UA72593C2 - Azetidine derivatives, a method for the preparation thereof (variants) and a pharmaceutical composition containing them - Google Patents

Abstract

The invention concerns a compound of formula (I) wherein R represents a CR1R2 radical, C=C(R5)SO2R6 or C=C(R7)SO2alk, their preparation and pharmaceutical compositions containing them. (I)

Description

The present invention relates to derivatives of formula (1): o - - and their salts, their preparation and medicinal products containing them.

In formula (1):

A means the radical СА", С-С(Н5)5О»Нв or С-С(Н7)5Огайк; and either Bi means a hydrogen atom and H2" means the radical -C(Pb)(H") (B0), -C(Av) (Bi) (Al12). -"SO-MA1zVcha,. -"СН2-СО-MVAizAta, -СН2-СО-Ав, -СО-Нв, -СО- cycloalkyl, -50-Нв, -502-Нв, -"СОН)(Виг)(Вв), -"С( OH)(Bev)(alkyl), -С(-МОаиюАв, -С(-МО-СН»-СНеСНг)Ав, -СНе-

CH(Bv)MAzi Azg, -"CHn-C(-MOaiyuBv, -CH(Hv)Mzi Vz2, -"CH(Be)MNZO-"aik, -"CH(VechnNSOMNaik or -CH(Ne chno aik; or Vi means alkyl, МН-А5, cyano group, -5-айКк-Мачв, В17, -"СНа2МайвАч1о or -МАгоВе2з and В" means a radical -

С(АВв(Апи)(Ви2);

Bz and Vy, the same or different, are either alkyl or cycloalkyl; or an aromatic radical selected from phenyl, naphthyl or indenyl, and these aromatic radicals are unsubstituted or substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, hydroxyl, trifluoromethyl groups, trifluoromethoxy groups, -CO-aikK groups, cyano groups, -СООН groups , -

СООайк, -СОМА»2А2з, /-СО-МН-МАгаВ»25, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonyl-alkyl, hydroxyalkyl groups or groups -айк-МагаНгв; or a heteroaromatic radical selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3 ,4-tetrahydroisoquinolyl, thiazolyl, thienyl rings, and these heteroaromatic radicals can be unsubstituted or substituted by one or more halogen atoms, alkyl, hydroxy, hydroxyl, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, -СООН, -СОДайк, -СО-МН- МАгаВгв, -"СОМА22Б23з, -аик-МАгаВ?гв, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkyl, or hydroxyalkyl groups;

B" means a hydrogen atom or alkyl;

Aye means the radical Ag or Nei;

AND? means cycloalkyl, heterocycloalkyl or heterocyclenyl, possibly substituted by -C5O-phenyl;

Ag means hydrogen atom or alkyl;

A" means the radical -СО-МАгвР27, -СООН, -СО0айк, -СНгОН, -МН-СО-МН-айк, -СНо-МНА:в or -МН-СООайк;

Vio means the Ag or Nei radical;

You means the radical -5O02-aiK, -«502-Ag, -5O02-Nei;

Vi means a hydrogen atom or an Ag or Nei radical;

Wiz means a hydrogen or alkyl atom;

Via" means the radical Ag, Nei, -aik-Ag or -aik-Nei;

Wiz means alkyl, cycloalkyl or -alkyl-MAHenzo;

Biv and Bi7, the same or different, represent a hydrogen or alkyl atom, or Biv and Bi7, together with the nitrogen atom to which they are bonded, form a saturated or unsaturated 3-10-membered mono- or biheterocycle, which may contain one or several other heteroatoms selected from oxygen, sulfur and nitrogen atoms, and possibly substituted by one or more alkyl radicals;

Viv means a hydrogen or alkyl atom;

Vito means a hydrogen atom or alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5Oalkyl, -CO-MNayl or -SOOalkyl; or Viv and Vo, together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, which may contain one or more heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and possibly substituted by one or more alkyl radicals; -MAgoB21i means a saturated or unsaturated 3-8-ene monoheterocycle, which may contain another heteroatom selected from oxygen, nitrogen and sulfur atoms;

Bg" and Bgz, the same or different, mean a hydrogen or alkyl atom, or B2g and Bgz, together with the nitrogen atom to which they are connected, form a saturated 3-10-ene mono- or bigheterocycle, which may contain another heteroatom , which is selected from oxygen, sulfur and nitrogen atoms, and may be substituted by one or more alkyl radicals;

Vga and Bo5, the same or different, mean a hydrogen atom or alkyl, -boOaik, cycloalkyl, alkylcycloalkyl, -aiYik-

O-aikK, hydroxyalkyl, or Aga and B25, together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, which may contain another heteroatom selected from oxygen, sulfur atoms and nitrogen, which may be substituted by one or more alkyl radicals, radicals -СОайк, -СОдайк, -СО-МНайк, -С5-mnНайк, oxo groups, hydroxyalkyl radicals, radicals -айк-О-айк, -СО-МН»;

Bzv and 27, the same or different, mean a hydrogen atom or alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, - aik-COo-aik, -aik-Ag, -aik-Nei, Nei, -aik-M(aiKyu)2; Hb and B27 with the nitrogen atom to which they are bonded may also form an unsaturated or saturated 3- to 10-membered mono- or bigheterocycle, which may contain one or more other heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and possibly substituted by one or more alkyl, alkyl radicals, halogen atoms;

АНгв means the radical -СиН2-айк, benzyl, -5ОгайК, -СбОМНайк, -СОайК, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -СО-(СНо ОН;

n equals 1, 2 or 3;

Ho and Bzo, the same or different, mean a hydrogen or alkyl atom, or Po» and Bzo, together with the nitrogen atom to which they are bound, form a saturated 3-10-ene mono- or bigheterocycle, which may contain another heteroatom , which is selected from oxygen, sulfur and nitrogen atoms, and may be substituted by one or more alkyl radicals;

Bzi and Vzg, the same or different, mean a hydrogen atom or an alkyl, Ag or -аИК-Аг, or Bzi and Vzg2 together with the nitrogen atom to which they are connected form a heterocycle selected from among aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl; aikK means sleeper or alkylene radical;

Ag means phenyl or naphthyl, possibly substituted by one or more substituents selected from a halogen atom, alkyl, alkyl, -СО-акК, cyano group, -СООН, -СОДаик, -СОМА22А2з, -СО-МН-МАгаВб, alkylsulfanil )

Her, -O-aik-MH-cycloalkyl or 5O02MH";

It means an unsaturated or saturated 3-10-membered mono- or bigheterocycle containing one or more heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and possibly substituted by one or more halogen atoms, alkyl, alkyl, alkoxycarbonyl groups, groups -

СооМАг2Агз, hydroxyl, hydroxyalkyl groups, oxo groups or 5О2МН groups".

In the definitions above and below, unless otherwise indicated, alkyl and alkylene radicals and moieties and alkyl radicals and moieties have a linear or branched chain and contain 1-6 carbon atoms; cycloalkyl radicals contain 3-10 carbon atoms and heterocycloalkyl and heterocyclenyl radicals contain 3-10 carbon atoms.

Alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl. Aluoxyl radicals can be called methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, pentyloxy-radical.

Cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Heterocycloalkyl radicals are cycloalkyl radicals in which at least one of the carbon atoms is replaced by a heteroatom selected from nitrogen, sulfur, and oxygen atoms. These radicals can be called pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl cycles.

Heterocyclenyl radicals are cycloalkyl radicals in which at least one carbon atom is replaced by a heteroatom selected from oxygen, sulfur, and nitrogen atoms, and which contains at least one carbon-carbon or carbon-nitrogen double bond. Heterocyclenyl radicals can be named 1,2,3,4-tetrahydropyridinyl, 3,b-dihydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6 -tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl and fluorodihydrofuranyl rings. Preferred are 3,6-dihydropyridyl rings.

The term "halogen" means chlorine, fluorine, bromine and iodine.

The following heterocycles can be named from the heterocycles that denote Her: benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4- tetrahydroquinolyl, thiazolyl, thienyl.

When B3 and/or B4 independently represent substituted phenyl, it is preferably mono-, di- or tri-substituted.

When Viv and Vi? together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

When Viv and Vio, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

The heterocycle formed from MAgoB2i is mainly azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazolyl.

When? and Vgz, together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is mainly an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

When ВРп»а and А25, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is mostly an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

When Pb and B27, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

When P2" and ABzo, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

When Bzi and АВзг2, together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, then it is mostly an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl cycle.

Mainly,

A means the radical CA", and either Bi means a hydrogen atom and P" means the radical -C(Pb)(Bi1)(Vig) or C(Hb) (He) (Bo); or Bi means alkyl and P» means the radical -С(Ав)(А11)(А12);

Az and Ba, the same or different, mean either phenyl, unsubstituted or substituted by one or more halogen atoms, alkyl, alkyl, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, -SOMNA22H2z groups, hydroxyalkyl groups or -aiKk-MAhaH25 groups; or a heteroaromatic radical selected from pyridyl, pyrimidine, thiazolyl, thienyl rings, and these heteroaromatic radicals can be unsubstituted or substituted by one or more halogen atoms, alkyl, hydroxy, hydroxyl, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, -СОМА22А2гз, -айк -MAhaVg5 or hydroxyalkyl groups;

Vio means hydrogen atom;

A" means the radical -СО-МАгвР27, -СООайк, -СНгОН, -МН-СО-МН-айк, -"СНо-МНА:в or -"МН-СООайк;

Vio means the Ag or Nei radical;

You means the radical -5O02-aiK, -«502-Ag, -5O02-Nei;

Vi means a hydrogen atom or an Ag or Nei radical;

Bg" and Bgz, the same or different, mean a hydrogen or alkyl atom, or B2g and Bgz, together with the nitrogen atom to which they are connected, form a saturated 3-10-ene mono- or bigheterocycle, which may contain another heteroatom , which is chosen among oxygen, sulfur and nitrogen atoms, may be substituted by one or more alkyl radicals;

Vga and Bo5, the same or different, mean a hydrogen atom or alkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, or Aga and Ag together with the nitrogen atom to which they are connected form a saturated or unsaturated 3-10-membered mono- or bigheterocycle , which may contain another heteroatom selected from oxygen, sulfur, and nitrogen atoms, and may be substituted by one or more alkyl radicals, -COaik, -bOoOaik, -CO-MNaik, -C5-MNaik radicals, oxo groups, -СО-МН groups »g;

Ag means phenyl or naphthyl, possibly substituted by 1 or 2 substituents selected from halogen atom, alkyl, alkyl, -CO-аиК, cyano group, -СОДаик, -СОМА22Б2С, alkylsulfonyl, hydroxyalkyl, -аик-

MAhaBgzv, -MAhaB2g5, hydroxyl, CEz, OSEz, -O-aik-MN-cycloalkyl or 502MH?;

It means a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring.

Compounds of formula (I) can be in the form of enantiomers and diastereoisomers. These optical isomers and their mixtures form part of the invention.

Compounds of the formula (I), in which AB means the radical CB", where Ni means a hydrogen atom and B" means the radical

C(Av)(Achti)(Bi2), in which Nav means a hydrogen atom, Nii means a radical -502-Ag, -502-Nei or -50Ogaik and Bi2 means a hydrogen atom or a radical Ag or Nei, and compounds of formula (I) , in which A means the radical -С-С(Н5)5О2Нев or -С-С(БА7)5ОгаикК, can be obtained according to the following reaction scheme: I am from the village of with a o Vova yah n

Ba-ravens yang,

I-th in her "ek A

Oh -

PP pc

Skowann and and urania in What and in

FROM

, and ra Ko penny p peonivzh, nan I

S von MK dn

Beya di Vo ke "de me i

A; ve soosnesn, syuoosnyen, in SU

M; tu Kt on

Oscillating K-e Ka in Ko, and in these formulas, either Ba means alkyl, Nei or Ag, and AB means a hydrogen atom or an Ag radical or

Her, or Ba means Ag radical or Her and VB means a hydrogen atom or alkyl, or Ba means alkyl and Bb means cycloalkyl, heterocycloalkyl or heterocyclenyl, possibly substituted by -C5O-phenyl, Ne means a hydrogen atom or acetyl, z, Ba, Ag and It has the same values as specified in the case of formula (1).

Reactions "a" and "e" can be carried out only when AB means a hydrogen atom.

Reaction "a" is usually carried out in an inert solvent, such as a simple ether (for example, tetrahydrofuran), in the presence of a strong base, such as tert-butyllithium, n-butyllithium, lithium diisopropylamide, potassium tert-butylate, at a temperature of -707C to -1576.

Dehydration reaction "p" is usually carried out by any dehydration method known to a specialist, which allows dehydrating alcohol to obtain the corresponding alkene. Preferably, the acetyloxy derivative is obtained by exposure to acetyl chloride in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (for example, dichloromethane, chloroform) at a temperature of 5"C to 20"C, then treated with a base such as hydroxide alkali metal (e.g., sodium hydroxide), alkali metal carbonate (e.g., sodium or potassium carbonate), amine such as trialkylamine (e.g., triethylamine), 4-dimethylaminopyridine, diaza-1,8-bicyclo/5,4,01undec -7-ene, at a temperature from 0"C to the boiling temperature of the reaction medium. The intermediate acetyloxy derivative can be isolated or not.

Acetyloxy derivative can also be obtained directly in the reaction medium of reaction "a".

Reduction of "c" is usually carried out in an inert solvent, such as an aliphatic alcohol (with 1-4 carbon atoms) (for example, methanol), a chlorinated solvent (for example, chloroform, dichloromethane) or a mixture of these solvents, in the presence of MavNa, at a temperature from 0"C to the boiling point of the reaction medium.

Reaction "a" is carried out by exposure to trimethylsilyl chloride in an inert solvent, such as a simple ether (for example, tetrahydrofuran), in the presence of n-butyllithium, at a temperature of -7076.

Reaction "e" is usually carried out in an inert solvent, such as a simple ether (for example, tetrahydrofuran), in the presence of a strong base, such as tert-butyllithium, n-butyllithium, lithium diisopropylamide, potassium tert-butylate, at a temperature of -707C to -1576.

The """ reaction is usually carried out in a chlorinated solvent (for example, dichloromethane, chloroform), at a temperature from 0"C to the boiling point of the reaction medium.

Hydrolysis "d" is carried out in an inert solvent, such as a simple ether (for example, dioxane), with the help of hydrochloric acid, at a temperature of about 2070.

Reactions "p" and "7" are preferably performed in an inert solvent, such as acetonitrile, in the presence of a base, such as an alkali metal carbonate (for example, potassium carbonate), at the boiling temperature of the reaction medium.

Reaction "i" is carried out in a hydrogen atmosphere, in the presence of a catalyst, such as palladium or its derivatives, in an inert solvent, such as methanol or ethanol, at a temperature from 157C to 607C.

Reaction "K" is performed in an inert solvent, such as a chlorinated solvent (for example, dichloromethane, chloroform), at a temperature from 0"C to the boiling point of the reaction mixture.

Derivatives of AzCH(VON.) are commercially available or can be obtained by applying or adapting the method described by M/.E. VASNMAMM, U. At. Spet. os, 2135 (1933). Usually, the corresponding alcohol AVZSNONNAH: brominated using hydrobromic acid in acetic acid at a temperature from 0"C to the boiling point of the reaction medium.

Corresponding AzSNONAH alcohols are on sale or can be obtained by applying or adapting the methods described by A.S.RI AB and others, 9). Spent 5 people Spent Sott., 527 (1972).

Intermediate products of formula 2 can be obtained by applying or adapting the methods described in the examples. In particular, they arrive according to the following reaction schemes:

Kab5Ma

VBSNUNA 00 as NBSNY Ka a

Wa Am, U.

I-: o and oxidation

B-CH, Оу On 2 channels

And what about sleep is0amilitTrit

Namn, tes NavsN, - Kazo,sn, pvshi 9 And ! MeZVoome

Kana! moreover, in these formulas Nai means a halogen atom and, preferably, an atom of chlorine, bromine or iodine; Va and Vr have the same values as indicated above for derivative 2.

Reaction "a" is usually carried out in an inert solvent, such as dimethylformamide or an aliphatic alcohol with 1-4 carbon atoms, at a temperature from 207C to 30"C.

Reactions "B" and "e" are carried out by any known methods that allow oxidizing the sulfur-containing derivative without touching the other part of the molecule, such as the methods described by M. NOSI SKU, Ohidayope ip Ogdapis Spetivigu,

AS5 Mopodgarii, 186, 252-263 (1990). They come, for example, by exposure to an organic peracid or a salt of such a peracid (percarboxylic acids or persulfonic acids, in particular, perbenzoic acid, 3-chloroperbenzoic acid, 4-nitronadebenzoic acid, peracetic acid, trifluoroperacetic acid, performic acid, monoperphthalic acid) or inorganic peracids or salts of such acid (for example, periodic acid or persulphuric acid), in an inert solvent, such as a chlorinated solvent (for example, chloroform, dichloromethane), at a temperature of 0"C to 25"C. Hydrogen peroxide can also be used, if necessary, in the presence of a metal oxide (sodium tungstate) or a periodate (eg, sodium periodate), in an inert solvent such as an aliphatic alcohol with 1-4 carbon atoms (eg, methanol, ethanol), acetic acid, water or a mixture of these solvents, at a temperature from 0"C to 60"C. It is also possible to influence with the help of tert-butyl hydroperoxide in the presence of titanium tetraisopropylate in an aliphatic alcohol with 1-4 carbon atoms (for example, methanol, ethanol) or a mixture of water and alcohol, at a temperature of about 25 "С, or with the help of oxone (potassium peroxymonosulfate) in an aliphatic alcohol with 1-4 carbon atoms (for example, methanol, ethanol), in the presence of water, acetic acid or sulfuric acid, at a temperature of about 2076.

Reaction "c" is preferably carried out in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms (for example, methanol, ethanol), at a temperature from 20"C to the boiling point of the reaction medium.

Reaction "a" is carried out in an inert atmosphere (argon), at a temperature from 50"C to the boiling point of the reaction medium.

The reaction is usually carried out in an inert solvent, such as tetrahydrofuran or a simple aliphatic ether (for example, diethyl ether), at a temperature of about -7076.

Reaction "d" is usually carried out in an inert solvent, such as dimethylformamide, a simple aliphatic ether (for example, diethyl ether) or an aliphatic alcohol with 1-4 carbon atoms, in the presence of a base (for example, sodium hydride), at a temperature from 0"C to 6070.

Derivatives of the formulas AB-СНо-НАИ are commercially available or can be obtained by applying or adapting the methods described in the examples. In particular, the methyl derivative or the corresponding alcohol is halogenated with a halogenating agent such as hydrobromic acid in acetic acid at a temperature of about 207C, or M-bromo- or M-chlorosuccinimide in the presence of benzoyl peroxide in an inert solvent such as tetrachloromethane at boiling point of the reaction medium. Methyl derivatives or corresponding alcohols are on sale or can be obtained according to the methods described by S.A.VVIME and others, 9. Neiegosusi. Spet., 26, 677 (1989), and O. MASAVATNMAM, 5Zupipezviv, 8, 743 (1992), and in the examples.

Azetidinones of formula 3 can be obtained by applying or adapting the methods described

A.A. KATAUTAKU and others, 9. Neiegosusi. Spet., 271 (1994), or R. VA. OAME, 9. Ogd. Spet., 61, 5453 (1996), and in examples. They usually arrive according to the following reaction scheme: o shcha A m'on

Kk, pepdyn I Y HydroxylamiIN drank, in '

Vg M M i. It's okay

V, vk, E v. 4 a s; SA on o'

Mr. H

M -8 AH viv, M

With in» B. and in these formulas with and Na have the same values as in the case of formula (I), and Na! means a chlorine or bromine atom.

At stage A, it is preferable to work in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms (for example, ethanol, methanol), if necessary, in the presence of alkali metal hydroxide, at the boiling temperature of the reaction medium.

At stage B, reduction is usually carried out using lithium aluminum hydride in tetrahydrofuran at the boiling temperature of the reaction medium.

At stage C, they mostly work in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms (for example, ethanol, methanol), in the presence of sodium bicarbonate, at a temperature from 207C to the boiling point of the reaction medium.

At stage O, oxidation is carried out mainly in dimethylsulfoxide with the help of a complex of sulfur trioxide with pyridine at a temperature of about 20"C or with the help of dimethylsulfoxide in the presence of oxalyl chloride and triethylamine at a temperature from -707C to -5076C.

At stage E, they work according to the method described by M.SVI5AV et al. in U. Med. Spet., 885 (1973).

A magnesium bromide derivative is obtained, then it is reacted with a nitrile in a simple ether, such as diethyl ether, at a temperature from 0"C to the boiling point of the reaction medium. Then it is hydrolyzed with alcohol, the intermediate imine is reduced by sodium borohydride at a temperature from 0 "C to the boiling point of the reaction medium.

Derivatives of Az-SO-Na are on sale or can be obtained by applying or adapting the methods described by M.2. KOMOEV and others, U. Spet. boss. Reykip Tgapv, i, 2815 (1997); M. MOVEMO-M ANNA, Yeitg. in. Mea.

Spet., 23 (5), 477 (1988); 5KIMMEV et al., 9). Honey. Speth, 14 (6), 546 (1971); M.K.NOVM, Tei. Hey., 36 (52), 9453

(1995); A. MEOISI and others, Tei. Gay., 24 (28), 2901 (1983); A.O. VIESKE and others, 9. Ogud. Spet., 62 (20), 6921 (1997);

U. KMAVE and others, Agop. React., 306 (9), 648 (1973); A. SOMSOMKMI and others, U. Spet. boss. Reykip Tgapv, I, 1809 (1996); French patent EN-96-2481 and Japanese patent UR-94-261393.

Derivatives of EzHg are commercially available or can be obtained by applying or adapting the methods described

II VAVAMO5MA and others, Zupii. Sott., 20 (11), 1697 and 3153 (1990); M. GEMAIIINE et al., Zupii!. Sott., 24 (1), 95 (1994); N. SOBA et al., Zupipeviv, 9, 849 (1992); R. VAYESHENVI E et al., U. Snet. boss. Rekip Tgapv., 2, 489 (1993).

Derivatives of VASM are commercially available or can be obtained by applying or adapting the methods described

R. VOSHOU5BOSH and others, 9. Her. Snet., 29 (4), 895 (1992); M. BYISHKI and others, U. Spet. wasps Snet Sott., 1523 (1984); 5. MAVVYNVO and others, 9. Her. Snpet., D, 1333 (1980); M. REVSES, u). Ogd. Spet., 60 (21), 6895 (1995).

Compounds of the formula (I), in which AB means the radical CB", where Ni means a hydrogen atom and B" means the radical

С(АВв)(Р»)(Вио), in which Nav means a hydrogen atom, Ne means the radical -СО-МАг2гвА27, -СООН, -СОООАЙК, -СНГОН, -

МНООаайк or -МН-СО-МнН-айкК and Во means the radical Аг or Ней, can be obtained according to the following reaction scheme: b t osvva z o ke i" teh V 3 i

Sh-t from M

S sooovkh pe shk sbov v, Y M M ya va uv h What am I,

SD onan and tu vo va kt S son a rai ie i in the same NM and also:

HC she in.

S she yi " in uyu

In "mV, it yaru vu Brovy d "- or MN OS-MNYAK schenya and SU novo ev yu di them and in these formulas з, Ва, Нио, Н2в and Н27 have the same values as in the case of formula (1), and ak means alkyl.

Derivatives of formula 4 are commercially available or can be obtained by esterification of the corresponding acids, if necessary, in an activated form such as acid chloride. Acids are commercially available or can be obtained from the corresponding metal derivatives by the method described in UR. NAM5EM et al., in Neiegosus, 10, 711 (1973).

Reaction "a" is usually carried out in an inert solvent, such as a simple ether (for example, tetrahydrofuran), in the presence of a strong base, such as tert-butyllithium, n-butyllithium, lithium diisopropylamide, potassium tert-butylate, at a temperature of -707C to -1576.

Reaction "p" is usually carried out by any dehydration method known to a specialist, which allows dehydrating alcohol to obtain the corresponding alkene, and, in particular, by the above-mentioned methods.

The reduction of "c" is usually carried out in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms, such as methanol, a chlorinated solvent, such as chloroform, dichloromethane, or a mixture of these solvents, in the presence of MavENEa, at a temperature from 0 "C to the boiling point of the reaction medium.

Reaction "a" is carried out by any method known to a specialist, which allows to pass from the ester to the corresponding acid without touching the other part of the molecule. They work mainly in an inert solvent, such as dioxane, in the presence of hydrochloric acid, at the boiling temperature of the reaction medium.

Reaction "e" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching another part of the molecule. When an acid is used, it is preferred to work in the presence of a condensing agent used in peptide chemistry, such as a carbodiimide (e.g., M,M'-dicyclohexylcarbodiimide) or carbonyl-M,M'-diimidazole, in an inert solvent such as an ether (e.g. , tetrahydrofuran, dioxane), amide (dimethylformamide) or a chlorinated solvent (for example, dichloromethane, 1,2-dichloroethane, chloroform), at a temperature from 0"C to the boiling temperature with an inverted refrigerator of the reaction mixture. When a reactive acid derivative is used, it is possible to introduce an anhydride, a mixed anhydride, or an ester (which may be selected from activated or unactivated acid esters) are reacted; then run in an organic medium, if necessary, in the presence of an acid acceptor such as an organic nitrogen-containing base (e.g., trialkylamine, pyridine, 1,8-diazabicyclo 1(|5,4,01undec-7-ene or 1,5-

diazabicyclo(4,3,0|non-5-ene), in a solvent such as the one mentioned above, or in a mixture of these solvents, at a temperature from 0"C to the boiling point with an inverted refrigerator of the reaction mixture, or in a two-phase aqueous in an organic environment in the presence of an alkaline or alkaline earth base (sodium hydroxide, potassium hydroxide) or carbonate or bicarbonate of an alkaline or alkaline earth metal, at a temperature from 0"C to 40"C.

Reaction "7" is carried out by Curtius rearrangement in the presence of diphenyl phosphorazide and triethylamine, in toluene, at a temperature of about 5026.

In the case of reactions "d" and "n", they work directly in the reaction medium of stage "d" at a temperature of about 2076.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

С(Ав)(Р»)(Ачо), in which Нв means a hydrogen atom, Не means the radical -СН2-МНВ 28 and Вио means the radical Ag or

They can be obtained according to the following reaction scheme:

V, g

My body is not my body

M

V ho sivO ve A v b M cho MNZOKe k«tso u n 4 (ss iy schu Vo

Х шк

M ut ovo mash

PI ok what

In these formulas PN", Va. and Vo have the same values as in the case of formula (I); Va means alkyl or phenyl; Does not mean alkyl; BE stands for alkyl; Nd means alkyl, cycloalkylalkyl, cycloalkyl, -"CHOn, n equals 1, 2, 3.

Step "a" is usually carried out in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms (for example, methanol), a chlorinated solvent (for example, dichloromethane, dichloroethane), or tetrahydrofuran, in the presence of a base, such as MaVN(IOSOcSNH3) with, at a temperature of about 202C.

Stage "p" is usually carried out in an inert solvent, such as a halogenated solvent (for example, dichloromethane), in the presence of an organic base, such as triethylamine, dimethylaminopyridine, at a temperature from 0°C to the boiling point of the reaction medium.

Stage "c" is usually carried out in an inert solvent, such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (for example, chloroform, 1,2-dichloroethane), an aromatic solvent (for example, benzene, toluene), at a temperature from 107C to the boiling point of the reaction medium .

Stage "a" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and in particular by the above-mentioned preferred methods.

Derivatives 6 can be obtained according to the following reaction scheme: c V kA Mesii vh

Shchi and "7 ih usnon and 4 bnovosn, "Shsh

Co. Co. and

In, i: t p

Mn,

Not

In these formulas, Наз, На4 and Ніо have the same values as in the case of formula (I), and M5 is a methylsulfonyloxy group.

Stage "a" is usually carried out in an inert solvent, such as tetrahydrofuran, in the presence of triethylamine, at a temperature from 107C to 2076.

Stage "p" is usually carried out with liquid ammonium hydroxide in methanol, in an autoclave, at a temperature of about 6070.

Compounds of the formula (I), in which A means the radical SV", where Ni means a hydrogen atom and B" means a radical -

SOMVI!zVia, can be obtained according to the following reaction scheme:

i oh oh

A "A juice

M M5SI M masMm M I---I I--fY what a shi Ю І І n ОМ5 in, in s |chusneniya s schu to Va mn Her

Gee, it's SOMNA and soon

In these formulas, Naz, Na, Niz and Ri. have the same meanings as in the case of formula (I), M5 means methylsulfonyloxy and Ex means ethyl.

Stage "a" is carried out in the presence of triethylamine, in an inert solvent, such as a simple ether (for example, tetrahydrofuran), at a temperature of about 0"C.

Stage "p" is usually carried out in an inert solvent, such as a mixture of water and dimethylformamide, at a temperature from 30"C to 7570.

Stage "c" is carried out by any method known to a specialist, which allows to pass from the nitrile to the corresponding acid without touching the other part of the molecule. They mainly work with the help of potassium hydroxide in an aliphatic alcohol with 1-4 carbon atoms (such as, for example, ethanol) or in an aqueous medium, at the boiling temperature of the reaction medium.

Stage "a" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and, in particular, by the above-described better methods.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

CHno-SOMVIzVia, can be obtained according to the following reaction scheme:

B B B I se me

M EYUOS-RO(OE), M M noti lo inn that in the I shd oon tu and "i schu

M kavtsmn m

From sleep With | | soon

And 7

In these formulas, B", Ba, Wiz and Vi" have the same meanings as in the case of formula (I), and Ex means ethyl.

Reaction "a" is usually carried out in an inert solvent, such as tetrahydrofuran, in the presence of a base, such as sodium hydride or alkali metal carbonate (for example, potassium carbonate), at a temperature from 20"C to the boiling point of the reaction medium.

The "p" reaction is usually carried out with the help of MavNa, in ethanol, at a temperature of about 0"C.

Reaction "c" is carried out by any method known to a specialist, which allows to pass from the ester to the corresponding acid without touching the other part of the molecule. They mainly work in an inert solvent, such as dioxane, in the presence of hydrochloric acid, at the boiling temperature of the reaction medium.

Reaction "a" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching another part of the molecule, and, in particular, by the above-described better methods.

Intermediates 7 can also be obtained by malonic synthesis according to the following reaction scheme:

In c A « p-ts4 -1

OM A shhnh she soos,n, 7

In these formulas, Me means a methylsulfonyloxy group; Az and B4 have the same values as in the case of formula (1).

Reaction "a" is usually carried out by exposure to diethylmalonate in an inert solvent, such as tetrahydrofuran, in the presence of freshly prepared sodium ethylate, at the boiling temperature of the reaction medium.

Reaction "p" is usually carried out in an aqueous solution of hydrochloric acid at the boiling temperature of the reaction medium.

Compounds Ip can also be obtained according to the following reaction scheme:

NMA ay

RO(OS,N,»СН,СООН -- RO(OS.N.).SNISOMK. ZK, in

In in in In o

V. Vh

M -Y3- M

And sia, sleepy

Iy

In these formulas, B", Ba, Viz and Vi" have the same values as in the case of formula (I).

Stage "a" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and, in particular, by the above-described better methods.

Stage "p" is usually carried out in an inert solvent, such as tetrahydrofuran, in the presence of a base, such as sodium hydride or potassium carbonate, at a temperature from 20"C to the boiling point of the reaction mixture.

Recovery in the case of stage "c" is usually carried out with MaBvNa in ethanol at a temperature of about 2076.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

ZON or -502Нав6 can be obtained according to the following reaction scheme: т Я вх к-х

M inv. zZn M inv. as per-- ts

OM: FOR t v |» kA kA

M M

What - ts

Yves Od, I'm OK

In these formulas, H3, H1, and N1 have the same meanings as in the case of formula (I), where M5 is a methylsulfonyloxy group.

Stage "a" is usually performed in an inert solvent, such as tetrahydrofuran, in the presence of an inorganic base, such as sodium hydride, at a temperature from 0°C to the boiling point of the reaction medium.

Stage "p" is usually carried out by any specialist known to the method of oxidation of a sulfur-containing derivative, such as the methods described by M. NOSHISKU, Ohidayope ip Ogdapis Spetivigu, AS5 Mopodgary, 186, 252-263 (1990). They work, for example, by exposure to an organic peracid or a salt of such a peracid (percarboxylic acids or persulfonic acids, in particular, perbenzoic acid, 3-chloroperbenzoic acid, 4-nitronadebenzoic acid, peracetic acid, trifluoroperacetic acid, performic acid, monoperphthalic acid) or inorganic peracids or salts such an acid (for example, iodic acid or persulphuric acid), in an inert solvent, such as a chlorinated solvent (for example, chloroform, dichloromethane), at a temperature from 0"C to 25"C, or with the help of oxon in a mixture of water and alcohol (methanol, ethanol).

Stage "c" is usually carried out by any method of oxidation of the sulfinyl derivative known to a specialist. They mainly work by exposure to an organic peracid or a salt of such a peracid (percarboxylic acids or persulfonic acids, in particular perbenzoic acid, 3-chloroperbenzoic acid, 4-nitro-perbenzoic acid, peracetic acid, trifluoroperacetic acid, performic acid, monoperphthalic acid), or with the help of oxon in a mixture water with alcohol (methanol, ethanol).

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

COg or -CO-cycloalkyl can be obtained according to the following reaction scheme:

and Ve v-A A

M nusnMosn, M po V soon som(sNu sn, / nmove this vh sov

In these formulas, z and Ba have the same values as in the case of formula (I), and BA has the same values as

Ve, or means cycloalkyl with 3-10 carbon atoms.

Stage "a" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and, in particular, by the above-described better methods.

The "p" stage is usually carried out in an inert solvent, such as a simple ether, such as tetrahydrofuran, at a temperature of about 0"C. Organomagnesium compounds are obtained by methods known to a specialist, such as the methods described in the examples.

Compounds of formula (I), in which Ni means a hydrogen atom and Vo means the radical -C(OH)(Hv)(Bi2), /-

С(OH)(Ав)(alkyl), -С(-МО-СНо-СН-СТНг)Ае or -С(-МАайк)Ав, can be obtained according to the following reaction scheme:

Ve v-K e

M VH

A dov VIyumn, Tsidrom t y sov, і "/kavovh a vkh

M with what

Ki V,

In these formulas PN", Va and Ne have the same values as in the case of formula (I); Bi has the same values as Bi2, or means alkyl (with 1-6 carbon atoms in a linear or branched chain); and B| means alkyl (with 1-6 carbon atoms in a linear or branched chain) or -"СН»А-СНЕСН".

Stage "a" is usually carried out in an inert solvent, such as an aliphatic alcohol (for example, ethanol), in the presence of sodium acetate, at a temperature from 20"C to the boiling point of the reaction medium.

The "p" stage is usually carried out in an inert solvent, such as a simple ether, such as tetrahydrofuran, at a temperature of about 0"C. Organomagnesium compounds are obtained by methods known to a specialist, such as the methods described in the examples.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

CH(Av)MAzi1Azg2, in which Hzi and Az" mean hydrogen atoms, -CH(ВНе)МНЗО»айк, -CH(ВеоМнСОМНак or -

CH(Bv)MnNoSOVz can be obtained according to the following reaction scheme:

in and mouth and Asya sh pov. ; he t v, ra

V, ra vs Y

S-4 collects her 1st day in the 13th day of the "MN akyard day and Shi MEZO 7 SavOzhih t"; Mr. JAKKSO and re

In the Wind your NO and sho Nana as 7 and she k

In these formulas, Az, Ni, Ne, and Nzi have the same meanings as in the case of formula (I); M5 means a methylsulfonyloxy group; aiC means alkyl.

Reaction "a" is usually carried out with the help of MavVnNa in ethanol, at a temperature of about 20760.

Reaction "p" is carried out in the presence of triethylamine in an inert solvent, such as a simple ether (for example, tetrahydrofuran), at a temperature of about 0"C.

Stage "c" is carried out with the help of liquid ammonium hydroxide in methanol, in an autoclave, at a temperature of about 60"C.

Step "a" is usually carried out in an inert solvent such as a halogenated solvent (e.g. dichloromethane) or tetrahydrofuran in the presence of an organic base such as triethylamine, dimethylaminopyridine at a temperature of about 2076.

Stage "e" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and, in particular, by the above-described better methods.

The "" stage is usually carried out in an inert solvent, such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (for example, chloroform, dichloroethane), an aromatic solvent (for example, benzene, toluene), at a temperature from 107C to the boiling point of the reaction medium.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

СН(Вб)Маз1Аз2, where Hzi is a hydrogen atom and Hz2 is an alkyl, Ag or -aik-Ag, can be obtained by the action of the NaIRzi halide on a compound of the formula (I), in which A is the radical CB», where Bi is a hydrogen atom and P" means the radical -CH(He)MAzi Bz2, and z and Bz" mean hydrogen atoms.

This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran, or dimethylformamide, in the presence of an organic or inorganic base (e.g., alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine), at a temperature from 0 "C to the boiling point of the solvent, if necessary, in the presence of palladium or one of its salts or one of its complexes.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

СН(Вв)МАзиАз2, and Hz1 means a hydrogen atom and ВНз2 means an alkyl, can be obtained by exposure to the corresponding compound of the formula (I), in which A means the radical СВ», where Бі means a hydrogen atom and B2 means the radical -СО-Нв, to the amine НМАз1Аз2, in which Bzi means a hydrogen atom and Bzg2 means alkyl.

This reaction is usually carried out in an inert solvent, such as a chlorinated solvent (e.g., dichloromethane, dichloroethane), in the presence of a reducing agent, such as sodium triacetoxyborohydride, at a temperature of 0°C to 70°C.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

CH(Pv)MAziBz2, and z and Az" mean alkyl radicals, Ag or -aIKk-Ag, can be obtained by the action of the halide Na!IRzg on the compounds of the formula (I), in which A means the radical CB", where Bi means the atom hydrogen and B" means the radical -CH(He)MAziAz2, and Hzi means a hydrogen atom and Vzg means alkyl, Ag or -aIkK-Ag.

This reaction is carried out in an inert polar solvent, such as acetonitrile, tetrahydrofuran, or dimethylformamide, in the presence of an organic or inorganic base (e.g., alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine)), at a temperature from 0"C to the boiling point of the solvent, if necessary, in the presence of palladium or one of its salts or one of its complexes.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

CH(Bv)MAziAz2, and Bzi means a hydrogen atom and Vzg2 means an alkyl (with 2-6 carbon atoms) or a radical -aik

(with 2-6 carbon atoms)-Ag, can be obtained by the action of the aldehyde Nasno, in which Na means alkyl or -aIk-Ag, on compounds of the formula (I), in which A means the radical CB", where Bi means a hydrogen atom and Pg means the radical -CH(He)MAZi Bzg2, and z and Bz2 mean hydrogen atoms.

This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran at a temperature of 0"C to 50"C, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

СН(Вв)МАзиАз2, and Взи means alkyl, Аг or -аЙК-Аг and Az» means alkyl (with 2-6 carbon atoms) or the radical -аікК (with 2-6 carbon atoms)-Аг, can be obtained by exposure aldehyde Vasno, in which Ba means alkyl or -aiK-Ag, to the compound of the formula (I), in which A means the radical SAN", where Bi means a hydrogen atom and

Ag means the radical -CH(He)МазиВзг, and Hзі means a hydrogen atom and Vзг2 means alkyl, Аг or -аКК-Аг.

This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran at a temperature of 0"C to 50"C, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

CH(Bv)MAzAz2g, and Asia and Bz2, together with the nitrogen atom to which they are bound, form a heterocycle, which is chosen among aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, can be obtained by exposure to the dihalide Nai!-aiK (from 2- 5 carbon atoms)-Nai! to the compound of formula (I), in which A means the radical CA", where

Bi means a hydrogen atom and Pg means the radical -CH(He)MAziAz2, and Bzi and Bz»2 mean hydrogen atoms.

This reaction is carried out in an inert polar solvent, such as acetonitrile, tetrahydrofuran, or dimethylformamide, in the presence of an organic or inorganic base (e.g., alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine)), at a temperature from 0"C to the boiling point of the solvent, if necessary, in the presence of palladium or one of its salts or one of its complexes.

Compounds of the formula (I), in which A means the radical SV", where Bi means a hydrogen atom and P" means a radical -

СНо-СОВв, -СН»-СН(Ав)Мази Вз2, «СНо-С(-МОай!юЮнВв, can be obtained according to the following reaction scheme:

Their іn pohosdagetosnu pet -і st іosmeyunuyuen, k as. i 2 take away, present

She 5 that ; --SSMSVTSOSN, 8 vAmuVe

Yaga akokn, Yaet and MOV ssannia | o pd TO

Kk I them in

And and she and: vyt

Pe še Ча у

In these formulas, B», Ba, Hb, Hz, Hzg2 have the same meanings as in the case of formula (I), and ayl means alkyl.

Stage "a" is usually carried out in a solvent, such as tetrahydrofuran, at a temperature from 207C to the boiling point of the reaction medium.

Stage "p" is usually carried out in an inert solvent, such as an aliphatic alcohol (for example, methanol), a chlorinated solvent (chloroform, dichloromethane) or a mixture of these solvents, in the presence of a reducing agent, such as MavNa, at a temperature from 0"C to boiling of the reaction medium.

Stage "c" is carried out by any method known to a specialist, which allows to pass from an acid or a reactive derivative of this acid to a carboxamide, without touching the other part of the molecule, and, in particular, by the above-described better methods.

Stage "a" is usually carried out in an inert solvent, such as a simple ether, such as tetrahydrofuran, at a temperature of about 0"C. Organomagnesium compounds are obtained by methods known to a specialist, such as those described in the examples.

Stage "e" is usually carried out in an inert solvent, such as an aliphatic alcohol with 1-4 carbon atoms, such as methanol, in the presence of sodium acetate, at a temperature from 20"C to the boiling point of the reaction medium.

Step "" is carried out in an inert solvent, such as a chlorinated solvent (for example, dichloromethane, dichloroethane), in the presence of a reducing agent, such as sodium triacetoxyborohydride, at a temperature of 0"C to 7026.

Compounds of the formula (I), in which A means the radical SV", where B means the cyano group, -5-aik-MATeBi17, -MNA 5, alkyl or -MAgoBez and B2 means the radical -C(Pb) (P) (Ag), in which Ne means a hydrogen atom, can be obtained according to the following reaction scheme: in c

My

Sht tka masm ra ha syu i Yama i, yah i-h still NV ant, M- Ve sh v sh -V levi ts i ne I Sh-- MK, VKM ve ve se soty 0 B

Shh, what a chnny. 8 che - Y 1. in, in io what

Still se M put te shu Se» iga 12 | u2

Mo, ki ak

In these formulas, B", Ba, Ni, Nig2, Niv, Viv and Vi7 have the same values as in the case of formula (1); aic means alkyl; Nai means halogen atom and M means metal and mostly copper.

Stage "a" is preferably carried out in a polar solvent, such as dimethyl sulfoxide, at a temperature from 207C to 5070C.

Stage "p" is preferably carried out in an inert solvent, such as dimethyl sulfoxide, tetrahydrofuran, acetonitrile, in the presence of a base, such as alkali metal carbonate (for example, potassium carbonate) or ammonium hydroxide, at a temperature from 207C to the boiling point of the reaction medium.

Stage "c" is preferably carried out in an inert solvent, such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, in the presence of a base, such as alkali metal carbonate (for example, potassium carbonate) or ammonium hydroxide, at a temperature from 207C to the boiling point of the reaction medium.

Stage "a" is preferably carried out in an inert solvent, such as a simple ether (diethyl ether), tetrahydrofuran, at a temperature from -787C to 2076.

Stage "e" is preferably carried out in an inert solvent, such as dimethylsulfoxide, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, in the presence of a base, such as alkali metal carbonate (for example, potassium carbonate) or ammonium hydroxide, at a temperature of 20"С to the boiling point of the reaction medium.

Compounds of the formula (I), in which A means the radical SV", where Ni means the radical -aiKk-MAivAch", and Vivi

Viv mean a hydrogen atom, can be obtained by reduction of the corresponding compound of formula (I), in which

A stands for the SV radical, where Ni stands for the cyano group.

This reaction is usually carried out in an inert solvent, such as tetrahydrofuran, diethyl ether, toluene, at a temperature from 0"C to the boiling point of the reaction medium, in the presence of a reducing agent, such as aluminum hydride.

Compounds of the formula (I), in which AB means the radical SAN", where Bi means the radical -aik-MAzvAch", and Viv means a hydrogen atom and Vio means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5O2halic, -CO-MNaic or -SOOalicK , can be obtained by exposure to Nai!V:io halide, where Na! means a halogen atom, for a compound of formula (I), in which A means the radical CA:P", where Vi means the radical -aik-MAivAt", and Viv and Viv mean a hydrogen atom.

This reaction is carried out in an inert polar solvent, such as acetonitrile, tetrahydrofuran, or dimethylformamide, in the presence of an organic or inorganic base (e.g., alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine)), with temperature from 0"C to the boiling point of the solvent, if necessary, in the presence of palladium or one of its salts or one of its complexes.

Compounds of the formula (I), in which AB means the radical SAN", where Bi means the radical -aik-MAzvAch", and Viv means alkyl and Vio means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5Oalkyl, -bO-MNayl or -

Dogs, can be obtained by the action of an alkyl halide on a compound of the formula (I), in which A means the radical CB", where Bi means the radical -aik-MAiaA:", and Viv means a hydrogen atom and Nio means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5Ogaik, -SO-MNaik or -SOOaik.

This reaction is carried out in an inert polar solvent, such as acetonitrile, tetrahydrofuran, or dimethylformamide, in the presence of an organic or inorganic base (e.g., alkali metal carbonate (e.g., sodium, potassium), trialkylamine (e.g., triethylamine, dimethylaminopyridine)), with temperature from 0"C to the boiling point of the solvent, if necessary, in the presence of palladium or one of its salts or one of its complexes.

Compounds of the formula (I), in which A means the radical SNINg, where either Ві means a hydrogen atom and Аг means the radical -С(Пв)(В»а)(Віо) or -С(Ав)(Вій)(Ві2), or Vi means alkyl, МН-А:5, cyano group, -5-аіКк-МатеВі?, -аік-

MAza8Ate or -MAgoB2i and Ag means the radical -С(АНв)(Ві)(Рі2) and Av means alkyl, can be obtained by alkylation of the corresponding compound of formula (I), in which Bz means a hydrogen atom.

This reaction is preferably carried out with a base such as an alkali metal hydride (eg sodium hydride), an alkali metal amide (eg sodium amide) or an organometallic derivative in an inert solvent such as a simple aliphatic ether (diethyl ether) or tetrahydrofuran , at a temperature from -18"7C to 30"C, using an alkylating agent such as an alkyl halide or an alkyl sulfonate.

Compounds of formula (I), in which A means the radical -С-С(НА7)5ОгайкК, can be obtained according to the following reaction scheme: arnsaН

C) Zv ac

VYSNUROZE, nak -

A ROSE, a)n-S. Not

C) t and SHI

V. i) and Yah

M M shi s what

In, in,

In these formulas VN", Va and B? have the same values as in the case of formula (1); aic means alkyl and Nay means halogen atom.

Reaction A is usually carried out in an inert solvent, such as a simple ether (for example, diethyl ether), in the presence of a strong base, such as tert-butyllithium or n-butyllithium, at a temperature from -707C to -50"C, then sulfur is added , then an alkyl halide (eg, iodide, bromide).

Reaction B is usually carried out in an inert solvent, such as a simple ether (for example, tetrahydrofuran), in the presence of a strong base, such as tert-butyllithium or n-butyllithium, at a temperature from -702C to -507C, then adding azetidine-3- on, brought to room temperature and hydrolyzed.

Reaction C is carried out by any known methods that allow oxidizing the sulfur-containing derivative without touching the other part of the molecule, such as the methods described above.

A person skilled in the art will understand that for the implementation of the above-mentioned methods according to the invention, it may be necessary to introduce protective groups for amino groups, hydroxyl groups and carboxyl groups in order to avoid repeated reactions. These groups are such groups that can be removed without touching another part of the molecule. Examples of protective groups for the amino group include tert-butylcarbamate or methylcarbamate, which can be regenerated with iodotrimethylsilane or an allylic compound using palladium-based catalysts. Examples of protective groups for the hydroxyl group include triethylsilyl, tert-butyldimethylsilyl, which can be regenerated with tetrabutylammonium fluoride, or asymmetric acetals (for example, methoxymethyl, tetrahydropyranyl) with regeneration with hydrochloric acid. As protective groups for carboxyl groups, esters (for example, allyl, benzyl), oxazoles, and 2-alkyl-1,3-oxazolines can be mentioned. Other protective groups used are described by T.MU.2VAEEME et al., "Rgoiesiipd Stoirv ip Ogdapis Zupineviv", second edition, 1991, donp

UMieu apa 5opv.

Compounds of formula (I) can be purified by conventional known methods, for example by crystallization, chromatography or extraction.

Enantiomers of compounds of formula (I) can be obtained by splitting racemates, for example by chromatography on a column with a chiral phase according to M.N. RIVSIE et al., "Asymmetric Synthesis", Vol. 1, Asadetis Rge55 (1983), either by salt formation or by synthesis from chiral precursors. Diastereoisomers can be obtained by known classical methods (crystallization, chromatography or from chiral precursors).

Compounds of formula (I), if necessary, can be converted into addition salts with an inorganic or organic acid by exposure to such acid in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. These salts also form part of the invention.

Examples of pharmaceutically acceptable salts include the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene bis-B-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate , succinate, sulfate, tartrate, theophylline acetate, and p-toluenesulfonate.

Compounds of formula (I) have pharmacological properties of interest. These compounds have a strong affinity for cannabinoid receptors and especially for those of the SVI type. These compounds are antagonists of the SVI receptor and, accordingly, are suitable in the treatment and prevention of disorders related to the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal system, and disorders in relation to reproduction (Noiijivieg, RNagt. Neu., 38, 1-20, (1986); Nepu and Bipna,

Year Ogad Nez., 36, 71-114 (1991); Sopvzgoye and ZapauK, in the book "Magi)inapa/Sappabipoiaz, Meshyigobrioodu apa

Meshgorpuzioiodu", 459, under the editorship of I. Mygrpu and Avaine, SAS Rhevzz, 1992).

Thus, these compounds can be used to treat or prevent psychoses, including schizophrenia, anxiety, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive impairment, traumatic brain injury, panic attacks, peripheral neuropathies, glaucoma, migraine, disease Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, drug-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in case of interruption of treatment of chronic diseases and abuse of alcohol or drugs (such as opiates, barbiturates, hashish, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines), as analgesics or potentiators of analgesic activity, and narcotic and non-narcotic drugs. They can also be used to treat or prevent intestinal transit.

The affinity of compounds of formula (I) to cannabinoid receptors was determined by the method described

UE.KO5TEV, 9.I.5TEMEMBOM, 5.9U.MMAVO, T.E.S'AMVVAA, O.A. Nakhsosk in .).Rpaptasaoi. Ex. Tpeg., 264, 1352-1363 (1993).

In this test, the ISvo (5095 inhibitory concentration) of compounds of formula (I) is below or equal to 1000 Onmol. their antagonistic activity was shown using the model of hypothermia caused by the agonist of cannabinoid receptors (SR-55940) in mice, according to the method described by V. Sh. Regmuye in the book "Mapi|chapa" ed. O. U. Naguieu, 84, Oxford IVI. Rgevs, 263-277 (1985).

In this test, the OEzo (5095 effective dose) of compounds of formula (I) is less than or equal to 5O0mg/kg.

The compounds of formula (I) have negligible toxicity. their ОЙ ho (lethal dose at 5095) is higher than 4 Омг/kg when administered subcutaneously in the case of mice.

The best compounds of formula (I) are the following: (85)-1-Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)(methylsulfonyl) methyl|azetidine; (2)-1-(bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)(methylsulfonyl) methyl azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-( 3,5-Difluorophenyl)(methylsulfonyl)methylazetidine; (85)-1-Ibis(4-chlorophenyl)methyl|-3-(pyrid-3-yl(methylsulfonyl)methylazetidine; (2)-1-(bis(4- chlorophenyl)methyl|-3-(pyrid-3-yl(methylsulfonyl) methyl|azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-(pyrid-3-yl(imethylsulfonyl)methyl|azetidine; (85)-1-Ibis(3-fluorophenyl)methyl-3-((3,5-difluorophenyl)(methylsulfonyl)methylazetidine; (2)-1-(bis(3-fluorophenyl)methyl-3-((3, 5-difluorophenyl)(methylsulfonyl) methyl azetidine; (5)-1-Ibis(3-fluorophenyl)methyl|-3-(3,5-difluorophenyl) (methylsulfonyl) methyl azetidine; 1-(bis(4-chlorophenyl)methyl|- 3-(А85)-(3-azetidin-1-ylphenyl|Imethylsulfonyl-methyl)azetidine; 1-(bis(4-chlorophenyl)methyl|-3-(H)-(3-azetidin-1-ylphenyl|Imethylsulfonyl- methyl)azetidine; 1-(bis(4-chlorophenyl)methyl|-3-(5)-I3-azetidin-1-ylphenyl|methylsulfonyl-methyl)azetidine; (A5)-1-IZ3-(11-Ibis(4 -chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl-methyl)phenyl|pyrrolidine ; (8)-1-I3-(11-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl-methyl)phenyl|pyrrolidine; (5)-1-I3-(11-Ibis(4-chlorophenyl)methyl |azetidin-3-ylmethylsulfonyl-methyl)phenyl|pyrrolidine; (A5)-IR-I3-(11-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl-methyl)phenyl|-M-methylamine; (in )-Ich-I3-(11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylylmethylsulfonyl-methyl)phenyl|-M-methylamine; (5)-M-I3-(1-I(bis(4-chlorophenyl )methyl|azetidin-3-ylylmethylsulfonyl-methyl)phenyl|-M-methylamine; (85)-1-Ibis(4-chlorophenyl)methyl-3-(3,5-bistrifluoromethylphenyl)methylsulfonyl-methyl|azetidine; (8) -1-(bis(4-chlorophenyl)methyl|-3-((3,5-bistrifluoromethylphenyl)methylsulfonyl-methyl|azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-(3,5 -bistrifluoromethylphenyl)methylsulfonylmethyl-azetidine; 1-(bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethyl)azetidine; (85)-1-Ibis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonylmethyl |-3-methyl-azetidine; (8)-1-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|-3-methyl-azetidine; (5)-1-Ibis( 4-chlorophenyl)methyl|-3-( 3,5-difluorophenyl)methylsulfonylmethyl|-3-methyl-azetidine; (85)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide; (b8)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide; (5)-2-11-(Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide; (85)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isobutylacetamide; (b8)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isobutylacetamide; (5)-2-11-(Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-N-isobutylacetamide; (85)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide; (b2)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide; (5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)y-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide; (85)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide; (b2)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide; (5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide; (85)-1-Ibis(4-chlorophenyl)methyl-3-(11-(3,5-difluorophenyl)-1-methylsulfonyl-ethyl|azetidine; (8)-1-(bis(4-chlorophenyl)methyl| -3-(1-3,5-difluorophenyl)-1-methylsulfonyl-ethyl|azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)-1-methylsulfonyl- ethylazetidine; (85)-1-Bis(4-fluorophenyl)methyl-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (2)-1-(bis(4-fluorophenyl)methyl-3-( (3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (5)-1-Ibis(4-fluorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (85)-1-( 3-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl-yl-azetidine; (55)-1-KZ-pyridyl)(4-chlorophenyl)methyl|-3-(3,5- difluorophenyl)methylsulfonyl-methyl|azetidine; (АР)-1-К(3-pyridyl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl-methyliazetidine; (58)-1-К( 3-pyridyl) (4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonyl-methylylazetidine;

(85)-1-K4-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methylylazetidine; (55)-1-K4-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (8РО-1-К(4-pyridyl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl-methyliazetidine; (85)-1-К4-pyridyl)(4-chlorophenyl)methyl| -3-(3,5-difluorophenyl)methylsulfonyl-methyliazetidine; (85)-5-((4-chlorophenyl)-(3-(3,5-difluorophenyl)methylsulfonylmethyliazetidin-1-ylmethyl)pyrimidine; (58)-5 -((4-chlorophenyl)-(3-(3,5-difluorophenyl)methylsulfonylmethyliazetidine-1-ylmethyl)pyrimidine; (8 A)-5-(4-chlorophenyl)-(3-((3,5-difluorophenyl) methylsulfonylmethylazetidin-1-ylylmethyl)pyrimidine; (55)-5-((4-chlorophenyl)-(3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-1-ylylmethyl)pyrimidine; (55)-1-K2- chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methyl-sulfonylmethyl|azetidine; (АР)-1-К(2-chloropyrid-5-yl)(4-chlorophenyl) methyl|-3-(3,5-difluorophenyl)methyl-sulfonylmethyliazetidine; (85)-1-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methyl -sulfonylmethyl|azetidine; (58)-1-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methyl-sulfonylmethyl|azetidine; their optical isomers and their pharmaceutical acceptable salts.

The following examples illustrate the invention.

Example 1 (A85)-1-Bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl) (methylsulfonyl)methyl|azetidine can be obtained starting from 1.0 g of 1-Bis(4-chlorophenyl)methyl /|-3-((3,5-difluorophenyl) (methylsulfonyl)methylene azetidine in 40 cm3 of methanol, to which 96 mg of sodium borohydride is added and stirred for 3 hours at a temperature of 20"C. After adding 100 cm of dichloromethane, the reaction mixture is washed twice with 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).

The crude product is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height bcm, diameter

Ccm), eluting under argon pressure of 0.8 bar using dichloromethane, then a mixture of dichloromethane with 195 methanol, and collecting fractions of 80 cm3. Fractions 13-15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.55 g of a white solid is obtained, which is treated with 50 cm3 of diisopropyl ether, filtered and dried, obtaining 0.47 g of (85)-1-Ibis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl) (methylsulfonyl)methyl azetidine as a white solid.

H-NMR spectrum (400 MHz, (СбО3)250О - dv with the addition of a few drops of СОЗСОООЙ - дя, at a temperature of 353 K) b (in ppm): 2.46 (t, 9-7.5Hz:1Н ); 2.77 (c:Z3H); 3.15 (m:2H); 3.40 (m:1H); 3.49 (t ush., y9-:7.5HC1H); 4.46 (s :1H); 4.81 (d, 9-9 Hz:1H); 7.05-7.20 (m:ZH); 7.15-7.45 (m:vH)|. 1-(Bis( 4-chlorophenyl)methyl-3-(3,5-difluorophenyl)(methylsulfonyl)methylene|azetidine can be obtained in two ways:

Method 1

To a solution of 2.94 g of 1-ibis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)(methyl-sulfonyl)methyl-(H5)|azetidin-3-ol in 250 cm3 of dichloromethane at a temperature of 22"С add 0.65 cm of methylsulfonyl chloride, then add 2.42 g of 4-dimethylaminopyridine in small portions over 15 minutes; the yellow-hot solution is stirred for 2 hours at room temperature. The reaction mixture is washed three times with 150 cm3 of distilled water and once with 150 cm3 of saturated sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is chromatographed on a column with silica gel (granulometry 0.04-0.0 mm; diameter 5.5 cm, height 15 cm) under an argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 1:9 by volume) as an eluent, collecting fractions of 70 cm3. Fractions 15-36 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1 is obtained, 86 g of white meringue, which is crystallized from diisopropyl ether, obtaining a solid substance that melts at a temperature of 1902С. Recrystallization from 45 cm3 of ethanol gives 1.08 g of 1-bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)"methyl-sulfonyl)methylene azetidine, which melts at a temperature of 20670.

H-NMR spectrum (300 MHz; DMSO-dv, at ZOOK temperature) b (in ppm): 3.00 (ЗН, с, 5СН»З), 3.87 (2Н, с, МОН»), 4.20 (2H, c, MON), 4.75 (1H, c, MON), 7.15 (2H, d, 9U-8Hz, 2CH arom.), 7.30 (5H, m, 5CH arom. .), 7.45 (4H, d,

Uye7Huts, 4SN arom.)i.

To a solution of 6.8 g of bis(4-chlorophenyl)bromomethane in 300 cm3 of acetonitrile, add 6.75 g of 3-I|(3,5-difluorophenyl) (methylsulfonyl)methyl-(AZ)|azetidin-3-ol hydrochloride, then 2.97 g potassium carbonate. The reaction mixture is boiled for 1 hour with an inverted refrigerator, cooled to room temperature, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The obtained residue is chromatographed on a column with silica gel (granulometry 0.04-0.06 mm; diameter 8.5 cm, height 22 cm) under an argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 25:75 by volume) as of eluents, collecting fractions of 250 cm3. Fractions 11-48 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 5,3g of 1-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl) (methylsulfonyl)methyl-(A5))azetidin-3-ol is obtained.

IS spectrum "H-NMR (300 MHz; (СО3)250.-ав) b (in ppm): 2.00 (с:ЗН); 2.94 (с:ЗН); 3.25 (m:2Н ); 3.48 (d, 9-9HgciH); 3.80 (d, U59HcC1H); 4.54 (s:1H); 5.34 (s); 7.15 (d, 9-8.5Hz: 2H); 7.20-7.40 (m: 8H); 7.50 (t ush., U9-29Hz: 1H)|.

Bis(4-chlorophenyl/bromomethane can be obtained according to the method described by M.E. VASNMAMM, U,

At. Spent boss, 2135 (1933).

Hydrochloride 3-(3,5-difluorophenyl)(methylsulfonyl)methyl-(A5)|azetidin-Z3-ol can be obtained in the following way: to a solution of 37 g of 3-((3,5-difluorophenyl)(methylsulfonyl)methyl-( A5)|-1-(vinyloxycarbonyl)azetidine-

160 cm3 of a 2N solution of hydrogen chloride in dioxane is added to 160 cm3 of dioxane. After standing for 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa).

The resulting residue is treated with 320 cm3 of ethanol, boiled for 1 hour with an inverted refrigerator and cooled in a bath with a mixture of water and ice. The isolated solid substance is filtered, washed with diethyl ether and dried at a temperature of 40"C under reduced pressure (2.7 kPa).

29.85 g of white crystals are obtained, the melting point of which is higher than 2607C. 3-(3,5-Difluorophenyl)(methylsulfonyl)methyl-(AB)|-1-(vinyloxycarbonyl)y azetidin-3-ol can be obtained in the following way; to a solution of 60.18 g of 1-benzhydryl-3-((3,5-difluorophenyl) (methylsulfonyl)methyl-(A5))azetidin-3-ol in 1000 cm3 of dichloromethane at a temperature of 5"C, add a solution of 14 cm3 of vinyl chloroformate in

ZBcm3 of dichloromethane. After standing for 20 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The obtained residue is chromatographed on a column with silica gel (granulometry 0.04-0.06 mm; diameter 11 cm, height 32 cm) under an argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 3:7 by volume) as eluents means, collecting fractions of 1000 cm3. Fractions 8-18 are combined, then concentrated to dryness under reduced pressure (2.7 kPa).

37 g of 3-((3,5-difluorophenyl)u(methyl-sulfonyl)methyl-(A5)|-1-(vinyloxycarbonyl)azetidin-3-ol.-:- are obtained in the form of white crystals melting at a temperature of 19576 1-Benzhydryl-3-(3,5-difluorophenyl)(methylsulfonyl)methyl-(A5)|azetidin-3-ol can be obtained in the following way: to a solution of 6.73 cm3 of diisopropylamine in 110 cm3 of tetrahydrofuran, cooled to a temperature of -70C, in an argon atmosphere, add 29.5cm3 of a 1.6N solution of n-butyllithium in hexane. After 30 minutes, add a mixture of 8.7g of 3,5-difluorobenzylmethylsulfone in 200cm3 of tetrahydrofuran and keep it under stirring for 45 minutes at a temperature of -70"C. Add 10g of 1-benzhydrylazetidin-3-one dissolved in boOsm3 of tetrahydrofuran, then stir for 20 minutes, leaving the mixture to return to room temperature. The reaction mixture is hydrolyzed with 400cm3 of saturated ammonium chloride solution, extracted with dichloromethane, washed three times with 500cm3 of water, then with using a saturated solution of sodium chloride the overnight phase is dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue in the amount of 19 g is treated with isopropyl ether, from which it crystallizes. After filtering and drying, 15.35 g of 1-benzhydryl-3-|(3,5-difluorophenyl)(methylsulfonyl)methyl-(85)|azetidin-3-ol are obtained in the form of white crystals. 1-Benzhydrylazetidin-3-one can be obtained according to the method described by A.A. KATVITAKU and others, 9.

Self-employed. Spet., 271 (1994). 3,5-Difluorobenzylmethylsulfone can be obtained in the following way: 129.9g of oxone is added to 334A6bg of 3,5-difluorobenzylmethylsulfide in 318cm3 of water, 318cm3 of acetic acid and 318cm3 of ethanol at a temperature of 5"C. After standing for 16 hours at room temperature the reaction mixture is diluted with dichloromethane, washed with water and a saturated solution of sodium chloride, dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 3,5-Difluorobenzylmethylsulfide can be obtained in the following way, starting from 40g of 3,5-difluorobenzylbromide and 16.25g of sodium methylthiolate in dimethylformamide at a temperature of 60"C, after processing, 33.46g of 3,5-difluorobenzylmethylsulfide is obtained in the form of a yellow oil color

Method 2

At room temperature, 0 80 g of crushed sodium hydroxide.

After standing for 16 hours at room temperature, add 50 cm3 of water and 100 cm3 of ethyl acetate.

The mixture is decanted, the organic phase is washed again with 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). A white meringue is obtained, which is crystallized from diisopropyl ether, obtaining 0.85 g of a solid substance that melts at a temperature of 1907C. Recrystallization from 20 cm3 of ethanol leads to 0.70 g of 1-bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)(methylsulfonyl)methylene) azetidine melting at a temperature of 20576.

To a solution of 4.77 g of (3,5-difluorobenzyl)methylsulfone in 70 cm? of tetrahydrofuran, in an atmosphere of argon and at a temperature of -702С, add 14cm3 of a 1.v6N solution of n-butyllithium in hexane. After standing for 1 hour at a temperature of -70C, add a solution of 6b.8g of /1-I(bis(4-chlorophenyl)methyl|iazetidin-3-one in Zbcm3 of tetrahydrofuran, then, after 1 hour, a solution of 2.34cm3 of acetyl chloride in 20cm3 of tetrahydrofuran and the temperature of the reaction mixture is raised to 20"C for 1 hour. 5Ocm3 of water and 200cm3 of ethyl acetate are added. The mixture is decanted, the organic phase is washed with 100cm3 of water, 100cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure ( 14 Ag of 3-acetoxy-1-bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)(methylsulfonyl)methyl-(H5)|azetidine are obtained in the form of a yellow oil.

H-NMR spectrum (400 MHz, SOSIv) b in ppm: 45 (c1H); 3.81 (d, U59HzC1H); 4.32 (c:1H); 4.49 (c:1H); 6.88 (t, 9U-9 and 2.5Hz:1H); 7 ,20-7.35 (m'1OH)|. 1-(Bis(4-chlorophenyl)methyl|azetidin-3-one can be obtained according to the following method: to a solution of 5.0 cm3 of oxalyl chloride in 73 cm3 of dichloromethane, cooled to temperature -78"C, add a solution of 8.1cm3 of dimethylsulfoxide in 17.6cm3 of dichloromethane. After standing for 0.5 hours at a temperature of -78"С, add a solution of 16.0g of 1-(bis(4-chlorophenyl)methyl|iazetidine-Z3 -ol in 50 cm3 of dichloromethane. After standing for 5 hours at a temperature of -78"C, 26.6 cm3 of triethylamine is added dropwise and the reaction mixture is left to stand until it returns to room temperature. After 16 hours, the reaction mixture is washed 4 times with 200 cm3 of water, then with 200 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). the residue is chromatographed on a column with silica gel (granulometry 0.04-0.0 mm; diameter 9.2 cm, height 21 cm) under an argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 40:60 by volume) as eluents, collecting fractions of 200 cm3. Fractions 15-25 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 8.9 g of 1-I(bis(4-chlorophenyl)methyl|azetidin-Z-one is obtained in the form of pale yellow crystals that melt at a temperature of 11176. 1-(Bis(4-chlorophenyl)methyl|azetidin-3- ol can be obtained according to the method described by A.A. KATAITAKU et al., U. Neiegosusi. Spet., 271 (1994), starting from 35.5 g of hydrochloride (bis(4-chlorophenyl) methyl amine and 11.0 cm3 of epichlorohydrin 9.0 g of 1-(bis(4-chlorophenyl)methyl|azetidin-3-ol) is isolated.

Hydrochloride (bis(4-chlorophenyl)methyl|amine can be obtained by the method described by M.SVI5ZAV and others, 9.

Mea. Spet., 885 (1973).

Example 2 (-)-1-(Bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl) (methylsulfonyl) methyl|iazetidine (and //((k)-1-I(bis(4 - chlorophenyl)methyl|-3-((3,5-difluorophenyl) (methyl-sulfonyl)umethyl|azetidine can be obtained by separation using HPLC (high performance liquid chromatography) on a column with a chiral phase

SNIVAG RAK ABZ (granulometry 20μm, height 23cm, diameter bcm) 0.52g of the racemate obtained according to example 1. Eluting with a mixture of heptane and ethanol (in a ratio of 90:10) with a flow rate of 8Osm3/min. and after concentrating the collected fractions to dryness under reduced pressure (2.7 kPa), 110 mg of (-)-1-(bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl)methyl|azetidine is obtained, ( so|--6.37 (c-0.5M in methanol), in the form of a white solid, which melts at a temperature of 178"С, and 134 mg of (w)-1-(bis(4-chlorophenyl)methyl|- 3-((3,5-difluorophenyl) (methylsulfonyl)methyl azetidine, (so|-5.87 (c-0.5M in methanol), in the form of a white solid, which melts at a temperature of 17876.

Example C

A mixture of 2 diastereoisomeric forms of A 1-14-(A8")-(4-chlorophenyl)-(3-(3,5-difluorophenyl)methylsulfonylmethyl- (E)Y azetidin-1-ylmethyl|benzyl| pyrrolidine and 1-I4- (8")-(4-chlorophenyl)-(3-(3,5-difluorophenyl)methylsulfonyl-methyl-(5)|azetidin-1-ylmethyl|benzyl|Ipyrrolidine can be obtained according to the following method: to a solution of bomg 1 -(87)-(4-(4-chlorophenyl)-(3-((3,5-difluorophenyl)methylsulfonylmethylene|azetidin-1-ylylmethyl)benzyl pyrrolidine, isomeric form A, add 20 mg of sodium borohydride to 2 cm3 of ethanol and 2 cm3 of dichloromethane After stirring for 20 hours at a temperature of 20"C, add 0.25 cm3 of water, 20 cm3 of dichloromethane, stir and dry the mixture over magnesium sulfate, then filter and concentrate to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure of 0.1 bar with dichloromethane, then with a mixture of dichloromethane and methanol (95:5 by volume) and collecting fractions of 5 cm3.

Fractions 13-18 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). Zd8mg of a mixture of 2 diastereoisomeric forms of A/1-4-(8")-(4-chlorophenyl)(3-(3,5-difluorophenyl)methylsulfonylmethyl-(A)|-azetidin-1-ilyumethyl|benzyl pyrrolidine and 1- I4-((A")-(4-chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonylmethyl-(5))azetidin-1-yl)umethylbenzyl pyrrolidine in the form of a white meringue.

H-NMR spectrum (400 MHz, SOSIv) b (in ppm): 1.77 (m:4H); 2.40-2.60 (m:5H); 2.67 (s:ZH) ; 3.10-3.25 (m:2H); 3.38 (m:1H); 3.50-3.70 (m:ZH); 4.24 (s:1H); 4.25 (d , U-11Hz:1H); 6.83 (t ush., U-29Hz:1H); 6.94 (m:2H); 7.10-7.35 (m:8H)). 1-(873 -I4-(4-Chlorophenyl)-(3-I((3,5-difluorophenyl)methylsulfonylmethylene azetidin-1-ylylmethyl)benzyl|pyrrolidine, isomeric form A, can be obtained according to the following method: to a solution of 0.32 g 1 -(873-(4-(chloromethyl)phenyl|-(4-chlorophenyl)methyl)-3-(3,5-difluorophenyl)methylsulfonyl-methylene| azetidine, isomeric form A, and 5 mg of sodium iodide in 10 cm3 of dichloromethane add 50 mm? pyrrolidine.

After stirring for 20 hours at a temperature of 207C, 50 mm3 of pyrrolidine is added to the mixture, stirred for 8 hours, then 50 mm? pyrrolidine and stir for 20 hours at a temperature of 20"C. The reaction mixture is washed with water, then the organic phase is dried over magnesium sulfate, concentrated to dryness in a vacuum (2.7 kPa). The resulting residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm ; diameter 1.2 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with dichloromethane, then with a mixture of dichloromethane and methanol (in a ratio of 97.5:2.5 by volume) and collecting fractions of 3 cm3. Fractions 12-40 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-(А7)-(4-(4-chlorophenyl)-(3-(3,5-difluorophenyl) is obtained) methylsulfonylmethylene|azetidin-1-ylylmethyl)benzyl|pyrrolidine, isomeric form A, in the form of a white meringue (9479 Zbb5nm - -22.52750.7 (c-0.595; dichloromethane).

H-NMR spectrum (300 MHz, SOCI3) b (in ppm): 1.78 (m:4H); 2.51 (m:4H); 2.81 (s:ZN); 3.58 (c:-2H); 3.84 (m:2H); 4.33 (m:2H); 4.50 (c:1H); 6.84 (t, 9-9 and 2.5HC:1H); 6.98 (m:2H); 7.20-7.40 (m:8H)|. 1-(87-(4-Chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-I(3,5 -difluorophenyl) methylsulfonylmethylene|azetidine, isomeric form A, can be obtained according to the following method: to a solution of 28.0 g of a mixture of 2 diastereoisomers (forms A), /(1-(873-(4-chloromethyl)phenyl)|(4- chlorophenyl)methyl)-3-((H)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol and 1-4(87-((4-chloromethyl)phenyl)|(4-chlorophenyl)methyl)- 3-I|(8)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol, 32 g of 4-dimethylaminopyridine in 500 cm? of dichloromethane add 12.4 cm3 of methylsulfonyl chloride. After stirring for an hour at a temperature of 102С, then for an hour at a temperature 20"C, the reaction mixture is washed with 500 cm3 of water, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The chromatograph residue on a column with silica gel (granulometry 0.06-0.200 mm; diameter bcm, height ZO0 cm), under argon pressure of 0.2 bar, eluting with dichloromethane and collecting fractions of 250 cm3. Fractions 9-25 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 6.3 g of 1-(А83-(4-chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-((3,5 -difluorophenyl)methylsulfonylmethylene|azetidine, isomeric form A, in the form of a white meringue.

A mixture of 2 diastereoisomers (forms A) of 1-(87-K(К4-chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-(А)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol and 1 -87)-(4-chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-((5)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol can be obtained according to the following method: to the solution 0.20 g of a mixture of 2 diastereoisomers (form A) 1-(87)-(4-chlorophenyl)(4-(hydroxymethyl)phenyl|methyl)u-3-(A)-(3,5-difluorophenyl)methylsulfonylmethyl|iazetidine- Z-ol and 1-(8")-(4-chlorophenyl)(4-hydroxymethyl)phenyl|methyl)-3-

I(5)-(3,5-difluorophenyl)methylsulfonylmethyl| to azetidine-Z-ol in 10 cm3 of dichloromethane, add bcm3 of thionyl chloride. After stirring for 20 hours at a temperature of 20"C, add to the reaction mixture

B5cm3 of saturated aqueous solution of sodium bicarbonate, then stir for 15 minutes. The mixture is decanted, the organic phase is washed with water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.04-

Oh, Obmm; diameter 1.0 cm, height 20 cm), under an argon pressure of 0.2 bar, eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 75:25 by volume) and collecting fractions of 20 cm3. Fractions 4-7 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of a mixture of 2 diastereoisomers (form A) 1- (AM-((4-chloromethyl)phenyl|(4-chlorophenyl)methyl)u-3-|(8)-(3,5-difluorophenyl)methyl-sulfonylmethyl |azetidin-3-ol and 1-(87U-(4-chloromethyl)phenyl)|(4-chlorophenyl)methyl)-3-I(5)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol in in the form of white meringue.

A mixture of two diastereoisomers (forms A) 1-(8")-(4-chlorophenyl)(4-(hydroxymethyl)phenyl|methyl)u-3-|(A)-(3,5-difluorophenyl)methylsulfonylmethyl azetidine-3- ol and 1-(8")-(4-chlorophenyl)(4-"(hydroxymethyl)phenyl|methyl)-3-

I(5)-(3,5-difluorophenyl)methylsulfonylmethyl|iazetidin-Z3-ol can be obtained according to the following method: to a solution of 0.58 g of a mixture of 2 diastereoisomers (form A) maintained in an argon atmosphere and cooled to a temperature of -30"C ) 3-acetoxy-1-(A")-(4-chlorophenyl)|(4-(methoxycarbonyl/phenyl|methyl)-3-|(A)-(3,5- difluorophenyl) methylsulfonylmethyl|azetidine and 3-acetoxy -1-(8")-(4-chlorophenyl)|4- (methoxycarbonyl)phenyl|methyl)-3-|(5)-(3,5-difluorophenyl) methylsulfonylmethyl|azetidine in 10cm3 of anhydrous toluene add 1.bcm3 1 .5M solution of diisobutylaluminum hydride in toluene. After stirring for 15 minutes at a temperature of -30"C, 1.0cm3 of the same diisobutylaluminum hydride solution is added again, then the mixture is left to stand until the temperature reaches 0"C. After stirring for 30 minutes, 3cm3 of water is added to the stirred mixture and bcm3 of 1N sodium hydroxide solution, then extracted with 25cm3 of dichloromethane.The organic phase is washed with 5cm3 of water, 5cm3 of brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.06-0.200 mm; diameter 1.2 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions by ZOcm3. Fractions 4-12 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 00.42 g of a mixture of 2 diastereoisomers (form A) is obtained 1-(8")-(4-chlorophenyl)|4-(hydroxymethyl)phenyl| methyl)-3-(A)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol and /0/1-(A)-(4-chlorophenyl)|4-(hydroxymethyl)phenyl|methyl)-3 -|(5)-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ol in the form of a white varnish.

A mixture of 2 diastereoisomers (forms A) 3-acetoxy-1-(A")-(4-chlorophenyl)|(4-(methoxycarbonyl|methyl)-3-

KA)-(3,5-difluorophenyl)methylsulfonylmethyl of azetidine and 3-acetoxy-1-(8")-(4-chlorophenyl)|4-(methoxycarbonyl)phenyl|methyl/)-3-I|(5)-( 3,5-difluorophenyl)methylsulfonylmethyl|azetidine can be obtained according to the following method: to a solution of 1.0g of (3,5-difluorobenzyl)methylsulfone in 30 cm3 of tetrahydrofuran, cooled to a temperature of -60"C, in an argon atmosphere, for 5 minutes, add

Ccm3 1.bn of a solution of n-butyllithium in hexane. After stirring for 1 hour at a temperature of -602C, then for 30 minutes at a temperature of -30"C, a solution of 1.45 g of 1-(B8")-(4-chlorophenyl) previously cooled to a temperature of -60"C is added dropwise to this mixture )(4-(methoxycarbonyl)phenyl|methyl)u azetidin-3-one, isomeric form A, in 15 cm3 of tetrahydrofuran. After stirring for 30 minutes at a temperature of -602C, then for 30 minutes at a temperature of -30"C, add 0, 43 cm3 of acetyl chloride, after which the reaction mixture is left to stand until the temperature reaches 0"C. Then, with stirring, 40 cm3 of water and 40 cm3 of dichloromethane are added to the medium, after which it is left to stand to return to room temperature and decanted. The organic phase is washed with 20 cm3 of water, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7kKPa). The residue is chromatographed on a column with silica gel (granulometry 0.040-0.063 mm; diameter 3 cm, height 30 cm), eluting under argon pressure of 0.5 bar using sum of cyclohexane and ethyl acetate (in a ratio of 75:25 by volume) and collecting the fractions

Zosm3. Fractions 21-35 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1.28 g of a mixture of 2 diastereoisomers (form A) 3-acetoxy-1-(8")-(4-chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)-3-(A)-(3,5- difluorophenyl)methylsulfonyl-methyl| azetidine and 3-acetoxy-1-(8")-(4-chlorophenyl) I4-(methoxycarbonyl)phenyl|methyl)-3-1(5)-(3,5-difluorophenyl)methylsulfonylmethyl| azetidine in the form of cream-colored meringue. 1-(87)-(4-Chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)iazetidin-3-one, isomeric form A, can be obtained according to the following method: to a solution cooled to a temperature of -607C, 0.55 cm3 oxalyl chloride in 5 cm? of dichloromethane for 10 minutes, add 0.90 cm3 of dimethyl sulfoxide. After stirring for 30 minutes at a temperature of -60"C, a solution of 1.75 g of 1-(8)-(4-chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)azetidin-3-ol is added to the mixture for 15 minutes. isomeric form A, in 20 cm3 of dichloromethane. After stirring for 3 hours at a temperature of -60C, add 2.70 cm3 of triethylamine, then leave the reaction medium until the temperature reaches 02C. Then add 20 cm3 of water, mix, then decant. The organic phase is dried over magnesium sulfate, filtered , then concentrated to dryness at a temperature of 50"C and under reduced pressure (2.7 kPa).

The obtained yellow-hot oil is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 2 cm, height 30 cm), under an argon pressure of 0.5 bar, eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 75:25 by volume) and collecting fractions by ZOcm3.

Fractions 2-15 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 1.45 g of 1-(A-(4-chlorophenyl)(4-(methoxycarbonyl/phenyl|methyl)azetidin-Z-one, isomeric form A, in the form of a yellow meringue) is obtained. 1-(87)-(4-Chlorophenyl )|(4-(methoxycarbonyl)phenyl|methyl)u azetidin-3-ol, isomeric form A, can be obtained according to the following method: to a suspension of 2.0 g of methyl-(-)-4-((A")- of amino(4-chlorophenyl)methyl|benzoate in 30cm3 of ethanol, add 0.605g of sodium bicarbonate, then 0.60cm3 of epibromohydrin. After stirring for 20 hours at a temperature of 60"C, the reaction mixture is concentrated to dryness under reduced pressure (2.7kPa). The residue is chromatographed on columns with silica gel (granulometry 0.06-0.200 mm; diameter 3 cm, height 35 cm), eluting under argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume for fractions 6-10, then 60 :40 for fractions 18-27, then 50:50) and collecting fractions according to bosm3. Fractions 15-40 are combined, then concentrated to dryness under reduced pressure (2.7kPa). The residue is treated with 30Osm3 ethanol, sweat m add 0.20 g of sodium bicarbonate and 0.2 cm3 of epibromohydrin. After stirring for 48 hours. at a temperature of 202C, then for 24 hours at a temperature of 35"C, the mixture is filtered and the filtrate is concentrated to dryness at a temperature of 60"C and under reduced pressure (2.7 kPa)» 1.76 g of 1-(8")-(4-chlorophenyl) is obtained )|4-(methoxycarbonyl)phenyl|methyl)azetidin-3-ol, isomeric form A, in the form of a pasty solid.

Methyl-(-)-4-(A")-amino-(4-chlorophenyl)methyl|benzoate can be obtained according to the following method: to a solution of 9.2 g of methyl-4-I(85)-amino(4-chlorophenyl )methyl|benzoate in 10 cm3 of methanol, add 2.51 g of O-(-)-tartaric acid. The solution is concentrated to dryness under reduced pressure (2.7 kPa). The resulting cream-colored meringue is dissolved in 50 cm3 of ethanol containing 595 g of water, and the resulting the solution is left to stand for crystallization for 20 hours at a temperature of 20"C. The crystals are filtered off, washed with ethanol at 595% water, filtered under vacuum, then dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained, which are called "A crystals". this name is retained in the case of the subsequent preparation of the second enantiomer methyl-(-)-4-(A")-amino-(4-chlorophenyl)umethyl|benzoate|Y. The mother solutions are concentrated to dryness and a white meringue is obtained in the amount of 8.1 g, which is dissolved in 100 cm3 of ethyl acetate.50 cm3 of 1N sodium hydroxide solution is added to the obtained solution, mixed, decanted.

The organic phase is washed with 50 cm3 of water, then dried over magnesium sulfate and concentrated under reduced pressure (2.7 kPa). A yellow solid is obtained, which is dissolved in 100 cm3 of methanol. 1.85 g of 1-(-)-tartaric acid is added to the resulting solution and the resulting solution is concentrated to dryness under reduced pressure (2.7 kPa). A cream-colored meringue is obtained, which, dissolved once in 27 cm3 of ethanol from 495 water, is left to crystallize for 20 hours at a temperature of 2026.

The crystals are filtered, washed with ethanol from 495 water, filtered under vacuum, then dried under reduced pressure (2.7 kPa). 3.4 g of crystals of 1-(-)-tartrate of methyl-(-)-4-(8")-amino-(4-chlorophenyl)methyl|benzoate are obtained, which are recrystallized from bOsm3 of ethanol from 595 water. After filtering under vacuum, then drying, 2.78 g of white crystals are obtained, which are dissolved in 50 cm3 of ethyl acetate. The resulting solution is added to 100 cm3 of sodium hydroxide solution, mixed, decanted. The organic phase is washed with 50 cm3 of water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.1 g of methyl-(-)-4-(А7-amino(4-chlorophenyl)methyl benzoate is obtained as a white solid.

Methyl 4-(А5)-amino(4-chlorophenyl)methyl|benzoate can be obtained according to the following method: to a suspension of 16.3 g of methyl-4-((85)-phthalimido-(4-chlorophenyl)methyl|benzoate in 3.9 cm3 of hydrazine hydrate is added to 200 cm? of methanol. After stirring for 5 hours at the boiling temperature with an inverted refrigerator, then for 20 hours at a temperature of 20 "С, the reaction mixture is filtered, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is treated a mixture of 200 cm3 of water and 200 cm3 of ethyl acetate.

After stirring for 15 minutes, the resulting suspension is filtered, the filtrate is decanted using a separatory funnel, and the organic phase is washed with 50 cm3 of water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). 8.4 g of methyl-4-((A5)-amino(4-chlorophenyl) methyl) benzoate is obtained in the form of pale yellow oil.

Methyl-4-(А5)-phthalimido(4-chlorophenyl)methyl|benzoate can be obtained according to the following method: to a solution of 11.6 g of methyl-4-(85)-bromo(4-chlorophenyl)methyl|benzoate in 70 cm3 M 12.6 g of potassium phthalimide is added to M-dimethylformamide. After stirring for 3 hours at boiling temperature with an inverted refrigerator, the reaction mixture is cooled to a temperature of 202C, then 300 cm3 of ethyl acetate and 300 cm3 of water are added. After stirring, the mixture is decanted, the aqueous phase is re-extracted twice with 100 cm3 of ethyl acetate, the combined organic phases are washed twice with 400 cm3 of water, then dried over magnesium sulfate and concentrated in a vacuum under reduced pressure (2.7 kPa). 16.3 g of methyl-4-((А5)-phthalimido(4-chlorophenyl)methyl|benzoate is obtained in the form of a yellow pasty solid.

Methyl-4-(А5)-bromo(4-chlorophenyl)methyl|benzoate can be obtained according to the following method: to a solution of 17.4 g of methyl-4-(85)-(4-chlorophenyl) (hydroxy)methyl|benzoate in 10.18 g is added to 200 cm3 of acetonitrile

M,M'-carbonyldiimidazole and 54.3 cm3 of allyl bromide. After stirring for 30 minutes at a temperature of 20°C, the reaction mixture is boiled with an inverted refrigerator for 2 hours, stirred for 20 hours at a temperature of 207°C and concentrated to almost dryness under reduced pressure (2.7 kPa). The mixture treated with dichloromethane is chromatographed on a column with silica gel (granulometry 0.06-0.200mm; diameter 7cm, height

30 cm), under argon pressure of 0.5 bar, eluting with dichloromethane and collecting fractions of 500 cm3. Fractions 3-6 are combined, then concentrated under reduced pressure (2.7 kPa). 11.6 g of methyl-4-((A5)-bromo-(4-chlorophenyl)methylibenzoate is obtained in the form of oil, which is used as it is in the next stage.

Methyl-4-((A5)-(4-chlorophenyl)(hydroxy)methyl|benzoate can be obtained according to the following method: to a suspension of 2.75 g of methyl-4-(4-chlorobenzoylbenzoate) in 200 cm3 of methanol at a temperature of 207C, slowly add small in portions (the medium is heated up to a temperature of 5070) 1.21 g of sodium borohydride. After stirring for 20 hours at a temperature of 20"C, the reaction mixture is concentrated to a smaller volume, then 150 cm? of dichloromethane and, with stirring, 100 cmU3 of 0.5 N saline acid. After decantation, the organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of methyl 4-|(85)-(4-chlorophenyl)(hydroxy)methyl|benzoate is obtained in the form of a colorless oil , which slowly crystallizes at a temperature of 207C and which is used as it is in the next stage.

Methyl 4-(4-chlorobenzoyl)benzoate can be obtained according to the following method: 27.4 cm3 of tri-n-butylphosphine is added to a solution of 19.3 g of monomethyl ether of terephthalic acid chloride in 200 cm3 of tetrahydrofuran in an argon atmosphere cooled to a temperature of -227C. After stirring for a few minutes at a temperature of -22"C, a solution of 4-xchlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene, 2.43 g of magnesium and an iodine crystal in 100 cm3 of diethyl ether at boiling temperature with an inverted refrigerator) is added while maintaining this temperature. After stirring for 30 minutes at a temperature of -22"С, slowly add 150cm3 of hydrochloric acid, leave the reaction mixture to stand until the temperature reaches 202С, then dilute the medium with 200cm3 of diethyl ether. The obtained white suspension is filtered, the solid substance is washed twice with 50 cm? of water, then twice of 50 cm3 of diethyl ether. After filtering under vacuum, then drying under reduced pressure (2.7 kPa), 16.2 g of methyl-4-(4-chlorobenzoyl)benzoate is obtained as a white solid, which melts at a temperature of 17070.

Example 4

A mixture of 2 diastereoisomeric forms of 1-I14-(А8")-(4-chlorophenyl)-(3-(3,5-difluorophenyl)methylsulfonylmethyl- (AE)Iazetidin-1-ylylmethylibenzyl|pyrrolidine and 1-4-KA") -(4-chlorophenyl)-(3-((3,5-difluorophenyl)methylsulfonylmethyl-(5)|azetidin-1-ylmethylIbenzyl|pyrrolidine can be obtained according to the method described in example C, starting from 50 mg of (w)- 1-I4-(8")-(4-chlorophenyl)-/3-((3,5-difluorophenyl)methylsulfonylmethylene azetidin-1-ylmethyl)benzyl| pyrrolidine, isomeric form B, 1.5 cm3 of ethanol, 1.5 cm3 of dichloromethane and 18 mg of sodium borohydride, stirring for 8 hours at a temperature of 502C, then for 48 hours at a temperature of 20"C. 50 mg of a mixture of 2 diastereoisomeric forms of B 1-I|4-

A-(4-chlorophenyl)-(3-((3,5-difluorophenyl)methylsulfonylmethyl-(H)|azetidin-1-ylylmethylibenzyl|pyrrolidine and 1-(14-((8")-(4-chlorophenyl)- (3-(3,5-difluorophenyl)methyl sulfonylmethyl-(5)|azetidin-1-ylmethyl|benzyl|pyrrolidine in the form of a white meringue.

H-NMR spectrum (300 MHz, SOCI3) b (in ppm): a mixture of diastereoisomers is observed in the ratio 60:40, 71.79 (m:4H); 2.45-2.60 (m:5H); 2.67 (c:ZN); 3.10-3.30 (m:2H); 3.40 (mn); 3.57 and 3.60 (2c:2H as a whole); 3.65 (t ush ,, ue7.5HCIN); 4.26 and 4.30 (2c:2Н as a whole); 6.84 (t, 9-9 and 2Гц1Н); 6.96 (m:2Н); 7.25-7, 40 (m: 8H). (-)-1-I4-(87)-(4-Chlorophenyl)-/(3-((3,5-difluorophenyl) methyl sulfonylmethylene|azetidin-1-ylmethyl)benzyl|pyrrolidine, isomeric form B, can be obtained according to the method described in example C, starting from 0.50 g of 1-(A")-(4-(chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-((3, 5-difluorophenyl) (methyl-sulfonyl)methylene|azetidine, isomeric form B, 5 mg of sodium iodide, 15 cm3 of dichloromethane and 0.190 g of pyrrolidine.

The crude product is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 1.5 cm, height 20 cm), under an argon pressure of 0.1 bar, eluting with dichloromethane, then with a mixture of dichloromethane and methanol (in a ratio of 95:5 by volume ) and collecting fractions of 25 cm3. Fractions 20-40 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 0.28 g of 5-difluorophenyl)methylsulfonylmethylene|azetidin-1-ylmethyl)benzyl pyrrolidine, isomeric form B, in the form of a white meringue, (c429 Zb5nm «26.8270.8 (c-0.595; dichloromethane).

H-NMR IS spectrum (Z00MHZc, SOSIzv) b (in ppm): 1.78 (m:4H); 2.50 (m:4H); 2.80 (c:ZN); 3.57 ( s:2H); 3.84 (m:2H); 4.34 (m:2H); 4.50 (sn); 6.84 (t, 9-9 and 2.5HC:1H); 6.98 ( m:2H); 7.20-7.40 (m:8H)|. 1-(87)-(4--"Chloromethyl)phenyl)|-(4-chlorophenyl)methyl)-3-I((3 ,5-difluorophenyl) (methyl sulfonyl)methylene|azetidine, isomeric form B, can be obtained according to the method described in example C, starting from 7.3 g of a mixture of 2 diastereoisomeric forms of B 1-(8")-(4-( chloromethyl)phenyl|-(4-chlorophenyl)methyl)-3-|(A)-(3,5-difluorophenyl) (methylsulfonyl)methyl|azetidin-3-ol and 1-(87-14- (chloromethyl)phenyl) -(4-chlorophenyl)methyl)-3-((5)-(3,5-difluorophenyl) (methylsulfonyl)methyl azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm3 of dichloromethane and 3.2 cm3 of methylsulfonyl chloride. Crude product chromatograph on a column with silica gel (granulometry 0.04-0.06 mm; diameter 3 cm, height 30 cm), under an argon pressure of 0.2 bar, eluting with dichloromethane and collecting fractions of 100 cm 3. Fractions 15-30 are combined, then concentrated to dryness under reduced pressure in (2.7 kPa). 2.50 g of 2 1-(8")-(4-(chloromethyl)phenyl|-(4-chlorophenyl)methyl)-3-|(3,5-difluorophenyl)(methylsulfonyl)methylene| azetidine, isomeric form B, are obtained. in the form of white meringue.

A mixture of 2 diastereoisomeric forms B 1-(А8М)-(4-(chloromethyl)phenyl|-(4-chlorophenyl)methyl)-3-(А)-(3,5-difluorophenyl)(methylsulfonyl)methyl|Iiazetidine-Z- ol and 1-(87)-(4-(chloromethyl)phenyl|-(4-chlorophenyl)methyl)-3-

I(5)-(3,5-difluorophenyl)methylsulfonyl)methyl|Iazetidin-3-ol can be obtained according to the method described in example C, starting from 11.0 g of a mixture of 2 diastereoisomeric forms of B 1-(8")- (4-(chlorophenyl)|4-(hydroxymethyl)phenyl|methyl)-3-(A)-(3,5-difluorophenyl) (methylsulfonyl)methyl|iazetidin-3-ol and 1-(8")-(4 - (chlorophenyl) (|4-(hydroxymethyl)phenyl|methyl)-3-((5)-(3,5-difluorophenyl) methylsulfonyl)methyl|azetidin-3-ol, 250 cm3 of dichloromethane and 33.1 cm3 of thionyl chloride. Raw product chromatographed on a column with silica gel (granulometry 0.04-0.0b6mm; diameter 3cm, height 30cm), under an argon pressure of 0.2bar, eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume) and collecting fractions of 50cm3 . Fractions 9-25 are combined, then concentrated to dryness under reduced pressure (2.7 kPa)" 7.3 g of a mixture of 2 diastereoisomeric forms B /(1-(А87)-(4-(chloromethyl)phenyl)|-(4- chlorophenyl)methyl)-3-((H)-(3,5-difluorophenyl) (methylsulfonyl)methyliazetidin-3-ol and 1-(87)-(4-(chloromethyl)phenyl|-(4-chlorophenyl)methyl) -3-( (5)-(3,5-difluorophenyl) (methylsulfonyl)methyl|azetidin-3-ol in the form of a white meringue.

A mixture of 2 diastereoisomeric forms of 1-(A")-(4-(chlorophenyl) (4-(hydroxy-methyl)phenyl|methyl)-3-(A)-(3,5- difluorophenyl)(methylsulfonyl)methyl azetidine- 3-ol and 1-((8")-(4-(chlorophenyl) I(4-(hydroxymethyl)phenyl|methyl)u- 3-KA)-(3,5-difluorophenyl) (methylsulfonyl)methyl|azetidin- 3-ol can be obtained according to the method described in example 3, starting from 18.0 g of a mixture of two diastereoisomeric forms of 33-acetoxy-1-(8")-(4-chlorophenyl)|4-(methoxycarbonyl)phenyl|methyl )-3-((A)-(3,5-difluorophenyl)(methylsulfonyl)methyl|azetidine and 3-acetoxy-1-(8")-(4-chlorophenyl)(4-(methoxycarbonyl/phenyl|methyl)u -3-I(5)-(3,5- difluorophenyl)(methylsulfonyl)methyl|iazetidine, 150 cm3 of anhydrous toluene and 100 cm3 of a 2095 solution of diisobutylaluminum hydride in toluene. The crude product is chromatographed on a silica gel column (granulometry 0.06- 0.200 mm; diameter 3 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 50:50 by volume) and collecting fractions of 50 cm3. Fractions 15-30 are combined , then concentrated to dryness under reduced pressure (2.7 kPa). 11.0 g of a mixture of 2 diastereoisomeric forms of B 1- (AM)-(4-(chlorophenyl)|(4-(hydroxymethyl)phenyl|methyl)u-3-|(A)-(3,5-difluorophenyl) (methylsulfonyl )methyl|iazetidin-3-ol and 1-(8")-(4-(chlorophenyl) (|4-(hydroxymethyl)phenyl|methyl)-3-I(5)-(3,5-difluorophenyl)(methylsulfonyl ) methyl|azetidin-3-ol in the form of a white meringue.

A mixture of 2 diastereoisomeric forms in 3-acetoxy-1-(A")-(4-chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)-3-

KA)-(3,5-difluorophenyl)(methylsulfonyl)methyl azetidine and 3-acetoxy-1-(8")-(4-chlorophenyl)|4-

(methoxycarbonyl)phenyl|methyl)-3-((5)-(3,5-difluorophenyl)x(methylsulfonyl)methyl|Iazetidine can be obtained according to the method described in example 3, starting from 11.2 g (3.5 -difluorobenzyl)methylsulfone,

C50cm3 of tetrahydrofuran, 34cm3 of a 1.6bn solution of n-butyllithium in hexane, 11.2g of 1-(8)-(4-chlorophenyl)|4-(methoxycarbonyl)phenyl|methyl)azetidin-3-one, isomeric form B, and 5 .5 cm3 of acetyl chloride. The crude product is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 4 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume) and collecting fractions of 100 cm3.

Fractions 10-30 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 21 g of still contaminated cream-colored meringue is obtained, which is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting fractions of 100 cm3. Fractions 11-

ZO are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of a mixture of 2 diastereoisomeric forms in 3-acetoxy-1-(A")-(4-chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)u-3-(A)-(3,5-difluorophenyl) are obtained )(methylsulfonyl)methyl)|azetidine and 3-acetoxy-1-((87)-(4-chlorophenyl)|4-(methoxycarbonyl)phenyl|methyl)-3-I|(5)-(3,5-difluorophenyl ) (methylsulfonyl)methyl|azetidine in the form of a white meringue. 1-(87)-(4-Chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyliazetidin-3-one, isomeric form B, can be obtained according to the method, described in example 3, based on 8.7 cm3 of oxalyl chloride, 350 cm3 of dichloromethane, 14 2 cm3 of dimethyl sulfoxide, 29.0 g of 1-(87)-(4-chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)azetidin-3-ol, isomeric form B, and 43 cm3 of triethylamine. The crude product is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting fractions of 250 cm3. Fractions 7-25 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of 1-(A")-(4-chlorophenyl)|4-(methoxycarbonyl)phenyl|meth l)azetidin-3-one, isomeric form B, in the form of a yellow-brown oil. 1-(87)-(4-Chlorophenyl)|(4-(methoxycarbonyl)phenyl|methyl)azetidin-3-ol, isomeric form B, can be obtained according to the method described in example C, starting from 25.5 g of methyl -(-)-4-(A")-amino(4-chlorophenyl)methyl|benzoate, 250 cm3 of ethanol, 7.9 g of sodium bicarbonate and 7.7 cm3 of epibromohydrin. 29 g of 1-(87)-(4-chlorophenyl)( 4-(Methoxycarbonyl)phenyl|methyl)azetidin-3-ol, isomeric form B, in the form of a yellow oil.

Methyl-(-)-4-KA")-amino(4-chlorophenyl)methyl|I|benzoate can be obtained by carrying out two successive recrystallizations of white crystals in the amount of 3.4 g, called "crystals A" according to example 3, of bdsm? ethanol from 595 water at boiling temperature with an inverted refrigerator. The resulting crystals are filtered, squeezed, then dried under reduced pressure (2.7 kPa). 2.2 g of ethyl-(-)-4-tartrate is obtained -(A")-amino-(4-chlorophenyl)umethyl| benzoate in the form of white crystals, which are dissolved in 50 cm3 of ethyl acetate. Add 50 cm3 of sodium hydroxide solution to the resulting solution, mix, then decant. The organic phase is washed with 50 cm3 of water, then dried over magnesium sulfate and concentrated under reduced pressure (2.7 kPa). 1.9 g of methyl-(-)-4-(A")-amino(4-chlorophenyl)methylibenzoate is obtained in the form of a white solid.

Example 5 1-(Bis(thien-2-yl)umethyl-3-(A5)-(3,5-difluorophenyl)methylsulfonylmethyl| azetidine can be obtained according to the method described in example 3, starting from 0.10 g of 1- Ibis(thien-2-yl)umethyl-3-(3,5-difluorophenyl)methylsulfonyl-methylene| azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 25 mg of sodium borohydride, with stirring for 3 hours at a temperature of 20"C. The crude product is chromatographed on columns with silica gel (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure of 0.1 bar with dichloromethane and collecting fractions of 4 cm 3. Fractions 2-5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 83 mg of 1-Ibis(thien-2-yl)umethylI|-3-KA5)-(9,5-difluorophenyl)methylsulfonylmethyliazetidine is obtained as a white solid.

H-NMR spectrum (400MHz, SOSIz) b (in ppm): 2.60-2.70 (m:"1Н); 2.66 (c:ZN); 3.31 (m:2H); 3.40 (m:1H); 3.73 (t ush., uU-7.5Hz:1H); 4.27 (d, 9-11 Hz: 1H); 4.92 (c:1H); 6.83 (t, U29 and 2.5Hz:1H); 6.85-7.00 (m:bN); 7.21 (m:2H)|. 1-(Bis(thien-2-yl)umethylI-3-((3,5-difluorophenyl)umethylsulfonylmethylene) azetidine can be obtained according to the method described in example b, starting from 2.2 g of 1-I(bis(thiene -2-yl)umethyl|-3-|(3,5-difluorophenyl)methylsulfonyl-methyl-(B5)| azetidin-3-ol, 0.64 cm3 of methylsulfonyl chloride, 2.3 g of 4-dimethylaminopyridine and 75 cm3 of dichloromethane; after purification by chromatography and crystallization from diisopropyl ether yield 1.3 g of 1-I|bis(thien-2-ylmethyl)|-3-(3,5-difluorophenyl)methylsulfonylmethylene|azetidine in the form of white crystals that melt at a temperature of 16570. 1-(Bis(thien-2-yl)umethyl-3-((3,5-difluorophenyl)methylsulfonylmethyl-(H5)|azetidin-3-ol) can be obtained according to the following method: to cooled to a temperature of -60"С of a solution of 1.3g of (3,5-difluorobenzyl)methylsulfone in 20cm3 of tetrahydrofuran in an argon atmosphere for 10 minutes, add 4cm3 of a 1.bn solution of n-butyllithium in hexane. After stirring for 45 minutes at a temperature of -707C, add more for 10 minutes 1.5 g of 1-bis(thien-2-yl)umethyl solution of azetidine-Z-one in 20 cm3 of tetrahydrofuran. After stirring for 3 hours at a temperature of -70"C, the reaction mixture is left to stand until it cools to room temperature, then 10 cm3 of an aqueous saturated ammonium chloride solution is added. The mixture is decanted, the organic phase is dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2 .7kKPa). The residue is treated with 20 cm3 of a mixture of cyclohexane and ethyl acetate (in a ratio of 60:40 by volume), the resulting suspension is filtered, the solid substance is squeezed out, then dried in air. 2.2 g of 1-Ibis (thien-2- yl)umethyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl- (A5))azetidin-3-ol in the form of white crystals that melt at a temperature of 14576. 1-Bis(thien-2-ylylmethylIiazetidin-3-one can be obtained according to the method described in example 1 (method 2), starting from 4g of 1-bis(thien-2-ylmethyliazetidin-3-ol, 2.bcm3 of dimethylsulfoxide, 7.7cm3 of triethylamine, 7.7cm3 of oxalyl chloride and 100cm3 of dichloromethane The resulting residue is purified by chromium tography on a column with silica gel (granulometry 0.04-0.0 mm; diameter 3cm, height 3cm), using a mixture of cyclohexane and ethyl acetate (1:1 by volume) as an eluent. The resulting fractions are evaporated to dryness under reduced pressure (2.7 kPa). 3.2 g of 1-Ibis(thien-2-yl)umethyl|azetidin-3-one are obtained in the form of cream-colored crystals that melt at a temperature of 7070. 1-Ibis(thien-2-yl)umethyl|iazetidin-3-ol can be obtained according to the method described in example 3, starting from 1-Ibis(thien-2-yl)umethyliamine, 2.5 cm3 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm3 of ethanol.

4 g of 1-|bis(thien-2-ylmethyl-Iiazetidin-3-ol) are obtained in the form of beige crystals that melt at a temperature of 11576. 1-Bis(thien-2-ylmethyl|amine can be obtained in the following way: in an argon atmosphere to to a suspension of thien-2-ylmagnesium bromide cooled to a temperature of 102C (obtained from 1.29 g of magnesium and 3.22 cm3 of 2-bromothiophene in 75 cm3 of diethyl ether) a solution of 5 cm3 of thiophene-2-ylcarbonitrile in 50 cm3 of diethyl ether is added dropwise. After boiling with inverted in a refrigerator for 1 hour 30 minutes, the reaction medium is cooled to a temperature of 5"C, then 20 cm3 of methanol is added dropwise, the suspension is filtered, the solid substance is washed with methanol. The resulting filtrate is a chestnut-colored solution. In an argon atmosphere, several portions of 2 are added to this solution ,45 g of sodium borohydride. The mixture is stirred at room temperature for 16 hours, then diluted with ethyl acetate and water is slowly added. The organic phase is separated, washed with water, dried over su with magnesium sulfate and evaporated to dryness under reduced pressure (2.7 kPa) at a temperature of 557"C. A chestnut-colored oil is obtained, which is chromatographed on a column with silica gel (granulometry 0.2-0.063 mm; diameter 8 cm, height 25 cm) and eluted with a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10, then 85:15, by volume) . Fractions 21-30 are evaporated to dryness under reduced pressure (2.7 kPa). 11 g of 1-bis(thien-2-ylmethyl)amine are obtained in the form of a crystalline solid.

Example 6 1-(Bis(p-tolylmethyl-3-((A5)-methylsulfonylphenylmethyl) azetidine can be obtained according to the method described in example C, starting from Kk! 0 1og 1-(bis(p-tolylmethyl) (methylsulfonylphenylmethylene)azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 25 mg of sodium borohydride.

The crude product is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure of 0.1 bar with dichloromethane and collecting fractions of 4 cm3. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 35 mg of 1-Ibis(p-tolyl)umethylI-3-(А5Б)-methylsulfonylphenylmethyliazetidine is obtained in the form of a white solid.

H-NMR spectrum (Z0O0MHCz, SOSIv) b (in ppm): 2.24 (c:ZN); 2.27 (C:ZN); 2.53 (t, 9u-7.5HtsiN); 2.58 (s:ZN); 3.19 (m:2H); 3.49 (m:1H); 3.69 (t ush, 9U-7.5HzC:1H); 4.22 (s:/ 1H); 4.28 (d, 9-11.5 Hz: 1H); 6.95-7.45 (multiplets: 1Z3H)). 1-(Bis(p-tolyl)umethyl|-3-methylsulfonylphenylmethylene)azetidine can be obtained according to the following method: 0.125 cm3 of methylsulfonyl chloride is added to a solution of 0.48 g of 1-bis(p-tolylumethyl|-3-(Imethylsulfonylphenylmethyl-(KI)azetidin-3-ol) in 25 cm3 of anhydrous dichloromethane, then, in small portions, 0.465 g 4-dimethylaminopyridine. After stirring for 20 hours at a temperature of 20"C, the reaction mixture is washed twice with 80 cm3 of water, with the help of 80 cm3 of brine, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.040-0.063 mm; height 17 cm, diameter 3.2 cm), eluting under argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 80:20 by volume ah) and collecting fractions of 40 cm3. Fractions 5-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is mixed with isopropyl ether, the solid substance is filtered, squeezed, then dried under reduced pressure (2.7 kPa).

0.25 g of 1-Ibis(p-tolyl)umethyl|-3--"methylsulfonylphenylmethylene)azetidine is obtained in the form of a white solid substance.

H-NMR spectrum (250 MHz, DMSO-av, T-ZOOK) b (in ppm): З), 3.76 (2Н, с, МОН»), 4.20 (2Н, с, МОН»), 5.55 (1Н, с, MSN), 7.10 (4Н, d, 9-7 Hz , 4 CH arom.), 7.32 (AN, d, 9-7 Hz, 4 CH arom.), 7.AZ (5H, c, Phenyl))|. 1-(Bis(p-tolylumethylI|-3 -(methylsulfonyl)phenylmethyl-(85)|azetidin-3-ol can be obtained according to the following method: to a solution of 0.59 g of bromo(bis-p-tolyl)methane in 20 cm3 of acetonitrile, 0.6 mg of 3-Kmethyl-sulfonyl hydrochloride is added )(phenylmethyl-(A5)|azetidin-Z-ol, then 0.3 g of potassium carbonate. After boiling with an inverted refrigerator for 1 hour and 15 minutes, the reaction mixture is cooled to a temperature of 20"C and filtered. The filtrate is concentrated to dryness under reduced pressure (2.7kPa) and the residue is chromatographed on a column with silica gel (granulometry 0.04-0.0bmm; diameter 4cm, height 1bsm), eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume) and collecting the fractions 50 cm3 each. Fractions 8-13 are concentrated to dryness under reduced pressure pressure (2.7 kPa) 0.48 g of 1-I(bis(p-tolyl)methyl|-3- (methylsulfonyl(phenyl)methyl-(H5)|azetidin-3-ol) is obtained as a white solid.

Bromobis-p-tolylumethane can be obtained according to the method described by M.E. VASNMAMM, 9. At.

Spent os, 2135 (1933).

Hydrochloride 3-((methylsulfonyl)/phenylmethyl-(А5)|azetidin-3-ol can be obtained according to the following method: to a solution of 2.62 g of 3-(methyl sulfonyl)(phenyl)methyl-(НА5)|-1- (vinyloxycarbonyl)azetidin-3-ol in 12.6 cm3 of dioxane add 12.6 cm3 of a 6b.2N solution of hydrogen chloride in dioxane. After stirring for 20 hours at a temperature of 20"C, the mixture is concentrated to dryness at a temperature of 50"C under reduced pressure (2.7KkPa ).

The residue is treated with 25 cm3 of ethanol, boiled with an inverted refrigerator for 1 hour, then left to stand until the temperature returns to 20"C and filtered. The solid is washed with diethyl ether, then squeezed and dried under reduced pressure (2.7 kPa). 1.89 g of 3-((methylsulfonyl)phenylmethyl-(A5)|azetidin-3-ol hydrochloride is obtained in the form of white crystals. 3-(Methylsulfonyl)(phenyl)methyl-(A5)|-1-(vinyloxycarbonylluazetidin-3- ol can be obtained according to the following method: to a mixture cooled to a temperature of 5"C, 3.92 g of 1-benzhydryl-3-

I(methylsulfonyl)(phenyl)methyl-(H5))| of azetidin-3Z-ol in 500 cm3 of anhydrous dichloromethane is added dropwise to a solution of 0.99 cm3 of vinyl chloroformate in 4 cm3 of anhydrous dichloromethane. After stirring for 48 hours at a temperature of 207"C, the reaction mixture is concentrated to dryness under reduced pressure (2.7kPa). The residue is chromatographed on a column with silica gel (granulometry 0.04-0.06bmm; diameter 5.bsm, height 15.5cm),

eluting with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting fractions of 50 cm3. Fractions 17-36 are concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of 3-(methylsulfonyl)u(phenyl)methyl-(A5)|-1-(vinyloxycarbonyl)azetidin-3-ol is obtained as a white solid. 1-Benzhydryl-3-((methylsulfonylluphenyl)methyl-(HA5)|azetidin-3-sl can be obtained according to the method described in example 1 (method 1), starting from 47 cm3 of diisopropyl alcohol, 205.6 cm3 of a 1.6 M solution of - butyllithium in hexane, 2.2 l of tetrahydrofuran, 50 g of benzyl methyl sulfone and 9 cm3 of 1-benz-hydrylazetidin-3-one.

94.3 g of 1-benzhydryl-3-(methylsulfonyl)(phenyl)methyl-(A5)azetidin-3-ol are obtained in the form of white crystals.

Example 7 1-(Bis(3-fluorophenyl)methyl|-3-(85)-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine can be obtained according to the method described in example 3, starting from 0.10 g of 1 -I(bis(3-fluorophenyl)methyl|-3-|(3,5- difluorophenyl)methylsulfonylmethylene| azetidine, 2 cm3 of methanol, 2 cm? of dichloromethane and 20 mg of sodium borohydride, with stirring for 48 hours at a temperature of 20"C. Raw product chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure

0.1 bar dichloromethane and collecting fractions of 4 cm3. Fractions 3-7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 95 mg of 1-Ibis(3-fluorophenyl)methyl|-3-(А85)-((3,5-difluorophenyl)methyl-sulfonylmethyliazetidine is obtained in the form of white crystals.

IS spectrum "H-NMR (30 MHz; SOSIv) b (in ppm): m:2H); 3.30-3.50 (m:H); 3.66 (t ush., U-27.5Hz:1H); 4.27 (d, 9211.5Hz:1H); 4, 28 (c:1H); 6.75-7.35 (m.11H)|. 1-(Bis(3-fluorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethylene|azetidine can be obtained according to of the method described in example b, starting from 1.15 g of 1-|bis(33-fluorophenyl)methyl|-3-|(3,5-difluorophenyl) (methylsulfonyl)methyl-(А5)|azetidin-3-ol, ЗОсm3 of dichloromethane, 0.264 cm3 of methylsulfonyl chloride and 0.98 g of 4-dimethylaminopyridine. After chromatography on a column with silica gel (granulometry 0.06-0.200 mm; diameter 2.8 cm, height 25 cm), under an argon pressure of 1 bar, with a mixture of ethyl acetate and cyclohexane (using ratio 15:85 by volume) as an eluent, and collecting fractions according to bosm3, 0.55 g of 1-(bis(3-fluorophenyl)methyl|-3-((3,5-difluorophenyl)(methylsulfonyl)methylene) is obtained azetidine in the form of a white solid that melts at a temperature of 17826. 1-(Bis(3-fluoro enyl)methyl|-3-(3,5-difluorophenyl). (methylsulfonyl)methyl-(A5)|-azetidin-3-ol can be obtained according to the following method: to a mixture of diisopropylamine and 10 cm3 of tetrahydrofuran cooled to a temperature of -60"С, 3.65 cm3 of a 1.6 M solution of n-butyllithium is added for 10 minutes in hexane, stir for 10 minutes at a temperature of -30"C, then cool to a temperature of -707C. After that, a solution of 1.2 g of (3,5-difluorobenzyl)methylsulfone in 300 cm3 of tetrahydrofuran is added for 20 minutes.

After stirring for 30 minutes at a temperature of -707"C, a solution of 1.5 g of 1-(bis(z-fluorophenyl)methyl|iazetidin-Z3-one in 10 cm3 of tetrahydrofuran is added to the mixture for 30 minutes. After stirring for 2 hours at a temperature of -70 The reaction mixture is brought to room temperature, then 20 cm3 of a saturated aqueous solution of ammonium chloride and 100 cm3 of dichloromethane are added. The mixture is decanted, the organic phase is washed with water, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed. on a column with silica gel (granulometry 0.06-0.200 mm; diameter 3.2 cm, height 30 cm), eluting under 1 bar argon pressure with a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions by bosm3. Fractions 9-20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.95 g of 1-bis(3z-fluorophenyl)methyl|-3-(3,5-difluorophenyl)(methylsulfonyl)methyl-(H5) are obtained )|azetidin-Z-ol in the form of a white solid substance, i ka melts at a temperature of 1707C (decomposition). 1-(Bis(3-fluorophenyl)methyl|iazetidin-3-one can be obtained according to the method described in example 1 (method 2), starting from 0.7 cm? of oxalyl chloride, 16 cm3 of dichloromethane, 1.12 cm3 of dimethyl sulfoxide, 2 g 1 -(bis(3-fluorophenyl)methyl|azetidin-3-ol and 33.7 cm3 of triethylamine. 1.55 g of 1-(bis(3-fluorophenyl)methyl|azetidin-3-one is obtained in the form of oil, which crystallizes at a temperature of 2076 1-(Bis(3-fluorophenyl)methyl|iazetidin-3-ol can be obtained according to the method described

A.V. KATVIT5KU u u). Selfish people. Spet., 31, 271 (1994), based on 4.9 g of bis(33-fluorophenyl)methyliamine and 1.78 cm3 of epichlorohydrin.

Ibis(3-fluorophenyl)methylamine can be obtained as follows: a solution of 5.17 g of 3,3'-difluorobenzophenonexime in 30 cm3 of tetrahydrofuran is added to a suspension of 1.27 g of lithium aluminum hydride in 80 cm3 of tetrahydrofuran in an argon atmosphere for 30 minutes. After stirring for 5 hours, while boiling with the refrigerator inverted, 1.3 cm3 of water, 1.3 cm? 4N sodium hydroxide solution, 2.6 cm3 of water, then 50 cm3 of ethyl acetate. After drying over magnesium sulfate and concentration to dryness under reduced pressure (2.7 kPa), 4.9 g of bis(3-fluorophenyl)methyliamine is obtained in the form of a yellow oil. ,0g of 3,3'-difluorobenzophenone in 10cm3 of ethanol, a solution of 1.6g of hydroxylamine hydrochloride in 8cm3 of water is added dropwise, then 1.2g of sodium hydroxide in tablets is added in small portions. The reaction mixture, after boiling with an inverted refrigerator for 10 minutes, is cooled to a temperature of 20"C, then acidified using 7.5 cm3 of 4N hydrochloric acid. The obtained oily precipitate, subjected to powdering once, becomes a white solid substance, which is filtered, washed with water, then dried at a temperature of 35"C under reduced pressure (2 5.17 g of 3,3'-difluorobenzophenone oxime are obtained in the form of a white solid.

Example 8 1-(Bis(4-chlorophenyl)methyl-3-(A85)-((3-azetidin-1-ylphenyl|methylsulfonylmethyl)iazetidine can be obtained according to the method described in example C, starting from 0.10 g of 1 -(bis(4-chlorophenyl)methyl|-3-

Casetidin-1-ylphenyl)umethylsulfonylmethylene| of azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and Zomg of sodium borohydride, with stirring for 24 hours at a temperature of 20"C. The crude product is chromatographed on a silica gel column (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure 0, 1 bar dichloromethane and collecting fractions of 4 cm3. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 20 mg of 1-Ibis(4-chlorophenyl)methyl|-3-(A5)-(IZ-azetidine) are obtained -1-ylphenyl|methylsulfonylmethyl)azetidine in the form of an off-white varnish.

IS spectrum "H-NMR (ZOOMHCts, SOSIzv) b (in ppm): ; 3.20 (m:2H); 3.47 (m/n); 3.66 (t ush., 9-7 Hz: H); 3.89 (t ush., 9U-7.5Hz: 4H ); 4.20 (d, 9-11 Hz: 1H); 4.26 (s: 1H); 6.35-6.50 (m: 2H); 6.67 (d ear, uU-7.5Hz :1H); 7.10-7.40 (m:9H)I). 1-IBis(4-chlorophenyl)methyl|-3-casetidin-1-ylphenyl) methylsulfonyl-methylene|azetidine can be obtained according to the method, described in example b, based on 0.83 g of 1-(bis(4-chlorophenyl)methyl|-3-

Casetidin-1-ylphenyl)umethylsulfonylmethyl-(H5)|azetidin-3-ol, 20 cm3 of dichloromethane, 0.18 cm3 of methylsulfonyl chloride and 0.75 g of 4-dimethylaminopyridine. Get 0.40 g of 1-I(bis(4-chlorophenyl)methyl|-3-

Casetidin-1-ylphenyl) methylsulfonyl-methyleneiazetidine in the form of a white meringue. 1-(Bis(4-chlorophenyl)methylI-3-K(azetidin-1-ylphenylmethylsulfonylmethyl-(A5)|azetidin-3-ol can be obtained according to the method described in example 5, starting from (From 1.55g of 1- (3-methylsulfonylmethylphenyl)azetidine, 5.2cm3 of a 1.6M solution of n-butyllithium in hexane, 30cm3 of tetrahydrofuran and 2x11g of 1-bis(4-chlorophenyl)methyl|iazetidin-Z-one. 0.83g of 1-I(bis( 4-Chlorophenyl)methyl|-3-Cazetidin-1-ylphenyl)methylsulfonylmethyl-(H5)|azetidin-3-ol in the form of an ochre-colored solid which melts at a temperature of 17276. 1--3-Methylsulfonylmethylphenyl)jazetidine can be obtained in the following way; to a mixture of 10 cm3 of water, 5 cm3 of acetic acid, 1.5 cm3 of Zbn sulfuric acid and 6.15 g of oxone, cooled to a temperature of 0"C, a solution of 1.9 g of 1-(3-methylsulfanylmethylphenyl)azetidine in 10 cm? of ethanol is added. After mixing for 20 hours at a temperature of 20"C, 100 cm3 of water, 100 cm3 of ethyl acetate are added to the reaction mixture, then neutralized by mixing with sodium bicarbonate. The resulting mixture is decanted are added, the organic phase is dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa).

1.55 g of i--(3-methylsulfonylmethylphenyl) azetidine is obtained in the form of a light brown resinous substance. 1-(3-"Methylsulfanylmethyl)phenyl|iazetidine can be obtained in the following way: to a solution of 4.6g of 1-iodo-3-(methylsulfanylmethyl)benzene in b0cm3 of tetrahydrofuran in an argon atmosphere, add 2.57g of potassium tert-butylate, 0. 64g of 1,1-bisidiphenylphosphino)ferrocenylpalladium chloride, 1,49g of 1,1"-bisidiphenylphosphino)ferrocene, 0.12g of copper iodide and 2.0g of azetidine. After boiling with an inverted refrigerator for 3 hours, the reaction mixture is cooled to room temperature and filtered through celite, washing it with 150 cm3 of ethyl acetate. The combined filtrate and ethyl acetate, which was used for washing, are acidified with 120 cm3 of 1 N hydrochloric acid, then decanted. Bosm3 of ethyl acetate is added to the aqueous phase, then alkalinized with sodium bicarbonate and the mixture is decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 3.5 cm, height 50 cm), eluting under argon pressure

0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions of 100 cm3. Fractions 1-3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.9 g of 1-I(3-(methylsulfanylmethyl)phenyl azetidine is obtained in the form of an oil. 1,1-Bisidiphenylphosphino)ferrocenylpalladium chloride can be obtained according to T. Nauazvpi et al., in

U. At. Spent boss, 106,158 (1984). 1-Iodo-3-(methylsulfanylmethyl)benzene can be obtained in the following way; 6.4 g of sodium methylthiolate is added to a solution of 25 g of Z3-iodobenzyl bromide in 80 cm3 of M,M-dimethylformamide. After stirring for 20 hours at a temperature of 20"C, 250cm3 of water, 200cm3 of ethyl acetate are added to the reaction mixture and mixed, then decanted. The organic phase is washed 4 times with 200cm3 of water, dried over magnesium sulfate, filtered, concentrated to dryness at a temperature of 50"C and reduced pressure (2.7 kPa). 22 g of 1-iodo-3-(methylsulfanylmethyl)benzene are obtained in the form of a resinous substance.

Example 9

A mixture of 2 diastereoisomeric forms of A 1-(87)-4-(4-chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonylmethyl- (A2)|-3-imidazolylazetidin-1-ylylmethyl| benzyl)-1H-imidazole And 1-(87)-14-(4-chlorophenyl)(3-|(3,5-difluorophenyl)methyl-sulfonylmethyl-(5)|-3-imidazolylazetidin-1-ylliummethyl|benzyl)-1H-imidazole can be obtained in the following way to a solution of 50 mg of 1-(A")-(4-(chloromethyl)phenyl)|(4-chlorophenyl)methyl)-3-((3,5-difluorophenyl) methylsulfonyl-methylene|azetidine, isomeric form A, 13.bmg of imidazole is added to 1 cm3 of dichloromethane. After stirring for 20 hours at a temperature of 20"C, the reaction mixture is directly chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 7 cm, diameter 1 cm), eluting under argon pressure 0, 1 bar using a mixture of dichloromethane and methanol (in a ratio of 98:22 by volume) and collecting fractions of 4 cm3.Fractions 4-9 are combined and concentrated to dryness under reduced pressure (2.7 kPa).

20 mg of a mixture of 2 diastereoisomeric forms of A 1-(87)-14-((4-chlorophenyl)(3-(3,5-difluorophenyl)methylsulfonylmethyl-(H)|-3-imidazolylazetidin-1-ylylmethyl|benzyl)|- 1H-imidazole and 1-(87)-(4-(4-chlorophenyl)-(3-((3,5-difluorophenyl)umethylsulfonylmethyl-(5)|-3- imidazolylazetidin-1-ylylmethyl|benzyl)-1H- imidazole in the form of a white varnish.

IS spectrum "H-NMR (300 MHz, SOSIzv) b (in ppm): a mixture of diastereoisomers is observed, " 2.64 (c:ZN); 3.42 (d, u8HC:1H); 3.50 (d, 9U58HzC:1H); 3.75 (m:1H); 4.31 (d ear., U-8Hz:1H); 4.40 (si); 4.54 and 4.55 (2c:2H in general); 4.72 (sn); 6.84 (m:2H); 6.87 (c: 1H); 6.95 (min); 7.11 (Sun); 7.20-7.40 (mi12H)I).

Example 10 (1-Benzhydrylazetidin-3-yl)uphenylmethanone-O-methyloxime, a mixture of 2 isomers of 7 and E, can be obtained in the following way: to a suspension of 0.80g of 1-benzhydryl-3-benzoylazetidine in 30cm3 of ethanol, add 0.286bg of O - methylhydroxylamine hydrochloride and 0.32 g of sodium acetate. After stirring for 24 hours at boiling temperature with an inverted refrigerator, the reaction mixture is left to cool to room temperature and filtered. The filtrate is concentrated to dryness at a temperature of 507C under reduced pressure (2.7 kPa).

The residue is treated with 100 cm3 of dichloromethane and 20 cm? water and Tn hydrochloric acid with stirring until the acidic pH value is reached. The organic phase is decanted, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height Zbsm, diameter 33.8 cm), eluting under an argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in the ratio 95:5, 92:8, then 80:20 , by volume) and collecting fractions by ZOcm3. Fractions 8-14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.20 g of (1-benzhydrylazetidin-3-yl)uphenylmethanone-O-methyloxime, a mixture of 2 isomers 2 and E, is obtained as a white solid.

H-NMR spectrum (250 MHz, (C03)250 - av) b (in ppm): a mixture of isomers is observed in the ratio 65:35, 7 2.68-3.02 and 3.25-3.90 ( multiplets: 5Н as a whole); 3.76 and 3.80 (2с:ЗН as a whole); 4.26 and 4.38 (2с1Н as a whole); 7.10-7.50 (m:15Н)). 1 - Benzhydryl-3-benzoylazetidine can be obtained in the following way: to cooled to temperature

To a solution of 11.5 g of M-methoxy-M-methylamide (1-benzhydrylazetidin-3-yl) carboxylic acid in 350 cm3 of tetrahydrofuran in an argon atmosphere, 112 cm3 of a 1 M solution of phenylmagnesium bromide in tetrahydrofuran is added dropwise, then the mixture is left to stand until it cools to room temperature. After stirring for 20 hours at a temperature of 207C, 400 cm3 of an aqueous saturated solution of ammonium chloride, then 250 cm3 of ethyl acetate are added to the reaction mixture. After stirring, the mixture is decanted, the aqueous phase is extracted again with 250 cm3 of ethyl acetate, and both combined organic phases are washed twice with 250 cm3 of water, dried over magnesium sulfate, then filtered and concentrated to dryness at a temperature of 502C and reduced pressure (2.7 kPa). The residue is mixed with 50 cm3 of isopropyl ether, the suspension is filtered, the solid substance is squeezed out, then dried under reduced pressure (2.7 kPa). 9.76 g of 1-benzhydryl-3-benzoylazetidine is obtained as a cream-colored solid.

M-Methoxy-M-methylamide (1-benzhydrylazetidin-3-yl) carboxylic acid can be obtained in the following way; 13.35 g of (1-benzhydrylazetidin-3-ylcarboxylic acid and 1.0 g of hydroxybenzotriazole hydrate are added to a suspension of M,O-dimethylhydroxylamine hydrochloride in 250 cm3 of dichloromethane with stirring. To this mixture, which is in an argon atmosphere and cooled to a temperature of 5"C, add 6.92 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 8.8 cm3 of M,M-diisopropylethylamine. After stirring for 3 hours at a temperature of 57°C, then for 20 hours at a temperature of 20°C, add to the reaction mixture 200 cm3 of water, then decanted. The organic phase is washed with 300 cm3 of water, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 100 cmU of isopropyl ether, the suspension is filtered and the solid is squeezed out, then dried at under reduced pressure (2.7 kPa). 10.76 g of M-methoxy-M-methylamide (1-benzhydrylazetidin-

Z-il)ucarboxylic acid in the form of a cream-colored solid. (1-Benzhydrylazetidin-3-yl)ucarboxylic acid can be obtained in the following way: to a suspension of 14g of (1-benzhydrylazetidin-3-yl)carbonitrile in 140cm3 of 2-ethoxyethanol, cooled to a temperature of 52C, a solution of 11g of potassium hydroxide in Uscm3 of water is added dropwise , then the mixture is heated to 95"C. After stirring for 16 hours at this temperature, the reaction mixture is slowly, with stirring, poured onto ice and kept at a temperature of 0"C for 68 hours, then concentrated to dryness at a temperature of 50"C and reduced pressure ( 2.7 kPa). The residue is treated with 400 cm3 of water, the resulting solution is acidified to pH 4 with the help of bn hydrochloric acid, then 400 cm3 of ethyl acetate is added. The suspension obtained as a result is filtered, the solid substance is squeezed out, then dried at a temperature of 507C and reduced pressure ( 2.7 kPa). 13.55 g of (1-benzhydrylazetidin-3-yl)ucarboxylic acid is obtained as a cream-colored solid. (1-Benzhydrylazetidin-3-yl)ucarbonitrile can be obtained in this way. a solution of 18.54 g of sodium cyanide in 25 cm3 of water is added dropwise to a solution of 40 g of 1-benzhydrylazetidin-3-ylmethylsulfonate in 350 cm3 of M,M-dimethylformamide, then the mixture is heated to 652C. After stirring for 24 hours at a temperature of 65"C, the reaction mixture, after cooling to room temperature, is poured into the mixture with 550 cm3 of water and 3300 g of ice. The resulting suspension is filtered, the solid is washed three times with 110 cm3 of water, then dissolved in 350 cm3 of dichloromethane. The solution dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue was mixed with 200 cm3 of diisopropyl ether, the suspension was filtered, the solid was squeezed out, then dried under reduced pressure (2.7 kPa). 28.4 g (1- benzhydrylazetidin-3-yl)carbonitrile in the form of a pink-cream solid.

3-ol, 800 cm3 of dichloromethane, 31 cm3 of methylsulfonyl chloride and 35 cm3 of pyridine. The crude product obtained is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 50 cm, diameter 11 cm), eluting under argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in the ratio of 80:20, 75:25, then 70:30 and 60:40 by volume) and collecting fractions of 1 l. Fractions 12-31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6b6g of 1-benzhydrylazetidin-3-ylmethylsulfonate is obtained as a yellow-white solid. 1-Benzhydrylazetidin-3-ol can be obtained in accordance with the method described by Aiap V. KATAITAKU et al.

Example 11 (A5)-1-3-(11-IBis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl-methyl)phenyl|pyrrolidine can be obtained according to the method described in example C, starting from 0.10 g of 1 -I3-(1-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)methylsulfonylmethylene)phenyl|pyrrolidine, 71.5 cm? of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 30 g of sodium borohydride, stirring for 3 hours at a temperature of 20"C, then for 8 hours at a temperature of 50"C. The crude product is chromatographed on a column with silica gel (granulometry 0.040-0.063 mm; height 8 cm, diameter 1 cm), eluting under an argon pressure of 0.8 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 80:20 by volume) and collecting fractions of 5 cm3 . Fractions 22-

28 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is mixed with 5 cm3 of pentane, the solid is filtered off, squeezed and dried. 18 mg of (A5B)-1-I3-(11-(bis(4-chlorophenyl)methyliazetidine-3-yliumethylsulfonylmethyl)phenyl|pyrrolidine is obtained in the form of a white powder.

H-NMR IS spectrum (30 MHz; SOSIv) b (in ppm): 2.01 (m:4Н); 2.59 (m:1Н); 2.61 (c:ZN); 3.10-3.25 (m:2H); 3.27 (m:4H); 3.40-3.55 (m.1N); 3.66 (m:1H); 4.20 (d, 9U-12Hz:1H); 4.25 (c:1H); 6.45-6.65 (m:ZN); 7.10-7.35 (m:9H)). 1-I3-(1-(Bis(4-chlorophenyl)methyl|azetidin-3-yl) methylsulfonylmethylene)phenyl|pyrrolidine can be obtained according to the method described in example b, starting from 0.6 g of 1-(bis(4 -chlorophenyl)methyl-3-

I(methylsulfonyl)(Z-pyrrolidinylphenyl)methyl-(85)|azetidin-Z-ol, 0.1 cm3 of methylsulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the obtained residue is purified by chromatography on a column with silica gel (granulometry 0.04-0, 06bmm; diameter 2cm, height 30cm), under a nitrogen pressure of 0.5bar, using a mixture of dichloromethane and ethanol (in a ratio of 98.5:1.5 by volume) as an eluent, and collecting fractions of 10cm3. Fraction 4 is concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from

Bcm3 of diethyl ether yield 0.5 g of 1-3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl methylsulfonylmethylene)phenyl|pyrrolidine in the form of a solid, which melts at a temperature of 13370. 1-(Bis(4 -chlorophenyl)methyl|-3-(methylsulfonyl)(33-pyrrolidinylphenyl)methyl-(A5)|azetidin-3-ol can be obtained according to the method described in example 5, starting from 0.5 g of 1-IZ--" methylsulfonylmethyl)phenyl) pyrrolidine, 0.bg of 1-(bis(4-chlorophenyl)methyl|azetidin-3-one in 15 cm3 of tetrahydrofuran and 1.4 cm3 of a 1.v solution of n-butyllithium in hexane. 0.bg of 1-(bis (4-chlorophenyl)methyl|-3-(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(H5)|azetidin-3-ol as a cream-colored solid. 1-(3-"Methylsulfonylmethyl)phenyl|pyrrolidine can be obtained according to the method described in example 8, based on bcm3 of water, bcm3 of 10095 acetic acid, 3.5 cm3 of Zbn hydrochloric acid, 3.11 g of oxone, be9bg 0 1-IZ--"methylsulfanylmethyl)phenyl|pyrrolidine and bcm3 of ethanol. 0.478 g of 1-I(3- (methylsulfonylmethyl)phen) is obtained il|pyrrolidine in the form of a light brown resinous substance. 1-(3-"Methylsulfanylmethyl)phenyl|pyrrolidine can be obtained according to the method described in example 8, starting from 4.0g of 1-iodo-3-(methylsulfanylmethyl)benzene, 120cm3 of tetrahydrofuran, 2.2g of sodium tert-butylate, 0.556g of 1,1-bisidiphenylphosphino)ferrocenylpalladium chloride, 1.26g of 1,7-bisidiphenylphosphino)ferrocene and 2.6g of pyrrolidine. 1.9g of 1-IZ-(methylsulfanylmethyl)phenyl|pyrrolidine is obtained in the form of oil.

Example 12

M-(A5)-I3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|-M-methylcarbamic acid tert-butyl ether can be obtained according to the method described in example 3, based on with 00.10 g of tert-butyl ether M-I3-(11-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethylene)phenyl|-M-methylcarbamic acid, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 30 mg of sodium borohydride, stirring for 3 hours at a temperature of 20°C. The crude product is mixed with 10 cm3 of isopropyl ether, the solid substance is filtered off, squeezed, then dried under reduced pressure (2.7 kPa). 94 mg of tert-butyl ether /M-(A5) is obtained )-I3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)umethylsulfonylmethyl)phenyl|-M-methylcarbamic acid in the form of a white powder.

H-NMR spectrum (300 MHz; (CO3)250O-dv) b (in ppm): 1.36 (c:9H); 2.46 (t, 9uU-7.5HC1H); 2.75 ( s:ZN); 3.00-3.55 (m:4H); 3.17 (s:ZN); 4.45 (sn); 4.78 (d, 9-11Hz:1H); 7.20 -7.50 (m12Н)I.

Tert-butyl ether /M-I3-(1-(bis(4-chlorophenyl)umethyl|azetidin-3-ylmethylsulfonylmethylene)phenyl|-M- methylcarbamic acid can be obtained according to the method described in example b, starting from 5, 1-(bis(4-chlorophenyl)methyl/|-3-3-(M-tert-butyloxycarbonyl-M-methylamino)phenyl|methylsulfonylmethyl- (85))azetidin-3-ol, 100 cm³ of dichloromethane, 1 .59 g of methylsulfonyl chloride and 4.5 g of 4-dimethylaminopyridine.

The crude product obtained is purified by chromatography on a column with silica gel (granulometry 0.04-

Oh, Obmm; diameter 4 cm and the mass of silicon dioxide 250 g), eluting under a nitrogen pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 30:70 by volume) and collecting fractions of 100 cm3. Fractions 12-18 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 3.2 g of tert-butyl ether M-I3-(1-I(bis(4-chlorophenyl) methyl|azetidin-3-yliumethylsulfonylmethylene)phenyl|-M-methylcarbamic acid is obtained in the form of a white meringue. 1-(Bis(4 -chlorophenyl)methyl|-3-1I3-(M-tert-butyloxycarbonyl-M-methylamino)phenyl|Imethylsulfonylmethyl-(A5))azetidin-3-ol can be obtained according to the method described in example 5, starting from tert- of butyl ether M-III--"methylsulfonylmethyl)phenyl|-M-methylcarbamic acid, 50 cm? tetrahydrofuran, 9.5 cm3 of a 1.6 N solution of n-butyllithium in hexane and 3.82 g of 1-I(bis(4-chlorophenyl)methyl|azetidin-3-one. The crude product is purified by chromatography on a column with silica gel (granulometry 0.04 -0.0bmm; diameter 4cm, mass of silicon dioxide 250g), eluting under a nitrogen pressure of 0.5 bar with dichloromethane, then using a mixture of dichloromethane and ethanol (in a ratio of 99:1 by volume) and collecting fractions of 500 cm3. Fractions 10- 16 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 1-|bis(4-chlorophenyl)methyl|-3-(3-(M-tert-butyloxycarbonyl-M-methyl-amino) is obtained phenyl|methylsulfonylmethyl-(A5)) oazetidin-Z-ol in the form of meringue.

The tert-butyl ether of M-III-"("methylsulfonylmethyl)phenyl|-M-methylcarbamic acid can be obtained in the following way. 3.7 g of di-tert-butyl dicarbonate is added to a solution of Zg M-IZ--"methylsulfonylmethyl)phenyl|-M-methylamine in 80 cm3 of dichloromethane. After stirring for 20 hours at a temperature of 207C, add 100 cm3 of water to the reaction mixture, then decant. The organic phase is dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.04-0.06 mm; diameter 4 cm and mass of silicon dioxide

300 g), eluting under a nitrogen pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 45:55 by volume) and collecting fractions of 100 cm3. Fractions 11-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.8 g of tert-butyl ether M-III-(methylsulfonylmethyl)phenyl|-M-methylcarbamic acid is obtained in the form of a resinous substance that crystallizes.

M-I3-"Methylsulfonylmethyl)phenyl|-M-methylamine can be obtained in the following way: at a temperature

502C for 3 hours in an argon atmosphere, heat a mixture of 9.65cm3 of formic acid and 19.63cm3 of acetic anhydride, then leave the resulting solution to cool to room temperature. Add 40 cm3 of tetrahydrofuran and cool the medium to a temperature of -202C. After stirring for 2 hours at a temperature of -20"C, a solution of 14.8 g of 3--"methylsulfonylmethyl)phenylamine was added while maintaining this temperature. After stirring for 2 hours at a temperature of -20"С, then for 48 hours at a temperature of 207С, the mixture is filtered, the solid substance is squeezed out, then washed three times with 50 cm3 of isopropyl ether and dried under reduced pressure (2.7 kPa). Solid substance A is obtained. The filtrate is concentrated to half the volume, the suspension obtained as a result is filtered, the solid substance is squeezed out,

Wash with diisopropyl ether and dry. Solid substance B is obtained. Both solid substances A and

They are combined, treated with 375 cm3 of tetrahydrofuran, and 80 cm3 of a 2M solution of the dimethyl sulfide-borane complex in tetrahydrofuran is added to the mixture cooled to 0C for 20 minutes, then boiled for 3 hours with an inverted refrigerator. To the reaction mixture, cooled to a temperature of 5"C, bosm? of methanol is added for 20 minutes, stirred for an hour at room temperature, then gaseous hydrogen chloride is passed to the pH-1 value. The mixture is boiled with an inverted refrigerator for 1 hour, then 30Osm3 is added of water and Zn solution of sodium hydroxide to the value of рН-а8.

The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with an aqueous saturated solution of sodium hydrogen carbonate and brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated with 100 cm3 of 4N sulfuric acid, the resulting solution is washed with 100 cm3 of ethyl acetate, then it is made alkaline up to pH 8 with the help of a Zn solution of sodium hydroxide and an aqueous saturated solution of sodium carbonate, after which it is extracted twice with 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of M-IZ--"methylsulfonylmethyl)phenyl|-M-methylamine are obtained in the form of a pink solid substance. 3-(Methylsulfonylmethyluphenylamine can be obtained in the following way. a suspension of 23.7 g of 1-(methylsulfonylmethyl)-3-nitrobenzene in 150 cm3 of methanol and b5 cm3 of 36b95-hydrochloric acid is heated to the boiling point with an inverted refrigerator, then carefully, for 10 minutes, small 18.5g of iron are added in portions.After refluxing for 4 hours, then stirring at room temperature for 20 hours, 5g of iron is added to the reaction mixture, then again refluxing for one hour, then kept for 20 hours at room temperature. The mixture is then alkalinized to pH-39 using ammonium hydroxide and sodium bicarbonate, after which it is extracted three times with 250 cm3 of ethyl acetate, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of 3 are obtained -"methylsulfonylmethyl)phenylamine in the form of a beige powder. 1-"""Methylsulfonylmethyl)-Z-nitrobenzene can be obtained by boiling with an inverted refrigerator 23.8 g of Z-nitrobenzyl chloride, 20 g of sodium methyl sulfinate and 250 cm3 of absolute ethanol.

23.74 g of 1-(methylsulfonylmethyl)-3-nitrobenzene is obtained in the form of a white powder.

Example 13 (A5)-M-3-(1-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)methylsulfonyl-methyl)phenyl|-M-methylamine can be obtained according to the method described in example 3 , based on 0.10 g /M-I3-(1-(bis(4-chlorophenyl)methylIazetidin-3-ylmethylsulfonylmethylene)phenyl|-M-methylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, stirring for 20 hours at a temperature of 20"C, then for 5 hours at a temperature of 50"C. The crude product is chromatographed on a silica gel column (granulometry 0.04-0.063mm; height 10cm, diameter 1cm), eluting under argon pressure 0, 8 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 80:20, then 60:40 by volume) and collecting fractions of 5 cm3.

Fractions 20-26 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is mixed with 5 cm3 of pentane, the solid is filtered off, squeezed and dried. 20 mg of (AB)-M-(3-(11-(bis(4-chlorophenyl)methyl|azetidin-3-yliumethylsulfonylmethyl)phenyl|-M-methylamine) is obtained in the form of a white powder.

H-NMR spectrum (300 MHz, SOSIv) b (in ppm): 2.50-2.65 (min); 2.60 (s:ZN); 2.82 (d, 925Hz:ZN); 3.18 (m:2H); 3.35-3.50 (m:1H); 3.64 (t ush, 9U-7.5HZ:1H); 3.80 (m:1H); 4.18 (d, U-11.5HzC:1H); 4.24 (sn); 6.50-6.70 (m:ZN); 7.10-7.35 (m:9NI.

M-I3-(11-(Bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethylene)phenyl|-M-methylamine can be obtained in the following way: for 20 hours, stir 2.7 g of 1-(bis(4- chlorophenyl)methyl|-3-13-(M-tert-butyloxycarbonyl-M-methylamino)phenyl|Imethylsulfonylmethylene azetidine in ZO0cm3 of dioxane and ZOcm3 of a 4.7N solution of hydrogen chloride in dioxane. The reaction medium is evaporated to dryness under reduced pressure (2.7kPa), processed with the help of 50 cm3 of water and 50 cm3 of ethyl acetate, mix and carefully neutralize with the help of an aqueous saturated solution of sodium hydrogen carbonate. The organic phase is separated, dried over magnesium sulfate, treated with animal charcoal, then concentrated under reduced pressure (2.7 kPa) to a volume of approximately 25 cm3, then filtered, concentrated to dryness under reduced pressure. 1.3 g of M-I|3- (11-I(bis(4-chlorophenyl)methyl|azetidin-3-ylmethyl-sulfonylmethylene)phenyl|-M-methylamine is obtained in the form of white crystals colors that melt at a temperature of 22826.

Example 14 (85)-1-IBis(4-chlorophenyl)methyl|-3-(3,5-bistrifluoromethylphenyl)methyl-sulfonylmethyl|azetidine can be obtained according to the method described in example 3, starting from 0.10 g of 1- Ibis(4-chlorophenyl)methyl!-3-|(3,5- bistrifluoromethylphenyl)methylsulfonylmethylene|azetidine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 15 mg of sodium borohydride, stirring for 3 hours at a temperature of 20"C. Crude the product is mixed with 5 cm3 of pentane, the solid substance is filtered off, squeezed and dried.

H-NMR IS spectrum (400MHz, (CO3)250O-y6) b (in ppm): 2.84 (C:ZN); 3.08 (mt:2H); 3.25-3.40 ( mt1H); 3.45-3.65 (mt2H); 4.45 (s:1H); 5.13 (d, U-10.5HzC:1H); 7.25-7.50 (mt:8H) ; 8.11 (with ear: 2H); 8.15 (with ear. 1H)|.

1-(Bis(4-chlorophenyl)methyl-3-(3,5-bistrifluoromethylphenyl)methyl-sulfonylmethyleneiazetidine can be obtained in the following way: to a solution of 3.16 g of 3-acetoxy-1-(bis(4-chlorophenyl)methyl| -3-1І3,5- bis(trifluoromethyl)phenyl|methylsulfonylmethyl-(5))azetidine in 40 cm3 of dioxane, 0.96 g of powdered sodium hydroxide is added in portions. After stirring for an hour at room temperature, 200 cm3 of ethyl acetate, 200 cm3 of water are added to the reaction mixture. then it is decanted. The organic phase is washed twice with 80 cm3 of water, then with the help of 80 cm3 of brine, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.040-0.063 mm; height 14.5 cm, diameter 4.8 cm), eluting under an argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 85:15 by volume) and collecting fractions of 4Ocm3. Fractions 8-15 are combined and concentrated to dryness under reduced pressure (2.7 kKPa). 1.49 g of 1-I(bis(4-chlorph enyl)methyl|-3-I(3,5-bistrifluoromethylphenyl)methylsulfonylmethylene azetidine in the form of a white meringue.

3-Acetoxy-1-|bis(4-chlorophenyl)methyl|-3-(3,5-bis(trifluoromethyl)phenyl)| methylsulfonylmethyl- (A5)) azetidine can be obtained in the following way: to a solution of 2.0 g of I3,5-bis(trifluoromethyl) benzyl|methylsulfone cooled to a temperature of -787C in 35 cm3 of tetrahydrofuran in an argon atmosphere, 4.1 cm3 of 1.6 n is added dropwise of a solution of n-butyllithium in hexane. After stirring for an hour. at a temperature of -702C, a solution of 2.0 g of 1-bis(4-chlorophenyl)methyl|iazetidin-3-one in Zbsm3 of tetrahydrofuran is added dropwise. After stirring for 2 hours at a temperature of -78C, add a solution of 0.7 cm? acetyl chloride in 5 cm3 of anhydrous diethyl ether, then the mixture is left to stand until it cools to room temperature.

After stirring for 2 hours 30 minutes, add 100 cm3 of water to the reaction mixture and decant.

The organic phase is washed with 100 cm3 of water, then with 100 cm3 of brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.04-0.0bmm; diameter 5.bcm, height 16bcm), eluting under argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 10:90, then 40:60, by volume) and collecting fractions of 100 cm3. Fractions 37-52 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.56 g of 3-acetoxy-1-(bis(4-chlorophenyl)methyl|-3-1І3,5-bis(trifluoromethyl)phenyl|methyl-sulfonylmethyl-(H5))-azetidine is obtained in the form of a white meringue.

13,5-Bis(trifluoromethyl)benzyl|Imethylsulfone can be obtained by refluxing 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride, 50 cm? absolute ethanol and 1.22 g of sodium methylsulfinate. 1.86 g of (13,5-bis(trifluoromethyl)benzyl) methyl sulfone is obtained as a white solid.

Example 15

M-I4-(4-Chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonylmethyl-(H5)|azetidin-1-yl)umethyl-(H5))benzyl-

M,M-dimethylamine, a mixture of two diastereoisomers, can be obtained according to the method described in example C, starting from 0.10 g of M-I4-(4-chlorophenyl)(3-(3,5-difluorophenyl)methyl-sulfonylmethylene azetidine -1-yl)umethyl-(85))benzyl|-M,M-dimethylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, stirring for 16 hours at a temperature of 207C, then for 16 hours at a temperature of 50"С. The crude product is chromatographed on a column with silica gel (granulometry 0.040-0.063 mm; height 22 cm, diameter 1 cm), eluting under argon pressure of 0.8 bar with a mixture of ethyl acetate and methanol (in a ratio of 97:3 by volume) and collecting fractions of 20 cm3. Fractions 17-25 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is mixed with 5 cm3 of pentane, the solid is filtered off, squeezed and dried. Bmg M-I4-((4-chlorophenyl) is obtained (3-(3,5-difluorophenyl)methylsulfonylmethyl- (A5))|-azetidin-1-yl methyl-(H5))benzyl|-M,M-dimethylamine, a mixture of two di stereoisomers, in the form of a white powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.20 (sbH); 2.53 (t, 9e7Hz:1H); 2.65 (s:ZH); 3.10- 3.25 (m:2H); 3.30-3.45 (m:1H); 3.35 (with ear.:2H); 3.63 (t ear, d9-7Hz:1H); 4.24 (c:1H); 4.25 (d, 2U-11Hz:1H); 6.82 (t, 9U-9 and 2HzC1H); 6.94 (m:2H); 7.15-7.35 (m :8H)).

M-I4-(4-Chlorophenyl)(3-I((3,5-difluorophenyl)methylsulfonyl-methylene|azetidin-1-yl)umethyl-(H!5))benzyl|-M,M-dimethylamine can be obtained as follows: to a solution of 0.93 cm3 of a 2M solution of dimethylamine in methanol in

1.0 g of (85)-4-((4-chlorophenyl)/3-|(3,5-difluorophenyl)methylsulfonylmethylene|azetidin-1-yl)methyl)benzaldehyde is added to 3.0 g of anhydrous 1,2-dichloroethane in an argon atmosphere . After stirring for 30 minutes at room temperature, add 0.9 g of triacetoxy sodium borohydride in small portions. After stirring for 48 hours, 2.65 cm3 of 1 N sodium hydroxide solution, 100 cm3 of water and 100 cm3 of dichloromethane are added to the reaction mixture, then decanted. The organic phase is washed twice with 80 cm3 of water and with 80 cm3 of brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.04-0.0 mm; diameter 4 cm, height 17.5 cm), eluting under argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (in a ratio of 30:70 by volume) and collecting fractions of 40 cm3. Fractions 48-53 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.46 g of M-I4-((4-chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonylmethylene|azetidin-1-yl)umethyl-(A5))benzyl|-M,M-dimethylamine is obtained in the form of a solid white substances. (85)-4-(4-Chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonylmethylene | azetidin-1-ylmethyl)benzaldehyde can be obtained in the following way: to a solution of 18.9 g of 1-( (4-chlorophenyl)(4-(1,3|dioxolan-2-ylphenyl)methyl|i-(A5)- 3-(3,5-difluorophenyl)umethylsulfonylmethyleneiazetidine in 80 cm3 of tetrahydrofuran add 75.6 bcm3 of 5N hydrochloric acid. After standing for 3 hours at room temperature, the mixture is treated with dichloromethane and distilled water, then the pH value is brought to 14 by adding a 3095 solution of sodium hydroxide and decanted. The organic phase is washed twice with 100 cm3 of water, then with the help of 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (Н5Б)-4-(4-chlorophenyl)(3-|(3,5- difluorophenyl)methylsulfonylmethylene) are obtained and azetidin-1-ylmethyl) benzaldehyde in the form of a white meringue. 1-(4-Chlorophenyl)(4-(/1,3Z|dioxolan-2-ylphenyl)methyl|-(А85)-3-(3,5-difluorophenyl)methylsulfonylmethylene azetidine can be obtained in the following way; to a solution of 34 .45 g of a mixture of two diastereoisomers 1-|((4-chlorophenyl)(4-(1,3|dioxolan-2-ylphenyl)methyl-(A5)1-3-((3,5-difluorophenyl)methylsulfonyl-methyl-( H5)I of azetidin-Z-yl acetate in 400 cm3 of tetrahydrofuran in an argon atmosphere and at a temperature of 0C, 13.0 cm3 of 1,8-diazabi-cyclo|5,4,Fundec-7-ene are added dropwise and, after the usual treatment, the product is chromatographed on a column with silica gel (granulometry 0.04-0.06 mm; diameter 10.2 cm, height 23 cm), eluting under argon pressure

0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions of 250 cm3. 16.6 g of 1-((4-chlorophenyl)(4-I1,3|dioxolan-2-ylphenyl)methylI-(A5)-3-(3,5-difluorophenyl)methylsulfonylmethyleneiazetidine is obtained in the form of a white solid.

A mixture of two diastereoisomers 1-(4-chlorophenyl)(4-H1,3|dioxolan-2-ylphenyl)methyl-(A5)1-3-((3,5-difluorophenyl)methylsulfonylmethyl-(A5)|azetidine-Z- yl acetate can be obtained in the following way: according to the method of example 1 (method 2), starting from 11.6 g of (3,5-difluorobenzyl)methylsulfone, 35.1 cm3 of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of 1- (4-chlorophenyl) (4-(1,3|dioxolan-2-iluphenyl|methyl-(A5))azetidin-3-one and 8.8 cm3 of acetyl chloride in 500 cm3 of tetrahydrofuran, 37.8 g of a mixture of two diastereoisomers of 1-|( 4-chlorophenyl)(4-(1,3|dioxolan-2-ylphenyl)methyl-(A5)1-3-((3,5-difluorophenyl)methylsulfonylmethyl-(H5)|azetidin-

Z-ylacetate in the form of a white meringue. 1-(4-Chlorophenyl)(4-(P1,3|dioxolan-2-yl)uphenyl|methyl-(H5))azetidin-3-one can be obtained in the following way; to a solution of 28.32 g of 1-(4-chlorophenyl)(4-(P1,3|dioxolan-2-yl)uphenyl|methyl-(85))azetidin-Z-ol in 200 cm3 of dimethyl sulfoxide at room temperature, add 46 bsm? triethylamine, then a solution of 34 g of sulfur trioxide complex with pyridine in 100 cm3 of dimethyl sulfoxide is added dropwise. After standing for 0.25 hours. at room temperature, the reaction mixture is poured onto ice, extracted with ethyl acetate, washed three times with 400 cm3 of water, then with 400 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The obtained residue is chromatographed on a column with silica gel (granulometry 0.04-0.0 mm; diameter 9.2 cm, height 21 cm), under an argon pressure of 0.5 bar, using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) as an eluent, and collecting fractions of 250 cm3. Fractions 9-18 are combined, then concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of 1-(4-chlorophenyl)(4-(P1,3|dioxolan-2-yl/uphenyl|methyl-(A5))azetidin-3-one is obtained in the form of a yellow oil. 1-(4-Chlorophenyl )(4-(P1,3|dioxolan-2-yl)uphenyl|methyl-(H5))azetidin-3-ol can be obtained according to the method described in example C, starting from 35.0 g "(4-chlorophenyl )(4-(1,3-dioxolan-2-yl)phenyl|methyl)amine, 8.3 g of epibromohydrin, 5.1 g of sodium bicarbonate and 400 cm3 of ethanol. 30.3 g of 1-(4-chlorophenyl)|4-( 1,3-dioxolan-2-yl)uphenyl|methyl-(H5))zazetidin-3-ol. (4-Chlorophenyl)|4-(1,Z|dioxolan-2-yl)/phenyl|methyl-(AB))amine can be obtained according to the method described by M. SVIZAV et al., U. Med. Spet., 885 (1973), based on 67.2 g of 4-(1,Z|dioxolan-2-yl)benzonitrile, 88.2 g of 1-bromo-4-chlorobenzene, 11 g of magnesium and b00 cm3 of diethyl ether. 42.3 g of ((4-chlorophenyl)|4-(1,3|dioxolan-2-yl)uphenyl|methyl-(B5)) amine is obtained in the form of a yellow oil.

Example 16 1-(4-Chlorophenyl)(thien-2-yl)umethyl-(A5)1-3-((3,5-difluorophenyl)methyl-sulfonylmethyl-(H5)|azetidine, a mixture of two diastereoisomers, can be obtained according to the method described in example C, based on 0.10 g of 1-(4-chlorophenyl)(thien-2-ylmethyl-(A5)I-3-((3,5-difluorophenyl)methylsulfonyl-methylene| azetidine, 1 .5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, stirring for 16 hours at a temperature of 20"C, then for 16 hours at a temperature of 50"C. The crude product is chromatographed on a silica gel column (granulometry 0.040-0.063mm; height 25 cm, diameter 1 cm), eluting under argon bar pressure with a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10 by volume) and collecting fractions of 20 cm3. Fractions 37-42 are combined and concentrated to dryness under reduced pressure (2, 7 kPa), the residue is mixed with 5 cm3 of pentane, the solid substance is filtered, squeezed and dried. 8 mg of 1- ((4-chlorophenyl)(thien-2-ylmethyl-(А5)1-3-(3,5-difluorophenyl)methyl) are obtained sulfonyl-methyl-(H5)| azetidine, a mixture of two diastereoisomers, in the form of a white powder. (IN-NMR spectrum (300 MHz; SOSIiz) b (in ppm): a mixture of two diastereoisomers is observed: 2.50-2.70 (m:1H); 2.66 and 2.68 (2C:ZH as a whole ); 3.15-3.80 (m:4Н); 4.20-4.30 (m:"1Н); 4.31 and 4.57 (2с1Н as a whole); 6.80-7.00 and 7.10-7.40 (multiplets: 10H in total).1-(4-Chlorophenyl)(thien-2-yl)umethyl-(A5)1-3-((3,5-difluorophenyl)methyl-sulfonylmethylene| iazetidine can be obtained according to the method described in example 6, starting from 0.52 g of a mixture of two diastereoisomers of 1-

I(4-chlorophenyl)(thien-2-yl)umethyl-(B85)1-3-(3,5-difluorophenyl)methylsulfonylmethyl-(B5)|azetidin-3-ol, 0.14 cm3 of methylsulfonyl chloride and 0.49 g of 4 -dimethylamino-pyridine. After chromatography on a column with silica gel (granulometry 0.06-0.200 mm; diameter 2.4 cm, height 20 cm), eluting under an argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions according to ZOosm3U, obtain 0.32 g of (85)-1-K(4-chlorophenyl)(thien-2-yl)umethyl/|-3-(3,5-difluorophenyl)methylsulfonyl-methylene azetidine as a white solid, which melts at a temperature of 17676.

A mixture of two diastereoisomers of 1-(4-chlorophenyl(thien-2-yl)umethyl-(A5)1-3-I(3,5-difluorophenyl)methylsulfonylmethyl-(H5)azetidin-Z3-ol can be obtained according to the methodology, described in example OO, based on 1.60cm3 of a 1.6N solution of n-butyllithium in hexane, 0.83g of (3,5-difluorobenzyl)methylsulfone and 1.06g of 1-(4-chlorophenyl)(thien-2-yl) umethyl-(A5)|azetidin-3-one. After purification on a column with silica gel (granulometry 0.06-0.200 mm; diameter 2.8 cm, height 30 cm), eluting under argon pressure of 0.5 bar using a mixture of ethyl acetate and cyclohexane ( in a ratio of 25:75 by volume) and collecting fractions of 40 cm3, 0.55 g of a mixture of diastereoisomers 1-((4-chlorophenyl)(thien-2-ylylmethyl-(85)1-3-I((3.5 - difluorophenyl)methylsulfonylmethyl-(H5)| azetidin-3-ol in the form of an off-white solid. 1-(4-Chlorophenyl)(thien-2-yl)umethyl-(A5))azetidin-3-one can be obtained according to the method described in example 71 (method 2), starting from 1.83 cm3 of oxalyl chloride, 20 cm3 of dichloromethane, 3.04 cm3 of dimethylsulf oxide, 5.2 g of 1-((4-chlorophenyl)(thien-2-yl) methyl-(B5)|azetidin-3-ol, 80 cm3 of dichloromethane and

9.12 cm3 of triethylamine. 3,3g of 1-((4-chlorophenyl)(thien-2-yl)umethyl-(85)|azetidin-3-one is obtained as a yellow oil that crystallizes at room temperature. 1-(4-Chlorophenyl)( thien-2-yl)umethyl-(A5)|azetidin-3-ol can be obtained in the following way: to a solution of 11.0 g

4.12 g of sodium bicarbonate is added to 1(4-chlorophenyl)(thien-2-yl)umethyl-(B5)amine in 80 cm3 of ethanol. 4.03 cm3 of epibromohydrin is added to the mixture heated to a temperature of 65 "C. After stirring for 20 hours at a temperature of 65 "C, the cooled mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 3.0 cm, height 32 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (in a ratio of 25:75 by volume) and collecting fractions by bOsm3. 6.3 g of 1-(4-chlorophenyl)(thien-2-yl)umethyl-(A5)|azetidin-3-ol are obtained in the form of a pale yellow oil. ((4-Chlorophenyl)(thien-2-ylmethyl-"(AZ)amine can be obtained in the following way. to a suspension of 4-chlorophenylmagnesium bromide (obtained from 19.15 g of 4-bromochlorobenzene and 2, 43g of magnesium) in 120cm3 of anhydrous diethyl ether is slowly added to a solution of 10.92g of 2-thiophenecarbonitrile in 80cm3 of diethyl ether. After boiling with an inverted refrigerator for one hour, the mixture is cooled to a temperature of 102C, 40cm3 of methanol is slowly added and then filtered through Supercell. In the atmosphere of argon and 4.54 g of sodium borohydride are added in small portions for 15 minutes, then the reaction medium is stirred for 20 hours at a temperature of 20"C. The resulting mixture is diluted with ethyl acetate, then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at a temperature of 50"C and reduced pressure (2.7 kKPa). The residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 5 cm, height 42 cm), eluting under an argon pressure of 0.5 bar with the help of of ethyl acetate and cyclohexane (in a ratio of 4:6 by volume) and collecting fractions of 100 cm3. Fractions 6-12, concentrated to dryness, correspond to 13 g of imine in the form of yellow oil, which is treated with 100 cm3 of methanol. Add 2.4 g of sodium borohydride to the resulting solution and stir for 1 hour. at a temperature of 5"C. The resulting mixture is diluted with ethyl acetate, then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at a temperature of 507C and reduced pressure (2.7 kPa).

The residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 3.2 cm, height 40 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (in a ratio of 4:6 by volume) and collecting fractions per b0cm3. 11.0 g of (4-chlorophenyl)(thien-2-yl)umethyl-(B5))amine is obtained in the form of a yellow oil.

Example 17 (85)-I3-(11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl) methylsulfonylmethyl)phenyl|methanol can be obtained according to the method described in example C, starting from 0.050 g of 2 I3- (1-(bis(4-chlorophenyl)methylIazetidin-3-ylmethylsulfonylmethylene) phenyl|methanol, 1.0 cm3 of anhydrous methanol, 1.0 cm3 of anhydrous dichloromethane and 20 mg of sodium borohydride, stirring for 3 hours at a temperature of 20"C. The crude product is chromatographed on column with silica gel (granulometry 0.040-0.06 mm; height 20 cm, diameter 1 cm), eluting under argon pressure of 0.8 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10 by volume) and collecting fractions of 10 cm3. Fractions 30 -38 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is mixed with 5 cm3 of pentane, the solid is filtered off, squeezed and dried. 13 mg of (85)-I3-(1-I(bis(4- chlorophenyl)methyl|azetidin-3-yl methylsulfonylmethyl)phenyl|methanol in the form of a white powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.75 (t, U-6Hz:1H); 2.52 (t, 9U-7.5Hz:1H); 2.59 (c:ZN); 3.17 (t ush., ue7.5HC:2H); 3.48 (mn); 3.65 (m:1H); 4.23 (c:1H); 4.28 ( d, 9-11.5Hz:1H); 4.70 (d, 9-6Hz:2H); 7.15-7.40 (m12H)).

IZ-Ch1-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)methylsulfonylmethylene)phenyl|methanol can be obtained in the following way: to a solution cooled to a temperature of 57C, 5.1 g of 1-(bis(4-chlorophenyl)methyl |-3-(3-(tert-butyl-dimethylsilyloxymethyl)phenyl|methylsulfonylmethylene) azetidine in 51 cm3 of tetrahydrofuran is added with 17 cm3 of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After stirring for minutes under cooling, then for 3 hours at a temperature of 20"C, the reaction mixture is poured into a mixture of 200 cm3 water and 100 cm3 ethyl acetate, then decanted. The organic phase is washed with water, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by chromatography on a column with silica gel (granulometry 0 ,04-0.06bmm; diameter 2cm, height 30cm), eluting under a nitrogen pressure of 0.5bar with a mixture of dichloromethane and ethanol (in a ratio of 97:3 by volume) and collecting fractions of 100cm3. Fractions of 10-14 volumes combine, concentrate to dryness and at reduced pressure (2.7 kPa). The resulting yellow solid is treated with 2 cm3 of dichloromethane and 10 cm3 of ethyl acetate, then filtered through a glass porous filter and washed with 2 cm3 of ethyl acetate. 1.6 g of I3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)umethylsulfonylmethylene)phenyl| of methanol in the form of a white solid, which melts at a temperature of 21476. 1-IBis(4-chlorophenyl)methyl|-3-(I3-(tert-butyldimethylsilyloxymethyl)phenyl|Imethylsulfonylmethyleneiazetidine can be obtained according to the method of example 1, based on C 10 .8 g of 1-bis(4-chlorophenyl)methyl|-3-(I3-(tert-butyldimethylsilyloxymethyl)phenyl|methylsulfonylmethyl-(A5))azetidin-3-ol, 2 cm3 of methylsulfonyl chloride and 8.5 g of 4-dimethylaminopyridine, the resulting residue is purified by chromatography on a column with silica gel (granulometry 0.04-0.06 mm; diameter 4 cm, height 40 cm), under a nitrogen pressure of 0.5 bar, using dichloromethane as an eluent, and collecting fractions of 100 cm3. Fractions 12-29 vol. combine, concentrate to dryness under reduced pressure (2.7 kPa). 5.2 g of 1-|bis(4-chlorophenyl)methyl|-3-

IIZ-"tert-butyldimethylsilyloxymethyl)phenyl|Imethylsulfonylmethylene)azetidine in the form of a resinous substance. 1-(Bis(4-chlorophenyl)methyl|-3-|3-(tert-butyldimethylsilyloxymethyl)phenyl|methylsulfonylmethyl-(H5))azetidin-3-ol can be obtained according to the method of example 5, starting from 5.8g tert-butyl-(3-methyl-sulfonylmethylbenzyloxy) dimethylsilane and 5.6 g of 1-bis(4-chlorophenyl)methyl| azetidin-3-one. They receive 10.8 g

1-(bis(4-chlorophenyl)methyl|-3-13-(tert-butyl-dimethylsilyloxymethyl)phenyl|methylsulfonylmethyl-(H5), azetidin-3-ol in the form of a resinous substance. tert-Butyl-(3-methylsulfonylmethylbenzyloxy) Udimethylsilane can be obtained in the following way: to a solution of 5.73 g of (33-methylsulfonylmethyl-phenyl)umethanol in 50 cm3 of M,M-dimethylformamide, 4.87 g of imidazole is added, then 10.3 cm3 of tert-butylchlorodimethylsilane. After stirring for 20 hours at room temperature the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.06-0.200 mm; diameter 3.5 cm, mass of silicon dioxide 100 g), eluting under a nitrogen pressure of 0.5 bar with the help of dichloromethane and collecting fractions of 100 cm3. Fractions 2-7 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.8 g of oil is obtained, which crystallizes at room temperature. M.p.-7576. (3-Methylsulfonylmethylphenyl)methanol can be obtained in this way, a mixture of 26 g of 3- (methylsulfonylmethyl)ben zoic acid and 4.6 g of lithium aluminum hydride in 100 cm3 of tetrahydrofuran are stirred for 18 hours at a temperature of about 20"C. The solution is cooled to a temperature of 0"C, then 15 cm3 of ethyl acetate, 5 cm3 of water, 5 cm3 of 1595% aqueous sodium hydroxide solution and, finally, 30 cm3 of water are added successively. The mixture is filtered through celite, the filtrate is treated with 00 cm3 of ethyl acetate. The organic phase is treated with 500 cm3 of water, then 200 cm3 of a saturated aqueous solution of sodium chloride, decant, dry over anhydrous magnesium sulfate, filter and concentrate to dryness under reduced pressure (2.7 kPa). 10.4 g of (3-methylsulfonylmethylphenyl)methanol is obtained in the form of a resinous substance. 3-( Methylsulfonylmethyl)benzoic acid can be obtained in the following way: following the method of example 14, from 23.3g of 3-chloromethylbenzoic acid and 23.3g of sodium methanesulfinate, 26g of 3-(methylsulfonylmethyl)benzoic acid is obtained in the form of a white solid that melts at a temperature of 21076.

Example 18 1-(Bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethyl)azetidine can be obtained in the following way: to a solution of 0.15 g of 1-|bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethylene)azetidine 13 mg of sodium borohydride is added to 3 cm3 of anhydrous ethanol and 3.5 cm3 of anhydrous dichloromethane under an argon atmosphere. After stirring for 1 hour 45 minutes, 14 mg of sodium borohydride is added again, then stirred for 20 hours at a temperature of 20 °C. The reaction mixture is then heated to a temperature 50"C, add 9.5 mg of sodium borohydride and stir for 2 hours 30 minutes at a temperature of 50"C, then cool to room temperature. Then add 0.5 cm3 of water, 10 cm3 of dichloromethane, then 5 mg of magnesium sulfate and filter, then evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 15 cm, diameter 1 cm), eluting under argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 80:20 by volumes) and collecting fractions of 5cm3.

Fractions 12-19 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 29 mg of 1-bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethyl)azetidine is obtained as a white solid.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.75-8.90 (m:ZN); 3.32 (m:2H); 3.37 (d, 9-7Hz :2H); 4.22 (syn); 7.20-7.30 (m:8H); 7.57 (t ush., U27.5HC:2H); 7.67 (t, 97.51 1, 5 Hz: 1 H); 7.88 (d ear, 9-7.5 Hz: 2 H)|.

Example 19 1-(Bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethylene) azetidine can be obtained in the following way: in an argon atmosphere to a cooled to -06 temperature solution of 4.ZAg (phenylsulfonylmethyl)trimethylsilane in 40 cm3 of dimethyl ether for 5 minutes, add 12cm3 of a 1.6M solution of n-butyllithium in hexane. After stirring the mixture for 30 minutes at a temperature of -607C, a solution of 1-bis(4-chlorophenyl)methyl|azetidin-3-one in 30cm3 of dimethyl ether is added for 10 minutes

The product in the form of a base obtained by treating a solution of 7.35 g of 1-I(bis(4-chlorophenyl)methyl|azetidin-3-one hydrobromide in 30 cm3 of water with 25 cm3 of 1 N sodium hydroxide solution and extracting the resulting base with 30 cm3 of diethyl ether , then drying and concentration to dryness under reduced pressure (2.7 kPa). After stirring for 45 minutes at a temperature of -70"C, then for 2 hours at a temperature of 20"C, 12 cm3 of an aqueous saturated solution of ammonium chloride, 20 cm3 of water, then extracted twice with 40 cm3 of ethyl acetate.The combined organic phases are washed with 40 cm3 of water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa).

The obtained oil is chromatographed on a column with silica gel (granulometry 0.063-0.200 mm; height 40 cm, diameter 5 cm), eluting under argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10, then 85:15, by volume ) and collecting fractions of 100 cm3. Fractions 10-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The obtained oil is powdered in 10 cm3 of diethyl ether, the suspension is filtered and the solid substance is dried. 1.17 g of 1-bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethylene)azetidine is obtained as a white solid.

H-NMR spectrum (Z0O0MHZc; SOCI3) b (in ppm): 3.88 (m:2H); 4.29 (m:2H); 4.50 (s/1H); 6.17 ( mn); 7.20-7.40 (m:8H); 7.56 (t ush, 1-7.5HzC:2H); 7.64 (t, U-7,511.5HzC1H); 7.87 (d (Phenylsulfonylmethyl)utrimethylsilane can be obtained in this way to a solution of 3g methylphenylsulfone in 40 cm3 of anhydrous tetrahydrofuran cooled to -702C, while stirring and in an argon atmosphere for 20 minutes, add 13 cm3 of 1, 6M solution of n-butyllithium in hexane. After stirring for 30 minutes at -702C, 2.66 cm3 of trimethylchlorosilane was added to the mixture and heating was stopped. After stirring for 4 hours at room temperature, 30 cm3 of water was added to the reaction mixture and extracted with 30 cm3 ethyl acetate. The organic phase is washed with 30 ml of water, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). 4.34 g of (phenylsulfonylmethyl)trimethylsilane is obtained as a yellow liquid.

Example 20 2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine can be obtained in the following way: to a solution of 0.25 g of 2-(11-Ibis(4-chlorophenyl)methyl|azetidin-3Z- ylidenemethylsulfonyl) of pyridine in 20 cm3 of a mixture of dichloromethane and ethanol in a ratio of 50:50, add 0.125 g of sodium borohydride. After stirring for an hour. at a temperature of 50"С, the reaction mixture is cooled to a temperature of 20"С, 20cm3 of dichloromethane, 1cm3 of water and 0.1g of magnesium sulfate are added. The mixture is filtered and the filtrate is concentrated at a temperature of 507C and reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.040-0.06 mm; height 15 cm, diameter 1 cm), eluting under argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (in a ratio of 40:60 by volume) and collecting fractions of 10 cm3 . Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 2-11-bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine is obtained in the form of a white powder.

H-NMR spectrum (300MHz; SOSIz) b (in ppm): 2.80-3.00 (m:ZN); 3.34 (m:2H); 3.70 (d, 9-7Hz :2H); 4.25 (sn); 7.20-7.40 (m:8H); 7.57 (ddd, 9U-8-5 and 1HtsC:1H); 7.97 (t bifurcated, 9- 8 and 1.5 HzC:1H); 8.07 (d ush., U-8HC:1H); 8.75 (d ush., UZ Hz). 2-11-IBis(4-chlorophenyl)methyl|azetidine- 3-ylidenemethylsulfonylupyridine can be obtained in the following way: to a solution of 0.9 g of 1-bis(4-chlorophenyl)methyl|-3-(pyrid-2-ylsulfonylmethyl)azetidin-3-ol in 50 cm3 of dichloromethane, add 0.25 cm3 of methylsulfonyl chloride, mix for 15 minutes and add 0.9 g of 4-dimethylaminopyridine. After stirring for 3 hours at a temperature of 202C, 30 cm3 of water and 30 cm3 of dichloromethane are added to the mixture, then the organic phase is decanted, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa ). about volumes) and collecting fractions of 20 cm3. Fractions 4-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa)". 0.50 g of 2-11-bis(4-chlorophenyl)methyl|azetidin-3-ylidenemethylsulfonyl)pyridine is obtained in the form of a yellow powder. 1-(Bis(4-chlorophenyl)methyl|-3-(pyrid-2-ileoulfonylmethyl)azetidin-3-ol can be obtained in the following way: in an atmosphere of argon, to a solution cooled to a temperature of -78"С, 2.92g 1 -Ibis(4-chlorophenyl)methylI|azetidin-3-one and Zg 2-methylsulfonylpyridine in 50 cm3 of tetrahydrofuran add 2.13 g of potassium tert-butylate. After stirring for 3 hours at a temperature of -78"C, the reaction mixture is left to stand to raise the temperature to 02С, then add 50 cm3 of diethyl ether, 10 cm3 of water and 10 cm3 of an aqueous saturated solution of ammonium chloride. The organic phase is decanted, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.063- 0.200mm; height 30cm, diameter 3cm), eluting under argon pressure

0.5 bar, first using dichloromethane, then using a mixture of dichloromethane and methanol (in a ratio of 97:3 by volume) and collecting fractions of 20 cm3. Fractions 8-15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). A still contaminated brown oil is obtained, which is chromatographed on a column with silica gel (granulometry 0.04-0.063 mm; height 20 cm, diameter 2 cm), eluting under under an argon pressure of 0.5 bar, first using dichloromethane, then using a mixture of dichloromethane and methanol (in a ratio of 97:3 by volume) and collecting fractions of 20 cm3. Fractions 5-25 are combined and concentrated to dryness and the resulting residue is again chromatographed on the same column and under the same conditions, but eluting with dichloromethane. Fractions 12-20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of 1-I(bis(4-chlorophenyl)methyl|-3-(pyrid-2-ylsulfonylmethyl)azetidin-3-ol.- is obtained in the form of a white meringue. 2-Methylsulfonylpyridine can be obtained in the following way: to of a solution of 20 g of sodium tungstate dihydrate in 10 cm3 of water, with stirring and in an argon atmosphere, add 0.25 cm3 of 10095 acetic acid, then 7.0 g of 2-methylsulfanylpyridine. This mixture is heated to a temperature of 65 "C, slowly, for 15 minutes, topped up 10 cm3 of Z095 hydrogen peroxide, then stir at a temperature of 852C for

30 minutes, after which the mixture is cooled to a temperature of 10"C. 1.0 cm3 of a 329.5% ammonium hydroxide solution, 5.0 cm3 of an aqueous 37.595% solution of sodium hydrosulfite, then 10 cm3 of water and 50 cm3 of dichloromethane are added to the medium. The mixture is decanted, the organic phase dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting colorless oil is treated with 50 cm3 of petroleum ether, and the insoluble resinous substance is filtered off and treated with 30 cm3 of dichloromethane. The resulting solution is concentrated to dryness at a temperature of 50"C and reduced pressure (2.7 kPa).

3.5 g of 2-methylsulfonylpyridine is obtained in the form of a colorless oil. 2-Methylsulfanylpyridine can be obtained in the following way: 6.2 methyl iodide is slowly added to a solution of 11.0 g of 2-mercaptopyridine in 105 cm3 of 1 N sodium hydroxide solution. The reaction mixture, the temperature of which rises to 30"C, is cooled to room temperature. After stirring for 2 hours, the mixture is extracted with 100 cm3 of dichloromethane, the organic phase is dried over magnesium sulfate and concentrated to dryness at a temperature of 50"C and reduced pressure (2.7kPa) . The resulting oil is purified by distillation under reduced pressure. 9.0 g of 2-methylsulfanylpyridine is obtained in the form of a colorless liquid.

Boiling point: 847C at 45 mm Hg. Art.

Example 21 3-11-(Bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine can be obtained according to the method described in example 20, starting from 0.15 g of 3-11-Ibis(4-chlorophenyl) quail| azetidine-3-ylidenemethyl-sulfonyl)pyridine, 20 cm3 of a mixture of dichloromethane and ethanol in a ratio of 50:50 and 8 mg of sodium borohydride.

0.11 g of 3-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine is obtained in the form of a white powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.75-2.95 (m:ZN); 3.35 (m:2H); 3.43 (d, 9U-6 ,5Hz:2H); 4.25 (syn); 7.20-7.40 (m:8H); 7.54 (ddd, U-8-5 and 1Hz:1H); 8.18 (ddd, U -8-2.5 and 1.5Hz:1H); 8.90 (dd, uU2511.5Hz:1H); 9.11 (dd, uh2.511Hz). 3-11-(Bis(4-chlorophenyl) methyl|azetidin-3-ylidenemethylsulfonyl)pyridine can be obtained according to the method described in example 20, starting from 0.8 g of 1-(bis(4-chlorophenyl)methyl|-3-(pyrid-3-ylsulfonyl-methyl)azetidine -3-ol, 50 cm3 of dichloromethane, 0.22 cm3 of methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine.

0.50 g of 3-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylidenemethylsulfonyl)pyridine is obtained in the form of a cream-colored powder.

1-(Bis(4-chlorophenyl)methyl|-3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol can be obtained according to the method described in example 20, starting from 3,Zg 1-(bis(4- chlorophenyl)methyliazetidin-3Z-one, 50 cm3 of tetrahydrofuran, 3.5 g of 3-methylsulfonylpyridine and 2.4 g of potassium tert-butylate. 1.4 g of 1-bis(4-chlorophenyl)methyl|-3-(pyrid-3-ylsulfonylmethyl) is obtained. azetidin-3-ol in the form of a white powder.

3-Methylsulfonylpyridine can be obtained according to the method described in example 20, starting from 33 g of sodium tungstate, 10 cm3 of water, 0.25 cm3 of 10095 acetic acid, 9.5 g of 3-methylsulfanylpyridine, 15 cm3 of 3095 hydrogen peroxide, then 2 cm3 of 3295 -% solution of ammonium hydroxide and 2 cm3 of an aqueous 37.595% solution of sodium hydrosulfite. The resulting brown oil is crystallized from 20 cm3 of isopropyl ether, the crystals are filtered under vacuum and dried under reduced pressure (2.7 kPa). 4.5 g of 3-methylsulfonylpyridine is obtained in the form of white crystals. T.pl.: 5870.

C3-Methylsulfanylpyridine can be obtained in the following way; in an argon atmosphere, 20 cm3 of isoamyl nitrite is added to a mixture of 9.4 g of 3-aminopyridine and 100 cm3 of dimethyl disulfide heated to a temperature of 80°C.

After stirring for 2 hours at a temperature of 90"C, the reaction mixture is cooled to a temperature of 20"C, then purified by fractional distillation under reduced pressure. 8.4 g of 3-methylsulfanylpyridine is obtained in the form of a pale yellow liquid. Boiling point: 907C at 30 mm Hg. Art.

Example 22 4-1-(Bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine can be obtained according to the method described in example 20, starting from 0.15 g of 4-11-Ibis(4-chlorophenyl) quail| azetidine-3-ylidenemethyl-sulfonyl) pyridine, 20 cm3 of a mixture of dichloromethane and ethanol in a ratio of 50:50 and 8 mg of sodium borohydride.

0.13 g of 4-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonyl)pyridine is obtained in the form of a white powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.75-2.90 (mn); 2.88 (t, U-7HC:2H); 3.36 (t, 9 -7Hz:2H); 9.42 (d, in 7Hz:2H); 4.25 (CH); 7.20-7.35 (m:8H); 7.75 (d ear., U-6Hz: 2H); 8.93 (d., U9-6Hz:2H)| , based on 0.8g of 1-(bis(4-chlorophenyl)methyl|-3-(pyrid-4-ylsulfonylmethyl)azetidin-3-ol, 50cm3 of dichloromethane, 0.22cm3 of methylsulfonyl chloride and 0.8g of 4-dimethylaminopyridine.

The crude product is purified by chromatography on a column with silica gel (granulometry 0.04-0.063 mm; height 20 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (in a ratio of 40:60 by volume) and collecting fractions of 20 cm3. Fractions 5-10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of 4-11-bis(4-chlorophenyl)methyl|azetidin-3-ylidenemethyl-sulfonyl)pyridine is obtained in the form of a crystalline white powder. 1-(Bis(4-chlorophenyl)methyl|-3-(pyrid-4-ylsulfonylmethyl)azetidin-3-ol can be obtained according to the method described in example 20, starting from 2.5 g of 1-Ibis(4-chlorophenyl )methyl|iazetidin-3-one, 50 cm3 of tetrahydrofuran, 2.6 g of 4-methylsulfonylpyridine and 1.8 g of potassium tert-butylate. The crude product obtained is purified by chromatography on a column with silica gel (granulometry 0.04-0.063 mm; height Zosm, diameter

Ccm), eluting under argon pressure of 0.5 bar with dichloromethane, then with a mixture of dichloromethane and methanol (in a ratio of 98:2 by volume) and collecting fractions of 20 cm3. Fractions 8-27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). A cream-colored powder is obtained, which is recrystallized from 5 cm3 of acetonitrile. The crystals are filtered, squeezed and dried under reduced pressure (2.7 kPa). 1.4 g of 1-Ibis(4-chlorophenyl)methyl|-3-(pyrid-4-ylsulfonyl-methyl)azetidin-

Z-ol in the form of white crystals. Melting point: 13070. 4-Methylsulfonylpyridine can be obtained according to the method described in example 20, starting from 14g of sodium tungstate, 4cm?3 of water, 0.05cm3 of 10095-acetic acid, 3.3g of 4-methylsulfanylpyridine, 6 .5cm3 of 3095% hydrogen peroxide, then 0.25cm3 of 3295% ammonium hydroxide solution and 1cm3 of an aqueous 37.5965% solution of sodium hydrosulfite. The resulting brown oil is crystallized from 10 cm3 of diisopropyl ether, the crystals are filtered, squeezed and dried under reduced pressure (2.7 kPa).

2.6 g of 4-methylsulfonylpyridine is obtained in the form of white crystals. 4-Methylsulfanylpyridine can be obtained according to the method described in example 20, starting from 11.0g of 4-mercaptopyridine, 105cm3 of 1N sodium hydroxide solution and 6.2cm of methyl iodide. The resulting crude oil is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanylpyridine is obtained in the form of a white paste. Boiling point: 1207C at 45 mm Hg. Art.

Example 23 1-(Bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)sulfonyl-methyl|iazetidine can be obtained in the following way: to a solution of 0.50 g of 1-I(bis(4-chlorophenyl) 78 mg of sodium borohydride is added to methyl-3-(3,5-difluorophenyl)sulfonylmethylene|azetidine in 25 cm3 of anhydrous methanol and 25 cm3 of anhydrous dichloromethane in an argon atmosphere.

After stirring for 24 hours, add 80cm3 of water and 50cm? of dichloromethane, decanted, washed with 80 cm3 of water, then 80 cm3 of saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column with silica gel (granulometry 0.02-0.04 mm; height 20 cm, diameter 14 cm), eluting under an argon pressure of 0.7 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10 by volume) and collecting the fractions 5 cm3 each. Fractions 60-82 are combined and concentrated to dryness under reduced pressure (2.7 kPa).

0.29 g of 1-Ibis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)sulfonylmethyl|azetidine) is obtained in the form of a white solid.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 2.75-2.95 (min); 2.88 (t, U-7HzC:2H); 3.36 (t, 9 -7 HzC:2H); 3.41 (d, 1-7Hz:2H); 4.26 (s:1H); 7.13 (tt, U-912.5Hz:1H); 7.20-7, 35 (m:8H); 7.44 (m:2H)).

Example 24 1-(Bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)sulfonyl-methylene|azetidine can be obtained in the following way: to a solution of 18.8 g of 1-I(bis(4-chlorophenyl)methyl |-3-((3,5-difluorophenyl)sulfonylmethyl|iazetidin-3-ol.- in 800 cm3 of dichloromethane at room temperature add 4.3 cm? of methylsulfonyl chloride, then, in small portions, 16 g of 4-dimethylamino-pyridine. After 22 hours of reaction the mixture is washed three times with 700 cm3 of water, then with 700 cm3 of an aqueous saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered, and then evaporated to dryness under reduced pressure (2.7 kPa). The residue in the amount of 25 g is chromatographed on a silica gel column (granulometry 0.02-0.04 mm; height Zbsm, diameter 8.5 cm), eluting under argon pressure of 0.7 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 90:10 by volume) and collecting fractions of 250 cm3. Fractions 2- 148 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2.79 g of 1-Ibis(4-chlorophenyl)methyl|-3-I(3,5- difluorophenyl)sulfonylmethylene|azetidine as a white solid.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 3.91 (m:2H); 4.28 (m:2H); 4.51 (c:1H); 6.15 ( m:1H); 7.08 (t, uU29 and 2.5HC:1H); 7.25-7.40 (m:8H); 7.40 (m:2H)|. 1-(Bis(4- chlorophenyl)methylI-3-(3,5-difluorophenyl)sulfonyl-methyl|iazetidin-3-sl can be obtained in the following way: to a solution of 13.2 g of (3,5-difluorophenyl)methylsulfone in 800 cm3 of tetrahydrofuran, add 42, 9 cm? of a 1.6M solution of butyllithium in hexane. After standing for 0.5 hours at a temperature of -70"C and 0.5 hours at a temperature of -30"C, at a temperature of -70"C a solution of 14g of 1-I( bis(4-chlorophenyl)methyliazetidin-3-one in 150 cm3 of tetrahydrofuran. After standing for 3 hours at a temperature of -70"C, the reaction mixture is poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed twice with 400 cm3 of water, then with 400 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa). The residue in the amount of 25.1 4 g is chromatographed on a column with silica gel (granulometry 0.06-0.04 mm; height 31 cm, diameter 7.5 cm), eluting under argon pressure of 0.5 bar using a mixture of cyclohexane and ethyl acetate (in a ratio of 85:15 by volume) and collecting fractions of 200 cm3. Fractions 13-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from diethyl ether, filtering and drying, 45 g of 1-bis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)sulfonylmethyl|azetidin-3-ol are obtained as a white solid. (3,p5-Difluorophenylmethylsulfone can be obtained in the following way. to a solution of 13.3g of (3,5-difluorophenyl)methylsulfide in 450cm3 of methanol, 225cm33 of water and, in small quantities at a temperature of 5"C, 56.3g of oxonufF are added. After standing for For 20 hours at room temperature, the reaction mixture is diluted with dichloromethane and water and decanted. The organic phase is washed twice with 700 cm3 of water, then with 700 cm3 of an aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered, then evaporated to dryness under reduced pressure (2.7 kPa ). 13.2g of (3,5-difluorophenyl)methylsulfone is obtained as a white solid. (3,5-Difluorophenyl)methylsulfide can be obtained in the following way; to 11.8cm3 of 1-bromo-3,5-difluorobenzene, diluted with 200 cm³ of diethyl ether, at a temperature of -707C, add 6b4cm3 of a 1.6M solution of n-butyllithium in hexane dropwise. After standing for 0.5 hours at a temperature of -707C, add dropwise, at a temperature of -70"C,a solution of 14.2 g of 5-methyl-methylthiosulfonate in bosm3 of tetrahydrofuran. After standing for 3 hours at a temperature of -70°C, then for 18 hours at room temperature, the reaction mixture is poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed twice with 300 cm3 of water, then with the help of 300 cm3 of an aqueous saturated solution of sodium chloride , dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2.7 kPa). 13.3 g of (3,5-difluorophenyl)methyl sulfide was obtained in the form of a yellow oil.

Example 25

0.25 g of m-chloroperbenzoic acid is added to a solution of 0.40 g of 1-bis(4-chlorophenyl)methyl|-3-(phenyl-sulfanyl)azetidine in 20 cm3 of dichloromethane at room temperature. After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm3 of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a column with silica gel (granulometry 0.06-0.200 mm; height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions bosm3, fractions 9-16 are combined and concentrated to dryness under reduced pressure (2.7 kPa), treated with heptane, releasing 100 mg of 1-Ibis(4-chlorophenyl)methyl|-3-((A5)-phenylsulfinyl|azetidine in the form of a solid white substances.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 3.01 (t ush., 927.5 Hz: 1H); 3.32 (t ush., 9U-7.5 Hz ЦН); 3 .45 (t ush., ue7.5Hz: 2H); 3.59 (m/n); 4.45 (s ush.: 1H); 7.15-7.65 (multiplets: 1ZH)).

Example 26

Several portions of 1.2 g of oxon F. After stirring for 20 hours at room temperature, the reaction mixture is diluted with 100 cm3 of dichloromethane, washed three times with 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After column chromatography with silica gel (granulometry 0.06-0.200 mm; height 40 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar using a mixture of ethyl acetate and cyclohexane (in a ratio of 20:80 by volume) and collecting fractions by bosm3, fractions 9 - combine and concentrate to dryness under reduced pressure (2.7 kPa), treat with heptane, isolating 0.23 g of 1-

Ibis(4-chlorophenyl)methyl|-3-(phenyl-sulfonyl)azetidine as a white solid.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 3.35-3.50 (m:4H); 3.96 (m:1H); 4.44 (s:1H); 7.20-7.35 (m:8H); 7.57 (t ush., 9U-7.5Hz:2H); 7.68 (t, 9-7.511.5Hz1H); 7.88 (d ush. , 9-7.5HZ:2NO.

Example 27

To a solution of 0.6 g of methyl-5-(/1-(bis(4-chlorophenyl)methyl|azetidin-3-ylidene)umethylsulfonylmethyl)uthien-2-ylcarboxylate in 70 cm3 of methanol, cooled to a temperature of 0"C, add 43.5 mg sodium borohydride.

The reaction mixture is stirred for 15 minutes at this temperature, then for 5 hours at a temperature of 20"C, then cooled again to a temperature of about 0"C and 8.7 mg of sodium borohydride is added.

After standing for 18 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). 100 cm3 of dichloromethane and 20 cm3 of distilled water are added to the resulting residue.

The mixture is decanted, the organic phase is washed twice with 20 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting residue is purified by flash chromatography on silica gel (eluent: a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume). 0.18 g of methyl-(A5)-5-(1-(bis(4-chlorophenyl) is obtained )methyl|azetidin-3-ylmethylsulfonylmethyl)thien-2-ylcarboxylate in the form of a white powder.

IS spectrum "H-NMR (400 MHz; (СО3)250-ав) b (in ppm): 2.60 (t, 9У-7.5ХЦ:1Н); 2.86 (с:ЗН); 3, 14 (m:2H); 3.20-3.35 (m:1H); 3.45 (t ush., 1-7.5 HzC:1H); 3.82 (c:3H); 4.47 ( sn); 5.27 (d, U-11Hts1H); 7.28 (d, 9y-4Hts:1H); 7.30-7.50 (m:8H); 7.72 (d, yUx4HtsiH).

Methyl 5-(/11-(bis(4-chlorophenyl)methyl|azetidin-3-ylidene) methylsulfonyl-methyl)thien-2-ylcarboxylate can be obtained in the following way; to a solution of 6.12 g of 1-I(bis(4-chlorophenyl)methyl|iazetidin-Z-one in 200 cm3 of tetrahydrofuran at room temperature in an argon atmosphere, 5.15 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate, then obtained the suspension is cooled to a temperature of -7076.

Add 2.47g of potassium tert-butylate successively, then, after 1 hour. 30 minutes, at the same temperature for 2 minutes, a solution of 1.7 cm3 of methylsulfonyl chloride in vcm? diethyl ether. The reaction medium is maintained for an hour. at a temperature of -70"С, then left to stand until cooling to a temperature of about 207С, after which 80 cm3 of distilled water is added. Tetrahydrofuran is distilled off under reduced pressure, and the resulting aqueous residue is extracted with 500 cm3 of dichloromethane. The mixture is decanted, the organic phase is washed three times with 80 cm? of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa)" The obtained residue is purified by flash chromatography on silica gel (eluent: a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume)| 1.6 g of methyl-5-(1-|bis(4-chlorophenyl)methyl|azetidin-3-ylidene) methyl-sulfonylmethyl)uthien-2-ylcarboxylate are obtained in the form of a cream-colored meringue.

Methyl-5-(methylsulfonylmethyl)thien-2-ylcarboxylate can be obtained in the following way: 31.7g of sodium methylsulfinate is added to a solution of 7g of methyl-5-(bromomethyl)thien-2-ylcarboxylate in 150cm3 of ethanol and the resulting suspension is boiled with in an inverted refrigerator for 7 hours. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted four times with 500 cm3 of ethyl acetate, the combined organic phases are washed successively with 250 cm3 of distilled water and 250 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and incompletely concentrated under reduced pressure. The isolated solid substance is filtered, washed three times with 25 cm3 of cooled ethyl acetate, and 21.4 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate is obtained in the form of a cream-colored powder.

Methyl-5-(bromomethyl)/)thien-2-ylcarboxylate can be obtained according to the method described by 9.M/yuak et al., Visogd. Honey. Spent I ey., 5 (18), 97-100 (1995).

Example 28 (A85)-1-Bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonyl-methyl-azetidin-3-ylcyclopropylamine can be obtained in the following way: to a solution of Zg 1-(bis(4- chlorophenyl) methyl|-3-|(3,5- difluorophenyl)(methylsulfonyl) methylene|azetidine in 30 cm3 of dichloromethane, at a temperature of about 22 C and in an inert atmosphere of argon, add 2.52 cm3 of cyclopropylamine. After standing for 39 hours at a temperature of about 24 "C, the reaction medium is concentrated under reduced pressure (Zmbar) at a temperature of about 40"C. In this way, 3.26 g of pale yellow meringue is obtained, which is processed using

Zoscm3 of dichloromethane and 2.52cm3 of cyclopropylamine. The resulting solution is stirred in an inert atmosphere of argon at a temperature of about 217C for 87 hours, then concentrated at a pressure of Zmbar at a temperature of about 4076. in this way, 3.64 g of (85)-1-Ibis(4-chlorophenyl)methyl|-3-| (3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-ylcyclopropylamine in the form of a pale yellow meringue.

IS spectrum "H-NMR (30 MHz; SOSIv) b (in ppm): 0.29 (m:1H); 0.40-0.75 (m:3H); 2.50 (m:1H); 2.73 (s:ZH); 2.90 (array:1H); 3.45-3.70 (m:Z3H); 4.36 (s ush.1H); 4.60-4.80 (array ear: 1H); 6.87 (t, 9U-9 and 2.5HzC1H); 7.20-7.40 (m/TON)).

Example 29 (85)-11-Bis(4-chlorophenyl)methyl|i-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-yl2-pyrrolidin-1-ylethyl)uamine can be obtained in the following way; 0.076 cm3 of 1 -(2-aminoethyl)pyrrolidine. The resulting solution is stirred at a temperature of about 217C for 22 hours in an argon atmosphere, concentrated under the influence of air flow at a temperature of about 42"C, then the crude residue obtained is dried under reduced pressure (approx.

Zmbar) at a temperature of about 40"C. (НА5Б)-(1-Ibis(4-chlorophenyl)methyl|-3-(33,5-difluorophenyl)methylsulfonylmethyliazetidin-3-yl2-pyrrolidin-1-ylethyl)amine is obtained in the form ocher meringues.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.75-1.95 (m:4H); 2.55-2.85 (m:bH); 2.79 (s :ZN); 2.91 (t, 96.5Hz:2H); 3.06 (d, 9U-8.5HzC:1H); 3.17 (d, U-8.5HzC:1H); 3.32 (d, U-8.5Hz:1H); 3.41 (d, 9-8.5Hz:1H); 4.31 (sn); 4.56 (s:1H); 6.88 (t, U -8.512.5Hz:1H); 7.22 (SAN); 7.25 (s:4H); 7.34 (m:2H)).

Example 30 (85)-11-Ibis(4-chlorophenyl)methyl-3-((33,5-difluorophenyl)methylsulfonyl-methylIazetidin-3-ylmethylamine can be obtained according to the method of example 29, starting from 50 mg of 1-Ibis(4 -chlorophenyl)methyl|-3-|(3,5-difluorophenyl)(methylsulfonyl)methylene of azetidine in 0.5 cm3 of dichloromethane and 0.3 cm3 of a 2M solution of methylamine in tetrahydrofuran. (НА5Б)-11-Ibis(4-chlorophenyl)methyl is obtained |-3-(3,5-difluorophenyl)methylsulfonylmethyl)azetidine-3-ylylmethylamine in the form of a yellow resinous substance.

H-NMR spectrum (400MHz; SOSIz) b (in ppm): 2.00-2.20 (array ush.1H); 2.62 (C:ZN); 2.76 (C:ZN) ; 3.04 (d, ear 9Hz:1H); 3.18 (d, 9-9Hz:1H); 3.37 (AB, 9U-9Hz:2H); 4.31 (s:1H); 4, 55 (sn); 6.89 (t, 9-9 and 2.5Hz:1H); 7.22 (SAN); 7.24 (shAN); 7.32 (m:2H).

Example 31

(85)-11-IBis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-ylisobutylamine can be obtained according to the method of example 29, starting from 50 mg of 1-IBis( 4-chlorophenyl)methyl|-3-|(3,5- difluorophenyl)(methylsulfonyl)methylene| azetidine, 0.5om3 of dichloromethane and 0.0596cm3 of isobutylamine.

(85)-11-Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-yl)isobutylamine is obtained in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.01 (2d, 9-7 Hz: 6H); 1.70-2.15 (ear array: 1H); 1.76 (mn); 2.51 (dd, 9U-10.5 and 7Hz1H); 2.76 (c:ZN); 2.80 (dd, 9U-10.5 and 6Hz:1H); 3.01 (d , 9-8.5Hz:1H); 3.14 (d, 9-8.5Hz:1H); 3.32 (d, 9u8.5HziH); 3.44 (d, 9uU-8.5Hz1H); 4 ... :2H)I.

Example 32 (85)-11-IBis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-yl)ethylamine can be obtained according to the method of example 29, starting from 50 mg 1-I|bis(4-chlorophenyl)methyl|-3-|(3,5-difluoro-phenyl)(methylsulfonyl)methylene-iazetidine, 0.5 cm? of dichloromethane and 0.3 cm3 of a 2M solution of ethylamine in tetrahydrofuran. Obtain (85)-11-(bis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-yl)ethylamine in the form of a yellow resinous substance.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.22 (t, ch27HzC:ZN); 2.70-2.85 (m:2N); 2.77 (s:ZN ); 2.95-3.10 (array:1H); 3.05 (d, U-8.5Hz:1H); 3.17 (d, 9-8.5HzC:1H); 3.33 (d , 9-8.5Hz:1H); 3.40 (d, 9-8.5Hz:1H); 4.30 (CH); 4.54 (s); 6.89 (t, 9-9 12, 5Hz: 1H); 7.15-7.30 (m: 8H); 7.34 (m: 2NO.

Example 33 (A85)-M-11-(Bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-yl)-IM,M'-dimethylethane-1,2- diamine can be obtained according to the method of example 29, starting from 50 mg of 1-bis(4-chlorophenyl)methyl/-3-(3,5-difluorophenyl) (methylsulfonyl)methylene|iazetidine, 0.5 cm3 of dichloromethane and 0.0659 cm3 M, M-dimethylethylenediamine. Obtained (85)-M-11-(bis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylII-M',M'-dimethylethane-1,2-diamine in the form of white meringue.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.32 (s:bH); 2.53 (t, 9-6HzC2H); 2.79 (s:ZH); 2, 94 (t, U-6Hz:2H); 3.06 (d, 9-8.5Hz:1H); 3.16 (d, 9-8.5Hz:1H); 3.30 (d, 9U-28 ... ); 7.21 (c:4H); 7.24 (c:4H); 7.34 (m:2H)|.

Example 34 (A85)-1-Bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methanesulfonyl-methyl|-3-methylazetidine can be obtained in the following way: in an argon atmosphere at a temperature of about 24"С a few drops of pure methyl iodide are added to a suspension of 400 mg of magnesium in the form of shavings in 2.5 cm3 of anhydrous diethyl ether, then 1 cm3 of methyl iodide in the form of a solution in 22.5 cm3 of diethyl ether. The resulting suspension is stirred for minutes at a temperature of about 247"C, then cooled to a temperature of about 0"C using a mixture of water and ice. At a temperature of about 0"C, 1.65 g of the SiVg-(CH3)25 complex is added, then the reaction mixture is stirred for 15 minutes at a temperature of about 0"C. At a temperature of about 0"C to the obtained add a solution of 0.5 g of /1-Ibis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)(methylsulfonyl)methylene| azetidine in a mixture with 1 cm3 of tetrahydrofuran and 1 cm3 of diethyl ether. The resulting suspension is stirred for 4 hours at a temperature of about 0"C, then for 16 hours at a temperature of about 25"C. The resulting black suspension is diluted with 100 cm3 of ethyl acetate and 15 cm3 of saturated ammonium chloride solution. The reaction mixture is filtered through a porous glass filter filled with celite, the solid residue is washed with ethyl acetate, then with water. After decantation of the filtrate, the organic phase is separated, washed with 10 cm3 of water, 10 cm? of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered through a glass porous filter and concentrated under reduced pressure (20 mbar) at a temperature of about 43"C. In this way, 550 mg of a yellow-hot meringue is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide (14 preparative plates MegsK KiezeYide! b60B254; 20x20 cm; thickness 0.5 mm; precipitation from a solution in dichloromethane|, eluting with a mixture of methanol and dichloromethane (in a ratio of 0.5:99.5 by volume).

After elution of the zone corresponding to the desired product using a mixture of methanol and dichloromethane (in a ratio of 15:85 by volume), filtration through a porous glass filter, then evaporation of the solvents under reduced pressure and at a temperature of about 40"C, 290 mg of white meringue is obtained, which it is dissolved in 15 cm3 of anhydrous dichloromethane and introduced into interaction with 500 mg of thiophenol resin (supplier Agdopatsi, 1.45 mmol/g) and 1 g of resin based on ethylenediamine (0.8 mmol/g) for 38 hours at a temperature of about 20"C. The suspension is filtered through a glass porous filter, the resins are washed with dichloromethane and the filtrate is concentrated under reduced pressure (5 mbar) at a temperature of about 4376.

272.8 mg of white meringue is obtained, which is dissolved in 2 cm of dichloromethane and brought into interaction with 1 cm of ethylenediamine for 72 hours at a temperature of about 24"C. The resulting crude residue is treated with 50 cm3 of ethyl acetate and 10 cm3 of water. After decantation, the organic phase is washed with 10cm3 of a 1N aqueous solution of hydrochloric acid, 10cm3 of an aqueous saturated solution of sodium bicarbonate, 10cm3 of water, 10cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered through a glass porous filter and concentrated under reduced pressure (d8mbar) at a temperature of about 4276.

263.4 mg of pale yellow meringue is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide (7 preparative plates Meg"skK Kiezede! 60254; 20x20 cm; thickness 0.5 mm; precipitation from a solution in dichloromethane|, eluting with a mixture of methanol and dichloromethane ( in a ratio of 0.5:99.5 by volume).After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in a ratio of 15:85 by volume), filtration through a porous glass filter, then evaporation of the solvents at reduced pressure and at a temperature of about 40"C, 191.4 mg of (НА5)-1-

Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methanesulfonylmethyl|-3-methylazetidine in the form of a white meringue.

H-NMR spectrum (30 MHz; SOSIzv) b (in ppm): 1.75 (s:ZN); 2.67 (s:ZN); 2.74 (d ush, 9-7.5 HzCyN) ; 2.93 (d, 9U-7.5Hz:1H); 3.21 (d ear., 9U-7.5HzC:1H); 3.46 (d, 9-7.5Hz:1H); 4, 33 (with ear: 2H); 6.87 (t, U-9 and 2.5 Hz: 1H); 7.12 (m: 2H); 7.15-7.35 (m: 8H)|.

Example 35 (85)-1-(2-11-IBis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylsulfanyl)ethyl)-4-methylpiperazine can be obtained in the following method: at a temperature of about 207C, 128 mg of 1-(ethanethiol-2- yl)-4-methylpiperazine. After stirring overnight at a temperature of about 207C, 706 bmg of Methene resin (1.7 mmol/g) is added. After stirring overnight at a temperature of about 202C, the suspension is filtered and the resin is washed twice with 1 cm3 of dichloromethane. The filtrate is concentrated under reduced pressure. In this way 125 mg of white oil is obtained, which is purified by chromatography on silicon dioxide (13 cm3 of silicon dioxide; 0.06-0.2 mm), eluting with a mixture of methanol and dichloromethane (in a ratio of 0:100, then 5:95 by volume ). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. In this way, 62 mg of (85)-1-(2-11-I(bis(4-chlorophenyl)methyl|-3-I) is obtained ((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylsulfanyl)ethyl)-4-methylpiperazine in the form of white crystals.

IS spectrum "H-NMR (300 MHz; (СО3)250-dv) b (in ppm): 2.15 (c:ZN); 2.30 and 2.41 (2 array: 8Н); 2.55 (m:2H); 2.85 (s:3H); 3.02 (m:2H); 3.09 (d, 9U-8.5HzC:1H); 3.38 (d, 9-8.5HzC :1H); 3.42 (d, 9-8.5Hz:1H); 3.79 (d, U-8.5Hz1H); 4.68 (sn); 5.37 (c:1H); 7, 30-7.50 (m:11H)).

Example 36 (85)-(2-11-IBis(4-chlorophenyl)methyl|-3-I((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylsulfanyl)ethyl)dimethylamine can be obtained according to the method of example 35 , based on 99 mg 1-

Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl) (methylsulfonyl)methylene|azetidine, 2 cm3 of dichloromethane, 84 mg of 2-(dimethylamino)ethanethiol and 70 mg of Mettiei resin (1.7 mmol/g). In this way, Zbmg (H5B)-(2-11-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl azetidin-3-ylsulfanyl)ethyl)dimethylamine is obtained in the form of an off-white powder.

Example 37 (85)-11-(4-(chloromethyl)phenyl)|(4-chlorophenyl)methyl|i-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-yl)ethylamine can be obtained in the following way; a solution of 40 mg of (A5)-1-((4-(chloromethyl)phenyl|(4-chlorophenyl)methyl)-3-(3,5-difluorophenyl)methylsulfonylmethylene|azetidine in 0.1125 cm3 of ethylamine (2M solution in tetrahydrofuran), containing a grain of sodium iodide, stirred at a temperature of about 207C for 2 hours, then diluted with 20 cm3 of ethyl acetate and 5 cm3 of an aqueous saturated solution of sodium hydrogencarbonate. The separated organic phase was washed with 5 cm3 of water, 5 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered through glass porous filter and concentrate under reduced pressure (15mbar) at a temperature of about 40"C. The resulting yellow oil is purified by preparative thin-layer chromatography on silicon dioxide (2 preparative plates Megsk Kiezede! 60254; 20x20cm; thickness 0.5mm; precipitation from a solution in dichloromethane|, eluting with a mixture of methanol and dichloromethane (in a ratio of 3:97 by volume). After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane rmethane (in a ratio of 15:85 by volume), filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, 17 mg of (85)-11-((4-(chloromethyl)phenyl)|( 4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylethylamine as a white solid.

H-NMR spectrum (400MHz; (CO3)250O-yv) b (in M.D.): 1.11 (t, uche7Hz:ZN); 2.10-3.55 (m:8Н); 2, 95 (s:ZN); 4.44 (s/1H); 5.09 (s:1H); 7.10-7.55 (m:11H)). (85)-1-(4-(« Chloromethyl)phenyl|(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonylmethylene|azetidine can be obtained in the following way: to a solution of 590 mg of (НА5)-И4-((4-chlorophenyl)(3- (3,5-difluorophenyl)methyl-sulfonylmethylene|azetidin-1-yl)umethyl)phenyl|methanol in 5 cm3 of anhydrous dichloromethane at a temperature of about 217C, add 0.525 cm3 of M,M-diisopropylethylamine, then 0.19 cm3 of methanesulfonyl chloride. After standing for 1 hour. at a temperature of about 217C, add 2 cm3 of a mixture of methanol and dichloromethane (in a ratio of 2.5:97.5 by volume), then, after 5 minutes, the reaction mixture is concentrated under reduced pressure (20 mbar) at a temperature of about 40"C. The resulting meringue yellow color is purified by chromatography on silicon dioxide (50 g of silicon dioxide with a particle size of 0.06-0.2 mm contained in a column with a diameter of

Ccm), eluting with a mixture of methanol and dichloromethane (in a ratio of 0:100, then 1:99, by volume) and collecting fractions of 10cm3. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. In this way, 421.2 mg of (85)-1-((4-(chloromethyl)phenyl)|(4-chlorophenyl)methyl|-3-

I((3,5-difluorophenyl)methylsulfonylmethylene|azetidine in the form of a yellow meringue. (85)-14-(4-Chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonyl-methylene|azetidin-1-yllium)) phenyl|methanol can be obtained in the following way: to a solution of 420 mg of (85)-4-((4-chlorophenyl)(3-((3,5-difluorophenyl)methylsulfonyl)) cooled to a temperature of about 0"C (ice and water) methylene|azetidin-1-ilyumethyl) benzaldehyde in 7 cm3 of methanol, 49 mg of sodium tetraborohydride is added in portions. After standing for 2 hours at a temperature of about 0"C, the reaction medium is concentrated under reduced pressure (15 mbar) at a temperature of about 357C. The obtained residue is purified by chromatography on dioxide silicon (40 g of silicon dioxide with a particle size of 0.06-0.2 mm contained in a column with a diameter of 3 cm), eluting with a mixture of methanol and dichloromethane (in a ratio of 1:99, then 2.5:97.5, by volume ) and collecting fractions of 10 cm3. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure . In this way, A18mg of (85)-I4-((4-chlorophenyl)(3-((3,5-difluoro-phenyl)methylsulfonylmethylene|azetidin-1-ylylmethyl)phenyl)methanol is obtained in the form of a white meringue.

Example 38 (85)-11-IBis(4-chlorophenyl)methyl|i-3-((3,5-bistrifluoromethylphenyl)methyl-sulfonylmethyl|azetidin-3-yl) isobutylamine can be obtained according to the method of example 29, based on 5O0mg 1-I(bis(4-

chlorophenyl)methyl-3-((3,5-bistrifluoromethylphenyl)(methylsulfonyl)methylene|azetidine, 0.5 cm3 of dichloromethane and 0.05 cm3 of isobutylamine. 57 mg of (85)-/1-Ibis(4-chloro-phenyl) are obtained methyl|-3-I((3,5-bistrifluoromethylphenyl)methylsulfonylmethyl|azetidin-3-yl)isobutylamine in the form of a pale yellow meringue.

H-NMR spectrum (300MHz; SOSIz) b (in ppm): 1.01 (d, 9-7.5 Hz:vH); 1.76 (m/n); 2.47 (dd, U -10.5 and 7.5 Хц1Н); 2.75-2.85 (m: 1Н); 2.79 (s: 3Н); 2.82 (dd, 9U-10.5 and 5.5 Хцц: 1Н) ; 3.00 (d, 1-9HzC:1H); 3.10 (d, U-9Hz:1H); 3.91 (d, uh 9Hz:1H); 3.40 (d, 9-9Hz:1H ); 4.30 (c:1H); 4.74 (Cs1H); 7.13 (d, U-28.5Hz:2H); 7.15-7.25 (m:bH); 7.96 ( dry 1H); 8.31 (dry 2 NO).

Example 39 (85)-1-Ibis(4-chlorophenyl)methyl|-3-cyano-3-((3,5-difluorophenyl)methyl-sulfonylmethyl|iazetidine can be obtained in the following way: to a solution of 99 mg of 1-Ibis( 4-chlorophenyl)methyl|-3-I|(3,5-difluorophenyl)(methylsulfonyl)methylene|iazetidine in 2.50 ml of dimethylsulfoxide at a temperature of about 20"С, 17 mg of potassium cyanide is added. The resulting yellow, then chestnut-colored solution is heated for minutes at a temperature of about 40"C, then cooled to a temperature of about 20"C. The reaction mixture is concentrated under reduced pressure, then treated with 10 cm3 of dichloromethane, washed three times with 5 cm3 of water. The obtained organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. In this way, 100 mg of a yellow pasty substance is obtained, which is purified by chromatography on silicon dioxide (10 cm3 of silicon dioxide with a particle size of 0.06-0.2 mm, contained in a column with a diameter of 1 cm), eluting with dichloromethane. contain only the searched pr aduct, combine and concentrate to dryness under reduced pressure. In this way, bomg (A5)-1-|(bis(4-chlorophenyl)methyl|-Zcyano-3-(3,5-difluorophenyl)methylsulfonylmethyl|iazetidine is obtained in the form of a pasty substance of pale yellow color.

H-NMR spectrum (300 MHz; (CO3)250-ydv) b (in ppm): 2.94 (s:ZN); 3.07 (d, 1-7.5 Hz:1H); 3, 20-3.40 (min); 3.61 (d ear, 157.5Hz1H); 3.68 (d ear, U-2:7.5 Hz:1H); 4.64 (s:1H) 5.51 (c:1H), 7.25-7.50 (mi11H) |

Example 40 (85)-11-Bis(4-chlorophenyl)methyl|i-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-ylmethyl(1-cyclopropylethyl)amine can be obtained in the following way. to a solution of 5 mg (A5B)-C-11-I(bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl) methylsulfonylmethyl|azetidin-3-yl) o methylamine in 2 cm3 of 1,2-dichloroethane at a temperature of about 0.03 cm3 of cyclopropyl methyl ketone, 0.006 bcm3 of acetic acid, then 32 mg of sodium triacetoxyborohydride are added sequentially at 207 C. The resulting solution is stirred at a temperature of about 207 C for 18 hours, then 2 cm3 of an aqueous saturated solution of sodium hydrogen carbonate is added.

After decantation, the organic phase is concentrated under reduced pressure. Thus, a bomg of yellow viscous oil is obtained, which is powdered with the help of isopropyl ether, petroleum ether. After drying at a pressure of 0.1 mbar, 55 mg of the residue is obtained, which is purified by chromatography on silicon dioxide (4 cm3 of silicon dioxide with a particle size of 0.06-0.2 mm contained in a column with a diameter of 1.2 cm), eluting with a mixture of methanol and dichloromethane (in a ratio of 0:100, then 5:95, by volume). Fractions containing only the desired product are combined, concentrated to dryness under reduced pressure and re-purified by chromatography on silicon dioxide (4 cm3 of silicon dioxide with a particle size of 0.04-0.0b6Zmm contained in a column with a diameter of 1.2 cm), eluting using a mixture of methanol and dichloromethane (in a ratio of 0:100, then 1:99, by volume). Fractions containing only the desired product are combined and concentrated to dryness. Thus, 20 mg of (НА5)-11-Ibis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonyl-methyl-Iazetidin-3-ylmethyl)-(1-cyclopropylethyl)amine are obtained.

H-NMR spectrum (30 MHz; SOCIz) b (in ppm): 0.00-0.30 and 0.40-0.80 (multiplets: 5H); 1.09 and 1.17 (g2d, 96.5 HzC: ЗН as a whole); 1.87 (m: 1Н); 2.55-2.75, 2.75-2.95 and 3.25-3.55 (multiplets: 4Н); 2.68 (c:3H); 3.12 (d, u8.5HCN); 3.80-3.90 (m:1H); 4.42 and 4.43 (2sy1H as a whole); 4.79 and 4.84 (2с1Н as a whole); 6.89 (t, U-9 and 2.5Гци1Н); 7.16 (m:2Н); 7.15-7.35 (m:8Н)). (85)-0- 11-(IBis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-yl)umethylamine can be obtained in the following way: to a solution cooled to a temperature of about 0"C, 250 mg ( A5)-1-

Ibis(4-chlorophenyl)methyl)|-3-cyano-3-((3,5-difluorophenyl)methylsulfonyl-methyl|iazetidine in 10cm3 of anhydrous tetrahydrofuran is added dropwise to 1.27cm3 of a 1.5M solution of diisobutylaluminum hydride in tetrahydrofuran.

After standing for 30 minutes at a temperature of about 0"C, then for 4 hours at a temperature of about 20"C, the solution is cooled again to a temperature of 0"C. 6.35cm3 of water are added successively, then 1.0 in 6cm3 of 12N hydrochloric acid. After decantation, aqueous phase is extracted three times with 10 cm of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. In this way, 0.42 g of a dark yellow oil is obtained, which is purified by chromatography on silicon dioxide (40 cm3 of silicon dioxide with a particle size of 0.063-0.2 mm contained in a column with a diameter of 2.7 cm), eluting with a mixture of methanol and dichloromethane (in a ratio of 0:100, then 5:95, by volume).

Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. In this way, 110 mg of (85)-C-11-(bis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonylmethyliazetidin-3-ylmethylamine is obtained.

Example 41 (A85)-M-11-(Bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-ylmethyl)isobutyramide can be obtained in the following way: to a solution of 5 mg (85)-C-11-Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)umethylsulfonylmethyl|azetidin-3-yl) methylamine in 2 cm3 of anhydrous dichloromethane at a temperature of about 20"C is successively added 0.0187 cm3 of isobutyric acid, 0.032 cm3 of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine. After stirring for 72 hours at a temperature of about 20 C, 2 cm3 of water is added, decanted, then the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Obtained the crude residue is purified by preparative thin-layer chromatography on silicon dioxide (1! preparative plate Megsk Kiese!/dei! bOg254; 20x20 cm; thickness 1 mm, eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 5:95 by volume). After elution, the corresponding desired product zone, filtration through porous glass filter,

then evaporation of solvents under reduced pressure at a temperature of about 40"С, 16 mg of (A5)-M-11-(bis(4-chlorophenyl)methyl-3-((3,5-difluorophenyl)methylsulfonylmethyl | azetidin-3Z-ylmethyl) is obtained isobutyramide in the form of a pale yellow powder.

H-NMR spectrum (300 MHz; SOSI33) b (in ppm): 1.22 (d, 927 Hz:6vH); 2.46 (m:1H); 2.69 (s:ZH); 2 ... 4.5Hz:1H); 4.09 (dd, 9U-14 and 7.5Hz:1H); 4.34 (CH); 4.35 (s:1H); 6.71 (dd, 9-7.514, 5HzC:1H); 6.95 (t, U-912.5HzCy1H); 7.10 and 7.35 (m.10H)).

Example 42 (A85)-M-11-(Bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethyl)ucyclopropanecarboxamide can be obtained according to a method similar to that of Example 39, based on 53 mg of (A5)-C-11-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methanesulfonyl-methyl|azetidine-

Z-yl)umethylamine, 2cm3 of anhydrous dichloromethane, 0.0167cm? of cyclopropanecarboxylic acid, 0.032 cm3 of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine. 28 mg of (A5)-M-11-(bis(4-chlorophenyl)methyl|-3- ((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethyl)ucyclopropane-carboxamide is obtained in the form of a beige powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 0.81 (m:2H); 1.01 (m:2H); 1.35-1.55 (m:1H); 2.70 (c:ZN); 3.02 (d, y8.5Htsn); 3.21 (AB limited, U-8Hts2H); 3.45 (d, 9U-8.5Hts1H); 3.62 (dd , 9-14th 4.5Hz:1H); 4.10 (dd, 9-14th 7.5Hz:1H); 4.31 (sn); 4.36 (s:1H); 6.75 (dd , 957.51 4.5HzC:1H); 6.95 (t, y and 2Hz:1H); 7.15-7.35 (mon).

Example 43 (85)-11-IBis(4-chlorophenyl)methyl|i-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-3-ylmethyl)diethylamine can be obtained according to a method similar to the following example 40, based on 5 mg of (A5)-0-11-(bis(4-chlorophenyl)methyl|/|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethylamine, 2 cm3 of 1,2-dichloroethane, 0.017 cm3 of acetaldehyde, 0.006 cm3 of acetic acid and 32 mg of sodium triacetoxyborohydride.

In this way, 12 mg of (H5)-1-ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethyl)diethylamine were obtained in the form of an off-white powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.00 (t, dU27HzC:6N); 2.49 (q, 9-7Hz:4Nn); 2.54 (d, 9U -13.5HzCyN); 2.69 (s:ZN); 2.76 (d ear., 9U-7.5HzC:1H); 3.07 (d ear., 9-7.5HzC:1H); 3 .15 (d, 9U-13.5HzC:1H); 3.24 (d ear., 9U-7.5HzC1H); 4.06 (d ear., U9-:7.5HzC:1H); 4.35 (s:1H); 5.02 (s/1H); 6.91 (m:1H); 7.15-7.40 (mon).

Example 44 (A85)-M-11-(Bis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonyl-methyl-azetidin-3-ylmethylumethanesulfonamide can be obtained in the following way; to a solution of 53 mg of (K8)- C-11-(bis(4-chlorophenyl)methyl-3-(3,5-difluoro-phenyl)methylsulfonylmethyl|azetidin-3-yl) methylamine in 2 cm3 of ethyl acetate at a temperature of about 20"С add 150 mg of dry resin IVA-68, then 0.012 cm3 of methylsulfonyl chloride.

After stirring overnight at a temperature of about 207C, add 0.001 cm3 of water, then 150 mg of dry INA-68 resin. After stirring for 1 hour. at a temperature of about 20"C, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. In this way, 81 mg of a yellow pasty substance is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide (1 preparative plate Megsk KieseYdeI bOR254; 20x20 cm; thickness 1 mm, eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 5:95 by volume). After elution of the zone corresponding to the desired product, filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, 25 mg of (НА5)-М is obtained -(-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethylimethanesulfonamide) in the form of a pale yellow powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.70 (s:ZN); 2.95-3.10 (m:2H); 3.05 (s:ZN); 3.22 (d ush., U-8HtsiN); 3.52 (d, uhaHts1H); 3.74 (dd, U-13.5 and 8Hts:1H); 3.90 (dd, 9U-13.5 and 5.5Hz:1H); 4.23 (sn); 4.46 (s:1H); 5.54 (mn); 7.00 (t, U-912Hz:1H); 7.05-7, 35 (m1OH)|.

Example 45 (85)-1-11-(IBis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl-Iazetidin-3-ylmethyl)-3-isopropylurea can be obtained in the following way: to the solution 5 Zmg (A5)-C-11-(bis(4-chlorophenyl)methyl|-3-

I(3,5-difluorophenyl)methylsulfonylmethyl| of azetidine-Z-ylylmethylamine in 2 cm3 of dichloromethane at a temperature of about 207C, add 0.0197 cm3 of isopropyl isocyanate. After stirring overnight at a temperature of about 207C, 0.05 cm3 of water is added, then, after stirring for 15 minutes at a temperature of about 20C, the reaction mixture is dried over magnesium sulfate, filtered and concentrated under reduced pressure.

The obtained residue in the amount of 75 mg is purified by preparative thin-layer chromatography on silicon dioxide (1 preparative plate Megsk KieseIde! 60254; 20x20 cm; thickness 1 mm|, eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 5:95 by volume). After elution, the corresponding desired product zone, filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, 1 mg of (A5)-1-11-Ibis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl) is obtained methylulfonyl-methyl|azetidin-3-ylmethyl)-3-isopropylurea in the form of a pale yellow powder.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.17 (d, 9-7 Hz: 6H); 2.68 (c:ZN); 3.00 (d us., 9U -8.5Hz:1H); 3.11 (d, 98.5Hz:1H); 3.17 (d, 9U-8.5Hz:1H); 3.46 (d ear., 9U-8.5Hz: 1H); 3.64 (dd, 9-14 and 5Hz:1H); 3.86 (m:1H); 3.96 (dd, 9-14 and 7.5Hz1H); 4.15 (d, 9- 8Hz:1H); 4.29 (s:1H); 4.43 (s:1H); 5.11 (m.1H); 6.94 (t, U-91 and 2Hz1H); 7.10-7.30 (m1OH)).

Example 46

Isobutyl ether (A5)-11-(bis(4-chlorophenyl)methyl|-3-(3,5-difluoro-phenyl)umethylsulfonylmethyl|azetidin-

Z-ylmethyl carbamic acid can be obtained in the following way: to a solution of 5 mg of (AB5)-C-11-Ibis(4-chlorophenyl)methyl-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethylamine in 2 cm3 of pyridine at a temperature of about 20"C, add 0.016 cm3 of isobutyl chloroformate. After stirring overnight at a temperature of about 20"C, the reaction mixture is concentrated under reduced pressure. Thus, bZmg of a pasty substance of pale yellow color is obtained, which is purified by preparative thin-layer chromatography on silicon dioxide (1 preparative plate Megsk KiezeYide! 6О0Б254; 20х20 cm; thickness 1 mm, eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 5:95 by volume After elution of the zone corresponding to the desired product, filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, 14 mg of isobutyl ether (A5)-(1-

Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethylcarbamic acid in the form of an off-white powder.

H-NMR spectrum (300 MHz; SOSI»z) b (in ppm): 0.96 (d, 927 Hz:bH); 1.95 (mn); 2.68 (s:ZN); 3 ... -4.00 (m:ZN); 4.30 (sn); 4.34 (syn); 5.63 (array:1H); 6.95 (t, 9-9 and 2Hz:1H); 7, 10-7.30 (m/1OH)).

Example 47 (85)-11-IBis(4-chlorophenyl)methyl|i-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-3-ylmethyl)dimethylamine can be obtained in the following way: to a solution of 52 mg (A5) -C-11-(bis(4-chlorophenyl)methyl|- 3-(3,5-difluorophenyl)umethylsulfonylmethyl azetidin-3-ylmethylamine in 2 cm3 of acetonitrile at a temperature of about 202C, add 138 mg of potassium carbonate, then 0.0075 cm3 of methyl iodide. After stirring during the night at a temperature of about 207"C, the reaction mixture is filtered through a glass porous filter, the solid substance is washed with dichloromethane and the filtrate is concentrated under reduced pressure. The obtained crude residue in the amount of 9 Ω is purified by preparative thin-layer chromatography on silicon dioxide |! preparative plate Megsk KieseYideI bOR254; 20x20cm ; thickness 1 mm|, eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 5:95 by volume). After elution of the zone corresponding to the desired product, filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 407, 11 mg of (85)-11-Ibis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyliazetidin-3Z-ylmethyldimethylamine are obtained.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.18 (s: bH); 2.30 (d, 9-13 Hz: 1H); 4.65-4.78 (m :1H); 2.70 (c:ZN); 2.98 (d, 9-13Hz:1H); 3.09 (d, U28Hz:1H); 3.32 (d, 9-7.5Hz:1H ); 4.11 (d, U-8Hz:1H); 4.35 (s:1H); 4.94 (sn); 6.92 (min); 7.10-7.40 (m/1OH) ).

Example 48 (85)-1-Bis(4-chlorophenyl)methyl|-3-(4-methoxyphenyl)methylsulfonyl-methyl|azetidine can be obtained in the following way: to a solution of 40 Omg of 1-I(bis(4-chlorophenyl)methyl |-3-|(4-Methoxyphenyl)methylsulfonylmethylene Iiazetidine in 4.5 cm3 of ethanol in an argon atmosphere at a temperature of about 207"C, add 25.5 mg of sodium tetraborohydride. After stirring for 16 hours at a temperature of about 20"C, add 26 mg of sodium borohydride. Reaction medium stirred at a temperature of about 20"C for 4.5 hours, then at a temperature of about 507C for 3 hours. After cooling to a temperature of about 207"C, the reaction medium is concentrated under reduced pressure.

The resulting white precipitate is treated with 2 cm3 of water and 2 cm3 of dichloromethane. After decantation, the organic phase is concentrated under reduced pressure and the resulting yellow meringue is purified by preparative thin-layer chromatography on silicon dioxide (2 preparative plates Megsk KiezeiIidei! bOg254; 20x20cm; thickness 0.5mm|, eluting with a mixture of methanol and dichloromethane (in a ratio of 1:99 After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in a ratio of 10:90 by volume), filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40 "С, 14 mg are obtained (A5)-1-Ibis(4-chlorophenyl)methyl|-3-((4-methoxyphenyl)methylsulfonylmethyl|azetidine) in the form of white meringue.

H-NMR spectrum (300 MHz; SOCIz) b (in ppm): 2.56 (mt:1H); 2.58 (s:ZN); 3.20 (m:2H); 3.35- 3.55 (m.1H); 3.66 (t ush, uU-7.5Hz:1H); 3.81 (s:ZH); 4.21 (d, 9-4.5Hz:1H); 4 .26 (c.: 1H); 6.90 (d, 9-8.5Hz: 2H); 7.15-7.40 (m/1OH) I. 1-(Bis(4-chlorophenyl)methyl I- 3-(4-Methoxyphenyl)umethylsulfonyl-methyleneiazetidine can be obtained according to the method described in example 1, starting from 1g of (A5)-1-Ibis(4-chlorophenyl)methyl|-3-

Imethylsulfonyl(4-methoxyphenyl)methyl|azetidin-3-ol, 20 cm3 of dichloromethane, 0.229 cm3 of methylsulfonyl chloride and 722 mg of 4-dimethylaminopyridine. After purification by chromatography on silicon dioxide at atmospheric pressure (100 g of silicon dioxide with a particle size of 0.063-0.2 mm, contained in a column with a diameter of 3 cm) with dichloromethane elution, the fractions containing only the desired product are combined and concentrated under reduced pressure. In this way, 650 mg of 1-|bis(4-chlorophenyl)methyl|-3- ((4-methoxyphenyl)methyl-sulfonylmethylene|azetidine is obtained in the form of a yellow resinous substance. (A85)-1-IBis(4-chlorophenyl)methyl |-3-(methylsulfonyl(4-methoxyphenyl)methyl|azetidin-3-ol can be obtained according to the method described in example 1, starting from 19.b6cm3 of a 1.6N solution of n-butyllithium in hexane, 5.7g of 4- methoxybenzylmethylsulfone and 8.71 g of 1-bis(4-chlorophenyl)methyl|azetidin-3-one in 450 cm3 of tetrahydrofuran. In this way, 8.3 g of (НА5Б)-1-bis(4-chlorophenyl)methyl|-3-(methylsulfonyl) are obtained (4-Methoxyphenyl)methyl|azetidin-3-ol as a beige solid 4-Methoxybenzylmethylsulfone can be obtained according to the procedure described in Example 27, starting from 13.6cm3 of 4-methoxybenzyl chloride, 30mg of sodium iodide, 14.4g of sodium methylsulfinate in 125cm3 of ethanol.In this way, 5.75g of 4-methoxybenzylmethylsulfone is obtained in the form of a white powder.

Example 49 (85)-2-11-IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylmorpholine can be obtained in the following way. 252 mg of 1-ethyl-3-I (Z- of (dimethylamino)propylcarbodiimide hydrochloride (EHOSI) (2.3 equivalents; the supported EOSI reagent is commercially available and can also be obtained according to the following reference: M.Oegzai, I.5igatiiyu,

Temanedgtop I etseg5, 34, 48, 7685-7688 (1993)), 2 cm3 of anhydrous dichloromethane, 0.00 bcm3 of morpholine, then 0.010 cm3 of triethylamine. After stirring for 12 hours at a temperature of about 207C. the reaction mixture is filtered through a glass porous filter. The filtrate is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 20"C. In this way, 15 mg of (H5)-2-11-Ibis(4-chlorophenyl) is obtained methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylmorpholine in the form of a beige meringue.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 2.60-3.80 (m:13Н); 3.93 (d, U9-10ХЦ1Н); 4.27 (syn); 6.65-6.85

(m:ZN); 7.20-7.40 (mt: 8H)|.

Example 50 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide can be obtained in the following way: to a solution of 250 mg of hydrochloride (A5)-(11-Ibis(4-chlorophenyl)methyl-Iazetidin-3-yl3,5-difluorophenyl)acetic acid in 10 cm3 of anhydrous dichloromethane at a temperature of about 207C, successively add 0.070 cm3 of cyclohexylamine, 144 mg of 1-(3-dimethylaminopropyl)-3- of ethyl carbodiimide hydrochloride, 0.141 cm3 of triethylamine, then 4 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (25 cm3), filled with 12 g of fine-grained silicon dioxide (0.040-0.06 mm), which is conditioned, then eluted with a mixture of dichloromethane and petroleum ether (in the ratio 80:20 by volume) using a rigatai pump, collecting fractions of 1.5 cm3. Fractions 11-17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 "С. In this way, 169 mg of (A5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide were obtained in the form of a white meringue.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 0.90-1.45 (m:bH); 1.50-1.90 (m:4H); 2.66 (m :1H); 2.90 (mn); 3.00-3.15 (m:2H); 3.42 (t ush., U-7.5Hz:1H); 3.52 (d, 9-10 ... 5HcCyH); 6.82 (m:2H); 7.20-7.35 (m:8H)|.

Example 51 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylpiperidine can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207C, successively add 0.012 cm3 of piperidine, 29 mg of 1-(3Z-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzo-triazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Mayap column (bsm3) filled with Zg of fine-grained silicon dioxide (0.040-0.063 mm), eluting with dichloromethane using an Oigatai pump.

The fractions selected between 8 and 15 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 "C. In this way, 29 mg of (A5B)-2-11-Ibis(4-chlorophenyl)methyl|azetidine is obtained -3-yl)-2-(3,5-difluorophenyl)-M-acetyl-piperidine in the form of a white crystalline powder.

IS spectrum "H-NMR (Z0OMHCc; SOSIZ) b (in ppm): 0.95-1.15 and 1.30-1.50 (2 multiplets:bH in total); 2.74 (m:2Н ); 3.00-3.15 (m:2H); 3.30-3.45 (m:4H); 3.55-3.70 (m:1H); 3.95 (d, U-10Hz :1H); 4.26 (c:1H); 6.68 (t, uU-2912.5Hz1H); 6.80 (m:2H); 7.20-7.35 (m:8H)).

Example 52 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylpyrrolidine can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5- difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207C, sequentially add 0.010 cm3 of pyrrolidine, 0.023 cm3 of diisopropylcarbodiimide, 0.028 cm3 of triethylamine and 1, 5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction medium is placed in a Maijap column (bsm3) filled with 3g of fine-grained silicon dioxide (0.040-0.063mm), eluting with dichloromethane using a Yuigatai pump. The fractions selected between 11 and 19 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 "C. In this way, 29 mg of (85)-2-11-(bis(4-chlorophenyl)methyl) is obtained. azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylpyrrolidine in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIv) b (in ppm): 1.75-2.00 (m:4H); 2.74 (mt:2H); 3.00-3.30 (m :ZH); 3.35-3.60 (m:4H); 3.80 (d, U-10.5Hz:1H); 4.25 (s:1H); 6.68 (t, 9-9 and 2.5HzC:1H); 6.84 (m:2H); 7.20-7.40 (m:8H)I.

Example 53 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 202С, sequentially add 0.009 cm3 of cyclopropylamine, 29 mg of 1-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Maiap column (bcm3) filled with Zg of fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned, then eluted with dichloromethane using a Yuigatai pump, collecting fractions of 2 cm3. Fractions 2-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 29 mg of (H5B)-2-11-(bis(4-chlorophenyl)methyl|azetidine-3- yl)y-2-(3,5-difluorophenyl)-M-cyclopropylacetamide in the form of a white meringue.

H-NMR IS spectrum (300 MHz; SOSIv) b (in ppm): 0.40 (mt:2H); 0.74 (m:2H); 2.64 (mt:2H); 2.89 ( dd, 97.5 and 5HzCy1H); 3.08 (m:2H); 3.42 (t ush., 927.5Hz:1H); 3.51 (d, U-10.5Hz:1H); 4, 25 (s/1H); 5.50 (mass: H); 6.70 (t, 9U-912.5Htsi1H); 6.81 (m:2H); 7.15-7.35 (m:8H) ).

Example 54 (85)-2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexyl-M-methylacetamide can be obtained as follows: to a solution of 50 mg of hydrochloride (A5)-1-(bis(4-chlorophenyl)methyl|azetidine-

C-yl3,5-difluoro-phenyl)acetic acid in 2 cm? of anhydrous dichloromethane at a temperature of about 2070, sequentially add 0.016 cm3 of M-methylcyclohexylamine, 29 mg of 1--3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (bsmu) filled with Zg of fine-grained silicon dioxide (0.040-0.06Zmm), which is conditioned, then eluted with dichloromethane using a Yuigatai pump, collecting fractions 2cm3 each. Fractions 4-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 17 mg of (H5B)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexyl-M-methyl-acetamide were obtained in in the form of white meringue.

H-NMR spectrum (250 MHz; (CO3)250-dv; at a temperature of 373K) 5 (in ppm): 0.98-1.85 (m"1OH); 2.60-3.05 (m: 8H); 3.26 (tash, u9-7.5Hz: 1H); 4.25 (d ear., Uh9Hz:1H); 4.45 (s); 7.00 (m:ZN); 7.25-7.45 (m:8H)I).

Example 55 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(tetrahydrofuran-2-ylmethyluluacetamide) can be obtained in the following way 0.013 cm3 of tetrahydro-furfurylamine is successively added to a solution of 5 mg of hydrochloride (НА5)-11-Ibis(4-chlorophenyl)methyl-Iazetidin-3-ylLi(3,5-difluorophenyl)acetic acid in 2 cm? of anhydrous dichloromethane at a temperature of about 207"C, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction medium is placed in a Mayap column (bcm3) filled with 3 g of fine-grained carbon dioxide silicon (0.040-0.06Z3mm), which is conditioned, then eluted with dichloromethane using a pump

Oigatai, collecting fractions of 2 cm3. Fractions 3-8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 27 mg of (A5)-2-11-(bis(4-chlorophenyl)methyl|azetidine-3- yl)-2-(3,5-difluorophenyl)-M-(tetrahydrofuran-2-ylmethyl)acetamide as a white solid.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 1.65-1.95 (m:4H); 2.64 (m:1H); 2.89 (dd, 9U27.5 and 5.5HzC1Hn); 3.00-3.20 (m:ZH); 3.30-3.60 (m:2H); 3.58 (d, 9U-10.5HzC:1H); 3.65 -3.95 (m:ZN); 4.25 (s/1N); 5.81 (m/n); 6.68 (t, Ugo and 2.5HC:1N); 6.82 (m:2N ); 7.15-7.35 (m:8H)).

Example 56 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(2-morpholin-4-ylethyl)acetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (A5)-1-(bis(4-chlorophenyl)methyl|azetidine-

(3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 2020 is successively added to 0.016 cm3 of aminoethylmorpholine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred. at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (bsm3) filled with fine-grained silicon dioxide (0.040-0.063mm), which is conditioned with dichloromethane using a Yuigatai pump, eluted sequentially with a mixture of dichloromethane and ethyl acetate (in a ratio of 70:30 by volume) , collecting fractions of 2cm3, for fractions 1-12, then using a mixture of dichloromethane and methanol (in a ratio of 98:2 by volume), collecting fractions of 2cm3, for fractions 12-27. Fractions 13-27 are combined and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 40"C. In this way, 4 mg of (H5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl is obtained. )-2-(3,5-difluorophenyl)-M-(2-morpholin-4-ylethyl) acetamide in the form of a white meringue.

"H-NMR" spectrum (300 MHz; SOSIz) b (in ppm): 2.33 (t us., U25Hz:AN); 2.38 (t, U27Hz:2H); 2.65 (m.1H ); 2.85-3.20 (m:3H); 3.25 (sq. ear., U-7Hz:2H); 3.43 (m:1H); 3.57 (t, U-5Hz4H) ; 3.61 (d, 9U-10.5Hz1H); 4.26 (s1H); 5.98 (array: 1H); 6.70 (t, 9-29 and 2.5Hz: 1H); 6.83 (m:2H); 7.15-7.35 (m:8H)|.

Example 57 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(1-ethylpyrrolidin-2-ylmethyluluacetamide) can be obtained in the following method. to a solution of 5 mg of hydrochloride (НА5)-11-Ibis(4-chlorophenyl)methyl-Iazetidin-3-ylLi(3,5-difluorophenyl)acetic acid in 2 cm? of anhydrous dichloromethane at a temperature of about 20 "С, 0.018 cm3 of aminomethylethyl- pyrrolidine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Maiap column (diameter 12 mm), filled with 4cm3 of silicon dioxide (0.060-0.200mm), which is conditioned with dichloromethane using a vacuum device, eluted with dichloromethane between 0 and bsmu, then with a mixture of dichloromethane and methanol (95:5 by volume). Fractions containing the desired product , combine and concentrate to dryness under reduced pressure (2.7kPa) at temperature of 40"C for 2 hours. Thus, the resulting yellow paste-like substance is treated with 2 cm3 of ethyl acetate, then with 2 cm3 of distilled water. After stirring, the mixture solidifies, the organic phase is concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 407C. The resulting residue is treated with 2 cm3 of isopropyl ether, then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40°C. In this way, 38 mg of (85)-2-11-I(bis(4-chlorophenyl)methyl|azetidine) is obtained -3-yl)-2-(3,5-difluorophenyl)-M-(1-ethyl-pyrrolidin-2-ylmethyl)acetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOCIz with the addition of a few drops of SOZSOOY-al) b (in ppm): 0.96 and 1.17 (2t, 9U-7.5Hz: ЗН as a whole); 1.60 -2.00 (m:4H); 2.50-2.95, 3.10-3.85 (multiplets:11H); 3.95-4.10 (m'1H); 4.10 and 4, 14 (2d, uU10.5Hz1N as a whole); 5.18 and 5.25 (2s ush. 1N as a whole); 6.66 (m:1N); 6.80-7.00 (m:2N); 7.15-7.45 (m:vH).

Example 58 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isobutylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207С, 0.012 cm3 of isobutylamine, 29 mg of 1-(Z-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzo-triazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Maiyap column (diameter 12 mm), filled with 5 cm3 of silicon dioxide (0.060-0.200 mm), which is conditioned with dichloromethane using a vacuum device, eluted with dichloromethane between 0 and bcm3 , then using a mixture of dichloromethane and ethyl acetate (in a ratio of 95:5 by volume). The fractions that contain only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 40 mg of (85)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isobutylacetamide is obtained in the form of a white meringue.

H-NMR spectrum (300 MHz; (CO3)250-yv) b (in ppm): 0.75 (d, U-7.5HC:6N); 1.62 (m:1N); 2, 61 (m:1H); 2.70-2.95 (m:ZN); 3.03 (m:2H); 3.22 (t ush., U-7HC:1H); 3.83 (d, 9-10.5Hz:1H); 4.45 (s:1H); 7.00 (m:2H); 7.08 (t, 9-912.5Hz1H);

7.25-1.45 (m: 8H); 8.11 (t, u9-6HcCy1H)I).

Example 59 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M,M-dimethylacetamide can be obtained in the following way: to the solution 50 mg of (H5)-11-bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane at a temperature of about 207C, successively add 0.060 cm3 of dimethylamine in the form of a 2 M solution in tetrahydrofuran, 29 mg 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (diameter 12 mm), filled with 4.4 cm3 of silicon dioxide (0.060-0.200 mm), which is conditioned with dichloromethane using a vacuum device, eluted with dichloromethane between 0 and bsmU, then using a mixture of dichloromethane and ethyl acetate (in a ratio of 95:5 by volume). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 1 mg of (85)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M,M-dimethylacetamide is obtained in the form of a white powder.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 2.70-2.80 (m:2H); 2.92 (s:ZN); 2.95 (s:ZN); 3.00-3.15 (m:2H); 3.38 (tush., 9U-7.5HzC:1H); 3.96 (d, 9-10Hz:1H); 4.26 (s:1H) 6.69 (t, 9-29 and 2.5Hz: 1H); 6.81 (m: 2H); 7.20-7.35 (m: 8H)).

Example 60 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-benzylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207C, sequentially add 0.013 cm3 of benzylamine, 29 mg of 1-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Maiyap column (diameter 12 mm), filled with 4.4 cm? of silicon dioxide (0.060-0.200 mm), which is conditioned with dichloromethane using a vacuum device, eluted with dichloromethane between 0 and bcm3, then using a mixture of dichloromethane and ethyl acetate (in a ratio of 95:5 by volume). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"С. In this way, 37 mg of (85)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-benzylacetamide are obtained in the form of white crystals.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 2.67 (m:1H); 2.93 (m:1H); 3.11 (m:2H); 3.43 ( t ush., 9U-7.5Hz 1); 3.62 (d, 9U-10.5Hz:1H); 4.26 (sy1H); 4.38 (m:2H); 5.71 (m/n ); 6.71 (t ush., U-9Hz:1n); 6.83 (m:2H); 7.10-7.40 (m:1ZH)I.

Example 61 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylmethylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (A5)-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluoro-phenyl)acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20 is successively added 0.016 cm3 of amsomethylcyclohexane, 29 mg of 1--Z- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Maiap column (bsm3) filled with Zg of fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned, then eluted with dichloromethane using a Yuigatai pump, collecting fractions 2cm3. Fractions 2-3 are combined and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 40"C. In this way, 49 mg of (НА5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylmethylacetamide were obtained in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIv) b (in ppm): 0.75-1.75 (mt:11H); 2.65 (m:1H); 2.85-3.15 (m :5H); 3.42 (t ush., ue7.5HCIN); 3.57 (d, 9-10.5Hz:1H); 4.27 (sn); 5.40 (m1H); 6.71 ( t ush., Ux9Hc1H); 6.83 (m:2H); 7.15-7.40 (m:8H)|.

Example 62 (85)-2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-3-(2-oxopyrrolidin-1-yl propyl)acetamide can be obtained in the following way. 0.017 cm3 of aminopropyl-pyrrolidinone is sequentially added to a solution of 5O0 mg of (AB5)-11-I(bis(4-chlorophenyl)methyl-azetidin-3-yl(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane at a temperature of about 20"C, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine, and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction medium is placed in a Maijap column (bcm3) filled with 3g of fine-grained silicon dioxide ( 0.040-0.063 mm), which is conditioned, then eluted with dichloromethane using a pump

Oigatai, collecting fractions of 2 cm3. Fractions 4-12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 35 mg of (A5)-2-11-I(bis(4-chlorophenyl)methyl|azetidine-3) is obtained - yl)-2-(3,5-difluorophenyl)-M-|3-(2-oxopyrrolidin-1-yl)propyl|acetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.50-1.65 (m:2H); 2.04 (m:2H); 2.43 (t, 9-8Hz :2H); 2.64 (min); 2.88 (dd, 9U-7.5 and 5.5HzC:1H); 3.00-3.30 (m:bH); 3.30-3.45 (m:ZN); 3.64 (d, 9-10.5Hz:1H); 4.27 (s:1H); 6.67 (t, u9 and 2.5Hz:1H); 6.90 (m :2Н); 7.15 (t, U-6Hz:1Н); 7.20-7.35 (m:8Н)).

Example 63 (85)-2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetyl(4-methylpiperazine) can be obtained in the following way : to a solution of 50 mg of hydrochloride (A5)-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluoro-phenyl)acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20 successively add 0.013 cm3 M- methylpiperazine, 29 mg of 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (bsm3) filled with fine-grained silicon dioxide (0.040-0.063mm), which is conditioned with dichloromethane using a Yuigatai pump, eluted with a mixture of dichloromethane and ethanol (in a ratio of 98:2 by volume), collecting fractions of 2 cm3. Fractions 10-24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40°C. In this way, 39 mg of (НА5Б)-2-11-Ibis(4-chlorophenyl)methyl azetidin-3-yl) is obtained. -2-(3,5-difluorophenyl)-M-acetyl(4-methyl-piperazine) in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 1.83 (m:1); 2.10-2.45 (m:ZN); 2.21 (s:ZN); 2.74 (m:2H); 2.95-3.15 (m:2H); 3.30-3.55 (m:4H); 3.73 (m:1H); 3.93 (d, 9-10Hz:1H); 4.25 (s/1H); 6.69 (t, 9-9 and 2.5Hz:1H); 6.78 (m:2H); 7.15-7.35 ( m:8H)I).

Example 64 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(2,2-dimethylpropyl)acetamide can be obtained in the following method: to a solution of 50 mg of hydrochloride (A5)-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20C, 0.014 cm3 of neopentylamine, 29 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction medium is placed in a Magiap column (bsm3) filled with Zg of fine-grained silicon dioxide (0.040 -0.063 mm), which is conditioned with dichloromethane using a Yuigatai pump, eluted with a mixture of dichloromethane and petroleum ether (in a ratio of 80:20 by volume), collecting fractions of 1.5 cm3. Fractions 4-8 are combined and concentrated to dryness at under reduced pressure (2.7kKPa) at a temperature of 40"C. In this way, 40 mg (НА5 B)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(2,2-dimethylpropyl)acetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIZ) b (in ppm): 0.81 (c:9H); 2.66 (m:1H); 2.90-3.20 (m:5H); 3.44 (t ush., 9U-7.5Hz:1H); 3.61 (d, 9U-10.5Hz 1); 4.28 (s:11H); 5.40 (m:/1H); 6.72 (t, 9-9 and 2.5HzCN), 6.85 (m:2H), 7.20-7.35 (m:8H)I.

Example 65 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(2-pyrrolidin-1-ylethyl)acetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (A5)-1-(bis(4-chlorophenyl)methyl|azetidine-

3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 2020, successively add 0.015 cm3 of aminoethylpyrrolidine, 29 mm of 1--3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Magiap column (bcm3) filled with 3g of fine-grained silicon dioxide (0.040-0.0633mm), which is conditioned with dichloromethane using a Yuigatai pump, eluted with a mixture of dichloromethane and ethanol (in a ratio of 98:2 by volume), collecting fractions of 1.5 cm3. Fractions 13-20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"С. In this way, ZZmg (НА5Б)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-N-(2-pyrrolidin-1-ylethyl)luacetamide is obtained in the form of white meringue.

H-NMR spectrum (30 MHz; SOSI) b (in ppm): 1.78 (m:4H); 2.50-2.70 (m:ZN); 2.54 (m:4AN ); 2.91 (dd, 9-75 and 5Htsin); 3.10 (m:2H); 3.20-3.45 (m:ZH); 3.64 (d, U-10.5HtsTs:1H ); 4.27 (sn); 6.67 (t, 9-9 12.5 Hz); 6.86 (m:2H); 7.15-7.35 (m:8H).

Example 66 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (A5)-/1-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluoro-phenyl)acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20 sequentially add 0.011 cm3 of cyclopropanemethylamine, 29 mg of 1--Z- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Maiap column (bsm3) filled with fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned, then eluted with a mixture of dichloromethane and petroleum ether (in a ratio of 80 :20 by volume) using a Yuigatai pump, collecting fractions of 1.5cm3. Fractions 3-8 are combined and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 40"C. In this way, 37 mg of (НА5Б)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)y-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide are obtained in the form of a white meringue.

H-NMR IS spectrum (300 MHz; SOCI3) b (in ppm): 0.13 (mt:2H); 0.45 (mt:2H); 0.86 (mt:1H); 2.65 ( m:1H); 2.91 (dd, u7.515 Hz:1H); 3.00-3.15 (m:4H); 3.41 (t ush., 9U-7.5HzC:1H); 3 .57 (d, 9U-10.5Hz: 1H); 4.25 (s: 1H); 5.50 (m"1H); 6.70 (t, 3-9 12.5Hz:1H); 6.84 (m:2H); 7.15-7.35 (m:8H)).

Example 67 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-propylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207C, successively add 0.015 cm3 of propylamine, 29 mg of 1-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzo-triazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Mayap column (bsm3) filled with Zg fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned and eluted with dichloromethane using a Yuigatai pump. Fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40°C. In this way, 21 mg of (НА5Б)-2-11-(bis(4-chlorophenyl)methyl|azetidine) is obtained -3-yl)-2-(3,5-difluorophenyl)-M-propylacetamide as a white solid.

H-NMR spectrum (300 MHz; SOSIv) b (in ppm): 0.84 (t, 9U-7.5 Hz:ZN); 1.45 (m:2H); 2.65 (m:1H ); 2.92 (dd, 97.5 and 5.5Hz:1H); 3.00-3.20 (m:2H); 3.15 (q, 1-7Hz:2H); 4.43 (t ear, 9U-7.5HzC:1H); 3.56 (d, 9U-10.5Hz:1H); 4.26 (s/1H); 5.39 (m:1H); 6.70 (t , 9-9 12.5Hz:1H); 6.83 (m:2H); 7.15-7.35 (m:8H)).

Example 68 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-methylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5- difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 202 successively add 0.050 cm3 of a 2M solution of methylamine in tetrahydrofuran, 29 mg of 1-(Z- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"7C for about 12 hours.

The reaction medium is placed in a Mapyap column (bsm3) filled with Zg of fine-grained silicon dioxide (0.040-0.06Zmm), which is conditioned and eluted with dichloromethane using an Oigatai pump. Fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 19 mg of (H5)-2-11-I(bis(4-chlorophenyl)methyl) are obtained. azetidin-3-yl)-2-(3,5-difluorophenyl)-M-methylacetamide as a white solid.

H-NMR spectrum (300 MHz; SOCIz) b (in ppm): 2.66 (m:1H); 2.76 (d, 9-5 HzC:ZN); 2.93 (m:1H) ; 3.10 (m:2H); 3.44 (t ush., uUsh7.5Hz:1H); 3.59 (d, 9-10.5Hz:1H); 4.28 (СН); 5.41 (array: 1H); 6.71 (t, 9U-29 and 2.5 Hz: 1H); 6.83 (m: 2H); 7.20-7.35 (m: 8H)I).

Example 69 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 202 successively add 0.011 cm3 of isopropylamine, 29 mg of 1-(3-dimethylaminopropyl)-3 -ethyl carbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzo-triazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Maiap column (bcm3) filled with Zg of fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned, then eluted with dichloromethane using a Yuigatai pump, collecting fractions of 1.5 cm3. Fractions 6-14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 21 mg of (H5B)-2-11-(bis(4-chlorophenyl)methyl azetidin-3-yl) is obtained )-2-(3,5-difluorophenyl)-M-isopropylacetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIv) b (in ppm): 1.05 (d, 9-7Hz:ZN); 1.10 (d, 9-7Hz:ZN); 2.65 (m :1H); 2.90 (dd, 97.5 and 5.5HzCy1H); 3.00-3.15 (m:2H); 3.42 (t ush., 9-7.5HzC:1H); 3 .51 (d, 9U-10.5Hz:1H); 4.00 (m:1H); 4.26 (s1H); 5.19 (shower, 9-7.5Hz1H); 6.70 (t, 9 -9 and 2.5 HZ:1H); 6.82 (m:2H); 7.20-7 40 (m:v8H)).

Example 70 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-piperidin-1-ylacetamide can be obtained in the following way: 0.013 cm3 of aminopiperidine, 29 mg of 1-(Z- dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Mayap column (bsm3) filled with fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned with dichloromethane using a pump

Oigatai, eluted with a mixture of dichloromethane and ethanol (in a ratio of 98:2 by volume), collecting fractions of 2 cm3. Fractions 7-12 are combined and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 40°C. In this way, ZZmg (H5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl is obtained )-2-(3,5-difluorophenyl)-M-piperidin-1-ylacetamide as a white solid.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): from 0.95 to 1.85-2.05 and 2.29 (multiplets: 10Н); 2.60-2.80 (m :2H); 3.00-3.20 (m:2H); 3.39 (t ush., 9-7.5Hz:1H); 4.26 (s/1H); 4.32 (d, 9 -10.5Hz:1H); 6.00 (s:1H); 6.65 (t, 3-9 and 2.5Hz and 1H); 6.85 (m:2H); 7.15-7.35 (m :8H)).

Example 71 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cycloheptylacetamide can be obtained in the following way: to a solution of 50 mg of hydrochloride (H5)-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl) acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 207 sequentially add 0.015 cm3 of cycloheptylamine, 29 mg of 1-(3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 202C for about 12 hours. The reaction medium is placed in a Mayap column (bcm3) filled with fine-grained silica (0.040-0.06Zmm), which is conditioned, then eluted with dichloromethane using a Yuigatai pump, collecting fractions of 2 cm3. Fractions 3-6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 24 mg of (H5B)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl are obtained )y-2-(3,5-difluorophenyl)-M-cycloheptylacetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOCI3) b (in ppm): 1.20-1.95 (m:12N); 2.65 (m:1N); 2.90 (dd, 9-7 .5 and 5.5Hz1H); 3.00-3.15 (m:2H); 3.42 (t ush., 9U-7.5Hz:1H); 3.52 (d, U-10.5Hz: 1); 3.86 (m:1H); 4.26 (s/1H); 5.31 (d ear, 9U-7.5Hz:1H); 6.70 (t, 9U-912.5Hz: 1H); 6.82 (m:2H); 7.20-7.35 (m:8H)).

Example 72 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)acetamide can be obtained in the following way: to a solution of 98 mg of hydrochloride (A5) -11-Ibis(4-chlorophenyl)methyl| azetidin-3-yl(3,5-difluorophenyl) acetic acid in 4 cm? of anhydrous dichloroethane at a temperature of about 207C, successively add one gram of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and one gram of hydroxybenzotriazole hydrate, pass through by bubbling ammonia for 2 hours with stirring at a temperature of about 20"C. The reaction medium is washed with water, then placed in a Maiap column (bsmu) filled with fine-grained silicon dioxide (0.040-0.063mm), which is conditioned and eluted with a mixture of dichloromethane and ethyl acetate (in a ratio of 9:1 by volume) using an Oigatai pump.

Fractions selected between 36 and 8 Oml are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 402С. In this way, 32 mg of (K5)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-

difluorophenyl)-M-cycloheptylacetamide in the form of a white meringue.

H-NMR spectrum (300 MHz; SOSIz) b (in ppm): 2.66 (m:1H); 2.95 (dd, 9U-7 and 5Hz:1H); 2.95-3.15 (m:2H); 3.45 (t ush., in 7Htsi1H); 3.67 (d, 9U-10.5Hts:1H); 4.27 (s:1H); 5.20-5.40 ( array: 2H); 6.72 (t, 9-29 and 2.5 Hz: 1H); 6.84 (m: 2H); 7.20-7.35 (m: 8H) I.

Example 73

Methyl-(A5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylaminoacetate can be obtained in the following way: to a solution of 200 mg of hydrochloride (H5)-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)acetic acid in 1 cm3 of dichloroethane at a temperature of about 207C, sequentially add 10 mg of glycine methyl ether hydrochloride, 115 mg of 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride and bmg hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction medium is washed with water, dried, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way the resulting residue is treated with dichloromethane, then placed in an IZT BiazpRask column, standard 51I/-020-005, which is conditioned and eluted with a mixture of dichloromethane and ethyl acetate (in a ratio of 95:5 by volume) using a Yuigatai pump. selected between 18 and 42 ml, combine and concentrate to dry under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 8 mg of methyl-(H5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-acetylaminoacetate are obtained in the form of "fluffy" crystals white color

H-NMR spectrum (Z00MHZc; SOCIz) b (in ppm): 2.67 (mn); 2.93 (dc us., U-7.5 and 5Hz:1H); 3.00-3 ,15 (m:2H); 3.41 (t ush, 9U-7.5HZ:1H); 3.68 (d, 9U-10.5HZ:1H); 3.74 (s:3H); 3, 93 (dd, U-18 and 5Hz1N); 4.03 (dd, 9-18 and 5Hz1n); 4.27 (s/1N); 5.96 (m:1N); 6.71 (t, 9- 9 and 2HC:1H); 6.85 (m:2H); 7.20-7.35 (m:vH)|.

Example 74 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(3-dimethylaminopropyl)acetamide can be obtained in the following way : to a solution of 50 mg of hydrochloride (A5)-1-(bis(4-chlorophenyl)methyl|azetidine-

3-yl3,5-difluorophenyl)acetic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 202C, successively add 0.015 cm3 of M,M-dimethylpropane-1,3-diamine, 29 mg of 1--3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a Mapyap column (diameter 12 mm), filled with 4 cm3 of silicon dioxide (0.060-0.200 mm), which is conditioned with dichloromethane using a vacuum device, eluted with dichloromethane between 0 and bcm3 , then with a mixture of dichloromethane and methanol (in a ratio of 95:5 by volume). Fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of 40"C. In this way, ZZmg (85)-2-11-I(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(3-dimethylaminopropyl)acetamide is obtained in the form white crystals.

H-NMR spectrum (300 MHz; SOSIS with the addition of a few drops of COzZSOOY-da) b (in ppm): 1.91 (mt:2H); 2.71 (s:bH); 2.95 (m: 2H); 3.15-3.40 (m:2H); 3.40-3.60 (m:1H); 3.60-3.80 (m:2H); 4.00 (m:2H) ; 4.28 (d, 9-10.5Hz:1H); 5.22 (sn); 6.68 (t, 9-9 12.5HzC:1H); 6.90 (m:2H); 7, 33 (m:4H); 7.46 (d, U-8Hz:4H)I).

Example 75 (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-(2-hydroxyethyl)acetamide can be obtained in the following way : 0.024 cm3 of ethanolamine, 29 mg of ethanolamine, 29 mg 1-(3-dimethylaminopropyl)-33-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzo-triazole hydrate. The resulting solution is stirred at a temperature of about 20"C. The reaction medium is washed with 2 cm3 of a saturated sodium bicarbonate solution, dried over magnesium sulfate, then placed on an IT RiazpRask column, standard 51-020-005, which is conditioned with dichloromethane and eluted with a mixture of dichloromethane and ethyl acetate (95:5 by volume) using an Omgatai pump. Fractions collected between 25 and bosm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. The resulting residue is again chromatographed on an IZT column

RiazpRask, standard 51-020-005, which is conditioned with dichloromethane and eluted with a mixture of dichloromethane and ethyl acetate (95:5 by volume) using an Oigatai pump. The fractions selected between 25 and 55 cm are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 °C. In this way, 14 mg of (85)-2-11-ibis(4-chlorophenyl)methyl|azetidine is obtained. -3-yl)-2-(3,5-difluorophenyl)-M-(2-hydroxyethyl)acetamide as a white solid.

IS spectrum "H-NMR (ZO0MHCc; SOSIv) b (in ppm): 2.65 (m:1H); 2.91 (m:1H); 3.00-3.15 (m:2H); 3.30-3.50 (m:ZN); 3.60 (d, 9-10.5Hz:1H); 3.66 (t, 9-5.5HzC:2H); 4.26 (s:1H ); 5.88 (m: 1H); 6.71 (tt, 9U-9 and 2HzC: 1H); 6.84 (m: 2H); 7.20-7.35 (m: 8H)I.

Example 76 (85)-1-41-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)methyl|-3-propylurea can be obtained in the following way: to the solution 50 mg of (H5)-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)acetic acid hydrochloride in 3 cm3 of anhydrous toluene in an inert atmosphere of argon at a temperature of about 207C is successively added to 0.056 cm3 of triethylamine and 0.064 cm3 of diphenylphosphonoazide. The resulting solution is stirred at a temperature of about 50"C for about an hour. 0.016 cm3 of propylamine is added, stirring is carried out at a temperature of about 20"C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. The residue is treated with 1 cm3 of dichloromethane, then placed in a Mayap column (bcm3) filled with 3g of fine-grained silicon dioxide (0.040-0.063 mm), which is conditioned and eluted with a mixture of dichloromethane and ethyl acetate (in a ratio of 95:5 by volume) using an Oigatai pump. Fractions collected between 12 and 16 bsmu are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 "C. In this way, 1 mg of (85)-1-41-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)methyl|-3-propylurea is obtained as a beige solid .

H-NMR spectrum (400MHz; SOSIzv) b (in ppm): 0.92 (t, 9U-7.5Hz:ZN); 1.53 (m:2H); 2.55-2.75 (min); 2.80-3.25 (m:bN); 4.26 (t, U-5.5HC:1N); 4.29 (c1N); 4.92 (t, 9-7HC:1N ); 5.31 (d, 9U-5.5HzC:1H); 6.66 (t, 9-9 and 2.5HzCy1H); 6.79 (m:2H); 7.15-7.40 (m :8H)|.

Example 77

Hydrochloride (A5)-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)acetic acid can be obtained in the following way: to a solution of 0.44 g of ethyl ether (A5)-(1-Ibis (4-Chlorophenyl)methylIazetidin-3-yl3,5-difluorophenyl)acetic acid in 7cm3 dioxane add 3cm3 bn hydrochloric acid. The resulting solution is stirred at boiling with an inverted refrigerator for about 2 hours, then left to stand at a temperature of about 207C for about 12 hours. The precipitate that has fallen out is filtered on a glass porous Me3 filter, washed with 10 cm3 of diisopropyl ether, then dried under reduced pressure (0.27 kPa) at a temperature of about 40"C. In this way, 0.185 g of hydrochloride (A5B)-11-( bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)acetic acid in the form of a white powder.

H-NMR IS spectrum (400 MHz, (CO3)250-uv, at a temperature of 363 K) b (in ppm): 2.87 (dd, 9-14 and 4АГЦ1Н); 2.95 (m:1Н); 3.18 (m:1H); 3.96 (d, 9-10.5Hz:1H); 4.18 (t, U59Hz11H); 4.72 (t, U-9Htsi11H); 5.26 (array: 1H); 7.00 (m:2H); 7.06 (t, U29.5 and 2.5 Hz: 1H); 7.30-7.60 (m:8H)|.

Example 78

Ethyl ether (A5)-11-(bis(4-chlorophenyl)methyl|azetidin-3-ylL3,5-difluorophenyl)acetic acid can be obtained in the following way: to a suspension of 0.78 g of ethyl ether (A5)-11-Ibis (4-chlorophenyl)methyl|azetidin-3-ylideneX3,5-difluorophenyl)acetic acid in 20 cm? of ethanol at a temperature of about 0C is added to 121 mg of sodium borohydride. The resulting suspension is stirred at a temperature of about 207C for about 12 hours. The reaction medium is poured into 200 cm3 of distilled water, then extracted three times with 40 cm3 of ethyl acetate. The organic phase is successively washed three times with 40 cm3 of distilled water, then with 40 cm3 of saturated sodium chloride solution. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7kPa) at a temperature of about 40"C. The resulting residue is chromatographed on a column filled with 75cm3 of fine-grained silicon dioxide (0.040-0.06Zmm) under a pressure of 0 .7 bar, using a mixture of dichloromethane and ethyl acetate (the percentage content of ethyl acetate varies from 0 to 1095), collecting fractions of 15 cm3. Fractions 4-11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 "С. In this way, 0.46 g of ethyl ether (85)-11-

Ibis(4-chlorophenyl)methyl|azetidin-3-yl(3,5-difluorophenyl) acetic acid in the form of yellow varnish.

H-NMR spectrum (Z00MHCc, SOCIz) b (in ppm): 1.19 (t, uUe7Hz:ZN); 2.62 (t ush, 9-6HzCyN); 2.87 (dd, 9U- 7.5 and bHgcCyH); 2.95-3.15 (m:2H); 3.39 (t ush, 9U-7.5HzC:1H); 3.78 (d, 9-10.5Hz:1H) ; 4.10 (m:2H); 4.25 (sn); 6.69 (t, Uu-9 and 2.5HC:1H); 6.80 (m:2H); 7.20-7.35 (m:8H)).

Fractions 16-26, selected during preliminary chromatography, are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40 °C. In this way, 0.24 g of (H5B)-2-11-Ibis(4-chlorophenyl )methyl|azetidin-3-yl(3,5-difluorophenyl)ethanol in the form of a yellow meringue.

H-NMR spectrum (300 MHz, SOSISMU) b (in ppm): 1.98 (array: 1H); 2.69 (mn); 2.70-2.85 (min); 2.90- 3.10 (m:2N); 3.18 (m:1N); 3.44 (m:1N); 3.65-3.85 (m:2N); 4.28 (s/1N); 6 ,60-6,80 (m:ZN); 7,20-7,35 (m:vH)|.

Ethyl ether of 41-(bis(4-chlorophenyl)methyl|azetidin-3-ylidene) (3,5-difluorophenyl)acetic acid can be obtained in the following way: to a solution of 9.1 g of ethyl ether (1-(bis(4- chlorophenyl)methyl|-3-hydroxyazetidin-3-yl3,5-difluorophenyl)acetic acid in 200 cm3 of dichloromethane add 6.bg of 4-dimethylaminopyridine, 2.1 cm3 of methylsulfonyl chloride. The resulting solution is stirred at a temperature of about 207C for about 12 hours.

The reaction mixture is washed three times with 250 cm3 of distilled water, then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40".

The resulting residue is processed by heating with 50cm? of diisopropyl ether, then left to stand at a temperature of about 207"C for about 12 hours. The resulting white suspension is filtered through a porous glass filter, washed with 20 cm3 of petroleum ether, then dried in a vacuum under reduced pressure (0.27 kPa) at a temperature of about 40 "C for 2 hours. In this way, 7.9 g of 41-bis(4-chlorophenyl)methyl-ylazetidin-3-ylidenex3,5-difluorophenyl)acetic acid ethyl ether is obtained in the form of a cream-colored powder.

H-NMR spectrum (ZOOMHCts, SOSIzv) b (in ppm): 1.25 (t, ue7HzC:ZN); 3.85 (m:2H); 4.12 (AB, 9-7.5Hz :2H); 4.23 (m:2H); 4.51 (s:1H); 6.65-6.80 (m:ZH); 7.20-7.40 (m:8H)).

The ethyl ester of 41-(bis(4-chlorophenyl)methyl|-3-hydroxyazetidin-3-ylL3,5-difluorophenyl)acetic acid can be obtained in the following way: to a solution of 7.73 cm3 of diisopropylamine in 125 cm3 of anhydrous tetrahydrofuran in an inert nitrogen atmosphere at at a temperature of about -70"C for 15 minutes, add dropwise 34.54 cm3 of a 1.6 M solution of butyllithium in hexane, keep at this temperature with stirring for 45 minutes, add a solution of 11.01 g of ethyl-3,5-difluorophenylacetate in 85 cm3 for 15 minutes of anhydrous tetrahydrofuran, stirring is continued for 1 hour at a temperature of -78"C, add 16.84 g of 1-

Ibis(4-chlorophenyl)methyl| of azetidin-3-one in 90 cm3 of anhydrous tetrahydrofuran, stirring is continued for an hour. at a temperature of -70"C, at a temperature of 0"C with intensive stirring for 30 minutes add 300 cm3 of a saturated solution of ammonium chloride, after 12 hours the reaction mixture is decanted, the organic phase is washed three times with an aqueous saturated solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, then concentrate to dryness under reduced pressure (2.7 kPa). The obtained residue is chromatographed on a column with a diameter of 70 mm, filled with 200 cm3 of fine-grained silicon dioxide (0.040-0.06 bZmm), under a pressure of 0.7 bar, using a mixture of dichloromethane and ethyl acetate (in a ratio of 99:1 by volume). Fractions that contain only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 407"C for 2 hours. In this way, 9.1 g of ethyl ether 51-(Ibis(4-chlorophenyl)methyl) is obtained /|-3-hydroxyazetidin-3-ylLEZ,5-difluorophenyl) acetic acid as a cream-colored solid.

H-NMR spectrum (300 MHz, SOSI3) b (in ppm): 1.25 (t, U27Hz:ZN); 2.87 (d, U9-8Hz1H); 3.07 (d, U958Hz1H); 3.13 (d ear., U8Hz: 1); 3.28 (d ear., U-8Hz:1H); 4.12 (s:2H); 4.21 (m:2H); 4.36 ( s: 1H); 6.78 (t, U-9 and 2.5Hz: 1H); 6.98 (m: 2H); 7.20-7.40 (m: 8H)|.

Ethyl-3,5-difluorophenylacetate can be obtained in the following way: to a solution of 12cm3 of ethanol in 300cm3 of anhydrous dichloromethane at a temperature of about 20" successively add 20.4cm3 of triethylamine, then 27.g of 3,5-difluorophenylacetic acid chloride in the form of a solution in 0cm3 of dichloromethane. The resulting solution is stirred at a temperature of about 207C for about 12 hours. The reaction mixture is successively washed twice with 150 cm3 of decinormal hydrochloric acid, then twice with 150 cm3 of saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure ( 2.7kPa) at a temperature of about 40"C. In this way, 29 g of ethyl-3,5-difluorophenylacetate are obtained in the form of a yellow oil.

Chloroanhydride of 3,5-difluorophenylacetic acid can be obtained in the following way: to a solution of 3,5-difluorophenylacetic acid in 350 cm3 of 1,2-dichloroethane at a temperature of about 20"C, 19.3 cm3 of oxalyl chloride is successively added, then a few drops of dimethylformamide, after stirring for After hours, at a temperature of about 207C, 30 cm3 of oxalyl chloride is again successively added, then a few drops of dimethylformamide. The reaction medium is concentrated to dryness under reduced pressure (2.7kPa) at a temperature of about 40"C. In this way, 27.6 g of 3,5-difluorophenylacetic acid chloride is obtained in the form of a yellow oil.

Example 79 (85)-1-IBis(4-chlorophenyl)methyl|-3-(1-(3,5-difluorophenyl)-1-methyl-sulfonylethyl|Iazetidine is obtained as follows: to a solution of 0.5 g of (85)- 1-Ibis(4-chlorophenyl)methyl|-3-I((3,5-difluorophenyl)(methylsulfonyl)methyl|azetidine in 10 cm3 of tetrahydrofuran, cooled to a temperature of -782C and maintained in an inert atmosphere, add 0.5 cm3 of a 2M solution of lithium diisopropylamide. The temperature is allowed to rise to -202C, then 0.0 bcm3 of iodomethane is added. The temperature is allowed to rise to 0"C for 2 hours, then 20cm3 of an aqueous saturated ammonium chloride solution is added. The reaction medium is decanted and the aqueous phases are extracted twice with 20cm3 of ethyl acetate. the extracts are combined, dried over magnesium sulfate and evaporated to dryness at a pressure of 2.7 kPa, obtaining 550 mg of a cream-colored residue. The residue is chromatographed on a silica column (Oupatakh, standard 83-121-C; size 21, 4mmx250mm; previous column 21, 4 mmx5 Ohm, standard HO0O831212, silicon dioxide 8 microns, porosity 60 An gstrem;

Waipip Ipzigitepi So. Ipso Mas NRoai, MMorit, MA 01801, USA), eluting with a mixture of heptane and isopropanol (in a ratio of 99:1 by volume) at 15 cm3 per minute (detection at 254 nm, fractions of 10 cmU). The fractions containing the compound with Nee32/77 (cyclohexane-ethyl acetate-70:30; 254 nm; plates with silicon dioxide, standard 1.05719, Megek KSaA, 64271 Darmstadt, Germany) are combined and evaporated at a temperature of 40"C under a pressure of 2 ,7 k"Pa, obtaining 80 mg of 1-(bis(4-chlorophenyl)methyl|-3-11-(3,5-difluorophenyl)-1-methylsulfonylethyl azetidine in the form of a white amorphous powder.

H-NMR spectrum (30 MHz, SOSIz) b (in ppm): 2.05 (c:ZN); 2.54 (C:ZN); 2.63 (t, 9U-7.5HzC:1H ); 3.17 (t ush., u8Hz1H); 3.32 (m); 3.44 (t ush, U-8Hz:1H); 3.71 (m:1H); 4.27 (s:1H ); 6.83 (t, 3-9 1 2.5HzC:1H); 7.15 (m:2H); 7.20-7.40 (m:8H).

Example 80 (A85)-1-Bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine can be obtained in the following way: to a suspension of 0.191 cm3 of bis(4-fluorophenyl)chloromethane, ZbOmg of (85)-3-((3,5-difluorophenyl)methylsulfonyl-methyliazetidine hydrochloride and 167mg of potassium carbonate in 5cm3 of acetonitrile at a temperature of about 207"C, a few grains of potassium iodide are added. After standing for 48 hours at a temperature of about 20"C, the reaction medium filtered through a glass porous filter, the solid substance is washed with acetonitrile and the filtrate is purified by thin-layer preparative chromatography on silicon dioxide (with preparative plates MegekK Kiezede! bOB254; 20x20cm; thickness 1mm, eluting with a mixture of methanol and dichloromethane (in a ratio of 1:99 by volume) After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in a ratio of 10:90 by volume), filtration through a glass porous filter, then evaporation of the solvents under reduced pressure and at a temperature of about 40, 39 mg of (85)-1-ibis(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonylmethyl azetidine is obtained in the form of a yellow meringue.

IS spectrum "H-NMR (ZO0MHZc, SOCIz) b (in ppm): 2.54 (t ush., U27 Hz: 1); 2.66 (s:ZN); 3.18 (m:2Н) ; 3.20-3.45 (min); 3.63 (t ush, 9-7 Hz1N); 4.27 (s:1N); 4.28 (d, 9-11 Hz:1N); 6, 83 (t, U-9 and 2Hz:1H); 6.90-7.05 (m:bH); 7.25-7.40 (m:4H)I). (85)-3-((3 ,5-Difluorophenyl)methylsulfonylmethyl|azetidine hydrochloride can be obtained in the following way: a suspension of 8.5 g of 1-benzhydryl-3-((3,5-difluorophenyl) (methylsulfonyl)methylene azetidine and 1.3 g of palladium hydroxide (20 wt.95 palladium) in 600 cm3 of methanol, 20 cm3 of hydrochloric acid and 4 cm3 of acetic acid are mixed at a temperature of about 207C in a hydrogen atmosphere (1.5 bar) until the volume of 2.1 L of hydrogen is completely absorbed. The reaction medium is then filtered through a porous glass filter compacted with carbon black. The filtrate is concentrated to dryness under reduced pressure, then the obtained residue is treated with ethanol. The white crystalline product is filtered off and dried. In this way, 5.4 g of (A5)-3-((3,5-difluorophenyl)methylsulfonylmethyliazetidine hydrochloride is obtained in the form of a crystal in white. 1-Benzhydryl-3-(3,5-difluorophenyl)(methylsulfonyl)methylene| azetidine can be obtained in the following way: a mixture of 18.68 g of 3-acetoxy-1-benzhydryl-3-(3,5-difluorophenyl)(methylsulfonyl) methyl azetidine and 3.9 g of lithium hydroxide monohydrate in 120 cm3 of acetonitrile is kept at a temperature of about 70 "C for 3 hours. After cooling to a temperature of about 2"C, 120 cm3 of methyl tert-butyl ether, 0 cm3 of distilled water, then slowly 5 cm3 of acetic acid are successively added. After decantation, the organic phase is washed with 80 cm3 of saturated aqueous solution of sodium bicarbonate, 80 cm3 of distilled water, 80 cm3 of aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting residue is treated with ethanol. After standing overnight at a temperature of about 207"C, the resulting mixture is filtered through a glass porous filter, the obtained white crystals are washed with ethanol, diisopropyl ether and dried under reduced pressure at a temperature of about 45"C. In this way, 14.6 g of 1-benzhydryl-3-|((3,5-difluorophenyl) (methylsulfonyl)methylene|azetidine is obtained in the form of white crystals.

3-Acetoxy-1-benzhydryl-3-|(3,5-difluorophenyl) (methylsulfonylmethyliazetidine can be obtained in the following way: to a suspension of 12.37g of 3,5-difluorobenzylmethylsulfone in 200 cm of tetrahydrofuran in an inert nitrogen atmosphere at a temperature of about -30" About 47.1cm3 of a 1.6N solution of n-butyllithium in hexane is added dropwise over a period of 25 minutes.

The cloudy yellow solution is stirred at a temperature of about -30"C for 2 hours, then a solution of 11.87 g of 1-benzhydryl-azetidin-3-one in 75 cm3 of dichloromethane is added dropwise. The reaction mixture is stirred for 1.5 hours at a temperature of about -307C , then add 6.07 cm3 of acetyl chloride and leave to stand for about 30 minutes to raise the temperature of the medium to about - 1026. Add 200 cm3 of water and 100 cm3 of dichloromethane. After vigorous stirring for 30 minutes and decantation, the organic phase is washed three times with 150 cm3 of aqueous saturated sodium bicarbonate solution, 150 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The obtained crystalline residue is treated with 50 cm3 of boiling ethanol. The resulting white suspension is left to stand overnight at a temperature of about 20 "C, then the obtained solid substance is filtered under vacuum through a porous glass filter p, washed with diisopropyl ether and dried under reduced pressure at a temperature of about 5070. In this way, 19.5 g of 3-acetoxy-1-benzhydryl-3-((3,5-difluorophenyl) (methylsulfonyl)methyl|azetidine are obtained in the form of white crystals color 1-Benzhydrylazetidin-3-one can be obtained according to the method described by A.V. KATVIT2KU in u.

Selfish people. Spet., 271 (1994). 3,5-Difluorobenzylmethylsulfone can be obtained in the following way. a mixture of 66.69 cm3 of 3,5-difluorobenzyl bromide, 71.97 g of the sodium salt of methanesulfonic acid and 150 mg of sodium iodide in 625 cm3 of ethanol is boiled with an inverted refrigerator for about 16 hours in an argon atmosphere. After cooling to a temperature of about 20"C, the reaction medium is diluted with ethyl acetate, washed with 500 cm3 of water, 500 cm3 of an aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (300 mbar) at a temperature of about 40"C . The resulting residue is treated with 300 cm3 of diethyl ether and the solid substance is filtered on a glass porous filter, washed with 200 cm3 of diethyl ether, dried under reduced pressure at a temperature of about 20 "C. In this way, 86.9 g of 3,5-difluorobenzylmethylsulfone is obtained in the form of a powder white color

Example 81 (85)-11-(3-Pyridyl)(4-chlorophenyl)methyl-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidine can be obtained in the following way: a mixture of 47 mg of (3-pyridyl)-(4 -chlorophenyl) bromomethane, 50 mg of (A5)-3-I(3,5-difluorophenyl) methylsulfonylmethyl|azetidine hydrochloride and 58 mg of potassium carbonate in 2 cm3 of acetonitrile are stirred for about 3 hours at a temperature of about 207"C, for 2 hours at a boiling temperature with inverted with a solvent refrigerator, for about 16 hours at a temperature of about 20"C, then for 1.5 hours at the boiling temperature of the solvent with an inverted refrigerator. Then a few grains of potassium iodide are added and the reaction mixture is kept for about 2 hours at a boiling temperature with an inverted solvent refrigerator. After cooling to a temperature of about 20"C, the reaction medium is purified by thin-layer preparative chromatography on silicon dioxide (2 preparative plates MegsK Kieseide! 60254; 20x20cm; thickness 0.5mm|, eluting with a mixture of methanol and ichloromethane (in a ratio of 2.5:97.5 by volume). After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in a ratio of 10:90 by volume), filtration through a glass porous filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"С, 11 mg of (85)-1- (Z-pyridyl)(4-chlorophenyl)methyl|-3-I((3,5-difluorophenyl)methylsulfonylmethyl azetidine in the form of a colorless varnish.

IS spectrum "H-NMR (SO0MHCz, SOSIz) b (in ppm): 2.59 (m:1H); 2.66 (s:ZH); 3.21 (m:2H); 3.30- 3.50 (min); 3.67 (m/n); 4.28 (d ear., U-11Hz:1H); 4.32 (s ear.1H); 6.84 (t, U-sh9 and 2HzC1H); 6.95 (m:2H); 7.19 (dd ear., 9-8 and 5Hz1n); 7.20-7.40 (m:4H); 7.64 (d ear., U -8Hz:1H); 8.45 (m.1H); 8.59 (s very ush.1H) |. (3-Pyridyl)(4-chlorophenyl/bromomethane can be obtained in the following way: a mixture of 150 mg pyridyl)(4-chlorophenyl) methanol in 0.356 cm3 of hydrobromic acid (3395-Na in acetic acid) and 0.101 cm3 of acetyl bromide are boiled with an inverted refrigerator for 1 hour, then kept for 2 hours at a temperature of about 202C, after which it is concentrated at reduced pressure and evaporated together with several cm3 of toluene. In this way, 234 mg of (3-pyridyl)(4-chlorophenyl) bromomethane is obtained as a beige resinous solid. (3-Pyridyl)(4-chlorophenylmethanol) can be obtained in the following way. to of a solution of 5.83 cm3 of 4-chlorophenylmagnesium bromide (1M solution in diethyl ether) in 5 cm3 of tetrahydrofuran in 0.5 cm3 of Z-pyridinecarboxaldehyde is slowly added to the mercurial atmosphere of argon. After about 10 minutes, add Ccm? aqueous saturated solution of ammonium chloride and 10 cm3 of water. After stirring for 5 minutes at a temperature of about 20"C, the reaction medium is acidified to a pH value of about 2 using an aqueous solution of hydrochloric acid. The aqueous phase is extracted three times with 15 cm3 of dichloromethane.

The remaining aqueous phase is treated with 10 cm3 of an aqueous solution of sodium hydroxide and re-extracted three times with 15 cm3 of ethyl acetate. The organic phases containing ethyl acetate are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. In this way, 46 mg of (3-pyridyl)(4-chlorophenyl)methanol is obtained in the form of a bright yellow solid.

Example 82 (85)-11-(4-Pyridyl)(4-chlorophenyl)methyl-3-((3,5-difluorophenyl)methyl-sulfonylmethyl|iazetidine can be obtained in the following way: a mixture of 160 mg of (4-pyridyl)( 4-chlorophenyl) bromomethane, 169 mg of (A5)-3-Y(3,5-difluorophenyl) methylsulfonylmethyl|azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm3 of acetonitrile are stirred for about 17 hours at a temperature of about 20"C. Then a few grains of sodium iodide are added and after stirring for 2 hours at a temperature of about 20"C, the reaction mixture is kept for about 1.5 hours at the boiling temperature of the solvent with an inverted refrigerator. After cooling to a temperature of about 20"C, the reaction medium is purified by thin-layer preparative chromatography on silicon dioxide (4 preparative plates Megsk KiezeiYide! bOB254; 20x20cm; thickness 0.5 mm, eluting with a mixture of methanol and dichloromethane (in a ratio of 2.5:97.5 by volume). After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in ratio of 10:90 by volume), filtration through a porous glass filter, then evaporation of solvents under reduced pressure at a temperature of about 40"С, the first mixture of diastereoisomers is obtained, or 24 mg of (A5)-1-(4-pyridyl)(4-chlorophenyl) )methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidine in the form of a yellow varnish, and the second mixture of diastereoisomers, or 31mMg (85)-11-(4-pyridyl)(4-chlorophenyl)methyl|-3-I (3,5-difluorophenyl) methylsulfonylmethyl azetidine in the form of a yellow meringue. The first mixture of diastereoisomers has the following characteristics: H-NMR spectrum (300 MHz, SOCI3) b (in ppm) 2.62 (t, 9U57Hz1H); 2.67 (c:ZN); 3.21 (t ush, 927Hz:2H); 3.42 (mn); 3.70 (t ush., U957HC1H); 4.28 (s1H); 4.28 (d, 9-11HC:1H); 6.85 (t, 9U -9 and 2.5HzC1Hn); 6.97 (m:2H); 7.20-7.35 (m:bH); 8.52 (dd, 1-4.5 and 1.5Hz:2H).

The second mixture of diastereoisomers has the following characteristics: H-NMR spectrum (Z0O0MHCz, SOCI3) b (in ppm) 2.59 (t, U-7Hz1H); 2.67 (c:ZN); 3.26 (m :2Н); 3.35-3.50 (m:1Н); 3.63 (t ush., 9-7 Hz:1Н); 4.28 (s/1Н); 4.28 (d, U- 11Hz:1H); 6.85 (t, 3-9 and 2Hz:1H); 6.97 (m:2H); 7.20-7.40 (m:6bH); 8.50 (dd, uh4, (4-Pyridyl)(4-chlorophenyl)bromomethane can be obtained in the following way: a solution of 100 mg of (4-pyridyl)(4-chlorophenyl) methanol in 0.24 cm3 of hydrobromic acid (3395 in acetic acid) is boiled with the refrigerator inverted for 1 hour, then left to stand until it returns to a temperature of about 20"C. Then 0.675 cm3 of acetyl bromide is added and the reaction mixture is boiled with an inverted refrigerator for 1.5 hours, after which it is left to stand until the temperature returns to about 20"C, then concentrated under reduced pressure. In this way, 163 mg of (4-pyridyl)( 4-Chlorophenyl/bromomethane in the form of a beige meringue-resinous substance. (4-Pyridyl)(4-chlorophenyl)umethanol can be obtained in this way to a solution of 2 g of 4-(4-chlorobenzoyl)pyridine in 160 cm3 of ethanol at a temperature of about 202С 348 mg of sodium borohydride. After stirring for 2 hours at a temperature of about 20"C, 9 mg of sodium borohydride is added. After standing for about 1.5 hours at the same temperature, the reaction medium is diluted with 200 cm3 of dichloromethane and 200 cm3 of water. The pH value of the aqueous phase is set to approximately by adding approximately 13 cm3 of an aqueous solution of hydrochloric acid. After decantation, the aqueous phase is extracted three times with 100 cm3 of dichloromethane. The organic phases of combine, dry over magnesium sulfate, filter and concentrate under reduced pressure. In this way, 2 g of (4-pyridyl)(4-chlorophenyl)methanol is obtained in the form of a white powder.

Example 83 (85)-11-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidine can be obtained in the following way: a mixture of Zbomg (2-chloropyrid -5-yl)(4-chlorophenyl)bromomethane, 225 mg of (A5)-3-(3,5-difluorophenyl) methylsulfonylmethyl Iazetidine hydrochloride, 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm3 of acetonitrile are heated for about 2 hours at the boiling temperature with an inverted solvent cooler . After cooling to a temperature of about 20"C, the reaction medium is filtered through a glass porous filter. The solid residue is washed with dichloromethane and the filtrates are evaporated under reduced pressure. In this way, 402 mg of chocolate-colored meringue is obtained, which is purified by thin-layer preparative chromatography on silicon dioxide (4 preparative plates

MegsoK Kieseide! b6O0B254; 20x20 cm; thickness 0.5 mm, eluting with a mixture of methanol and dichloromethane (in a ratio of 2.5:97.5 by volume). After elution of the zone corresponding to the desired product using a mixture of methanol and dichloromethane (in a ratio of 10:90 by volume), filtration through a glass porous filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, the first mixture of diastereoisomers is obtained, or 14 mg ( 85)-11-((d-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-|(3,5-difluorophenyl)methylsulfonylmethyl|iazetidine in the form of a chestnut-colored meringue, and the second mixture of diastereoisomers, or 10 mg ( 85)-11-((d-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-|(3,5- difluorophenyl)methylsulfonylmethyliazetidine in the form of a meringue of beige color. The first mixture of diastereoisomers has the following characteristics: spectrum "H - NMR (300 MHz, SOSIz") b (in ppm): 2.57 (t, 927.5 Hz: 1H); 2.65 (s: ЗН); 3.15-3.30 (m: 2Н ); 3.40 (m'1H); 3.63 (t ush., U-7.5HzC:1H); 4.27 (d, 9511 Hz:1H); 4.31 (s:1H); 6 .84 (t, 9-9 and 2Hz:1H); 6.95 (m:2H); 7.20-7.35 (m:5H); 7.63 (dd, U-8 and 2.5Hz: 1H); 8.38 (d, 9-2.5HC1H).

The second mixture of diastereoisomers has the following characteristics: H-NMR spectrum (300 MHz, SOCI3) b (in ppm): 2.57 (t, 9-7.5 HZN); 2.6.4 (c:ZN); 3, 18 (t ush, 9U-7.5Hz:2H); 3.38 (m/n); 3.63 (t ush, U-7.5Hz:1H); 4.24 (d, 9-11.5Hz :1H); 4.29 (c:1H); 6.83 (tt, U-9 and 2Hz1H); 6.94 (m:2H); 7.20 (d,

UVG NN); 7.20-7.35 (m:4H); 7.59 (dd, uv and 2.5Hz: 1H); 8.34 (d, 9U-2.5 Hz H). (2-Chlorpyrid-5-yl)(4-chlorophenyl)bromomethane can be obtained in the following way: to a solution of 100 mg of (2-chloropyrid-5-yl)(4-chlorophenylmethanol) in 2 cm3 of carbon tetrachloride in an inert atmosphere of argon at a temperature of about 0С add 0.153 cm3 of thionyl bromide. After standing for 3.5 hours at a temperature of about 0"C, the reaction mixture is concentrated under reduced pressure and evaporated together with several cm of toluene. In this way, 1.3 g of a brown liquid is obtained, which is treated with dichloromethane, water is added and sodium dithionite. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. In this way, 0.33 g of (2-chloropyrid-5-yl)(4-chlorophenyl)bromomethane is obtained as a brown oil. (2 -Chloropyrid-5-yl)(4-chlorophenyl)methanol can be prepared according to a procedure similar to that of Example 84, starting from 22.5 cm3 of 4-chlorophenylmagnesium bromide (1M solution in diethyl ether) in 300 cm3 of tetrahydrofuran under an inert atmosphere of argon , and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran. In this way, 3.42 g of (2-chloropyrid-5-yl)(4-chlorophenyl)methanol is obtained in the form of a pale green powder. 2-Chloropyridine-5-carboxaldehyde can be obtained according to the following reference: a. Rapavieu, t. T. O. Vadii, A. K. Zapoo, U. Ogd. Spet., 63, 760-768 (1998).

Example 84 (85)-5-((4-Chlorophenyl)-/3-I((3,5-difluorophenyl)methylsulfonyl-methyl|azetidin-1-yl)umethyl)pyrimidine can be obtained in the following way: a mixture of 5O0mg 5 -Ibromo(4-chlorophenyl)methyl|pyrimidine, 52.bmg (АБ5)-3-((3,5- difluorophenyl) methylsulfonylmethyl Iazetidine hydrochloride, 44mg of potassium iodide and 7Zmg of potassium carbonate in 2cm3 of acetonitrile are heated for about 5 hours at the boiling temperature with reversed after cooling to a temperature of about 20"C, the reaction medium is purified by direct application to a thin layer of silicon dioxide in accordance with thin-layer preparative chromatography (2 preparative plates MegskK KieezeYide! bOB254; 20x20cm; thickness 0.5mm|, eluting with a mixture of methanol and dichloromethane ( (in a ratio of 2.5:97.5 by volume). t lawsuit at a temperature close to the first mixture of diastereoisomers, or Zm (85)-5-(4-chlorophenyl)-3-|(3,5- difluorophenyl)methylsulfonylmethylilazetidin-1-ylylmethyl)pyrimidine in the form of a yellow meringue, and the second mixture of diastereomers , or bmg (85)-5-((4-chlorophenyl)-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-1-yllium)pyrimidine in the form of a yellow meringue.

The first mixture of diastereoisomers has the following characteristics: H-NMR spectrum (300MHz, SOCI3) b (in ppm): 2.60 (t ush., d9-7Hz:1H); 2.66 (s:ZN); 3.24 (t ush, 9-7 HzC:2H); 3.41 (m/n); 3.66 (t ush, U9-7HzC:1H); 4.28 (d, 9-11.5Hz: 1H); 4.33 (with ush."H); 6.84 (t ush., U-9Hz:1H); 6.95 (m:2H); 7.25-7.35 (m:4H); 8.71 (with ear. 2H); 9.08 (dry/1H).

The second mixture of diastereoisomers has the following characteristics: H-NMR spectrum (300 MHz, SOCI3) b (in ppm): 2.61 (t, U27Hcy1 1); 2.66 (c:ZN); 3.24 (t ush., Uy27HzC:2H); 3.43 (MH); 3.65 (t ush., 9-7HzCyH); 4.28 (d, 9-11.5Hz:1H); 4.33 (sn); 6.85 (t, 9-9 and 2Hz1H); 6.96 (m:2H); 7.25-7.35 (m:4H); 8.69 (s:2H); 9.06 (sn) 5-(Bromo(4-chlorophenyl)methyl|Ipyrimidine can be obtained in the following way: to a solution of 205 mg of (4-chlorophenyl)pyrimidin-5-ylmethanol in 1 cm? of carbon tetrachloride and 1 cm3 of dichloromethane in an inert atmosphere of argon at a temperature of about 0" 0.36 bcm3 of thionyl bromide is added to C. After standing for 2.5 hours at a temperature of about 0"C, the reaction medium is brought to a temperature of about 20"C, concentrated under reduced pressure and evaporated together with several cm3 of toluene. The resulting brown liquid is treated with 10 cm3 of dichloromethane , washed with 5 cm3 of saturated aqueous solution of sodium dithionite, then with water. After decantation, the organic phase is dried over sulfate of magnesium, filter and concentrate to dryness under reduced pressure. Thus, 227 mg of a viscous beige liquid is obtained, which is treated with a minimum amount of dichloromethane and purified by thin-layer preparative chromatography on silicon dioxide (2 preparative plates Megsk KiezeYide! 60B254; 20x20 cm; thickness 0.5 mm|, eluting with a mixture of methanol and dichloromethane (in ratio 2.5:97.5 by volume).After elution of the zone corresponding to the desired product with a mixture of methanol and dichloromethane (in a ratio of 10:90 by volume), filtration through a porous glass filter, then evaporation of the solvents under reduced pressure at a temperature of about 40"C, 51 mg of 5-(bromo(4-chlorophenyl)methyl|pyrimidine is obtained in the form of a yellow meringue. (4-Chlorophenyl)pyrimidin-5-ylmethanol can be obtained according to a method similar to the following example 83: to of a solution of 63 mg of 5-bromopyrimidine in 10 cm3 of tetrahydrofuran in an inert atmosphere of argon at a temperature of about -782C, 2.5 cm3 of a 1.6 M solution of n-butyllithium in hexane is added dropwise. over 10 minutes at a temperature of about -78"C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm3 of tetrahydrofuran is added dropwise. After stirring for 30 minutes at a temperature of about -78°C, the temperature of the reaction medium is left to rise slowly to about 20°C, and 15cm3 of a saturated aqueous solution of ammonium chloride, bOscm3 of ethyl acetate and 10cmU of water are successively added.

The aqueous phase is extracted with 15 cm3 of ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered through a glass porous filter and concentrated under reduced pressure (20 mbar) at a temperature of about 44"C. The obtained yellow-brown oil in the amount of 1.09 g is purified by chromatography on a column with a diameter of 3 mm, filled with medium-sized silicon dioxide (0.063-0.200 mm), at atmospheric pressure, eluting with a gradient of a mixture of methanol and dichloromethane (in a ratio from 0:100 to 7:93 by volume). Fractions containing the desired product, combine and concentrate to dryness under reduced pressure to obtain 293 mg of (4-chlorophenyl)pyrimidin-5-ylmethanol as a yellow oil.

Example 85

Ester of 4-(1-I(bis(4-chlorophenyl)methyl|azetidin-3-ylidene)methylsulfonyl-methyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid with phenol can be obtained as follows: to a solution of 0 .23g of 4-(1-I(bis(4-chlorophenyl)methyl|-3-hydroxyazetidin-3-ylylmethylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid ether/- with phenol in Bcm3 of dichloromethane add 0.140 g of 4-dimethylaminopyridine, then 0.042 cm3 of methanesulfonyl chloride. The reaction mixture is stirred for 20 hours at a temperature of 20"C, then diluted with 10 cm3 of water. After decantation, the organic phase is washed successively with 100 cm3 of water and 100 cm3 of saturated Massey solution, dried over sulfate magnesium and concentrate to dryness at a temperature of 40"C under a pressure of 2.7 kPa. The resulting oil is powdered for 45 minutes in 50 cm3 of diisopropyl ether. The isolated solid substance is filtered, obtaining 120 mg of 4-(1-(bis(4-chlorophenyl)methyliazetidine-3- ylideniumethyl-sulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acids With phenol in the form of solids beige substance that melts at a temperature of 18476.

H-NMR spectrum (400MHz, SOSIz) b (in ppm): 2.53 (array: 2H); 2.95 (c:ZN): 3.90 (array: 2H): 4.04 ( t, ude5.5HZ:1H): 4.24 (m:ZN); 4.49 (array:2H); 4.60 (mt:1H); 5.90 (array:1H); 7.05-7 .50 (m:1ZN)|.

4-(1-Bis(4-chlorophenyl)methyl|-3-hydroxyazetidin-3-ylylmethyl-sulfonylmethyl)-3,b-dihydro-2H-pyridine-1-carboxylic acid ester with phenol can be obtained in the following way, to the mixture 0.72 g of 4-methylsulfonylmethyl-3,b-dihydro-2H-pyridine-1-carbothioic acid ester with phenol and 0.708 g of 1-I(bis(4-chlorophenyl)methyl|azetidin-3-one in 15 cm3 of anhydrous tetrahydrofuran, cooled to at a temperature of -782C in an inert atmosphere, add 0.52g of potassium tert-butylate. The reaction mixture is stirred at a temperature of -787C for 4 hours, then add 0.354g of 1-(bis(4-chlorophenyl)umethyl|iazetidin-3-one). After standing for two hours at a temperature of -78"C, bring it to a temperature of 20"C. The reaction mixture is diluted with 100cm3 of water, then tetrahydrofuran is evaporated under a pressure of 2.7kPa at a temperature of 40"C. The aqueous phase is extracted twice with 100cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under a pressure of 2.7 kPa and a temperature of 40"C. The obtained residue is chromatographed on dioxide and silicon (200 g of silicon dioxide, Artichoke, 20-45 μm with a porosity of 60 Angstroms; column with a diameter of 5 cm), eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 6:4 by volume). Fractions from B-11/64 (cyclohexane-ethyl acetate-6:4; plate with silicon dioxide, MegseK, standard 1.05719, Megok KsaA, 64271,

Darmstadt, Germany) are combined and concentrated under a pressure of 2.7 kPa at a temperature of 40 "С, obtaining 240 mg of ether /4-(1-(bis(4-chlorophenyl)methyl)|-3-hydroxyazetidin-3-ylylmethylsulfonylmethyl)-3 ,b-dihydro-2H-pyridine-1-carbothioic acids with phenol.

Ester of 4-methylsulfonylmethyl-3,b-dihydro-2H-pyridine-1-carboxylic acid with phenol can be obtained in the following way. 0.778 cm3 of phenylthiochloroformate is added to a solution of g of 1-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydropyridine in 10 cm3 of dichloromethane in an argon atmosphere. The solution immediately turns a very dark amber color. The reaction mixture is stirred for 4 hours at a temperature of 21"C, then diluted with 100cm3 of dichloromethane. The organic medium is washed twice with 50cm3 of water, dried over magnesium sulfate and evaporated to dryness at a temperature of 40"C under a pressure of 2.7 kPa. The obtained residue is purified by chromatography on a column with silicon dioxide (standard 51I-020-005, RiazpRask,

Uopez Spgothaiodgarpu IGitiei, Mezh/ Nova, Mia Siatogdap, CE82 VA, Vouate Shopi), eluting with a mixture of cyclohexane and ethyl acetate in a ratio of 6:4 (10cm3/min., fractions of 5cm3). Fractions with Be-12/74 (cyclohexane-ethyl acetate-1:1; plate with silicon dioxide, MegsK, standard 1.05719, Megok KsaA, 64271,

Darmstadt, Germany) are combined and concentrated under a pressure of 2.7 kPa at a temperature of 40 "С, obtaining 700 mg of 4-methylsulfonylmethyl-3,b-dihydro-2H-pyridine-1-carbothioic acid ester with phenol. 1-Benzyl-4-methylsulfonylmethyl -1,2,3,b6-tetrahydropyridine can be obtained as follows: to a solution of 17.6 g of 1-benzyl-4-methylsulfonylmethyl-pyridinium bromide in 700 cm3 of water, cooled to a temperature of 5"С, for 1 hour. a solution of 5.14 g of sodium borohydride and 25 g of sodium carbonate in 700 cm3 of water is added dropwise, without exceeding the temperature of 5"C in the reaction medium. The reaction medium is stirred for 4 hours at a temperature of 0"C, then left to return to room temperature overnight. The isolated yellow solid substance is filtered and dried under a pressure of 2.7 kPa, obtaining 9.6 g of 1-benzyl-4-methylsulfonyl-methyl-1,2,3,6-tetrahydropyridine with H-44/81 (dichloromethane:methanol--95 :5 by volume, wafer with silicon dioxide, Megsk, standard 1.05719, Megek KOsaA, 64271 Darmstadt, Germany). 1-Benzyl-4-methylsulfonylmethylpyridinium bromide can be obtained in the following way: 14 cm3 of benzyl bromide is added to a solution of 10 g of 4-methylsulfonylmethylpyridine in 200 cm3 of acetonitrile, then boiled with an inverted refrigerator for 3 hours, after which it is left to return to room temperature overnight. The isolated solid substance is filtered off, dried in a vacuum at 2.7kPa, obtaining 17.6bg of 1-benzyl-4-methylsulfonylmethylpyridinium bromide. 4-Methylsulfonylmethylpyridine can be obtained in the following way. to a solution of 57.4 g of 4-chloromethylpyridine hydrochloride in 700 cm3 of ethanol, slowly add 14 g of sodium hydroxide in tablets, then 35.7 g of sodium methanesulfinate. After addition, the temperature is 28°C. The reaction mixture is boiled with an inverted refrigerator for two hours, then left to return to room temperature overnight. The reaction medium is brought to a temperature of 50°C, then filtered while hot through a paper filter. The filtrate is evaporated to dryness at a temperature of 40"C and a pressure of 2.7 kPa.

The residue is recrystallized from 300 cm3 of isopropanol, obtaining 29.6 g of 4-methylsulfonylmethylpyridine.

Example 86 (A85)-1-(2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|-3-propylurea can be obtained in the following way , to a solution of Ubmg (A5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethylamine in 5 cm3 of tetrahydrofuran, 0.052 cm3 of n-propyl isocyanate is added. After mixing for about 72 hours at a temperature of about 207"C, the reaction mixture is filtered, concentrated to dryness under reduced pressure, treated with diisopropyl ether. The resulting mixture is filtered and concentrated to dryness under reduced pressure. In this way, 80 mg of a pale yellow solid is obtained, which is dissolved in 5 cm ? of tetrahydrofuran and to which 8mg of the acceptor resin is added. After stirring for about 18 hours at a temperature of about 207C, the reaction mixture is filtered, then concentrated to dryness under reduced pressure. Thus, Zbmg of a pasty solid is obtained, which is purified by pressure chromatography on a column of silicon dioxide, eluting with a mixture of cyclohexane and ethyl acetate (50:50 by volume). Fractions 16-20 are combined and concentrated to dryness under reduced pressure.

Bmg (A5)-1-(2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|-3-propylurea is obtained in the form of oil.

H-NMR spectrum (300 MHz, SOSIz) b (in ppm): 0.88 (t, 9-7.5 HzC:ZN); 1.35-1.60 (m:2H); 2.25 -2.55 and 2.65-3.05 (2 series of multiplets:bH as a whole); 3.04 (m:2H); 3.22 (m:1H); 3.38 (m:1H); 4 .07 (m:1H); 4.10-4.20 (m'1H); 4.17 (s:1H); 6.62 (t, 9U-912.5Hz:1H); 6.82 (m :2H); 7.20-7.45 (m:8NI. (85)-2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethylamine can be obtained in the following way: 1.2 g of ethyl ether (A5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl) y-2-(3,5-difluorophenyl) methanesulfonic acid in the form of a solution in 10 cm3 of methanol, then a solution of 30 cm3 of ammonia in 30 cm3 of methanol. The contents of the closed autoclave are stirred and kept at a temperature of about 60"C for 24 hours. After cooling to a temperature of about 207 "C is left to stand for evaporation of ammonia in the air at a temperature of about 20"C, then the rest of the solution is concentrated to dryness under reduced pressure. In this way, a resinous substance is obtained inu that it is powdered with diethyl ether at a temperature of about 207 for about 16 hours. The obtained insoluble part is filtered, dried in a desiccator for three hours. In this way, 830 mg of /(A5)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethylamine is obtained in the form of a whitish solid.

Ethyl ether (H5B)-2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)methanesulfonic acid can be obtained in the following way: to a solution of 1.9 g (A5) -2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethanol in 20 cm3 of dichloromethane at a temperature of about 20"C, add 0.34 cm3 of methanesulfonyl chloride. After cooling the reaction mixture to at a temperature of about 102 C, add 0.89 cm3 of triethylamine. After stirring the solution for 20 hours at a temperature of about 207 C, add 100 cm3 of water dropwise, then 150 cm3 of dichloromethane. The decanted and separated organic phase is washed twice with 50 cm3 of water, 50 cm3 of a saturated aqueous solution of sodium chloride, 50 cm3 of water, then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. In this way, the yellow meringue obtained in the amount of 2 g is purified on a column with silicon dioxide (granulometry 0.020-0.045 mm), under pressure

0.4 bar, eluting with a mixture of cyclohexane and ethyl acetate (80:20 by volume). Fractions 49-111 are combined and concentrated to dryness under reduced pressure. 1.2 g of ethyl ether (A5)-2-11-|bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)methanesulfonic acid is obtained in the form of a white meringue.

Example 87 (A85)-M-(2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|cyclopropanecarboxamide can be obtained in the following way: to the solution 90 mg of (A5)-2-11-Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethylamine in 5 cm3 of tetrahydrofuran at a temperature of about 202C, sequentially add 0.018 cm3 of diisopropylcarbodiimide, 10 mg of cyclopropanecarboxylic acid , 16 mg of hydroxybenzotriazole hydrate, then 0.4 g of morpholine applied to polystyrene. The resulting suspension is stirred at a temperature of about 2070 for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. In this way, 80 mg of a pasty product is obtained, which is purified by passing through a 5PE column (phase 5СХ, 1g phase). In this way, 7 mg of the residue is obtained, which is purified by pressure chromatography on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (70:30 by volume). Fractions 9-19 are combined and concentrated to dryness under reduced pressure. They receive 12 mg (B85)-

M-(2-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl| cyclopropanecarboxamide in the form of a colorless oil.

IS spectrum "H-NMR (ZO00MHZc, SOSIz) b (in ppm): 0.70 (m:1H); 0.80-1.00 (m:2H); 1.15-1.35 (m :1Н); 2.35-2.55 and 2.70-3.10 (2 series of multiplets:7Н as a whole); 3.26 (m:1Н); 3 47 (m/n); 4.19 ( sn); 5.63 (m:/1Н); 6.62 (t, 9-9 and 2.5BGCN); 6.81 (m:2Н); 7.20-7.45 (m:8Н)) .

Example 88 (A5)-H-(2-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|-3-methylbutyramide can be obtained in the following way to a solution of 45 mg of (НА5Б)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5- difluorophenyl)ethylamine in 5 cm3 of tetrahydrofuran at a temperature of about 202С, add 114 mg of NATY, 30 bmg of isovaleric acid, then 0.2 g of morpholine applied to polystyrene. The resulting suspension is stirred at a temperature of about 207C for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. In this way, 4 bmg of a yellow-hot oil is obtained, which is purified by pressure chromatography on a column of 5 g of silicon dioxide, eluting with a mixture of cyclohexane and ethyl acetate (in a ratio of 70:30 by volume). Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. Bmg (AB5)-M- is obtained (2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|-3-methylbutyramide in the form of a colorless mass la

H-NMR spectrum (300 MHz, SOSIz) b (in ppm): 0.88 (d, 9U-6.5 HzC:ZN); 0.91 (d, 9-6.5 HzC:ZN); 1 ,85-2.10 (m:ZN); 2.30-2.55 and 2.70-3.10 (2 series of multiplets:bH as a whole); 3.37(m:2H); 4.19 ( s/1Н); 5.45 (m:1Н); 6.65 (t, 9U-912.5ГциН); 6.82 (m:2Н); 7.20-7.45 (m:8Н)).

Example 89 (A5)-H-(2-11-(Bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethylisobutyramide can be obtained according to a method similar to this example 3: based on 45 mg of (A5)-2-11-(bis(4-chlorophenyl)methylyazetidin-3-yl)-2-(3,5-difluorophenyl)ethylamine, 5 cm3 of tetrahydrofuran, 114 mg of NATI, 26 mg of isobutyric acid and 0, 2 g of morpholine applied to polystyrene yield 10 mg of (AB5)-M-(2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)ethyl|isobutyramide in the form of opaque oils

H-NMR IS spectrum (400 MHz, (CO3)250-yv b (in ppm): 0.87 (d, 9-7Hz:ZN); 0.93 (d, 927Hz:ZN); 2.15 -2.85 (m:7N); 3.00-3.25 (m:2N); 4.40 (s:1N); 7.00-7.20 (m:ZN); 7.38 (m :4Н); 7.52 (m:4Н); 7.77 (m/n).

Example 90 11-Bis(4-chlorophenyl)methyl-Iazetidin-3-yl3,4-difluorophenyl)methanone can be obtained in the following way: to a solution of 128 mg of M-methoxy-M-methylamide 1-I|bis-(4-chlorophenyl)methylIazetidine -Z-carboxylic acid in 3 cm3 of tetrahydrofuran, cooled in a bath with acetone and dry ice, add 3 cm3 of a 0.5 N solution of 3,4-difluorophenylmagnesium bromide in tetrahydrofuran. After stirring for 20 hours at a temperature of about 0"C, add 10 cm? of water, then the reaction medium is stirred for 1 hour at a temperature of about 20"C. The decanted aqueous phase is extracted with 20 cm3 of ethyl acetate. The combined organic phases are washed twice with 15 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. In this way, 123 mg of the residue is obtained, which is purified by pressure chromatography on a column with 20 g of silicon dioxide, eluting with dichloromethane (stabilized by amylene). In this way, 47 mg of 41-bis(4-chlorophenyl)methyl|azetidin-3-yl(3,4-difluorophenyl)methanone is obtained in the form of a white powder.

H-NMR spectrum (ZOOMHCz, SOSIZz) 6 (in ppm): 3.34 (t, 9-7.5Hz:2H); 3.56 (t, U28Hz:2H); 4.05 (mn ); 4.35 (CH); 7.15-7.40 (m:9H); 7.58 (dm, U-9Hz:1H); 7.70 (ddd, 9U-9/7.5 and 2 ,5HzCy1NO.

M-Methoxy-M-methylamide of 1-I(bis-(4-chlorophenyl)methyl|azetidine-3-carboxylic acid can be obtained in the following way: to a suspension of 2.03 g of M,.O-dimethylhydroxylamine hydrochloride in 40 cm3 of dichloromethane, cooled to at a temperature of about 0"C in a bath with a mixture of water and ice, add 2.65 cm3 of 1-methylpiperidine. The resulting yellow solution (solution A) is stored at a temperature of about 0"C. To the suspension 7g of 1-I(bis-(4-chlorophenyl ) of methyl Iiazetidine-3-carboxylic acid in 300 cm3 of dichloromethane and 40 cm3 of tetrahydrofuran, cooled to a temperature of about -82C in an ice bath and isopropanol, 2.65 cm3 of 1-methylpiperidine, then 1.6 cm3 of methyl chloroformate are successively added. After stirring for about 5 minutes at at a temperature of about -8"C, the solution A obtained above is added dropwise. After stirring for 10 minutes at a temperature of about -8"C, the cooled bath is removed and the reaction mixture is stirred at a temperature of about 20"C for about 20 hours, then washed three times with 150 cm3 of water and concentrated to dryness under reduced pressure. In this way, 8.19 g of the residue is obtained, which is purified under pressure on 500 g of Artichoke silicon dioxide (particle diameter 20-45 mm), eluting with a mixture of ethyl acetate and dichloromethane (in a ratio of 8:92 by volume). In this way, 6.6 g of M-methoxy-M-methylamide 1-

Ibis-(4-chlorophenyl)methyl|azetidine-3-carboxylic acid in the form of a pale yellow oil. 1-(Bis-(4-chlorophenyl)umethyl|azetidine-3-carboxylic acid can be obtained according to a method similar to that described by A. (. AMOENVNBOM and ALOK, 9.Ogd.Spet., 37, 3953-3955 (1972 ), starting from 1-benzhydrylazetidin-3-ol when using 1-I(bis(4-chlorophenyl)methyl|azetidin-3-ol as a starting material.

Example 91 11-Bis(4-chlorophenyl)methyl|Iazetidin-3-yl3,5-difluorophenyl)umethanone can be obtained according to the method for obtaining (1-|bis(4-chlorophenyl)methyl|azetidin-3-yl3,4 -difluorophenyl)methanone, based on 1.1 g

M-methoxy-M-methylamide of 1-(bis-(4-chlorophenyl)methyliazetidine-3-carboxylic acid, 1.5 ml of 1-bromo-3,5-difluorobenzene and 331 mg of magnesium in the form of chips. In this way, 880 mg of 41 -Ibis(4-chlorophenyl)methyliazetidin-3-yl3,5-difluorophenyl)methanone in the form of a pale yellow viscous oil.

H-NMR spectrum (ZOOMHCc, SOCIz) b (in ppm): 3.34 (t, 9-7.5HzC:2H); 3.55 (t, U-8Hz:2H); 4.03 (m: "1H); 4.44 (sn); 7.01 (t, Ush912.5HzC:1H); 7.20-7.40 (M'TON)I.

Example 92 11-Bis(4-chlorophenyl)methyl|iazetidine-3-yl cyclohexylmethanone can be obtained according to the method for obtaining (1-Bis(4-chlorophenyl)methyl|azetidin-3-ylL3,4-difluorophenyl)methanone, based on 284 mg of M-methoxy-M-methylamide of 1-I|bis-(4-chlorophenyl)methylI|azetidine-3-carboxylic acid and 1.68 cm3 of a 2N solution of cyclohexylmagnesium chloride in tetrahydrofuran. In this way, 116 mg of /41-Ibis(4-chlorophenyl) is obtained. methyl|azetidin-3-yl cyclohexylmethanone in the form of a yellow viscous oil.

H-NMR spectrum (400MHz, SOSIz) b (in ppm): 1.10-1.35 and 1.55-1.85 (2 series m'1OH as a whole); 2.30 (mn) ; 3.14 (t, uU-8Hz:2N); 3.36 (t, U-8Hz:2N); 3.56 (m:1N); 4.31 (s:1N); 7.20-7 .35 (m:8H))|.

Example 93 11-Bis(4-chlorophenyl)methylIazetidin-3-iluphenylmethanone can be obtained according to the method for obtaining 41-I(bis(4-chlorophenyl)methyl|azetidin-3-ylL3,4-difluorophenyl)methanone, starting from 258 mg M-methoxy-

M-methylamide of 1-(bis-(4-chlorophenyl)umethyl|azetidine-3-carboxylic acid and 1.02 cm3 Zn of a solution of phenylmagnesium bromide in tetrahydrofuran. In this way, 208 mg of 11-bis(4-chlorophenyl)methylazetidine-

Z-iluphenylmethanone in the form of a yellow viscous oil.

H-NMR spectrum (300 MHz, SOCI3) b (in ppm): 3.35 (t, U28Hz:2H); 3.57 (t, U28Hz:2H); 4.13 (mn); 4.35 (son); 7.25 (dm, U-8Hz:4H); 7.34 (dm, U-8HzC:4H); 7.45 (t ear., U-8Hz:2H); 7, 56 (t, U-8 and 1.5Hz1H); 7.84 (dm, U-8Hz:2H)I).

Example 94 (85)-1-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-1-(3,5-difluorophenyl)ethanol can be obtained in the following way; to a solution of 100 mg of /41-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-1-(3,5-difluorophenyl)methanone in 4 cm3 of tetrahydrofuran, cooled to a temperature below -407C, add 0.167 cm3 of Zn solution of methylmagnesium bromide. After stirring for 20 hours at room temperature, 5 cm3 of water is added, then the decanted aqueous phase is extracted with 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. In this way, 91 mg of the residue is obtained, which is purified by pressure chromatography on a column with 10 g of silicon dioxide, eluting with a mixture of ethyl acetate and cyclohexane (in a ratio of 1:9 by volume). In this way, 74 mg of (A5)-1-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-1-(3,5-difluorophenyl)ethanol is obtained in the form of a colorless oil.

H-NMR spectrum (300 MHz, SOSIv) b (in ppm): 1.46 (c:ZN); 2.71 (m:1H); 2.82 (m.1H); 2.98 ( t, 9-7.5 HZ:1H); 9.24 (t, ue7.5 HZ1H); 3.34 (m/n); 4.31 (s/1H); 4.33 (array: 1H); 6 .67 (t, U-9 and 2.5HzC:1H); 6.98 (m:2H); 7.25-7.35 (m:8H)|.

Example 95 11-Bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methanone-O-allyloxime can be obtained in the following way: a solution of 100 mg (1-(bis(4-chlorophenyl)methyl|iazetidine- 3-yl3,5-difluorophenyl)methanone and 101 mg of O-allylhydroxylamine hydrochloride in 5 cm3 of pyridine are mixed at a temperature of about 202C for 20 hours.

Then 5 cm3 of water is added and the reaction mixture is extracted twice with 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, then concentrated to dryness under reduced pressure. Thus, 111 mg of yellow oil is obtained, which is purified by pressure chromatography on a column of 20 g of silicon dioxide (particle diameter 0.04-0.063 mm), eluting with a mixture of ethyl acetate and cyclohexane (in a ratio of 2:98 by volume). In this way, 8 mg of o/(1-I(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methanone-O-allyloxime is obtained in the form of a viscous colorless oil.

IS spectrum "H-NMR (30 MHz, SOSI3) b (in ppm). A mixture of two isomers 7 and E is observed in approximate ratios of 65:35 or vice versa; 2.84 and 3.11 (2 t., respectively) -8Hz and 9-7.5Hz:2H as a whole); 3.44 and 3.66 (2 tons, respectively 1-7.5Hz and dU-8Hz:2H as a whole); 3.58 and 3.81 (2 multiplets: 1H as a whole); 4.16 and 4.30 (2sy1H as a whole); 4.59 (m:2H); 5.22 (dm, 9U9-11HzC: 1H); 5.27 (dm, U-18HC: 1); 5.96 (m:1H); 6.80 (t, 9uU-9 and 2.5HzC1H); 6.91 (m:2H); 7.20-7.35 (m: 8H)).

Example 96 11-IBis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)umethanone-O-ethyloxime can be obtained according to the method for obtaining 41-I(bis(4-chlorophenyl)methyl|azetidin-3 -yl3,5-difluorophenyl)methanone-O-allyloxime: starting from 100 mg of 41-(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methanone and 90 mg of O-ethyl-hydroxylamine hydrochloride, thus, 8 mg of 41-I(bis(4-chlorophenyl)methyl-azetidin-3-yl3,5-difluorophenyl)methanone-O-ethyloxime in the form of a viscous, colorless mass.

H-NMR spectrum (30 MHz, SOSI3) b (in ppm). A mixture of two isomers 2 and E is observed in approximate ratios of 65:35 or vice versa; 1.25 and 1.27 (2 t, 97 HZ:ZN as a whole); 2.82 and 3.12 (2 tons, respectively 9U-8Hz and 9U27.5Hz:2H as a whole); 3.45 and 3.66 (2 tons, respectively U-7.5Hz and U-8Hz: 2H as a whole); 3.58 and 3.78 (2 multiplets: as a whole); 4.05-4.20 (m:2H); 4.16 and 4.30 (2 s1H as a whole) ; 6.80 (t, U-9 and 2.5HtsiN); 6.91 (m:2N); 7.20-7.35 (m:8N)).

Example 97 (85)-1-41-(Bis(4-chlorophenyl)methylIazetidin-3-yl3,5-difluorophenyl)methyl|-3-methylurea can be obtained in the following way. to a solution of ZbOmg of hydrochloride (1-Ibis(4-chlorophenyl)methylIazetidin-3-yl3,5-difluorophenyl) acetic acid in 15 cm? of anhydrous toluene in an inert nitrogen atmosphere at a temperature of about 20"С, 0.336 bcm of triethylamine and 0.384 cm3 of diphenylphosphonoazide are successively added. The resulting solution is stirred at a temperature of about 607С for about 90 minutes. 2.6 cm3 of a 2M solution of methylamine in tetrahydrofuran is added, stirring is continued at a temperature of about 207C for about 12 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7kPa) at a temperature of about 40"C. The residue is treated with 1 cm3 of methanol, then placed in a VOMO-EG OT 5СХ column

MAVIAM from 5 g of standard 1225-6027, which is conditioned with methanol. The column is washed with methanol, then eluted with a 2N solution of ammonia in methanol. Fractions in a solution of ammonia in methanol are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. In this way, 250 mg of transparent oil is obtained, which is treated with 1 cm? of dichloromethane, then placed in a column with a diameter of 1 mm, filled with 5 g of silica with a particle size of 0.015-0.035 mm, which is conditioned and eluted with dichloromethane between 0 and 40 cm3, then eluted with a mixture of dichloromethane and ethyl acetate (80:20 by volume) using the injection system. Fractions taken between 50 and 80 cm3 , combine and concentrate to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 140 mg of (A5)-1-(1-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-(3,5-difluorophenyl)methyl|-3-methylurea is obtained in the form of meringue.

H-NMR spectrum (400MHz, SOSIv) b (in ppm): 2.66 (m:1H); 2.82 (d, U-5HzC:ZN); 2.95 (min); 3, 03 (min); 3.18 (m:2H); 4.24 (min); 4.30 (sn); 4.92 (t, d9-57HZ:1H); 5.36 (d ush, U9- 7HzC:1H); 6.67 (t, 9-9 and 2.5Hz1H); 6.80 (m:2H); 7.20-7.30 (m:8H)|.

Preparation of (1-(bis(4-chlorophenyl)methyl|azetidin-3-ylL3,5-difluorophenyl)acetic acid hydrochloride is described in the patent "Carbon Derivatives", example 77.

Example 98 (85)-1-41-(Bis(4-chlorophenyl)methylIazetidin-3-yl3,5-difluorophenyl)methyl|-3-isopropylurea can be obtained in the following way: to a solution of 17 μl of isopropylamine in 1 cm3 of anhydrous toluene in an inert 3 cm3, or 0.1 mM, of the freshly prepared solution of (B5)-1-I|bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)isocyanatomethyl|iazetidine) is added to a nitrogen atmosphere at a temperature of about 207C. The resulting solution stirred at a temperature of about 20"C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. The solid residue is treated with 1 cm3 of methanol, then placed in a VOMO-EGOT 5СХ MAVIAM column with 500 mg standard 1210-2040, which is conditioned with methanol.The column is washed with methanol, then eluted with a 2N solution of ammonia in methanol.

Fractions in a solution of ammonia in methanol are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. The solid residue obtained in this way is treated with 1 cm3 of dichloromethane, then placed in a column 157 RiIazpRask, standard 5 016- 002, filled with 2 g of silica (0.065-0.090 mm), which is conditioned with dichloromethane and eluted with a mixture of dichloromethane and ethyl acetate (in the ratio of 90:10 by volume) using the injection system. Fractions taken between 20 and 8 cm3 are combined and concentrate to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 14 mg of (85)-1-C41-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-(3,5-difluorophenyl)methyl|-3-isopropylurea is obtained in the form of a white meringue.

H-NMR spectrum (400 MHz, SOSIz) b (in ppm): 1.14 (d, 9U-6.5Hz:ZN); 1.15 (d, 926.5HzC:ZN); 2.66 (mn); 2.92 (dd ush, uU-8 and 5.5HZ:1H); 3.01 (dd ush, U-8 and 5.5HZ:1H); 3.16 (t, U-8HZ: 1); 3.20 (t, 9-8HzC:1n); 3.85 (m:1H); 4.06 (d, uE8HgcN); 4.29 (s1H); 4.91 (t, d9-7HC1H ); 5.17 (d, 9-6.5Hz:1H); 6.66 (t, 9-9 and 2HzC1H); 6.78 (m:2H); 7.20-7.35 (m:8H ) I. (85)-1-IBis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)isocyanatomethyl| azetidine can be obtained in the following way: to a solution of 150 mg of 11-ibis(4-chlorophenyl)methyl hydrochloride 0.126 cm3 of triethylamine and 0.195 cm3 of diphenylphosphonoazide are successively added to azetidin-3-yl3,5-difluorophenyl)acetic acid in 9 cm3 of anhydrous toluene in an inert nitrogen atmosphere at a temperature of about 207C. The resulting solution is stirred at a temperature of about 507C for about 17 hours. Leave to cool and thus obtain (НА5)-1-Ibis(4-chlorophenyl)methyl/|-3-(3,5-difluorophenyl)isocyanatomethyl|azetidine.-:- in the form of a solution in toluene, which is then used in this form

Example 99 (85)-1-41-(Bis(4-chlorophenyl)methyl-azetidin-3-yl3,5-difluorophenyl)-methyl|-3-isobutylurea can be obtained in the following way: to a solution of 20 μl of isobutylamine in 1 cm3 of anhydrous toluene in to an inert nitrogen atmosphere at a temperature of about 207C, add 3 cm3, or 0.1 mM, of the freshly prepared solution of (B5)-1-I|bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)isocyanatomethyl|iazetidine. The obtained the solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. The solid residue is treated with 1 cm3 of methanol, then placed in a VOMO-EGOT 50СХ MANVIAM column with 500 mg of standard 1210-2040 conditioned with methanol.The column is washed with methanol, then eluted with 2N ammonia in methanol.

Fractions in a solution of ammonia in methanol are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. The residue obtained in this way is treated with 1 cm of dichloromethane, then placed in a column of IZT RiazpRask, standard 5 016-002, filled with 2g of silicon dioxide (0.065-0.090mm), which is conditioned with dichloromethane and eluted with a mixture of dichloromethane and ethyl acetate (in the ratio of 90:10 by volume) using an injection system. Fractions taken between 0 and 15 cm3 are combined and concentrated to dryness at reduced pressure (2.7kPa) at a temperature of 40"C. In this way, 14 mg of (85)-1-41-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-(3,5-difluorophenyl)methyl|-3-isobutylurea is obtained in the form of a white meringue.

H-NMR spectrum (400 MHz, SOSIz) b (in ppm): 0.89 (d, 9U-6.5 HzC:ZN); 0.90 (d, 9U-6.5 HzC:ZN); 1 ... ; 5.34 (d ush., 9U-6.5Hz:1H): 6.66 (t, 9-9 and 2Hz1H); 6.80 (m:2H); 7.20-7.35 (m: 8H)).

Example 100

M-Methyl-M-phenyl-1-Ibis(4-chlorophenyl)methyl|iazetidine-3-carboxamide can be obtained in the following way: to a solution of 100 mg of 1-|bis(4-chlorophenyl)methyl|azetidine-3-carboxylic acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20 "C, successively add: 0.039 cm3 of M-methylaniline, 87 mg of 1-(3-dimethylaminopropyl)-

3-ethylcarbodiimide hydrochloride, 0.063 cm3 of triethylamine, then 4 mg of hydroxybenzotriazole hydrate. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in an IZT RiazpRask column, standard 5II 016-002, filled with 5g of silicon dioxide (0.065-0.090 mm), which is conditioned with dichloromethane and eluted with a gradient of a mixture of dichloromethane and ethyl acetate ( the content of ethyl acetate varies from 0 to 5 by volume) using a pumping system, collecting fractions of 1.5 cm3. Fractions 3-15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 50 "С. In this way, 95 mg of 1-I(bis(4-chlorophenyl)methyl|azetidine-M-methyl-M-phenyl-3-carboxamide is obtained in the form of a cream-colored meringue.

H-NMR spectrum (400 MHz, SOSIv) b (in ppm): 3.08 (m:2H); 3.21 (m:ZN); 3.27 (s:ZN); 4.35 (sn); 7.06 (d, u7.5GHz:2N); 7.15-7.45 (m11N)).

Example 101 1-(Bis(4-chlorophenyl)methyl|azetidine-M-benzyl-M-methyl-3-carboxamide can be obtained in the following way: to a suspension of 150 mg of 1-I(bis(4-chlorophenyl)methyl|iazetidine- 0.0213 cm3 of M-benzylmethylamine is added to 3-carboxylic acid activated on TER resin (165 μM) in 2 cm3 of dichloromethane.

The suspension is stirred at a temperature of about 20"C for 22 hours, then filtered through a frit.

Is the solid residue washed twice by 1 cm? dichloromethane. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40°C. In this way, 38 mg of 1-bis(4-chlorophenyl)methyl|azetidine-M-benzyl-M-methyl-3-carboxamide is obtained in the form of a colorless resinous substance.

IS spectrum "H-NMR (ZOOMHC, SOSIz) b (in ppm): 2.78 (c:ZN); 3.25-3.55 (m:5N); 4.38 (mt:2N); 4.57 (s/1H); 7.15-7.40 (m ZNI. 1-(Bis(4-chlorophenyl)methyl|azetidine-3-carboxylic acid, activated on TER resin, can be obtained in the following way: to a suspension of 2.7 g of TER resin (free phenolic functional group, 1.1 mmol/g, or 2.975 mmol) in 40 cm3 of anhydrous dimethylformamide, add: 2 g of 1-bis(4-chlorophenyl)methyl|azetidine-3-carboxylic acid, 73 mg of 4- of dimethylaminopyridine, 0.927cm3 of 1,3-isopropylcarbodiimide. After stirring for 19 hours at a temperature of about 20C, the suspension is filtered, the resin is washed with 40cm3 of dimethylformamide, 40cm3 of tetrahydrofuran, 40cm3 of dichloromethane, then dried in a vacuum to a constant weight. In this way, 3.6g are obtained 1-Bis(4-chlorophenyl)methyl|azetidine-3-carboxylic acid activated on TER resin 1-(Bis(4-chlorophenyl)methyl|azetidine-3-carboxylic acid can be obtained according to a procedure similar to that described in A ..AMOENBOM and ALOK, 9U.Ogd.Spet., 37, 39 53-3955 (1972), based on 1-benzhydrylazetidin-3-ol, using 1-I(bis(4-chlorophenyl)methyl|iazetidin-3-ol as a starting material.

TER resin (free phenolic functional group) can be obtained according to the method described in the patent MUO-9967228.

Example 102 (85)-I1-(IBis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methyl methylamine can be obtained in the following way: to a solution of 108 mg /1-ibis(4-chlorophenyl)methylIazetidin- 3-yl(3,5-difluorophenyl)methanone is added to 2 cm3 of anhydrous 1,2-dichloroethane with 0.099 cm3 of methylamine, followed by 84 mg of sodium triacetoxyborohydride, and 0.014 cm3 of acetic acid. After stirring for 12 hours at a temperature of about 20°C, 0.992 cm3 of methylamine, 85 mg of sodium triacetoxyborohydride, then 0.143 cm3 of acetic acid are again added sequentially. The resulting solution is stirred at a temperature of about 20°C for about 24 hours, then washed with 4 cm3 of a saturated solution sodium bicarbonate. The organic phase is decanted, then dried over magnesium sulfate, filtered, then concentrated under reduced pressure (2.7 kPa). Thus, the obtained residue is purified on a column of IZT RiazpRask, standard 5II. 016-002, filled with 2 g of silicon dioxide (0.065-0.090 mm), which is conditioned with dichloromethane and eluted with a gradient of a mixture of dichloromethane and methanol (the percentage of methanol varies from 0 to b by volume) using a pumping system, collecting fractions of 1 cm3. Fractions 8-18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 5076. In this way, bbmg (85)-C1-(bis(4-chlorophenyl)methyl|azetidin-3-ylI(3, 5-difluorophenyl)methyl|methylamine in the form of a colorless honey-like substance.

H-NMR spectrum (300 MHz, SOSIz) b (in ppm): 2.25 (s:ZN); 2.60 (min); 2.68 (t, 9U57HtsiN); 2.94 (t, 9U27HgciN); 3.02 (t ush., U27Hz:1H); 3.34 (t ush, 927 Hz:1H); 3.58 (d, 9-59Hz:1H); 4.25 (s:1H) 6.67 (t, U-912.5Hz1H); 6.80 (m:2H); 7.20-7.35 (m:8H)|.

Example 103 (85)-I1-(IBis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methyl isobutylamine can be obtained in the following way: to a solution of 109 mg /41-(bis(4-chlorophenyl)methyl |azetidin-3-yl3,5-difluorophenyl)methanone in 2cm3 of anhydrous 1,2-dichloroethane add 0.028cm3 of isobutylamine, then sequentially: 85mg of sodium triacetoxyborohydride, 0.015cm3 of acetic acid. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is introduced into a column filled with 5 g of silicon dioxide, which is conditioned with dichloromethane and eluted with a gradient of a mixture of dichloromethane and ethyl acetate (the percentage content of ethyl acetate varies from 0 to 10 by volume) fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, 8 mg of (A5)-(1-Bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methylisobutylamine is obtained.

H-NMR spectrum (ZO0OMHCc, SOCIz) b (in ppm): 0.85 (d, 9-7Hz:ZN); 0.87 (d, Uu57Hz:ZN); 1.63 (m:1H ); 2.15 (dd, uUzh11 and 7.5 ГгциНн); 2.25 (dd, 9-11 and 7Гци1Н); 2.57 (m:1Н); 2.70 (t, у5:7Гцци1Н); 2, 92 (t, h957HzC1H); 3.01 (t ush, 9U-7.5Hz:1H); 3.33 (t ush., 9-7.5Hz:1H); 3.66 (d, U-9Hz: 11H); 4.25 (c:1H); 6.66 (t, 9-9 and 2.5Hz:1H); 6.81 (m:2H); 7.20-7.35 (m:8H) AND).

Example 104 (85)-I1-(IBis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methyl butylamine can be obtained in the following way: to a solution of 108 mg /1-I(bis(4-chlorophenyl) methylI|azetidin-3-ylL3,5-difluorophenyl)methanone in 2cm3 of anhydrous 1,2-dichloroethane add 0.0265cm3 of n-butylamine, then successively 95mg of sodium triacetoxyborohydride, 0.0143cm3 of acetic acid. After stirring for about 16 hours at a temperature of about 202°С, 0.0265 cm3 of n-butylamine, 85 mg of sodium triacetoxyborohydride, then 0.1433 cm3 of acetic acid are again added sequentially. The resulting solution is stirred at a temperature of about 202°C for about 24 hours, then washed with 4 cm3 of saturated sodium hydrogen carbonate solution. The organic phase is decanted, then dried over magnesium sulfate, filtered, then concentrated under reduced pressure (2.7 kPa). The residue obtained in this way is purified on an IZT RiazpRask column, standard 5 016-002, filled with 2 g of silicon dioxide (0.065 -0.090 mm), which is conditioned with dichloromethane and eluted with a gradient of a mixture of dichloromethane and methanol (the percentage of methanol varies from 0 to 6 by volume) using a pumping system, collecting fractions of 1 cm3. Fractions 25-30 are combined and concentrated to dryness at under reduced pressure (2.7 kPa) at a temperature of 50"C. In this way, 37 mg of (85)-II/1-(bis(4-chlorophenyl)methyl|azetidin-

C-yl3,5-difluorophenyl)methyl|butylamine in the form of a colorless honey-like substance.

H-NMR spectrum (300 MHz, SOSIz) b (in ppm): 0.85 (t, y-7.5Hz:ZN); 1.20-1.50 (m:4Н); 2.37 (t ush., d27HC:2H); 2.56 (m/n); 2.67 (t, U-7HcC1H); 2.89 (t, 9-7HcCy1H); 2.99 (t ush, U- 7HzC:1H); 3.32 (t ush., d-7HzC1H); 3.67 (d, 9u9GHz:1 NN); 4.24 (s:1H); 6.65 (t, U-9 12, 5Hz: 1H); 6.80 (m: 2H); 7.20-7.35 (m: 8H)).

Example 105 (85)-M-(1-(Bis(4-chlorophenyl)methyl|azetidin-3-ylL3,5-difluorophenyl)methyl|-33-methylbutyramide can be obtained in the following way: to a solution of 0.017 cm3 of isovaleric acid in 2 cm3 of anhydrous dichloromethane at a temperature of about 20 °C are added sequentially: 0.025 cm3 /M,M'-isopropyl carbodiimide, 10 mg of hydroxybenzotriazole hydrate, ZOmg of (85)-C-11-Ibis(4-chlorophenyl)methyl|azetidin-3-yl) -C-(3,5-difluorophenyl)methylamine. The resulting solution is stirred at a temperature of about 20"C for about 12 hours. The reaction medium is placed in a column VOMO-EG OT 5СХ MAVIAM with 500 mg of standard 1210-2040, conditioned with methanol. The column is washed with methanol, then eluted with a 2N solution of ammonia in methanol. Fractions in a solution of ammonia in methanol are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 40"C. In this way, 35 mg of (A5)-M-((1-(bis(4-chlorophenyl)methyl) is obtained |azetidin-3-yl3,5-difluorophenyl)methyl|-3-methylbutyramide in the form of a yellow honey-like substance.

IS spectrum "H-NMR (ZO0MHZc, SOCIz) b (in ppm): 0.98 (d, U-5Hz:6H); 2.05-2.25 (m:ZN); 2.71 (m :1H); 2.90 (m/n); 3.00 (mn); 3.20 (m:2H); 4.30 (sy); 5.14 (t, 9U-7.5HZ:1H) 6.48 (d ush, 9U-7.5Hz:1H); 6.67 (t, 9-9 and 2.5Hz:1H); 6.75 (m:2H); 7.20-7.40 (m:8H)|. (85)-C-11-(IBis(4-chlorophenyl)methyl|azetidin-3-yl)-C-(3,5-difluorophenyl)methylamine can be obtained in the following way: to the solution 216 mg of (A5)-(1-I(bis(4-chlorophenyl)methyl|azetidin-3-yl3,5-difluorophenyl)methanone in 10 cm3 of methanol is then sequentially added with 385 mg of ammonium acetate and 29 mg of sodium cyanoborohydride. The resulting solution is stirred at a temperature of about 207С for about 12 hours, then heated at 4570 for 6 hours. To this solution was added 29 mg of sodium cyanoborohydride. Stirring was continued at a temperature of about 202C for 72 hours. The reaction medium was poured into a mixture of 30 cm3 of ice water with 5 cm3 of 4N aqueous sodium hydroxide solution, then extracted twice with 30 cm3 of ethyl acetate, the organic phase is extracted twice with 30 cm3 of ethanol of hydrochloric acid, thus, the obtained aqueous phase is alkalized with an aqueous solution of sodium hydroxide, then extracted three times with 20 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 40"C. In this way, ZBmg (H5)-C-11-Ibis(4-chlorophenyl)methyl is obtained. azetidin-3-yl)-C-(3,5-difluorophenyl)methylamine in the form of a yellow honey-like substance.

Medicinal products according to the invention are formed by a compound of formula (I) or an isomer or a salt of such a compound, in its pure state or in the form of a composition in which it is associated with any other pharmaceutically acceptable product, which may be inert or physiologically active. Medicines according to the invention can be administered orally, parenterally, rectally or locally.

Tablets, pills, powders (gelatin capsules, starch wafers) or granules can be used as solid compositions for oral administration. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silicon dioxide, in a flow of argon. These compositions may also include substances other than diluents, such as one or more lubricants such as magnesium stearate or talc, a dye, a protective coating (dragé) or varnish.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerin, vegetable oils or paraffin oil can be used. These compositions may include substances other than diluents, such as wetting agents, sweeteners, thickeners, flavors or stabilizers.

Sterile compositions for parenteral administration can be mainly aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic esters for injections such as ethyl oleate, or other suitable organic solvents can be used as a solvent or excipient. These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example, by aseptic filtration by including sterilizing components in the composition, by irradiation or by heating. They can also be made in the form of sterile solid compositions that can be dissolved at the time of use in sterile water or any other sterile injection medium.

Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for local administration can be, for example, creams, lotions, eye lotions, mouthwashes and gum applications, nose drops or aerosols.

In human therapy, the compounds according to the invention are particularly suitable for the treatment and/or prevention of psychoses, including schizophrenia, anxiety states, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, brain injuries, panic attacks, peripheral neuropathies, glaucoma , migraines, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, obsessive-compulsive disorder, senile dementia, thymus disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, drug-induced movement disorders, dystonias, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, when interrupting the treatment of chronic diseases and abuse of alcohol or drugs ( such as opioids , barbiturates, hashish, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines), as analgesics or potentiators of the analgesic activity of narcotic or non-narcotic medications.

Doses depend on the desired effect, the duration of treatment and the route of administration used; usually they are from 5 mg to 1000 mg per day when administered orally to an adult with single doses from 1 mg to 250 mg of the active substance.

In general, the doctor determines the appropriate dosage depending on the age, weight and all other factors characteristic of the subject being treated.

The following examples illustrate the compositions according to the invention:

Example A

According to the usual method, gelatin capsules are prepared, which contain 50 g of the active product and have the following composition: compound of formula (I) 50 mg cellulose 18 mg lactose 55 mg colloidal silicon dioxide 1 mg sodium salt of carboxymethyl starch 10 mg talc 10 mg magnesium stearate 1 mg

Example B

According to the usual method, tablets are prepared that contain 50 mg of the active product and have the following composition: compound of the formula (I) 50 mg of lactose 104 mg of cellulose 4 mg of polyvidone 10 mg of sodium salt of carboxymethyl starch 22 mg of talc 10 mg of magnesium stearate 2 mg of colloidal silicon dioxide 2 mg of a mixture of hydroxymethyl cellulose, glycerin, titanium dioxide 72-3.5-24.5) to the total weight of 1 film-coated tablet of 245mg/245mg

Example C

A solution for injection is prepared, which contains 10 mg of the active product and has the following composition: compound of formula (I) 10 mg benzoic acid 80 mg benzyl alcohol o, Obml sodium benzoate 80 mg ethanol 9595 O.4 ml sodium hydroxide 24 mm propylene glycol 1.b6 ml water to total amount of 4 ml

Claims (56)

1. Compounds of formula (1): i ve. 4 17 Fo in which A means the radical SVIA", C-C(H5)5O"Ne or C-C(H7)5OgaikK; moreover, either Bi means a hydrogen atom and B" means the radical -С(Рв)(Р") (Во), -С(Вв)(АВ)(Ви2г), -СО-МаизАти», -СН2-СО-МаизАия, -СНо-СО-Ав, -СО-Нв, -СО-cycloalkyl, -50-Нв, -502-Нв, -С(ОН)(Виг)(Бв), С - С(ОН)У(Бе)( alkyl), -C(-MOayuAv, -C(-MO-Sna.-SnNeCHg)Av, -"СН2-СН(Но)Мазі Vzg,,і "СНа-С(-MOаІувВве, -СН(Нв)Мзі Az2 . the radical -C(Av)(Bi1)(Ai2); Bz and Ba, the same or different, are either alkyl or cycloalkyl; or an aromatic radical selected from phenyl, naphthyl or indenyl, and these aromatic radicals are unsubstituted or substituted by one or more halogen atoms, alkyl, hydroxy, formyl, hydroxyl, trifluoromethyl groups, trifluoromethoxy groups, -СО-аикК groups, cyano groups, -СООН, -СОДяик, -СОМАг2А2з, -СО-МН-МАГаВгв, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, Alkylsulfa nilalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl groups or -aik-MAhaN25 groups; or a heteroaromatic radical selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3 ,4-tetrahydroisoquinolyl, thiazolyl, thienyl rings, and these heteroaromatic radicals can be unsubstituted or substituted by one or more halogen atoms, alkyl, hydroxy, hydroxyl, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, groups -"СООН, -СООАик, - СО-МН -МагаВг25, -СОМА22Аз23з, -аІіКк-МагаВ25, alkylsulfonyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl groups; B5 means a hydrogen or alkyl atom; Aye means the radical Ag or Nei; AND; means cycloalkyl, heterocycloalkyl or heterocyclenyl, possibly substituted by -C5O-phenyl; Hg means a hydrogen atom or alkyl; B" means the radical -СО-МАгвН27, -СООН, -СООайк, -СНонН, -МН-СО-МН-айк, -СНо-МНА»в or -МН-СООайк; Vio means the Ag or Nei radical; You mean the radical -50»-aik, -502-Ag, -502-Nei; Бі2 means a hydrogen atom or an Ag or Nei radical; Wiz means a hydrogen or alkyl atom; Vi" means the radical Ag, Nei, -aIk-Ag or -aik-Neb; Wiz means alkyl, cycloalkyl or -alkyl-MAgoB20; Viv and Vi are the same or different, represent a hydrogen or alkyl atom, or Viv and Vi7, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or biheterocycle, which may contain one or more other heteroatoms selected from oxygen, sulfur and nitrogen atoms, and possibly substituted by one or more alkyl radicals; Viv means a hydrogen or alkyl atom; AB:io means a hydrogen atom or alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5Oalkyl, -CO-MNayl or -COayl; or Viv and Kio, together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3- to 10-membered mono- or bigheterocycle, possibly containing one or more heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and possibly substituted by one or more alkyl radicals; -MAgoAgi means a saturated or unsaturated 3-8-ene monoheterocycle, which may contain another heteroatom selected from oxygen, nitrogen and sulfur atoms; Ag: and Bgz, the same or different, mean a hydrogen or alkyl atom, or Rg: and Bgz, together with the nitrogen atom to which they are connected, form a saturated 3-10-membered mono- or bigheterocycle, which may contain another heteroatom selected from oxygen, sulfur and nitrogen atoms, and possibly substituted by one or more alkyl radicals; Vga and Bo5, the same or different, mean a hydrogen atom or alkyl, -COOyk, cycloalkyl, alkylcycloalkyl, -aik-O-alkyl, hydroxyalkyl, or Vga and B25, together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-membered mono- or bigheterocycle, which may contain another heteroatom selected from oxygen, sulfur, and nitrogen atoms, and may be substituted by one or more alkyl radicals, radicals -COaik, -SOOaik, -CO-MNaik, -C5- maik, oxo groups, hydroxyalkyl radicals, radicals -aik-O-aik, -СО-МНе»g; Vzv and Vo, the same or different, mean a hydrogen atom or an alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -aik-COO- aik, -aik-Ag, -aik-Nei, Nei, -aik-m(aIuYu"; Bgv and B27 with the nitrogen atom to which they are connected, can also form an unsaturated or saturated 3-10-membered mono- or bigheterocycle, which may contain one or more other heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and may be substituted by one or several alkyl, alkoxyl radicals, halogen atoms; Agv means the radical -SnNog-aiK, benzyl, -5Ogaik, -SOMNaik, -SOaikK, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, - Co-(SnaOn; n equals 1, 2 or 3; Ago and Bzo, the same or different, denote a hydrogen or alkyl atom, or Pg" and Bzo, together with the nitrogen atom to which they are bound, form a saturated 3-10-membered mono- or bigheterocycle, which may contain another a heteroatom selected from among oxygen, sulfur and nitrogen atoms and possibly substituted by one or more alkyl radicals; Bz and Bz2, the same or different, denote a hydrogen or alkyl atom, Ag or -aIK-Ag, or Baz and Azg2, together with the nitrogen atom to which they are bonded, form a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl, and piperidinyl ; ak means alkyl or alkylene radical; Ag means phenyl or naphthyl, possibly substituted by one or more substituents selected from halogen, alkyl, alkoxyl, -CO-аіК, cyano group, -"СООН, -СООаК" , alkylsulfonyl, alkylsulfonylalkyl, alkylsulfonylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alkyl-MAgaB2b5, -MAgaB25, alkylthioalkyl, formyl, hydroxyl, CEz, OSE»z, Nei, -O-alkyl-MN-cycloalkyl or 5O»MNeg; It means an unsaturated or saturated 3-10-membered mono- or bigheterocycle containing one or more heteroatoms selected from oxygen, sulfur, and nitrogen atoms, and possibly substituted by one or more halogen atoms, alkyl, alkyl, alkoxycarbonyl groups, -СОМА22А2з groups , hydroxyl, hydroxyalkyl groups, oxo groups or 5О2МН groups"; moreover, alkyl and alkylene radicals and parts and alkyl radicals and parts have a linear or branched chain and contain 1-6 carbon atoms; cycloalkyl radicals contain 3-10 carbon atoms and heterocycloalkyl and heterocyclenyl radicals contain 3 carbon atoms; their optical isomers and their salts with an inorganic or organic acid. 2. Compounds according to p.i., in which Ni is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl, pyrrolyl, pyridyl , pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl thiazolyl thienyl. C. Compounds of formula (I) according to claim 1, in which, when Niv and Ni7 together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 4. Compounds of formula (I) according to claim 1, in which, when Wiz and Nio together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 5. Compounds of formula (I) according to p. 1-7, in which the heterocycle formed by MEgoP21 is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl or imidazolyl ring. b. Compounds of formula (I) according to claim 1, in which, when Ag and H2z together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 7. Compounds of formula (I) according to claim 1, in which, when Hg" and Ah together with the nitrogen atom to which they are connected, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl , pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 8. Compounds of formula (I) according to claim 1, in which, when Nov and A27 together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 9. Compounds of formula (I) according to claim 1, in which, when N0 and N0 together with the nitrogen atom to which they are bound, form a saturated or unsaturated 3-10-ene mono- or bigheterocycle, it is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 10. Compounds of the formula (Her) according to claim 1, in which A means the radical SABA", and either Ni means a hydrogen atom and Ag means the radical -С(Нв)(А11)(Ви12) or- С(Ав)(А") ) (Vo); or Ki means alkyl and E2 means the radical -С(Ав)(А11)(Ри12); Az and Be, the same or different, mean either phenyl, unsubstituted or substituted by one or more halogen atoms, alkyl, alkyl, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, -SOMA»22A2z groups, hydroxyalkyl groups or -aik-MAhaHg5 groups; or a heteroaromatic radical selected from pyridyl, pyrimidinyl, thiazolyl, thienyl rings, and these heteroaromatic radicals can be unsubstituted or substituted by one or more halogen atoms, alkyl, hydroxy, trifluoromethyl groups, trifluoromethoxy groups, cyano groups, groups - СОМЕА22А2з, -aiКк- МагаВ25 or hydroxyalkyl groups; Av means a hydrogen atom; A" means the radical -СО-МАгвН27, -СООайк, -"СНгОН, -МН-СО-МН-айк, -СНо-МНА»в or -"МН-СООайк; Vio means Ag or Nei radical; You mean the radical -505-aiK, -502-Ag, -502-Nei; Бі2 means a hydrogen atom or an Ag or Nei radical; Ag: and Bgz, the same or different, mean a hydrogen or alkyl atom, or Rg: and Bgz, together with the nitrogen atom to which they are connected, form a saturated 3-10-membered mono- or bigheterocycle, which may contain another heteroatom selected from oxygen, sulfur and nitrogen atoms, and possibly substituted by one or more alkyl radicals; IN? and B25, the same or different, mean a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, or Kg and Ag together with the nitrogen atom to which they are connected form a saturated or unsaturated 3-10-membered mono- or a bigheterocycle, which may contain another heteroatom selected from oxygen, sulfur, and nitrogen atoms, and may be substituted by one or more alkyl radicals, radicals -COaik, -SOOaik, -CO-MNaik, -С5-mnaik, oxo groups, groups -СО-МН "; Ag means phenyl or naphthyl, possibly substituted by 1 or 2 substituents selected from halogen, alkyl, hydroxy, -CO-alkyl, cyano group, COOalk, -SOMA»22A2z, alkylsulfonyl, hydroxyalkyl, -alk-MAhaH»2z, MAhaHgv, hydroxyl , CEz, OSEz, -O-alkyl-MH-cycloalkyl or 5О2МН5; It means benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring, their optical isomers and their salts with an inorganic or organic acid. 11. A compound selected from the following compounds: (85)-1-Bis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl) (methylsulfonyl)methyliazetidine; (8)-1-(bis(4 -chlorophenyl)methyl|-3-(3,5-difluorophenyl) (methylsulfonyl)methyl|azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)(methylsulfonyl) methyl|azetidine; (85)-1-Bis(4-chlorophenyl)methyl|-3-pyrid-3-yl)u(methylsulfonyl)methyl|azetidine; (2)-1-(bis(4-chlorophenyl)methyl- 3-Cpyrid-3-yl)u(methylsulfonyl)methyl-azetidine; (5)-1-Bis(4-chlorophenyl)methyl-3-(pyrid-3-yloxymethylsulfonyl)methyl-azetidine; (85)-1- Ibis(3-fluorophenyl)methyl|-3-(3,5-difluorophenyl)(methylsulfonyl)methyl|azetidine; (2)-1-(bis(3-fluorophenyl)methyl-3-((3,5-difluorophenyl) (methylsulfonyl)methyl|azetidine; (5)-1-Ibis(3-fluorophenyl)methyl|-3-(3,5-difluorophenyl)(methylsulfonyl)methyl|azetidine; 1-(bis(4-chlorophenyl)methyl|- 3-(85)-(3-azetidin-1-ylphenyl|Imethylsulfonylmethyliazetidine; 1-(bis(4-chlorophenyl)methyl|-3-(H2)-(3-azetidin-1-ylphenyl|Imethylsulfonylmethyliazetidine; 1-(bis) (4-Chlorophenyl)methyl|-3-(5)-IZ-azetides n-1-ylphenyl|methylsulfonylmethyl)azetidine; (85)-I-I3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|pyrrolidine; (2)-1-I3-(11-(bis(4-chlorophenyl)methyl| azetidin-3-ylmethylsulfonylmethyl)phenyl|pyrrolidine; (5)-I-I3-41-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|pyrrolidine; (85)-M-I3-(1- Ibis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|-M-methylamine; (2)-M-I3-(11-Ibis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|-M -methylamine; (5)-M-II3-(1-(bis(4-chlorophenyl)methyl|azetidin-3-ylmethylsulfonylmethyl)phenyl|-M-methylamine; (85)-1-Ibis(4-chlorophenyl)methyl- 3-(3,5-bistrifluoromethylphenyl)methylsulfonylmethyl|azetidine; (2)-Chbis(4-chlorophenyl)methyl-3-I((3,5-bistrifluoromethylphenyl)methylsulfonylmethyl|azetidine; (5)-1-Ibis(4- chlorophenyl)methyl|-3-I((3,5-bistrifluoromethylphenyl)methylsulfonylmethyl|azetidine; 1-(bis(4-chlorophenyl)methyl|-3-(phenylsulfonylmethyl)azetidine; (85)-1-Ibis(4-chlorophenyl )methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|-3-methylazetidine; (2)-1-(bis(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)me tylsulfonylmethyl|-3-methylazetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonylmethyl|-3-methylazetidine; (85)-2-11-(bis(4-chlorophenyl)methyl|azetidine -3-yl)-2-(3,5-difluorophenyl)-M cyclohexylacetamide; (8)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5- difluorophenyl)-M-cyclohexylacetamide; (5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclohexylacetamide; (85)-2 -11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isobutylacetamide; (8)-2-11-(bis(4-chlorophenyl)methyl| azetidin-3-yl)-2-(3,5-difluorophenyl)-N-isobutylacetamide; (5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5 -difluorophenyl)-M-isobutylacetamide; (85)-2-11-(bis(4-chlorophenyl)methyl azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide; (8)-2 -11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-cyclopropylmethylacetamide; (5)-2-11-(bis(4-chlorophenyl)methyl| azetidin-3-yl-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide; (85)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5 -difluorophenyl)-M-isopropylacetamide ; (2)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide; (5)-2-11-(bis(4-chlorophenyl)methyl|azetidin-3-yl)-2-(3,5-difluorophenyl)-M-isopropylacetamide; (85)-1-Bis(4-chlorophenyl)methyl -3-11-(3,5-difluorophenyl)-1-methylsulfonylethyl|azetidine; (2)-1-(bis(4-chlorophenyl)methyl|-3-1P1-(3,5-difluorophenyl)-1-methylsulfonylethyl |azetidine; (5)-1-Ibis(4-chlorophenyl)methyl|-3-(1-(3,5-difluorophenyl)-1-methylsulfonylethyl|azetidine; (85)-1-Ibis(4-fluorophenyl)methyl |-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidine; (2)-1-(bis(4-fluorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidine; (5)-1 -Ibis(4-fluorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonylmethyl|azetidine; (85)-1-(3-pyridyl)(4-chlorophenyl)methyl|-3-((3,5- difluorophenyl)methylsulfonyl-methyl|azetidine; (55)-1-(3-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (AA)-1-( Z-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (58)-1-(Z-pyridyl)(4-chlorophenyl)methyl|-3-(( 3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (85)-1-(4-pyridyl)(4-chlorophenyl)methyl|-3-((3,5-diph torphenyl)methylsulfonyl-methyl|azetidine; (55)-1-(4-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (8 I)-1-(4-pyridyl)(4-chlorophenyl)methyl|-3-(3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (58)-1-(4-pyridyl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methylsulfonyl-methyl|azetidine; (85)-5-((4-chlorophenyl)-(3 -I((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-1-ylmethyl)pyrimidine; (58)-5-((4-chlorophenyl)-(3-I((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-1 -ylylmethyl)pyrimidine; (AB)-5-((4-chlorophenyl)-(3-((3,5-difluorophenyl)methylsulfonylmethyliazetidin-1-ylylmethyl)pyrimidine; (55)-5-((4-chlorophenyl)- /(3-((3,5-difluorophenyl)methylsulfonylmethyl|azetidin-1-yl-methyl)pyrimidine; (55)-1-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl-3-(3 ,5-difluorophenyl)methyl-sulfonylmethyliazetidine; (AA)-1-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl/|-3-Y(3,5-difluorophenyl)methyl-sulfonylmethyliazetidine; (85) -1-(2-chloropyrid-5-yl)(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methyl-sulfonylmethyl|azetidine; (58)-1-(2-chloropyrid-5-yl) )(4-chlorophenyl)methyl|-3-((3,5-difluorophenyl)methyl-sulfonylmethyl|azetidine; their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid. 12. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Ni means a hydrogen atom and B2 means the radical C(Hv)(А11)(Vig), in which Hv means a hydrogen atom, Vii means The radical -502-Ag, -502-Nei or - ZOgaik and Bi2 means a hydrogen atom or a radical Ag or Nei, which differs in that it reduces the derivative of the formula: лк вы M damage b in which Ba means alkyl, Her radical or Ag and AB means a hydrogen atom or Ag or Her radical, and alkyl, Ag and Her have the same meanings as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 13. The method of obtaining compounds of formula (I) according to claim 1, in which A means the radical СВ», where Ві means a hydrogen atom and Р» means the radical С(Нв)(А11)(Віг), in which Нв means a hydrogen atom, Viі means the radical -505-Ag, -502-Nei or - 5Ozaik and Bi" means a hydrogen atom or the radical Ag or Nei, which differs in that the derivative AzCH(Bg) Ba is introduced into the interaction with the derivative of the formula: nm sho b z in which Ba means an alkyl, a radical of Ni or Ag and AB means a hydrogen atom or a radical of Ag or Ni, and alkyl, Ag and Ni have the same meanings as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 14. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical С-С(Н5)5О»2Нв or С-С(Н7)5ОгайК, which differs in that it dehydrates the derivative of the formula: А - М кс ЗО Ka v in which either Ka means the Ag or Her radical and Kb means a hydrogen atom or alkyl, or Ka means alkyl and Kb means cycloalkyl, heterocycloalkyl or heterocyclenyl, possibly substituted by -"C5O-phenyl; Bc means a hydrogen atom or acetyl, and Pz, Ba, Ag and Nei have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 15. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical C-C(H5)5O»2Hv or C-C(H7)5OhaiK, which differs in that AzCH(Bg)Na is introduced into the interaction with derivative of the formula: ni nd! 50,-Ba b in which either Ba means the Ag or Her radical and AB means a hydrogen atom or alkyl, or Ba means alkyl and KB means cycloalkyl, heterocycloalkyl or heterocyclenyl, possibly substituted by -"C5O-phenyl; Bc means a hydrogen atom or acetyl, and P", Ba, Ag and Nei have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 16. The method of obtaining compounds of the formula (I) according to claim 1, in which КЕ means the radical СВ», where Ві means a hydrogen atom and Р» means the radical С(Пв)(Н»)(Niо), in which Нв means a hydrogen atom, Ne means the radical -CO-MAgA27 and Vio means the Ag or Nei radical, which differs in that the amine NMAgeR27, in which B2zv and B27 have the same values as in claim 1, is introduced into interaction with the acid of the formula: ВАХ M С осон Ко in which Az, Va and Vio have the same values as in claim 1, the product is isolated and, if necessary, converted into a salt with an inorganic or organic acid. 17. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical СВ», where Ві means a hydrogen atom and Р» means the radical С(Пв)(Ре)(Рио), in which Вв means a hydrogen atom, Ne means the radical -COOH and Nio means the Ag or Ni radical, which differs in that it hydrolyzes the corresponding complex ester of the formula: K, B--X M Sobak Ko in which Az, Va and Vio have the same values as in claim 1, and ak means alkyl (with 1-6 carbon atoms in a straight or branched chain), the product is isolated and, if necessary, converted to a salt with an inorganic or organic acid. 18. The method of obtaining compounds of the formula (I) according to claim 1, in which КЕ means the radical SKIR», where Ki means a hydrogen atom and Р» means the radical С(Пв)(Н»)(А:о), in which Na means the atom hydrogen, Но", means the radical -СООайк or -СНОН and Во means the radical Аг or Ней, which differs in that it reduces the compound of the formula: В Кк, М С осов Ко in which Az, Va and Nio have the same values as in claim 1, and ak means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated, and, if necessary, it is converted into a salt with an inorganic or organic acid. 19. The method of obtaining compounds of formula (I) according to claim 1, in which A means the radical СВ», where Бі means a hydrogen atom and Р» means the radical С(Пв)(Н»)(Віо), in which Na means a hydrogen atom, Ne means the radical -αHСООайк and Аіо means the radical Аг or Ней, which differs in that the alcohol Аікон, in which аіК means alkyl (with 1-6 carbon atoms in a linear or branched chain), is introduced into the interaction with the derivative of the formula: в-- K 4 M M-S-O Ko in which Az, Va and Vio have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 20. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical SAN", where Ki means a hydrogen atom and P" means the radical С(Рв)(Р»)(А:о), in which Нв means an atom hydrogen, Ne means the radical -MH-CO-MnH-aik and AVio means the radical Ag or Nei, which differs in that amine aikmNa", in which aik means alkyl (with 1-6 carbon atoms in a linear or branched chain), enter in interaction with a derivative of the formula: А, в-К 4 МА эх Ко in which Az, Va and Vio have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid . 21. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Bi means a hydrogen atom and P" means the radical -С(Рв)(Н»)(А:о), Нв means a hydrogen atom , Ne means the radical -СНо-МНПР 28, Вгв means the radical - СННЕ-аикК or benzyl, and Вио means the radical Аг or Ней, which differs in that the derivative of the formula: where in My Co in which Az, Ba and Vio have the same values as in claim 1, is introduced into the interaction with the aldehyde Nasno, in which Ba means the radical -SNeg-alylK or benzyl and ak means alkyl (with 1-6 atoms carbon in a linear or branched chain), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 22. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical SAN", where Ki means a hydrogen atom and P" means the radical -С(Рв)(Н»)(А1о), Вв means a hydrogen atom, Ne means the radical -СНо-МНА:8, Вгв means the radical - 5О»-аіК, and Віо means the radical Аг or Ней, which differs in that the amine of the formula: В ВХ Мо Ко in which Az, Va and Vo have the same values , as in claim 1, is introduced into the interaction with the derivative SibO»Ne, in which Be means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid 23. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Bi means a hydrogen atom and P" means the radical -С(Рв)(Н»)(А1о), Вв means a hydrogen atom, means the radical -СНо-МНА:8, Вгв means the radical - СОо-Ммнакк, and Вио means the radical Аг or Ней, which differs in that the derivative of the formulas: E and M! - Co, in which B", Va and Vo have the same values as in claim 1, are introduced into the interaction with a derivative of ВИМСО, in which В means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and , if necessary, it is converted into a salt with an inorganic or organic acid. 24. The method of obtaining compounds of formula (I) according to claim 1, in which E means the radical СВ», where Ki means a hydrogen atom and Р» means the radical -С(Рв)(ВН») (Во), Вв means a hydrogen atom, Ка means the radical -СНо-МНПР 28, Нгв means the radical - Со-айкК, cycloalkylalkylcarbonyl, cycloalkylcarbonyl, -СО-(СНо)пОН, and Аио means the radical Аг or Ней, which differs in that the derivative of the formula: where вх М в Ко в in which Az, Ba and Vio have the same values as in claim 1, are introduced into interaction with the acid HOOSNO, in which Hd means alkyl (with 1-6 carbon atoms in a linear or branched chain), cycloalkyl (with 3-10 carbon atoms ), alkyl (with 1-6 carbon atoms in a linear or branched chain), cycloalkyl (with 3-10 carbon atoms), -"СН2) OH and n equals 1, 2, C, the product is isolated and, if necessary, its converted into a salt with an inorganic or organic acid. 25. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Vi means a hydrogen atom and P" means the radical -SOMNA1zАх4, which differs in that the amine НМА1зНАчи4, in which Viz and VХ4 have the same values, as in claim 1, are entered into interaction with the derivative of the formula: KE, t. D Ssoon in which Az and Ka" have the same values as in formula (I), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 26. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical SKIR", where Ki means a hydrogen atom and Ko means the radical -СН2о-СОМВИзАча, which differs in that the amine НМВізАча, in which Viz and АВі" have the same values as in claim 1 are introduced into the interaction with the derivative of the formula: Кк, ВХ M СооНн in which Az and Ba have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 27. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Vi means a hydrogen atom and P" means the radical -СН2-СОМВИзВ4, which differs in that they reduce the derivative of the formula: ZK in which B", Na, Wiz and Vi" have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 28. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical SKIR", where Ki means a hydrogen atom and P" means the radical -5ОНв, which is distinguished by the fact that they oxidize the derivative of the formula: В, АХ ЗА, in which Az, Va and Ve have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 29. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Vi means a hydrogen atom and P" means the radical -502Nv, which differs in that it oxidizes the derivative of the formula: вх у Ов, in which Az , Wa and Ne have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 30. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical СВ», where Ki means a hydrogen atom and 2 means the radical -СОН» or -СО-cycloalkyl, which differs in that the derivative of the formula: ВХ ц a compound in which Az, Ba have the same values as in claim 1, is introduced into the interaction with the APMOV'H derivative, in which BA has the same values as Kb in claim 1, or means cycloalkyl (with 3-10 atoms carbon), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 31. The method of obtaining compounds of the formula (I) according to claim 1, in which KE means the radical SKP", where Ki means a hydrogen atom and 2 means the radical -C(OH) (Hv) (Vig) or -C(OH) (He) (alkyl), which differs in that the derivative of the formula: still ВХ цд Сов in which Нз, В". and No have the same values as in claim 1, are introduced into the interaction with the derivative VIMOV'H", in which Bi has the same values as Bi2 in claim 1, or means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 32. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SB", where Ki means a hydrogen atom and 2 means the radical -C(-MOaik)Av or -C(-MO-СНо-СН-СНе" d) Hv, which differs in that the derivative of the formula: B in C Sov, in which Az, Ba and Hv have the same values as in claim 1, is brought into interaction with the derivative VIOMN", in which B) means alkyl (from 1-6 carbon atoms in a linear or branched chain) or the radical -СНо-СН:СН», the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 33. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical SER", where Ki means a hydrogen atom and 2 means the radical -CH(He)MAzi Hzg, Nzi and Bz"2 mean hydrogen atoms, which differs in that , that ammonium hydroxide is introduced into the interaction with the derivative of the formula: shi Kk; M in -OM5 in which Az, Ba, Ne have the same values as in claim 1, and Me means a methylsulfonyloxy group, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 34. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Bi means a hydrogen atom and 2 means the radical -CH(He)МазиНАзг, Hzi means a hydrogen atom and Nzo" means alkyl, the Ag radical or -aiYIK-Ag, which is distinguished by the fact that the halide Na!Nzi is introduced into the interaction with the corresponding compound of the formula (I), in which K means the radical SK», where Ki means a hydrogen atom and H2 means the radical -CH(Hv)MAzi Bz2, Nzi and Az2 mean hydrogen atoms, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 35. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical SER", where Ki means a hydrogen atom and 2 means the radical -CH(He)МАзиНАз2, Нзи and ВНз" mean alkyl radicals, Аг radicals or -аикК -Ag, which differs in that the halide Na!Vzg is introduced into the interaction with the corresponding compound of the formula (I), in which K means the radical SKIR", where Ki means a hydrogen atom and Ko means the radical -CH(Ne)MAziHzg, Hzi means an atom hydrogen and Hz2 means alkyl, radical Ag or -aiKk-Ag, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 36. The method of obtaining compounds of formula (I) according to claim 1, in which K means the radical SER", where Ki means a hydrogen atom and K2 means the radical -CH(He)Мазі Вз2, Нзі means a hydrogen atom and Взг means alkyl (from 2- 6 carbon atoms) or -aiK (with 2 carbon atoms)-Ag, which differs in that the aldehyde Nasno, in which Na means alkyl or -aiKk-Ag, is introduced into the interaction with the corresponding compound of the formula (I), in which A means the radical SV", where Ni means a hydrogen atom and Pg means the radical -CH(He)MNAz Bz2, Bzi and Bz"2 mean hydrogen atoms, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 37. The method of obtaining compounds of formula (I) according to claim 1, in which КЕ means the radical SER", where В means a hydrogen atom and 2 means the radical -CH(He)МазіБз2, Нзі means alkyl, the radical Аг or -айЙК-Аг and Az » means alkyl (with 2-6 carbon atoms) or -AlKys with 2-6 carbon atoms)-Ag, which differs in that the aldehyde Vasno, in which Ka means alkyl or -AlK-Ag, is introduced into the interaction with the corresponding compound of the formula ( I), in which KE means the radical SER", where Bi means a hydrogen atom and Ko means the radical -CH(He)MAZi Bz2, HAZi means a hydrogen atom and Vzg2 means an alkyl, a radical Ag or -aik-Ag, the product is isolated and, in if necessary, it is converted into a salt with an inorganic or organic acid. 38. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical SER", where Ki means a hydrogen atom and K2 means the radical -CH(He)MAziAzg2, Nzi and Az" together with the nitrogen atom with which they are combined formed a heterocycle selected from among aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, which differs in that the dihalide NaCl (with 2-5 carbon atoms)-Na!I is introduced into the interaction with the corresponding compound of the formula (I), in which K stands for the radical SK", where Ki stands for a hydrogen atom and Kg stands for the radical -CH(Hv)MAzi Bz2, Hzi and Az2 stand for hydrogen atoms, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 39. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SV", where Vi means a hydrogen atom and 2 means the radical -CH(He)MNZOHaik, which differs in that the derivative of the formula: nik Kk; M in MH, in which Az, Ba and Ne have the same values as in claim 1, is introduced into the interaction with the derivative SiboOgaiK, in which ak means alkyl (with 1-6 carbon atoms in a linear or branched chain), a product, isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 40. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical СК:Р», where Ki means a hydrogen atom and Ko means the radical -СН(Бе)МнСОМНайк, which differs in that the derivative of the formula: А, вн ) МН, Кк in which з, Ба and Не have the same values as in claim 1, are introduced into the interaction with the derivative аикМсСОо, in which аИК means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and , if necessary, it is converted into a salt with an inorganic or organic acid. 41. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Vi means a hydrogen atom and P" means the radical -СН(Не)МНСО з, which differs in that the derivative of the formula: Shk Kk; М У -МН, in which Az, Va and Ve have the same values as in claim 1, are introduced into the interaction with the derivative NziСООН, in which Azi has the same values as in claim 1, the product is isolated and, if necessary , it is converted into a salt with an inorganic or organic acid. 42. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical SAN", where Ki means a hydrogen atom and P" means the radical -СН2-СОН5, which differs in that the derivative of the formula: What Kk; Mzh -co-SHSNOSsN, in which Vz and Ka have the same values as in claim 1, are introduced into the interaction with a derivative of the formula NeMoOV', in which Ne has the same values as in claim 1, the product is isolated and, in the case needs, it is converted into a salt with an inorganic or organic acid. 43. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical SAN", where Vi means a hydrogen atom and P" means the radical -CH2-CH(Hv)-MAzi Vzg, which differs in that the derivative of the formula: schu y, in which Bz and Ba have the same values as in claim 1, are introduced into the interaction with the derivative of the formula HMAz1z2, in which Bzi and Az2 have the same values as in claim 1, the product is isolated and, if necessary, its converted into a salt with an inorganic or organic acid. 44. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical СК:Р», where Ki means a hydrogen atom and Ko means the radical -СН2-С(-MOaik) Abe, which differs in that the derivative of the formula: t wine what; in which Az and Ba have the same values as in claim 1, are introduced into the interaction with a derivative of the formula acomMnH", in which aik means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and, if necessary , it is converted into a salt with an inorganic or organic acid. 45. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Bi means the cyano group and B2 means the radical -C(Pb)(B11)(Bi2), in which Hb means a hydrogen atom, which is different by the fact that the derivative of the formula: V M i in which Az, Ba, Vii and Vi2 have the same values as in claim 1, is brought into interaction with sodium cyanide, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 46. The method of obtaining compounds of formula (I) according to claim 1, in which E means the radical SV", where Ki means the radical -5-aik-MATeVi"? and K2 means the radical -C(Pb)(Bi1)(Bi2), in which Hb means a hydrogen atom, which differs in that the derivative of the formula: R. M Kk, in which B", Va, Wiz and Ki" have the same values as in claim 1, are introduced into the interaction with the derivative No-aIk-MacheVi", in which aik means alkyl (with 1-6 carbon atoms in linear or branched chain) and Viv and Vi7 have the same values as in claim 1, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 47. The method of obtaining compounds of the formula (Yii) according to claim 1, in which A means the radical SV", where Vi means the radical -MNBA 55 and Ag means the radical -С(Нв)(А11)(Аі2), in which Не means a hydrogen atom , which differs in that the derivative of the formula: В, вых М Х Кк Кк in which Az, Ва, Вій and Ві2 have the same values as in claim 1, is brought into interaction with the derivative Не", in which Viz has the same values , as in claim 1, the product is isolated and, if necessary, converted into a salt with an inorganic or organic acid. 48. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical SKP", where Bi means alkyl and E2 means the radical -C(Pb)(A1)(Bi2g), in which Hz means a hydrogen atom, which is different by the fact that the derivative of the formula: РЕ, t M x B, Ko in which P», Ba, Wiz and Ki» have the same values as in claim 1, is brought into interaction with the derivative aikMnNaiY, in which ak means alkyl (from 1 -6 carbon atoms in a linear or branched chain) and M is a metal, the product is isolated and, if necessary, converted into a salt with an inorganic or organic acid. 49. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Bi means the radical -МргоРг1 and Рг means the radical -С(Рв)(Вч11)(Виг2), in which Нв means a hydrogen atom, which differs in that the derivative of the formula: Р, ВХ M -х Кк, in which Вз, Ва, Виз and Ви2 have the same values as in claim 1, is introduced into the interaction with the derivative НМРгоВ21, in which МегоН2гии has the same values, as in claim 1, the product is isolated and, if necessary, converted into a salt with an inorganic or organic acid. 50. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical СК:Р», where Ki means the radical -aik- MAiv8y», Viv and Aio mean hydrogen atoms, which are distinguished by the fact that they reduce the corresponding compound of the formula ( I), in which Ki represents a cyano group, the product is isolated and, if necessary, converted into a salt with an inorganic or organic acid. 51. The method of obtaining compounds of formula (I) according to claim 1, in which K means the radical SK", where Ki means the radical -aik- MAcha8A", Viv means a hydrogen atom and K1io means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -50O2aiK, - CO-MNnaik or -SOdaik, which differs in that the halide Nai!Vch», Na! means a halogen, is brought into interaction with the corresponding compound of the formula (I), in which K means the radical СК», where Ki means the radical -аіКк-МАівВ9, Vіv and Kto mean a hydrogen atom, the product is isolated and, if necessary, it is converted into a salt with inorganic or organic acid. 52. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Vi means the radical -aik- MAch8A", Viv means alkyl and Vito means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -"5Ogaik, - СО-МНайк or -СОДайк, which differs in that the alkyl halide is introduced into the interaction with the corresponding compound of the formula (I), in which K means the radical SAN», where Ki means the radical -айк-МАзвА19, Viv means a hydrogen atom and Ko means alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -5O2aikK, -CO-MNaik or -SOdaikK, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 53. The method of obtaining compounds of the formula (I) according to claim 1, in which E means the radical CB", where either Ki means a hydrogen atom and B" means the radical -С(Рв)(Ае) (Во) or -С(АВв)( АВы)(Ві2), or Кі means alkyl, МН-Ах5, cyano group, -5-аіКк-МахвВі7, -аік-МАівАіюо or -МагоВ2і and АВ» means the radical -С(Пв)(А11)(Віг) and Вв means alkyl, which is characterized by alkylation of the corresponding compound of formula (1) in which Az represents a hydrogen atom, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 54. The method of obtaining compounds of the formula (I) according to claim 1, in which K means the radical -С-С(Н7)5ОгайкК, which differs in that it oxidizes the derivative of the formula: Р, ВХ М о зайк Б, in which Az, Ba and B7 have the same meanings as in claim 1, and alkyl means alkyl (with 1-6 carbon atoms in a linear or branched chain), the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 55. The method of obtaining compounds of the formula (I) according to claim 1, in which A means the radical CB", where Bi means a hydrogen atom and 2 means the radical -CH(He)MAziNAz2, Hzi means a hydrogen atom and Nzo" means alkyl, which differs in that , that the corresponding compound of the formula (I), in which K means the radical SKIR", where Ki means a hydrogen atom and Pg means the radical - СО-Нав, are brought into interaction with the amine НМВз1Вз2, in which Взіо denotes a hydrogen atom and Вз2 means an alkyl, the product is isolated and, if necessary, it is converted into a salt with an inorganic or organic acid. 56. Pharmaceutical composition containing as active ingredient at least one compound of formula (I) according to any of claims 1-11.