.53; N, 6.48%. d (DMSOd6): 1.31 (t, 3H), 1.68 (m, 2H), 1.86 (m, 2H), 2.20 (s, 3H), 2.65 (m, 1 H), 3.00 (m, 2H), 3.72 ( m, 2H), 3.86 (s, 2H), 4.03 (q, 2H), 6.80-6.90 (m, 3H), 7.10 (s, 2H), 7.17 (s, 1H), 7.30 (t, 1H), 9.20 (sa, 1H), 10.8 (sa, 1H). LRMS (APCl): 433 (M + H) +.

EXAMPLE 32 N-Hydroxy-2- (4-r4- (3-ethoxyphenyl) -3-methylphenupropylperidin-1-ylsulfonyl> -2- methylpropananfil Obtained as a colorless solid (53%), m.p. 172-174 ° C (crystallized from diisopropyl ether), from the title compound of preparation 84, using the procedure of Example 19. Found: C, 62.20; H, 6.99; N, 6.02. C 24 H 32 N 2 O 5 S requires C, 62.58; H, 7.00; N, 6.08%. d (DMSOd6): 1.31 (t, 3H), 1.50 (s, 6H), 1.61 (m, 2H), 1.79 (m, 2H), 2. 20 (s, 3H), 2.65 (m, 1H), 3.05 (m, 2H), 3.75 (m, 2H), 4.03 (q, 2H), 6.80-6.90 (m, 3H), 7.08-7.18 (m, 3H), 7.30 (dd, 1 H), 8.98 (sa, 1 H), 10.75 (sa, 1 H). LRMS (APCl): 461 (M + H) +.

EXAMPLE 33 N-Hydroxy-2-f4-r3-methyl-4- (pyridin-2-infenip-1 .2,3,6-tetrahydropyridin-1-ylsulfonyl acetamide Obtained as a colorless amorphous solid (50%) from the title compound of preparation 85, using the procedure of example 17. d (DMSOd6): 2.33 (s, 3H), 2.60 (m, 2H), 3.46 (t, 2H), 3.91 (s, 2H), 3.97 (m, 2H), 6.12 (sa, 1 H), 7.30-7.40 (m, 4H), 7.50 (d, 1 H), 7.84 (dd, 1 H), 8.63 (d, 1 H), 9.20 (sa, 1 H), 10.8 (sa, 1 H). LRMS (APCl): 388 (M + H) +.

EXAMPLE 34 N-Hydroxy-2-.4-r 3 -methyl-4- (pyridn-3-yl) phenin-1,2,3,6-tetrahydroxy-d-n- 1-ylsulfonyl acetamide Obtained as a colorless solid (57%), m.p. 132-136 ° C, from the title compound of Preparation 86, using the procedure of Example 31. d (DMSOd6): 2.23 (s, 3H), 2.60 (m, 2H), 3.46 (t, 2H), 3.91 (s, 2H), 3. 97 (m, 2H), 6.12 (sa, 1 H), 7.21 (d, 1 H), 7.35 (d, 1 H), 7.40 (s, 1 H), 7.45 (dd, 1 H), 7.78 (d) , 1 H), 8.55 (m, 2H), 9.20 (sa, 1 H), 10.8 (sa, 1 H). LRMS (APCl): 388 (M + H) +.

EXAMPLE 35 N-Hydroxy-2- (4-r3-methyl-4- (pyridin-4-yl) -phenyl-1,2,3,6-tetrahydropyridin-1-ylsulfonyl acetamide Obtained as a colorless solid (20%), m.p. 165-167 ° C, from the title compound of Preparation 87, using the procedure of Example 31. d (DMSOd6): 2.26 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.92 (s, 2H), 3.97 (m, 2H), 6.12 (sa, 1 H), 7.22 (d, 1 H), 7.35-7.42 (m, 4H), 8.62 (d, 2H), 9.20 (sa, 1 H), 10.8 (sa, 1 H). LRMS (APCl): 388 (M + H) +.

EXAMPLE 36 N-Hydroxy-2-. { 4-r4- (6-ethoxy-pyridin-2-yl) -3-methylphenipiperidin-1-ylsulfonyl > -2- methylpropanamide Obtained as a colorless solid (30%), m.p. 184-187 ° C, from the title compound of preparation 91, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography using dichloromethane: ethanol (98: 2) as eluent. d (DMSOd6): 1.30 (t, 3H), 1.48 (s, 6H), 1.63 (m, 2H), 1.79 (m, 2H), 2.35 (s, 3H), 2.67 (m, 1 H), 3.05 ( t, 2H), 3.75 (d, 2H), 4.30 (q, 2H), 6.72 (d, 1 H), 7.05 (d, 1 H), 7.15 (m, 2H), 7.34 (d, 1 H), 7.73 (t, 1 H), 9.00 (sa, 1 H), 10.75 (sa, 1 H). HRMS (Positive ion thermonebulization): 462.206 (M + H) +.

EXAMPLE 37 N-Hydroxy-4-. { 4-r4- (4-pheny, fer_l) -1, 2,3,6-tetrahydro-pyridin-1-ylsulfon-tetrahydropyran-4-carboxamide Obtained as a colorless solid (68%), m.p. 191-193 ° C, from the title compound of Preparation 93, using the procedure of Example 19, but with crystallization of the residue in methanol. d (DMSOd6): 1.93 (m, 2H), 2.40 (d, 2H), 2.55 (m, 2H), 3.20 (t, 2H), 3.48 (m, 2H), 3.85 (m, 2H), 4.00 (m, 2H), 6.1 1 (sa, 1 H), 7.35 (t, 1 H), 7.44 (m, 2H), 7.52 ( d, 2H), 7.65 (m, 4H), 9.22 (sa, 1 H), 1.05 (sa, 1 H). LRMS (APCl): 443 (M + H) +.

EXAMPLE 38 N-Hydroxy-4-4-r4- (4-ethoxyphenyl) -3-methylphenylH-1, 2,3,6-tetrahydropyridin-1-ylsulfonylmetrahydropyran-4-carboxamide Obtained as a colorless solid (36%), m.p. 159-161 ° C, from the title compound of preparation 95, using the procedure of Example 19, but with crystallization of the residue in dichloromethane-diisopropyl ether. d (DMSOd6): 1.35 (t, 3H), 1.94 (m, 2H), 2.22 (s, 3H), 2.38 (d, 2H), 2.50 (s, 2H), 3.20 (t, 2H), 3.50 (s) , 2H), 3.87 (dd, 2H), 3.98 (sa, 2H), 4.04 (q, 2H), 6.15 (sa, 1 H), 6.96 (d, 2H), 7.13 (d, 1 H), 7.22 ( d, 2H), 7.28 (d, 1 H), 7.33 (s, 1 H), 9.20 (ss, 1 H), 11.05 (ss, 1 H). LRMS (Thermospray): 515 (M + NH4) +.

EXAMPLE 39 N-Hydroxy-2-f4-r4- (3-hydroxyethyl-phenyl) -3-methylene-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl} acetamide Obtained as a colorless solid (63%), m.p. 174-176 ° C, (crystallized from methanol-diisopropyl ether), from the title compound of preparation 97, using the procedure of example 17. Found: C, 6.35; H, 5.75; N, 6.70. C2? H24N2O5S requires C, 60.56; H, 5.81; N, 6.73%. d (DMSOd6): 2.22 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.93 (s, 2H), 3.97 (s, 2H), 4.53 (d, 2H), 5.19 (t , 1 H interchangeable), 6.20 (sa, 1 H), 7.15-7.42 (m, 7H), 9.20 (sa, 1 H), 10.18 (sa, 1 H). LRMS (APCl): 417 (M + H) +.

EXAMPLE 40 N-Hydroxy-2-methyl-2-f4-r3-methyl-4- (quinolin-3-yl) phenin-1,2,3,6-tetrahydropyridin-1-ylsuifonyl} propanamide Obtained as a colorless solid (51%), m.p. 158-160 ° C, from the title compound of preparation 100, using the procedure of example 19. d (DMSOd6): 1.50 (s, 6H), 2.32 (s, 3H), 2.57 (m, 2H), 3.53 (m, 2H), 4.03 (m, 2H), 6.23 (sa, 1 H), 7.34-7.48 (m, 3H), 7.63 (t, 1 H), 7.79 (t, 1 H), 8.04 (t , 2H), 8.37 (s, 1 H), 8.91 (s, 1 H), 9.04 (sa, 1 H), 10.8 (sa, 1 H). LRMS (APCl): 466 (M + H) +.

EXAMPLE 41 N-Hydroxy-2-.4-r3-methyl-4- (3-methyltiophen) phenyl-1,2,3,6-tetrahydropyridin-1-ylsulfonyl-acetamide Obtained as a colorless solid (17%), from the title compound of preparation 102, using the procedure of example 1. d (DMSOd6): 2.23 (s, 3H), 2.49 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3. 91 (s, 2H), 3.97 (s, 2H), 6.22 (sa, 1 H), 7.08 (d, 1 H), 7.17 (m, 2H), 7.24 (d, 1 H), 7.34 (m, 3H) ), 9.22 (sa, 1 H), 10.80 (sa, 1 H). LRMS (APCl): 432 (M) +.

EXAMPLE 42 N-Hydroxy-2- (4-l4- (3-methoxymethyl-phenin-3-methylene-1,2,3,6-tetrahydropyridin-1-ylsulfonyl) acetamide Obtained as a colorless solid (28%), m.p. 151-153 ° C (crystallized from ethyl acetate-diisopropyl ether), from the title compound of preparation 104, using the procedure of example 17. Found: C, 60.16; H, 6.00; N, 6.28. C22H26N2O5S; 0.10 H2O requires C, 60.1 1; H, 6.19; N, 6.37%. d (DMSOd6): 2.22 (s, 3H), 2.60 (m, 2H), 3.30 (s, 3H), 3.47 (t, 2H), 3.93 (s, 2H), 3.97 (s, 2H), 4.04 (s) , 2H), 6.20 (sa, 1 H), 7.17 (d, 1 H), 7.21-7.42 (m, 6H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermospray): 432 (M) +.

EXAMPLE 43 N-Hydroxy-2-. { 4-r4- (3-r2-methoxyethoxyphenyl) -3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl} acetamide Obtained as a colorless solid (64%), m.p. 158-160 ° C (crystallized from ethyl acetate), from the title compound of preparation 107, using the procedure of example 17. Found: C, 59.78; H, 6.10; N, 6.01. C23H28N2O6S requires C, 59.98; H, 6.13; N, 6.08%. d (DMSOdβ): 2.24 (s, 3H), 2.60 (m, 2H), 3.30 (s, 3H), 3.47 (t, 2H), 3.66 (m, 2H), 3.92 (s, 2H), 3.97 (m , 2H), 4.12 (t, 2H), 6.20 (sa, 1 H), 6.89 (m, 3H), 7.18 (d, 1 H), 7.34 (m, 3H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermospray): 460 (M) +.

EXAMPLE 44 N-Hydroxy-2-f4-r4- (2,3-dihydrobenzofuran-5-yl) -3-methylfenin-1,2,3,6-tetrahydropyridin-1-ylsulfonyl} Acetamida Obtained as a colorless solid (56%), m.p. 158-162 ° C, from the title compound of preparation 12, using the procedure of example 17. Found: C, 57.01; H, 5.47; N, 5.26. C23H26N2O5S 0.60 CH2Cl2 requires C, 56.61; H, 5.30; N, 5.84%. d (DMSOd6): 2.23 (s, 3H), 2.58 (m, 2H), 3.20 (t, 2H), 3.44 (t, 2H), 3. 92 (s, 2H), 3.96 (s, 2H), 4.55 (t, 2H), 6.20 (sa, 1 H), 6.78 (d, 1 H), 7.01 (d, 1 H), 7.12 (d, 1 H), 7.17 (s, 1 H), 7.27 (d, 1 H), 7.33 (s, 1 H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (APCl): 428 (M + H) +.

EXAMPLE 45 N-Hydroxy-2-f4r3-methyl-4- (3-trifluoronyl-phenyl-phein-1,2,3,6-tetrahydropyridin-1-ylsulfonyl-O-acetamide Obtained as a colorless solid (50%), m.p. 168-170 ° C (crystallized from diisopropyl ether), from the title compound of Preparation 116, using the procedure of Example 17, with the exception that tetrahydrofuran was used as co-solvent for the reaction. Found: C, 54.96; H, 4.73; N, 5.97. C2.H21F3N2O4S; 0.25 H2O requires C, 54.96; H, 4.72; N, 6.10%. d (DMSOd6): 2.24 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.93 (s, 2H), 3.97 (m, 2H), 6.22 (sa, 1 H), 7.23 ( d, 1 H), 7.36 (d, 1 H), 7.41 (s, 1 H), 7.68 (m, 4 H), 9.20 (s, 1 H), 10.80 (s, 1 H). LRMS (APCl): 455 (M + H) +.

EXAMPLE 46 N-Hydroxy-2-r4- (4-phenoxyphenol) piperidin-1-lysulfonyl-acetamide Obtained as a colorless solid (13%), m.p. 176-179 ° C, from the title compound of Preparation 119, using the procedure of Example 17, with the exception that dichloromethane was used as the cosolvent for the reaction. Found: C, 57.92; H, 5.62; N, 6.97. C19H22N2O5S; 0.20 H2O requires C, 57.91; H, 5.73; N, 7.11%. d (DMSOd6): 1.63 (m, 2H), 1.84 (m, 2H), 2.63 (m, 1 H), 2.98 (t, 2H), 3.69 (m, 2H), 3.85 (s, 2H), 6.96 ( m, 4H), 7.10 (t, 1 H), 7.27 (d, 2H), 7.36 (t, 2H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermospray): 392 (M + H) +.

EXAMPLE 47 N-Hydroxy-2-f4-r4- (3-r2-methoxyethoxy-1-phenyl) -3-methyl-phenylpiperidin-1-ylsulfonyl} -2-methylpropanamide Obtained as a colorless solid (42%), m.p. 155-156 ° C, from the compound of preparation 122, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography, using dichloromethane: methanol (97: 3) as eluent, before the crystallization from dichloromethane-diisopropyl ether. d (DMSOd6): 1.50 (s, 6H), 1.60 (m, 2H), 1.80 (m, 2H), 2.20 (s, 3H), 2.65 (m, 1 H), 3.05 (t, 2H), 3.30 ( s, 3H), 3.62 (t, 2H), 3.74 (d, 2H), 4.10 (t, 2H), 6.80-6-92 (m, 3H), 7.10-7.17 (m, 3H), 7.30 (t, 1 H), 9.02 (sa, 1 H), 10.7 (sa, 1 H). LRMS (Electronebulization): 513 (M + Na) +.

EXAMPLE 48 N-Hydroxy-4-methoxy-2 (R.sub.S) -r4- (3-methyl-4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfonylbutanamide Obtained as a colorless solid (39%), m.p. 135-136 ° C, from the title compound of Preparation 124, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography using dichloromethane: methanol (97: 3) as eluent, before crystallization in diisopropyl ether. d (DMSOd6): 2.10 (m, 2H), 2.23 (s, 3H), 2.57 (m, 2H), 3.20 (s, 4H), 3.36 (m, 1H), 3.48 (m, 2H), 3.87 (dd) , 1 H), 3.98 (m, 2H), 6.20 (sa, 1H), 7.16 (d, 1 H), 7.32 (m, 5H), 7.43 (m, 2H), 9.22 (sa, 1 H), 10.95 (sa, 1 H). LRMS (Thermospray): 444 (M) +.

EXAMPLE 49 N-H -droxy-4-r4- (3-methyl-4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-lsulfonintetrahldropyran-4-carboxamide Obtained as a colorless solid (91%), m.p. 188-190 ° C, from the title compound of preparation 126, using the procedure of Example 38. Found: C, 61.89; H, 6.15; N, 5.94. C 24 H 28 N 2 O 5 S; 0.50 H2O requires C, 61.91; H, 6.28; N, 6.02%. d (DMSOd6): 1.95 (m, 2H), 2.22 (s, 3H), 2.39 (d, 2H), 2.50 (m, 2H), 3.20 (t, 2H), 3.48 (sa, 2H), 3.87 (dd) , 2H), 4.00 (sa, 2H), 6.17 (sa, 1 H), 7.16 (d, 1 H), 7.31 (m, 5H), 7.42 (m, 2H), 9.22 (sa, 1 H), 1 1.05 (sa, 1 H). LRMS (APCl): 457 (M + H) +.

EXAMPLE 50 N-Hydroxy-2-. { 4-R4- (3-methoxyphenyl) -3-methylphenylpiperidin-1-ylsulfonyl > indane- 2 -carboxamide Obtained as a colorless solid (63%), m.p. 199-202 ° C, from the title compound of preparation 130, using the procedure of Example 19, but with crystallization of the residue in diisopropyl ether. Found: C, 66.25; H, 6.18; N, 5.18 C 29 H 32 N 2 O 5 S; 0.30 H2O requires C, 61.21; H, 6.25; N, 5.33%. d (DMSOd6): 1.55 (m, 2H), 1.76 (m, 2H), 2.20 (s, 3H), 2.54 (m, 1 H), 2.89 (t, 2H), 3.48 (m, 2H), 3.77 (m, 7H), 6.87 (m, 3H), 7.07-7.35 (m, 8H), 9.10 (sa, 1 H), 11.05 (sa, 1 H).

EXAMPLE 51 N-Hydroxy-1 - (4-r4- (3-methoxyphenyl) -3-methylphenylpiperidin-1-ylsulfonyl &cyclobutanecarboxamide Obtained as a colorless solid (52%), m.p. 157-160 ° C, from the title compound of preparation 132, using the procedure of Example 50. Found: C, 62.79; H, 6.60; N, 5.93. C2 H3oN2? 5S requires C, 62.86; H, 6.59; N, 6.11%. d (DMSOd6): 1.60 (m, 2H), 1.78 (m, 3H), 1.93 (m, 1 H), 2.20 (s, 3H), 2.57 (m, 5H), 2.97 (t, 2H), 3.72 ( m, 2H), 3.77 (s, 3H), 6.87 (m, 3H), 7.11 (s, 2H), 7.15 (s, 1 H), 7.36 (t, 1 H). 9.10 (s a, 1 H), 10.92 (s a, 1 H). LRMS (Thermospray): 459 (M + H) +.

EXAMPLE 52 N-Hydroxy-4-f4-r4- (3-methoxyphenyl) -3-methypheninpiperidin-1-ylsulfonyl-1-methylpiperidine-4-caboxamide Obtained as a colorless solid (13%), from the compound of preparation 134, using the procedure of Example 19, except that the residue was purified by flash chromatography using dichloromethane: methanol: concentrated aqueous solution of ammonia (90: 10: 1) as eluent. d (CDCl 3): 1.79 (m, 2H), 1.90 (m, 2H), 2.16 (m, 2H), 2.27 (s, 3H), 2.30 (s, 3H), 2.33 (m, 4H), 2.64 (m , 1 H), 2.91 (day, 2H), 3.10 (t, 2H). 3.83 (s, 3H), 3.91 (m, 2H), 6.88 (m, 3H), 7.08 (m, 2H), 7.18 (d, 1 H), 7.30 (t, 1 H). LRMS (Thermospray): 502 (M + H) +.

EXAMPLE 53 N-Hydroxy-3-phenyl-2 (R.S) -r4- (4-phenylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonpropropanamide Obtained as a colorless solid (31%), m.p. 202-205 ° C, from the title compound of preparation 136, using the procedure of Example 19, with the exception that the residue was triturated with dichloromethane. Found: C, 66.05; H, 5.82; N, 6.15. C26H26N2O4S; 0.50 H2O requires C, 66.22; H, 5.77; N, 5.94%. d (DMSOd6): 2.60 (m, 2H), 3.15 (m, 2H), 3.57 (m, 2H), 4.03 (m, 3H), 6.07 (sa, 1 H), 7.16-7.36 (m, 6H), 7.45 (m, 2H), 7.57 (m, 2H), 7.65 (m, 4H), 9.17 (sa, 1 H), 10.70 (sa, 1 H). LRMS (APCl): 463 (M + H) +.

EXAMPLE 54 N-Hydroxy-2-r4- (4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfoninindane-2-carboxamide Obtained as a colorless solid (27%), m.p. 159-161 ° C, from the title compound of Preparation 138, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography using dichloromethane.methanol (98: 2) as eluent, followed by trituration with diisopropyl ether. d (DMSOd6): 2.55 (m, 2H), 3.41 (m, 2H), 3.53 (d, 2H), 3.77 (d, 2H), 3.96 (m, 2H), 6.18 (sa, 1 H), 7.16 ( m, 2H), 7.23 (m, 2H), 7.34-7.53 (m, 5H), 7.65 (m, 4H), 9.15 (sa, 1 H), 11.10 (sa, 1 H). LRMS (APCl): 463 (M + H) +.

EXAMPLE 55 N-Hydroxy-2- ^ 4-r4- (3-chloro-4-fluorophenyl) -3-methylphen-1.2.3.6-tetrahydropyridin-1-sulfonyl} acetamide Obtained as a colorless solid (60%), m.p. 181-183 ° C (crystallized from ether), from the title compound of preparation 142, using the procedure of Example 17, with the exception that tetrahydrofuran was used as co-solvent for the reaction. Found: C, 54.65; H, 4.61; N, 6.13. C20H20CIFN2O4S requires C, 54.73; H, 4.59; N, 6.38%. d (DMSOd6): 2.24 (s, 3H), 2.60 (m, 2H), 3.47 (t, 2H), 3.90 (s, 2H), 3.97 (m, 2H), 6.22 (sa, 1H), 7.20 (d , 1H), 7.30-7.40 (m, 3H), 7.45 (t, 1H), 7.56 (m, 1H), 9.20 (sa, 1H), 10.80 (sa, 1H). LRMS (APCl): 439 (M + H) +.

EXAMPLE 56 N-Hydroxy-2-y4-r4-f1,3-benzodioxol-5-yl) -3-methylphen-1,2,3,6-tetrahydropyridin-1-ylsulfonyl} Acetamida Obtained as a colorless solid (69%), p.f.165-167 ° C, from the title compound of preparation 146, using the procedure of Example 45. Found: C, 58.60; H, 5.10; H, 6.01. C 21 H 22 N 2 O 6 S requires C, 58.59; H, 5.15; N, 6.51%. d (DMSOd6): 2.22 (s, 3H), 2.59 (m, 2H), 3.46 (t, 2H), 3.90 (s, 2H), 3.96 (m, 2H), 6.04 (s, 2H), 6.20 (s) , 1H), 6.76 (d, 1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.15 (d, 1H), 7.28 (d, 1H), 7.35 (s, 1H), 9.20 (sa, 1H), 10.80 (ss, 1H). LRMS (APCl): 431 (M + H) +.

EXAMPLE 57 N-Hydroxy-2-γ4-r4- (2-fluorophenyl) -3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfoniumDacetamide Obtained as a colorless solid (32%), m.p. 160-163 ° C, from the title compound of preparation 150, using the procedure of Example 17, with the exception that tetrahydrofuran was used as the solvent code for the reaction. d (DMSOd6): 2.12 (s, 3H), 2.60 (m, 2H), 3.48 (t, 2H), 3.84 (s, 2H), 3.98 (m, 2H), 6.21 (sa, 1 H), 7.17 ( d, 1 H), 7.23-7.35 (m, 4H), 7.40 (s, 1 H), 7.42 (m, 1 H). LRMS (APCl): 405 (M + H) +.

EXAMPLE 58 N-Hydroxy-2-. { 4-l4- (3,4-dimethoxyphenyl) -3-methy! Phen-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl acetamide Obtained as a colorless solid (61%), m.p. 172-174 ° C, from the title compound of preparation 151, using the procedure of example 157. Found: C, 59.36; H, 6.08; N, 5.87. C 22 H 26 N 2 O 6 S requires C, 59.18; H, 5.87; N, 6.27%. d (DMSOd6): 2.25 (s, 3H), 2.60 (m, 2H), 3.48 (t, 2H), 3.75 (s, 3H), 3.78 (s, 3H), 3.90 (s, 2H), 3.96 (m , 2H), 6.19 (sa, 1 H), 6.82 (d, 1 H), 6.88 (s, 1 H), 7.00 (d, 1 H), 7.19 (d, 1 H), 7.29 (d, 1 H) ), 7.36 (s, 1 H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (APCl): 447 (M + H) +.

EXAMPLE 59 N-Hydroxy-2-f4-r4- (indan-5-yl) -3-methylphenyl-1,2,3,6-tetrahydropyridin-1-ylsulfonyl} acetamide Obtained as a colorless solid (58%), m.p. 149-152 ° C, from the title compound of preparation 152, using the procedure of example 17. d (DMSOd6): 2.03 (m, 2H), 2.22 (s, 3H), 2.59 (m, 2H), 2.90 (m, 4H), 3.47 (m, 2H), 3.90 (s, 2H), 3.96 (m, 2H), 6.19 (s, 1 H), 7.05 (d, 1 H), 7.15 (m, 2H) , 7.23-7.30 (m, 2H), 7.36 (s, 1 H), 9.20 (ss, 1 H), 10.80 (ss, 1 H). LRMS (APCl): 427 (M + H) +.

EXAMPLE 60 N-Hydroxy-2- ^ 4-r3-methyl-4-3-trifluoromethoxy-phenyl) -phenn-1, 2.3.6-tetrahydropyridin-1-ylsulfonyl > acetamide Obtained as a colorless solid (13%), m.p. 154 ° C (crystallized from dichloromethane-diisopropyl ether), from the title compound of preparation 153, using the procedure of example 17. d (DMSOd6): 2.23 (s, 3H), 2.59 (m, 2H), 3.47 (t, 2H), 3.90 (s, 2H), 3.96 (m, 2H), 6.22 (sa, 1 H), 7.20 (d, 1 H), 7.30-7.40 (m, 5H), 7.58 (t, 1) H), 9.20 (sa, 1 H), 10.80 (sa, 1 H). LRMS (Thermospray): 488 (M + NHf.

EXAMPLE 61 N-Hydroxy-2-r4- (4-phenyl-3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfonyl acetamide Obtained as a colorless solid (43%), m.p. 143-145 ° C, from the title compound of preparation 157, using the procedure of example 17. Found: C, 54.63; H, 4.35; N, 5.90. C20H19F3N2O4S requires C, 54.54; H, 4.35; N, 6.36%. d (DMSOd6): 2.66 (m, 2H), 3.50 (m, 2H), 3.93 (s, 2H), 4.00 (m, 2H), 6.38 (s a, 1 H). 7.30 (m, 2H), 7.35-7.47 (m, 4H), 7.79 (d, 1 H), 7.82 (s, 1 H), 9.20 (s a, 1 H), 10.80 (s a, 1 H). LRMS (Thermospray): 458 (M + NH4) +.

EXAMPLE 62 N-Hydroxy-2-. { 4-r4- (2,2-d5methyl-1,3-benzodioxol-5-yl) -3-methylphenid-piperidin-1-ylsulfonyl} -2-methylpropionamide Obtained as a colorless solid (52%), m.p. 184-186 ° C, from the title compound of Preparation 161, using the procedure of Example 19. d (DMSOd6): 1.47 (s, 6H), 1.60 (m, 2H), 1.65 (s, 6H), 1.78 (m, 2H), 2.20 (s, 3H), 2.65 (m, 1 H), 3.04 (m, 2H), 3.73 (m, 2H), 6.68 (d, 1 H), 6.77 (s, 1 H) ), 6.83 (d, 1 H), 7.07 (s, 2H), 7.12 (s, 1 H), 9.00 (sa, 1 H), 10.75 (sa, 1 H). LRMS (APCl): 489 (M + H) +.

EXAMPLE 63 N-Hydroxy-2-f4-r4- (1,2-dimethylbenzoimidazol-5-yl) -3-methylphenylpiperidin-1-ylsulfonip-2-methylpropionamide Obtained as a colorless solid (22%), m.p. 213-215 ° C, from the title compound of preparation 165, using the procedure of example 19. d (DMSOd6): 1.48 (s, 6H), 1.62 (m, 2H), 1.80 (m, 2H), 2.20 (s, 3H), 2.52 (s, 3H), 2.67 (m, 1 H), 3.08 (t, 2H), 3.73 (s, 3H), 3.75 (m, 2H), 7.08-7.15 (m, 4H), 7.39 ( s, 1 H), 7.47 (d, 1 H), 9.00 (sa, 1 H), 11.75 (sa, 1 H). LRMS (Thermospray): 485 (M + H) +.

EXAMPLE 64 N-Hydroxy ^ - ^^ - cyanopheniD-S-methylphenpipiperidln-l-ylsulfonyl) ^ - methylpropionamide Palladium on barium sulfate (5%, 10 mg) was added to a stirred solution of the title compound of preparation 168 (70 mg, 0.13, mmol) in methanol (2 ml), and then the reaction mixture was hydrogenated a pressure of 345 kPa (50 psi) for approximately 20 hours. An additional portion of palladium was added to barium sulfate (5%, 10 mg) and the hydrogenation was continued for an additional period of 4 days. The catalyst was removed by filtration, the solvent was evaporated under reduced pressure and the residue was subjected to flash chromatography, using methanohdichloromethane (5:95) as eluent, to give the title compound (13 mg, 23%) as a colorless amorphous solid. d (CDCl 3): 1.63 (s, 6H), 1.63-1.95 (m, 4H), 2.26 (s, 3H), 2.67 (m, 1 H), 3.10 (m, 2H), 3.96 (m, 2H), 7.04-7.20 (m, 3H), 7.50-7.70 (m, 4H). IR (KBr) 2240 cm "1 for cyano.

EXAMPLE 65 N-Hydroxy-2-f4-r4- (5-ethoxypyridin-3-yl) -3-methylphenin-p-peridin-1-ylsulfonyl > -2- methylpropionamide Obtained in the form of a colorless foam (62%), from the compound of preparation 172, using the procedure of Example 19, with the exception that the residue was purified by flash chromatography, using dichloromethane: methanol (95: 5) as eluent. d (DMSOd6): 1.32 (t, 3H), 1.48 (s, 6H), 1.61 (m, 2H), 1.79 (m, 2H), 2.21 (s, 3H), 2.67 (m, 1 H), 3.05 ( t, 2H), (d, 2H), 4.13 (q, 2H), 7.15-7.20 (m, 3H), 7.30 (s, 1 H) 8.10 (s, 1 H), 8.23 (s, 1 H), 8.98 (sa, 1 H), 10.75 (sa, 1 H). LRMS (Thermospray): 462 (M + H) +.

EXAMPLE 66 N-Hydroxy-2-f4-r4- (3- (2-hydroxyethoxy-1-phenyl) -3-methylphenin-piperidin-1-ylsulfonyl} -2-methylpropionamide O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (510 mg, 1.15 mmol) was added to a stirred solution of the title compound of preparation 178 (530 mg , 0.76 mmoles) and N-ethyldiisopropylamine (0.20 ml, 0.9 mmoles) in anhydrous dimethylformamide (4 ml), under nitrogen, at room temperature. After 15 minutes, hydroxylamine hydrochloride (188 mg, 2.2 mmol) and N-ethyldiisopropylamine (0.6 ml, 2.7 mmol) were added, the reaction mixture was stirred for 16 hours, and then partitioned between ethyl acetate and phosphate buffer. aqueous (pH 7). The organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (15 ml), tetra-n-butylammonium fluoride (1.4 ml of a 1.0 M solution in tetrahydrofuran) was added.; 1.4 mmoles) and the resulting solution was stirred at room temperature for 1.5 hours and then partitioned between ethyl acetate and aqueous phosphate buffer (pH 7). The organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. Purification of the residue by flash chromatography, using dichloromethane: methanol: concentrated ammonia solution (90: 10: 1) as eluent, followed by crystallization from methanol-water, provided the product as a colorless solid (155 mg, 43% ), pf 147-150 ° C. Found: C, 60.26; H, 6.81; N, 5.76. C2 H32N2? 6S requires C, 60.48; H, 6.77; N, 5.88%. d (DMSOd6): 1.49 (s, 6H), 1.63 (m, 2H), 1.80 (m, 2H), 2.21 (s, 3H), 2.67 (m, 1 H), 3.08 (t, 2H), 3.74 ( m, 4H), 4.02 (t, 2H), 4.83 (t, 1 H), 6.82-6.92 (m, 3H), 7.10 (s, 2H), 7.16 (s, 1 H), 7.30 (t, 1 H) ), 9.00 (s, a, 1 H), 10.75 (s, a, 1 H).

PREPARATION 1 4-Hydroxy-4- (4-phenylphenyl) p -peridin-1-t-butylcarboxylate A solution of 2.5 M n-butyllithium in hexane (8 ml, 20 mmol) was added over about 10 minutes to a stirred mixture of 4-bromobiphenyl (4.66 g, 20 mmol), anhydrous ether (100 ml) and anhydrous tetrahydrofuran (10 ml), under nitrogen, at about -75 ° C. After an additional 1 hour, a solution of t-butyl 4-oxopiperidin-1-carboxylate (3.98 g, mmoles) in anhydrous tetrahydrofuran (10 ml) was added, at such a rate that the reaction temperature was maintained below -60 ° C. The reaction mixture was stirred at about -75 ° C for 3 hours and quenched with aqueous ammonium chloride solution, and then the organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. Crystallization of the residue in diisopropyl ether gave the title compound (4.29 g) as a colorless solid, m.p. 144-146 ° C. d (CDCl 3): 1.50 (s, 9H), 1.78 (d, 2H), 2.06 (m, 2H), 3.28 (dd, 2H), 4.06 (m, 2H), 7.35 (t, 1 H), 7.43 ( m, 2H), 7.50-7.65 (m, 6H). LRMS (APCl): 354 (M + H) + PREPARATION 2 4- (4-Phenylphenyl) -1, 2,3,6-tetrahydropyridine Trifluoroacetic acid (20 ml) was added to a stirred solution of the title compound of preparation 1 (4.2 g, 1.9 mmol) in dichloromethane (20 ml), at room temperature. After 3 more hours, the reaction mixture was evaporated under reduced pressure and the residue was basified with 1 M aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane, and then the combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure, yielding the title compound (2.79 g) as a colorless solid. d (CDCl 3): 1.53 (s, 1 H), 2.50 (m, 2 H), 3.14 (t, 2 H), 3.58 (m, 2 H), 6.20 (sa, 1 H), 7.34 (t, 1 H), 7.45 (m, 4H), 7.60 (m, 4H). LRMS (Thermospray): 236 (M + H) + PREPARATION 3 1-Benzyl-4-hydroxy-4- (4-phenylphenyl) piperidine A solution of 1.6 M n-butyllithium in hexane (39 ml, 63 mmol) was added to a stirred solution of 4-bromobiphenyl (1.7 g, 50 mmol) in anhydrous tetrahydrofuran (50 ml), under nitrogen, at approximately -50 ° C, while ensuring that the reaction temperature remained below -40 ° C. After an additional 1 hour, a solution of 1-benzyl-4-oxopiperidine (10.4 g, 55 mmol) in anhydrous tetrahydrofuran (30 ml) was added at a rate such that the reaction temperature was maintained below -40 ° C. . The cooling bath was then removed and, after an additional 1 hour, the reaction mixture was partitioned between dichloromethane (400 ml) and brine (200 ml). The organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure, then the residue was crystallized from ethyl acetate to yield the title compound (13.9 g) as a colorless solid. d (DMSOd6): 1.80 (d, 2H), 2.52 (m, 2H), 3.24 (m, 4H), 4.33 (d, 2H), 7.28-7.75 (m, 14H), 1 1.30 (sa, 1 H).

PREPARATION 4 1 -Benzyl-4- (4-phenylphenyl) -1, 2,3,6-tetrahydropyridine A solution of the title compound of Preparation 3 (13.8 g, 40.2 mmol) and p-toluenesulfonic acid (15.3 g, 80.4 mmol) in toluene (100 mL) was heated to reflux in a Dean-Stark apparatus until it was removed all the water (ca. 2 hours), then allowed to cool and diluted with water (200 ml). The resulting mixture was basified with concentrated aqueous ammonia solution and extracted with dichloromethane (4 x 200 ml), then the combined extracts were dried (MgSO) and evaporated under reduced pressure to give the title compound (10.6 g) as of a whitish solid. d (CDCl 3): 2.57 (m, 2H), 2.70 (m, 2H), 3.18 (m, 2H), 3.62 (s, 2H), 6.10 (s, at 1H), 7.20-7.60 (m, 14H).

PREPARATION 5 4- (4-Phenylphenyl) piperidine A stirred mixture of the title compound of preparation 4 (5.07 g, 15.6 mmol), ammonium formate (4 g, 62 mmol), palladium hydroxide on carbon (500 mg) and methanol (50 ml), it was heated to reflux for 4.5 hours, allowed to cool and filtered. The filtrate was evaporated under reduced pressure and the residue partitioned between 2M aqueous sodium hydroxide solution and dichloromethane. The organic phase was separated and combined with dichloromethane extracts (3 x 100 ml) of the aqueous phase, and then the combined dichloromethane solutions were dried (MgSO) and evaporated under pressure to yield the title compound (3.5 g) in the form of a whitish solid, mp 104-107 ° C. d (CDCl 3): 1.50 (br s, 1 H), 1.63 (m, 2H), 1.83 (m, 2H), 2.62 (m, 1 H), 2.75 (m, 2H), 3.19 (d, 2H), 7.25 (m, 3H), 7.40 (m, 2H), 7.53 (m, 4H).

PREPARATION 6 4-Hydroxy-4- (3-methyl-4-phenylphenyl) piperidine-1-t-butylcarboxylate Obtained as a colorless solid (60%), m.p. 142-144 ° C, from 4-bromo-2-methylbiphenyl (J. Amer. Chem. Soc, 1926, 48, 1372) and t-butyl 4-oxopiperidin-1-carboxylate, using the procedure of the preparation 1. d (CDCl 3): 1.48 (s, 9H), 1.78 (m, 2H), 2.04 (m, 2H), 2.30 (s, 3H), 3.28 (m, 2H), 4.05 (m, 2H), 7.20 -7.42 (m, 8H). LRMS (Thermospray): 468 (M + H) +.

PREPARATION 7 4- (3-Methyl-4-phenylphenn-1.2.3.6-tetrahydropyridine Obtained as a colorless solid (90%) from the title compound of preparation 6, using the procedure of preparation 2. d (CDCl 3): 1.85 (s, 1 H), 2.28 (s, 3H), 2.50 (m, 2H), 3.14 (t, 2H), 3.57 (m, 2H), 6.18 (sa, 1 H), 7.20-7.42 (m 8H). LRMS (APCl): 250 (M + H) +.

PREPARATION 8 2-í4- (4-Phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-methyl sulphonyl acetate A solution of methyl chlorosulfonylacetate (0.35 g, 2 mmol) in dichloromethane (2 ml) was added dropwise to a stirred solution of the title compound of preparation 2 (470 mg, 2 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.3 ml, 2 mmol) in dichloromethane (8 ml) at about 0 ° C, the cooling bath was removed, the reaction mixture was stirred at room temperature for 4 hours and then it was diluted with dichloromethane. The resulting mixture was washed with 0.1 M hydrochloric acid, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography using dichloromethane as eluent, followed by crystallization from diisopropyl ether to give the title compound (250 mg) as a colorless solid, m.p. 182-183 ° C. Found: C, 64.32; H, 5.59; N, 3.77. C2oH2.NO4S requires C, 64. 66; H, 5.70; N, 3.77%. d (CDCl 3): 2.66 (m, 2H), 3.62 (t, 2H), 3.78 (s, 3H), 3.99 (s, 2H), 4.08 (m, 2H), 6.08 (sa, 1 H), 7.32 ( m, 1 H), 7.38-7.44 (m, 4H), 7.53-7.60 (m, 4H). LRMS (APCl): 372 (M + H) +.

PREPARATION 9 2-r4- (3-Methyl-4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfoyl acetate methyl Obtained as a colorless solid (30%), m.p. 104-105 ° C, from the title compound of preparation 7 and methyl chlorosulfonylacetate, using the procedure of preparation 8. Found: C, 65.18; H, 6.03; N, 3.59. C2? H23NO4S requires C, 65.43; H, 6.01; N, 3.63%. d (CDCl 3): 2.28 (s, 3H), 2.68 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m, 2H), 6.08 (s) , 1 H), 7.20-7.47 (m, 8H). LRMS (Thermospray): 386 (M + H) +.

PREPARATION 10 2-r4- (4-Phenylphenyl) piperidin-1. Methyl sulphonyl acetate Obtained in the form of a colorless solid (27%), m.p. 169-170 ° C, from the title compound of preparation 5 and methyl chlorosulfonylacetate, using the procedure of preparation 8. Found: C, 63.99; H, 6.18; N, 3.69. C20H23NO4S requires C, 64. 32; H, 6.21; N, 3.75. d (CDCl 3): 1.83 (m, 2H), 1.95 (m, 2H), 2.68 (m, 1 H), 3.00 (t, 2H), 3.80 (s, 3H), 3.95 (s, 2H), 3.97 ( m, 2H), 7.20-7.35 (m, 3H), 7.40 (t, 2H), 7.50-7.60 (m, 4H).

PREPARATION 11 2- (4-Phenyl-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-methyl acetate) Obtained as a colorless solid (20%), m.p. 93-94 ° C, from 4-phenyl-1, 2,3,6-tetrahydropyridine and methyl chlorosulfonylacetate, using the procedure of preparation 8. Found: C, 56.86; H, 5.79; N, 4.7.6. C14H17NO4S requires C, 56.93; H, 5.80; N, 4.74%. d (CDCl 3): 2.62 (m, 2H), 3.60 (t, 2H), 3.78 (s, 3H), 3.99 (s, 2H), 4.05 (m, 2H), 6.00 (sa, 1 H), 7.22- 7.35 (m, 5H).

PREPARATION 12 2- (4-Phenylpiperidin-1-ylsulfoni-D-methyl acetate) Obtained as a colorless solid (35%), m.p. 98-100 ° C, from 4-phenylpiperidine and methyl chlorosulfonylacetate, using the procedure of preparation 8. Found: C, 56.43; H, 6.41; N, 4.64. C14H19NO4S requires C, 56. 55; H, 6.44; N, 4.71%. d (CDCl 3): 1.80 (m, 2H), 1.90 (m, 2H), 2.60 (m, 1 H), 2.97 (m, 2H), 3.80 (s, 3H), 3.92 (s, 2H), 3.93 ( m, 2H), 7.15-7.33 (m, 5H).

PREPARATION 13 2- methyl 4-Benzylpiperidin-1-ylsulfoni-D-acetate Obtained in the form of an amorphous solid (24%) from 4-benzylpiperidine and methyl chlorosulfonylacetate, using the procedure of Preparation 8, but with an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) for the chromatographic purification step. d (CDCl 3): 1.30 (m, 2H), 1.62 (m, 1 H), 1.70 (m, 2H), 2.54 (d, 2H) 2.78 (t, 2H), 3.73 (s, 3H), 3.76 (m , 2H), 3.88 (s, 2H), 7.08 (d, 2H), 7.17 (t, 1 H), 7.24 (m, 2H). LRMS (APCl): 312 (m + H) +.

PREPARATION 14 2- (R.S) -r4- (4-phenylpheniD-1, 2,3,6-tetrahydropyridin-1-ylsulfoninpent-4-enoate methyl) 60% sodium hydride in a dispersion in mineral oil (21 mg, 0.53 mmol) was added to a stirred solution of the title compound of preparation 8 (180 mg, 0.48 mmol) in a mixture of anhydrous tetrahydrofuran (1 ml) and Anhydrous dimethylformamide (1 ml), under nitrogen, at room temperature. After 30 minutes, allyl bromide (0.05 ml, 0.53 mmol) was added and stirring was continued for a further 2 hours, then the resulting mixture was partitioned between ethyl acetate and aqueous phosphate buffer (pH 7). The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure, then the residue was triturated with diisopropyl ether to yield the title compound (170 mg) as a colorless solid. d (CDCl 3): 2.60-2.85 (m, 4H), 3.55-3.77 (m, 2H), 3.79 (s, 3H), 4. 03 (dd, 1 H), 4.12 (m, 2H), 5.10-5.22 (m, 2H), 5.74 (m, 1 H), 6.08 (sa, 1 H), 7.36 (m, 1 H), 7.43 ( m, 4H), 7.60 (m, 4H). LRMS (APCl): 41 1 (M + H) +.

PREPARATION 15 Acid 2 (R.S) -r4- (4-phenylpheniD-1, 2.3.6-tetrahydropyridin-1-ylsulfonylpent-4-enoic) A 1 M aqueous solution of sodium hydroxide (1.2 ml, 1.2 mmol) was added to a stirred solution of the title compound of preparation 14 (160 mg, 0.39 mmol) in a mixture of tetrahydrofuran (5 ml) and methanol (10 ml). ). The resulting solution was heated at 50 ° C for 3 hours, then evaporated under reduced pressure and the residue was dissolved in water. This aqueous solution was acidified with concentrated hydrochloric acid and the resulting emulsion was extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated under reduced pressure, and then the residue was purified by flash chromatography, using an elution gradient of ethyl acetate: methane: glacial acetic acid (100: 0: 0 to 97: 3 : 0 to 96: 3: 1), followed by trituration with hexane, to yield the title compound (90 mg) as a colorless amorphous solid. d (CDCl 3): 2.60-2.87 (m, 4H), 3.60-3.72 (m, 2H), 4.05 (dd, 1 H), 4.12 (s, 2H), 5.10-5.23 (m, 2H), 5.79 (m , 1 H), 6.06 (sa, 1 H), 7.30-7.43 (m, 5H), 7.50-7.60 (m, 4H). LRMS (Thermonebulization): 415 (M + NH4) +.

PREPARATION 16 2 R, S) -r4- (3-Methyl-4-phenylphen-D-1,2,3,6-tetrahydropyridin-1-yl-sulfoninpent-4-enoate methyl) Obtained as a solid (67%) from the title compound of preparation 9 and allyl bromide, using the procedure of preparation 14, but with flash chromatography, using an elution gradient of hexane: ethyl acetate ( 100: 0 to 80:20), as a purification stage. d (CDCl 3): 2.30 (s, 3H), 2.68 (m, 2H), 2.85 (m, 2H), 3.56 (m, 1 H), 3.70 (m, 1 H), 3.80 (s, 3H), 4.03 (dd, 1 H), 4.10 (m, 2H), 5.10-5.22 (m, 2H), 5.73 (m, 1 H), 6.06 (sa, 1 H), 7.20-7.45 (m, 8H). LRMS (Thermospray): 426 (M + H) +.

PREPARATION 17 Acid 2, R, S) -r4- (3-methyl-4-phenylphenylD-1, 2,3,6-tetrahydropyridin-1-yl-lsufoninpent-4-enoic Obtained as an amorphous solid (46%) from the title compound of preparation 16, using the procedure of preparation 15. d (CDCl 3): 2.30 (s, 3H), 2.66 (m, 2H), 2.87 (m, 2H), 3.60 (m, 1 H), 3.70 (m, 1 H), 4.03 (dd, 1 H), 4.12 (m, 2H), 5.13-5.25 (m, 2H), 5.78 (m, 1 H), 6.04 (sa, 1 H), 7.20-7.43 (m, 8H). LRMS (Thermospray): 368 (M + H-CO2) +.

PREPARATION 18 5-Feni-2. R, S) -r4- (methyl 4-phenylphenyl-1, 2,3,6-tetrahydropyridin-1-ylsulfonylpentanoate) Obtained as a colorless solid (65%), m.p. 146-148 ° C, from the title compound of preparation 8 and 1-bromo-3-phenylpropane, using the procedure of preparation 14. d (CDCl 3): 1.70 (m, 2H), 2.15 (m, 2H ), 2.64 (m, 4H), 3.52 (m, 1 H), 3. 63 (m, 1 H), 3.79 (s, 3H), 3.89 (dd, 1 H), 4.06 (m, 2H), 6.05 (m, 1 H), 7.10-7.50 (m, 10H), 7.60 (m , 4H). LRMS (Thermospray): 490 (M + H) +.

PREPARATION 19 2-Methyl-2-_4- (4-phenylfeniD-1, 2,3,6-tetrahydropyridin-1-ylsulfonylpropanoic acid 60% sodium hydride in a dispersion in mineral oil (48 mg, 1.2 mmol) was added to a stirred solution of the title compound of preparation 8 (150 mg, 0.4 mmol) in a mixture of anhydrous tetrahydrofuran (3 ml) and Anhydrous dimethylformamide (1 ml), under nitrogen, at room temperature. After 30 minutes, methyl p-toluenesulfonate (220 mg, 1.2 mmol) was added and stirring was continued for a further 20 hours, then the resulting mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified with 2 M hydrochloric acid and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure, then the residue was purified by flash chromatography, using dichloromethane: methanol: glacial acetic acid (89: 10: 1) as eluent, to give the title compound (60 mL). mg) in the form of a pale yellow amorphous solid. d (CDCl 3): 1.70 (s, 6H), 2.63 (m, 2H), 3.67 (m, 2H), 4.17 (m, 2H), 6.08 (s a, 1 H), 7.25-7.70 (m, 9H).

PREPARATION 20 1 -, 4- (3-methyl-4-phenyl-phenyl-1, 2,3,6-tetrahydropyridin-1-methyl) -isulfonylcyclopentanecarboxylate 60% sodium hydride in a dispersion in mineral oil (43 mg, 1.07 mmol) was added to a stirred solution of the title compound of preparation 9 (380 mg, 0.99 mmol) in anhydrous dimethylformamide (5 mL), under nitrogen, at room temperature. After 30 minutes, 1,4-diiodobutane (0.14 ml, 1.06 mmol) was added and stirring was continued for 18 hours, then more 60% sodium hydride dispersion (43 mg, 1.07 mmol) was added and the Stir for 4 more hours. The resulting mixture was partitioned between ethyl acetate and water, then the organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using hexane: ethyl acetate (9: 1) as eluent, to give the title compound (340 mg) as an amorphous solid. d (CDCl 3): 1.64 (m, 2H), 1.88 (m, 2H), 2.28 (s, 3H), 2.37 (m, 2H), 2.52 (m, 2H), 2.63 (m, 2H), 3.60 (t , 2H), 3.80 (s, 3H), 4.10 (m, 2H), 6.03 (sa, 1 H), 7.20-7.43 (m, 8H). LRMS (Thermospray): 440 (M + H) +.

PREPARATION 21 1-r4- (3-methyl-4-phenyl-phenylD-1, 2,3,6-tetrahydropyridin-1-yl-sulfosyl-cyclopentanecarboxylic acid Obtained as a solid (54%) from the title compound of preparation 20, using the procedure of preparation 15, but with an elution gradient of hexane: ethyl acetate (75:25 to 0: 100) for the chromatography purification step. d (CDCl 3): 1.65 (m, 2H), 1.88 (m, 2H), 2.27 (s, 3H), 2.39 (m, 2H), 2.50 (m, 2H), 2.63 (m, 2H), 3.64 (t , 2H), 4.12 (m, 2H), 6.03 (sa, 1 H), 7.20-7.43 (m, 8H). LRMS (Thermospray): 426 (M + H) +.

PREPARATION 22 2-Eti | -2-r4- (4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-yl-sulfosylbutanoate methyl This was obtained as in the case of preparation 19 and on the same molar scale, using the title compound of preparation 18 and ethyl iodide. However, in this case, the hydrolysis of the co-ester was not observed and, therefore, the desired product was isolated from the organic phase during processing and purified by flash chromatography, using dichloromethane as eluent, to give the title (125 mg) in the form of a white amorphous solid. d (CDCl 3): 1.04 (t, 6H), 2.08-2.26 (m, 4H), 2.66 (m, 2H), 3.60 (m, 2H), 3.80 (s, 3H), 4.10 (m, 2H), 6.08 (sa, 1 H), 7.35 (m, 1 H), 7.43 (m, 4H), 7.60 (m, 4H).

PREPARATION 23 2-Ethyl-2-r4- (4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfonyl-butanoic acid A 1 M aqueous solution of sodium hydroxide (1.5 ml, 1. 5 mmol) was added to a stirred solution of the title compound of preparation 22 (120 mg, 0.28 mmol) in a mixture of tetrahydrofuran (5 ml) and methanol (2 ml). The resulting mixture was refluxed for 70 hours, allowed to cool to room temperature, acidified with 2M hydrochloric acid and extracted with dichloromethane (3 x 20 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound (95 mg) as a pale yellow amorphous solid. d (CDCl 3): 1.10 (t, 6H), 2.10-2.28 (m, 4H), 2.64 (m, 2H), 3.65 (m, 2H), 4.15 (m, 2H), 6.08 (sa, 1 H), 7.35 (m, 1 H), 7.43 (m, 4H), 7.58 (m, 4H).

PREPARATION 24 2 (R, SH4-, 4-phenylphenyl) -1, methyl 2,3,6-tetrahydropyridin-1-ylsulfonylhexanoate This was obtained essentially as in the case of the preparation 14, using the title compound of preparation 8 and n-butyl iodide, but employing 1.0 mole equivalents of sodium hydride, 1-methylpyrrolidin-2-one as solvent and an alkylation reaction time of 70 hours, to provide the compound of title (78%) as a colorless solid, m.p. 152-124 ° C. Found: C, 67.09; H, 6.76; N, 3.22. C2 H29 NO4S requires C, 67.42; H, 6.84; N, 3.28%. d (CDCl 3): 0.90 (t, 3 H), 1.30 (m, 4 H), 2.05 (m, 1 H), 2.15 (m, 1 H), 2.60-2.75 (m, 2 H), 3.55 (m, 1 H ), 3.70 (m, 1 H), 3.80 (s, 3H), 3.95 (dd, 1H), 4.10 (m, 2H), 6.08 (sa, 1 H), 7.35 (m, 1 H), 7.43 (m , 4H), 7.58 (m, 4H). LRMS (Thermospray): 428 (M + H) +.

PREPARATION 25 Acid 2 (R, S) -r4- (4-phenylphenylD-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-hexanoic acid A 1 M aqueous solution of sodium hydroxide (1.5 ml, 1.5 mmol) was added to a stirred solution of the title compound of preparation 24 (220 mg, 0.51 mmol) in a mixture of 1,4-dioxane (3 ml) and methanol (10 ml). The resulting mixture was refluxed for 45 minutes, diluted with water and acidified with concentrated hydrochloric acid, and then the precipitate was collected and dried under vacuum to provide the title compound (200 mg) as a crystalline solid colorless, pf 180-182 ° C. Found: C, 65.64; H, 6.42; N, 3.30. C23H27NO4S; 0.50 H2O requires C, 65.38; H, 6.68; N, 3.32%. d (DMSOd6): 0.83 (t, 3H), 1.27 (m, 4H), 1.81 (m, 1 H), 1.93 (m, 1 H), 2.58 (m, 2H), 3.50 (m, 2H), 4.00 (m, 2H), 4.05 (dd, 1 H), 6.22 (sa, 1 H), 7.33 (m, 1 H), 7.43 (m, 2H), 7.52 (m, 2H), 7.64 (m, 4H) , 13.30 (sa, 1 H). LRMS (Thermospray): 387 (M + NH 4 -CO 2) +.

PREPARATION 26 4-Methyl-2.R.S) -r4- (4-phenylpheniD-1, 2.3.6-tetrahydropyridin-1-ylsulfonylpent-4-enoate methyl) Obtained as a solid (79%), m.p. 149-151 ° C after crystallization from diisopropyl ether, from the title compound of preparation 8 and 3-bromo-2-methylprop-1-ene, using the procedure of preparation 14. d (CDCl 3): 1.77 (s, 3H), 2.60-2.75 (m, 3H), 2.80 (dd, 1 H), 3.57 (m, 1 H), 3.70 (m, 1 H), 3.78 (s, 3H), 4.10 (m, 2H), 4.18 (dd, 1 H), 4.75 (s, 1 H), 4.82 (s, 1 H), 6.10 (s, 1 H), 7.35 (m, 1 H), 7.44 (m, 4H), 7.60 (m, 4H).

LRMS (Thermospray): 426 (M + H) +.

PREPARATION 27 4-Methyl-2 (R, S) -r4- (4-phenylpheniP-1, 2,3,6-tetrahydropyridin-l-ylsulfoninpent-4-enoic acid Obtained as a colorless solid (94%), m.p. 153-155 ° C, from the title compound of preparation 26, using the procedure of preparation 15. d (CDCl 3): 1-79 (s, 3H), 2.65 (m, 2H), 2.75 (dd, 1 H), 2.90 (dd, 1 H), 3.60 (m, 1 H), 3.70 (m, 1 H), 4.13 (m, 2 H), 4.20 (d, 1 H), 4.80 (s, 1 H), 4.88 (s, 1 H) , 6.08 (s, 1 H), 7.35 (m, 1 H), 7.44 (m, 4H), 7.60 (m, 4H). LRMS (Thermospray): 368 (M + H-CO2) +.

PREPARATION 28 2 (R.S) -Methyl-2-r4- (3-methyl-4-phen-phenyl) -1,2,3,6-tetrahydropyridine-1-yl-sulfoninpent-4-enoate methyl 60% sodium hydride was added in a dispersion in mineral oil (70 mg, 1.75 mmol) was added to a stirred solution of the title compound of preparation 9 (600 mg, 1.56 mmol) in anhydrous dimethylformamide (5 ml), under nitrogen, at room temperature. After 20 minutes, allyl bromide (0.145 ml, 1.72 mmol) was added and stirring was continued for 2 hours, then more 60% sodium hydride dispersion (70 mg, 1.75 mmol) was added, followed by the addition, after 20 minutes, of methyl iodide (0.1 ml, 1.72 mmol). The reaction mixture was stirred for a further 20 hours and then partitioned between ethyl acetate and water. The organic phase was separated, dried (MgSO4) and evaporated under reduced pressure, then the residue was purified by flash chromatography using hexane: ethyl acetate (92.5: 7.5) as eluent, to yield the title compound (263 mg). in the form of a colorless gum. d (CDCl 3): 1.62 (s, 3H), 2.30 (s, 3H), 2.59 (m, 1 H), 2.66 (m, 2H), 3.14 (m, 1 H), 3.62 (m, 2H), 3.80 (s, 3H), 4.10 (m, 2H), 5.20 (m, 2H), 5.62 (m, 1 H), 6.08 (sa, 1 H), 7.20-7.44 (m, 8H). LRMS (Thermospray): 440 (M + H) +.

PREPARATION 29 Acid 2, R, S) -methyl-2-r4- (3-methyl-4-phenylphen-D-1, 2,3,6-tetrahydropyridin-1-yl-sulfonylpent-4-enoic Obtained as a colorless gum (90%) from the title compound of preparation 28, using the procedure of preparation 15, but with a reaction duration of 24 hours. d (CDCl 3): 1.63 (s, 3H), 2.30 (s, 3H), 2.62 (m, 3H), 3.13 (m, 1 H), 3.68 (m, 2H), 4.18 (m, 2H), 5.22 ( m, 2H), 5.70 (m, 1 H), 6.07 (s at, 1 H), 7.17-7.45 (m, 8H).

LRMS (Thermospray): 382 (M + H-CO2) +, 426 (M + H) + PREPARATION 30 1-Benzhydril-3- (4-phenylphenoxy) azetidine Potassium carbonate (2.39 g, 17.4 mmol) was added to a stirred mixture of 1-benzhydryl-3-methanesulfonyloxyazetidine (J. Org. Chem., 1972, 37, 3953, 5 g, 15.8 mmol), 4-phenylphenol ( 2.95 g, 17.4 mmol) and anhydrous dimethylformamide (65 ml), then, the resulting mixture was refluxed for 4 hours, allowed to cool and partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure, and then the residue was purified by flash chromatography, using hexane: ethyl acetate (95: 5) as eluent, to give the title compound (1.32 g) as a colorless amorphous solid. d (CDCl 3): 3.17 (dd, 2H), 3.75 (dd, 2H), 4.43 (s, 2H), 4.83 (m, 1 H), 6.81 (d, 1 H), 7.16-7.55 (m, 17H) . LRMS (Thermospray): 392 (M + H) +.

PREPARATION 31 3- (4-Phenolfenoxpazetidine) A stirred mixture of the title compound of preparation 30 (1.03 g, 2.63 mmol), 10% palladium hydroxide on activated carbon (100 mg), ethanol (100 ml), ethyl acetate (20 ml) and glacial acetic acid (10 ml), was hydrogenated at 345 kPa (50 psi) and 50 ° C for 20 hours and then filtered. The filter layer was washed with ethanol, the combined washings and the filtrate were evaporated under reduced pressure, and then the residue was basified with 2 M aqueous sodium hydroxide solution. This mixture was extracted with ethyl acetate and the combined extracts were dried (MgSO 4) and evaporated under reduced pressure, yielding the title compound containing 1 mole equivalent of diphenylmethane * (456 mg) as a colorless amorphous solid. d (CDCl 3): 1.75 (s a, 1 H), 3.83 (m, 2H), 3.94 (m, 2H), 3.98 (s, 2H) *, 6.82 (d, 2H), 7.20-7.55 (m, 17H) *. LRMS (Thermospray): 226 (M + H) +.

PREPARATION 32 2-r3- (4-Phenylphenoxy) azetidin-1-ylsulfonyl-1-methyl acetate Obtained as a colorless amorphous solid (22%) from the title compound of preparation 31 and methyl chlorosulfonylacetate, using the procedure of preparation 8. d (CDCl 3): 3.81 (s, 3H), 4.07 (s) , 2H), 4.23 (dd, 2H), 4.42 (dd, 2H), 4.98 (m, 1 H), 6.80 (d, 2H), 7.34 (m, 1 H), 7.42 (m, 2H), 7.54 ( m, 4H). LRMS (APCl): 362 (M + H) + PREPARATION 33 4- (4-Bromo-3-methylphenidyl-4-hydroxypiperidine-1-t-butylcarboxylate) A A 2.5 M solution of n-butyllithium in hexane (3.8 mL, 9.4 mmol) was added, over about 10 minutes, to a stirred mixture of 2,5-dibromotoluene (2.35 g, 9.4 mmol) in anhydrous ether (50 mL). , under nitrogen, at about -75 ° C. After a further 1 hour, a solution of 4-oxopiperidine-1-t-butylcarboxylate (1.7 g, 8.5 mmol) in anhydrous tetrahydrofuran (5 ml) was added at a rate such that the reaction temperature remained below -60 ° C. The reaction mixture was stirred at about -75 ° C for 1 hour, allowed to warm to about 0 ° C and quenched with aqueous ammonium chloride solution. The organic phase was prepared, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using ethexane (50:50) as eluent, to provide two isomer products. The less polar isomer (0.6 g, 20%) was isolated as a colorless foam and identified as 4- (4-bromo-2-methylphenyl) -4-hydroxypiperidine-1-t-butylcarboxylate. d (CDCl 3): 1-46 (s, 9H), 1.55 (s, 1 H), 1.82-2.03 (m, 4H), 2.58 (s, 3H), 3.23 (m, 2H), 4.01 (m, 2H) ), 7.20-7.33 (m, 3H). LRMS (Thermospray): 369/371 (M + H) +. The more polar isomer was collected as a 4: 1 mixture of the title compound: t-butyl 4-oxopiperidine-1-carboxylate (2.15 g), from which a portion was crystallized from diisopropyl ether to give the pure title compound ( 570 mg) in the form of a colorless solid, mp 102-103 ° C. Found: C, 55.14; H, 6.58; N, 3.76. C? 7H2 BrNO3 requires C, 55.14; H, 6.53; N, 3.78%. d (CDCl 3): 1.48 (s, 9H), 1.51 (s, 1 H), 1.70 (d, 2H), 1.96 (m, 2H), 2.40 (s, 3H), 3.22 (t, 2H), 4.02 ( m, 2H), 7.15 (dd, 1 H), 7.36 (d, 1 H), 7.50 (d, 1 H). LRMS (Thermospray): 369/371 (M + H) +. ^ A 2.5 M solution of n-butyl lithium in hexane (38 mL, 94 mmol) was added, over about 10 minutes, to a stirred mixture of 2-bromo-5-iodo-toluene (28 g, 94 mmol) in anhydrous ether (500 ml), under nitrogen, at about -75 ° C. After a further 15 minutes, a solution of t-butyium 4-oxopiperidine-1-carboxylate (17 g, 85 mmol) in anhydrous tetrahydrofuran (50 ml) was added at a rate such that the reaction temperature remained below -60 ° C. The reaction mixture was stirred at about -75 ° C for 1 hour, allowed to warm to 0 ° C and quenched with an aqueous solution of ammonium chloride. The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in pentane and the resulting solution was cooled to 0 ° C, at which time the title compound crystallized. This was collected and dried to yield a colorless solid (20.1 g, 64%), identical to that obtained in preparation 33A.

PREPARATION 34 4- (4-Bromophenyl) -4-hydroxypiperidine-1-t-butylcarboxylate Obtained in the form of an amorphous solid (74%), from 1,4-dibromobenzene and 4-oxopiperidine-1-t-butylcarboxylate, using the procedure of preparation 33. d (CDCl 3): 1.50 (s, 9H), 1.69 (m, 2H), 1.95 (m, 2H), 3.22 (t, 2H), 4.02 (m, 2H) 7.34 (d, 2H), 7.47 (d, 2H). LRMS (Thermospray): 357 (M + H) +.

PREPARATION 35 4- (4-Bromo-3-methylphen D-1,2,3,6-tetrahydropyridine Trifluoroacetic acid (100 ml) was added to a stirred solution of the title compound of preparation 33 (20 g) in dichloromethane (100 ml) at room temperature. After a further 18 hours, the reaction mixture was evaporated under reduced pressure and the residue was basified with 2 M aqueous sodium hydroxide solution at pH> 0.05. 12. The resulting mixture was extracted with ether, then the combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound (13.6 g) as a solid with low melting point. . d (CDCl 3): 1.60 (br s, 1 H), 2.40 (m, 5H), 3.10 (t, 2H), 3.52 (m, 2H), 6.10 (sa, 1 H), 7.05 (dd, 1 H), 7.22 (d, 1 H), 7.46 (d, 1 H). LRMS (Thermospray): 251/253 (M + H) +.

PREPARATION 36 4- 4-Bromophenyl-1,2,3,6-tetrahydropyridine Obtained as a solid (87%), m.p. 76-78 ° C, from the title compound of preparation 34 and trifluoroacetic acid, using the procedure of preparation 35. d (CDCl 3): 2.43 (m, 2H), 3.12 (t, 2H), 3.53 (m , 2H), 6.13 (s, 1 H), 7.25 (d, 2H), 7.44 (d, 2H).

LRMS (Thermospray): 239 (M + H) 4 PREPARATION 37 2-r4-.4-Bromo-3-methylphenid-1, 2,3,6-tetrahydropyldin-1-ylsulfonyl acetate ? /, O-bis (trimethylsilyl) acetamide (0.9 ml, 4.0 mmol) was added to a stirred solution of the title compound of preparation 35 (2 g, 7.9 mmol) in anhydrous tetrahydrofuran (40 ml), under nitrogen, at room temperature. Then a solution of methyl chlorosulfonylacetate (1.64 g, 9.5 mmol) in anhydrous tetrahydrofuran (15 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and then the organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography, using dichloromethane as eluent, followed by crystallization from diisopropyl ether, to yield the title compound (1.65 g, 55%) as a colorless solid, m.p. 1 10-1 12 ° C. Found: C, 46.32; H, 4.62; N, 3.55. C15H18BrNO4S requires C, 46.40; H, 4.67; N, 3.61%. d (CDCl 3): 2.4 (s, 3H), 2.60 (m, 2H), 3.60 (t, 2H), 3.80 (s, 3H), 4.01 (s, 2H), 4.07 (m, 2H), 6.02 (s) , 1 H), 7.02 (dd, 1 H), 7.21 (d, 1 H), 7.50 (d, 1 H). LRMS (Thermospray): 404/406 (M + NH4) + PREPARATION 38 2-.4- (4-Bromophen-P-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl acetate methyl) Obtained in a form of a colorless solid (32%), m.p. 100-102 ° C, from the title compound of preparation 36 and methyl chlorosulfonylacetate, using the procedure of preparation 37. Found: C, 44.95; H, 4.26; N, 3.65. C14H16BrNO4S requires C, 44.93; H, 4.31; N, 3.74%. d (DMSOd6): 2.47 (m, 2H), 3.46 (t, 2H), 3.70 (s, 3H), 3.94 (m, 2H), 4.37 (s, 2H), 6.03 (s, 1 H), 7.40 ( d, 2H), 7.55 (d, 2H). LRMS (Thermospray): 393 (M + NH4) + - PREPARATION 39 4-f4- (4-Bromo-3-methylphenyl-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-tetrahydropyran-4-carboxylic acid methyl) Bis-2-iodoethyl ether (3.9 g, 12 mmol) was added to a stirred mixture of the title compound of preparation 37 (3.6 g, 9.3 mmol), anhydrous potassium carbonate (3.8 g, 27.8 mmol) and anhydrous dimethylsulfoxide (50 g). ml), under nitrogen, at room temperature. After 18 hours, the reaction mixture was partitioned between ether and water, and then, the organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using dichloromethane: methanol (99: 1) as eluent, followed by crystallization from diisopropyl ether, to give the title compound (3.43 g, 80%) as a colorless solid, m.p. 128-130 ° C. Found: C, 49.92; H, 5.40; N, 2.90. C19H24.BrNO5S requires C, 49.78; H, 5.28; N, 3.06%. d (CDCl 3): 2.23 (m, 2H), 2.40 (s, 3H), 2.42 (m, 2H), 2.58 (m, 2H), 3.30 (m, 2H), 3.58 (m, 2H), 3.87 (s) , 3H), 4.00-4.10 (m, 4H), 6.00 (sa, 1 H), 7.02 (dd, 1 H), 7.21 (d, 1 H), 7.49 (d, 1 H). LRMS (Thermospray): 477 (M + NH4) +.

PREPARATION 40 2-í4- (4-Bromo-3-meti! Fenín-1.2.3.6-tetrahidropiridin-1-i! Sulfon¡n-2-methylpropanoate methyl) Iodomethane (2 mL, 32.1 mmol) was added to a stirred mixture of the title compound of Preparation 37 (5 g, 12.9 mmol), anhydrous potassium carbonate (5.4 g, 39.1 mmol) and anhydrous dimethylsulfoxide (50 mL), under nitrogen , at room temperature. After 24 hours, the reaction mixture was partitioned between ether and water, and then, the organic phase was washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an eluate gradient of etheptantane (40:60 to 100: 0), followed by crystallization from diisopropyl ether, to give the title compound (4.7 g, 87%) as a colorless solid. , pf 100-101 ° C. Found: C, 49.00; H, 5.33; N, 3.28. C17H22BrNO S requires C, 49.04; H, 5.33; N, 3.36%. d (CDCl 3): 1.67 (s, 6H), 2.40 (s, 3H), 2.58 (m, 2H), 3.60 (t, 2H), 3.80 (s, 3H), 4.08 (m, 2H), 6.00 (s) , 1 H), 7.03 (dd, 1 H), 7.21 (d, 1 H), 7.49 (d, 1 H).

PREPARATION 41 2- | 4-r4- (3-Ethoxy-phenyl-3-methylphen-1,2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) To a solution of the title compound of preparation 37 (776 mg, 2 mmol) in degassed 1,2-dimethoxyethane (20 ml), 3-ethoxyphenylboronic acid (430 mg, 2.6 mmol), cesium fluoride (790 mg, 5.2 mmol), tri-o-tolylphosphine ( 61 mg, 0.2 mmol) and tris (dibenzylideneacetone) dipalladium (0) (91 mg, 0.1 mmol), and then the reaction mixture was heated to reflux for about 3 hours under nitrogen. The resulting mixture was allowed to cool to room temperature, then diluted with dichloromethane and washed with water. The organic phase was dried (MgSO4) and evaporated under reduced pressure, and then, the residue was purified by flash chromatography, using dichloromethane as eluent, followed by crystallization from diisopropyl ether, to yield the title compound (665 mg, 78 mg). %) in the form of a colorless solid, mp 79-81 ° C. Found: C, 64.40; H, 6.37; N, 3.17. C23H27BrNO5S requires C, 64.31; H, 6.34; N, 3.26%. d (CDCl 3): 1 -43 (t, 3H), 2.31 (s, 3H), 2.70 (m, 2H), 3.63 (s, 2H), 3.82 (s, 3H), 4.03 (s, 2H), 4.10 (m, 4H), 6.08 (sa, 1 H), 6.84-6.93 (m, 3H), 7.20-7.37 (m, 4H). LRMS (Thermospray): 447 (M + NH4) +.

PREPARATION 42 4-Bromo-2-methoxybiphenyl N-amyl nitrite (8.1 ml, 60 mmol) was slowly added to a stirred mixture of 4-bromo-2-methoxyaniline (J. Med. Chem., 1989, 32, 1936, 8.1 g, 60 mmol) and benzene ( 175 ml), under nitrogen, at approximately 50 ° C. When the addiction was completed, the reaction mixture was heated to reflux for about 3 hours, and then allowed to cool to room temperature and evaporated under reduced pressure. The residue was azeotropically distilled with tetrahydrofuran, then with ethyl acetate and purified by flash chromatography using an elution gradient of hexane: ethyl acetate (100: 0 to 95: 5) to give the title compound (1.66 g), in the form of a colorless solid, mp 50-52 ° C. d (CDCl 3): 3.77 (s, 3 H), 7.08 (s, 1 H), 7.14 (s, 2 H), 7.30 (m, 1 H), 7. 36-7.41 (m, 2H), 7.41-7.49 (m, 2H).

PREPARATION 43 4-Hydroxy-4- (3-methoxy-4-phenylphenopiperidine-1-t-butylcarboxylate) A 2.5 M solution of n-butyllithium in hexane (4.4 ml, 11 mmol) was added over about 10 minutes to a stirred mixture of the title compound of preparation 42 (2.6 g, 10 mmol) in anhydrous tetrahydrofuran. (30 ml), under nitrogen, at about -75 ° C. After an additional 1 hour, a solution of t-butyl 4-oxopiperidine-1-carboxylate (2.2 g, 11 mmol) in anhydrous tetrahydrofuran (10 ml) was added, at such a rate that the reaction temperature was maintained by below -60 ° C. The reaction mixture was stirred at about -75 ° C for 1 hour, then warmed slowly to room temperature and quenched with aqueous sodium chloride solution. The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification of the residue by flash chromatography, using hexane: ethyl acetate (3: 1) as eluent, afforded the title compound (3.4 g) as a colorless semi-solid. d (CDCl 3): 1.50 (s, 9H), 1.78 (m, 2H), 2.04 (m, 2H), 3.27 (m, 2H), 3.83 (s, 3H), 4.08 (m, 2H), 7.09 (d, 1 H), 7.16 (s, 1 H), 7.27-7.37 (m, 2H), 7.40 (m, 2H), 7.52 (d, 2H).

PREPARATION 44 4- (3-Methoxy-4-phenylpheniP-1, 2,3,6-tetrahydropyridine Trifluoroacetic acid (20 ml) was added to a stirred solution of the title compound of preparation 43 (3.4 g, 1.9 mmol) in dichloromethane (20 ml) at room temperature. After a further 72 hours, the reaction mixture was evaporated under reduced pressure and the residue was basified with 1 M aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane, and then the combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound (2.79 g) as a pale yellow viscous oil. d (CDCl 3): 1.73 (s, 1 H), 2.51 (m, 2 H), 3.14 (t, 2 H), 3.57 (m, 2 H), 3.83 (s, 3 H), 6.19 (s, 1 H), 7.01 (s, 1 H), 7.05 (d, 2H), 7.27-7.37 (m, 2H), 7.40 (t, 2H), 7.52 (d, 2H). LRMS (Thermospray): 266 (M + H) +.

PREPARATION 45 2-r4- (3-Methoxy-4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfoyl acetate methyl Was added drop by drop? , O-bis (trimethylsilyl) acetamide (1.0 ml, 4.4 mmol) to a stirred solution of the title compound of preparation 44 (1.95 g, 7.3 mmol) in anhydrous tetrahydrofuran (40 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then a solution of methyl chlorosulfonylacetate (1.5 g, 8.8 mmol) in tetrahydrofuran (10 ml) was added. The resulting mixture was stirred at room temperature for about 1.5 hours and then saturated aqueous sodium bicarbonate solution (50 ml) was added. The mixture was extracted with dichloromethane (3 x 100 ml) and then the combined extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using dichloromethane as eluent, to give the title compound (1.0 g) as a pale yellow solid, m.p. 92-95 ° C. Found: C, 62.24; H, 5.70; N, 3.42. C21H23NO5S requires C, 62.82; H, 5.77; N, 3.49%. d (CDCl 3): 2.73 (m, 2H), 3.67 (t, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 4.06 (s, 2H), 4.08 (m, 2H), 6.12 (s) , 1 H), 6.98 (s, 1 H), 7.04 (d, 2H), 7.27-7.37 (m, 2H), 7.44 (t, 2H), 7.56 (d, 2H). LRMS (Thermonebuiization): 402 (M) +.

PREPARATION 46 4- (3-Fluoro-4-phenylphenyl) -4-hydroxypiperidine-1-t-butylcarboxylate Obtained in the form of a colorless oil (67%), from 4-bromo-3-fluorobiphenyl and 4-oxopiperidine-1-t-butylcarboxylate, using the procedure of preparation 43. d (CDCl 3): 1.50 (s, 9H), 1.78 (m, 2H), 2.03 (m, 2H), 3.26 (t, 2H), 4.05 (m, 2H), 7.27-7.51 (m, 6H), 7.57 (d, 2H) .

PREPARATION 47 4- (3-Fluoro-4-phenylpheniP-1,2,3,6-tetrahydropyridine Obtained as a colorless solid (90%), m.p. 79-82 ° C, from the title compound of preparation 46 and trifluoroacetic acid, using the procedure of preparation 44. d (CDCl 3): 1.85 (s, 1 H), 2.49 (m, 2H), 3.13 ( t, 2H), 3.58 (m, 2H), 6.24 (sa, 1 H), 7.12-7.27 (m, 2H), 7.35-7.52 (m, 4H), 7.59 (d, 2H). LRMS (Thermospray): 253 (M) +.

PREPARATION 48 2-r4- (3-Fluoro-4-phenylpheniP-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl acetate) Obtained as a colorless solid (38%) from the title compound of preparation 47 and methyl chlorosulfonylacetate, using the procedure of preparation 45. d (DMSOd6): 2.60 (m, 2H), 3.47 (t, 2H), 3.68 (s, 3H), 3.96 (s, 2H), 4.37 (s, 2H), 6.33 (sa, 1 H), 7.34-7.57 (m, 8H). LRMS (Thermospray): 407 (M + NH4) +.

PREPARATION 49 2-r4- (3-Methoxy-4-phenylphen-P-1,2,3,6-tetrahydropyridin-1-ylsulfonin-2-methylpropanoate methyl) Iodomethane (0.2 ml, 3.4 mmol) was added to a stirred mixture of the title compound of preparation 45 (0.54 g, 1.4 mmol), anhydrous potassium carbonate (0.56 g, 4.1 mmol) and anhydrous dimethylsulfoxide (5 ml), and then The reaction mixture was stirred at room temperature for approximately 16 hours. The resulting mixture was partitioned between ethyl acetate and water, then the organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure to yield the title compound (540 mg) as a yellow oil. pale. d (CDCl 3): 1.69 (s, 6H), 2.67 (m, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 4.14 (m, 2H), 6.09 (s) , 1 H), 6.98 (s, 1 H), 7.03 (d, 2H), 7.27-7.37 (m, 2H), 7.42 (t, 2H), 7.54 (d, 2H). LRMS (Thermospray): 430 (M + H) +.

PREPARATION 50 Acid 2-r4- (3-methoxy-4-phenylphenylD-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-2-methylpropanoic acid A 1 M aqueous solution of sodium hydroxide (1.2 ml, 1. 2 mmol) was added to a stirred solution of the title compound of preparation 49 (250 mg, 0.58 mmol) in methanol (5 mL). The resulting solution was heated at 50 ° C for about 2 hours, then allowed to cool to room temperature and poured into ethyl acetate. This mixture was washed with 2M hydrochloric acid, and then the organic phase was dried (MgSO) and evaporated under reduced pressure to give the title compound (210 mg) as a pale yellow semi-solid. d (CDCl 3): 1.69 (s, 6H), 2.67 (m, 2H), 3.64 (t, 2H), 3.83 (s, 3H), 4.17 (m, 2H), 6.08 (s, 1 H), 6.97 ( s, 1 H), 7.03 (d, 2H), 7.27-7.36 (m, 2H), 7.40 (t, 2H), 7.53 (d, 2H). LRMS (Thermospray): 433 (M + NH4) +.

PREPARATION 51 4-bromo-2-methoxyphenyldiazoium tetrafluoroborate A solution of 4-bromo-2-methoxyaniline (J. Med. Chem., 1989, 32, 1936; 17.9, 88.6 mmol) in anhydrous ether (350 ml) was added for about 1 hour to boron trifluoride etherate (27 ml. , 212 mmole) at -15 ° C. The resulting solution was stirred at -15 ° C for about 5 minutes and then a solution of t-butyl nitrite (1.4 ml, 106 mmol) in anhydrous ether (100 ml) was added slowly, keeping the internal temperature at about - 15 ° C. The reaction mixture was stirred at -15 ° C for a further 15 minutes and then at 4 ° C for about 4 hours. Pentane was added and the resulting precipitate was collected, washed with pentane and dried under reduced pressure, to yield the title compound (20.1 g) as a purple solid. d (CD3CN): 4.20 (s, 3H), 7.58 (d, 1 H), 7.80 (s, 1 H), 8.16 (d, 1 H). LRMS (Thermospray): 301 (M) +.

PREPARATION 52 4- (3-Ethoxyphene-3-methoxybromobenzene) Anhydrous 1,4-dioxane (80 ml) was added to a mixture of the title compound of preparation 51 (8.0 g, 26.6 mmol), 3-ethoxyphenylboronic acid (5.3 g, 31.9 mmol) and palladium (II) acetate ( 0.35 g, 1.3 mmol) and the reaction mixture was stirred at room temperature for about 16 hours. The resulting mixture was diluted with water (100 ml) and ether (100 ml), filtered and the filtrate was extracted with ether (2 x 100 ml). The combined extracts were dried (MgSO4) and then evaporated under reduced pressure. Purification of the residue by flash chromatography, using pentane: ether (20: 1) as eluent, afforded the title compound (6.9 g) as a colorless oil. d (CDCl 3): 1.45 (t, 3H), 3.83 (s, 3H), 4.10 (q, 2H), 6.89 (d, 1 H), 7.06 (d, 2H), 7.10-7.24 (m, 3H), 7.27-7.38 (m, 1 H). LRMS (APCl): 308 (M + H) +.

PREPARATION 53 4-r4- (3-EthoxyphenD-3-methoxyphenin-4-hydroxypiperidine-1-t-butylcarboxylate) Obtained in the form of a colorless oil (60%), from the title compound of preparation 52 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. d (CDCl 3): 1.44 ( t, 3H), 1.50 (s, 9H), 1.79 (m, 2H), 2.03 (m, 2H), 3.27 (t, 2H), 3.83 (s, 3H), 4.06 (m, 4H), 6.86 (d , 1 H), 7.08 (m, 3H), 7.15 (s, 1 H), 7.31 (m, 2H).

PREPARATION 54 4-r4- (3-EthoxypheniD-3-methoxyphenin-1, 2,3,6-tetrahydropyridine Obtained in the form of a pale yellow (91%) viscous oil, from the title compound of preparation 53 and trifluoroacetic acid, using the procedure of preparation 44. d (CDCl 3): 1.44 (t, 3H), 2.53 (m, 2H), 3.16 (t, 2H), 3.58 (s, 2H), 3.83 (s, 3H), 4.07 (q, 2H), 6.19 (sa, 1 H), 6.86 (d, 1 H) , 7.00 (s, 1 H), 7.07 (m, 3H), 7.31 (m, 2H). LRMS (Thermospray): 310 (M + H) +.

PREPARATION 55 2-. { 4-r4- (3-EtoxifeniD-3-methoxyphenn-1, 2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) Obtained in the form of a yellow semi-solid (22%), from the title compound of preparation 54 and methyl chlorosulfonylacetate, using the procedure of preparation 45. d (CDCl 3): 1.43 (t, 3H), 2.69 (m, 2H), 3.65 (t, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 4.04 (s, 2H), 4.08 (m, 4H), 6.10 (s, 1 H), 6.87 (d, 1 H), 6.96 (s, 1 H), 7.02 (d, 1 H), 7.09 (m, 2H), 7.31 (m, 2H). LRMS (Thermospray): 446 (M + H) +.

PREPARATION 56 2-. { 4-r4- (3-Etoxifen8Pfenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) To a solution of the title compound of preparation 38 (250 mg, 0.7 mmol) in 1,2-dimethoxyethane (8 ml), 3-ethoxyphenylboronic acid (168 mg, 1.0 mmol), cesium fluoride (226 mg, 1.5 mmol), tri-o-tolylphosphine (21 mg) was added. mg, 0.07 mmol) and tris (dibenzylideneacetone) dipalladium (0) (31 mg, 0.035 mmol), then the reaction mixture was heated to reflux for about 4 hours under nitrogen. The resulting mixture was allowed to cool to room temperature, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated under reduced pressure, and then the residue was triturated with hexane-ether to give the title compound (222 mg) as a pale yellow solid, m.p. 120-122 ° C. Found: C, 64.25; H, 6.01; N, 2.99. C22H25NO5S requires C, 63.60; H, 6.06; N, 3.37%. d (DMSOd6): 1 -32 (t, 3H), 2.62 (m, 2H), 3.50 (t, 2H), 3.71 (s, 3H), 3.98 (d, 2H), 4.10 (q, 2H), 4.37. (s, 2H), 6.27 (sa, 1 H), 6.91 (d, 1 H), 7.18 (s, 1 H), 7.22 (d, 1 H), 7.36 (t, 1 H), 7.52 (d, 2H), 7.66 (d, 2H). LRMS (Thermospray): 433 (M + NH4) \ PREPARATION 57 4-bromo-2-methylphenyldiazoium tetrafluoroborate Obtained as a yellow solid (93%), from 4-bromo-2-methylaniline and t-butyl nitrite, using the procedure of preparation 51. d (CD3CN): 2.70 (s, 3H), 7.93 (d, 1 H), 8.04 (s, 1 H), 8.50 (d, 1 H).

PREPARATION 58 4- (3-Methoxyphene-3-methylbromobenzene) Obtained as a pale yellow oil (25%), from the title compound of preparation 57 and 3-methoxyphenylboronic acid, using the procedure of preparation 52. d (CDCl 3): 2.15 (s, 3H), 3.84 (s, 3H), 6.79-6.94 (m, 3H), 7.09 (s, 1 H), 7.33 (d, 1 H), 7.37 (d, 1 H), 7.43 (s, 1 H).

PREPARATION 59 4-Hydroxy-4-r4- (3-methoxy-phenyl-3-methylphenylpiperidine-1-t-butylcarboxylate) Obtained in the form of a colorless oil (63%), from the title compound of preparation 58 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. d (CDCl 3): 1.50 ( s, 9H), 1.79 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H), 3.27 (t, 2H), 3.83 (s, 3H), 4.06 (m, 2H), 6.85 (s) , 1 H), 6.90 (d, 2H), 7.26 (m, 1 H), 7.34 (t, 2H), 7.38 (s, 1 H). LRMS (Thermospray): 399 (M + H) +.

PREPARATION 60 4-í4- (3-MethoxypheniP-3-methylphenyl, -1, 2,3,6-tetrahydropyridine Obtained as a pale yellow semi-solid (93%), from the title compound of preparation 59 and trifluoroacetic acid, using the procedure of preparation 44. d (CDCl 3): 2.30 (s, 3H), 2.42 (s, 2H), 3.15 (t, 2H), 3.57 (s, 2H), 3.83 (s, 3H), 6.18 (sa, 1 H), 6.90 (m, 3H), 7.16-7.36 (m, 4H) . LRMS (Thermospray): 280 (M + H) +.

PREPARATION 61 2- ^ 4-r4- (3-methoxypheniP-3-methylphenin-1,2,3,6-tetrahydropyridin-1-ylsulfonyl methyl acetate) A solution of methyl chlorosulfonylacetate (0.65 g, 3.7 mmol) in dichloromethane (10 ml) was added dropwise to a stirred solution of the title compound of preparation 60 (0.92 g, 3.3 mmol) and 1,8-diazabicyclo [ 5.4.0] undec-7-ene (0.76 g, 4.9 mmol) in dichloromethane (20 ml), at about 0 ° C, the cooling bath was removed, the reaction mixture was stirred at room temperature for 4 hours and then it was diluted with dichloromethane. The resulting mixture was washed with 0.1M hydrochloric acid, dried (MgSO4) and evaporated under reduced pressure, then, the residue was purified by flash chromatography, using dichloromethane as eluent, to provide the title compound (250 mg) in form of a colorless solid, mp 83-85 ° C. d (CDCl 3): 2.30 (s, 3H), 2.69 (m, 2H), 3.66 (t, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.03 (s, 2H), 4.1 1 ( m, 2H), 6.09 (br s, 1 H), 6.83-6.97 (m, 3H), 7.17-7.35 (m, 4H). LRMS (Thermospray): 416 (M + H) +.

PREPARATION 62 3-Ethylphenylboronic acid N-Butyllithium (1.1 mL of a 2.5M solution in hexane, 28 mmol) was added to a stirred solution of 3-ethylbromobenzene (Chem. Pharm. Bull., 1968, 16, 2456; 4.5 g, 25 mmol). in anhydrous tetrahydrofuran (50 ml), while maintaining the internal temperature below -60 ° C. the mixture was stirred at about -70 ° C for 1 hour and then trimethyl borate (4.4 ml, 38 mmol) was added dropwise, while maintaining the internal temperature below -60 ° C. The reaction mixture was stirred at -70 ° C for 30 minutes and then allowed to warm slowly to room temperature. 2 M hydrochloric acid was added, the mixture was extracted with dichloromethane (3 x 50 ml) and the combined extracts were concentrated under reduced pressure. The residue was dissolved in ether (50 ml), the solution was extracted with 1 M aqueous sodium hydroxide solution (2 x 30 ml), the aqueous phase was acidified with 2 M hydrochloric acid and then extracted with ether (3 x 50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound as a white solid (0.9 g, 24%). d (DMSOd6): 1.17 (t, 3H), 2.57 (q, 2H), 7.22 (t, 2H), 7.57 (t, 1 H), 7.61 (s 1 H), 7.93 (s, 2H).

PREPARATION 63 2- 4-r4- (3-EthylpheniP-3-methylphenin-1,2,3,6-tetrahydropyridin-1-yl-sulphonic acid methyl acetate) Obtained as a yellow solid (75%), m.p. 58-60 ° C, from the title compounds of preparation 62 and of preparation 37, using the procedure of preparation 41. d (CDCl 3): 1.27 (t, 3H), 2.50 (s, 3H), 2.68 (m, 4H), 3.64 (t, 2H), 3.82 (s, 3H), 4.03 (s, 2H), 4.10 (s, 2H), 6.08 (sa, 1 H), 7.14-7.37 (m, 7H) ). LRMS (Thermospray): 431 (M + NH4) +, PREPARATION 64 4-f4-r4- (3-MethoxypheniP-3-methylphenin-1, 2.3.6-tetrahydropyridin-1-methyl sulfonyl tetrahydropyran-4-carboxylate) Obtained in the form of a glassy solid (20%), from the title compound of preparation 61 and bis-2-iodoethyl ether, using the procedure of preparation 39. d (CDCl 3): 2.20-2.34 (m, 5H ), 2.45 (m, 2H), 2.67 (m, 2H), 3.33 (t, 2H), 3.62 (m, 2H), 3.83 (s, 3H), 3.89 (s, 3H), 4.01 (m, 2H) , 4.10 (m, 2H), 6.05 (sa, 1 H), 6.91 (m, 3H), 7.23-7.36 (m, 4H). LARMS (APCl): 486 (M + H) +.

PREPARATION 65 Acid 4-f4-r4- (3-methoxypheniP-3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfoni-tetrahydropyran-4-carboxylic acid Obtained as a pale yellow solid (93%), m.p. 180-190 ° C, from the title compound of preparation 64, using the procedure of preparation 50. d (CDCl 3): 2.20-2.33 (m, 5H), 2.43 (m, 2H), 2.65 (m, 2H), 3.43 (t, 2H), 3.67 (m, 2H), 3.82 (s, 3H), 4.04 (m, 2H), 4.14 (m, 2H), 6.04 (sa, 1 H), 6.88 (m, 3H), 7.21-7.36 (m, 4H).

PREPARATION 66 4- (4-f4- (3-MethoxypheniP-3-methylphenylpiperidin-1-ylsulfoniP-tetrahydropyran-4-carboxylic acid methyl ester A stirred mixture of the title compound of the preparation 64 (315 mg, 0.65 mmol), ammonium formate (200 mg, 3.2 mmol), 10% palladium on carbon (50 mg) and methanol (5 ml) was heated to reflux for 1.5 hours, then allowed to cool and filtered . The filtrate was evaporated under reduced pressure and the residue was partitioned between ether and water. The organic phase was dried (MgSO4) and evaporated under reduced pressure, and then the residue was crystallized from methanol to yield the title compound (215 mg) as a white solid, m.p. 137-139 ° C. d (CDCl 3): 1.75-1.94 (m, 4H), 2.19 (d, 1 H), 2.22 (d "1 H), 2.27 (s, 3H), 2.43 (m, 2H), 2.66 (m, 1 H) ), 3.07 (t, 2H), 3.32 (t, 2H), 3.83 (s, 3H), 3.90 (s, 3H), 3.96 (m, 2H), 4.00 (d, 1 H), 4.02 (d, 1) H), 6.87 (m, 3H), 7.08 (m, 2H), 7.19 (d, 1 H), 7.32 (m, 1 H). LRMS (APCl): 486 (M + H) +.

PREPARATION 67 Acid 4-. { 4-r4- (3-methoxypheniP-3-methylphenylpiperidin-1-ylsulfoni-tetrahydropyran-4-carboxylic acid) Obtained as a white solid (84%), m.p. 225-228 ° C, from the title compound of preparation 66, using the procedure of preparation 50, but with a mixture of methanol (5 ml) and tetrahydrofuran (10 ml) as solvent. Found: C, 63.04; H, 6.59; N, 2.91. C25H31NO6S requires C, 63.40; H, 6.60; N, 2.96%. d (DMSOd6): 1.60 (m, 2H), 1.80 (m, 2H), 1.93 (dt, 2H), 2.20 (s, 3H), 2.24 (m, 2H), 2.68 (m, 1 H), 3.05 ( t, 2H), 3.20 (t, 2H), 3.75 (s, 3H), 3.77 (m, 2H), 3.88 (d, 1 H), 3.92 (d, 1 H), 6.86 (m, 3H), 7.11 (m, 3H), 7.31 (m, 1 H), 13.80 (sa, 1 H). LRMS (APCl): 474 (M) +.

PREPARATION 68 3-Methoxy-4- (3-methoxypheniDbromobenzene Obtained in the form of a pale yellow oil (78%), from the title compound of preparation 51 and 3-methoxyphenylboronic acid, using the procedure of preparation 52. Found: C, 57.77; H, 4.51. C14H? 3BrO2 requires C, 57.36; H, .47. d (CDCl 3): 3.82 (s, 3H), 3.86 (s, 3H), 6.91 (d, 1 H), 7.03-7.39 (m, 6H). LRMS (Thermospray): 31 1 (M + NH 4) +.

PREPARATION 69 4-Hydroxy-4-r3-methoxy-4- (3-methoxyphenypiperpiperidine-1-t-butylcarboxylate) Obtained in the form of a colorless oil (67%), from the title compound of preparation 68 and t-butyl 4-oxopyridine-1-carboxylate, using the procedure of preparation 43. d (CDCl 3): 1.50 ( s, 9H), 1.79 (m, 2H), 2.06 (m, 2H), 3.28 (t, 2H), 3.83 (s, 6H), 4.06 (m, 2H), 6.88 (d, 1 H), 7.08 ( m, 3H), 7.14 (s, 1 H), 7.32 (m, 2H). LRMS (Thermospray): 436 (M + Na) +.

PREPARATION 70 4-r3-Methoxy-4- (3-methoxypheniPfenin-1, 2,3,6-tetrahydropyridine A stirred solution of the title compound of preparation 69 (6.7 g, 16.2 mmol) and p-toluenesulfonic acid (6.17 g, 32.5 mmol) in toluene (70 mL) was heated to reflux in a Dean-Stark apparatus until removed all the water (approximately 4 hours), then allowed to cool and diluted with ethyl acetate (100 ml). The resulting mixture was washed with 1 M aqueous sodium hydroxide solution (3 x 50 ml), and then the organic phase was dried (MgSO) and evaporated under reduced pressure to give the title compound (3.3 g) as an oil. yellow. d (CDCl 3): 1.80 (ss, 1 H), 2.50 (m, 2 H), 3.14 (t, 2 H), 3.57 (m, 2 H), 3.84 (s, 6 H), 6.20 (s, 1 H), 6.88 (d, 1 H), 6.98-7.36 (m, 6H). LRMS (Thermospray): 296 (M + H) +.

PREPARATION 71 2-f4-r3-Methoxy-4- 3-methoxypheniDfenin-1, 2,3,6-tetrahydropyridin-1-ylsulphon-methyl-acetate Obtained in the form of a yellow semi-solid (40%), from the compound of preparation 70 and methyl chlorosulfonylacetate, using the procedure of preparation 45. Found C, 58. 87; H, 5.65; N, 3.11. C22H25NO6S; 1.00 H2O requires C, 58.78; H, 6.05; N, 3.12%. d (CDCl 3): 2.71 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 3.84 (s, 6H), 44.02 (s, 2H), 4.1 1 (m, 2H), 6.10 ( sa, 1 H), 6.88 (d, 1 H), 6.97 (s, 1 H), 7.02 (d, 1 H), 7.12 (m, 2 H), 7.32 (m, 2 H). LRMS (Thermospray): 449 (M + H) +.

PREPARATION 72 2-f4-r3-Methoxy-4- (3-methoxypheniPfenin-1,2,3,6-tetrahydropyridin-1-ylsulfoniP-2-methylpropanoate methyl) Obtained in the form of a colorless semi-solid (40%), from the title compound of preparation 71 and iodomethane, using the procedure of Preparation 49. Found C, 62.30; H, 6.29; N, 3.00. C 24 H 29 NO 6 S requires C, 62.73; H, 6.36; N, 3.05%. d (CDCl 3): 1.68 (s, 6H), 2.67 (m, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 4.13 (m , 2H), 6.07 (sa, 1 H), 6.88 (d, 1 H), 6.97 (s, 1 H), 7.02 (d, 1 H), 7.13 (m, 2H), 7.31 (m, 2H). LRMS (Thermospray): 460 (M + H) +.

PREPARATION 73 2-. { 4-R3-Methoxy-4- (3-methoxypheniDfenipiperidin-1-ylsulfoniP-2-methylpropanoate methyl) Obtained as a colorless solid (80%), m.p. 140-142 ° C, from the title compound of preparation 72, using the procedure of Preparation 66. Found: C, 62.31; H, 6.87; N, 2.91. C2 H3? NO6S requires C, 62.45; H, 6.77; N, 3.03%. d (CDCl 3): 1-66 (s, 6H), 1.87 (m, 4H), 2.49 (m, 1 H), 3.09 (t, 2H), 3.82 (s, 6H), 3.84 (s, 3H), 3.93 (m, 2H), 6.81 (s, 1 H), 6.86 (d, 2H), 7.08 (m, 2H), 7.29 (m, 2H). LRMS (Thermospray): 462 (M + H) +.

PREPARATION 74 Acid 2-. { 4-R3-methoxy-4- (3-methoxyphenylPPenylpiperidin-1-ylsulfoniP-2-methylpropanoic acid Obtained as a colorless solid (80%), m.p. 164-165 ° C, from the title compound of preparation 73, using the procedure of preparation 50. Found: C, 61, 64; H, 6.53; N, 3.06. C23H29NO6S requires C, 61.73; H, 6.53; N, 3.13%. d (CDCl 3): 1.69 (s, 6H), 1.87 (m, 4H), 2.69 (m, 1 H), 3.10 (t, 2H), 3. 81 (s, 3H), 3.82 (s, 3H), 4.02 (m, 2H), 6.80 (s, 1 H), 6.87 (m, 2H), 7.07 (m, 2H), 7.27 (m, 2H). LRMS (Thermospray): 465 (M + NH 4) +.

PREPARATION 75 2-. { 4-r4- (3-EthoxypheniP-3-methoxyphen-1, 2,3,6-tetrahydropyridin-1-ylsulfoniP-2-methylpropanoate methyl) Obtained in the form of a pale yellow oil (29%), from the title compound of preparation 55 and iodomethane, using the procedure of preparation 49. Found: C, 62.99; H, 6.64; N, 2.88. C25H3? NO6S requires C, 63.40; H, 6.60; N, 2.96%. d (CDCl 3): 1-43 (t, 3H); 1.67 (s, 6H), 2.66 (m, 2H), 3.63 (t, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 4.07 (q, 2H), 4.13 (m, 2H), 6.07 (sa, 1 H), 6.87 (d, 1 H), 6.96 (s, 1 H), 7.02 (d, 1 H), 7.10 (m, 2H), 7.31 (m, 2H). LRMS (Thermospray): 474 (M + H) +.

PREPARATION 76 2-f4-r4- (3-Ethoxyphenid-3-methoxyphennpiperidin-1-ylsulfon-P-2-methylpropanoate methyl) Obtained as a colorless semi-solid (83%) from the title compound of preparation 75, using the procedure of Preparation 66. Found: C, 62.86; H, 7.12; N, 2.68. C25H33NO6S requires C, 63.14; H, 6.99; N, 2.95%. d (CDCl 3): 1-43 (t, 3H), 1.67 (s, 6H), 1.86 (m, 4H), 2.70 (m, 1 H), 3.09 (t, 2H), 3.82 (s, 6H), 3.97 (m, 2H), 4.06 (q, 2H), 6.80 (s, 1 H), 6.86 (m, 2H), 7.08 (m, 2H), 7.27 (m, 2H). LRMS (Thermospray): 476 (M + H) +.

PREPARATION 77 Acid 2-. { 4-r4- (3-EthoxypheniP-3-methoxy-phenyl-piperidin-1-ylsulfoni-P-2-methyl-propanoic) Obtained as a colorless solid (95%), from the title compound of preparation 76, using the procedure of preparation 50. Found: C, 61.92; H, 7.00; N, 2.72. C 24 H 3 NO 6 S requires C, 62.45; H, 6.77; N, 3.03. d (CDCl 3): 1.42 (t, 3H), 1.70 (s, 6H), 1.87 (m, 4H), 2.70 (m, 1 H), 3. 1 1 (t, 2H), 3.80 (s, 3H), 4.04 (m, 4H), 6.80 (s, 1 H), 6.85 (d, 2H), 7.08 (m, 2H), 7.27 (m, 2H) . LRMS (Thermospray): 479 (M + NH 4) +.

PREPARATION 78 4-f4-r4- 3-Ethoxyphenid-3-methylphen p-1,2,3,6-tetrahydropyridin-1-ylsulfoni-tetrahydropyran-4-carboxylic acid methyl Obtained in the form of a colorless foam (86%), from the title compound of preparation 39 and 3-ethoxyphenylboronic acid, using the procedure of preparation 41, but with methanol: dichloromethane (1: 99) as eluent. d (CDCl 3): 1.42 (t, 3H), 2.22 (m, 2H), 2.28 (s, 3H), 2.44 (d, 2H), 2.65 (m, 2H), 3.34 (dd, 2H), 3.60 (m , 2H), 3.90 (s, 3H), 4.00-4.15 (m, 6H), 6.03 (sa, 1 H), 6.83-6.92 (m, 3H), 7.20-7.36 (m, 4H). LRMS (Thermospray): 500 (M + H) +.

PREPARATION 79 Acid 4-f4-r4- (3-Ethoxyphenyl) -3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-tetrahydropyran-4-carboxylic acid 1 M aqueous sodium hydroxide solution (2.3 ml, 2.3 mmol) was added to a stirred solution of the title compound of preparation 78 (290 mg, 0.58 mmol) in a mixture of methanol (10 ml) and 1,4-dioxane. (2 ml). The resulting solution was heated at 80 ° C for about 5 hours, then allowed to cool to room temperature and evaporated under reduced pressure. The residue was partitioned between 1M hydrochloric acid and ethyl acetate, and then the organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (220 mg) as a colorless solid, m.p. 203-205 ° C. Found: C, 64.14; H, 6.47; N, 2.87. C26H31NO6S requires C, 64.31; H, 6.44; N, 2.89%. d (CDCl 3): 1.43 (t, 3H), 2.27 (m, 2H), 2.29 (s, 3H), 2.42 (d, 2H), 2.68 (m, 2H), 3.42 (dd, 2H), 3.67 (m , 2H), 4.00-4.18 (m, 6H), 6.04 (sa, 1 H), 6.82-6.93 (m, 3H), 7.20-7.35 (m, 4H). LRMS (Thermospray): 486 (M + H) +.

PREPARATION 80 2-f4-r4- (3-Ethoxyphenid-3-methylphen-1,2,3,6-tetrahydropyridin-1-ylsulfoniP-2-methylpropanoate methyl) Obtained as a colorless solid (80%), m.p. 75-76 ° C, from the title compound of preparation 41 and iodomethane, using the procedure of preparation 40. Found: C, 65.55; H, 6.82; N, 2.98. C25H31NO5S requires C, 65.62; H, 6.83; N, 3.06. d (CDCl 3): 1.43 (t, 3H), 1.68 (s, 6H), 2.28 (s, 3H), 2.65 (m, 2H), 3.62 (m, 2H), 3.81 (s, 3H), 4.06 (q , 2H), 4.12 (m, 2H), 6.60 (sa, 1 H), 6.83-6.92 (m, 3H), 7.20-7.35 (m, 4H).

LRMS (Thermospray): 458 (M + H) +.

PREPARATION 81 Acid 2-. { 4-r4- (3-EthoxypheniP-3-methylphen-1.2.3.6-tetrahydropyridin-l-ylsulfoniP-2-methylpropanoic acid Obtained as a colorless amorphous solid (50%), from the title compound of preparation 80, using the procedure of preparation 79, but with purification by flash chromatography using methanol: dichloromethane (2:98). d (CDCl 3): 1.43 (t, 3H), 1.68 (s, 6H), 2.25 (s, 3H), 2.60 (m, 2M), 3.62 (m, 2H), 4.05 (q, 2H), 4.15 (m , 2H), 6.03 (sa, 1 H), 6.78-6.90 (m, 3H), 7.20-7.35 (m, 4H). LRMS (APCl): 444 (M + H) +.

PREPARATION 82 2-f4-r4- (3-Ethoxyphenid-3-methylphenylpiperidin-1-ylsulfonium methyl acetate) Obtained as a colorless amorphous solid (99%), from the title compound of preparation 41, using the procedure of preparation 66. d (CDCl 3): 1.43 (t, 3H), 1.85 (m, 2H) , 1.97 (m, 2H), 2.28 (s, 3H), 2.67 (m, 1 H), 3.01 (m, 2H), 3.84 (s, 3H), 3.98 (s, 2H), 4.01 (m, 2H) , 4.05 (q, 2H), 6.80-6.90 (m, 3H), 7.05-7.34 (m, 4H). LRMS (Thermospray): 432 (M + H) +.

PREPARATION 83 2-. { 4-r4- (3-Ethoxyphen-P-3-methylphenyl) piperidin-1-ylsulfon-P-2-methyl-methylpropanoate Obtained as a colorless gum (91%), from the title compound of preparation 82, and iodomethane using the procedure of preparation 40. d (CDCl 3): 1.42 (t, 3H), 1.67 (s, 6H ), 1.80-1.95, (m, 4H), 2.29 (s, 3H), 2.67 (m, 1 H), 3.10 (m, 2H), 3.82 (s, 3H), 3.97 (m, 2H), 4.06 ( q, 2H), 6.82-6.90 (m, 3H), 7.06-7.35 (m, 4H). LRMS (Thermospray): 460 (M + H) +.

PREPARATION 84 2- (4-r4- (3-ethoxy-phenyl-3-methylphenylpyridin-1-sulfonyl-P-2-methylpropanoic acid Obtained as a colorless solid (72%), m.p. 125-128 ° C, from the title compound of Preparation 83, using the procedure of Preparation 79, except that the crude product was subjected to flash chromatography using methanol: dichloromethane (3:97), before crystallization in diisopropyl ether. Found: C, 64.14; H, 7.01; N, 3.06. C24H31NO5S requires C, 64.69; H, 7.01; N, 3.14%. d (CDCl 3): 1.41 (t, 3H), 1.68 (s, 6H), 1.77-1.97 (m, 4H), 2.26 (s, 3H), 2.66 (m, 1 H), 3.10 (m, 2H), 4.00-4.10 (m, 4H), 6.80-6.90 (m, 3H), 7.03-7.35 (m, 4H). LRMS (APCl): 444 (M + H) +.

PREPARATION 85 2-f4-R3-Methyl-4-pyridin-2-iPfenin-1.2.3.6-tetrahydropyridin-1-ylsulphon-methyl-acetate A stirred solution of the title compound of preparation 37 (206 mg, 0.53 mmol), 2- (tri-n-butylstannyl) pyridine (Tetrahedron, 1997, 53, 859, 295 mg, 0.80 mmol), tri-o-tolylphosphine (50 mg, 0.16 mmol), palladium (II) acetate (12 mg, 0.05 mmol) and triethylamine (0.2 ml, 1.44 mmol) in anhydrous acetonitrile (6 ml), under nitrogen, was heated to reflux for 6 hours. Additional portions of tri-o-tolylphosphine (50 mg, 0.16 mmol) and palladium (II) acetate (12 mg, 0.05 mmol) were added, and then the reflux was continued for a further 24 hours. The resulting cold mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, then the organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of hexane: ethyl acetate (100: 0 to 55:45), to yield the title compound (20 mg, 10%) as a colorless amorphous solid. d (CDCl 3): 2.39 (s, 3H), 2.68 (m, 2H), 3.65 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m, 2H), 6.10 (s) , 1 H), 7.23-7.30 (m, 3H), 7.40 (m, 2H), 7.75 (dd, 1 H), 8.70 (d, 1 H). LRMS (APCl): 387 (M + H) +.

PREPARATION 86 2-M-r3-Methyl-4- (pyridin-3-iPfenin-1,2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) Obtained as a colorless foam (78%), from the title compound of preparation 37 and 3- (tri-n-buty-istanil) pyridine, using the procedure of preparation 85, except that the time of reaction was 5 hours at reflux followed by 72 hours at room temperature. Found: C, 62.07; H, 5.78; N, 7.09. C20H22N2 O4S requires C, 62.16; H, 5.74; N, 7.25%. d (CDCl 3): 2.30 (s, 3H), 2.70 (m, 2H), 3.68 (t, 2H), 3.83 (s, 3H), 4.03 (s, 2H), 4.14 (m, 2H), 6.10 (s) , 1 H), 7.20-7.40 (m, 4H), 7.66 (d, 1 H), 8.60 (m, 2H). LRMS (APCl): 387 (M + H) +.

PREPARATION 87 2-f4-r3-Methyl-4- (pyridin-4-iPfenin-1.2.3.6-tetrahydropyridin-1-ylsulfonium methyl acetate) Obtained in the form of a colorless foam (54%), from the title compound of preparation 37 and 4- (tri-n-butylstannil) pyridine, using the procedure of Preparation 85. Found: C, 61.98; H, 5.80; N, 7.13. C20H22N2 O4S requires C, 62.16; H, 5.74; N, 7.25%. d (CDCÍ3): 2.30 (s, 3H), 2.70 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m, 2H), 6.10 (s) , 1 H), 7.20-7.30 (m, 5H), 8.66 (d, 2H). LRMS (APCl): 387 (M + H) +.

PREPARATION 88 6-Ethoxy-2- (tri-n-butylstannap Pyridine A 2.5 M solution of n-butyllithium in hexane (4.5 ml, 1.3 mmol) was added to a stirred solution of 2-bromo-6-ethoxypyridine (Rec. Trav. Chim., 1965, 84. 53, 2, 1 g, 11.3 mmol) in anhydrous ether (25 ml), under nitrogen, at about 40 ° C. After about 20 minutes, tri-n-butyltin chloride (3.1 ml, 1.4 mmol) was slowly added and after 15 minutes more, the reaction mixture was allowed to warm to room temperature. The resulting mixture was quenched by the addition of aqueous ammonium chloride solution, then the organic phase was separated, washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane: dichloromethane (100: 0 to 80:20), to give the title compound (1.6 g, 34%) as a colorless oil. d (CDCl 3): 0.90 (t, 9H), 1.08 (t, 6H), 1.30-1.42 (m, 9H), 1.58 (m, 6H), 4.40 (q, 2H), 6.53 (d, 1 H), 6.97 (d, 1 H), 7.39 (dd, 1 H).

PREPARATION 89 2- (4-r4- (6-Ethoxypyridane-2-iP-3-methylphen-1,2,3,6-tetrahydropyridin-1-ylsulfoniP-2-methylpropanoate methyl) A stirred mixture of the title compound of preparation 40 (500 mg, 1.2 mmol) and of preparation 88 (745 mg, 1.8 mmol), tri-o-tolylphosphine (109 mg, 0.36 mmol), palladium (II) acetate (30 mg, 0.13 mmol), tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.025 mmol), triethylamine (0.45 ml, 3.2 mmol) and anhydrous acetonitrile (15 ml), under nitrogen, was heated to reflux for 18 hours . The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, and then the organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane: ether (95: 5 to 80:20) to yield the title compound (290 mg, 52%) as a colorless foam. d (CDCl 3): 1.40 (t, 3H), 1.68 (s, 6H), 2.46 (s, 3H), 2.66 (m, 2H), 3.63 (m, 2H), 3.81 (s, 3H), 4.12 (m , 2H), 4.40 (q, 2H), 6.07 (sa, 1 H), 6.68 (d, 1 H), 6.98 (d, 1 H), 7.26 (m, 2H), 7.40 (d, 1 H), 7.60 (dd, 1 H). LRMS (APCl): 459 (M + H) +.

PREPARATION 90 2-f4-r4- (6-Ethoxypyridin-2-iP-3-methylphenylpiperidin-1-ylsulfoniP-2-methylpropanoate methyl) A stirred solution of the title compound of the preparation 89 (280 mg, 0.6 mmol) in methanol (12 ml) was hydrogenated at a pressure of 345 KPa (50 psi) on 10% palladium on carbon (50 mg) for 18 hours, and then the resulting mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography, using an elution gradient of pentane: ether (90:10 to 70:30), to give the title compound (70 mg, 25%) as of colorless foam. d (CDCl 3): 1.40 (t, 3H), 1.67 (s, 6H), 1.82 (m, 2H), 1.89 (m, 2H), 2.43 (s, 3H), 2.67 (m, 1 H), 3.08 ( m, 2H), 3.81 (s, 3H), 3.95 (day, 2H), 4.38 (q, 2H), 6.67 (d, 1 H), 6.96 (d, 1 H), 7.10 (m, 2H), 7.38 (d, 1 H), 7.60 (dd, 1 H). LRMS (APCl): 461 (M + H) +.

PREPARATION 91 Acid 2-f 4-r4- (6-ethoxypyridin-2-iP-3-methylphenylpiperidin-1-ylsulfoniP-2-methylpropanoic acid A stirred solution of the title compound of the preparation 91 (68 mg, 0.15 mmol) in a mixture of 1,4-dioxane (2 ml) and 1 M aqueous sodium hydroxide solution (0.26 ml, 0.26 mmol) was stirred at room temperature for 18 hours. The resulting solution was diluted with water (20 ml), acidified with glacial acetic acid to pH ~ 4 and extracted with ethyl acetate. The extract was dried (MgSO) and evaporated under reduced pressure to provide the title compound (60 mg, 87%) as a colorless solid, m.p.178-179 ° C. Found: C, 61.53; H, 6.81; N, 6.09. C23H30N2O5S requires C, 61.86; H, 6.77; N, 6.27%. d (CDCl 3): 1.39 (t, 3H), 1.68 (s, 6H), 1.82 (m, 2H), 1.90 (m, 2H), 2. 43 (s, 3H), 2.67 (m, 1 H), 3.10 (m, 2H), 4.00 (d a, 2H), 4.38 (q, 2H). 6.65 (d, 1 H), 6.96 (d, 1 H), 7.10 (m, 2H), 7.38 (d, 1 H), 7.60 (dd, 1 H).

PREPARATION 92 4-r4- (4-PhenylpheniP-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-tetrahydropyran-4-carboxylic acid methyl ester Obtained as a colorless solid (67%), m.p. 203-206 ° C, from the title compound of preparation 8 and bis-2-iodoethyl ether, using the procedure of preparation 39. d (CDCl 3): 2.25 (m, 2H), 2.44 (d, 2H) , 2.66 (m, 2H), 3.32 (t, 2H), 3. 61 (m, 2H), 3.90 (s, 3H), 4.01 (dd, 2H), 4.10 (m, 2H). 6.08 (s a, 1 H) .7.30- 7.62 (m, 9H). LRMS (Thermospray): 442 (M + H) +.

PREPARATION 93 4-R4- (4-phenylphenyl) -1,2,3,6-tetrahydropyridin-1-ylsulfonintetrahydropyran-4-carboxylic acid Obtained in the form of a colorless solid (66%), m.p. 214 ° C, from the title compound of preparation 92, using the procedure of preparation 79. d (CDCl 3): 2.27 (m, 2H), 2.42 (d, 2H), 2.66 (m, 2H), 3.41 (t, 2H), 3. 62 (m, 2H), 4.04 (dd, 2H), 4.15 (m, 2H). 6.08 (s a, 1 H), 7.30-7.48 (m, 5H), 7.58 (m, 4H). LRMS (APCl): 427 (M + H) +.

PREPARATION 94 -f4-r4- (4-Ethoxyphene-3-methylphen-1, 2,3,6-tetrahydropyridin-1-yl-sulfonyl-tetrahydropyran-4-carboxylic acid methyl) Obtained as a colorless solid (66%), 140-141 ° C, from the title compound of preparation 39 and 4-ethoxyphenylboronic acid, using the procedure of preparation 41, but with ethyl acetate: hexane ( 30:70) as an eluent. Found: C, 64.59; H, 6.60; N, 2.74. C27H33NO6S requires C, 64.91; H, 6.66; N, 2.80%. d (DMSOd6): 1.34 (t, 3H), 2.00 (m, 2H), 2.22 (s, 3H), 2.28 (d, 2H), 2.55 (sa, 2H), 3.19 (t, 2H), 3.50 (sa , 2H), 3.80 (s, 3H), 3.90 (dd, 2H), 3.99 (sa, 2H), 4.06 (q, 2H), 6.17 (sa, 1 H), 6.96 (d, 2H), 7.14 (d , 1 H), 7.22 (d, 2H), 7.28 (d, 1 H), 7.33 (s, 1 H). LRMS (Thermospray): 500 (M + H) +.

PREPARATION 95 Acid 4-. { 4-, 4- (4-Ethoxyphenid-3-methylphenip-1, 2,3,6-tetrahydropyridin-1-ylsulfonyltetrahydropyran-4-carboxylic acid Obtained as a colorless solid (56%), m.p. 212-214 ° C, from the title compound of preparation 94, using the procedure of preparation 79. d (DMSOd6): 1.34 (t, 3H), 1.98 (m, 2H), 2.22 (s, 3H), 2.24 (d, 2H), 2.55 (sa, 2H), 3.19 (t, 2H), 3.52 (s) , 2H), 3.90 (dd, 2H), 4.01 (sa, 2H), 4.04 (q, 2H), 6.17 (sa, 1 H), 6.96 (d, 2H), 7.13 (d, 1 H), 7.22 ( d, 2H), 7.28 (d, 1 H), 7.33 (s, 1 H). LRMS (Thermospray): 486 (M + H) +.

PREPARATION 96 2-. { 4- (4 - (- 3-Formyl-phenyl-3-methylphenyl-1, 2,3,6-tetrahydropyridin-1-ylsulphon-methyl-acetate) Obtained in the form of a colorless gum (86%), from the title compound of preparation 37 and 3-formylphenylboronic acid, using the procedure of preparation 41, but with methanokydloromethane (1: 91) as eluent. d (CDCl 3): 2.30 (s, 3H), 2.70 (m, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 4.02 (s, 2H), 4.12 (m, 2H), 6.10 (s) , 1 H), 7.20-7.33 (m, 3H), 7.60 (m, 2H), 7.85 (m, 2H), 10.08 (s, 1 H). LRMS (APCl): 414 (M + H) +.

PREPARATION 97 2-f4- (4 - (- 3-HydroxymethylpheniP-3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulphonomethyl acetate) The title compound of preparation 96 (303 mg, 0.73 mmol) was dissolved in a mixture of methanol (15 ml) and 1,2-dimethoxyethane (5 ml), boron hydride polymer-supported on Amberlite ™ IRA-400 ( 360 mg, 0.91 mmol) and the reaction mixture was stirred for 3 hours at room temperature. The resin was removed by filtration and the filtrate was evaporated under reduced pressure to yield the title compound as a colorless foam (270 mg, 90%). d (CDCl 3): 2.30 (s, 3H), 2.70 (m, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 4.02 (s., 2H), 4.12 (m, 2H), 4.77 ( sa, 2H), 6.10 (sa, 1 H), 7.20-7.50 (m, 7H). LRMS (Thermospray): 414 (M + H) +.

PREPARATION 98 Quinolin-3-ylboronic acid A 2.5 M solution of n-butyllithium in hexane (4.4 ml, 11 mmol) was slowly added to a solution of 3-bromoquinoline (2.08 g, 10 mmol) in anhydrous ether (20 ml)., under nitrogen, at -75 ° C. After a further 20 minutes at -75 ° C, trimethyl borate (1.46 ml, 13 mmol) was added, after which the red color changed to yellow. The reaction mixture was allowed to warm to room temperature and was quenched with water, followed by 1 m aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for 30 minutes and then glacial acetic acid was added until a pH of 5-6 was achieved, which generated a gummy precipitate. To this mixture was added diisopropyl ether, stirring was continued for 1 hour and then the transparent aqueous and organic phases were separated from the solid by decantation and discarded. The solid residue was dissolved in ethyl acetate and the solution was washed with water, dried (MgSO4) and evaporated under reduced pressure to give the title compound as a pale yellow solid (580 mg, 34%). Found: C, 62.74; H, 4.11; N, 7.92. C9H8BNO2 requires C, 62.49; H, 4.66; N, 8.10%. d (DMSOd6): 7.59 (t, 1 H), 7.76 (t, 1 H), 7.98 (m, 2H), 8.42 (sa, 2H, interchangeable), 8.70 (s, 1 H), 9.18 (s, 1 H).

PREPARATION 99 2-Methyl-2-y4-r3-methyl-4- (quinolin-3-iPfenip-1,2,3,6-tretrahydropyridin-1-ylphosphonopropionate methyl) Obtained as a colorless solid (82%), m.p. 149-151 ° C, from the title compounds of preparation 40 and of preparation 98, using the procedure of preparation 41, but using 25% of 1-methylpyrrolidin-2-one in 1,2-dimethoxyethane as solvent for the reaction and etheptantone (80:20) as eluent for flash chromatography.

Found: C, 67.02; H, 6.20; N, 5.78. C 26 H 2 S N 2 O 4 S requires C, 67.22; H, 6.08; N, 6.03%. d (CDCl 3): 1.67 (s, 6H), 2.36 (s, 3H), 2.67 (m, 2H), 3.65 (m, 2H), 3.82 (s, 3H), 4.13 (m, 2H), 6.10 (s) , 1 H), 7.32 (m, 3H), 7.60 (t, 1 H), 7.75 (t, 1 H), 7.87 (d, 1 H), 8.10 (s, 1 H), 8.16 (d, 1 H) ), 8.93 (s, 1 H). LRMS (Thermospray): 465 (M + H) +.

PREPARATION 100 2-Methyl-2-4-r3-methyl-4- (quinoxy-3-iDfenin-1,2,3,6-tetrahydropyridin-1-ylsulfonium-D-propionic acid A solution of the title compound of preparation 99 (500 mg, 1.08 mmol) is a mixture of 1,4-dioxane (5 ml), methanol (10 ml) and 1 M aqueous sodium hydroxide solution (3.2 ml, 3.2 mmol). ) was stirred at reflux for 30 minutes. The resulting solution was allowed to cool, acidified with glacial acetic acid until pH ~ 4, diluted with water (15 ml) and the resulting mixture partially evaporated under reduced pressure until crystallization occurred. The solid was collected and dried to yield the title compound (440 mg, 90%) as a colorless solid, m.p. 222-224 ° C. Found C, 66.17; H, 5.77; N, 6.15. C 25 H 26 N 2 O 4 S requires C, 66.64; H, 65.82; N, 6.22%. d (DMSOd6): 1.51 (s, 6H), 2.31 (s, 3H), 2.59 (m, 2H), 3.58 (m, 2H), 4.08 (m, 2H), 6.26 (s, 1 H), 7.33- 7.50 (m, 3H), 7.65 (t, 1 H), 7.78 (t, 1 H), 8.05 (t, 2H), 8.37 (s, 1 H), 8.90 (s, 1 H), 13.4 (s, 1 HOUR). LRMS (APCl): 451 (M + H) +.

PREPARATION 101 3-methylthiophenylboronic acid A solution of 3-bromothioanisole (10.3 g, 50.9 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a stirred mixture of magnesium filings (1.86 g, 75 mmol) and a crystal of iodine under nitrogen. Once the reaction was started, the rest of the solution was added at a rate such as to keep the reaction mixture under reflux. When the addition was complete, the mixture was stirred under reflux for an additional 1 hour, allowed to cool to room temperature and then added to a solution of trimethyl borate (5.8 ml, 51 mmol) in anhydrous tetrahydrofuran (25 ml), while that the internal temperature was maintained at approximately -10 ° C. The reaction mixture was allowed to warm to about 0 ° C, stirred for 30 minutes and then quenched with 2M hydrochloric acid. The resulting mixture was extracted with ether and then the combined extracts were extracted, in turn, with aqueous solution. 2 M sodium hydroxide. The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated under reduced pressure to provide the title compound (7.8 g, 100%) as a white solid. d (DMSOd6): 2.45 (s, 3H), 7.27 (m, 2H), 7.54 (m, 1 H), 7.67 (s, 1 H), 8.05 (s a, 2H).

PREPARATION 102 2-f4-r3-Methyl-4- (3-methylthiophenin-1, 2,3,6-tetrahydropyridin-1-ylsulphon-methyl acetate) Obtained as a colorless solid (83%), from the title compounds of preparation 101 and of preparation 37, using the procedure of preparation 41, but using dichloromethane: hexane (3: 1) as eluent. d (CDCl 3): 2.28 (s, 3H), 2.50 (s, 3H), 2.68 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m , 2H), 6.08 (sa, 1 H), 7.07 (d, 1 H), 7.20-7.36 (m, 6H). LRMS (APCl): 432 (M + H) +.

PREPARATION 103 3-Methoxymethylphenylboronic acid Obtained in the form of a yellow solid (100%), from 1-bromo-3-methoxymethylbenzene (J. Amer. Chem. Soc, 1989, 11 11, 631 1; Tetrahedron 1985, 41, 1435) and trimethyl borate. , using the procedure of the preparation101. d (DMSOd6): 3.27 (s, 3H), 4.38 (s, 2H), 7.31 (m, 2H), 7.68 (m, 2H), 7.98 (s a, 2H).

PREPARATION 104 2- 4-r4- (3-Methoxymethyl-phenyl-3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonyl methyl acetate) Obtained in the form of a colorless oil (35%), from the title compounds of preparation 103 and of preparation 37, using the procedure of preparation 41, but using etherphexane (60:40) as eluent. d (CDCl 3): 2.27 (s, 3H), 2.68 (m, 2H), 3.42 (s, 3H), 3.64 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m , 2H), 4.51 (s, 2H), 6.08 (sa, 1 H), 7.20-7.32 (m, 7H). LRMS (Thermospray): 430 (M + H) +.

PREPARATION 105 1-Bromo-3- (2-methoxyethoxy) benzene Anhydrous potassium carbonate (4.2 g, 30.4 mmol) was added to a stirred solution of 3-bromophenol (5.0 g, 28.9 mmol) in anhydrous dimethylformamide (10 mL). After 5 minutes, 1-iodo-2-methoxyethane (Annalen, 1967, 710, 59, 5.9 g, 31.8 mmol) was added and the reaction mixture was stirred at room temperature for approximately 16 hours. At this time, the mixture was heated to about 50 ° C for about 72 hours, before 1-chloro-2-methoxyethane (1.8 ml), 19.8 mmol) was added and heating continued for a further 24 hours. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated until a red oil was obtained, which was purified by flash chromatography using hexane: ethyl acetate (3: 1) as eluent, to provide the title compound as a colorless oil (1.7 g, 25%). d (CDCl 3): 3.43 (s, 3 H), 3.74 (t, 2 H), 4.10 (t, 2 H), 6.87 (d, 1 H), 7.10 (m, 3 H).

PREPARATION 106 3- (2-Methoxyethoxy) phenylboronic acid Obtained as a colorless solid (74%), m.p. 101-103 ° C, from the title compound of preparation 105 and trimethyl borate, using the procedure of Preparation 101. Found: C, 55.09; H, 6.70. C9H13BO4 requires C, 55.15; H, 6.69%. d (DMSOd6): 3.30 (s, 3H), 3.63 (t, 2H), 4.06 (t, 2H), 6.94 (d, 1 H), 7.22 (t, 1 H), 7.32 (m, 2H), 7.98 (sa, 2H). LRMS (Thermospray): 214 (M + NH4) +.

PREPARATION 107 2- | 4-í4- (3-í2-Methoxyethoxyphenol) -3-methyl-methyl-1,2,3,6-tetrahydro-disulfide-1-ylsulphon-methyl acetate Obtained in the form of a colorless oil (59%), from the title compounds of preparation 106 and of preparation 37, using the procedure of preparation 41, but using ether: hexane (1: 1) as eluent. d (CDCl 3): 2.28 (s, 3H), 2.67 (m, 2H), 3.45 (s, 3H), 3.63 (t, 2H), 3.77 (t, 2H), 3.80 (s, 3H), 4.02 (s) , 2H), 4.09 (s, 2H), 4.15 (s, 2H), 6.07 (sa, 1 H), 6.90 (m, 3H), 7.19-7.34 (m, 4H).

PREPARATION 108 2,3-Dihydrobenzofuran-5-ylboronic acid Obtained as a colorless solid (38%), m.p. > 240 ° C (decomp.), From 5-bromo-2,3-dihydrobenzofuran (Synthesis, 1988, 952) and trimethyl borate, using the procedure of Preparation 101. d (DMSOd6): 3.33 (t, 2H), 4.48 (t, 2H), 6.68 (d, 1 H), 7.56 (d, 1 H), 7.63 (s, 1 H), 7.70, (sa, 2H) .

PREPARATION 109 5- (4-Bromo-2-methylphen-D-2,3-dihydrobenzofuran) The title compound of Preparation 108 (2.0 g, 12.2 mmol) was added portionwise over 5 minutes to a stirred mixture of the title compound of preparation 57 (3.4 g, 12.0 mmol) and palladium (II) acetate ( 0.15g, 0.6 mmol) in anhydrous methanol (30 ml) and the reaction mixture was heated to reflux for 1.5 hours. The resulting mixture was allowed to cool to room temperature, filtered, then the filtrate was diluted with water (100 ml) and extracted with ether (2 x 100 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure and then the residue was purified by flash chromatography, using hexane as eluent, to give the title compound (1.7 g) as a pale orange oil. d (CDCl 3): 2.25 (s, 3H), 3.25 (t, 2H), 4.62 (t, 2H), 6.83 (d, 1 H), 7.02 (d, 1 H), 7.09 (m, 2H), 7.34 (d, 1 H), 7.60 (s, 1 H). LRMS (APCl): 289 (M) +.

PREPARATION 110 4-r4-f2.3-Dihydrobenzofuran-5-iD-3-methylphenyl-4-hydroxypiperidine-1-t-butyl carboxylate Obtained as a white solid (66%), from the title compound of preparation 109 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. d (CDCl 3): 1.50 ( s, 9H), 1.78 (m, 2H), 2.06 (m, 2H), 2.29 (s, 3H), 3.26 (m, 4H), 4.05 (m, 2H), 4.62 (t, 2H), 6.82 (d , 1 H), 7.05 (d, 1 H), 7.15 (s, 1 H), 7.21 (d, 1 H), 7.30 (m, 1 H), 7.36 (s, 1 H). LRMS (Thermospray): 432 (M + H) +.

PREPARATION 111 4-r4- (2,3-Dihydrobenzofuran-5-iD-3-methylphenn-1, 2,3,6-tetrahydropyridine Obtained in the form of a colorless viscous oil (98%), from the title compound of preparation 10 and trifluoroacetic acid, using the procedure of preparation 44. d (CDCl 3): 2.30 (s, 3H), 2.49 ( m, 2H), 3.12 (t, 2H), 3.26 (t, 2H), 3.56 (s, 2H), 4.62 (t, 2H), 6.17 (sa, 1 H), 6.82 (d, 1 H), 7.07 (d, 1 H), 7.16 (m, 2H), 7.26 (m, 2H). LRMS (Thermospray): 292 (M + H) +.

PREPARATION 112 2- (4-r4- (2,3-D-Hydrobenzofuran-5-D-3-methylphenyl-1, 2,3,6-tetrahydropyridin-1-ylsulfone-D-methyl-acetate) Obtained in the form of a pale yellow foamy solid (45%), m.p. 1 18-122 ° C, from the title compound of preparation 1 1 1 and methyl chlorosulfonylacetate, using the procedure of preparation 61. d (CDCl 3): 2.30 (s, 3H), 2.67 (m, 2H) , 3.24 (t, 2H), 3.62 (t, 2H), 3.79 (s, 3H), 4.01 (s, 2H), 4.06 (s, 2H), 4.62, (t, 2H), 6.08 (sa, 1 H) ), 6.82 (d, 1 H), 7.05 (d, 1 H), 7.26 (7.26 (m, 4H), LRMS (Thermospray): 428 (M + H) +.

PREPARATION 113 3-Methyl-4- (3-trifluoromethylphenhydrobenzene) Obtained in the form of a colorless oil (66%), from the title compound of preparation 57 and 3-trifluoromethylphenylboronic acid, using the procedure of preparation 109. d (CDCl 3): 2.33 (s, 3H), 7.08 ( d, 1 H), 7.40-7.64 (m, 6H).

PREPARATION 114 4-Hydroxy-4-r 3 -methyl-4- (3-trifluoromethylphenidonephenylpiperidine-1-t-butylcarboxylate) Obtained in the form of a yellow oil (54%), from the title compound of preparation 13 and 4-oxopiperidine-1-t-butylcarboxylate, using the procedure of preparation 43, but with hexane: ethyl (85:15) as eluent. d (CDCl 3): 1.50 (s, 9H), 1.77 (m, 2H), 2.04 (m, 2H), 2.27 (s, 3H), 3.26 (m, 2H), 4.05 (m, 2H), 7.04 (d, 1 H), 7.15 (s, 1 H), 7.37 (m, 2H), 7.55 (m, 4H). LRMS (Thermospray): 436 (M + H) +.

PREPARATION 115 4-r3-Methyl-4-f3-trifluoromethylphenDfenin-1, 2,3,6-tetrahydropyridine Obtained as a colorless oil (98%), from the title compound of preparation 14 and trifluoroacetic acid, using the procedure of preparation 44. Found: C, 70.90; H, 5.84; N, 4.38. C19H18F3N; 0.25 H2O requires C, 70.90; H, 5.79;; N, 4.35%. d (CDCI3): 2.26 (s, 3H), 2.49 (sa, 2H), 3.12 (sa, 2H), 3.56 (sa, 2H), 6.20 (sa 1 H), 7.18 (d, 1 H), 7.26 ( m, 2H), 7.55 (m, 4H).

LRMS (APCl): 318 (M) +.

PREPARATION 116 2-f4-r3-Met.l-4- (3-trifluoromTtllfeniDfenin-1, 2,3,6-tetrahydropyridin-1-ylsulphon-methyl) acetate Obtained in the form of a yellow foam (31%), from the title compound of preparation 15 and methyl chlorosulfonylacetate, using the procedure of preparation 61, but with dichloromethane: hexane (80:20) as eluent. Found: C, 56.38; H, 4.77; N, 2.96. C ^ H ^ FsNO ^; 0.25 CH2Cl2 requires C, 56.30; H, 4.78; N, 2.95%. d (CDCl 3): 2.27 (s, 3H), 2.70 (m, 2H), 3.64 (t, 2H), 3.82 (s, 3H), 4.03 (s, 2H), 4.1 1 (s, 2H), 6.10 ( sa, 1 H), 7.24 (m, 3H), 7.55 (m, 4H). LRMS (APCl): 453 (M) +.

PREPARATION 117 4-Hydroxy-4- (4-phenoxyphene) -piperidine-1-t-butylcarboxylate Obtained in the form of a white foam (54%), from 4-phenoxybromobenzene and 4-oxopiperidine-1-t-butylcarboxylate, using the procedure of preparation 43, but with an anhydrous tetrahydrofuran and anhydrous ether mixture as solvent and ether: hexane (60:40) as eluent. d (CDCU): 1.50 (s, 9H), 1.75 (m, 2H), 1.99 (m, 2H), 3.25 (m, 2H), 4.04 (m, 2H), 7.00 (m, 4H), 7.12 (t , 1 H), 7.37 (t, 2H), 7.44 (d, 2H).

PREPARATION 118 4- (4-Phenoxyphenyl) piperidine Triethylsilane (3.0 mL, 18.9 mmol) was added to a stirred solution of the title compound of Preparation 117 (775 g, 2.1 mmol) in anhydrous dichloromethane (10 mL), the resulting solution was cooled to about 0 ° C and then slowly added trifluoroacetic acid (10 ml). The reaction mixture was allowed to warm to room temperature and then stirred for about 1.5 hours. The resulting mixture was evaporated under reduced pressure, then the residue was dissolved in methanol and this solution was basified with 2 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and the combined extracts were dried (MgSO4) and evaporated under reduced pressure. This residue was dissolved in glacial acetic acid (20 ml) and the solution was hydrogenated over palladium on carbon (60 mg) at 345 kPa (50 psi) and at room temperature for 2 hours. The mixture was filtered, the filtrate was evaporated under reduced pressure and the residue was dissolved in methanol. This solution was then basified with 2 M aqueous sodium hydroxide solution, extracted with ethyl acetate and the combined extracts were dried (NaSO 4) and evaporated under reduced pressure to give the title compound as a yellow oil (550 mg , 100%). d (CDCl 3): 1.63 (m, 2 H), 1.84 (m, 2 H), 2.60 (m, 1 H), 2.74 (t, 2 H), 3.20 (m, 2 H), 6.95 (d, 2 H), 7.00 (m, 2 H), d, 2H), 7.07 (t, 1 H), 7.18 (d, 2H), 7.33 (m, 2H). LRMS (Thermospray): 254 (M + H) +.

PREPARATION 119 2-.4- (4-Phenoxyphen-Piperidin-1-sulphonyl-1-methyl acetate) Obtained as a colorless solid (38%), from the title compound of preparation 18 and methyl chlorosulfonylacetate, using the procedure of preparation 45. d (CDCl 3): 1.80 (m, 2H), 1.94 ( m, 2H), 2.64 (m, 1 H), 3.00 (t, 2H), 3. 83 (s, 3H), 3.95 (m, 4H), 6.95 (m, 4H), 7.10 (t, 1 H), 7.16 (d, 2H), 7.33 (m, 2H). LRMS (Thermospray): 407 (M + NH4) +.

PREPARATION 120 2- (4-r4- (3-r2-Methoxyethoxy-1-phenyl-3-methylphen-1,2,3,6-tetrahydropyridin-1-yl-sulfonyl-D-2-methylpropionate) Obtained as a pale yellow oil (97%), from the title compounds of preparation 106 and preparation 40, using the procedure of preparation 41, but with ethyl acetate: hexane (1: 3) as eluent. d (CDCl 3): 1.67 (s, 6H), 2.28 (s, 3H), 2.65 (m, 2H), 3.45 (s, 3H), 3.62 (m, 2H), 3.76 (m, 2H), 3.80 (s) , 3H), 4.13 (m, 4H), 6.06 (sa, 1 H), 6.90 (m, 3H), 7.19-7.35 (m, 4H).

PREPARATION 121 2-f4-r4- (3-r2-Methoxyethoxy-infen-phenyl-3-methylphenylpiperidin-1-ylsulfoniD-2-methylpropanoate methyl) Obtained as a pale yellow oil (83%), from the title compound of preparation 120, using the procedure of preparation 90. d (CDCl 3): 1.66 (s, 6H), 1.78-1.88 (m, 4H), 2.27 (s, 3H), 2.68 (m, 1 H), 3.09 (m, 2H), 3.45 (s, 3H), 3.77 (t, 2H), 3.81 (s, 3H), 3.96 (d, 2H), 4.15 (t, 2H), 6.90 (m, 3H), 7.10 (m, 2H), 7.18 (d, 1 H), 7.30 (t, 1 H). LRMS (Thermospray): 490 (M + H) +.

PREPARATION 122 Acid 2-. { 4-r4- (3-r2-Methoxy-ethoxy-phenyl-3-methylphenopyridin-1-ylsulfonyl-2-methylpropionic acid Obtained in the form of a colorless solid (78%). p.f. 140-141 ° C, from the title compound of preparation 121, using the procedure of preparation 79. Found: C, 62.89; H, 7.06; N, 2.85. C25H33NO6S requires C, 63.14; H, 6.99; N, 2.95%. d (CDCl 3): 1-68 (s, 6H), 1.78-188 (m, 4H), 2.27 (s, 3H), 2.68 (m, 1 H), 3.11 (m, 2H), 3.45 (s, 3H) ), 3.77 (t, 2H), 4.00 (d, 2H), 4.15 (t, 2H), 6.90 (m, 3H), 7.10 (m, 2H), 7.18 (d, 1 H), 7.30 (t, 1) H). LRMS (Thermospray): 475 (M + H) +.

PREPARATION 123 4-Methoxy-2 (R, S -r4- (3-methyl-4-phenylphen-D-1,2,3,6-tetrahydropyridin-1-yl-sulfonylbutanoate methyl) 60% sodium hydride dispersion in mineral oil (23 mg, 0.57 mmol) was added to a stirred solution of the title compound of preparation 9 (200 mg, 0.52 mmol) in 1-methylpyrrolidin-2-one. anhydrous (3 ml), under nitrogen, at room temperature. After 30 minutes, 1-iodo-2-methoxyethane (101 mg, 0.57 mmol) was added and stirring was continued for a further 16 hours, and then the resulting mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using dichloromethane as eluent, followed by trituration with diisopropyl ether, to yield the title compound (148 mg) as a colorless solid, m.p. 95-96 ° C. d (CDCl 3): 2.28 (s, 3H), 2.39 (m, 2H), 2.67 (m, 2H), 3.30 (s, 3H), 3.40 (m, 1 H), 3.54 (m, 2H), 3.67 ( m, 1 H), 3.80 (s, 3H), 4.10 (sa, 2H), 4.17 (dd, 1 H), 6.07 (sa, 1 H), 7.22 (m, 3H), 7.32 (m, 3H), 7.41 (m, 2H).

PREPARATION 124 4-Methoxy-2, R acid. S) -4- (3-m? Tl-4-phenylfeni!) - 1, 2.3.6-tetrahydropyridin-1-ylsulfonylbutanoic Aqueous 1 M aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) was added to a stirred solution of the title compound of Preparation 123 (148 mg, 0.33 mmol) in a mixture of methanol (5 mL) and 1,4-dioxane. (2 ml). The resulting solution was heated at 80 ° C for about 4 hours and then allowed to cool to room temperature and evaporated under reduced pressure. The residue was diluted with water, then the resulting mixture was acidified with glacial acetic acid and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give the title compound (145 mg) as a colorless solid, m.p. 108-109 ° C. d (CDCl 3): 2.28 (s, 3H), 2.39 (m, 2H), 2.67 (m, 2H), 3.36 (s, 3H), 3.53-3.73 (m, 5H), 4.12 (sa, 2H), 4.20 (dd, 1 H), 6.07 (sa, 1 H), 7.19-7.47 (m, 8H). LRMS (APCl): 429 (M + H) +.

PREPARATION 125 4-r4- (3-Methyl-4-phenyl-phenyl-D-1, 2,3,6-tetrahydropyridin-1-ylsulfonintetrahydropyran-4-carboxylic acid methyl ester A dispersion of 60% sodium hydride in mineral oil (34 mg, 0.86 mmol) was added to a stirred solution of the title compound of preparation 9 (300 mg, 0.78 mmol) in anhydrous 1-methylpyrrolidin-2-one (3 ml), under nitrogen, at room temperature. After 30 minutes, bis-2-iodoethyl ether (380 mg, 0.78 mmol) was added and stirring was continued for a further 4 hours, then more 60% sodium hydride dispersion in mineral oil (34 mg, 0.86 mmol) was added. ) and the mixture was stirred for a further 16 hours. The resulting mixture was partitioned between ethyl acetate and water, then the organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by crystallization from diisopropyl ether to give the title compound (188 mg) as a colorless solid, m.p. 117-1 19 ° C. Found: C, 65.70; H, 6.44; N, 2.98. C25H29NO5S requires C, 65.91; H, 6.42; N, 3.08%. d (CDCl 3): 2.22 (m, 2H), 2.29 (s, 3H), 2.47 (m, 2H), 2.64 (m, 2H), 3.33 (t, 2H), 3.60 (m, 2H), 3.87 (s) , 3H), 4.00 (dd, 2H), 4.10 (m, 2H), 6.07 (sa, 1 H), 7.20-7.43 (m, 8H). LRMS (Thermospray): 456 (M + H) +.

PREPARATION 126 4-r4- (3-Methyl-4-phenylphenylD-1, 2,3-6-tetrahydropyridin-1-l-sulfonyltetrahydropyran-4-carboxylic acid A 1M aqueous solution of sodium hydroxide (1.4 ml, 1.4 mmol) was added to a stirred solution of the title compound of preparation 125 (160 mg, 0.35 mmol) in a mixture of methanol (5 ml) and 1,4-dioxane ( 2 ml). The resulting solution was heated at 80 ° C for 4 hours, then allowed to cool to room temperature, diluted with water and concentrated under reduced pressure. The resulting mixture was acidified with 1M hydrochloric acid and the precipitate thus obtained was collected, washed with water and dried to yield the title compound (135 mg) as a colorless solid, m.p. 21 1-213 ° C. Found: C, 64.89; H, 6.14; N, 3.07. C 24 H 27 NO 5 S requires C, 65.28; H, 6.14; N, 3.17%. d (DMSOd6): 1.96 (m, 2H), 2.03 (s, 3H), 2.10 (m, 2H), 2.53 (m, 2H), 3.23 (t, 2H), 3.54 (m, 2H), 3.92 (dd) , 2H), 4.03 (m, 2H), 6.18 (sa, 1 H), 7.16 (d, 1 H), 7.28-7.43 (m, 7H), 13.7 (sa, 1 H). LRMS (APCl): 442 (M + H) +.

PREPARATION 127 4-r4- (3-MethoxypheniP-3-methylphenylpiperidine) Obtained as a rose oil (74%), from the title compound of preparation 59, using the procedure of preparation 118. d (CDCl 3): 1.67 (m, 2H), 1.88 (m, 2H), 2.29 (s, 3H), 2.63 (m, 1 H), 2. 57 (t, 2H), 3.22 (m, 2H), 3.83 (s, 3H), 6.89 (m, 3H), 7.10 (m, 2H), 7.18 (d, 1 H), 7.32 (t, 1 H) . LRMS (Thermonebuiization): 282 (M + H) +.

PREPARATION 128 2-. { Methyl 4-r4- (3-methoxyphenyl) -3-methylphenyl-1,1-pentyl-1-ylsulfonyl acetate Obtained as a colorless solid (47%), m.p. 96-98 ° C, from the title compound of preparation 127 and methyl chlorosulfonylacetate, using the procedure of preparation 45. d (CDCl 3): 1-83 (m, 2H), 1.96 (m, 2H ), 2.28 (s, 3H), 2.63 (m, 1 H), 3.02 (t, 2H), 3.83 (s, 6H), 4.01 (m, 4H), 6.89 (m, 3H), 7.10 (m, 2H) ), 7.20 (d, 1 H), 7.34 (t, 1 H).

LRMS (Thermospray): 418 (M + H) +.

PREPARATION 129 2-. { 4-r4- (3-Methoxyphenyl) -3-methylphenylpiperidin-1-ylsulfoniPinylene-2-methyl carboxylate 1,2-Di (bromomethyl) benzene (409 mg, 1.55 mmol) was added to a stirred mixture of the title compound of Preparation 128 (500 mg, 1.2 mmol) and anhydrous potassium carbonate (497 mg, 3.6 mmol) in 1 ml. , Anhydrous 2-dimethoxyethane (5 ml) and the resulting mixture was stirred at room temperature for 17 hours. A small reaction had occurred, so that the solvent was evaporated under reduced pressure and the residue was dissolved in 1-methylpyrrolidin-2-one (5 ml) and the solution was heated at 100 ° C for 2 hours. This mixture was allowed to cool to room temperature, partitioned between ether and water, then the organic phase was washed with water, dried (MgSO 4) and evaporated under reduced pressure, giving a yellow oil. Purification by flash chromatography, using an elution gradient of pentane: ethyl acetate (10: 1 to 3: 1), afforded the title compound as a white crystalline solid (160 mg), m.p. 174-176 ° C. Found: C, 68.95; H, 6.48; N, 2.56. C30H33NO5S requires C, 69. 3. 4; H, 6.40; N, 2.70%. d (CDCl 3): 1.74 (m, 2H), 1.85 (m, 2H), 2.27 (s, 3H), 2.57 (m, 1 H), 2.89 (t, 2H), 3.73-3.86 (m, 4H), 3.83 (s, 6H), 3.96 (m, 2H), 6.87 (m, 3H), 7.06 (m, 2H), 7.18-7.33 (m, 6H). LRMS (Thermospray): 520 (M + H) +.

PREPARATION 130 Acid 2-. { 4-r4- (3-Methoxy-phenyl-3-methylphenylpiperidin-1-ylsulfoni-phenylene-2-carboxylic acid) Obtained as a colorless solid (83%), m.p. 204-206 ° C, from the title compound of preparation 129, using the procedure of preparation 79. Found: C, 68.17; H, 6.22; N, 2.74. C29H3? NO5S; 0.30 H2O requires C, 68.16; H, 6.23; N, 2.74%. d (DMSOd6): 1.54 (m, 2H), 1.76 (m, 2H), 2.21 (s, 3H), 2.57 (m, 1 H), 2.89 (t, 2H), 3.55 (d, 2H), 3.72 ( d, 2H), 3.77 (s, 3H), 3.81 (m, 2H), 6.87 (m, 3H), 7.07 (m, 3H), 7.19 (m, 2H), 7.28 (m, 3H), 13.65 (s) , 1 HOUR). LRMS (Thermospray): 520 (M + NH4) +.

PREPARATION 131 1 - (4-r4- (3-Methoxyphenyl) -3-methylphenylpiperidin-1-ylsulfonyl.} - cyclobutanecarboxylate 1,3-Diiodopropane (513 mg, 1.73 mmol) was added to a stirred mixture of the title compound of Preparation 128 (557 mg, 1.33 mmol), anhydrous potassium carbonate (553 mg, 4.0 mmol) and 1,2-dimethoxyethane. anhydrous (8 ml), then the mixture was stirred at room temperature for 17 hours and refluxed for 72 hours. The resulting mixture was allowed to cool to room temperature and partitioned between ethyl acetate and water, then the organic phase was dried (MgSO) and evaporated under reduced pressure to give a yellow oil. Purification by flash chromatography, using pentane: ethyl acetate (3: 1) as eluent, afforded the title compound (472 mg) as a white crystalline solid, m.p. 97-101 ° C. d (CDCl 3): 1.75-2.02 (m, 5H), 2.13 (m, 1 H), 2.28 (s, 3H), 2.59-2.75 (m, 3H), 2.90 (m, 2H), 3.00 (t, 2H) ), 3.82 (s, 3H), 3.87 (s, 3H), 3.93 (m, 2H), 6.87 (m, 3H), 7.06 (m, 2H), 7.18 (d, 1 H), 7.32 (t, 1) H). LRMS (Thermospray): 458 (M + H) +.

PREPARATION 132 Acid 1 -. { 4-r4- (3-Methoxy-phenyl-3-methylphenylpiperidin-1-ylsulfoni-P-cyclobutanecarboxylic acid Obtained in the form of a colorless solid (100%), m.p. 155-160 ° C, from the title compound of preparation 131, using the procedure of preparation 79. d (CDCl 3): 1.80 (m, 2H), 1.91 (m, 2H), 2.12 (m, 2H) , 2.27 (s, 3H), 2.62 (m, 1 H), 2.74 (m, 2H), 2.91 (m, 2H), 3.04 (t, 2H), 3.82 (s, 3H), 3.99 (m, 2H) , 6.87 (m, 3H), 7.06 (m, 2H), 7.18 (d, 1 H), 7.32 (t, 1 H). LRMS (Thermospray): 444 (M + H) +.

PREPARATION 133 4-l'4-r4- (3-Methoxyphenid-3-methylphen- piperidin-1 -8-sulfonyl-D-1-methylpiperidine-4-carboxylic acid methyl ester The title compound of preparation 128 (500 mg, 1.2 mmol) and anhydrous potassium carbonate (553 mg, 4.0 mmol) were added, followed by anhydrous 1,2-dimethoxyethane (8 ml), to N-methyl-bis hydrochloride. (2-chloroethyl) amine (231 mg, 1.2 mmol) and the mixture was heated to reflux for 48 hours. The resulting mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with 5% aqueous solution of citric acid, dried (MgSO) and evaporated under reduced pressure to give a yellow oil. The residual oil was dissolved in ethyl acetate and the solution was washed successively with aqueous sodium bicarbonate solution / aqueous sodium hydroxide solution (pH 12) and aqueous sodium chloride solution, then dried (MgSO 4) and evaporated under reduced pressure. to provide the title compound in the form of a yellow gum (175 mg). d (CDCl 3): 1.87 (m, 6H), 2.20 (m, 2H), 2.25 (s, 3H), 2.27 (s, 3H), 2. 53 (m, 2H), 2.66 (m, 1 H), 2.90 (m, 2H), 3.07 (t, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 3.93 (m, 2H), 6.88 (m, 3H), 7.08 (m, 2H), 7.20 (d, 1 H), 7.32 (t, 1 H). LRMS (Thermospray): 501 (M + H) +.

PREPARATION 134 4- (4-R4- (3-MethoxypheniD-3-methylphenylpiperidin-1-ylsulphon-D-1-methyl-piperidine-4-carboxylic acid hydrochloride 1 M aqueous sodium hydroxide solution (1.4 ml, 1.4 mmol) was added to a stirred solution of the title compound of preparation 133 (172 mg, 0.34 mmol) in a mixture of methanol (5 ml) and 1,4-dioxane. (3 ml). The reaction solution was heated at 80 ° C for 10 hours, then allowed to cool to room temperature and concentrated under reduced pressure. The resulting mixture was acidified with 1M hydrochloric acid, washed with dichloromethane and evaporated under reduced pressure, then the residue was washed with water to yield the title compound (143 mg) as a colorless solid. d (CDCl 3): 1.67 (m, 2H), 1.84 (m, 2H), 2.20 (s, 3H), 2.30 (m, 2H), 2.62-2.90 (m, 7H), 3.12 (t, 2H), 3.48 (m, 2H), 3.77 (sa, 6H), 6.88 (m, 3H), 7.10 (sa, 2H), 7.18 (sa, 1 H), 7.32 (t, 1 H). LRMS (Thermospray): 523 (M + HCl) +.

PREPARATION 135 3-Phenyl-2, R, S .-. 4-.4-fenHfeniD-1, 2,3,6-tetrahydropyridin-1 - Methyl isulfonylpropanoate A dispersion of 60% sodium hydride in mineral oil (34 mg, 0.77 mmol) was added to a stirred solution of the title compound of Preparation 8 (288 mg, 0.77 mmol) in anhydrous dimethylformamide (5 mL), under nitrogen, at room temperature. After 30 minutes, benzyl bromide (0.1 ml, 0.82 mmol) was added and stirring was continued for a further 16 hours, and then the resulting mixture was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase was washed with ethyl acetate. The combined organic solutions were washed sequentially with water and aqueous sodium chloride solution, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with diisopropyl ether to give the title compound (170 mg) as a colorless solid, m.p. 137-138 ° C. d (CDCl 3): 2.68 (m, 2H), 3.42 (m, 2H), 3.59 (m, 1 H), 3.67 (s, 3H), 3.72 (m, 1 H), 4.14 (sa, 2H), 4.21 (dd, 1 H), 6.10 (sa, 1 H), 7.18-7.37 (m, 6H), 7.44 (m, 4H), 7.59 (m, 4H). LRMS (Thermospray): 462 (M + H) +.

PREPARATION 136 3-phenyl-2-acid (R.SH4- (4-phenylpheniD-1,2,3,6-tetrahydropyridin-1-ylsulfonylpropanoic acid Obtained as a colorless solid (50%), m.p. 164-165 ° C, from the title compound of preparation 135, using the procedure of preparation 79. d (CDCl 3): 2.68 (m, 2H), 3.41 (m, 2H), 3.60 (m, 1 H ), 3.72 (m, 1 H), 4.14 (sa, 2H), 4.24 (dd, 1 H), 6.08 (sa, 1 H), 7.20-7.37 (m, 6H), 7.43 (m, 4H), 7.59 (m, 4H). LRMS (APCl): 447 (M + H) +.

PREPARATION 137 2-r4- (4-PhenylphenylD-1, 2,3,6-tetrahydropyridin-1-ylsulfoninindane-2-methyl carboxylate) A dispersion of 60% sodium hydride in mineral oil (30 mg, 0.73 mmol) was added to a stirred solution of the title compound of preparation 8 (250 mg, 0.67 mmol) in anhydrous dimethylformamide (5 ml), under nitrogen , at room temperature. After 30 minutes, 1,2-di (bromomethyl) benzene (267 mg, 1.0 mmol) was added and stirring was continued for a further 16 hours. Then, an additional amount of sodium hydride dispersion in mineral oil (30 mg, 0.73 mmol) was added and the reaction mixture was stirred at room temperature for a further 2 hours. The resulting mixture was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic solutions were washed successively with water and aqueous sodium chloride solution, dried (MgSO4) and evaporated under reduced pressure, and then the residue was purified by flash chromatography, using pentane: ether (3: 1) as eluent, followed by trituration with diisopropyl ether, to yield the title compound (154 mg) as a colorless solid, mp 186-188 ° C. d (CDCl 3): 2.60 (m, 2H), 3.56 (m, 2H), 3.75-3.88 (m, 4H), 2.82 (s, 3H), 4.07 (sa, 2H), 6.05 (sa, 1 H), 7.19-7.28 (m, 4H), 7.34-7.45 (m, 5H), 7.59 (m, 4H). LRMS (APCl): 474 (M + H) +.

PREPARATION 138 Acid 2-r4- (4-phenylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulfonylindane-2-carboxylic acid Obtained as a colorless solid (67%), from the title compound of preparation 137, using the procedure of preparation 50, except that the residue was triturated with diisopropyl ether. d (CDCl 3): 2.60 (m, 2H), 3.56-3.84 (m, 6H), 4.07 (s a, 2H), 6.05 (s a, 1 H), 7.19-7.60 (m, 13H).

PREPARATION 139 4- (3-Chloro-4-fluoropheniD-3-methylbromobenzene Obtained in the form of a colorless oil (20%), from the title compound of preparation 57 and 3-chloro-4-fluorophenylboronic acid, using the procedure of preparation 109. d (CDCl 3): 2.22 (s, 3H ), 7.04 (d, 1 H), 7.10-7.20 (m, 2H), 7.28-7.39 (m, 2H), 7.42 (s, 1 H).

PREPARATION 140 4-r4- (3-Chloro-4-fluoropheniD-3-methylphenyl-1-4-hydroxypiperidine-1-t-butylcarboxylate) Obtained in the form of a colorless gum (39%), from the title compound of preparation 139 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. Found: C, 65.96; H, 6.64; N, 3.36. C23H27CIFNO3 requires C, 65.79; H, 6.48; N, 3.34%. d (CDCl 3): 1.50 (s 9H), 1.76 (s, 9H), 2.04 (m, 2H), 2.28 (s, 3H), 3.28 (t, 2H), 4.07 (m, 2H), 7.16-7.20 ( m, 3H), 7.30-7.40 (m, 3H). LRMS (APCl): 420 (M + H) +.

PREPARATION 141 4-r4- (3-Chloro-4-fluoropheniD-3-methylphenin-1, 2,3,6-tetrahydropyridine Obtained as a pale yellow oil (99%), from the title compound of preparation 140 and trifluoroacetic acid, using the procedure of preparation 35. d (CDCl 3): 2.26 (s, 3H), 2.50 (m , 2H), 3.12 (t, 2H), 3.56 (m, 2H), 6.16 (sa, 1 H), 7.15 (m, 3H), 7.27 (m, 2H), 7.35 (d, 1 H). LRMS (APCi): 302 (M + H) +.

PREPARATION 142 2-f4-r4- (3-Chloro-4-fluoropheniP-3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) Obtained as a colorless solid (37%), m.p. 125-126 ° C, from the title compound of preparation 141 and methyl chlorosulfonylacetate, using the procedure of preparation 61. Found: C, 57.46; H, 4.83; N, 3.14. C21H2? CIFNO4S requires C, 57.60; H, 4.83; N, 3.20%. d (CDCl 3): 2.28 (s, 3H), 2.67 (m, 2H), 3.62 (t, 2H), 3.80 (s, 3H), 4. 01 (s, 2H), 4.06 (s, 2H); 6.08 (s a, 1 H), 7.17 (m, 3H), 7.23 (m, 2H), 7.36 (d, 1 H). LRMS (Thermospray): 438 (M + H) +.

PREPARATION 143 4-1, 3-Benzodioxol-5-iP-3-methylbromobenzene Obtained in the form of a colorless oil (34%), from the title compound of preparation 57 and 1,3-benzodioxol-5-ylboronic acid, using the procedure of preparation 109. d (CDCl 3): 2.22 (s) , 3H), 6.00 (s, 2H), 6.70 (d, 1 H), 6.75 (s, 1 H), 6.85 (d, 1 H), 7.06 (d, 1 H), 7.33 (d, 1 H) 7.40 (s, 1 H).

PREPARATION 144 4-r4- 1, 3-Benzodioxol-5-iP-3-methylphen-4-hydroxypiperidine-1-t-butylcarboxylate Obtained in the form of a colorless solid (39%), m.p. 135-138 ° C, from the title compound of preparation 143 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. Found: C, 69.82; H, 7.15; N, 3.44. C 24 H 29 NO 5 requires C, 70.05; H, 7.10; N, 3.40%. d (CDCl 3): 1.50 (s, 9H), 1.76 (m, 2H), 2.04 (m, 2H), 2.29 (s, 3H), 3.28 (t, 2H), 4.04 (m, 2H), 6.00 (s) , 2H), 6.76 (d, 1 H), 6.79 (s, 1 H), 6.87 (d, 1 H), 7.20 (d, 1 H), 7.30 (d, 1 H), 7.37 (s, 1 H) ). LRMS (APCl): 412 (M + H) +.

PREPARATION 145 4-r4- (1,3-Benzodioxol-5-iP-3-methylphen-1, 2,3,6-tetrahydropyridine) Obtained as a pale yellow solid (96%), m.p. 105-108 ° C, from the title compound of preparation 144 and trifluoroacetic acid, using the procedure of preparation 35. d (CDCl 3): 2.28 (s, 3H), 2.50 (m, 2H), 3.12 (t , 2H), 3.56 (m, 2H), 6.00 (s, 2H), 6.17 (sa, 1 H), 6.75-6.82 (m, 2H), 6.87 (d, 1 H), 7.17 (d, 1 H) , 7.22-7.30 (m, 2H). LRMS (APCl): 294 (M + H) +.

PREPARATION 146 2-T4-r4-, 1, 3-Benzodoloxol-5-iP-3-methylphenip-1, 2,3,6-tetr abidropyridin-1-ylsulphon-methyl-acetate Obtained as a colorless solid (57%), m.p. 133-134 ° C, from the title compound of preparation 145 and methyl chlorosulfonylacetate, using the procedure of Preparation 61. Found: C, 61.15; H, 5.41; N, 3.15. C22H23NO6S requires C, 61.52; H, 5.40; N, 3.26%. d (CDCI3): 2.28 (s, 3H), 2.67 (m, 2H), 3.62 (t, 2H), 3.80 (s, 3H), 4.01 (s, 2H), 4.06 (s, 2H), 6.00 (s) , 2H), 6.08 (sa, 1 H), 6.78 (m, 2H), 6.87 (d, 1 H), 7.20 (m, 2H), 7.26 (m, 1 H).

PREPARATION 147 4- (2-FluoropheniD-3-methylbromobenzene Obtained in the form of a colorless oil (33%), from the title compound of preparation 57 and 3-fluorophenylboronic acid, using the procedure of preparation 109. d (CDCl 3): 2.20 (s, 3H), 7.06- 7.25 (m, 4H), 7.30-7.40 (m, 2H), 7.43 (s, 1 H).

PREPARATION 148 4-r4- (2-FluoropheniD-3-methylphenol l-4-hydroxypiperidine-1-t-butylcarboxylate) Obtained as a pale yellow amorphous solid (53%), from the title compound of preparation 147 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of preparation 43. Found: C 71.39; H, 7.37; N, 3.69. C23H28FNO3 requires C, 71.67; H, 7.32; N, 3.63%. d (CDCl 3): 1.50 (s, 9H), 1.78 (d, 2H), 2.04 (m, 2H), 2.22 (s, 3H), 3. 28 (t, 2H), 4.04 (m, 2H), 7.12 (t, 1 H), 7.16-7.26 (m, 3H), 7.35 (m, 2H), 7.40 (s, 1 H). LRMS (APCl): 386 (M + H) +.

PREPARATION 149 4-r4- (2-Fluorophenyl) -3-methylphenin-1, 2,3,6-tetrahydropyridine Obtained as a pale yellow oil (93%), from the title compound of preparation 148 and trifluoroacetic acid, using the procedure of preparation 35. d (CDCl 3): 1.80 (br, 1 H), 2.21 ( s, 3H), 2.50 (m, 2H), 3.12 (t, 2H), 3.57 (m, 2H), 6.19 (sa, 1 H), 7.10-7.38 (m, 7H). LRMS (APCl): 268 (M + H) +.

PREPARATION 150 2-4-r4- (2-FluoropheniP-3-methylphenin-1,2,3,6-tetrahydropyridin-1-ylsulfonyl methyl acetate) Obtained as a colorless solid (30%), m.p. 128-130 ° C, from the title compound of preparation 149 and methyl chlorosulfonylacetate, using the procedure of preparation 61. Found: C, 62.57; H, 5.71; N, 3.32. C ^ H ^ FNO ^ requires C, 62.52; H, 5.50; N, 3.47%. d (CDCl 3): 2.21 (s, 3H), 2.69 (m, 2H), 3.63 (t, 2H), 3.81 (s, 3H), 4. 01 (s, 2H), 4.10 (m, 2H), 6.09 (s a, 1 H), 7.14 (t, 1 H), 7.17-7.30 (m, 5H), 7.35 (m, 1 H). LRMS (APCl): 404 (M + H) +.

PREPARATION 151 2- (4-r4- (3,4-DimetoxifeniP-3-methylphenin-1, 2,3,6-tetrahydropyridin-1-ylsulfonium methyl acetate) Obtained as a colorless gum (76%), from the title compound of preparation 37 and 3,4-dimethoxyphenylboronic acid, using the procedure of preparation 41. Found: C, 61.71; H, 6.10; N, 2.91. C23H27NO6S requires C, 62.01; H, 6.11; N, 3.14%. d (CDCl 3): 2.30 (s, 3H), 2.67 (m, 2H), 3.62 (t, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 3.92 (s, 3H), 4.02 (s) , 2H), 4.10 (m, 2H), 6.08 (sa, 1 H), 6.83-6.97 (m, 3H), 7.20-7.30 (m, 3H). LRMS (APCl): 446 (M + H) +.

PREPARATION 152 2-. { 4-r4- (lndan-5-iD-3-methylpheniP-1, 2,3,6-tetrahydrop8ridin-1-ylsulphon-methyl) Obtained as a pale yellow solid (75%), from the title compound of preparation 37 and indan-5-ylboronic acid (WO-A-97/32853), using the procedure of preparation 41. d (CDCI3): 2.10 (m, 2H), 2.30 (s, 3H), 2.69 (m, 2H), 2.98 (m, 4H), 3.62 (t, 2H), 3.82 (s, 3H), 4.02 (s, 2H), 4.10 (m, 2H), 6.08 (sa, 1 H), 7.09 (d, 1 H), 7.18-7.35 (m, 5H). LRMS (Thermospray): 443 (M + NH 4) +.

PREPARATION 153 2-f4-r3-MetHl-4- (3-trifluoromethoxyphen) 3-phenyl-1,2,3,6-tetrahydropyridin-1-ylsulphon-methyl-acetate Obtaining as an amorphous solid (28%), from the title compound of preparation 37 and 3-trifluoromethoxypheniomeric acid (WO-A-96/13500, using the procedure of preparation 41. d (CDCl 3): 2.30 (s, 3H), 2.69 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 4.02 (s, 2H), 4.10 (m, 2H), 6.10 (sa, 1 H), 7.15-7.30 (m, 6H), 7.43 (t, 1 H), LRMS (APCl): 471 (M + H) +.

PREPARATION 154 4-Phenyl-3-trifluoromethylbromobenzene Obtained in the form of an orange oil (37%), from 4-bromo-2-trifluoromethylaniline, using the procedure of preparation 42. Found: C, 51.70; H, 2.61. C13H8BrF3 requires C, 51.86; H, 2.68%. d (CDCl 3): 7.19 (d, 1 H), 7.26 (m, 2 H), 7.38 (m, 3 H), 7.65 (d, 1 H), 7. 86 (s, 1 H).

PREPARATION 155 4-Hydroxy-4- (4-phenyl-3-trifluoromethylpheniDpiperidine-1-t-butylcarboxylate) Obtained as a colorless solid (53%), m.p. 153-155 ° C (in hexane), from the title compound of preparation 154 and t-butyl 4-oxopiperidine-1-carboxylate, using the procedure of Preparation 43. Found: C, 65-34; H, 6.22; N, 3.26. C23H26F3NO3 requires C, 65.55; H, 6.22; N, 3.32%. d (CDCl 3): 1.50 (s, 9H), 1.78 (d, 2H), 2.04 (m, 2H), 3.28 (t, 2H), 4.10 (m, 2H), 7.28-7.42 (m, 6H), 7.66 (d, 1 H), 7.88 (s, 1 H). LRMS (Thermospray): 422 (M + H) +.

PREPARATION 156 4- (4-Phenyl-3-trifluoromethylphenid-1, 2,3,6-tetrahydropyridine Obtained as a pale brown oil (90%), from the title compound of preparation 155 and p-toluenesulfonic acid, using the procedure of preparation 70. d (CDCl 3): 2.50 (m, 2H), 3.17 (t, 2H), 3.58 (m, 2H), 6.27 (sa, 1 H), 7.25-7.42 (m, 6H), 7.56 (d, 1 H), 7.75 (s, 1 H). LRMS (Thermospray): 304 (M + H) +.

PREPARATION 157 methyl 2-r4- (4-phenyl-3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridin-1-ylsulphonyl acetate Obtained as a pale yellow oil (59%), from the title compound of preparation 156 and methyl chlorosulfonylacetate, using the procedure of preparation 37. d (CDCl 3): 2.71 (m, 2H), 3.66 ( t, 2H), 3.82 (s, 3H), 4.02 (s, 2H), 4.12 (m, 2H), 6.18 (sa, 1 H), 7.28-7.42 (m, 6H), 7.55 (d, 1 H) 7.72 (s, 1 H). LRMS (APCl): 440 (M + H) +.

PREPARATION 158 2,2-Dimethyl, 3-benzodioxol-5-boronic acid Obtained as a green solid (47%), m.p. 174-176 ° C, from 5-bromo-2,2-dimethyl-1,3-benzodioxol (GB-A-2187452) trimethyl borate, using the procedure of preparation 101. d (DMSOd6): 1.60 (s, 6H), 6.77 (d, 1 H), 7.17 (s, 1 H), 7.28 (d, 1 H), 7.80 (s, 2H).

PREPARATION 159 methyl 2-f4-r4- (2,2-Dimethyl-1,3-benzodioxol-5-iD-3-methylphenin-1,2,3,6-tetrahydropyridin-1-ylsulfoniD-2-methylpropanoate) Obtained in the form of a colorless amorphous solid (33%), from the title compounds of preparation 158 and of preparation 40, using the procedure of preparation 41, but with etherhexane (1: 4) as eluent. d (CDCl 3): 1.67 (s, 6H), 1.73 (s, 6H), 2.30 (s, 3H), 2.65 (m, 2H), 3.62 (t, 2H), 3.80 (s, 3H), 4.13 (m , 2H), 6.05 (sa, 1 H), 6.70-6.78 (m, 3H), 7.19-7.30 (m, 3H). LRMS (Thermospray): 486 (M + H) +.

PREPARATION 160 2-. { Methyl 4-r4- (2,2-Dimethyl-1,3-benzodioxol-5-yl) -3-methylphenylmethyl-1-ylsulfoniD-2-methylpropanoate Obtained as a colorless amorphous solid (96%), from the title compound of preparation 159, using the procedure of preparation 90. d (CDCl 3): 1.64 (s, 6H), 1.72 (s, 6H) , 1.78-1.88 (m, 4H), 2.27 (s, 3H), 2.63 (m, 1 H), 3.09 (m, 2H), 3.81 (s, 3H), 3.98 (d, 2H), 6.68-6.77 ( m, 3H), 7.07 (m, 2H), 7.17 (d, 1 H).

LRMS (Thermospray): 488 (M + H) +.

PREPARATION 161 Acid 2-. { 4-r4- (2,2-Dimet? L-1, 3-benzodioxol-5-iD-3-methylphenylpiperidin-1-ylsulfoniD-2-methylpropanoic acid Obtained as a colorless amorphous solid (47%), from the title compound of preparation 160, using the procedure of preparation 79. d (CDCl 3): 1.67 (s, 6H), 1.72 (s, 6H) , 1.78-1.88 (m, 4H), 2.27 (s, 3H), 2.63 (m, 1 H), 3.10 (m, 2H), 4.00 (d, 2H), 6.68-6.77 (m, 3H), 7.05 (m, 2H), 7.16 (d, 1 H). LRMS (Thermospray): 474 (M + H) +.

PREPARATION 162 1, 2-Dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iD-benzoimidazole A mixture of 5-bromo-1,2-dimethylbenzoimidazole (J. Chem. Soc, 1931, 1143; 2 g, 8.88 mmol), 4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (2.06) ml, 14 mmol), triethylamine (3.9 ml, 28 mmol), [1, 1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) (224 mg, 0.27 mmoless) and anhydrous 1,4-dioxane (35 mg) , under nitrogen, stirred under reflux for 44 hours, then allowed to cool and partitioned between ethyl acetate and water. This mixture was filtered to remove the palladium residues, the layers were separated and the aqueous phase was washed with ethyl acetate. The combined organic solutions were dried (MgSO) and evaporated under reduced pressure, and then the residue was purified by flash chromatography, using methanol: dichloromethane (1: 3) as eluent, followed by trituration with diisopropyl ether, to give the title compound. title (356 mg, 15%) as a colorless amorphous solid. d (CDCl 3): 1.37 (s, 12H), 2.60 (s, 3H), 3.72 (s, 3H), 7.27 (d, 1 H), 7.70 (d, 1 H), 8.15 (s, 1 H). LRMS (Thermospray): 273 (M + H) +.

PREPARATION 163 2-4-r4- (1,2-Dimethylbenzoimidazol-5-yl) -3-methylphenin-1,2,3,6-tetrahydropyrid8n-1-ylsulfon-D-2-methylpropanoate methyl To a stirred solution of the title compound of preparation 40 (400 mg, 0.96 mmol) in degassed 1,2-dimethoxyethane (20 ml) was added the title compound of preparation 162 (351 mg, 1.29 mmol), fluoride cesium (380 mg, 2.5 mmol), tri-o-tolylphosphine (31 mg, 0.1 mmol) and tris (dibenzylideneacetone) dipalladium (0) (47 mg, 0.05 mmol), then the reaction mixture was heated to reflux for approximately 3 minutes. hours, under nitrogen. Because of the limited solubility, a portion of 1-methyIpyrrolidin-2-one (4 ml) was added and the resulting mixture was heated to reflux for 9 hours, then allowed to cool to room temperature, diluted with ethyl acetate , washed with water, dried (MgSO) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of methanol: dichloromethane (0: 100 to 2:98), followed by crystallization from diisopropyl ether, to give the title compound (261 mg, 56%) in form of a colorless solid, mp 148-151 ° C. d (CDCl 3): 1.67 (s, 6H), 2.30 (s, 3H), 2.63 (s, 3H), 2.67 (m, 2H), 3.63 (m, 2H), 3.77 (s, 3H), 3.81 (s) , 3H), 4.13 (m, 2H), 6.07 (sa, 1 H), 7.19-7.32 (m, 5H), 7.62 (s, 1 H). LRMS (Thermospray): 482 (M + H) +.

PREPARATION 164 methyl 2-f4-r4- (1, 2-D -methylbenzoimidazol-5-yl) -3-methylphenylmethyl-1-ylsulfoniD-2-methylpropanoate Obtained as a pale yellow gum (32%), from the title compound of preparation 163, using the procedure of preparation 90, with the exception that the hydrogenation was performed at 414 kPa (60 psi) and at 70 ° C for 24 hours and methanol: dichloromethane (3:97) was used as the eluent of the cormatography. d (CDCl 3): 1.65 (s, 6H), 1.78-1.88 (m, 4H), 2.27 (s, 3H), 2.62 (s, 3H), 2.65 (m, 1 H), 3.09 (m, 2H), 3.75 (s, 3H), 3.81 (s, 3H), 3.97 (m, 2H), 7.05-7.32 (m, 5H), 7.61 (s, 1 H).

LRMS (Thermospray): 484 (M + H) +.

PREPARATION 165 Acid 2-. { 4-f4- (1, 2-Dimethylbenzoamidazol-5-iD-3-methylphenidiperpiperidin-1-ylsulfoniD-2-methylpropanoic acid Obtained as a colorless solid (88%), m.p. 125-127 ° C, from the title compound of preparation 164, using the procedure of preparation 91. d (DMSOd6): 1.50 (s, 6H), 1.62 (m, 2H), 1.82 (m, 2H) , 2.20 (s, 3H), 2.70 (m, 1 H), 2.78 (s, 3H), 3.08 (t, 2H), 3.81 (d, 2H), 3.92 (s, 3H), 7.10-7.20 (m, 3H), 7.46 (d, 1 H), 7.65 (s, 1 H), 7.88 (d, 1 H). LRMS (Thermospray): 471 (M + H) +.

PREPARATION 166 Acid 2-.4- (4-Bromo-3-methylphenyl) -1, 2.3.6-tetrahSdropiridin-1 -8-sulfonyl-2-methylpropanoic acid A 1 M aqueous solution of sodium hydroxide (4.2 ml, 4.2 mmol) was added to a stirred solution of the title compound of the preparation 40 (500 mg, 1.2 mmol) in a mixture of methanol (3 ml) and 1,4-dioxane (3 ml). The resulting solution was heated at 50 ° C for 2 hours, and then allowed to cool to room temperature and poured into ethyl acetate. The mixture was washed with 2M hydrochloric acid, then the organic phase was dried (MgSO4) and evaporated under reduced pressure to yield the title compound (439 mg, 91%) as a colorless amorphous solid. d (CDCl 3): 1.67 (s, 6H), 2.40 (s, 3H), 2.58 (m, 2H), 3.64 (t, 2H), 4.11 (m, 2H), 6.00 (sa, 1 H), 7.03 ( d, 1 H), 7.21 (d, 1 H), 7.48 (d, 1 H). LRMS (Electrospray): 425 (M + Na) +.

PREPARATION 167 N-Benzyloxy 2-r4- (4-bromo-3-methylphenD-1, 2,3,6-tetrahydropyridin-1-ylsulfonin-2-methylpropionamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (274 mg, 1.43 mmol) was added to a stirred mixture of the title compound of preparation 166 (439 mg, 1.19 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmoles) O-benzylhydroxylamine hydrochloride (200 mg, 1.25 mmol), N-methylmorpholine (0.29 ml, 2.62 mmol) and anhydrous dichloromethane (8 ml). The reaction mixture was stirred at room temperature for 18 hours, diluted with dichloromethane, washed sequentially with dilute aqueous citric acid, water and aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to flash chromatography, using an elution gradient of methane-dichloromethane (1: 99 to 2:98), to give the title compound (553 mg, 91%) as a colorless oil. d (CDCl 3): 1.60 (s, 6H), 2.40 (s, 3H), 2.53 (m, 2H), 3.58 (t, 2H), 4.04 (m, 2H), 4.93 (s, 2H), 5.95 (s) , 1 H), 7.00 (d, 1 H), 7.20 (s, 1 H), 7.36-7.50 (m, 6H), 9.20 (s, 1 H). LRMS (Thermospray): 531 (M + Na) +.

PREPARATION 168 N -Benzyloxy 2-f4-r4- (3-cyanopheniD-3-methylphenyl1-1, 2,3,6-tetrahydropyridin-1-ylsulfoniD-2-methylpropionamide Obtained as an amorphous solid (30%), from the title compound of preparation 167 and 3-cyanophenylboronic acid (Arch. Pharm. 1996, 329, 73), using the procedure of preparation 41, but using a Elution gradient of ethyl acetate: pentane (10:90 to 50:50) for the chromatographic purification step. d (CDCl 3): 1.60 (s, 6H), 2.24 (s, 3H), 2.61 (m, 2H), 3.60 (t, 2H), 4. 08 (m, 2H), 4.95 (s, 2H), 6.03 (sa, 1 H), 7.15 (d, 1 H), 7.25 (m, 2H), 7.40 (m, 5H), 7.55 (m, 2H) 7.62 (m, 2H), 9.20 (s, 1 H). LRMS (Thermospray): 530 (M + H) +.

PREPARATION 169 3-Ethoxy-5- (tri-n-butylstannandPyridine A stirred mixture of 3-bromo-5-ethoxypyridine (Rec.Trav. Chim., 1948, 67, 377, 930 mg, 4.6 mmol), bis- (tri-n-butyltin) (3.46 ml, 6.9 mmol) , tri-o-tolylphosphine (420 mg, 1.37 mmol), palladium (II) acetate (78 mg, 0.35 mmol), triethylamine (1.23 mL, 8.84 mmol) and acetonitrile (15 mL), under nitrogen, was heated to reflux for 18 hours and then allowed to cool. The solution was separated from the black tar residue by decantation and evaporated under reduced pressure, then the resulting residue was subjected to flash chromatography, using an elution gradient of ethyl acetate: pentane (0: 100 to 5:95), to produce the title compound (600 mg, 32%) as a colorless oil. d (CDCl 3): 0.90 (t, 9H), 1.08 (t, 6H), 1.30-1.42 (m, 6H), 1.42 (t, 3H), 1.58 (m, 6H), 4.08 (q, 2H), 7.25 (s, 1 H), 8.17 (s, 1 H), 8.19 (s, 1 H).

PREPARATION 170 2-f4-r4- (3-Ethoxypyridin-5-iD-3-methylphenin) .2,3,6-tetrahydropyridin-1-ylsulfoniD-2-methylpropanoate methyl Obtained in the form of a gum (30%), from the title compounds of preparation 169 and of preparation 40, using the procedure of preparation 89. d (CDCl 3): 1.46 (t, 3H), 1.68 (s, 6H), 2.28 (s, 3H), 2.65 (m, 2H), 3.63 (m, 2H), 3.81 (s, 3H), 4.10 (m , 4H), 6.08 (sa, 1 H), 7.12 (s, 1 H), 7.20 (d, 1 H), 7.28 (m, 2H), 8.18 (s, 1 H), 8.28 (s, 1 H) . LRMS (APCl): 459 (M + H) +.

PREPARATION 171 2-f4-r4- (3-Ethoxypyridin-5-iD-3-methylphenid-piperidin-1-ylsulfoniD-2-methylpropanoate methyl) Obtained as a colorless solid (88%), m.p. 1 10-1 12 ° C, from the title compound of preparation 170, using the procedure of Preparation 66. Found: C, 62.24; H, 6.96; N, 5.97. C2 H32N2O5S requires C, 62.59; H, 7.00; N, 6.08%. d (CDCl 3): 1.44 (t, 3H), 1.67 (s, 3H), 1.82 (m, 2H), 1.89 (m, 2H), 2. 28 (s, 3H), 2.67 (m, 1 H), 3.08 (m, 2H), 3.81 (s, 3H), 3.96 (m, 2H), 4.12 (q, 2H), 7.10-7.20 (m, 4H) ), 8.17 (s, 1 H), 8.27 (s, 1 H). LRMS (Thermospray): 461 (M + H) +.

PREPARATION 172 Acid 2-. { 4-r4- (3-Ethoxypyridin-5-iD-3-methylphenid-piperidin-1-ylsulfoniD-2-methylpropanoic acid Obtained in the form of a colorless solid (98%), m.p. 202-203 ° C, from the title compound of preparation 171, using the procedure of preparation 91. d (CDCl 3): 1.44 (t, 3H), 1.70 (s, 6H), 1.80 (m, 4H), 2.18 (s, 3H), 2.60 (m, 1 H), 3.08 (m, 2H), 3.96 (m, 2H), 4.13 (q, 2H), 7.05-7.15 (m, 3H), 7.26 ( darkened by CHC13, 1 H), 8.22 (s, 1 H), 8.33 (s, 1 H). LRMS (Thermonebuiization): 447 (M + H) + - PREPARATION 173 3- (2-Hydroxyethoxy) bromobenzene Anhydrous potassium carbonate (18.0 g, 130 mmol) was added to a stirred solution of 3-bromophenol (6.0 mL, 52 mmol) in anhydrous dimethylformamide (120 mL), the mixture was heated to reflux for 45 minutes and then allowed to cool to room temperature. approximately 50 ° C. 2-Bromoethanol (3.1 ml, 43 mmol) was added and the reaction mixture was heated to reflux for a further 2 hours, before being allowed to cool slowly to room temperature. The resulting mixture was poured into ether, the mixture was washed with water and the organic phase was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography, using an elution gradient of pentane: ethyl acetate (10: 1 to 5: 1) to give the title compound as a colorless oil (6.4 g, 57%). d (CDCl 3): 1.98 (t, 1 H), 3.95 (t, 2H), 4.07 (m, 2H), 6.87 (d, 1 H), 7.08-7.17 (m, 3H).

PREPARATION 174 3- (2-t-Butyldiphenylsilyloxyethoxy) bromobenzene Triethylamine (1.7 mL, 9.2 mmol) was added to a stirred solution of the title compound of Preparation 173 (1.8 g, 8.2 mmol) in anhydrous dimethylformamide (30 mL) and the mixture was cooled to about 0 ° C. T-Butyldiphenylsilyl chloride (2.4 ml, 9.2 mmol) was added, the reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for approximately 16 hours, and then poured into ether. The resulting mixture was washed with 0.5 M hydrochloric acid and then the aqueous washings were back extracted with ether. The combined organic solutions were washed with water, dried (MgSO4) and evaporated under reduced pressure, then the residue was purified by flash chromatography, using an elution grad of pentane: dichloromethane (3: 1 to 2: 1 to 1: 1). ), to provide the title compound as a colorless oil (2.2 g, 62%). d (CDCl 3): 1.10 (S, 9H), 4.00 (t, 2H), 4.08 (t, 2H), 6.82 (m, 1 H), 7.03-7.29 (m, 4H), 7.38-7.48 (m, 5H) ), 7.71 (m, 4H).

LRMS (Thermospray): 474 (M + NH4) + PREPARATION 175 3- (2-t-Butyldiphenylsilyloxyethoxy) phenylboronic acid N-Butyllithium (2.3 ml of 2.5 M solution in hexane, 5.9 mmol) was added to a stirred solution of the title compound of preparation 174 (2.5 g, 5.6 mmol) in anhydrous tetrahydrofuran (25 ml), maintaining the temperature internal temperature below -60 ° C. The reaction mixture was stirred at about -70 ° C for 1 hour, then trimethyl borate (4.4 ml, 38 mmol) was added dropwise, again maintaining the internal temperature below -60 ° C. The reaction mixture was stirred at -70 ° C for 30 minutes, allowed to warm slowly to room temperature, quenched with a mixture of concentrated hydrochloric acid (12.5 ml) and water (30 ml), and then ether (30 ml) was added. ml). The layers were separated and the aqueous layer was washed with ether. The combined organic solutions were dried (MgSO) and evaporated under reduced pressure and then the residue was purified by flash chromatography, using ether as eluent, to give the title compound as a colorless oil (1.14 g, 50%). d (CDCl 3): 1.08 (s, 9H), 4.06 (t, 2H), 4.19 (t, 2H), 7.12 (m, 1 H), 7. 36-7.45 (m, 8H), 7.74 (m, 6H), 7.82 (m, 1 H). LRMS (Thermonebuiization): 438 (M + NH4) +.

PREPARATION 176 2-.4-r4- (3-r2-t-Butyl-phenylsilyloxyethoxy-1-methyl) -3-methylphenol-1,2,3,6-tetrahydropyridin-1-ylsulfoniD-2-methylpropionate methyl Obtained in the form of an oil (73%), from the title compounds of preparation 175 and of preparation 40, using the procedure of preparation 41, with the exception that the purification by flash chromatography involved elution in pentane grad: ethyl acetate (10: 1 to 5: 1). d (CDCl 3): 1.07 (s, 9H), 1.67 (s, 6H), 2.28 (s, 3H), 2.65 (m, 2H), 3.62 (m, 2H), 3.81 (s, 3H), 4.02 (m , 2H), 4.08-4.16 (m, 4H), 6.08 (sa, 1 H), 6.90 (m, 3H), 7.19-7.42 (m, 10H), 7.71 (d, 4H). LRMS (Thermospray): 438 (M + NH4) + PREPARATION 177 2-4-r4- (3-r2-t-Butyldiphenylsilyloxyethoxyphene-3-methylphenylpiperidin-1-ylsulfoniP-2-methylpropanoate methyl) Obtained in the form of a colorless oil (88%), from the title compound of preparation 176, using the procedure of preparation 66. d (CDCl 3): 1.07 (s, 9H), 1.67 (s, 6H), 1.80-1.95 (m, 4H), 2.28 (s, 3H), 2.65 (m, 1 H), 3.10 (t, 2H), 3.81 (s, 3H), 3.95 (m, 2H), 3.97 (t, 2H) ), 4.1 1 (t, H), 6.86 (m, 3H), 7.10 (m, 2H), 7.19 (d, 1 H), 7.34-7.47 (m, 6H), 7.71 (d, 4H). LRMS (Thermospray): 438 (M + NH4) +.

PREPARATION 178 Acid 2-f4-r4- (3-r2-t-Butyldiphenylsilyloxyethoxy-1-phenyl-3-methylphenylpiperidin-1-ylsulfonyl-P-2-methylpropanoic acid Obtained in the form of a colorless foam (88%), from the title compound of preparation 177, using the procedure of preparation 79, but carrying out the reaction at room temperature. (CDCI3): 1 -07 (s, 9H), 1.67 (s, 6H), 1.78-1.95 (m, 4H), 2.27 (s, 3H), 2.65 (m, 1 H), 3.1 1 (t, 2H) ), 3.97 (t, 2H), 4.02 (m, 2H), 4.1 1 (t, 2H), 6.86 (m, 3H), 7.10 (m, 2H), 7.18 (d, 1 H), 7.30 (d, 1 H), 7.34-7.43 (m, 6H), 7.71 (d, 4H).

Biological activity The following table illustrates the in vitro activities for a series of compounds of the invention as inhibitors of MMP.

PICTURE = no results

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (I): a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either of the two entities, wherein the dotted line represents an optional bond; A is C or CH; B is CH2, O or is absent; each of R1 and R2 is independently selected from hydrogen, C1 to C6 alkyl optionally substituted with C1 to C4 alkoxy or phenyl, and C1 to C6 alkenyl; or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group that optionally incorporates a bond with a heteroatom selected from O, SO, SO2 and NR6 or which is optionally condensed with benzene; R3 is hydrogen, halo, R7 or OR7; R 4 is hydrogen, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, trifluoromethyl or halo; R 6 is hydrogen or C 1 to C alkyl; R7 is a monocyclic or bicyclic ring system, selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, wherein any of the ring systems is optionally substituted with one or two substituents selected from Ci to C4 alkyl optionally substituted by Ci to C alkoxy or hydroxy, C?-C4 alkoxy optionally substituted by Ci to C4 alkoxy or hydroxy, CiX alkylthio C4, trifluoromethyl, trifluoromethoxy, halo and cyano; m is 1 or 2; and n is 0, 1 or 2; with the proviso that B is not O when A is C.

2. A compound according to claim 1, wherein B is absent; R1 is hydrogen, C1 to C4 alkyl optionally substituted with methoxy or phenyl, or Ci to C5 alkenyl; R2 is hydrogen or Ci to C4 alkyl; or R1 and R2, together with the carbon atom to which they are attached, form a C4 to C5 cycloalkyl group which optionally incorporates a bond with a heteroatom selected from O and NR6 or which is optionally condensed with benzene; R3 is selected from 4-phenyl, 4-pyridinyl, 4- (indan-5-yl), 4- (2,3-dihydrobenzofuran-5-yl), 4- (quinolin-3-yl), 4- (bezodioxol) -5-i) and 4- (benzoimidazo-5-yl), either of which being optionally substituted with one or two substituents selected from C1 to C3 alkyl optionally substituted by methoxy or hydroxy, C1 to C3 alkoxy optionally substituted by methoxy or hydroxy, methylthio, trifluoromethyl, trifluoromethoxy, fluorine, chlorine and cyano; R 4 is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluorine or chlorine; R6 is methyl; m is 2; and n is 1.

3. A compound according to claim 2, wherein R1 is hydrogen, methyl, ethyl, 2-methylprop-1-yl, but-1-yl, 2-methoxyethyl, benzyl, 3-phenylpropyl. -1-yl, allyl, 2-methylallyl, 3,3-dimethylallyl; R2 is hydrogen, methyl or ethyl; or R1 and R2, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl, 1-methylpiperidin-4,4-diyl or indan-2,2-diyl group; R3 is 4-phenyl, 4- (2-methylphenyl), 4- (3-methylphenyl), 4- (3-ethylphenyl), 4- [3- (prop-2-yl) phenyl], 4- ( 3,5-dimethylphenyl), 4- (3-methoxymethylphenyl), 4- (3-hydroxymethylphenyl), 4- (2-methoxyphenyl), 4- (3-methoxyphenyl), 4- (3-ethoxyphenyl), 4 - (4-ethoxyphenyl), 4- [3- (prop-1-oxy) phenyl], 4- [3- (prop-2-oxy) phenyl], 4- [4- (prop-2-oxy) phenyl ! o], 4- (3,4-dimethoxyphenyl), 4- [3- (2-methoxyethoxy) phenyl], 4- [3- (2-hydroxyethoxyl) phenyl], 4- (3-methylthiophenyl), 4- (3-trifluoromethylphenyl), 4- (3-trifluoromethoxyphenyl), 4- (2-fluorophenyl), 4- (3-chloro-4-fluorophenyl), 4- (3-cyanophenyl), 4- (pyridin-2-yl) ), 4- (pyridin-3-yl), 4- (pyridin-4-yl), 4- (6-ethoxypyridin-2-yl), 4- (5-ethoxypyridin-3-yl), 4- (indan -5-yl), 4- (2,3-dihydrobenzofuran-5-yl), 4- (quinolin-3-yl), 4-benzodioxol-5-yl), 4- (2,2-dimethylbenzodioxol-5-) Lo) and 4- (1, 2-dimethylbenzoimidazol-5-yl); and R 4 is hydrogen, 2-methyl, 3-methyl, 3-ethyl, 3-methoxy, 3-trifluoromethyl, 3-fluoro or 3-chloro.

4. A compound according to claim 3, wherein both R1 and R2 are hydrogens or methyl groups or, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4.4- group. diyl or 1-methylpiperidin-4,4-diyl; R3 is 4-phenyl, 4- (3-methoxyphenyl), 4- (3-ethoxyphenyl), 4- [3- (2-methoxyethoxy) phenyl], 4- [3- (2-hydroxyethoxy) phenol] 4- (6-ethoxypyridin-2-yl); and R 4 is 3-methyl or 3-methoxy.

5. A compound according to claim 4, wherein the compound of formula (I) is selected from N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methylphenyl] -1, 2,3,6-tetrahydropyridin-1-ylsulfonyl-acetamide, N-hydroxy-2-. { 4- [4- (3-Ethoxyphenyl) -3-methyphenyl] -1,2,3,6-tetrahydropyridin-1-ylsufonyl} -2-methylpropanamide; N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methylphenyl] -piperidin-1-yl-sulphonyl} -2-methylpropanamide; N-hydroxy-1-. { 4- [4- (3-methoxyphenyl) -3-methylphenyl] -piperidin-1-ylsulfonyl} Cyclopentanecarboxamide; N-hydroxy-1-. { 4- [4- (3-methoxyphenyl) -3-methylphenyl] piperidin-1-ylsulfonyl} Cyclobutanecarboxamide; N-hydroxy-2-. { 4- [4- (3-ethoxyphenyl) -3-methoxyphenyl] piperidin-1-ylsulfonyl} -2-methylpropanamide; N-hydroxy-2-. { 4- [4- (6-ethoxypyridin-2-yl) -3-methylphenyl] -piperidin-1-ylsulfonyl} -2-methylpropanamide; N-hydroxy-2-. { 4- [4- (3- [2-methoxyethoxy] phenyl) -3-methylphenyl] piperidin-1-ylsulfonyl} -2-methylpropanamide; and N-hydroxy-2-. { 4- [4- (3- [2-hydroxyethoxy] phenyl) -3-methylphenyl] piperidine-1-ylsulfonyl} -2-methylpropanamide.

6. A pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either of two entities, according to any one of claims 1 to 5, together with a diluent or pharmaceutically acceptable vehicle.

7. A veterinary formulation comprising a compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of two entities, according to any one of claims 1 to 5, together with diluent or veterinarily acceptable vehicle.

8. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either of two entities, according to any one of claims 1 to 5, or a pharmaceutical composition containing any of the above, according to claim 6, for use as a human medicament.

9. A compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of two entities, according to any one of claims 1 to 5, or a veterinary formulation containing any of the above, according to claim 7, for use as a medicament for an animal.

10. The use of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of either of two entities, according to any one of claims 1 to 5, for the manufacture of a medicament. human for the curative or prophylactic treatment of a medical condition for which an MMP inhibitor is indicated. 1. The use of a compound of formula (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either of two entities, according to any one of claims 1 to 5, for the manufacture of an animal medicament for the curative or prophylactic treatment of a medical condition for which an MMP inhibitor is indicated. 12. The use according to claim 10 or claim 11, wherein the inhibitor is an inhibitor of MMP-3. 13. The use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either of two entities, according to any one of claims 1 to 5, for the manufacture of a curative or prophylactic medication of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells. 14. The use of a compound of formula (I), a veterinarily acceptable salt thereof or a veterinarily acceptable solvate of either of two entities, according to any one of claims 1 to 5, for the manufacture of a medicament animal for the curative or prophylactic treatment of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, apoplexy, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, macular degeneration related to age, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells. 15. A compound of formula (II): wherein R5 is hydrogen or Ci to C3 alkyl, and the broken line. A, B, R 1, R 2, R 3, R 4, m and n are as previously defined for formula (I) in claim 1. 16. The use of a compound of formula (I), or a pharmaceutically or veterinarily salt effective thereof, or a pharmaceutically or veterinarily acceptable solvate of either of two entities, according to any one of claims 1 to 5, or a pharmaceutical composition or veterinary formulation containing any of the foregoing, according to claim 6 or claim 7 respectively for the manufacture of a medicament for the treatment or prevention of a medical condition for which an MMP inhibitor is indicated, in a mammal (including a human). 17. The use according to claim 16, wherein the inhibitor is an inhibitor of MMP-3. 18. The use of a compound of formula (I), or a pharmaceutically or veterinarily effective salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either of two entities, according to any of claims 1 to 5, or a pharmaceutical composition or veterinary formulation containing any of the above, according to claim 6 or claim 7, respectively for the manufacture of a medicament for the treatment or prevention of rupture of atherosclerotic plaques, myocardial infarction, heart failure, restenosis, apoplexy, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells, in a mammal (including a human being). 19. A process for the preparation of a compound of formula (I): a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either of the two entities, wherein the dotted line represents an optional bond; A is C or CH; B is CH2, O or is absent; each of R 1 and R 2 is independently selected from hydrogen, C 1 to C alkyl optionally substituted by C 1 to C 4 alkoxy or phenyl, and Ci to C 6 alkenyl; or, together with the carbon atom to which they are attached, form a C3 cycloalkyl group at Ce which optionally incorporates a bond with a heteroatom selected from O, SO, SO2 and NR6 or which is optionally condensed with benzene; R3 is hydrogen, halo, R7 or OR7; R 4 is hydrogen, alkyl d to C 4, alkoxy C 1 to C, trifluoromethyl or halo; R6 is hydrogen or C1 to C4 alkyl; R7 is a monocyclic or bicyclic ring system, selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, wherein any of the ring systems is optionally substituted by one or two substituents selected from C1 to C4 alkyl optionally substituted by C1 to C alkoxy or hydroxy, C1-C4 alkoxy optionally substituted by C1 to C4 alkoxy or hydroxy, C1 to C4 alkylthio , trifluoromethyl, trifluoromethoxy, halo and cyano; m is 1 or 2; and n is 0, 1, or 2; with the proviso that B is not O when A is C; which comprises reacting a compound of formula (II): wherein R5 is hydrogen or Ci to C3 alkyl, and dashed line A, B, R1, R2, R3, R4, and m are as previously defined for formula (I), with hydroxylamine, optionally followed by the formation of a pharmaceutically or veterinarily acceptable salt of the required product, or a pharmaceutically or veterinarily acceptable solvate of either of the two entities. 20. A process according to claim 19, wherein, when R5 is C1 to C3 alkyl, the ester of formula (II) is treated with an excess of up to 3 times of hydroxylamine hydrochloride, in the presence of an amount molar equivalent of a suitable base, in a suitable solvent, at a temperature from about room temperature to about 85 ° C. 21. A process according to claim 20, wherein the base is an alkali metal carbonate or bicarbonate, the solvent is methanol, optionally combined with tetrahydrofuran or dichloromethane with cosolvent, and the reaction temperature is about 65 to approximately 70 ° C. 22. A process according to claim 19, wherein, when R5 is hydrogen, the acid of formula (II) in the presence of 1.1 to 2.0 molecular equivalents of an activating agent and 1.0 to 4.0 molecular equivalents of an amine Tertiary, in a suitable solvent, is treated with an excess of up to about 3 times of hydroxylamine hydrochloride, optionally in the same solvent, at a temperature from about 0 ° C to about room temperature. 23. A process according to claim 22, wherein the agent is actively O- (7-azabenzotriazol-1-yl) -1,1, 3,3-tetramethyluronium hexafluorophosphate (HATU), the tertiary amine is N-ethyldiisopropylamine, the solvent is anhydrous dimethylformamide or anhydrous 1-methylpyrrolidin-2-one and the reaction temperature is about room temperature.