UA79323C2 - Selected cgrp antagonists, method for production and use thereof as medicament - Google Patents

Abstract

The invention relates to CGRP antagonists of general formula (I), (I), in which A, U, V, W, X and R2 to R3 are as defined in claim 1, the tautomers, diastereomers, enantiomers, hydrates, mixtures, salts, hydrates of the salts, in particular the physiologically-acceptable salts thereof with inorganic or organic acids, medicaments containing said compounds and the use and methods for production thereof.

Description

Description of the invention

This invention relates to SOKR-antagonists of the general formula () m . (5. and p

Kk of their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, as well as hydrates of salts, primarily their physiologically compatible salts with inorganic or organic acids, medicinal products containing these compounds, their use and the method of their preparation.

In the above general formula (I), the substituents according to the first embodiment of the invention have the following meanings:

A means an oxygen or sulfur atom, a phenylsulfonylimino group or a cyanimino group,

X means an oxygen or sulfur atom, an imino group optionally substituted by a C-alkyl group, or a methylene group optionally substituted by a C-alkyl group, Ge)

Mu means a C-Svalkynyl, Co-Svalkenyl or Co-Svalkynyl group in which each methylene group may be substituted by 1-2 fluorine atoms and each metal group may be substituted by 1-3 fluorine atoms,

M means a chlorine or bromine atom, an amino-, methylamino- or hydroxy group,

M means a hydrogen, fluorine, chlorine, bromine or iodine atom, a difluoro- or trifluoromethyl group, o

B" means a saturated or monounsaturated or doubly unsaturated 5-7-ene aza-, diaza-, triaza-, oxaza-, CM thiaza-, thiadiaza- or 5,5-dioxidotidiazaheterocycle, while the above-mentioned heterocycles are attached through a carbon or nitrogen atom , contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom, can be substituted for one of the nitrogen atoms Ф) by an alkyl group and can be substituted for one or two identical or different carbon atoms

With substituents selected from alkyl, phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl and 1- methylimidazolyl group, and the olefinic double bond of one of the above unsaturated heterocycles can be condensed with a phenyl, naphthyl, dipyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, M-methylpyrrole -o or quinoline ring , with an alkyl group optionally substituted on the nitrogen atom with a 1H-quinolin-2-one c ring or with an imidazole or M-methylimidazole ring, or each of the two olefinic double bonds :c» of one of the above unsaturated heterocycles can be condensed with phenyl ring, and /phenyl, pyridinyl, diazinyl, furyl, /thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-m ethylpyrazolyl, imidazolyl, or 1-methylimidazolyl-1-no groups, which are contained in K 1, as well as heterocycles condensed with benzene, thiene, pyridine, and diazine rings, can additionally be mono-, di-, or tri-substituted in the carbon skeleton identically or differently) by substituents selected from fluorine, chlorine, bromine and iodine atoms, an alkyl group, an alkoxy group, a nitro group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylsulfonylamino group, a phenyl group, a difluoromethyl group, a trifluoromethyl group, an alkoxycarbonyl group, a carboxy group, a hydroxy group, an amino group , alkylamino group, dialkylamino group, acetyl group, acetylamino group, propionylamino group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, (4-morpholinyl)carbonyl group, (1-pyrrolidinyl)carbonyl group, (1-piperidinyl)carbonyl group, (hexahydro- 1-azepinyl)carbonyl group, (4-methyl-1-piperazinyl)carbonyl group, methyl dioxy group, aminocarbonylamino group, alkanoyl group, cyano group, difluoromethoxy group, trifluoromethoxy group, trifluoromethylthio group, trifluoromethylsulfinyl group and trifluoromethylsulfonyl group, (F. B2 means a hydrogen atom, a C-phenylmethyl group or a C-C7 alkyl group, which can be substituted in the o-position by a cyclohexyl group, a phenyl group, a pyridinyl group, a diazinyl group, a hydroxy group, an amino group, a b alkylamino group, a dialkylamino group, a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group , aminocarbonylamino group, acetylamino group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-(1-piperidinyl)-1-piperidinyl group, 4-morpholinyl group, hexahydro-TH-1-azepinyl group,

ibis(2-hydroxyethyl))amino group, 4-alkyl-1-piperazinyl group or 4-(o-hydroxy-Co-STalkyl)-1-piperazinyl group, phenyl or pyridinyl group, 6E while the above heterocyclic residues and phenyl groups additionally can be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine atoms,

bromine and iodine, metal group, alkoxy group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, C.-Salkylamino group, di(C.--Salkyl)uamino group, acetylamino group, aminocarbonyl group, cyano group, methylsulfonyloxy group, difluoromethoxy group, trifluoromethoxy group, trifluoromethylthio group, 0 trifluoromethylsulfonyl group, trifluoromethylsulfonyl group, amino-C4-Salkyl group,

C.-Salkylamino-C.-Salkyl group and di(C.--Salkyl)amino-C 1-Salkyl group,

BZ means a hydrogen atom or a C 3-C alkyl group optionally substituted by a phenyl or pyridinyl group, while the specified C 1-C alkyl group can be connected to the one present in B? an alkyl group or a phenyl or pyridyl ring present in K2 and a nitrogen atom to which they are attached to form a 70 ring, or

B2 and BZ together with the nitrogen atom located between them form the remainder of the general formula (1) is (0,

Residential complex / -ev s e in which village

The same means a carbon atom or the same when VE? represents a free pair of electrons, also means a nitrogen atom, d and g, when U! represents a carbon atom, mean the number 0, 1 or 2 or o 9 and g, when M represents a nitrogen atom, mean the number 1 or 2,

B means a hydrogen atom, an amino group, an alkylamino group, a cycloalkylamino group, a dialkylamino group,

M-(cycloalkyl)alkylamino group, dicycloalkylamino group, hydroxy group, alkyl group, cycloalkyl group, "9 amino-C-Stalkyl group, alkylamino-Co-Stalkyl group, dialkylamino-Co-Stalkyl GROUP, aminoiminomethyl group, alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylamino group, alkylsulfonylamino group, M-alkylcarbonyl-M-alkylamino group, M-alkylsulfonyl-M-alkylamino group, FO aminocarbonylamino group, alkylaminocarbonylamino group, dialkylaminocarbonylamino group, Fo cycloalkylaminocarbonylamino group,

From a dicycloalkylaminocarbonylamino group, from a phenylaminocarbonylamino group, an aminocarbonylalkyl group, an alkylaminocarbonylalkyl group, a dialkylaminocarbonylalkyl group, an aminocarbonylaminoalkyl group, an oxycarbonyl group, an alkoxycarbonylalkyl group or a carboxyalkyl group, or when M! does not represent a nitrogen atom, means " also a carboxy group, an aminomethyl group, an alkylaminomethyl group, or a dialkylaminomethyl group, or means a phenyl, phenyl-C1-C alkyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, C c pyridinylcarbonyl, or phenylcarbonyl group, each of which can be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, an alkyl group, an alkoxy group, a methylsulfonyloxy group, a difluoromethyl group, a trifluoromethyl group, a hydroxy group, an amino group, an acetylamino group, an aminocarbonyl group, an aminocarbonylamino group, an aminocarbonylaminomethyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an alkanoyl group, an (o-(dialkylamino)alkanoyl group), (Te) (o-(dialkylamino)alkyl group, oF-( bialkylamino)hydroxyalkyl group, (o-(carboxy)alkanoyl group, difluoromethoxy group, trifluoromethoxy group and, trifluoromethylthio group, trifluoromethylsulfinyl group and

Mn trifluoromethylsulfonyl group, saturated or mono- or polyunsaturated 4-10-membered co 250 azacycloalkyl group, 5-10-membered oxaza-, thiaza-, diaza- or triazacycloalkyl group, 6-10-membered azabicyclo- or diazabicycloalkyl group, 1-alkyl-4-piperidinylcarbonyl or c» 4-alkyl-1-piperazinylcarbonyl group, 1-alkyl-4-piperidinylamino group, 1-alkyl-4-piperidinylaminocarbonyl group or 1-alkyl-4-piperidinylaminosulfonyl group, while the above mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in the above mono- and bicyclic heterocycles can be replaced by a carbonyl or

HF) sulfonyl group, which in the above mono- and bicyclic heterocycles is not directly connected to a nitrogen, oxygen or sulfur atom, the methylene group can be replaced by one or two fluorine atoms, the above mono- and bicyclic heterocycles, as well as //1-alkyl -4-piperidinylcarbonyl (and 60 4-alkyl-1-piperazinylcarbonyl group can be mono- or polysubstituted in the ring by a C4-Stalkyl group and/or monosubstituted in the ring by a benzyl group, alkanoyl group, dialkylamino group, phenylcarbonyl group, pyridinylcarbonyl group, carboxy group, a carboxyalkanoyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group or a cycloalkylalkyl group, or optionally substituted in the ring by an alkyl cycloalkylcarbonyl, azacycloalkylcarbonyl,

diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group, and the alicyclic fragments contained in these substituents have 3-10 ring members each, and the heteroalicyclic fragments have 4-10 ring members each, and the phenyl and pyridinyl residues contained in the above-mentioned residues, in turn, can be one -, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, an alkyl group, an alkoxy group, a methylsulfonyloxy group, a difluoromethyl group, a trifluoromethyl group, a hydroxy group, an amino group, an acetylamino group, an aminocarbonyl group, an aminocarbonylamino group, an aminocarbonylaminomethyl group, a cyano group ) and,

VZ stands for hydrogen atom,

C.-C/alkyl residue, while the unbranched alkyl residue can be substituted in the o-position 75 by a phenyl group, pyridinyl group, diazinyl group, amino group, alkylamino group, dialkylamino group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-methyl- 1-piperazinyl group, 4-morpholinyl group or hexahydro-T1H-1-azepinyl group, alkoxycarbonyl group, cyano group or aminocarbonyl group, or when U! represents a nitrogen atom, also means a free pair of electrons or, when

U does not represent a nitrogen atom, it also means a fluorine atom or

B" and B together, when U! represents a carbon atom, mean a 4-7-membered cycloaliphatic ring in which one or two methylene groups can be replaced by a -MH- or -M(alkyl)y- group and one or two other methylene groups can be replaced by one, respectively, two carbonyl groups, while the hydrogen atom attached to the nitrogen atom in the above-mentioned group K7 can be replaced by a protective group of ТRUPU, 29 and B" can have identical or different values and each of them means a hydrogen atom, a C4-C alkyl group o or a dialkylamino group or, when Y" is not a nitrogen atom, also means a fluorine atom and 8 and r can have identical or different values and each of them means a hydrogen atom or a C1-C alkyl group , a carboxy group or a C.-C.-C-Alkoxycarbonyl group, Ho) while all the above-mentioned alkyl groups and alkoxy groups, as well as alkyl groups present in other above-mentioned residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and each m the ethylene group may be substituted by 1-2 fluorine atoms, and each methyl group may be substituted by 1-3 fluorine atoms, all of the above cycloalkyl groups, as well as cycloalkyl groups present in the other above-mentioned residues may contain, unless otherwise specified, from C up to 10 carbon atoms, Ф and each methylene group can be replaced by 1-2 fluorine atoms, - all the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, and the protective groups indicated in the above and below values of the substituents usually mean "protective groups used in peptide chemistry, primarily optionally substituted in the phenyl nucleus by a halogen atom, a nitro group or a phenyl group, one or two methoxy groups, a phenyl oxycarbonyl group - c with 1-3 carbon atoms in the alkyl fragment, for example, benzyloxycarbonyl, h 2-nitrobenzyloxycar bonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, "» 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-biphenylyl-A, A-dimethylbenzyloxycarbonyl or 3,5-dimethoxy-A,A-dimethylbenzyloxycarbonyl group, alkoxycarbonyl group with a total of 1-5 carbon atoms in the alkyl fragment, for example - and methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, with 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert-butyloxycarbonyl group, allyloxycarbonyl, 2,2,2- a trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group (95) or a formyl, acetyl or trifluoroacetyl group. 50 In the second embodiment of the present invention, the substituents in the proposed compounds of the above general formula (I) have the following meanings: sb» A, U, M, MU, X, B2 and BZ have the values indicated above in the description of the first embodiment of the invention , a

B" means a singly or doubly unsaturated 5-7-membered aza-, diaza-, triaza- or thiazaheterocycle, while the above-mentioned heterocycles are attached through a carbon or nitrogen atom, contain one or two 22 carbonyl groups adjacent to a nitrogen atom, and may be substituted at the carbon atom by phenyl, pyridinyl,

GF! a diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl group, and the olefinic double bond of one of the above unsaturated heterocycles o may be condensed with a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline ring or with a 1H-quinolin-2-one ring optionally substituted for the nitrogen atom by a metal group, because the phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups contained in B , as well as heterocycles condensed with a benzene, pyridine, and diazine ring can additionally be mono-, di-, or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine, and iodine atoms, an alkyl group, an alkoxy group, a nitro group, a difluoromethyl group , trifluoromethyl group, hydroxy group, amino group, because alkylamino group, dialkylamino group, acetylamino group, acetyl group, these anogroup, difluoromethoxy group. and trifluoromethoxy groups, while all the above-mentioned alkyl groups or alkyl groups present in the above-mentioned residues contain, unless otherwise specified, from 1 to 7 carbon atoms and can be branched or unbranched, and each methylene group can be replaced by 1-2 fluorine atoms, and each methyl group may be substituted with 1-3 fluorine atoms, and the above aromatic and heteroaromatic residues may be additionally mono-, di-, or tri-substituted with identical or different substituents selected from fluorine, chlorine, bromine, cyano, and hydroxy groups.

In the third variant of the implementation of this invention, the substituents in the proposed compounds of the above general formula (I) have the following meanings:

and

B means a monounsaturated 5-7-ene diaza- or triazheterocycle, while the above-mentioned heterocycles are attached through a nitrogen atom, contain a carbonyl group adjacent to the nitrogen atom, and can additionally be substituted after the carbon atom by a phenyl group, and an olefinic double bond one of the above 75 unsaturated heterocycles can be condensed with a phenyl, thienyl or quinoline ring, and the phenyl groups contained in B, as well as heterocycles condensed with a benzene ring, can additionally be mono-, di- or tri-substituted in the carbon skeleton by identical or different substituents , selected from fluorine, chlorine, bromine and iodine atoms, metal group, methoxy group, nitro group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetylamino group, acetyl group, cyano group, difluoromethoxy group and trifluoromethoxy group, preferably, however, are unsubstituted or monosubstituted with a fluorine, chlorine or bromine atom, methyl g group or a methoxy group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be one -, di- or tri-substituted with identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano group and hydroxy group.

In the fourth embodiment of the present invention, the substituents in the proposed compounds of the above general formula (I) have the following meanings:

А, У, М, МУ, Х, В2 and ВЗ have the values indicated in the description of the first embodiment of the invention, and i) c! means 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl, c 4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl, and. 4-(2-oxo-1,2-dihydroimidazoi|4,5-s|quinolin-3-yl)/piperidin-1-yl, Ge»! 4-(2-oxo-1,2-dihydro-4H-thienoi3,4-si|pyrimidin-3-yl)piperidin-1-yl,

Zo 4-(2-oxo-1,4-dihydro-2H-thieno|Z,2-4|Ipyrimidin-3-yl)piperidin-1-yl, - 4-(5-oxo-4,5,7 8 -tetrahydro-2-thia-4,6-diazaazulen-b-yl)piperidin-1-yl, 4-(2-oxo-1,2,4,5-tetrahydrothieno|Z,2-4|-1,3 -diazepin-3-yl)piperidin-1-yl, 4-(2-oxo-1,2,4,5-tetrahydrothieno|2,3-41-1,3-diazepin-3-yl)upiperidin-1- yl or "4-(2-oxo-1,4-dihydro-2H-thieno|2,3-4|Ipyrimidin-3-yl)upiperidin-1-yl group, while the above-mentioned mono- and bicyclic heterocycles additionally can be monosubstituted in the carbon skeleton by a methoxy group, while the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di-, or tri-substituted by identical or different substituents selected from fluorine, chlorine, and bromine atoms, cyano groups, and hydroxy groups.

In the fifth embodiment of the present invention, the substituents in the compounds of the above general formula (I) proposed therein have the following meanings: A, U, M, MU, X and B! have the meanings specified above in the description of the first embodiment of the invention, and d) B2 means a hydrogen atom or a phenylmethyl group or a Co-C7 alkyl group, which in the o-position can be replaced by a phenyl group, a pyridinyl group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, a carboxy group, where an alkoxycarbonyl group, an aminocarbonyl group, an aminocarbonylamino group, an acetylamino group, c» a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group or

ibis(2-hydroxyethyl)) amino group, while the above-mentioned heterocyclic residues and phenyl groups can additionally be mono-, di-, or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine, and iodine atoms, metal groups, alkoxy groups , difluoromethyl group, trifluoromethyl group, hydroxy group, (F. amino group, C.-Salkylamino group, di(C.--Salkyl)uamino group, acetylamino group, aminocarbonyl group, co-cyano group, difluoromethoxy group, trifluoromethoxy group, amino-C.--Salkyl group,

C.-Salkylamino-C.--Salkyl group and di(C.--Salkyl)amino-C-Salkyl group, in VZ means a hydrogen atom or C.-Salkyl group, while the specified C.-Salkyl group can be from combined with an alkyl group present in K2 or with a phenyl or pyridyl ring present in K2 and the nitrogen atom to which they are attached, forming a 5-7-membered ring, or

B2 and BZ, together with the nitrogen atom located between them, form the remainder of the general formula б5 е ж т и бе ав Р in which

The same means a carbon atom or the same when VE? represents a free pair of electrons, also means a nitrogen atom, 75 d and g, when U! represents a carbon atom, mean the number 0 or 1 or 4 and g, when U! represents a nitrogen atom, means the number 1 or 2,

B means a hydrogen atom, a hydroxy group, an amino group, an alkylamino group, a C3-Cvcycloalkylamino group,

M-(C3-C.cycloalkyl)alkylamino group, dialkylamino group, alkyl group, trifluoromethyl group,

C3-C8cycloalkyl group, dialkylamino-C0-alkyl group, carboxyalkyl group, alkoxycarbonylalkyl group, alkylsulfonyl group, alkylsulfonylamino group or M-(alkylsulfonyl)alkylamino group, or when U! does not represent a nitrogen atom, also means a carboxy group or a dialkylaminomethyl group, or means a phenyl, phenyl-C-S alkyl, pyridinyl or diazinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a metal group or a methoxy group, saturated or a mono- or polyunsaturated 4-7-ene azacycloalkyl group, a 5-7-ene oxaza-, diaza- or triazacycloalkyl "SM" group, a 7-9-ene azabicyclo- or diazabicycloalkyl group, 1-alkyl-4- piperidinylamino group or o 1-alkyl-4-piperidinylaminosulfonyl group, while the above-mentioned mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in the above-mentioned mono- and bicyclic heterocycles can be replaced by a carbonyl or sulfonyl group, so in the above-mentioned mono- and bicyclic heterocycles, the methylene group not directly connected to a nitrogen, oxygen, or sulfur atom can be replaced by one or two fluorine atoms, the above mono- and bicyclic no cm heterocycles may be substituted with one or two C-C alkyl groups, in which each methylene group "9 may be substituted with 1-2 fluorine atoms, and each methyl group may be substituted with 1-3 fluorine atoms, and/or may be substituted with C3 -Socycloalkyl-C4-Salkyl group, benzyl group, C1-Salkanoyl group, F di(C1-Salkyl)amino group, C1-Salkylsulfonyl group, alkyloxycarbonyl group, benzyloxycarbonyl group, alkoxycarbonylalkyl group, carboxy group or carboxyalkyl group, 2? means a hydrogen atom, a C--S alkyl group or an alkoxycarbonyl group or, when U! is a nitrogen atom, also means a free pair of electrons or

In and VK? together, when U! represents a carbon atom, mean a 5-membered cycloaliphatic ring, in which one or two methylene groups can be replaced by a -МН- or -М(methyl)- group, and one or two other "» methylene groups can be replaced by one, respectively, two carbonyl groups, "29 and B" can have identical or different values and each of them means a hydrogen atom, a C-Salkyl group or a di(Ci-Salkyl)amino group and - 15 in8 and KU can have identical or different values, and each of them means a hydrogen atom, a C.i.-C.alkyl group, a carboxy group or a C.i.-C.alkyloxycarbonyl group, (Ce) while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues contain, if o otherwise, from 1 to 7 carbon atoms can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted with identical or up to 50 different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups. s" In the sixth var In the implementation of this invention, the substituents in the compounds of the above general formula (I) proposed therein have the following meanings:

A, U, M, MU, X and B! have the values specified in the description of the first embodiment of the invention, and 22 means a phenylmethyl group or a Co-Stalkyl group, which can be substituted in the o-position by a phenyl group, an amino group, an alkylamino group or a dialkylamino group, while the above-mentioned phenyl group can iF) be substituted by an amino- C--Salkyl, C-Salkylamino-C1-Salkyl or di(C-Salkyl)amino-C-Salkyl group,

VZ means a hydrogen atom or a C.-Szalkyl group, 60 in Y 3 together Kk! by the nitrogen atom to which they are attached mean 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3Z-yl or 2-amino-4,5,7 8-tetrahydrothiazolo|4,5-4| azepin-b6-yl group or

B2 and BZ, together with the nitrogen atom located between them, form the remainder of the general formula b5 t (1) and ion | (0, and 7 in which

The same means a carbon atom or the same when VE? represents a free pair of electrons, also means a nitrogen atom, 75 d and g, when U! represents a carbon atom, mean the number 0 or 1 or 4 and g, when U! represents a nitrogen atom, means the number 1 or 2,

B" means a hydrogen atom, a phenyl, benzyl or pyridinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, a hydroxy group, a carboxy group, a methyl group, a trifluoromethyl group, an n-propyl group, a phenyl group, p-tolyl group, p-trifluoromethylcarbonylphenyl group, p-(3-dimethylaminopropyl)phenyl group, amino group, benzyl group, tert-butylamino group, dimethylamino group, diethylamino group, diethylaminomethyl group, 2-dimethylaminoethyl group, 2-diethylaminoethyl group, 5- aminopentyl group, methoxycarbonyl group, methoxycarbonylmethyl group, perhydroazepin-1-yl group, 4-methylperhydro-1,4-diazepin-1-yl group, see 1-methyl-1-piperidinyl-4-yl group, 4-piperazin-1 -yl group, 4-acetylpiperazin-1-yl group, 4-cyclopropylmethylpiperazin-1-yl group, pyrrolidin-1-yl group, 4-ethylpiperazin-1-yl group, i) 4-isopropylpiperazin-1-yl group, piperidine -1-yl group, piperidine-4 -yl group, morpholin-4-yl group, 4,4-difluoro-1-piperidin-1-yl group, 1-methyl-1-azabicyclo|3.2.1)oct-4-yl group, 4-methylpiperazin-1 -yl group, 4-ethylpiperazin-1-yl group, 1-methylpiperidin-1-yl group, 4-carboxymethylpiperazin-1-yl group, "9 1-carboxymethylpiperidin-4-yl group, 4-benzyloxycarbonylpiperazin-1-yl group , 1-ethoxycarbonylmethylpiperidin-4-yl group, azetidin-1-yl group, c 5-methyl-2,5-diazabicyclo(2.2.1)hept-2-yl group, 1-benzylpiperidin-4-yl group, 4- benzylpiperazin-1-yl "95 group, 4-dimethylaminomethyl-1-phenyl group, 2,2,2-trifluoroethylpiperazin-1-yl group, 1-methylsulfonylpiperidin-4-yl group, piperidin-1-ylmethyl group, 1-methylpiperidine -4-ylamino group, o methylsulfonylamino group, M-methylsulfonyl-M-methylamino group, M-(cyclopentyl)methylamino group, rch-1,1-dioxo-X,9-isothiazolidin-2-yl group, 2-oxoperhydro-1,3- oxazin-Z-yl group, cyclohexyl group, 2-oxoimidazolidin-1-yl group, 2-methylimidazol-1-yl group, 4-m ethylimidazol-1-yl group, 4-thiazol-2-yl group, 2,4-dimethylimidazol-1-yl group, 4-imidazol-1-yl group, 1,2,4-triazol-1-yl group, 1-azabicyclo|2.2.2|oct-3-yl group, 1-methylpiperidin-4-ylmethylsulfonyl group,

3H-imidazol-4-yl group, 4-ethoxycarbonylmethylpiperazin-1-yl group, 1-ethoxycarbonylpiperidin-4-yl group, 4-tert-butoxycarbonylmethylpiperazin-1-yl group, 1-(2,2,2-trifluoroethyl )piperidin-4-yl group, h 4-methylsulfonylpiperazin-1-yl group, 2-carboxy-4-methylpiperazin-1-yl group, "3-carboxy-4-methylpiperazin-1-yl group, 2-ethoxycarbonyl- 4-methylpiperazin-1-yl group,

C-ethoxycarbonyl-4-methylpiperazin-1-yl group or 4-(2,2,2-trifluoroethyl)piperazin-1-yl group,

VE? means a hydrogen atom, a metal group, or when U! is a nitrogen atom, also means a free pair of electrons or

Gee) In? and B? together, when M! is a carbon atom, means 1-methylpiperidine-4-ylidene, cyclohexylidene or imidazolidine-2,4-dione-5-ylidene group,

Each of 5 and B" means a hydrogen atom or a dimethylamino group, and each of BZ and EZ means a hydrogen atom, a carboxy group or a co-ethoxycarbonyl group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, if not specified other, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups,

HF) and in each of the above-described embodiments of the invention, important importance is given to those 7 compounds in which (I) A means an oxygen atom, a cyanimino group or a phenylsulfonylimino group,

X means an oxygen atom, an imino group or a methylene group, / because MO means an unbranched C.--Svalkyl, Co-Svalkenyl or Co-Svalkynyl group, in which each methylene group can be replaced by 1-2 fluorine atoms, and the methyl group can be substituted 1-3 fluorine atoms,

M means an amino group or a hydroxy group

M means a hydrogen, chlorine or bromine atom or a trifluoromethyl group, especially important value is given 69 to those compounds in which

(II) A means an oxygen atom,

X means an oxygen atom, an imino group or a methylene group, OO means a metal, ethyl, Co-C;alkenyl or Co-C;alkynyl group, in which the methylene group can be replaced by 1-2 fluorine atoms, and the methyl group

Can be replaced by 1-3 fluorine atoms,

M means an amino group or a hydroxy group

MU means a hydrogen, chlorine or bromine atom or a trifluoromethyl group, and the most important meaning is given to compounds in which (I) A means an oxygen atom, 70 X means an oxygen atom, an imino group or a methylene group,

M means trifluoromethyl or pentafluoroethyl group

M means an amino or hydroxy group and

M represents a hydrogen, chlorine or bromine atom or a trifluoromethyl group.

In the seventh embodiment of the present invention, the substituents in the proposed compounds of the general formula (I) above have the following meanings:

A means an oxygen atom, a cyanimino group or a phenylsulfonylimino group,

X means an oxygen atom, an imino group or a methylene group,

MO means an unbranched C.i-Svalkynyl, Co-Svalkenyl or Co-Svalkynyl group, in which each methylene group may be substituted by 1-2 fluorine atoms, and the methyl group may be substituted by 1-3 fluorine atoms,

M means an amino or hydroxy group,

M means a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

B means a monounsaturated 5-7-ene diaza- or triazheterocycle, while the above-mentioned heterocycles are attached through a nitrogen atom, contain a carbonyl group adjacent to a nitrogen atom, and can additionally be substituted for a carbon atom by a phenyl group, and an olefinic double bond the bond of one of the above-mentioned unsaturated heterocycles can be condensed with a phenyl, thienyl or quinoline ring, and) and the phenyl groups contained in B", as well as heterocycles condensed with benzene, can additionally be mono-, di- or tri-substituted in the carbon skeleton identical or by various substituents selected from fluorine, chlorine, bromine and iodine atoms, metal group, methoxy group, nitro group, difluoromethyl group, "9 trifluoromethyl group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetylamino group, acetyl group, cyano group, difluoromethoxy group and trifluoromethoxy group, preferably, however, are unsubstituted or monosubstituted by a fluorine, chlorine or bromine atom, a metal group group or methoxy group, He)

B2 means a hydrogen atom or Fu phenylmethyl group or a Co-C7 alkyl group which can be substituted in the o-position by a phenyl group,

With a pyridinyl group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, etc. an alkoxycarbonyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, an acetylamino group, a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, or

ibis-(2-hydroxyethyl)) amino group, while the above-mentioned heterocyclic residues and phenyl groups can additionally be mono-, di-, or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, o) bromine, and iodine atoms , metal group, alkoxy group, difluoromethyl group, trifluoromethyl group, hydroxy group, "» amino group, C.-Salkylamino group, di(C.--Salkyl)uamino group, acetylamino group, aminocarbonyl group, " cyano group, difluoromethoxy group, trifluoromethoxy group, amino-C.- - Climbing group,

C.-Salkylamino-C.--Salkyl group and di(C.--Salkyl)amino-C-Salkyl group,

VZ means a hydrogen atom or a C-S alkyl group, while the specified C-S alkyl group can be connected to iv. with the present in B? alkyl group or present in B? by a phenyl or pyridyl ring and the nitrogen atom to which they are attached (Ce), with the formation of a 5-7-membered ring, or by B2 and BZ together with the nitrogen atom that is between them, form the residue of the general formula in 70 (ое сб » ion (0,

Residential complex / . i o sk, be de "y m 60 in which

U means a carbon atom, or when B? represents a free pair of electrons, also means a nitrogen atom, d and g, when U" represents a carbon atom, mean the number 0 or 1 or 4 and g, when U! represents a nitrogen atom, mean the number 1 or 2, b5 B means hydrogen atom, hydroxy group, amino group, alkylamino group, C3-Cvcycloalkylamino group,

M-(C3-C cycloalkyl) alkylamino group, dialkylamino group, alkyl group, trifluoromethyl group,

C3-C8cycloalkyl group, dialkylamino-Co-C7alkyl group, carboxyalkyl group, alkoxycarbonylalkyl group, alkylsulfonyl group, alkylsulfonylamino group or M-(alkylsulfonyl)alkylamino group, or when U! does not represent a nitrogen atom, also means a carboxy group or a dialkylaminomethyl group, or means a phenyl, phenyl-C-S alkyl, pyridinyl or diazinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, saturated or mono- or polyunsaturated 4-7-lene azacycloalkyl group, 5-7/--lene oxa-, diaza- or triazacycloalkyl group, 7-9--lene azabicyclo- or diazabicycloalkyl group, 70. 1-alkyl-4 -piperidinylamino group or 1-alkyl-4-piperidinylaminosulfonyl group, while the above-mentioned mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in the above-mentioned mono- and bicyclic heterocycles can be replaced by a carbonyl or sulfonyl group, in the above-mentioned mono- and in bicyclic heterocycles, the methylene group not directly connected to a nitrogen, oxygen, or sulfur atom can be replaced by one or two fluorine atoms, the above mono- and bicyclic heterocycles may be substituted with one or two C 1-3 alkyl groups, in which each methylene group may be substituted with 1-2 fluorine atoms, and each methyl group may be substituted with 1-3 fluorine atoms, and/or C 3-C 3-C cycloalkyl may be substituted -Ci-Salkyl group, benzyl group, C41-Slalkanoyl group, di(C1-Salkyl)amino group, C.--Salkylsulfonyl group, alkoxycarbonyl group, benzyloxycarbonyl group, alkoxycarbonylalkyl group, carboxy group or carboxyalkyl group, 2? means a hydrogen atom, a C--S alkyl group or an alkoxycarbonyl group or, when U! represents a nitrogen atom, also means a free pair of electrons or

In and VK? together, when U! represents a carbon atom, mean a 5-membered cycloaliphatic ring in which one or two methylene groups can be replaced by a -МН- or -М(methyl)- group, and one or two other CM methylene groups can be replaced by one, respectively, two carbonyl groups, o 29 and B" can have identical or different values and each of them means a hydrogen atom, a C4-Salkyl group or a di(C1-Salkyl)amino group and b8 and KU can have identical or different values and each of them means a hydrogen atom, C1-C6 alkyl group, carboxy group or C1-C6 carboxycarbonyl group, and all the above-mentioned alkyl groups or alkyl groups present in the above-mentioned residues contain, unless otherwise specified, from 1 to 7 carbon atoms and may be branched or unbranched, and the above-mentioned aromatic and heteroaromatic residues may additionally be mono-, di- or tri-substituted with identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano group and hydroxy group.

In the eighth embodiment of the present invention, the substituents in the compounds proposed therein are as follows

The above general formula (I) has the following meanings: -

A means an oxygen atom,

X means an oxygen atom, an imino group or a methylene group,

Mu means a metal, ethyl, Co-C alkenyl or Co-C alkynyl group, in which the methylene group can be substituted by 1-2 fluorine atoms, and the methyl group can be substituted by 1-3 fluorine atoms, - t0 M means amino - or a hydroxy group, c M means a hydrogen, chlorine or bromine atom or a trifluoromethyl group, "c" c means 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine -1-yl, 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1 ,2,4-triazol-1-yl)piperidin-1-yl, - 35 4-(2-oxo-1,2-dihydroimidazo|4,5-c)quinolin-3-yl)piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno|3,4-«1|pyrimidin-3-yl)piperidin-1-yl, se) 4-(2-oxo-1,4-dihydro -2H-thieno|YZ,2-4|Ipyrimidin-z-yl)piperidin-1-yl, with 4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diazaazulene -b-yl)piperidin-1-yl, 4-(2-oxo-1,2,4,5-tetrahydrothienoi3,2-4|-1,3-diazepin-3-yl)piperidin-1-yl, ) 20 4-(2-oxo-1,2,4,5-tetrahydrothieno|2,3-α41-1,3-diazepin-3-yl)upiperidin-1-yl or c» 4-(2-oxo- 1,4-dihyde ro-2H-thieno|(2,3-4|pyrimidin-3-yl)upsheridin-1-yl group, while the above mono- and bicyclic heterocycles can additionally be monosubstituted in the carbon skeleton by a methoxy group,

B2 means a phenylmethyl group or a C0-C6 alkyl group, which can be substituted in the o-position by a phenyl group, an amino group, an alkylamino group or a dialkylamino group, while the above-mentioned phenyl group can be substituted by an amino-C4-C6 alkyl group, a C1-C6 alkylamino-C4-C6 alkyl group group or (F) di(C1-Salkyl)amino-C4-Salkyl group, where VZ means a hydrogen atom or a C-Salkyl group, in Y 3 together Kk! by the nitrogen atom to which they are attached, mean 60 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl or 2-amino-4,5,7 8-tetrahydrothiazolo|4,5-4 |azepin-b6-yl group or

B2 and BZ, together with the nitrogen atom located between them, form the remainder of the general formula b5 t (1) and ion | (0, and 7 in which

The same means a carbon atom or the same when VE? represents a free pair of electrons, also means a nitrogen atom, 75 d and g, when U! represents a carbon atom, mean the number 0 or 1 or 4 and g, when U! represents a nitrogen atom, means the number 1 or 2,

B" means a hydrogen atom, a phenyl, benzyl or pyridinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, a hydroxy group, a carboxy group, a metal group, a trifluoromethyl group, an n-propyl group, a phenyl group, p-tolyl group, p-trifluoromethylcarbonylphenyl group, p-(3-dimethylaminopropyl)phenyl group, amino group, benzyl group, tert-butylamino group, dimethylamino group, diethylamino group, diethylaminomethyl group, 2-dimethylaminoethyl group, 2-diethylaminoethyl group, 5- aminopentyl group, methoxycarbonyl group, methoxycarbonylmethyl group, perhydroazepin-1-yl group, 4-methylperhydro-1,4-diazepin-1-yl group, see 1-methyl-1-piperidinyl-4-yl group, 4-piperazin-1 -yl group, 4-acetylpiperazin-1-yl group, 4-cyclopropylmethylpiperazin-1-yl group, pyrrolidin-1-yl group, 4-ethylpiperazin-1-yl group, i) 4-isopropylpiperazin-1-yl group, piperidine -1-yl group, piperidine-4 -yl group, morpholin-4-yl group, 4,4-difluoro-1-piperidin-1-yl group, 1-methyl-1-azabicyclo|3.2.1)oct-4-yl group, 4-methylpiperazin-1 -yl group, 4-ethylpiperazin-1-yl group, 1-methylpiperidin-1-yl group, 4-carboxymethylpiperazin-1-yl group, "9 1-carboxymethylpiperidin-4-yl group, 4-benzyloxycarbonylpiperazin-1-yl group , 1-ethoxycarbonylmethylpiperidin-4-yl group, azetidin-1-yl group, c 5-methyl-2,5-diazabicyclo(2.2.1)hept-2-yl group, 1-benzylpiperidin-4-yl group, 4- benzylpiperazin-1-yl "95 group, 4-dimethylaminomethyl-1-phenyl group, 2,2,2-trifluoroethylpiperazin-1-yl group, 1-methylsulfonylpiperidin-4-yl group, piperidin-1-ylmethyl group, 1-methylpiperidine -4-ylamino group, o methylsulfonylamino group, M-methylsulfonyl-M-methylamino group, M-(cyclopentyl)methylamino group, rch-1,1-dioxo-X,9-isothiazolidin-2-yl group, 2-oxoperhydro-1,3- oxazin-Z-yl group, cyclohexyl group, 2-oxoimidazolidin-1-yl group, 2-methylimidazol-1-yl group, 4-m ethylimidazol-1-yl group, 4-thiazol-2-yl group, 2,4-dimethylimidazol-1-yl group, 4-imidazol-1-yl group, 1,2,4-triazol-1-yl group, 1-azabicyclo|2.2.2|oct-3-yl group, 1-methylpiperidin-4-ylmethylsulfonyl group,

3H-imidazol-4-yl group, 4-ethoxycarbonylmethylpiperazin-1-yl group, 1-ethoxycarbonylpiperidin-4-yl group, 4-tert-butoxycarbonylmethylpiperazin-1-yl group, 1-(2,2,2-trifluoroethyl )piperidin-4-yl group, h 4-methylsulfonylpiperazin-1-yl group, 2-carboxy-4-methylpiperazin-1-yl group, "3-carboxy-4-methylpiperazin-1-yl group, 2-ethoxycarbonyl- 4-methylpiperazin-1-yl group,

C-ethoxycarbonyl-4-methylpiperazin-1-yl group or 4-(2,2,2-trifluoroethyl)piperazin-1-yl group,

VE? means a hydrogen atom, a metal group, or when U! is a nitrogen atom, also means a free pair of electrons or

Gee) In? and B? together, when M! represents a carbon atom, represents a 1-methylpiperidine-4-ylidene, cyclohexylidene, or imidazolidine-2,4-dione-5-ylidene group, each of KZ and B" represents a hydrogen atom or a dimethylamino group, and each of 28 and BU represents a hydrogen atom , ka 20 carboxyl group or ethoxycarbonyl group, with all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted with identical or 25 different substituents selected from fluorine, chlorine and bromine atoms, cyano group and hydroxy group.

ГФ) As an example of the most preferred compounds of the general formula (I) given above, the following can be named: име) 60 b5

1 nvjur 000 SHSS/ ts (0 l KI i z. BI,y, statement cm ivz yav kyy otv g I shk Ei nya Pe py VK v v v zuionn: J dyi ! zu "a kisa tin sk 2 FAK LI Z, Ka : i I. ! I su M fev o s y la, tega Z: br ne hosivytrvth oi JAK 4. | i . give Na ke p. y 53 i OO NM LIE 3e ek V shchi 1 | Baki: Y Y | 4 9 KO и и В : rev ZY pnia I veralakh iv ge cha

A -Y zea (nyu -penore zn kinnchvya ! pre v a z li y ia;

E ko M DEN NT IN EN; brother and

In F; ! i v payu Ye e pre yadre tt, I nayaoliv t y

Shk her: I ih hi I and I NI I dev, and Y | s ah tsk pyvu b ke iy sn se

It will be published in the ar» o

I... i re di tva KAN tia NYA Mon y Pe 1. sya ve , i: I Ж pn y E (ze) (ze) (is) o - s - y? -I (se) (9) d) 50 s» ko bo b5 g tent | I s mm -7Ooosh 1 zarukyuh 2 them, y х i what , and y r Matt: ze: seams EE VA t: poses o and s zh KA E shob; folders Ra Path yav: kori: sia . ak! ol ery d pi TAY". : her "will come" : re ashye Hygipereuniki Zdibutakni A virgins: 70 i-y

LIN Zh ad. y y se re g y DK ANNA LKADY "hot re teme pitve jalyn ajano wife 5 Where: Mch Aktiv a vinnaninYa.

E " even in the journey of Ya. Ku. E. sfeude u she : a. And there is etvy z iv vol VO KI NN NN dl idie that ; и : жк 4 m пий ия илишперцлие "ай тыпепачины" ищопговажаетоты овивиня "и І ш Ш Sho і s

Such and such. ethylene or Ge dami zli n eq 'He)

Gu. upuchivny Gpriytormetklibovvntni-okov-GYA- (3 temples Zh.

Sha. ve as PIV white nn » 1 horse Mon still and 6 masons same: ZV TT SHCHA p. sv her "and you are the ussr, dr o el "'

And more shchi zhigidya A mih ok, skal utryen y y- yod "still She 1 tiy pre y y Vey toverat i tone i a Slkiy yu ISAYI ma U, " KU (4 mine Zkhlornya | She!

I R dk; pro ota t B vna va y R "z ! OH. szhioyniai will sit in the var svi MEZH stv; v . "and envmechtni: Live. r. sho sov y rech net pt rev " And in I to her still YAVY NIgiDoV- Beta Vi Tva, Pi. mouth forces pk t kzhnisto in eight m a a t A yadnya zeoyatv otr tyka pet p - s-silyllnysya dod y "Eternal EE I and (se): or r. Z de M vyaschel ts vinky p I This Ж ж ж I and : I

OK, still valid wedge No. col

And Be sirnu 7 ' a a LY and in vsark iy fan uva. se v a Sh, che tyk y v pe Biy vni ko tt . : SYA and zadi din from evryvnovy to wash. , seti re t ih eitzhisya sa t shkh kt

Y ' dn - that gra kt NI KE, THAT I ge ek of these and-th.

Because; i I i Neurons (F) ! how not What and zkegmittv and, in NI Vski vshh ev: EK and. The winds Затв Б н! OS re INA KY 60 b5 i. Ibtruyuura 02000000 No

Ed NN Y . TK-ichiY - NOYA zv, She

I ee t. She ta 1, i ser t K re ;A I b "a z M y ii r. ie SHE a: How tati hryadyn -y "ili l peri, : SA V nia kova I A I tetu kridroyuki Z begkudiachennYak ik p SHE and y oaistai. ih EV s ia Moi that mk shk she oo SCHI. NDO Sh, and AN LYMAN era NV s shir; zhk: kn y v! Z : i y "CHO -ulyaschinya a za se price vk

SYA, wai zneritstoradety len ve (I state

And and about Ky and IT and and re loop Z BeclidinetneYA VEK, ZB PTS How, . she and I ai "SHE. armpit nak: кр я я 4. I What I stitched I eh Still uch, I, te 6 ik y | I spend money on cows. še Zponnjureinja "keribinnisnoi kablyuti" In:

In yes and I and. NIVI You and I about DI EN ZOLA"

Ye ey she eriakv kinni o rn: and I --a OTG Y ! all I gohik I M, kt ry HE NIM ayu, St. 1; 2 J in -I bake VV KI OV I "He. I; not eat-her ote V. in VYY

In approx. shi son hi Where is your teh ku t tt a sh - no

MTZ you Z NRU amyoz-kr-U

Ш Z ж. DN: and What R Still rods, I and no Where: p

Y r What ve EK valin y e te 7 pasiv Me tv shk, i y "Y zho -Z y y y sey Z g S s tan, VIYIYAK hu 3 t AD; VOLUME I es. EAT with a. (o) " yo Ve A KT. ply sia E edsh r ssha ske a adnke I ay t

MAO in Iovsost fell 4 losheoetrainyu- : in p: - i. : growth tya to NE, e s V i i dr no siv ot VIY v - 5 1:52 I pove UK U PI a A kova: t ili ch2vh kude nishk MN fr re rya sni nni :E I. and still E r I read sya kt nya: s v y ila 5 ih A, y. Me drawing Pot. and would this "and I - so same Se and - r ut then: tk and iya kl, II x g. 7 I sla -KI: 21. a | M

K - d Mia Y n sni yo e N y e K. KE and - Etikh or g E.

In I ZK Poliv amino kyu. "

Y - t LIN OVT Za oi KE SCHE SCHE her" - a y a i: p von pyv y doioeink vaa ZAY -h rik, shiya yana IN-T t oKocet y I YaveYu k I she: WE: MNYH Where are WE - I I: VD pineapple Z va peven i I . and. is" Sho me YN NN NI Nil nn NI WE

Ou o ak g Y iy ikh dk Z ns: se you still N

Y sho y svi PNO NMT KI yan OD E (se) ie sh: SHE TYA A Y snah st m BAKI V orotic SHE MEDY I I. E o still y. and KN sake Bere al Desna OA LE DAE

ГИ 50 Ot I ko atak di « ii: forests - 1: sgsmnnyi l these balyuoi:

S M zh at V "v t i - -i Chai "i Gngl M -EZ what cha IN o i

And with in for OTHERS and INV; what Oh my gosh y, 11 But i same, p i o She: Z ak o: But I ZNO. I. because b5

: "ND j GA na y - i ; shk VE: ; tsi o ki V. Y Shchy Ki se t.k y i tse (a SO "Aa. , v n che TV. zhk p, Z se shyi: shi polyn : IS

Hey niv eesrvnidvon tn bertyadiyezeshchiv, Z-i and zhrivkany

Z m. "- Y ! NI ON ved at TE. not av: vi. Y.M Y . "i-iya s.vtsynnI In tyazim, situ - - g Yaniv t olynint. high-quality foam. - y sty already t Where and Ye aa -k t n : as and as with - t: t, g e ' her iya naya sna yav; in. and I too! sa ii t Abipiporydianil and zb okosoatiemid y 5 SNOM 7 |ndooetyluvlkartovi y shki dev (bananas 777777 that, Still fe! k sa NIK GY I) and "I-th. go DK yongich (a ly psy v nie oy i i kosatana Osad. nn s: UVOuokredano and tys i 4 zhovshi b di sni koyu tya ke dvy SHYH she y What py a those m i de Y i y y. kraniv iy: Z 7 y. "De UE. SCHA S | t 0 ziri p poda IS ID ny kov V she BO tk u Shi ED B : sya roni y ; a. - kimi: Ia pibutii ila. I pn: ZY SHY Mishk Sh: shchi: also d. thrifter acts I: nya Kwi ki d ig tetu 212th vet, p

SON M NOVO A tetrigykniy-

I'm not a saint, I'm a woman, you're not me, SAUN. And Ge)

In y; . I THOSE EYE only I'M IN FASHION | NO NO Yes in Not what; i ha i- i Zv ad i, J. I i fa ai ZK, ND NI euro WALK KD I ; I Z is and S goes r v -v s m m crows da 5 nt ragi Dr I I -penadi avt i -. |BOpinerydts vk bu these you -I «i KOL rysi Y z y i y V p 1. Ve Oy dl Ann Ye E SON ; | y r ;, s 7 ky Cha Fri Mon y. KODChe pn IN PEN Hey i ih n y shchi dk i kore i che; pay pe and and rhetor and sec inii yin E in y; o Yi sh shk y ka, | and her zm: vi and v. m k Me Gay; L) g TSI p i schu Lzhy vi aschoiikh s" ben ee SHY FV DI a zhiya Sho viya yun sk sa lu y y v dn vay Ye ШИрЖ y Iova She sen y pod ENN tv, vi t -Щ 1. b sik. yes

GF). same ХК) ей За ство вv: zpiperidet idu a .. in I and B them! " ne fe y r still d still vu I

J DK and TYA, beletragiyaro" slang No: name) and. Night TV "Zhk voynkh is still calling for attention!"

ШЕ s y 0 плей а ува Де ! - -Ho KB Bll'yas" nyshishamniny person. we. significant mcheiasyal these went? Break me.

W KE av TYA s ne en I M OZ LONI Te |. | | Y sho B y Tsya ia te K|: in Vit seti li i-yi JHE re : zn U se SCHE (I me; V ED ak TYA y

She and и и ачия ха tA Zheni; half of the ZhK shiya, zr thx 1 ex VI N y

N liy ay 2 h ts Ta z - vv asla. Noah's neck is still there

Shk EN 3 more parts M thread them NN YN; read A a diov 4. cha | - Ne CHNYA p Io LEM ze dance EULYICHNY yannia CHIY s che Konni nys nia e di 70 e u. | DE I EK and dnk Ya a slba ry and pesen r a ZK ach oshoshni Z I bosuvnashini Z. " ; in and I IS Uk SCHI IN THEORY AND SNU DINA. -x 1, ly iperidinei: DE deya shchi and in lish GU Hydotiyu twitter days lndyov 75 nya i - Z: sei ry; reank ze M min finy a and I i st u ! "Y eoaMK; kuki TI all I te oalujhe ep; stylists)" ; Shchy y bi pamoroz I ounce and s and: "And and in. and I, and eta with Ya. t and syu, still that and . iy de shh sho ch es as I Ya

Sya 5 yr. sn Kol he sai KE Me u it Vitya May BOI: c) I ryy and Shchi S poshavryadin t zi routa in A yayu ! I . that and V

SCHI Sha I la u iv pn piny same this kose zaz k-zy i ii V

I ІІ and 5 are in ЖЕК і і. Ha eV r: NE TE, and "-4 and her PEN Y tea:

Shu | and: caution women in ТЯ oshchorea"

І и я лин ж че еВ сн 4. і Ш M бы стіре і Ше t ок A ІВ E | and)

TK | live y yar g a "ya yy. Ye, ye le TI Te - To m | so i I a - still V I EARTH stat tady t IN t Vo Nut 1 y shk (I tery J exit, Dan IF ko si Nadam cy but and ano and a variety of idiom and:

I van - Shkshe, Hanya IY deco la y sedya: falakryiny kt

Di ShK M, sh g cho ato uatdrunyaaya ,

Te shchi - a 7 n zi still ty ty, B E o Koka i: re BV IV i ' 3, ii. three Also and I In and. 1st "

In ko i rily I and tests: EH I and children and ; : Kk Ei z and E z Z YAK. ' se ch and some M -

Tuya Z te I I Wu IY sti: shk in ih DNA. nyk Re Ya Y "» GO) vok.: ru ia rizhi stan tka erzhi V gai v KK V Tl di de ie EV De OVO yah y 45 . and them: "PI in, per nii o rkh loyu You. nok B: I and Tk as a director of KY. sa RO ONY p. 6 and 7 | shrutvn this vov: from sa same "in " TSO can por a iftormethylovu-vet pil hvy 1. ; y In inv vn id age neti Ii. with p I prita ve. mu 20: Ek Y che "sa NIY sy vyk dv s" a Ky OAE pai, rinsttdnyaei i kn: i zhi Y 22 IC | | M. shk ish GA i Med pika ak viy i LE yag Y I myt g: ke s : o 0001 Genni 1-1 and nvnliyuya TK I och GA ko I I; "Y, SHY G.V y ren tsi tia PAN Y gri Mk shi: Y ; DIV v, drained alEv-1- : bo I sia I p I: b5 page ura DK NKKN

On S: B lot soty nn nin ni zhi i

HE IS NOT WITH EA! vu l I zi KI i Yak ra DID A ZY, " ry Vl what S y i yin Kto iya I braided y ! and S i aa s s r ha vk? KE: what I. E y z o tega tdneya a she d s De De CY IJ iya KuUmy- : , : ; ni v i i to ut E "Dn, U no aorty Or vna : ki Ou nat avt sl ini: kvi i

Y. zak zt, dyk, ! And Te UMA DN MAO SIDNI N nayra , si bo zol yak a sunny iti nan DN EK DN VADA: s

SCHI M ONA AV ar VV EM I

I І - и и І 4-5 Su Ak in nev V Ne | g: - yy i-y yad des 7 ML Ne DZ ON WTO I-y. More

SSS uyu neni inrnzhei i

KE: "he shi nyny: in tus "ogran rya sly sor nininnininnnnn nn ks chapitiiipiAMinnn zaitinin ele G. u i . Mnya vyri 1iE': 23" k E) klutrya a zhov oh peak: UK and oi and their a uk a azh t k n ne Ya A s a and 4 th SUA pak zhi i AES. and You and I 0! k. 3 In: A and r.

I and se Kl Still have 1 her those. ke pniv ucha svani soya "v he er y I still my N.V s i t a Vin Ya inn : ZV y ana ivan nya u 4. Esh sha. av pov oo sli kp Wiinni vo dolzh M ko vo z pe DA vet ; tuyu io PANE VIV il "uk SHI Y ne MD ie pettnakttu piyich nov SHY shchi shchi EE and at ped PEN shi prze yy V A I I. y zd chili ni lecho ale ! schu E ZE ev, pi ey om U LA RY MAYA mountains aye-ki 3 5 V Ge) . OK WHAT ih. pd y De AD yavy i. - dv dya y -y y s: i o 3 | Chek I re pet U d y . ESCAPE CHYN vira E B. y iya d kA v - zav « ' o, Ps r y iizzha NIKA Took weight DE KZ ik h

НИ: chl Y pe EN Z M u TAN: Dy t to which I k tak v ne: nyts pip uschtyindi DA s: sg VI

Ka zbu VNI pe THia puzzles to her enter. that I her - j shi - yayu a M cha me shk shooi y I y, yy and 7 THIS I y (Z -eminesi-yalori generic, si ko ІІ NYA - іі. my g « g v Ka i ; How ry hg : zhk y y y Yaryy ra ne. from pride I I: Й g shsh s Й a. -k я le Janv osv pov on. V. y she E so і і? H wo schoj I ml) zh TO a her. Where "nn u WRITE SHE SHE V I . ze ce Lk i yav Yes DK LI ROL A ELE WIN VOM Cadre cre da tsi -I | : I Where I S. va and yara sho and you I a EVANS Bio krekii - gaz Be zha ii i Y s. tu: t Voiliy ch she WE IY beleni zi i she YN I OM: z y y "ad y y y y t oso I: Ka I know. what tv. ' y pnia sr s No Z o i Ka I E Y yani pri: see: pryu ki: k.e sli ochvi so: VAV te | zv yo DeK rez zindiy: rmy iklo you. it is not necessary to go Ye ko : K y t I lo sh 4 i tav vi KO i. sit Ek t , y z ukiy Y za, CHI , Z Zh snevoya "DV g. ZY: gne y y vos R de ku 5 Y.

Fe SCHO U z B nah tya B tey et o, Ke oh ah SCHA NO Kg: chu MICE u I . 99 g V: I shi Y vo yo Y tiha ov kish va yy ii zr nazhiti tt Y he Y o Me ek ZM (ikhetnyapileridnt y idupiperaziv i Dey ; roya y id ME dva p U Yad lita in the ward in: pi : ko ! ay "v - Yar; KA. I su What else. Yan z and chi, PE Tykh V SA kon SCHE s r, 60 ; M POPY SCHA ven y Y y M ssh, - : b5

Class DE OhA of the 7th y j a n y (y is X, "A wn siv vela krmii is s y | v: r: ShK Ma tsyk A" z en yod. v sa-taa V iyav uva ! more " ak that give her and those zr in days and: u - sa

I and a, 4 7 V or, po VENI inYay DOL noi Gaia ko

B; And no tv Ba i t roti: in e! and h as in She Ya ER Sfny. And. ; I'm going to go with Kei still gia zt yo schu. : tet and oh : tse: , shchi I lir ' HER J Ei a: more Z Bk 11, and yaz pu v. t riv! and no e a ' | Duke; In what is and how and how! geni y s I Pan y I s uv, te iy nty kit y s

M nizh i shk y pe se ha ay pAkdai d B niy AK " sn k yo rak stva povnsissoas Y v. y A Za (bananas era t tinenin | o aiv Sh 4 Dy znesche-tol, Basetra native g Ol. ov Meznaineayny Us tennni i o chan 1 frame y. a ey TT. r, y a y her b. n. -y : 4. and t t is Y I I - ! and t, y G

Ed DY a Ve Kk I call her nn

She ay: SHE so pri Wu DNA ah ro A Tu "eta ik, I .

M zh - zve ONY a PYTNA Sapr AAVNA Tsai sl Because I Mezyki zhi poshi them "cha ' y AD VE, B uYA ki UZH zhi t tva! TI Shchne sia VA IV I forgive and sko and acti y, 1 salt AJ ore with

Iii , "li TI SON kana i Vestik or: vo i IC vi ii ZHAN Ban i I ! as so Za; 0 RN in the university aa DE I EE I YOU . 7 SYA shi pe a At y z s ssh Sha rya pa mk and Sy" 1-1 Kamagukaniov t reno

F y Goa a ia ery Airborne Forces I ko 20 t. g! still ShK what is happening with Kania and her 13. p sly peVtri . TI 7 J ot 0sya si i 41 that se» t Ies an R rad i "7 Z 7 mk, I dizhi ali, o I

E and I She shk and OKya t m I? t; three of them; THIS is a dream: the 7th MW power plant in the 18th century. Poison SN pere Y 22; N. Y. ve TYA and cane. of DK si:

GF) 7 - in: inst - pyaz IchaRh LOW ze 5 VyzlySvshe ne Eutsshchi renta sleep no nyu ko bo b5

Ge sg a ; ; - and | eat the son of EN and PM ON NE NAO- |. 95 M x i. ш- A, t. ш КУ ДИТ D DYCHINY" Bi-:

And according to Kn: pl M nih NYVA A OV shk o. deno ushtsia - sleep of an owl, my widow, what Ya

Konya B zhk A; a Yany Vk nan nan pat tanya |, tya ne an eamikny siy "trytor A Na r. y I gu I y y ak and how Za ry vodo BE Y v. s. y Sha Ege vrokiv, Y "ospntt, y y valiv shik Z B ven Y "a b shchi y Gai Gah RESHNA te A t: chem zi" Shk 3. ii IE a R NA , y z "Kl ia. is a verb:

Ky I enter, svi TANE Ytzuat IC za-duov u re, yar Seya GARDI "I a DY por OVT g ; and; i t i y shsh re i still g still Ok : ia rij u. NO action 13. :

Sha shpak ni "DY Hera epoch is all like: VAN OV

What are the actions of schools?

I NSS and an, IA proaetilainoetinupinery dan shchey 7 There is V "Pii aa KV U "kg dehai,x a Vs st Vir: koh kiv: y : y a lines al CHU Io ! more g | х b sne y se

K y y SCHE: schi Z what s KI v aa y y go y y y y y y y y y losses y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y ugh! and m bend ke ki ia LOW viv n nknii 1 Tr i .

I tiv - pt. N il RE DAY y Y at as still yad: PI y r. y ped VAN DYN OV TO ENN ;

S. shi still 7 (o not and sleep Pozhai Na ki gr DY LO Er: 8 - I nou and I E Sho dvi Eh nya ze intetragdueh 1-4

I | YOU ARE Ge. sv pon te Y. TE re: her and Yan ti and hi. i :3 In c. Me REIA and Ka and I. pt with PE ZB i and ke -I , and K -i . about ER-h A M PI and ge and akiydyu, svy v'kri re; in the mountain of scrap with 50 as a t more o zn more Y - y y ! Hey e: be N. and ' IN PIT | t: ritya. haha t p Piy zhk K. and ih

K Tv Y t y y y chu svv t Poni. parts and I and I: and yaya petrue tu and stimkiviy M.

Y Ksenia Still stump S i ve zhi iys still ZY 55: y r; For ME ХЧЕ хІ І сн І SE ШХХ Malinu: p and І

E (In Zh. t Ya. ki: . y g ay ; in ras that so | and zi - za. y

GF) : TE "in Z nuyut vit. St. HO IN; Pn I and sei: lai : ka | Already Yani V. was bleeding from the wound. because E. M. vd and AI! : : ko b5 and STUK Yaki: (BA , I rush gchamino Znkporberiftoye ev kin NIYAK y Ka shh y S» : | ! for Ve iili peri cy i: zak, and De di che

I. o NI Key ak z Shk piBlLa sk le zdiy o How Z Zak Be miki tet ve Yu yakke V TE Krah I: Z zp niiperi nin AL puta (fu ps E - t i v lk soni Neo ! 70 V AI !

What do you learn about DY and the Day of Yav B sing a new song to Her

Ши ей 1 et обов основ ДЯ, : Z 7 shchi: ". y Yana ET ; ve "y Viy yi Gb he I -ya Nai Re I sce K y y ay I y y fe : 15 . y s MO) ШЧХ shchi НЯ 15 се.

J. ps yo fashion MN; the same. g zh I ay banya vel ZiUnitreUVie E B irivtt '

OV Hi Zk zak tega young 1 her Ye KI ' | che ha g V di still ani x Ge) ele sth ШЯ yah okon won 4th sanu ZSh: v. and | IL DENNOMU "EK vn svi Mi i-y, se ne, U Ge) in zd 7 and den vavdst tyny pai o popi (E y y DA ny vla MDE BAD vyY Id I I se ta . Щ ЧИ и и М. E Gi tn same on t l dya ik

NN I trifluoromethioveniniu which are obvious

Zo y I: и и ЭХ no M НАLYеКВМ not - s kl vin o vn

IS ; ve , you I-extinguished BA on Shchi | Y I « t piva p pak - nya ie Prrtrev vid iv i vy z ZH I ope vav y. Che i vya s: A n s y. and R i y Knyi Ved svya, TYA zet Vya tsu Ma; : Y. Shi Al a. TA vno DA ote zhyuyi I" 3! »! y o oo chav s pni kin M SHE " ' : i p v Ek TSI VI ATS GT Opbutiini. . and shcha Z yiv eyi ! ,

V i i I) I that V TU dos sz aud MI state sli peril t I R ai o Chic . o Mans's CHIY and KE punk ak. nay g t NI Go Po N Y ime) (U. IDE svke M sya V NU i s" : ; r Y Z

GE z i ke eerovitstk m. konyu vo ta, zu: sik iy 4, pasvydinim nevy kivny. ! where Yi is also swarm as ED zv. flows | And And what And I shi and 60 Eng: kikplnilil lety saws; pe pntintn oinirnyni pri kaninnnny "tnit nchninych i b5

LYKU NI - I'm gray:

E S Y I 0) and; AK lir cereals PTOPMETY I swarm 9 | and in Ya in M. in g o in; I'm doing the same with KK as I did with Yani and brozhsoe. tk, i i , - g be i I ions Z i u i. . 4 s yer Ke, NI ze : Z I Piny SCHO p tii vu . Not and Kz n ts m St o sp Schi and vozhen still I with still Ua ali ee rogo: Y Feddym: ket pen mshelyki even under dk TK valin Yanko NE a iv I nok svo nir kv nenasnny

Gays "For her and AD ME" Sm y pe TYPES" ! . vii. t . : nn rea Ina a ETHNO

KE zhk y y : in iny y y y nd isee t ti her as ant Ж: B, y 1 KE

I am the most powerful titans:

M nick I am different from others

By: 5. rom Z i y y de pa a ay yiv M, dev E; si and tv ( EE. rve a Kk za : kt! on KK; le 3 Id zlii -m you ex « g s i in V (ry and Yad; і Y. E t N NU siy

And Zh. ivan i SHY: sy, and Yad ieverlyaro- 1st. , and I SHE and I kizgy sik ve for Ka tk ee day! k) fats t No. kt KI and KIT their co

And also 5. Seh ish div s

ST t "o and TIN po Ei iy g 4 I Noya them E I a ; NI t i AT fra sche -k i) : SYA uv Z I ! S with and for what THEY I sr sk KA (and longing Ge" !

With | y a Y Z y v sia v i y slave. The child is E and I 1, iv om rK: V i h-

Z и ях, и EE len Bk (Y мне я чн s 7 и и- GU ой - s, и; и. и бити вирв з з рок MAV sk .

N ssh table Zk a: zi Z o. those and U MRRY HASHIDAEaek. zay Another 81

Ge) , eat" tea bksni DYA eto ZAD yuyu shchi LU TYA in i 010 nia y Ya r noxoki Db ptregid sya : y y. y oy: cha y! WHITE r pevshen R "ide

E " y y no zaynoy s. i g .. (FI; ! 5 y TEN Zperichnnii moty z; l-vo b5

Her. - ryv, 0.0... NYM uh.

I am her. - WE Pe g! 1x SAME ON as Kz pd! accept t. SHHI - y I: : gr Shchl chn i e Su s. k E E E I ; sk V shk sh y Koh KE and vi y s y zha y: ' R y sa K !

And she: 2 ke I go MO Thanks No a. у и НЙ и І-и и ; le i 7 expinitnais i rit YOU EP dya rernnu I zhi ve i ! 4 Y Ya o dv Job y -i yrvk nt tia, zi u ! ; 70 | ААААЙ Шк . M PI PI SHYCHYNIA ! yam, te 7 iii: -"zdynn sin sia In shk CAR anod yak

GA z stori i gridtor Tov sk Z, Yasu phovaynya E and dya ziv ! o zhi K. y i zhk iy z shchi s i i BA E.u tya iy 15, t le 1 g : iya p, ti. a shchi p R ya - y " dya therapy, Menadivavny da T- ya ki shk pk. iye re; 5, Z 5 TIC, Y Z. 5, ' V ; rt puti rn ini of chn m u i s razhnjny nni Chn inii also I tati loni ee EE pi DE I oZAyakitchnvya p "Zhe : y 22 ia sen Ina NI A " | ON. Ho kny skopiki lay 1-1 peri

And what - ' | i s y y 14 Ii her se Ir A and I, ly kim y Z i sch T vnnadineen svya ne river o buyanI sany and sch z IV) Kn a nits o kn o p OV, o y y y s h dk Y ; Du and I - E. I td kn dit: inii J j si I "DSHNCHY or Ai milyy tu4,. hemisphere tv, VK kv ve B Zh. skh !

ION | Nowadays, the sun is not yet shining. І люга": This is What is the difference between І Кк Кичл ep 30 . and nyplilerts, inv deya! : Yani and | Ha still , MO oh and I, . PYRCHINYA 4. их Й и. Y (85) G. I - ON zanokh Zlyv I fer ri eV: uch t wa M s tik perazhnv- I uoevvani I F

Y i U. Ki RI kv SCHI 7 mg NYA : a 3, id vek tu: Da De : i Y, dae ik tati ory pr West stelya pros v rr or en go PRE 1 y sao ze t « tr: kv Pn sec in z sn ore nno ibn raninintrnnyvnnnn native union nni rn nini niya

With EM 1 I; shi, all zvecha rr Kk: zay, and with Him (I re Ts "» and nozzle 7 shu ek st: ik KK Mk kn V sn vi EY

СХ and I; (5 z a ARM nadInallene yat tara tni y "y le SHY NK. INNO NY; - Iy ay x BK; Po vaklnoe Z nor sauni gav shen: ra What Still And in zli. t y pol nya y tatryu YO zak shchi ZK zt Vk na: where I am.

I«e) ' shk i "tai and 7 shchi GAE byu saga I teh uvk i oo Y -5 da ve. -shk ek endo i peda and piade shchi "IV di. zv 1sh ei snuyut vin eh tiy idi ES li zt nenshy V t 50 U: ey. s.

Shk hu. her and rya shi: ticket ke ii ke yati: and KD. Y I - Mr I: zvst. and I eh otv, 5 not - "and krutii che ki her: A. Ya et kr Zhe 5 and o nous sah, | For ipiperidjn inii univni s dyon '

ЯЗ и ши и | and goes M K I because b5 rntnnktrtetnsnni and NORI vimy knowledge nn de

Co. I and ив и ее Кв ДИ Пн ЯК nnk, PV"; har and forks VIN JAK 7 ZhK Frzheni FC chok LE DachII Z anu svya ry (90 nya and EK, vtnya Myasya IY, vk VN Ol S Ya

If y sa rai j sl svi R YA EN SUKY DE VYK K st ve . ky 0 (INN akoiomytyurnnnia

ЕВ их пис важ here; all: I zenith E IZ ii ' y , o ashk: kil DV V in m i EV

G Yari shk a A EN EP MY I m r fin I o Z.

I! fight rn vi Alina li aziv ZIVA. her, Nissan Ya

And what is not A trovy vnost K.I ut I: i and SHY a ak Be zzh i pk ne iy. inn: li cat cheek

Z kuye Z shin nya in ish. E7 Giverininia pi i i v, 2: tini: I Ya pe i iv i y ke go Br yak y zga z mm ore ich 7 2:17 BIV yy s y g she y y. and! ah ah shh huh? th Cat xx 1 | SHI in. y y da: I o : y y "ya a ii DY boho sa: "y y pt ridn ; ve "i ve ' ! because they teach the same Hyryvzod-ulperidzhi-i Ob zo and vola:

And Jackdaw! t y - Ma, ku I: Щ Misya y tily "y Tent tu pactot ЯВ и т зво щ

With Hey action Ne g. where tik. kety chit u re te i r sh I chit sk i:-V is i oi vd sy sk i ot V p M z! g B) what m what o, pa a MIN Kla a a m aty On 1 M Pass r. pi v i is chai pin il " I shk siv rn ad o Te MN vo "

AD, God tidevtsyich" E KE y 1 Lu - I TYA san nya nya vvit yt: Y skan y KE tr Ya. What did you wear for a few minutes? Ot and nu a pet at Bon va ZVELY PIV No EE. WE and oyu SCHE Ko BKZ OY -viymo-aazr-veto; oon

Oh, and what, and oh, and I'm in Wu. Gaea pi N Io: zi y ah tek 7 nih dk g Betritevlt ; Who ate her s" and i. zh m i g geli lossi I sla delpingZ3» Pd levovatteny: Z Kt y : NYA; eat ii ee pra nd: ro (F; Ai v sche n. sha (DAM ze Kaya UNN ee vu, «ie tsa 00 Pebnavivnekavevaytsu oko 4 Mono

IS i, Pakzhtlefrtya osvdinkyniva RN ZK sa V i Ak NE ini ; tya yes aa 60 th .D- o EN piz styu tt. U kiz TEY ng h V POPY ANNA, shayyu and you an ln vv Tlo laIIY PA b5 i s sh re roya st Ba iy her her and her y Y i premiy Kg. : "

I Kur o, PN I order i reinannti p nitinripnny iya and in | With PeCv amovu beat And still more. t, shi s. ! A I 4 nen ZM "YAZ Bsmudiinatin-ya- t b td : x V z gev re Z za zavad eye I TU koy.";

ZE age 1 aa Teva is NCD with, with bapadiazaa-3- І : km і v pa і SL: І | | i iga V ' ki Bk she Ya sh che Hull: t KA kuraschetya Z; "KE and Z wife V Kf Ge dunetyh and achabitikust Z Tozhtnya 20 and i. Yalry still re NOCILOO o g Me

B b i ieksnyy shchi Z s Y i "Kl EV TE vomat tya ve, y s V POKY dk: b dya; ; : | (y etriagiluyuvsi Z ban zate Z ilinineridniki. ,

Yason R (5 KI el vta a and Tr MECH; o and her (with and V she. with what kN koty yak BY ЗB-1-44- zo Y Ж t piperaans And okisvtyuitsy obtained pe ШЯ i y y "sn ya t r doty red dip ti t y y WHERE ARE YOU WITH HER in i. s 1 GE 4. ii name Yakhno ztev vya fi-, maspiv nya se

SSS, IN iv dat doitervdv VAN

EV. | V y regi sf Te TIi KE tk oh in; I dream more: b with: U gu: her and 2: I: her. p ny r: y E bu ak y y "Di ne I Kk . is. Bai; ka Where we wash the lion Tina and POSI i « din Vak y na cha sl tv EY Zhe risi NUT: A ai u Z es 40 і і і” (Z і і. SH- DE MAINaV IN THIS NII i. KY: “This I'm more.

And had that hell

Yi ha Her No E | | What h bika Ba RE PED nyat NU in, s Beat, in V ime tv ry WE Ki i uten ik ih WE ! 00 Yan |Knoneminikonn (95) i. hi oo to kv AT Ya KM. NYM 7 50 and uh E schu sne cho "Fat rune KISNEV Ki: 1) and

And | v-i Lya i er pan i Vy pyt Z g o y r : 2 E. "y Ku yan y in re gr. ozh v what NT y y ZED they ni ne Shchi

Y s: M.N r I "Hera; dec koty tni on yuyu I i i -e t sht v. 12 sn RINIE YaEO i dyn.

To the horror of TAT nok ly Droimidazov, oz Kisyuliv"

E and she and Mr. Uv, AND SCHE MK EeE VIY: ю 1 I wrapped their letter Aediov

N i i sk that Sl R a, im i NI - v, - y NIS pl sho shk b5 shk A av ia

Ke ZKEL. ke r. y frac la i sa y I, i- i " zh ; : : v: De, "Щ I gas ХО x -ій Ж і stro supy Kk. y I io | half

Tk zhi i I kA m aint ya ta sv sk r p (-zy ne KI aoi pressure ZAYE: nka uch as autumn nin par in KI

E Ki Ya and shi shk dis KN Mineria ved sa uch ? and

And - What shk and I and pera t, - | I - : и я Я. "а ШЧе зас 1. kov NI" same s division a

And this blow. HC (bandage Cl I prirtorintya o: z y ay. I y ; ssh menya, alive as

I Ba Ya SCHO h one: "I went to the right place because of what happened

Te tannia oi g. ek yavy pishiy Eneis vicysa MINA ryy s panny ney HA vish lilIlI I.D God nada, y znajav y m y Vrrel nya yan y y - y yy pory sy I s Y ry Y "MEN , di U o U a t

M. ioodaletya UNI Yan ydkaya BO 3rd still a. se TZ ay in Ddshe m. ys ny va hya ee t Vij dose ak nni and sii y

Le. s y y also Ku y: y te Khyaviy y (y y y y b rika y testi; o Elen ty DNO tu y y: WE LOWYZY Uh

What is NOT: drinking, book 14; i 1 ays iy i honors schi! and | htrahydro-gy p i B "li MNE re g

Ka a or Bena and po I "and this iy you; pyt inn vo isuya i i t Eh z (Br I ; pnia t inininnia, ZAPopiti i. 'f a I what and da RU : well You drink and destroy and crash:

E ozh - M zahnya BI: pe LE NI HE ich in the fall with0 Gu t ! bull and lenses of the belt ve and. I'm with pt father, I ach Go and . y : i s Gai y y re zh y ry y Mich lis t y y y y y y y y y y y ZY : yy NED te ra pinysn dyka y

And I vych 1 -k chedyuv And KPsvA and, tipetu sho ; in draft | at

N zhki Y KE dya i 23 Y. - 5 V i PE: ri Sb iy that 7 i re ; chi Y shiyu S edetE drank and x, and that I TEA -- o. El s Sai ish;

Mne and nn and a Ge Severyn pupil ry vyb

MTEKH in the VA; o Go be i y peryannni ii piv Uk EI : bai I g schei a y 2 v g. ik M g. zoshchi 5. LE si mini NU Zh. 7 s

I St aa styu I zytinu Z ssh coffee railing about I | and he and pin linen, ; rods Ia ZD. y sia dn neninny : 40 . h sl V la dnya ha Gn ' o K. tia i sniy DY shchy! and

Ff i ev a g «och i-nbiln MU tovi ok , K ; ; them and : ; - Shchih Gai still and. iy WHAT pil what : I ns her : - ! Noah in the world; sdynovnine Ya. tri y tsk E y : roya ek se R tin y What t KIvans What "tn i ve i; ; Y -1 45 | vk Toy isidn in v; Id bull them! with: and I still swear by DEN I open - m 71 in I sia I still anis I Vkkre foams about

Ts rt tsya a "y v. zhk SE, Z. tstvs. pora gor polyany y (95) | Uk ty z nia shi z y y and slig g vrzhki. t vera: she yani In MYH s 1 ; Fo oyu zo y it and b: loops. thanks again. ko 20 t ee. . Y ? what are these totregidvyant dreams and x pd prin do? '

Fo. a aa tsy in 1 to be bored iii tk s

And to SO Pasee Arena beast

TE U and Ivan also killed his SONS in his sleep, Art

With How ' NN dya and sht them I With the same as before the updated i - pen I from 1-44 lich tych. I t | 254 Ga styko Obutannykdy mokvedin-y -y and also sia sii y | ; in VN. in prazanyat I uyestrafytog - -ai; -th r; J. z. zi y li ha SCHI piagn ini sini teru Kt yak yi bo I Shk. with: vve ID Ki and cheni yaki ev ay, fluor Ne ; and i et nysche De and I picovi ik i "r pu picharats - re re sn nIz NIY shnih tsii" saye ha. J i irivynnh MAYA si zmieviya t" de in: vti and ovi; " on 1 b5

Gnit tt natr ris spon un nt nt ntiv finik iks 0 FU yuury ZK... MES zy y " nim S shi SN y DNA y t y sn sviti s or ZHI y Tu , "Te ikh ibn s. BIK ach t sichi M ЩЩй ? x sho 5 y z I Go tsei ay a ukivi ps fs Z

І Ні lo і ек г Z і sr pe Пі pol іn lo tytsi і ту і в fu te mi dylan

Shenay, and their those and ES se TR set. "any; As a bond and LO .

I: in; A Z. Army essays: VI: fats; things! Fri. all zhk y V y shu y rech avt nya pernzyny t Olyvy arj tu BK Ya et. (okre khz bro with wool"

DU so Pana z i I ne ali i uki i vi u ak i THIS TO YOU

OO I t A ie vu li, TSO KY 75 E | In: Mr | AND

And casts and masses are Tsii: r and shk ; I'm the identity of I.K, and OB kN, SN as gay Pojnnnnnia ponaiky rynv I Peolerm i h In dream and I I I Y sia i ai De chn VIY: (WH DE char shik: me I is lchaye 1 RI V shi - SHI Kl : IC ko ME man DI ect riv) p. ny Y (19) and: vy ; rank OD RANK Or AD

And | uh th VYMY nie in the city of Belazh. oh and oh theo. I have TIN 1.

And we in |v vnraniro o bnedinnnYa and! AT

Vch "Zh, y vit De y pi ZE etiki pas se I cht shih What y tn y s arsizee y s NDI y

У : КИ в : ий ж ов дай и тя сот I ria "ts ryti umi IRYA be zy I so

Kg o oxo gali torn peri dinyi" ko zn NI - I and si dini pd v. . pesch y Shchi y Zhas ss VY KY abscess. NOT Vanya, s U se s ikhih 15 Mya ut ke :

Z annia OK Kk: shi Y still uky shaty tr t ie na TO mon: : so p Y M janv. TV shchi Ker Ya zhit rel kto;

KA Su! U, shchi 6. Z U I I NO ZL | and cha pk for I and Bez tanya t int tet vi naerah and I YOU, then, WHERE, With p. mele chaN u a PO A Pn m ' : : B. y Y eko Z iron ether I (loceoye Yak, Kay y " o. zkerairosi U ben uz 0 iz" KI e Ach pey da u ne 1 brom ne zy pay ee no IA ii o si-duyvsism M Zhnia shi it, tree WE ii 457 : And with this pa Lazy EP NE ii-. - OT p. sh MYLO MOSS also p. y - t NI SHK VYN KEZMINSHEKHIA Because, pe bokiv po kon oaoeisvms kina glorious M My nych i ZA RN

Kl YN and KY ny ky kinny B RK ski ny ys), 12 schi ' Tor tn VG YN: 5 vek i o E os KE N M i K y DYN rila not OKA nl ny yuyu sa and ato tek, GOYU DV ROD LV! c Late veriatnk and coffee-carrying flights; and I and TYA. Bai zavis it Ya vve and pre Ya kyu and mona tia

Vdizij km se dk a pe, I - yy pe " ek, - y y deya y Which under I s ah y Yad ze v, with the same Ba vkoov ni Ya chan A-LYA o | so vva sina spheres psa mowed.

E Ya vat vsta VVIV LI syauya Zh. Zh ska ?anih i: IY Y de i: NI:

dog; thing YOU IN; daily it and drink let sili nn NI r-n ky osv tor zt vlt tv tia pri pir-nns i pa 60 b5

: THINGS - I yah : z loh t 2. nny night nayuchy inn aby RA lany i- si ishEeeVy -e ant V rn -- em - yi do, i sch Her This 4. bro ЦЗ ie she pay for ЖК ж, зt ie nv i un vnay I

And MORE and dk and. Vk nik ek obu V ry DK sleep eotya y. y DE a Y t rbadova 70 cha Shk a NDO NNY y RachyO yarom i CYA M l 7 y t s Ii 2 Tr u zh mo i otvyne v

Я как ух S kivsh Z Aoioineryukh ki" and ve ba ' goes t tsa: id taya xx p ce Y y, ni 15 t "ZY shchi What I and pih "DK. schy yy I ! I NI E pri i that sgtovoy jacktpot

K y pechu stinoani zate: iv yo and ikh Kk : y brom g

I yy, with m her same and shsh action rea i; ay v te fiz nkyu sia B A SCHI 1 v y 20 : ry sa A chi v um ge t chat avt t aka B y lav sia ze g THIS Her Udi y, M y yavi zietvfev a THIS eye Ia

L ia Y. vi A chi z Y as sim tot ; with I) NDI Shchuy What is that: ! Wow, I'm a pipif! pt KE SHI: NUK ee i t "she. y. zh-z I koe: rizh tya penitekh ovo Vyayav so : I "Z pir is uko IA tru pev i zh chi: : I et leg At avy ly piperilyme o Ge)

I SE. is Y I g. OOLIEMY TK Kl MY NK dnih i sh 35 : p nay b " SHY and nis di ta, z "zve "Shk : u a vi chi zli 41. i ut tva. my ZU: h Bonnie she s M I ! E shchi i 40 ! I I How ; 1. sun : dr t ZE tey ka: "y u Y pt set li g Y 7 s | vi ik I. y g y S sini ; pbaniya "ME ket podsya pod" and 45 Misha | S i te iy I i ch nya vesen deta in Re V

In! | rai la in skivnezhaZ-You all nrynnYa i-o In yav tiy that V and B. in Aries no pratshon nnitychime Ek . (a A Do oche NI se a i, ad vh Steps! "FIGHT 1. ra mater nia der lii same" ! m a eye MY vo. j I zzhoya Al uyne A sen aznnnych LYA z ikink y NN y rechi u it Toya Nya che iVNO U YN nih I b5 pe mash y M flyt; ; | i i i i i ENN antiv ZU yo JAK tova I o POD i u SHE y. y g py nev o Kay Danya. : | schi ; Kisnyaya i sch son Yes!

Mr ursykh kin and poten or. zh - shchi r de stedbs r et vv a ; (S Minini, punk: p san. y t "AAU Yake Dr» sia

And | In and 0 Chicory

And whether zba vn Z lunivera And VU I. ex drank | I have M-eromkh and what is Na dna nokan SHHA.

WHAT IS I? "That's what I'm talking about

І |! Shk dya Ya. te Ul lk u ana ZT

And them. Shchi: I AG adigkyuttya lyh vo ob digidvo" with "I shcha : y IZ "la: yay-ZO i: ko ii KE. tags running NI and and about her yo NI schu, I and inert to Pi ZA 7 ve and I MAV of the braid: from ZS38) as T- 1-4 bro Z in-Y-OATS-: and ki poets and pr KI

Y SHO artsy and NA chit VI eh SHO same. y - i) pe I that Ia ibiniteridinile! Kale fanrtyuua zhkesloti F with Eh ay I | ik- kt yara ply ia p y Me i eple V v I EP EN vala" "me

Ж тя -Ж g y i she ee zo oksavv ore svn ovo p kavidNO-ZA : ih s :E t eivvonia- I IM karbchvevoi i ukikonuvy

El pniv PINA tlia Etiky ekhtati dn " 1a40u re vi re VC tyah VIY and I B chayu 0 Popovok oko thank you.

F: NSNHNE YOU Yavy nN oh SHY - so TV and Pai yulyur-i meplv vn YAM. 50. vyv KE and Y ok iy EI wiki EI her ay i ko | z n z their yo still "r y tai od che kopa p E g d Z yary rev, y ad pog gi pom : KE '

I) and and as, in; " ии ЦИ:и ss я Vu t. и и те | karbovukh z

M. is Zh. sf one PI ide night "fo zani ky o o shk BOI that Tra; UK ED DAE LA TOD B bo b5

-y y "OD that v y Kk ; mini I gi still ty re y y s zha - Her, le ik (r some shk par i y y, y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y t., "and soda ash

K ich GYA v eonly U navr Where does my BT reni n s ee ininniri with Vk Ha Penya and I ve hundred g: wai, sn y. t y 4 - cheese zpiksnt zvul SI t ZE iii p iii i in Z sht s More. i yno l i y t, s a iii inn v . hey punk te opal. and ! And there is: kp 22 V Z vi zhi "Van vv, kiag a, her ol dk tu i "k rivninnaya

K, oi y y m. still with nu y ka same TYA) in y with li as 4» 5 seessnechnya : : dance nya p MY | I and hprbeniyuini i Yani then F her Z. i, DA tya 24

E What she she Vus ze: Kpropiovind You 0 | With and | ze - po pnonyoininish u ykzyv i her 7 Ya. i i. 1; . и І и щ ще ел t ; g: And what I, yes, N

SO PA day roti GA isisori s onos OV ennie Ne: "SHE a and RY che muru and ziv seam. pino; k znaj

E | g A; rashnki pprtititlzher. a se y : their so y y y I and s y Ya. yah - - che urny y YANA son karbany

And I Ben Z and tai Ya wa. Bonnan, I, I, I, I, I, I, etc. Vr ENER rya. ish ih dai d sch ztz zh Ka Y BE Godtenakh Pisei sr, I, snu sa ryi nyin-1e y EI, ; ha aero drinky YANYI dv y M AV denne ik sna PN TIN: (5) ' Banettvntnaninn ; On ty VKEty V g: Ta ingiyaro Yara t shi ind Y Kt au ped ya I nay shchen -

OA Pen ut ban . work for the Day of Sprze What VO You ily And so ' ka et You BYDIONE ly I AL de and Z y zisk vyy sy di ay odgy a pled s ovinya ke aery y t i DIvsrzhn yadt sh eta ! s.g sk: it is difficult, iy tt, I . NE Y yad IN p ts. nie otim Fi s E.A i s g ia t-Ya t star event g chn ch v st - EE. zrvnenyi i t i di vit ; " » ' and ich sia ON I kt vaui y. y ny :, nyy V nish R - y Ne schi SCHI y signne I shiny She sey Y Poiknazytsrnn Ii in MM M se) zu no Pd Y "MT nia : i "in and po oy give NA sr issitnya pini ti in Y t p KIVNYt HE y o I ley Fight feints pini kPa no 1 nia more: shk what papi zh la y tya WASH sir and sh. ! with of doci Me he. You are in heaven and heaven, and my soul and soul. with 4 zolilitn ine butan ach NE, niya same in 1 Ї | y y y ka A ik NO war B, and SHO She t anshny y y z erushen yak era ; nstilbenznya, sun TOO.

Tek ionni rininnininy " dna vetkyu 11611 e svy that her tt iz tyar riv sna z de z en t! CZ KA | sini Shchi | | nina annia En Zpig shchi and not Koh i Shchy z tiy svi i. svy Z lati shilyak i and we wash

I 1 Ko and. s ren i ni ad y; With that we DV and sleeping pat sa

KB I Zhe 7 Y y annia Y DNYNY - pi y, ET bishche nya shi that these sia our |. skras: Z Z : same TA ayu 0 r, cha yap and I In her a na na and a

Schi s l ie write" t. gave: in and in - I " and

IBN sen V MOHY vk y 65 tttvettyaya i peechnkt ns i tt syny tntk cones niv sho vky nny i sti Y kovu " g 12 d y vhy ia iy PLAN ionicni, na" zva MONO OV Ts she shchy; , shchi I iN ne, SHY : nannia Their she K- a z i same ! his liey i- o t z -y demolished Yasya ge - sli: I DK ak I outline sli VE B: la Tse, "a How kam I z dit and I am still in si y Z as V i Y z t ZE, She i R g I iya -3 ii: ie i o ON pidVn- kv PUT vu i DNIA ekv i. ra nor ZA MOTO - 1 70 na ve Shkivy nd kn shi t i zva higher education

Y : s Z o y. 2.

Poor me Zhetan Although I: : neesty . . . Ptn gi still - Tue: se z ge i . . and BA and "DE and g hostov you foam" Ж гл! i Y va zapa lpiperaainn te PT Nte pev all: g. dit 4 well, I di po z SHE KN Ye z De KY 7 iy E

Suli deko ychyyudroga NOT ninvzhiina" et

V' oi en VU ad: --- sk: 222 s women szh- iizhot pis nis ini driver ino kti i y g al pinni dyk perspiration sly sa ntysini ti slizh disny st tr

Eh; E vashu et pub iz: myt kg I tyka il : y Zh I In oxo-a plov with stu i pasture styu KV ni OA and iiszht iv HENNY GO THAT Where, AND

Sht zt povi SHIK y PEN DA MI on IY s vaYetya siri yut i Tv: i koi TGhetilovy ether 1 15 roko»: ! z az METY chiYa uk y OA tt M, y t.z, this t. iga v i so chik ev "DK I chu Ma t. i y m z v ' ZE PN, Z

Х Как бый Э ней на ЗД жали И ЗЕ PL И Ди я Ня s -: V. Іі х ян я s ра N і Я. і і і і і і і зли - озер де ану»: I so

Hey, more, more. Don't cry

In I shk «shchi she shyne I. Zayusikmyas nykostiys i lsmistisyy non ste s - r sk knlya sna vaskoiikya s Mzhkhzh ko ; and. rt write In (is) to her I: ay MASS OP 2-0. y E ish p y

CHK sa a MY Dva o o a 1 DUDKO

I. Java. o a and ak Y NOYA. mm NnIyLYV Ii. NO

I Y "BO S ko RIDYASCHIA st BI. p y y 1- 1 "

I: Theo ekerovvova Vslote Her with s Be E zba et and ran o a an NI OT. h y chy y y She: liu. g si U VI dad EE dad 5 ; : Her i a vai div psi 11 ' "Bit ko KI and still it vv I 1 2 that she Yana i" iy. DYN Zhim IEE SIK pek in AI and -. I ; Y V v y y 7 y rev ny senia SMYV t: tanjam ovo t snt tyt no be Mr pni opa -I diky ku i ie: Ch і-o і t). "Oh, I still have At, I still have a bad day: y and Y and Z C Y - y and g. At, and A .-! Щ и Й -опш и я, 1 Й в ШЙК - Шчи 13. І Й - и -.. и Шчи Z ET. i Ts oo : i i I dir re GENA NN iya pd vih ik ti. vii - yuyu 50 : ШЙ и и и и ка и, ла щ зб И З ! ay J sti ie oren i y y What OS Pi with ss Also i and ; | SCHI de haiivo Z ikhanot oil t ifonin ikiyaie

GF) SU chan ov oi sa 3-3 ha watt. More ethylene and B! co no S yet. Ж I І І НЕ ПЛЛАЯ Хи и Шк с . whether TIRE I'm from. E and I; 60 b5

And DY g kr tkikh " and t, shk:

TA "dlrysh TYAG chlor- Z mstv y ovo" " y y I Zhe u. t, in sake Y E. I tpr te a o iz chok g. P IV I i: vo Y Y ty zhin al z UK I z , convocation of St

And res her Bezi linearann o og Ovy ey 0 ish-e--u On and bits Pitni uniya E "NU Gandhi 5 term V MO Vit IN I i. r d5 in I oi with Shev. |;

Co. I x OS DV ar PIV Deni y, Where is not sat DAK DNOI! EE KY DV veche ZA VC PI DE Yuni y : ; and you are hot. zh; the words of ours are those of us: For and not Shchi Y Ei zn i r y z ' NEW their vi. and: MN. Ii What gZai iii t. And ke be E i i . - y sia N Ge and ote sly pe yarn Y SMECHNYI yi ay Baly prov i- y t yat tyu. R i i i I I

Is KE KAVI 1 Zp okokine jaeet, te V y Ii MALYM zi sYAIi Her, M schu y (y V y also i se shk hkeani m yaya kro ZAZ" o

IN Z YASHA OYA ash | Kn kg melting of hay OK si 4 div msec play oso wok NIY IN v kino ie i i a A I A KN S. tey i v el da ry v u pu o V MY

LI SCHE a, Z Gaf 2 E El u EN SKSUNEYATE Vienna in shi - and g shk she and ar zale z: Zoya Z r: o chtrya: i I o ! y: sen y il otsen ziva iya Kutove DE En 1. Ge) 35). nishi kina Y so PON NyrorVyai same o kora dneva zzhleti i-

Tek "I I I ; I where the same and "o Do I chna them g "(y y-y ! pr y in p "8 y y. y How is it and N y Vk y y y y y Ag. types or aut ryk in pyzhlIidine Eric 1. s y I y s z z UT "I; nan GK. vti tyu Si v Ii; : I z . i DYA NA me perimenej dpiperizhynya ia Ya. ! ri ich ia shiy HOBOKI, ih; Data egramchiroki to single in: ov 1 -I 4 VM nn KN KAK YN u. re z: PZ i VE nivyny nia sia ! yy IN i Ge zahev i VI A I piy x ; I U MOKYA Her PED - di SCHO ZIB, v. 1: ro y z and sy E. yy which y

OO Y y ich ts "Va, yy, vyr shchi is, G-s nadi chn. to her, what is it?

NI slyv a tive ko I i shi. schi stubble schi Sol. aa chn ii i IIA ik a ЧNO I and I n V zhi (b-pkopn neni Kvkhinro-i tA tDanoni ! , tsa wk : oto ay sr ii or io feny

My name is SVY Da DNA shi KI er. a t cher: zd I i To : I: my sha vy nyk a vn t y she y TYNY ki I pPoshsche ENLI and 60 b5 x i t rt - to ha sht t v EE UDO v. schi ; seh navi pa vyg dan, LY still blue in. r o RY sho i M - p. : struyuura zhk ml Z "U y y Shk ET iO vra Ya Oko i ok Z-D ; V och zi nan 24 leno utsis y z y "v. th day of the week

OT y y yiv ky brdiyaky tyh ka MIY as that SYA , I ani and cht tk chi DI ron vostie pvh zielerevdtkh t "NO sur v chi

M. I. Ts. so sa Ta se and drink nau KI sew pt 1. y y. an cha Ivin sa: I. tey g; p «shchi sya y Yak Nypipershin PEN YOU Mito pe y mstamtikz Z

WITH !

Izha rev and Da a NNYA M".

Teren, Mol dyna wool

Shik si Mk ia all about ossiyai sas "GUILTY with 3 sk - ZL pf Ou zl okt Iv s V sch ; y z y z yad em I rigeli vada Me her Ta osho her: not "o tes (with her. o ' i y. ? M, sho ren, kn, Kg, E Ko o Y I dya i vi: I 3. ka t Vi Y Pitt i. i SHY -8 "u. sh "aug: ; PON E Ei mi! pIENY PNO relay zhi zi: t. vu t | i s zv |V Da Tan bram Yavorina (I: m ; zhi aa; At kana vt mu ps oz a re U chi petukh, y inn tn go EE o i and dya vlo odek tya: one ! Y i RN «i: ZALI ND NN NOVE, « then DIV) o NN Orov kor nevy і- ne g zhi; r (pni: mekv LISH sova kisna: 4 45. | bat i: -I z iontsiannny Sh. or i 2. V. PISHE o i Z YN p. M sto. Z i 19 y I y i. i o ik METO, Mu KE in VT i-o G I dni i m I ME li RODU I prila iZ ebovet i i left: o ; ' I, I and I GII zna ZI SHE i EE 12: 21. tro, Greek (sk dn KZ toi zori yan KI V TIV

And I KN brom klyu pstyaiysnziya| oko t y Ya ry I y WE y z y KE "y si yanya z o gu: Go No ; yo Gaya t IT: i» Z y o : i ko SHK A zKolavsgryu and I. carry, B. : b5

: Z r i zd E el, zal i C KA y- NAEK Ia Eli y. iy and on 2 ' C in I how next in lap 1 Zo ty the first! IR with

Y sk nii "Z Lyash -yi lai Uhzhi tyasany Zi A

HER Fk. he alone In the posts of fe avih: AD OT - : Sya lyy and somiv m I to I ZE: SHENE as Es shayBsiv Terv: in " vo) I AKA nv ev 5-1 (5-brom Yak ish Gn on

KE same Jov same. - dreams Y Ta E Ai ii x; ki TE ki Tv NK SHY i VO (I 1 SCHE t N yi A 6 A enbanko wife i vn her i" ; V. g Ki i Kh Ni ka ' i-y zhu i. pev tlia: I zega ti rya to her

And! I and before closing (Denie Ge II PE sh-raya I: in : Ka : ! z. and s prychi eyes ram and RI r a: and I INNY: is sik gai V EN, E this Ne

UA chi and their Savrani zatornya meto Se ra i Ach Ne kv lin sty in v chans and I about actions E is, and Kt and fay as: and de ry and Y " i "in and she Shana actions ZY IMK zro noshh ey ok shi shi Sho tsez Tsi ni st Vrash4 yadormlyna -okeoa sch

Щ и и А- я и вт Н- Ев г мч, Е 14 мы Ня (ш-Ои- и со дике З и Кк! Й и . и | и ий И / пе и о и Я и я е е е ту. r; yar three and ! ; ik z , EF shly yah To zlor-Ztriylormetinovnanyau I-1bsmetva-

UK that SHE Z SHK ak R de de o ndnah NA) MENE iz, t U Ne shen " to her with I ; y y y i PL sshoszhyu kish I y х ши - -y RAgid At LIYA mon sun d. и в и : Й о- и И | 1 - 1 (and that ЧК Гера лк Кн в ке ШІ

AND; and whether bipod eh Z: Dos oso s dey

AK Ninya voylalnydnknya Y y y y ; There is a vla and NODOANYAI. Sh 4, pd test Te: ; 5000 ancient yan ietfe tt tt vt tutu nttntsttstvezh tt seter pet y Vu. wow! и и ший ерилни ии А и и Я aoshyurnya 1. syu и 7 чи I Kent beach kt in MK uyu nd. and

And How 4 No an and y za Er s gami go I pinsyu pln I. and , ; y I feyu vk sv: zhrEENI : u EI I zo -i y | the trick of Judas: : yuyu : because b5 yuyu 7.

And | And Miyavrnyanem mdbuyyuka era

Isn't it? not shi MA

KO chu rfrornetyu tuo ni-svso-YA- TYA vosti

I'm pre and her She obozhrna-TK And obnikodikdnnia Ok roktooi

Mk What che leloty: | | IS

F; some KVN: 14-14 IA for ie Tana a-

B Tebopamatsivsi I was a river of faith and actions that A perijniy-i Ttoettvvy histu . 7 o Bu Yak g dose (7 ge "V y zhir te ide sametnya lyn Patsn! z and "I mete o and od ZY o, I I I You and Yazipporidvva ki pil nen TL" and

I she t i y, ik ro kan Za eralii". And there is also ZI Av Y so z o s shiy E | | | their enantiomers, their diastereomers, and their salts, and the following compounds are especially important: Ге) (у (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4 -methylpiperazin-1-yl)piperidin-1-yl|-4-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-33-yl)piperidin-1-yl |Ibutane-1,4-dione, i- (2) 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-I4,A4bipiperidinyl-1-yl)-4-I4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, « (3) 2-(4-amino-3-chloro-5 -trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I(4-(2-oxo-1,4-dihydro-2-s H-quinazolin- 3-yl)piperidin-1-yl|Ibutan-1,4-dione, "from (4) " 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(11,4bipiperidinyl-1"- yl-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (5) and 2-(4 -amino-3-chloro-5--trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylI|-1-(4-pyridines n-4-ylpiperazin-1-yl)butan-1,4-dione, (6) methyl ether (95) (1-22-(4-amino-3-chloro-5-trifluoromethylbenzyl )-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl 7 50 butyryl)-I(4,4Dbipiperidinyl-1-yl) acetic acid, (7). Kko-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1,4"-bipiperidinyl-1'-yl-2-oxoethyl]amide ,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (8). KKO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4- Dimethylaminopiperidin-1-yl)-2-oxoethylamide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (9). Kk )-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-pyridin-4-ylpiperazin-1-yl)ethylamide o 4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (10). (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2- (1"-Methyl-4"-bipiperidinyl-1-yl)-2-oxoethyl|amide ime) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )/piperidine-1-carboxylic acid, (11) benzyl ether of 4-(1-(k)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-carbonylamino)propionyl)utperidin-4-yl|Ipiperazine-1-carboxylic acid, (12) ethyl ether

H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-carbonylamino)propynyl)-4,4"-bipiperidinyl-1-yl)acetic acid, 65 (13). "k)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)- 2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)/piperidine-1-carboxylic acid,

4k)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (15). (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-azetidin-1-ylpiperidin-1-yl)-2-oxoethyl|amide 4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (16)

Cc)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(5-methyl-2,5-diazabicyclo|2.2.1)hept-2-yl)piperidin-1-yl |-2-oxoethyl)amide of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, 70 (17). (kK)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)lethylamide 4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (18)

H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-carbonylamino)propionyl)-4,4"-bipiperidinyl-1-yl)acetic acid, (19). (1-"4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1, 4-bipiperidinyl-1'-yl-2-oxoethylamide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (20) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-14-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (2) (5)-2-(4-amino-3 -bromo-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidin-1-yl|I-1-(4- pyridin-4-ylpiperazin-1-yl)butane-1,4-dione, (22) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-1,4"-bipiperidinyl- 1"-yl-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidin-1-yl|butane-1,4-dione, (23) o (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-(4-( 2-oxo-1,2,4,5-t etrahydro-1,3-b Enzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (24) c zo (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-(1" -methyl-4,4"-bipiperidinyl-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1- yl|butane-1,4-dione, c (25) c (5)-2-(4-amino-3-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1- yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, Me) (26) it- (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-dimethylaminopiperidin-1-yl)-4-(4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (27) (5)-2-(4-amino-3-chloro-5 -trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-(4-pyrrolidine -1-ylpiperidin-1-yl)butane-1,4-dione, from c (28). (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-4,4-bipiperidinyl-1-yl)-4-I(4-(2-oxo-1 ,2,4,5-tetrahydyl ro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (29) (5)-2-(4-amino-3 -chloro-5-trifluoromethylbenzyl)-1-I(4--4-cyclopropylmethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-ox-I o-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, (30) and, (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl )-1-(4-morpholin-4-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-2)1,3-benzdiazepin-3-yl)piperidine -1-yl|Ibutane-1,4-dione, o (F) o (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-4)yl|-1-(4-perhydroazepin-1-ylpiperidin-1-yl)butane-1,4-dione , (32) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(4-methylperhydro-1,4-diazepin-1-yl)upiperidin-1-yl)- 4-(4-(2-ocso-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (33)

F) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(4-isopropylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo -1,2,4 ka ,B-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (34) in (5)-2-(4- amino-3-chloro-5-trifluoromethylbenzyl)-1-1,4"-bipiperidinyl-1'-yl-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben zdiazepin-3-yl)upiperidin-1-yl|butane-1,4-dione, (35) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1- methylpiperidin-4-yl)perhydro-1,4-diazepin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) ipiperidin-1-yl|Ibutan-1,4-dione, b5 (36) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(3-(4-methylpiperazine-1- yl)azetidin-1-ylI-4-(4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butan-1, 4-dione, (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine -3-yl)piperidin-1-yl|I-1-"(3-pyrrolidin-1-ylazetidin-1-yl)butan-1,4-dione, (38) (5)-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)pipe eridine-1-ylI-1-"3-piperidin-1-ylazetidin-1-yl)butane-1,4-dione, (39) 70 (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-(4-azetidin-1-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin- 1-yl|Ibutan-1,4-dione, (40) (5)-1-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl|-2-(4-amino-3-chloro) -5--trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (41) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-diethylaminomethylpiperidin-1-yl)-4-(4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (42) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-I4-(4-ethylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepine- 3-yl)/piperidin-1-yl|butane-1,4-dione, (43) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-ethylpiperidine -4-yl)piperazin-1-yl|-4-(4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl| butane-1,4-dione, (44) ch (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)- 4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|-1-(3,4,5,6-tetrahydro -2H-4 4-bipyridinyl-1-yl)butan-1,4-dione, o (45) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-(4-pyridin-4-ylpiperazin-1-yl)butan- 1,4-dione, so z o (46) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5- Tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-cyl|-1-"3-perhydroazepin-1-ylazetvdin-1-yl)butane-1,4-dione, so (47) (5) -2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-benzylpiperidin-4-yl)piperazin-1-yl|-4-I(I4-(2-oxo-1, 2,4,5-Me tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, M (48) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-1-(4-(4-benzylpiperazin-1-yl)piperidin-1-yl|-4-I(I4-(2-oxo-1,2,4,5- tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (49) « (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-( 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-4-|4- with c (2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (50) ;» (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-(4--4-dimethylaminomethylphenyl)piperidin-1-ylI-4-I4-(2-oxo-1,2,4,

B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (51)-I (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|-1--4-(4-( 2,2,2-trifluoroethyl)piperazin-1-yl|Ipiperidin-1-yl)butan-1,4-dione, i-o (52) 2) (5)-2-(4-amino-3-chloro -5-trifluoromethylbenzyl)-1-1-methanesulfonyl-4,4"-bipiperidinyl-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piperidin-1-yl|Ibutan-1,4-dione, dk (53) 4) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(9-methyl- 3,9-diazaspiro|5,5)undec-3-yl)-4-(4-(2-oxo-1,2,4,5-tet rahydro-1,3-benzdiazepin-3-yl)piperidin-1- yl|butane-1,4-dione, (54) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-«4-piperidin-1-ylmethylpiperidin-1-yl)butan-1,4-dione, (F. (55 ) ka (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4--2-dimethylaminoethyl)piperidin-1-yl|-4-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, in (56) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-methyl-M-(2-(1-methylpiperidin-4-yl)ethyl1-4-oxo-4-I4 -(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|bsutyramide, (57) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-M-methyl-M-(1-methylpiperidin-4-ylmethyl)-4-oxo-4-I(4-(2-oxo-1,2,4, 65 B-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|bsutyramide, (58)

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-diethylaminoethyl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (59) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-(4-cyclopentylmethylamino)piperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine -1-yl|Ibutane-1,4-dione, (60) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(1,1-dioxo-1, 6-isothiazolidin-2-yl)piperidin-1-yl|-4-I4-(2-oC co-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl |Ibutane-1,4-dione, 70 (61) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-oxoperhydro-1,3-oxazin-3- yl)piperidin-1-ylI|-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4- dione, (62) methyl ether 1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)pyridin-1-ylbutyryl) piperidine-4-carboxylic acid, (63) 8-(5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepine-3-yl)pyridin-1-yl|Ibutyryl)-1,3,8-triazaspiro|4.5|decane-2,4-dione, (64) (5)-2 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutane-1,4-dione, (65) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl )-1-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3- yl)ipiperidin-1-yl|Ibutan-1,4-dione, sc ha (66) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(2-amino-4, 5,7 8-tetrahydrothiazolo|4,5-(1|azepin-6b-yl)-4-I4-(2-0i)xo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piperidin-1-yl|butane-1,4-dione, (67) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-methylimidazole-1 -yl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4,5-isotrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane -1,4-dione, (b8) c (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylimidazol-1-yl)piperidin-1-yl |-4-I4-(2-oxo-1,2,4,5-theso trahydro-1,3-benzdiazepine-3- yl)/piperidin-1-yl|butane-1,4-dione, (69) F (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-Myl|-1-(4-thiazol-2-ylpiperazin-1-yl)butan-1,4 -dione, (70) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(2,4-dimethylimidazol-1-yl)piperidin-1-yl|-4 -(4-(2-oxo-1,2,4,

B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, « with (t) 2 s (5)-2-(4-amino-3-chloro- 5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-.yl|-1-(4-1 ,2,4-triazol-1-ylpiperidin-1-yl)butan-1,4-dione, "" (73) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1- (4-(1-azabicyclo|2.2.2)oct-3-yl)piperazin-1-yl|-4-14-(2-oxo-1,2"4,5-tetrahydro-1,3-benzdiazepine- 3-yl)piperidin-1-yl|Ibutan-1,4-dione, - (74) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-(5-aminopentyl)- 4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdi,iazepin-3-yl)/piperidin-1-yl|butyramide, so (75) ( 5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-(3-aminomethylbenzyl)-4-oxo-4-|4-(2-oxo-1,2,4,5-tetrahydro -1,3-o benzdiazepin-3-yl)piperidin-1-yl|butyramide, si (76) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-( 8-methyl-8-azabicyclo/|3.2.1oct-3-yl)piperazin-1-yl|-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine- 3-yl)piperidin-1-yl|Ibutane-1,4-dione, (77) (5)-2-(4-amino-3-chloro-5-trifluorome tylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-

F) yl|I-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, t (78) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-I4-(1H-imidazol-4-yl)piperidin-1-ylI-4-I(I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine -3-yl)piperidin-1-yl|butane-1,4-dione, (79) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4- methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione , (80) 65 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4 -(5-oxo-3-phenyl-4,B-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|butane-1,4-dione,

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo- 1,2-dihyroimidazo|4,5-c|quinolin-3-yl)piperidin-1-yl|butane-1,4-dione, 8 (82) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,2-dihydro-4H-thieno|3, 4-e|Ipyrimidin-3-yl)piperidin-1-yl|butane-1,4-dione, (83) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4 -(5-methyl-2,5-diazabicyclo|2.2.1)hept-2-yl)piperidin-1-yl)-4- 70 4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (84) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4 -methylperhydro-1,4-diazepin-1-yl)/piperidin-1-yl|-4-(4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-yl|butane-1,4-dione, (85) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)perhydro -1,4-diazepin-1-yl|-4-(4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan- 1,4-dione, (86) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiper idin-4-yl)piperazin-1-yl|-4-(4-(2-oxo-1,2,4,5-tet rahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl| butane-1,4-dione, (87) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-azabicyclo|2.2.2|oct-3-yl)piperazin- 1-yl|-4-(4-(2-oxo-1,2,4,B-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (88) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4-(2-oxo -1,2,4,5-tet rahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (89) o (5)-2-(4- amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3Z-yl)ipiperidin-1-yl 1-1-(4- perhydroazepin-1-ylpiperidin-1-yl)butan-1,4-dione, (90) c zo (Z)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-1,4-bipiperidinyl-1 "-yl-4-|4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione, c (91) c (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3Z- yl)ipiperidin-1-yl 1-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, Me (9 2) eat-

O-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (93). (K)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl) amide 4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, « (94). (kK)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-1,4"-bipiperidinyl-1'-yl-2-oxoethyl|amide with 4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (95). (K)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-oxo -2-(4-piperazin-1-ylpiperidin-1-yl)ethylamide and 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1- carboxylic acid, (96) (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl ester -I 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (97). (1-(4-bromo- 3-methylbenzyl)-2-(1-methyl-14,4bipiperidinyl-1-yl)-2-oxoethylamide ise)4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/ of piperidine-1-carboxylic acid, 2) (98). 11-(4-bromo-3-methylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid amide, o (99). 11-(4-bromo-3-methylbenzyl)-2-( 4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4) 4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (100) 2-(4-bromo-3-methyl benzyl)-1-(1-methyl-I4 4bipiperidinyl-1- yl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (101)

F) 1-11,4Dbipiperidinyl-1'-yl-2-(4-bromo-3-methylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3Z-yl)ipiperidin- 1-yl co|Ibutane-1,4-dione, (102). 411-(4-chloro-3-methylbenzyl)-2-I4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide in 4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (103). 411-(4-chloro-3-methylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (104). (1-(4-chloro-3-methylbenzyl)-2-(1-methyl-I4 А4bipiperidinyl-1-yl)-2-oxoethylamide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)utperidine-1-carboxylic acid, 65 (105) 2-(4-chloro-3-methylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, 2-(4-chloro-3-methylbenzyl)-1-(4 -(1-methylpiperidin-4-yl)piperazin-1-ylI|-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/ piperidin-1-yl|Ibutan-1,4-dione, (107) 2-(4-chloro-3-methylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|- 4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione, (108) 70 2-(3-bromo-4-chloro-5-methylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (109) 2-(3-bromo-4-chloro-5-methylbenzyl)-1-(1 -methyl-(4,4bipiperidinyl-1-yl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (110) 2-(3-bromo-4-chloro-5-methylbenzyl)-1-I4-(1-methylpiperidine-4 -yl)piperazin-1-yl|-4-I4-(2-oxo-1,4-dihydro-2H-quinazo lin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (111 ). 41-(3-bromo-4-chloro-5-methylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (112). 41-(3-bromo-4-chloro-5-methylbenzyl)-2-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1, 4-dihydro-2//-quinazolin-3-yl)piperidine-1-carboxylic acid, (113). (1-(3-bromo-4-chloro-5-methylbenzyl)-2-(1-methyl-(4,4bipiperidinyl-1-yl)-2-oxoethyl|amide 4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (114) c ro 2-(a4-chloro-3-trifluoromethylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidine- 1-yl)-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, their enantiomers, their diastereomers and their salts, and the most important are the following compounds: -yl|-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione , (g) c 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-I4,A4bipiperidinyl-1-yl)-4-I4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (3) F 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I( 4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4-dihydro-2 M)

N-quinazolin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (4) 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1,4Dbipiperidinyl-1' -yl-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, « with B) 2 s 2-( 4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylI|-1-(4-pyrides n-4-ylpiperazin-1-yl)butan-1,4-dione, and (6). KKO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1,4"-bipiperidinyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid -1'-yl-2-oxoethylamide, (7). Kko-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-dimethylaminopiperidin-1-yl)-2-oxoethylamide -I 4-(2-oxo-1,2,4,5- tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (8). (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2- (4-pyridin-4-ylpiperazin-1-yl)ethylamide ise) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid , 2) (9). KKO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(1-methyl-4,4-bipiperidinyl-1-yl)-2-o 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid amide, o (10) ethyl ether 4) Г1-(РО -3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin- 1-carbonylamino)propionyl)-4,4-bispyridinyl-1-yl|acetic acid, (11) in HC)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(4 -methylpiperazin-1-yl)piperidin-1-yl)|-2-oxoethyl)amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin- 1-carboxylic acid,

F) (12). "k)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)ka amide 4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (13). (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-azetidin-1-ylpiperidin-1-yl)-2-oxoethyl|amide in 4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (14)

Cc)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(5-methyl-2,5-diazabicyclo|2.2.1)hept-2-yl)piperidin-1-yl |-2-oxoethyl)amide of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (153. (K)-1 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)lethylamide 65 4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (16)

H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-carbonylamino)propionyl)-4,4"-bipiperidinyl-1-yl)acetic acid, (17). (1-"4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1, 4-bipiperidinyl-1'-yl-2-oxoethylamide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (18) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-14-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (19) 70 (5)-2-(4-amino- 3-bromo-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidin-1-yl|I-1-(4 -pyridin-4-ylpiperazin-1-yl)butan-1,4-dione, (20) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-1,4"-bipiperidinyl -1"-yl-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidin-1-yl|butane-1,4-dione, (2) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-(4-(2 -oxo-1,2,4,5-t etrahydro-1,3-be Nzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (22) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-(1"-methyl -4,4"-bipiperidinyl-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl| butane-1,4-dione, (23) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5- Tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-(4-pyrrolidin-1-ylpiperidin-1-yl)butan-1,4-dione, (24) ch (5) -2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-4,4-bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, o (25) (5)-2-(4-amino-3-chloro- 5-trifluoromethylbenzyl)-1-I(4--4-cyclopropylmethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-ox o-1,2,4,5-tetrahydro-1, 3-Benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, so zo (26) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I (4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-cyl|-1-(4-perhydroazepin-1-ylpiperidin-1-yl) )butane-1,4-dione, so (27) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I 4-(4-methylperhydro-1,4-diazepin-1-yl)upiperidin-1-yl)-4-(4-(2-oc Meso-1,2,4,5-tetrahydro-1,3- Benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, M (28) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-1,4" -bipiperidinyl-1'-yl-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4 -dione, (25) « (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(1-methylpiperidin-4-yl)perhydro-1,4-diazepin-1- yl)-4-(4-(2-oc z c o-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutane-1,4-dione, (30) ;" (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(3-(4-methylpiperazin-1-yl)azetidin-1-ylI-4-(4- (2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (31) -And (5)- 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-azetidin-1-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro - 1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, i-o (32) 2) (5)-1-(4-(4-acetylpiperazin-1-yl) )piperidin-1-yl|-2-(4-amino-3-chloro-5--trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, dk (33) 4) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1 -(4-diethylaminomethylpiperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan- 1,4-dione, (34) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(4-ethylpiperazin-1-yl)piperidin-1-yl|-4 -(4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (F. (35) ka (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(1-ethylpiperidin-4-yl)piperazin-1-yl|-4-(4-( 2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, in (36) (5)-2- (4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl |-1-(3,4,5,6-tetrahydro-2H-4-4-bipyridinyl-1-yl)butan-1,4-dione, (37) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-65 yl|I-1-( 4-pyridin-4-ylpiperazin-1-yl)butane-1,4-dione, (38)

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-benzylpiperidin-4-yl)piperazin-1-yl|-4-I(I4-(2-oxo -1,2,4,5- tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (39) (5)-2-(4-amino-3 -chloro-5-trifluoromethylbenzyl)-1-(1-methanesulfonyl-4-4-bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3- Benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (40) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(9-methyl- 3,9-diazaspiro|5,5)undec-3-yl)-4-(4-(2-oxo-1,2,4,5-tet rahydro-1,3-benzdiazepin-3-yl)piperidin-1- yl|butane-1,4-dione, 70 (41) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-4-piperidin-1-ylmethylpiperidin-1-yl)butane-1,4-dione, (42) ( 5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4--2-dimethylaminoethyl)piperidin-1-yl|-4-(4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (43) (5)-2-(4-amino-3-chloro- 5-trifluoromethylbenzyl)-M-methyl-M-(2-(1-methylpiperidin-4-yl)ethyl1-4-oxo-4-I4-(2- oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|bsutyramide, (44) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-M-methyl-M-(1-methylpiperidin-4-ylmethyl)-4-oxo-4-I(4-(2-oxo-1,2,4,

B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|bsutyramide, (45) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-( 2-diethylaminoethyl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1 ,4-dione, sc 2 (8) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-oxoperhydro-1,3-oxazin-3-yl)piperidine -1-yl|-4-14-(2-oxoyl)-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione , (47) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)-4-(4-( 2-oxo-1,2,4,5 co zo -tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (48) with (5)-2- (4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-I4-(2-oxo-1,2,4,5 -t so tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (49) F (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-I4-(2-methylimidazol-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4,5-the M trahydro-1,3-benzdiazepine- 3-yl)/piperidin-1-yl|butane-1,4-dione, (50) (5 )-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylimidazol-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1, 2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, « i (B) 2 s (5)-2-(4- amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(2,4-dimethylimidazol-1-yl)piperidin-1-yl|-4-(4-(2-oxo-1,2,4, . B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, "" (52) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-(4-imidazol-1-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin- 1-yl|Ibutane-1,4-dione, - (53) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl)yl|-1-(4-1,2,4-triazol-1-ylpiperidin-1-yl)butan-1 ,4-dione, so (54) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(1-azabicyclo|2.2.2)oct-3-yl)piperazine -1-yl|-4-I4-(2-oxo-1,2 co'4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (55) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(8-methyl-8-azabicyclo/|3.2.1oct-3-yl)piperazin-1 -yl|-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (56 ) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3- yl)piperidine-1-

F) yl|I-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, t (57) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-I4-(1H-imidazol-4-yl)piperidin-1-ylI-4-I(I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine -3-yl)piperidin-1-yl|butane-1,4-dione, (58) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4- methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione , (59) 65 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4 -(5-oxo-3-phenyl-4,B-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|butane-1,4-dione,

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo- 1,2-dihyroimidazo|4,5-c|quinolin-3-yl)piperidin-1-yl|butane-1,4-dione, I (81) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,2-dihydro-4H-thieno|3, 4-a|pyrimidin-3-yl)piperidin-1-yl|butane-1,4-dione, (62) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4 -(5-methyl-2,5-diazabicyclo|2.2.1)hept-2-yl)piperidin-1-yl)-4- 70 4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (63) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4 -methylperhydro-1,4-diazepin-1-yl)/piperidin-1-yl|-4-(4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-yl|butane-1,4-dione, (64) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)perhydro -1,4-diazepin-1-yl|-4-(4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan- 1,4-dione, (65) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiper dyn-4-yl)piperazin-1-yl|-4-(4-(2-oxo-1,2,4,5-tet rahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl| butane-1,4-dione, (66) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-azabicyclo|2.2.2|oct-3-yl)piperazin- 1-yl|-4-(4-(2-oxo-1,2,4,B-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (67) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4-(2-oxo -1,2,4,5-teth rahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (68) o (5)-2-(4- amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3Z-yl)ipiperidin-1-yl 1-1-(4- perhydroazepin-1-ylpiperidin-1-yl)butan-1,4-dione, (69) c zo (Z)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-1,4-bipiperidinyl-1 "-yl-4-|4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione, c (70) c (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3Z- yl)ipiperidin-1-yl 1-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, Me (7) eat-

O-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethylamide 4-(2-ox o-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-carboxylic acid, (72)

O-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide « 4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, with (73) КРО-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2- 1,4-bipiperidinyl-1'-yl-2-oxoethylamide. 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, and (743. (KO-1-(4-amino-3 ,5-bistrifluoromethylbenzyl)-2-oxo-2-(4-tperazin-1-ylpiperidin-1-yl)ethylamide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)/piperidine-1-carboxylic acid, (75) -I (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl) Ipiperidin-1-yl|-2-oxoethyl ether of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, and, (76 ). -2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (77). 11-(4-bromo-3-methylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl|-2-oxoethyl)amide of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, 4) (78). 11-(4- bromo-3-methylbenzyl)-2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,4-dihydro-2H-quinazolin- 3-yl)/piperidine-1-carboxylic acid, (79). 11-(4-chloro-3-methylbenzyl)- 2-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine -1-carboxylic acid, (80) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid

F) 11-(4-chloro-3-methylbenzyl)-2-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl) amide, ka (81). 41-(3-bromo-4-chloro-5-methylbenzyl)-2-I4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethylamide 4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, in (82). 11-(3-bromo-4-chloro-5-methylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethylamide 4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, their enantiomers, their diastereomers and their salts.

Compounds of the general formula (I) are obtained by methods that are known in principle. The methods discussed below have proven to be the most suitable for obtaining the compounds of general formula (1) proposed in the invention. (a) In this embodiment, to prepare compounds of the general formula (I) in which X represents an oxygen atom or a group

MH, and K!-KZ have the above values, provided that 2 and BZ do not contain a free carboxyl function, piperidines of the general formula slum in which B! has the values specified above, are subjected to the interaction of (I) with carbonic acid derivatives of the general formula (M iv «i, in which A has the values specified above, and (z means a nucleophobic group, preferably a phenoxy group, a 1H-imidazol-1-yl group, 1H-1,2,4-triazol-1-yl group, trichloromethoxy group or 2,5-dioxopyrrolidine-i-yloxy group, provided that X is a MH group, or (II) with carbonic acid derivatives of the general formula (М - пт сч (8) in which A means an oxygen atom, and both C mean nucleophobic groups that can have identical or different values, preferably a chlorine atom, a p-nitrophenoxy group or a trichloromethoxy group, provided that X is an oxygen atom, and with compounds of the general formula p

And so and (22) and - - with ;" " in which X represents an oxygen atom or a -MH group, and 0, M, MU, K2 and BZ have the above values, provided that Kk? and BZ do not contain a free carboxyl function and/or other free primary or secondary aliphatic amino function or other free hydroxy function - The above reactions, which are basically two-step, are usually carried out by the

Ge) of reactions in one reaction vessel, which is applicable to this invention in the preferred version, consists in the fact that at the first stage one of the two components of the formula (I) or (M) is subjected to interaction with a carbonic acid derivative of the general formula used in equimolar amounts ( IM), carrying out the reaction in a solvent suitable for this purpose at a reduced temperature, and then adding at least in equimolar amounts another of the components of the formula (III) or (M), completing the reaction at an elevated temperature. c» Reactions with bis(trichloromethyl)carbonate are preferably carried out in the presence of at least 2 equivalents (in terms of bis(trichloromethyl)carbonate) of a tertiary base, for example, triethylamine, M-ethyldiisopropylamine, pyridine, 1,5-diazabicyclo-I(4 ,3,0|-non-5-neu, 1,4-diazabicyclo|2,2,X)octane or 25 1,8-diazabicyclo-1|5,4,01-undec-7-ene. As solvents, which must be anhydrous, use, for example,

HF) tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, M-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, and when using bis(trichloromethyl)carbonate as a carbonyl component, it is preferable to use anhydrous chlorinated hydrocarbons, for example, dichloromethane, 1,2-dichloroethane or trichloroethylene. The reaction temperature at the first stage is from -30 to 1252, preferably from -5 to -102C, and at the second stage it is from 41593 to the boiling temperature of the solvent used, preferably from -20 to 702 |see. also N.A. Ziaar and MU. Kopg, "Zupipezep tii Pe(egosusizspep Atidep (Agoiidep)", Metsege Meodep deg Rgaragaimep Ogdapizvspep Spetie, from Spetie, U/eippeit/Vegovig., 1967, vol.M, p.53-93; R.Ma|eg and K .5. Kapaaid, U. Ogud. Spet., 59, 1994, pp. 1937-1938; K. TaKeda, U. AKadi, A. Zaiki, T.

Zykapyaga and N. Odiga, Teigapedgop Ietseg5, 24(42), 1983, p. 4569-4572; 5. K. Zapaieg and MU. Kago, "Ogdapis bo Eshipsiopa! Stgoimr Rgeragayopvg", ed. Asadetiv Rgezv, Mem Hogk, 1971, vol. II, p. 223-245).

(b) In this embodiment, for the preparation of compounds of the general formula (I), in which X represents a methylene group and K1-23 have the above values, provided that these groups do not contain a free carboxyl function and/or other free primary or secondary aliphatic amino function, carboxylic acid of the general formula (M) and. in which М, М, МУ, В2 and ЕЗ have the values indicated above, is subjected to combination with piperidine of the general formula (1)

Wu su, in which V! has the above values. p. 29 The indicated coupling reaction is preferably carried out using methods known from the chemistry of peptides (see, Ge), for example, Noshrem-Uueu!, Meyipodep deg Ogdapizvspep Spetie, vol. 15/2), while using, for example, carbodiimides, such as dicyclohexylcarbodiimide (DCC, diisopropylcarbodiimide (DIK) or ethyl (3-dimethylaminopropyl)carbodiimide, hexafluorophosphate or tetrafluoroborate

O-(1H-benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium) (GBTU, respectively TBTU) or hexafluorophosphate o 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium (BOF). The addition of 1-hydroxybenzotriazole (HOBT) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (GOOBT) allows you to increase the reaction rate. Coupling reactions are usually carried out using equimolar amounts of the components that undergo coupling, as well as the coupling agent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, He»! dimethylformamide (DMF), dimethylacetamide (DMA), M-methylpyrrolidone (M-MP) or their mixtures, at a temperature from 30 to 309С, preferably from 20 to 2592С. If necessary, M-ethyldisopropylamine (DIEA) (Hunig's base) is preferably used as an additional auxiliary base.

Another coupling method suitable for the synthesis of compounds of the general formula (I) is the so-called "anhydride method" | see also M. Vodapza2Ku, "Reriide Spetivigu", ed. Zrgipdeg-Megiad, 1988, pp. 58-59; M. VodapzakKu, "Rgipsiriev oi Reriide bZupipeziv", ed. Zrhipdeg-Megiad, 1984, pp. 21-27). In this case, the "method of 10 mixed anhydrides" carried out according to the Matsdnap method (UK. Matsdnap Og., y) is preferable. Ateg. Spent os, 73, 1951, p. 3547, according to which, when using isobutyl ether of chlorocarbonic acid in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine, from carboxylic acid of the general formula (MI) and monoisobutyl ether of carbonic acid, which are subjected to combination, get a mixed anhydride. The process of obtaining such a mixed anhydride and the coupling reaction with amines is carried out by the so-called method 75 of carrying out reactions in one reaction vessel with the use of the above-mentioned solvents at a temperature of - and . -20 to 252C, preferably from 0 to 2596. d) (c) In this variant, for obtaining compounds of the general formula (I), in which X represents a methylene group, and co, K2 and BZ have the above values, provided that these groups do not contain a free primary or secondary amine, a compound of the general formula ime) "co (M)

M

Ф) about KUM), 60 in which M, M, MU, B2 and BZ have the above values, provided that 22 and BZ do not contain a free primary or secondary amine, and My means a group that is removed, for example, an atom a halogen, such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1-10 carbon atoms in the alkyl fragment, a phenylsulfonyloxy or naphthylsulfonyloxy group, optionally mono-, di- or tri-substituted with identical or different substituents selected from chlorine and bromine atoms, metal groups and nitro groups, 1H-imidazol-1-yl group, optionally substituted by one or two metal groups in the carbon skeleton 1H-pyrazol-1-yl, 1H-1,2,4-triazol-1-yl, 1H-1 ,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl, pyridinyl group, dimethylaminoloxy-, 2(1H)-oxopyridin-1-yloxy-, 2,5-dioxopyrrolidin-1-yloxy-, phthalimidyloxy-, 1H-benzotriazol-1-yloxy group or azide group subjected to combination with piperidine /o of the general formula (1)

Wu -x in which V! has the above values.

The above-described interaction is carried out under the conditions of the Schotten-Baumann reaction or the Einhorn reaction, that is, the components are subjected to interaction with each other in the presence of at least one equivalent of an auxiliary base at a temperature from -50 to 1202С, preferably from -10 to 309С, and optionally in the presence of solvents. As auxiliary bases it is preferable to use hydroxides of alkali and alkaline earth metals, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for example sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, for example sodium or potassium acetate, as well as tertiary amines, for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, M-ethyldiisopropylamine,

M-ethyldicyclohexylamine, 1,4-diazabicyclo|2,2,2)octane or 1,8-diazabicyclo|5,4,Fundec-7-ene, and it is preferable to use, for example, dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetonitrile, (In dimethylformamide, dimethylacetamide, M-methylpyrrolidone or their mixtures, while using as auxiliary bases hydroxides of alkali or alkaline earth metals or carbonates or acetates of alkali metals, water can also be added to the reaction mixture as a co-solvent. (d) In this variant, to obtain compounds of the general formula (I), in which all residues have the Shk values indicated above, a carboxylic acid of the general formula c (mM) and,

In F i - (their "- c z" pn in which all residues have the above values, are subjected to coupling with an amine of the general formula - 2053 5 r? a r ; ; ;

NMK-KU, in which K- and K7 have the above values, provided that they do not contain a free carboxyl function (Ce) and/or other free primary or secondary aliphatic amino function.

The indicated coupling reaction is preferably carried out using methods known from the chemistry of peptides (see, for example, NocireM-UUeuYi, Mei(iodep deg Ogdapizspep Spetie, vol. 15/2), while using, for example, ko 250 carbodiimides, such as dicyclohexylcarbodiimide (DCC, diisopropylcarbodiimide (DIK) or co-ethyl(3-dimethylaminopropyl)carbodiimide, hexafluorophosphate or tetrafluoroborate

O-(1H-benzotriazol-1-yl)-M,M,M',M'-tetramethyluronium) (GBTU, respectively TBTU) or 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOF). The addition of 1-hydroxybenzotriazole (HOBT) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (GOOBT) can increase the reaction rate. Coupling reactions are usually carried out using equimolar amounts of the reacting components

HF) coupling, as well as the coupling agent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, with dimethylformamide (DMF), dimethylacetamide (DMA), M-methylpyrrolidone (M-MP) or their mixtures, at a temperature from

ZO to zh302C, - mainly from 20 to zh259C. If necessary, M-ethyldisopropylamine (DIEA) (Hunig's base) is preferably used as an additional auxiliary base. 60 Another coupling method suitable for the synthesis of compounds of the general formula (I) is the so-called "anhydride method" | see also M. Vodapza2Ku, "Reriide Spetivigu", ed. Zrgipdeg-Megiad, 1988, pp. 58-59; M. VodapzakKu, "Rgipsiriev oi Reriiide bZupipeziv", ed. Zrgipdeg-Megiad, 1984, pp. 21-27). In this case, the "mixed anhydride method", carried out according to the Matsdnap method (UK. Matsdnap Og., y), is preferable. Ateg. Spent os, 73, 1951, p. 3547|Y, according to which, when using isobutyl ether of chlorocarbonic acid in the presence of 65 bases, such as 4-methylmorpholine or 4-ethylmorpholine, with carboxylic acid of the general formula (MI) and monoisobutyl ether of carbonic acid acids give a mixed anhydride. The process of obtaining such a mixed anhydride and the coupling reaction with amines of the general formula NMAE2BZ are carried out by the so-called method of conducting reactions in one reaction vessel with the use of the above-mentioned solvents at a temperature from -20 to k252C, preferably from 0 to 2590. (e) In this version, for obtaining compounds of the general formula (I), in which B ! has the above values, provided that it does not contain a free primary or secondary amine, a compound of the general formula (x) 70 i 5 ah e in which all residues have the above values, and My means a group that is removed, for example, an atom a halogen, such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1-10 carbon atoms in the alkyl fragment, a phenylsulfonyloxy or naphthylsulfonyloxy group, optionally mono-, di- or tri-substituted with identical or different substituents selected from chlorine and bromine atoms , metal group and nitro group, 1H-imidazol-1-yl group, optionally substituted by one or two methyl groups in the carbon skeleton (o) 1H-pyrazol-1-yl, 1H-1,2,4-triazol-1- yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl, pyridinyl group, dimethylaminyloxy-, 2(1H)-oxopyridin-1-yloxy-, c 2,5-dioxopyrrolidin-1-yloxy -, phthalimidyloxy-, 1H-benzotriazol-1-yloxy group or azide group, are subjected to coupling with an amine of the general formula НМК2ВЗ, in which К2 and ВЗ have the above values, provided that these EM groups do not contain a free carboxyl function and/or other free primary or secondary aliphatic co-amino function.

The above-described interaction is carried out under the conditions of the Schotten-Baumann reaction or the Einhorn reaction, i.e. (22)

35 The components are subjected to interaction with each other in the presence of at least one equivalent of an auxiliary base at a temperature of -50 to 1202C, preferably from -10 to 302C, and optionally in the presence of solvents. As auxiliary bases, it is preferable to use hydroxides of alkali and alkaline earth metals, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for example sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, for example sodium or potassium acetate, as well as tertiary amines, « for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, M-ethyldiisopropylamine, -pnu) with M-ethyldicyclohexylamine, 1,4-diazabicyclo|2,2,2)octane or 1,8-diazabicyclo|5, 4, Fundets-7-ene, and as solvents. it is preferable to use, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, "" dimethylformamide, dimethylacetamide, M-methylpyrrolidone or their mixtures, while using as auxiliary bases hydroxides of alkali or alkaline earth metals or carbonates or acetates of alkali metals in the reaction water can also be added as a co-solvent. -I The new compounds of the general formula (I) proposed in the invention contain one or more chiral centers.

In the presence of, for example, two chiral centers, such compounds can also exist in the form of two diastereomeric pairs of antipodes. The scope of this invention includes individual isomers, as well as their mixtures.

Ha Corresponding diastereomers are separated on the basis of differences in their physicochemical properties, for example, by fractional crystallization from solvents suitable for this purpose, high pressure liquid chromatography (HPLC) or column chromatography using chiral or predominantly achiral stationary phases. c» Racemates that fall under the general formula (I) are separated, for example, by means of RHVT into chiral stationary phases suitable for this purpose (for example, Spiga | ASR, SpigaIrak AB). Racemates, which contain a basic or acidic function, can also be separated by obtaining their diastereomeric, optically active salts, which are formed upon interaction with an optically active acid, for example with (g)- or (-)-tartaric acid, (g)- or (-Y-diadetyltartaric acid, (i)- or (-)-monomethyltartrate or (g) camphorsulfonic acid,

F) respectively with an optically active base, for example with (K)-(-)-1-phenylethylamine, (5)-(-)-1-phenylethylamine or ka (5)-brucine.

According to one of the usual methods for the separation of racemate isomers, compounds of the general formula (1) 60 are reacted in an equimolar amount in a solvent with one of the above-mentioned optically active acids, respectively, with one of the above-mentioned optically active bases, and the obtained crystalline diastereomeric optically active salts are separated on the basis of differences their solubility. A similar interaction can be carried out in solvents of any kind, provided that such solvents are able to dissolve the specified salts to a degree sufficient for the separation of such salts. In this case, it is preferable to use methanol, ethanol or their b5 mixtures, for example in a volume ratio of 50:50. In this approach, each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid such as dilute hydrochloric acid or aqueous methanesulfonic acid, and the corresponding free compound in (x )- or (-)-form.

In addition, there is also the possibility to immediately obtain only the corresponding (K)- or (5)-enantiomer,

Accordingly, a mixture of two optically active diastereomeric compounds, which fall under the general formula (I), if each of the synthesis processes discussed above is carried out using a reagent that has the corresponding (K)- or (5)-configuration.

The starting compounds of the general formula (I) are obtained, if they are not known from the literature or are not available for sale, in accordance with the methods (described in the application MUO 98/11128 and in OE 19952146). Starting compounds of general formula (IM) 70 are commercially available. Compounds of general formula (M) can be obtained by methods known to a specialist in peptide chemistry from protected phenylalanines and amines of general formula NMU.

The phenylalanine derivatives necessary for the synthesis of optically pure compounds of the general formula (M) can be obtained from compounds of the general formula 00 сх, in which U, M and M/ have the above values, and K is an unbranched alkyl group, preferably a metal or ethyl group , by splitting the racemates.

Enzymatic methods can be used to split racemates, with the help of which only one enantiomer of the racemate is transformed, and the resulting mixture is then separated using physicochemical methods, preferably using chromatographic methods. As an example of an enzymatic SM system that can be used at this stage, we can name the enzyme alcalase 2.4 I go (Momogutevs company

A/5, located at the address: OK 2880 Vadvzmuaega). Compounds of the general formula (X) can then be converted into enantiomerically pure compounds of the general formula (M) by methods known to a specialist in peptide chemistry. (is)

In the case when group X in compounds of the general formula (M) represents an oxygen atom, necessary for the synthesis of hydroxycarboxylic acids of the general formula (Xi) -

I.Y? art -i se) (95) of 50 in which У, М and М/ have the values indicated above, can be obtained from compounds of the general formula (X), provided that K in it is a hydrogen atom. c» Compounds of the general formula (XI), provided that M does not mean an amino or methylamino group, can be obtained by diazotizing compounds of the general formula (X) under the action of a suitable diazotizing agent, preferably sodium nitrite, in an acidic environment. When using enantiomerically pure compounds, respectively, enantiomerically pure hydroxycarboxylic acids are obtained, while the reaction is carried out with preservation of the configuration of the original compounds in the obtained compounds.

Ф, Another possible approach to obtaining compounds of the general formula (XI), in which OO, M and M/ have the values specified above, consists in the alkylation of compound 60 b5

(x1)

SU, c under the action of appropriately substituted benzyl chlorides, benzyl bromides or benzyl iodides of the general formula (ХИЙЙ) (хт

M

Ah. (shku, c o in which U, M, and MU have the values indicated above, and X denotes a chlorine, bromine, or iodine atom, similar to the methods known from the literature. Wow. Hey, 2, 2000, pp. 2165-2167).

The obtained diastereomeric products can then be separated using physicochemical methods, preferably (9) using chromatographic methods. Enantiomerically pure hydroxycarboxylic acids of the general formula (M) can also be obtained by hydrolytic cleavage of the chiral auxiliary group, coupling with amines of the general formula HME2BZ and cleavage of the benzylic protective groups.me)

The starting compounds of the general formula (MI) are obtained, for example, by the interaction of amines of the general formula Fd)

НМК2рВ3 with 2-(Alkoxycarbonylmethyl)-3-arylpropionic acids followed by hydrolytic cleavage of the alkyl group. 2-(Alkoxycarbonylmethyl)-3-arylpropionic acids necessary for this interaction can be obtained analogously to the methods known from the literature | Oamid A. Emapz, I eevieg Yu. UMy, supplement y). M. UMiepeg,

U9epyteu 5. doppzop, YuOamiy N. V. Kirip and dazop 5. Tedygomu, U. Ogd. Spet., 64, 1999, pp. 6411-6417; Zatsi Fr.

Sopep and AIekzapdeg Miomapomis, U. At. Spent Zos, 90, 1968, pp. 3495-3502; Nigoushtski Kazhapo, Mocisni IzpPii, « 20 Takao IKagua, Mazayiko Zarygi, Zadao Mozpikaja, Mazigo Ospida and Nidepogi Kytobauazgzpi, Teigapedgop I eKegv, -v 28, 1987, pp. 1905-1908). Carboxylic acids of the general formula (MI) can be obtained by the method proposed (in application MO 98/11128) from publicly available starting materials. :z» The obtained compounds of the general formula (I), if they have the corresponding basic functions, can be translated primarily for pharmaceutical use into their physiologically compatible salts with inorganic or organic acids. Examples of acids suitable for this purpose include hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, i-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid (se ) acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid and maleic acid.

In addition, new compounds of the formula (I), if they have a carboxyl function, can, if necessary, be converted into their additive salts with inorganic or organic bases, primarily for pharmaceutical use in their physiologically compatible additive salts. Examples of bases suitable for this purpose include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The present invention also relates to racemates in the presence of only one 59 chiral element in the compounds of the general formula (I). The scope of this invention also includes individual diastereomeric pairs of antipodes or them

HF) mixtures that exist in the presence of more than one chiral element in the compounds of the general formula (I), as well as individual optically active enantiomers that make up the above-mentioned racemates.

Likewise, the scope of this invention in accordance with its object includes the compounds proposed in the invention, including their salts, in which one or more hydrogen atoms are replaced by deuterium. because the new compounds of the general formula (I) and their physiologically compatible salts have valuable pharmacological properties due to the presence in them of the properties of selective SOKR antagonists. According to this, another object of this invention is medicinal products containing these compounds, their use and their preparation.

The above new compounds of the general formula (I) and their physiologically compatible salts have properties

COoR-antagonists and show high affinity to the COKR-receptor in experiments on the binding of b5 to it. The compounds proposed in the invention show the properties of SOKR antagonists in the pharmacological test systems described below.

The following experiments were conducted to reveal the affinity of the above-mentioned compounds to human SOKR receptors and their antagonistic properties.

A. Experiments on the study of binding to the SOKR-receptor using (expressing human

SOKR receptor) cells of the ZK-M-MS line

Cells of the z-K-M-MS line are cultivated in OMEM medium (medium modified according to the Dulbecco method

Needle). The medium with stuck cultures is removed. Cells are washed twice with SFR (phosphate-buffered saline) (Sibso 041-04190 M), separated by adding SFR mixed with 0.0295 EDTC, and 7/0 Isolate by centrifugation. After resuspension in 20 ml of balanced salt solution |ZSR, composition (in mM): Mass 120, KSI 54, MansSo»z 16.2, Mo5O) 0.8, ManHnRO, 1.0, SasSi» 1.8, O-glucose 5.5, NEREZ (M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid) 30, pH7.40| cells are centrifuged twice at 1009 and resuspended in ZSR. After determining the number of cells, they are homogenized using a homogenizer

Okha-Tygtgah and centrifuged for 1 Ohv. at 30009. The supernatant is discarded, and the sediment after 7/5 centrifugation is re-centrifuged in Tris buffer (10 mM Tris, 50 mM Mass, 5 mM Mosi, mM EDTC, pH7 40) enriched with 190 bovine serum albumin (BSA) and 0.195 bacitracin, and resuspend (1 ml/1000000 cells). The homogenate is frozen by cooling to -802C. Under these conditions, preparations of cell membranes remain stable for more than 6 weeks.

After thawing, the homogenate is diluted in a ratio of 1:10 with a buffer for analysis (50 mM Tris, 150 mM Mass, 5 mM Mosi, 1 mM EDTC, pH 7.40) and homogenized for 30 seconds using a Shiga-Tiggah homogenizer. 23 μl of homogenate for 180 minutes. incubated at room temperature with 729I-iodotyrosyl-labeled calcitonin gene-linked peptide (SOKR, Ategepat company) at a concentration of 50 pM and with the tested compounds in increasing concentrations in a total volume of 250 μl. Incubation is terminated by rapid filtration through polyethylenimine (0.195) glass fiber filters of SOE/B mud using a cell harvester. SU

Protein-bound radioactivity is determined using a gamma counter. The measure of nonspecific binding is bound radioactivity, which is determined during incubation in the presence of 1 μM human

COgkR-alpha.

Concentration-binding curves are analyzed by computer nonlinear curve fitting.

In the described experiment, the IC50 values of the above-mentioned compounds are "10,000 OHnM. co

B. SOKR-antagonism in the cells of the ZK-M-MS line of sch

Cells of the ZK-M-MS line (Imln cells) are washed twice with 250 μl of buffer for incubation (HERE5 medium

Hanks, 1mM 3-isobutyl-1-methylxanthine, 190 BSA, pH? 4) and pre-incubate at 372C for 15 minutes. After the addition of SOBR (10 μl) as an agonist in increasing concentrations (from 10,777 to 109M), respectively, after the additional addition of the tested substance in 3-4 different concentrations, the incubation is continued for

From 15 min. uh-

Then intracellular CAMP (cyclic adenosine monophosphate) is extracted by adding 20 μl of 1-molar NSI and centrifugation (20009, 42, for 15 minutes). Supernatants are frozen in liquid nitrogen and stored at -202С. "

The content of CAMP in the samples is determined using radioimmunoassay (Ategennat company), and the pA»o value of compounds that have an antagonistic effect is determined by constructing the corresponding graphs. c The compounds proposed in the invention show in the above-described test model the properties of CO2R antagonists in the concentration range from 1071! to 102M.

Due to their pharmacological properties and their salts with physiologically compatible acids, the compounds proposed in the invention are therefore suitable for emergency and prophylactic treatment of headaches, primarily migraines, respectively, cluster headaches, vasomotor headaches and chronic headaches. The compounds proposed in the invention are also suitable for the prevention of migraine in the period (Ce) of the prodromal phenomenon or for the prevention and treatment of migraine that occurs before menstruation or during menstruation. The compounds proposed in the invention also have a positive effect in the following diseases: in non-insulin-dependent diabetes (IND), in cardiovascular diseases, in tolerance of 50% to morphine, in diseases caused by clostridial toxin, which are accompanied by diarrhea, in diseases of the skin, primarily in thermal and radiation damage to the skin, including solar erythema, in inflammatory diseases, primarily in inflammatory diseases of the joints (in arthritis), in neurogenic inflammations of the mucous membrane of the oral cavity, in inflammatory lung diseases, in allergic rhinitis, in asthma, in diseases caused by excessive vasodilation and the associated reduced blood supply to tissues, primarily in shock or sepsis or in reddened skin. In addition, they are proposed in the invention

GF) compounds have a sedative effect in pain conditions in general, primarily in neuropathic pain, such as, for example, complex regional pain syndrome (CRPS), at. neuropathic pain conditions that accompany systemic diseases with toxic damage to the nervous system, such as diabetes mellitus, as well as pain conditions caused by inflammatory processes. Positive prophylactic and emergency treatment is possible for the symptomatic manifestation of hot flashes due to vasodilation and increased blood flow during menopause in women with estrogen deficiency, as well as hot flashes in patients suffering from prostate cancer, after hormone therapy, thanks to the use of SoKR antagonists provided in accordance with the invention therapeutic effect, while this therapeutic approach is preferred over hormone replacement therapy, as it is characterized by an almost complete absence of side effects. -BO0-

To achieve the appropriate effect, the compounds proposed in the invention should be administered into the body from 1 to

From times a day in a dose that when administered intravenously or subcutaneously is from 0.0001 to Zmg/kg of body weight, preferably from 0.01 to mg/kg of body weight, and when administered orally, nasally or by inhalation is from 0.01 up to 1 Ω/kg of body weight, preferably from 0.1 to 1 Ω/kg of body weight.

When using SOKR antagonists and/or inhibitors of SOKR release for preventive and/or therapeutic purposes, in addition to traditional hormone replacement therapy, it is recommended to use them in smaller doses compared to the above, which in this case can be from 1/5 of the above minimum values to 1/1 of the maximum values indicated above. 70 The compounds proposed in the invention can be introduced into the body either individually or, if necessary, in combination with other active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, while preparations suitable primarily for inhalation for aerosol inhalation. In such combinations, the active substances can be introduced into the body either simultaneously or sequentially.

The compounds proposed in the invention, if necessary in combination with other active substances, as an example of which can be named antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine NO receptor antagonists, antimuscarinic agents, B-blockers,

A-agonists and A-antagonists, ergot alkaloids, mild analgesics, nonsteroidal anti-inflammatory drugs, corticosteroids, calcium antagonists, 5-HT.β/1β-agonists, or other antimigraine agents, together with one or more of the usual inert carriers and/or diluents , for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fat-containing substances, such as hardened fat, or their respective mixtures, can be processed into conventional galenic forms, such as tablets, dragees, capsules, powders, suspensions, solutions, metered aerosols or suppositories.

As an example of other active substances from the list of nonsteroidal anti-inflammatory drugs, which can be used in the above combination with the compounds proposed in the invention, we can name aceclofenac, acemethacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, sozo fenoprofen, flurbiprofen, ibuprofen, indomethacin , ketoprofen, leflunomide, lornoxicam, mefenamino acid, naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts, as well as meloxicam and other selective COX2 inhibitors, such as, for example, rofecoxib and celecoxib.

In combination with the compounds proposed in the invention, you can also use ergotamine, b» dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, M timolol, isomethepten, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochlorperazine , dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitriptyline, lidocaine or diltiazem and other 5-HTb/1p-agonists, such as, for example, almotriptan, avitriptan , eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. In this case, it is advisable to use such active substances in a dose that is from 1/5 of the usually recommended minimum dose to 1/1 of the usually recommended dose, i.e., for example, applicable to ;" this dose of sumatriptan is from 20 to 10 mg.

Another object of the invention is the use of the compounds proposed in it as valuable auxiliary substances for the production and purification (affinity chromatography) of antibodies, as well as after the introduction of a suitable radioactive -I label, for example by tritiuration of the corresponding precursors, for example by catalytic hydrogenation with tritium or substitution of atoms halogen on tritium, in radioimmunoassay (RIA) and solid-phase enzyme immunoassay (EGIZA), as well as as diagnostic or analytical aids in neurotransmitter studies. oo Experimental part

For the compounds obtained in the examples discussed below, there is usually data on their IR spectrum, H-NMR spectrum and/or mass spectrum. Unless otherwise indicated, to determine the values of K (retention time), ready-made c» plates were used for thin-layer chromatography (TLC) clay "Silica gel 60 Ezvu/" (firm E. MegsK, Darmstadt, article

Mo1.05714) without saturation in the chamber. The values of K, which were determined using the material marked as "alox", were obtained using ready plates for TLC of tin "Aluminum oxide 6O GE o5y" (firm E. MegskK, Darmstadt, article Mo1.05713) without saturation in the chamber. The ratios between their components specified in the examples for systems of solvents (eluents) refer to a unit volume of the corresponding solvent. Indicated in

F, in the examples for MH" from a unit volume refer to a concentrated solution of MH" in water. The solutions of acids, bases, and salts used in the processing of reaction solutions are, unless otherwise specified, aqueous systems of the specified concentrations. As silica gel for chromatographic purification, we used silica gel produced by the company Miiiiroge (MATKEH tm, 35-7O0μm). Alox material was used as aluminum oxide for chromatographic purification (firm E. MegsK, Darmstadt, aluminum oxide 90 standardized, 63-200μm, article number Мо1.01097.9050).

The data of HCVT analysis indicated in the examples were obtained under the following conditions and parameters: analytical column 7 ogra (Adiepi TesppoYodiev company), ZV (5Z(arie Vopa)-C18; Z, 5μm; 4,x75mm; column temperature 309C; 65 Flow rate 0, vml/min., injected volume 5 μl, detection at a wavelength of 254 nm.

Method A yuyu

MON DRINK SWEAT PON POLO yus yuyu

When purifying compounds by preparative HCVT, the same gradients are usually used as for obtaining data during analytical HCVT. Products are collected in fractions of a given volume, the fractions containing the product are combined and dried by lyophilization.

In the absence of more detailed data on the configurations of one or another compound, the question of whether it is pure enantiomers or whether partial or complete racemization has occurred remains open. /5 In the following experimental part of the description, the following abbreviations are used: 2 с : : З Ге) яд зо сч со

F zv cha « no) s and g. ! . Recommendations for obtaining used amines (starting compounds) and? Example A1 2-methyl-5-piperidin-4-yl-2,5-diazabicyclo|2.2.1|heptane (examples 7.9 and 10.79) -I

Te) Ach

Ah 2-(1-benzylpiperidin-4-yl)-5-methyl-2,5-diazabicyclo|2.2.1)heptane co 50 To a solution of 2.3 in 8 mmol (12.7 mmol) of 1-benzylpiperidin-4-one Y Z, To 5 g (12.77 mmol) of 2-methyl-2,5-diazabicyclo|2.2.1|)heptane in 100 ml of Meon, 0.7 ml (12.7 mmol) of acetic acid was added, and the reaction mixture for 1 h. stirred at CT. Then, 0.99 g (15.0 mmol) of Mavn zcm was added in a stream of nitrogen, and the reaction solution was left to stir overnight at room temperature. After that, 7 ml of conc. NOSI, then stirred for an hour. at CT and concentrated in vacuum. The residue was mixed with 20000 ml of a 1595 solution of K»CO»z, extracted twice with DCM in portions of 200 ml, and the combined organic phases were dried over Ma 550.4.

HF) After removing the desiccant and solvent, the residue was purified by chromatography (silica gel, gradient elution:

HF with a change from DCM to DCM/Meon/MmN" in the ratio 10:85:5).

Yield: 2.1g (5895 from theory). in MS(EB5I): (MN) -286.

Eche 0.15 (silica gel, DXM/MeoN/MH" in the ratio 80:20:2).

A16. 2-methyl-5-piperidin-4-yl-2,5-diazabicyclo|2.2.1|Heptane

A solution of 2.1 g (7.3 mmol) of 2-(1-benzylpiperidin-4-yl)-5-methyl-2,5-diazabicyclo|2.2.1|heptane in 100 ml of Meon was mixed with 500 mg of 1095 Ra/s and hydrogenated during the Agreement at KT and pressure No 5Opounds/sq. inch. After that, the catalyst was separated by vacuum filtration and the solvent was removed in vacuo. The product without purification was used in the following reactions.

Yield: 1.4g (9795 from theory).

MS(EB5I): (MN) -196.

Eche 0.10 (silica gel, DCM/MeoN/MN" in the ratio 80:20:2).

Example A2 1-cyclopropylmethyl-4-piperidin-4-ylpiperazine (Example 10.4) Anavet,

Aha. 4-(4-cyclopropylmethylpiperazin-1-yl)piperidine-1-carboxylic acid tert-Butyl ester

1.26 g ( 20, Ommoliv)

The mixture and the reaction mixture were left to stir overnight at RT. Then the reaction mixture was concentrated in a vacuum, the residue was dissolved in a saturated solution of Manso with, carefully extracted with E(Ac) and the organic phase was dried over Ma»ZO. After removing the desiccant and solvent, the residue was purified by chromatography (silica gel,

ESO/Meon/mn with the ratio 90:10:0.5).

Yield: 1.36g (84905 from theory).

MS(E):XM) -323.

A26. 1-cyclopropylmethyl-4-piperidin-4-ylpiperazine

To a solution of 1.36 g (4.2 mmol) of tert-butyl ether of 4-(4-cyclopropylmethylpiperazin-1-yl)-piperidine-1-carboxylic acid in 30 ml of DCM, 1 ml of TFOK and the reaction mixture were added for 4 hours. stirred at CT. Then the reaction solution was concentrated in a vacuum, the residue was mixed with diethyl ether, the precipitate was separated by vacuum filtration and dried. The product fell out. SU precipitate in the form of tristrifluoroacetate salt. at

Yield: 1.86g (78905 from theory).

MS(EI): (M) -223.

Example AZ 4-azetidin-1-ylpiperidine (example 10.15) (ze) sch

Am, so (22)

Aza. 4-azetidin-1-yl-1-benzylpiperidine

1.Oml (17.49 mmol) of acetic acid was added to a solution of 3.0 ml (16.45 mmol) of 1-benzylpiperidin-4-one and 1.0 g (17.51 mmol) of azetidine in 100 ml of DCM, and the reaction mixture was stirred for an hour. at CT. Further, when cooling with ice in 4 portions within an hour. b.0 g (39.55 mmol) of Mavn(OAc) was added and the reaction solution was left to stir overnight at room temperature. Then it was mixed with a 1595% solution of KSO»z and after that, it was stirred for the next hour. Next, 200 ml of EtOAc was added, the organic phase was separated and dried over M950. After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, gradient elution: with a change from DCM to Meon/MchN in the ratio 9:1). :z» Output: Z,2g (8495 from the theory).

MSc(EI!): (M)7-230.

Eche 0.57 (silica gel, DHMMeOH/Sus/MH" in the ratio 70:15:15:2). - And AZb. 4-azetidin-1-ylpiperidine

A solution of 3.2 g (13.89 mmol) of 4-azetidin-1-yl-1-benzylpiperidine in Homl MeonH was mixed with 500 mg of 1095-ni, Ra/C and hydrogenated for 7.bh. at CT and pressure H 5" C bar. After that, the catalyst was separated by vacuum filtration and the solvent was removed in vacuo. The product without purification was used in the following reactions. Output: 1.9g (9895 from theory). p» MS(EBZI)(M AN) 7 -141.

Eche 0.19 (silica gel, DXM/MeonH/MH" in the ratio 70:25:5).

Example A4 1-azetidine-Z-ylperhydroazepine (example 10.22)

F) name) 60 Ada. 1-(1-benzhydrylazetidin-3-yl)perhydroazepine

31.7 g (320 mmol) of perhydroazepine was added to a solution of 31.7 g (100 mmol) of 1,1-dibenzylazetidin-3-yl ether of methanesulfonic acid in 200 ml of DMF under a nitrogen atmosphere, and the mixture was stirred for 7 days at 5026.

Then the reaction solution was mixed with Tl of water, the aqueous phase was extracted twice with E(Ac, the combined organic phases were washed twice with water and dried over Na»3O,). After removing the desiccant and solvent, the residue was purified twice by chromatography (silica gel, 1st column: DXM/Meon/MmNz in the ratio 19:1:0.025 and 2nd column:

tert-butyl methyl ether).

Yield: 22.2g (69905 from theory).

GE e0.82 (silica gel, DXM/MeoN/MH" in the ratio 19:1:0.025).

Ad4b. 1-azetidin-3-ylperhydroazepine

To a solution of 22.0g (68.bmmol) 1-(1-benzhydrylazetidin-3-yl)/perhydroazepine in 400ml Meon and bOml 2n. Carriers were added 5g of 1095 Pa/cС and the reaction mixture was hydrogenated at 452С until the theoretical absorption of H" (Agree). After filtration, the solvent was removed in vacuo and the product formed as dihydrochloride was used without purification in the next reaction.

Output: 15.5g (100905 from theory).

Melting point: 205-22096.

Ee0.08 (silica gel, DCH/MeoN/MH" in the ratio 9:1:0.1).

Example A5 1-benzyl-4-piperidin-4-ylpiperazine (example 10.24) k ik and how

Aba. tert-Butyl ester of 4-(4-benzylpiperazin-1-yl)piperidine-1-carboxylic acid

The pH value of a solution of 66 b.7 ml (38 mmol) of 1-benzylpiperazine and 75.8 g (38 mmol) of tert-butyl ether of 4-oxopiperidine-1-carboxylic acid in THF was set to 5 with the help of glacial acetic acid, after which for 2 hours while cooling with ice, 100 g (448 mmol) of Mavn(OdAs) was added in portions, and the reaction mixture was left to stir overnight at room temperature. Then the reaction solution was carefully alkalized with a 2.2-molar solution of K 2CO3, stirred for 1 hour, carefully extracted with EOAc, and the combined organic phases were dried over Na»5O). After removal of the desiccant and solvent, the residue without purification was used in the next reaction.

Output: 114g (8395 from theory).

MS(E5I): (Mother) -382.

GE 0.74 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2). at

AB5b. 1-benzyl-4-piperidin-4-ylpiperazine

To a solution of 5 g (13.91 mmol) of 4-(4-benzylpiperazin-1-yl)/piperidine-1-carboxylic acid tert-butyl ether in 200 ml of DCM, 20 ml of TFOC was added and the reaction mixture was left to stir overnight at room temperature. Then it was concentrated in a vacuum, the residue was mixed with 200 ml of a 1595% solution of CoCO»z, extracted three times with DMSO in portions of 100 ml each, and the combined organic phases were dried over Mo5O5. After removing the desiccant and the solvent

The target product was obtained, which was used without purification in the next reaction. -

Yield: 2.9g (8095 from theory).

MS(EB5I): (MN) -260.

Ee0.58 (silica gel, DHMMeon/MH" in the ratio 70:25:5). "

Example Ab C c 10 Dimethyl/(2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylmethyl)amine (Example 10.25) xz fey kt

She

- Aba. 1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoroethanone so To a solution of 4.5 g (16.59 mmol) 3-(2,2 ,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde, 11.7 ml (23.4 mmol) of a 2-molar solution of dimethylamine in THF was added to 150 ml of THF, and the pH value of the solution was set to by 5 using ml of glacial acetic acid. Through ЗОхв. added 4.62 g (21.79 mmol) g) 50 Mav(OAc)»z and the reaction mixture was left to stir overnight at room temperature. Then the reaction solution was carefully mixed with a saturated solution of ManHsSoO»z, after which it was stirred for 30 minutes, carefully extracted with EtOAc, the organic phase was separated and dried over Ma»5O). After removal of the desiccant and solvent, the target product was obtained, which was used without purification in the next reaction.

Yield: 4.5g (9095 from theory).

MS(EBI)(MaN) 301.

HF) GE e0.76 (silica gel, DXM/MeOH/Sus/MH" in the ratio 70:15:15:2).

Abb. Dimethyl(2,3,4,5-tetrahydro-1U-3-benzazepin-7-ylmethyl)amine o To a solution of 4.5 g (14.98 mmol) 1-7-dimethylaminomethyl-1,2,4,5-tetrahydro -3-benzazepin-3-yl)-2,2,2-trifluoroethanone in BbBOml of MeonH was added 60 BOml of water and 8.5g (61.51mmol) KSO" and the reaction mixture was stirred for 72 hours. at CT. Then the reaction solution was concentrated under vacuum, the residue was mixed with DCM, the components that did not dissolve were filtered off and concentrated under vacuum. In this way, the target product was obtained in the form of a light brown oil.

Output: 2.9g (9595 from theory.).

MS(EBI): (MN) -205. for E-e0.39 (silica gel, DCM/MeOH/Sus/MH" in the ratio 70:15:15:2). -B4-

Example A7 1-piperidin-4-yl-4-(2,2,2-trifluoroethyl)piperazine (example 10.27) n - sia (um "sv,

AtTa. 1-I4-1-benzylpiperidin-4-yl)piperazin-1-yl|-2,2,2-trifluoroethanone

A solution of 8.21 ml (57.8 mmol) of anhydride 70 was added dropwise to a solution of 15.0 g (57.83 mmol) of 1-(1-benzylpiperidin-4-yl)upiperazine and 20 ml (14 mmol) of triethylamine in 200 DM, cooled to 09 of trifluoroacetic acid in 40 ml of DCM and the reaction mixture for 5 hours. stirred at CT. Then it was mixed with water, the organic phase was separated and dried over NaCl. After removal of the desiccant and solvent, the crude product was used without purification in the next reaction.

Output: 8.3g (4095 from theory).

MSc(EI!): (M)7-205. 0.48 (silica gel, DXM/MeonH/MH" in the ratio 90:10:1).

A7b. 1-(1-benzylpiperidin-4-yl)-4-(2,2,2-trifluoroethyl)piperazine

To a solution of 1.0 g (2.8 mmol) of 1-I4-(1-benzylpiperidin-4-yl)piperazin-1-yl|-2,2,2-riftorethanone in 1 ml of 1,4-dioxane and 1 ml of THF was added 0 .53 g (14.07 mmol) of Mavn and then to the obtained suspension within 1 hr. a solution of 1.08 ml (14.07 mmol) of TFOK in 10 ml of 1,4-dioxane was added dropwise. Then the reaction solution for 5 hours. boiled with a reflux condenser, after cooling the excess Mavn,y was decomposed with water and concentrated in a vacuum. The obtained residue was purified by chromatography (silica gel, EtOAc/Meon/MH3 in the ratio 95:5:0.5).

Yield: 0.41g (43905 from theory).

MS(EB5I): (MN) -342. with

E0.45 (silica gel, EOAc/Meon/mMnH" in the ratio 80:20:2). Gee)

Av. 1-piperidin-4-yl-4-(2,2,2-trifluoroethyl)piperazine

To a solution of 0.41 g (1.20 mmol) of 1-(1-benzylpiperidin-4-yl)-4-(2,2,2-trifluoroethyl)piperazine in 20 ml of Meon, 5 mg of 10956 Ra/C was added and the reaction mixture was stirred for 2 5 hours hydrogenated at CT and pressure H» 3 bar. To complete the reaction, OC(OH) 5 was added to the tip of the spatula and hydrogenated for another 1.5 hours. After and. separation of the catalyst by vacuum filtration and removal of the solvent yielded the target product. Ha

Yield: 0.28g (94965 from theory).

MS(EB5I): (MN) 252. Fr

GE e0.05 (silica gel, EUDAs/Meon/mn" in the ratio 70:30:3). Ge")

Example AB

Methyl-1(2-(1-methylpiperidin-4-yl)ethylamine (example 10.32) - "t"

AvVa. (M,M-dimethyl-2-(1-methylpiperidin-4-yl)acetamide - with a solution of 9.3 g (5 mmol) of ethyl ether of H-methylpiperidinyl-4-acetic acid in 500 ml of a 4095% aqueous solution of methylamine was stirred for 15 hours . at 802C in a thick-walled glass tube sealed at one end. The solvent was then removed in vacuo and the residue was dissolved in EtOAc. The organic phase was dried over Mo5O and the solvent was removed in vacuo.

Yield: 4.7g (5595 from theory). -| E-e0.53 (silica gel, DCM/MeOH in the ratio 21:1).

Av8b. Methyl(|2-(1-methylpiperidin-4-yl)ethyl|amine

33.1 g (95) (20 mmol) of N,M-dimethyl-2-(1-methylpiperidin-4-yl)lacetamide in 4 Oml of THF was added dropwise to a solution of 1.1 g (ZOmmol) of lithium aluminum hydride in bOml of diethyl ether. Then the mixture for 2 hours. boiled with 50 reflux, after which it was left to stir overnight at RT. After adding water, bn. The solution was stirred again for 30 minutes. After filtration, the solvent was removed under vacuum. The residue was dissolved in diethyl ether, dried over Mo53O, and the solvent was removed under vacuum.

Output: 2.5g (8095 from theory).

Ee0.29 (alox, DHM/MeOynH in the ratio 21:1).

Example AZ9 o Cyclopentylmethylpiperidin-4-ylamine (example 10.41) ime) 60

Ada. (1-benzylpiperidin-4-yl)cyclopentylmethylamine

To a solution of 6.5 g (31.mmol) of (1-benzylpiperidin-4-yl)methylamine and 2.7 g (32.0 mmol) of cyclopentanone in 200 ml

6 ml (105 mmol) of glacial acetic acid was added to THF and the reaction mixture was stirred for 1 h. heated to 5596. 65 After cooling to 152, 10.6 bg (50.Omol) of Mavn(oOAc)" was added in portions and the reaction solution was left to stir overnight at room temperature. To complete the reaction, 33.0 g (14.2 mmol) of Movn(ods) was added again and stirred for the next few hours. at CT. Then 100 ml of water was carefully added, the pH value was set to alkaline with the help of Ma»CO»z, carefully extracted with diethyl ether, the combined organic phases were washed with water and concentrated in a vacuum. After removing the solvent, the residue was purified

Chromatography (silica gel, EtOAc/Meon/mN" in the ratio 9:1:0.3).

Output: 5.Ohm (5895 from theory).

MS(EI): (M)7-272.

GE e0.6 (silica gel, EUDADs/Meon/MH" in the ratio 9:1:0.3).

A9b. Cyclopentylmethylpiperidin-4-ylamine 70 To a solution of 5.0g (18.35mmol) of (1-benzylpiperidin-4-yl)cyclopentylmethylamine in 100ml of Meon, 1.0g of 1096 Ra/cС was added and the reaction mixture was added for were hydrogenated at CT and a pressure of 5 bar. After separating the catalyst by vacuum filtration and removing the solvent, the target product was obtained, which was used without purification in the next reaction.

Output: Z,Og (9095 from the theory).

GE e0.05 (silica gel, EUDAs/Meon/mn" in the ratio 9:1:0 4).

Example A10 4-(1,1-dioxo-15,5-isothiazolidin-2-yl)piperidine (example 10.46) with "АХ,

At1oa. 1-benzyl-4-(1,1-dioxo-15,9-isothiazolidin-2-yl)piperidine

3-chloro-propane-1-sulfonyl chloride was added dropwise to a solution of 19.0 g (1000 mmol) of 1-benzylpiperidin-4-ylamine and 27.2 g (197 mmol) of CoCO3 in 200 ml of acetonitrile SM at RT. Then the reaction solution was left to stand overnight. After filtration, the solvent was removed by distillation. The residue was dissolved in 120 ml of EUN and mixed with 6.2 g (111 mmol) of KOH. The mixture for an hour. boiled under reflux and acidified after cooling

NOAH The precipitate was separated by vacuum filtration and dried.

Output: 15.4g (46905 from theory). co

Melting point: 255-25720. high school

A106. 4-(1 1-dioxo-15/9-isothiazolidin-2-yl)piperidine

Similarly to example 17g, the target product was obtained from 16.5g (56.1mmol) of 1-benzyl-4-(1,1-dioxo-1XA8-isothiazolidin-2-yl)piperidine. Ge")

Output: 8.5g (7495 from theory).

Melting point: 89-9290. -

Ee0.13 (silica gel, DHM/MesynH in the ratio 8:2).

Example A 11 tert-Butylpiperidin-4-ylamine (example 10.50) "- c ;" 15 A11a. (1-benzylpiperidin-4-yl)-tert-butylamine -1 To a cooled to 09C solution of 24.ml (13 mmoles) of 1-benzylpiperidin-4-one and 5 ppm (519 mmoles) of tert-butylamine in 200 ml of toluene in an argon atmosphere, was added dropwise solution of 8.bml (78mmol) TiiCl / in is), 100ml of toluene in such a way that the internal temperature did not exceed 1520. Then the reaction mixture was left to stir overnight at room temperature, after which the precipitate that fell out was separated by vacuum filtration and in Vozchin , which remained after the addition of 5 mg of platinum oxide, was hydrogenated to the theoretical absorption of H »5. After the completion of hydrogenation, 1 ml of 2N was added to the suspension. Mahon's solution, filtered, the organic phase was separated, the aqueous solution was extracted three times with toluene, and the combined organic phases were dried over Mahon's solution. After removing the desiccant and solvent, the product was used without purification in the next reaction.

Yield: 13.9g (43905 from theory).

A116. tert-Butylpiperidine-4-ylamine

To a solution of 13.9 g (56.0 mmol) of (1-benzylpiperidin-4-yl)-tert-butylamine in 140 ml of Meon was added 1.5 g of (F. 1096 Ra/C) and the reaction mixture was hydrogenated at CT until the theoretical absorption of H 2 (2 hours). After the department

Dilution of the catalyst by vacuum filtration and removal of the solvent gave the target product, which was used without purification in the next reaction. in Output: 8.3g (9595 from theory).

Example A12 4-(2-methylimidazol-1-yl)upiperidine (example 10.58) b5 -58c-

A12a. tert-Butyl ether of 4-(2-methylimidazol-1-yl)/piperidine-1-carboxylic acid

To a solution of 2.0 g (21.92 mmol) of 2-methyl-1H-imidazole in 20 ml of DMF in a nitrogen atmosphere under RT in portions for 20 min. 1.0 g (22.92 mmol) of Mann (5595 g in mineral oil) was added, and the reaction mixture was then stirred for 30 min. 70 was stirred at this temperature. Next, a solution of 4.0 g (14.32 mmol) of tert-butyl ether of 4-methanesulfonyloxypiperidine-1-carboxylic acid in BOml of DMF was slowly added dropwise, and the reaction solution was then stirred for 2.5 hours. at 10020. After that, it was concentrated in a vacuum, the residue was dissolved in 150 ml

DCM, the organic phase was washed twice with water in portions of 5 Oml and dried over Mo5O. After removal of the desiccant and solvent, the residue without purification was used in the next reaction.

Yield: 0.65g (1790 from theory).

MS(EB5I): (Ma-H) -266.

Ee0.56 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2).

A126. 4-(2-methylimidazol-1-yl)piperidine

A solution of 6b5Omg (2.45 mmol) of tert-butyl ether of 4-(2-methylimidazol-1-yl)upiperidine-1-carboxylic acid was dissolved in 1Oml of 4-molar NOSI in 1,4-dioxane and the reaction mixture was stirred for 2 hours. stirred at CT. Then it was concentrated in vacuo, the residue was mixed with isopropyl ether and a small amount of isopropanol, the precipitate was separated by vacuum filtration and dried in an oven with air circulation. The target product was obtained in the form of dihydrochloride.

Output: 43Omg (7495 from theory). with

MS (EZUO: (MN) -166. o

Ee0.54 (silica gel, DXM/Meon/MH" in the ratio 75:25:5).

Example A13 4-(2,4-dimethylimidazol-1-yl)upiperidine (Example 10.61) with sch so (22)

At13Za. tert-Butyl ether of 4-(2,4-dimethylimidazol-1-yl)/piperidine-1-carboxylic acid -

The indicated compound was obtained similarly to example A12a from 2.2 g (22.20 mmol) of 2,4-dimethyl-1H-imidazole and 4.0 g (14.32 mmol) of tert-butyl ether of 4-methanesulfonyloxypiperidine-1-carboxylic acid.

Yield: 0.45g (11905 from theory). "

MS(EB5I): (MN) -280.

Ech20,51 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2). o) with A136. 4-(2,4-dimethylimidazol-1-yl)piperidine "" This compound was obtained similarly to example A126 from 450 mg (1.6 mmol) of tert-butyl ether " 4-(2,4-dimethylimidazol-1-yl)piperidine- 1-carboxylic acid. The target product was obtained in the form of dihydrochloride.

Output: Zb0Omg (7495 from the theory). 7 MC(EBI)(MAN) -180. (Te) GE e0.63 (silica gel, DXM/Meon/MH" in the ratio 75:25:5).

Example A14 o (1-methylpiperidin-4-yl)amide of piperazine-1-sulfonic acid (example 10.66) d) 50 siu» I ; iF) A14a. (1-methylpiperidin-4-yl)amide of 4-benzylpiperazine-1-sulfonic acid. To a solution cooled to 09C, 1.0g (8.7/bmmol) of 1-methylpiperidin-4-ylamine and 1.25ml (9.Ommol) 1.89 g (11, Ommol) of 1,3,2-benzdioxathiol 2,2-dioxide was added to triethylamine in 100 ml of DCM, the cooling bath was removed, and the reaction mixture was left to stir overnight at room temperature. It was then concentrated in vacuo, the residue was stirred with diethyl ether/diisopropyl ether, the crude product was filtered and dried.

Next, this crude product (2.5 g) and 3.16 g (17.4 mmol) of 1-benzylpiperazine were dissolved in a nitrogen atmosphere in 100 ml of 1,4-dioxane and the reaction mixture was stirred for 2 hours. boiled under reflux. Then it was concentrated in vacuo and the residue was purified by chromatography (silica gel, DCM/Meon/MchN" in the ratio 90:10:1). 65 Yield: 1.1g (3695 from theory).

MS(EBI): (MAN) -353.

Eche 0.50 (silica gel, DXM/MeoN/MN" in the ratio 80:20:1).

A146. Piperazine-1-sulfonic acid (1-methylpiperidin-4-yl)amide

To a solution of 1.1 g (3.12 mmol) of (1-methylpiperidin-4-yl)amide of 4-benzylpiperazine-1-sulfonic acid in 100 ml

Meon was added with 500 mg of 109o Ra/s and the reaction mixture was hydrogenated at CT until the theoretical absorption of H o (2.5 hours). After separating the catalyst by vacuum filtration and removing the solvent, the target product was obtained, which was used without purification in the next reaction.

Yield: 0.82g (10090 from theory).

MS(EB5I): (MN) -263. 70 GE e0.05 (silica gel, EUDAs/Meon/mN" in the ratio 90:10:1).

Example A15

Ethyl ether of 1-(1-methylpiperidin-4-yl)piperazine-2-carboxylic acid im dk

And 15a. 4-(1-Methylpiperidin-4-yl)piperazine-1,3-dicarboxylic acid 3-ethyl, 1-tert-butyl ester

The pH value of a solution of 1.0 g (3.87 mmol) of 3-ethyl, 1-tert-butyl piperazine-1,3-dicarboxylic ether

Acids and 0.45 ml (3.87 mmol) of 1-methylpiperidin-4-one in 25 ml of THF were adjusted to values in the range from 5 to b with the help of glacial acetic acid, after which 1.0 g (4.48 mmol) of Mavn(ogAs ) with and the reaction mixture was left to stir overnight at RT. To complete the reaction, Tml (8.bmmol) 1-methylpiperidin-4-one and 0.2g (00.bmmol) Mavn(oOAc) were added again and stirred for the next 2 hours. at CT. Next, the excess Mavn(OAs)z was decomposed by adding a small amount of water, the mixture was saturated with K»COz Ga | stirred Then K»oCO3 was filtered and the organic phase was concentrated and purified by chromatography (silica gel, EtOAc/Meon/mChN in the ratio 90:10:1). and)

Yield: 0.78g (5790 from theory).

MS(EB5I): (Ma-H) -356.

GE e0.46 (silica gel, EUDAs/Meon/mn" in the ratio 80:20:2). co

A156. 1-(1-Methylpiperidin-4-yl)piperazine-2-carboxylic acid ethyl ester

To a solution of 0.7 in 8 g (2.20 mmol) of 3-ethyl, 1-tert-butyl ether cm 4-(1-methylpiperidin-4-yl)piperazine-1,3-dicarboxylic acid in 30 ml of DCM while cooling with ice was added so 2, 0ml of TFOK and the reaction mixture during stirred at CT. Then it was concentrated in a vacuum and the product, which was obtained in the form of a tristrifluoroacetate salt, was used without purification in the next reaction. F

Output: quantitative. -

MS(EI): (M) -255.

Eche 0.11 (silica gel, EUDAs/Meon/mn" in the ratio 70:30:3).

Example A16 "

Ethyl ether of 4-(1-methylpiperidin-4-yl)piperazine-2-carboxylic acid - c;» in and A 16ba. 3-ethyl, 1-tert-butyl ether of 4-benzylpiperazine-1,3-dicarboxylic acid (Ce) To a solution of 10.69 g (41.39 mmol) of 3-ethyl, 1-tert-butyl ether of piperazine-1,3-dicarboxylic acid acid and 7.32 ml (42 mmol) of ethyldisopropylamine in 150 ml of THF was added dropwise to a solution of 5.00 ml (42.10 mmol)

Add benzyl bromide in 5 Oml of THF, stir for 2 hours. at CT and then during the Agreement. boiled with a reflux co 20 refrigerator. To complete the reaction, 0.5 ml (4.21 mmol) of benzyl bromide was added again and refluxed for another 3 hours. Then, after cooling, the reaction solution was filtered, the filtrate was concentrated in a vacuum and the residue was purified by chromatography (silica gel, Sus/E(OAc in the ratio 8:2).

Output: 13.04g (9090 from theory).

MS(EBI): (MeN)" -349.

HF) Eche 0.51 (silica gel, Sus/EUAs in the ratio 8:2). 7 A166. Ethyl ether of 1-benzylpiperazine-2-carboxylic acid

To a solution of 13.04 g (37.42 mmol) of 3-ethyl, 1-tert-butyl ether of 4-benzylpiperazine-1,3-dicarboxylic acid in 200 ml of DCM while cooling with ice was added Zb5 ml of TFOK and the reaction mixture for 5 hours. because they stirred during CT. Then it was concentrated in a vacuum and the product, which was obtained in the form of a bistrifluoroacetate salt, was used without purification in the next reaction.

Output: quantitative.

MS(EBI): (MN) -249. 65 A16v. 1-Benzyl-4-(1-methylpiperidin-4-yl)piperazine-2-carboxylic acid ethyl ester

To a solution of 8.15 g (17.11 mmol) of ethyl ether of 1-benzylpiperazine-2-carboxylic acid (which was used in the form of a bistrifluoroacetate salt) and 2.05 ml (17.22 mmol) of 1-methylpiperidin-4-one in 200 ml

THF was added with 4.0 g (17.9 mmol) of Mavn(oOAs)» and the reaction mixture was left to stir overnight at RT. Then it was concentrated in vacuo and the residue was purified by chromatography (silica gel, gradient elution: with a change from

EUAs to EOAs/Meon/mn" in the ratio 50:50:2).

Yield: 5.91g (100905 from theory).

MS(EB5I): (MN) -346.

Ee0.53 (silica gel, EUDAs/Meon/mn" in the ratio 80:20:2).

A16g. 4-(1-methylpiperidin-4-yl)piperazine-2-carboxylic acid ethyl ether 70 To a solution of 5.91 g (17.11 mmol) of 1-benzyl-4-(1-methylpiperidin-4-yl)piperazine-2-ethyl ether -carboxylic acid, 0.5 g of PaY(OH)" and the reaction mixture were added to 150 ml of ЕУН for 33.5 hours. hydrogenated at CT and a pressure of 3 bar. After separating the catalyst by vacuum filtration and removing the solvent, the target product was obtained, which was used without purification in the next reaction.

Output: 4.44g (100905 from theory).

MS(E5I): (MAN) -256.

GE e0.24 (silica gel, EUDAs/Meon/mn" in the ratio 70:30:3).

Example A17

Ethyl ether of 1-methyl-4-piperidin-4-ylpiperazine-2-carboxylic acid em mito

And 17a. 3-ethyl, 1-tert-butyl ester of 4-methylpiperazine-1,3-dicarboxylic acid c

To a solution of 5.04 g (19.51 mmol) of 3-ethyl, 1-tert-butyl ether of piperazine-1,3-dicarboxylic acid and g)

A solution of 1.25 mL (19.90 mmol) of iodomethane in 20 mL of THF was slowly added dropwise to 4 ml (19.52 mmol) of ethyldiisopropylamine in 10 ml of THF at CT, after which the reaction mixture was stirred for 20 hours, and then heated to 602C and kept at this temperature for According to For complete completion of the reaction, 0.2 ml (3.18 mmol) of iodomethane was added again and kept for the following hours. at 75 2С. After cooling and. components that did not dissolve were filtered off, the filtrate was concentrated and the residue was purified by He chromatography (silica gel, EOАСС).

Yield: 4.2g (7995 from theory). at

MS(EB5I): (MAN) -273. (22)

Eche 0.58 (silica gel, EUAcC). m

A176. Ethyl ether of 1-methylpiperazine-2-carboxylic acid

To a solution of 4.20 g (15.42 mmol) of 3-ethyl, 1-tert-butyl ether of 4-methylpiperazine-1,3-dicarboxylic acid in 10 ml of DCM under ice cooling, 20 ml of TFOK was added and the reaction mixture was stirred for 1 hour. at CT. Then it was concentrated in a vacuum and the product, which was obtained in the form of a bistrifluoroacetate salt, was used in the next reaction without purification. -

Output: quantitative. with MS(EBI)(M AN) -173. :z" Ee0.16 (silica gel, EUDAs/Meon/mn" in the ratio 70:30:3).

A17c. 4-(1-Benzylpiperidin-4-yl)-1-methylpiperazine-2-carboxylic acid ethyl ester

To a solution of 6.17 g (15.41 mmol) of ethyl ether of 1-methylpiperazine-2-carboxylic acid (used -1 in the form of a bistrifluoroacetate salt) and 3.77 ml (19.93 mmol) of 1-benzylpiperidin-4-one in 10 ml of THF was added in portions 4.5 g (20.17 mmol) of Movn(oOAc) and the reaction mixture was stirred for 2 hours. at CT. Excess re) Meon(OdAc)z was decomposed by adding a small amount of water, the reaction solution was concentrated in vacuo, and the residue was purified by chromatography (silica gel, gradient elution with a mixture of EtOAc/Meon/mMChNz in a ratio varying from 90:10:1 to 80: 20:2). name) Output: quantitative. 4) MS(EBI)(MaN) -345.

GE E0.41 (silica gel, EUDAs/Meon/mn" in the ratio 80:20:2).

A17g. 1-Methyl-4-piperidin-4-ylpiperazine-2-carboxylic acid ethyl ester

To a solution of the crude product from example A17b in 200 ml of EN, 1 g of 1095 Ra/sC was added and the reaction mixture was hydrogenated for 17.5 hours. at KT and pressure No» Z bar. After separation of the catalyst by vacuum filtration and (F, removal of the solvent), the target product was obtained, which was used without purification in the next reaction. Yield: 5.32 g (10095 from theory, based on the compound from example A17a).

MS(E5I): (MAN) -256. 60 EE0.1 (silica gel, EUDADs/Meon/MH" in the ratio 50:50:5).

Example A18

4-Methyl-1-piperidin-4-ylpiperazine-2-carboxylic acid ethyl ester

At18a. Ethyl ether of 1-benzyl-4-methylpiperazine-2-carboxylic acid

To a solution of 10.3 g (21.64 mmol) of ethyl ether of 1-benzylpiperazine-2-carboxylic acid (see example A166, 70 used in the form of a bistrifluoroacetate salt) and 12 ml (68.89 mmol) of ethyldiisopropylamine in 200 ml of THF, solution 1 was slowly added dropwise .4 ml (22.29 mmol) of iodomethane in 5 O ml of THF and the reaction mixture was left to stir overnight at RT. To complete the reaction, 0.2 ml (3.18 mmol) of iodomethane was added again and stirred for the next 2 hours. at CT. The precipitate that formed was filtered off, the filtrate was concentrated in vacuo and the residue was purified by chromatography (silica gel, EHUOAc/Meo/MNUz. In the ratio of 75...90:10:1).

Yield: 4.1g (7295 from theory).

MS(E5I): (MaMa) -285.

GE e0.83 (silica gel, EUAs/Meon/MnH" in the ratio 90:10:1).

A186. Ethyl ether of 4-methylpiperazine-2-carboxylic acid

To a solution of 4.1 g (15.63 mmol) of 1-benzyl-4-methylpiperazine-2-carboxylic acid ethyl ether in 100 ml

45 mg of 1095 Ra/cС was added to the EUN and the reaction mixture was hydrogenated for 11 hours. at CT and No pressure of 5 bar. To complete the reaction, 450 mg of RaY(OH)" was added and the reaction mixture was hydrogenated for the next 2.5 hours. at 502 and pressure No» Z bar. After that, the catalyst was separated by vacuum filtration, the filtrate was concentrated, and the residue was purified by chromatography (silica gel, EtOAc/Meon/Mn»z in the ratio 80:20:2). with

Yield: 2.18g (8195 from theory). at

MS(EBI)(M AN) -173.

Ee0.56 (silica gel, EUDAs/Meon/mn" in the ratio 80:20:2).

A18c. 1-(1-Benzylpiperidin-4-yl)-4-methylpiperazine-2-carboxylic acid ethyl ester

The pH value of a solution of 1.58 g (9.17 mmol) of ethyl ether of 4-methylpiperazine-2-carboxylic acid and 1.68 ml of i. (9.2 mmol) of 1-benzylpiperidin-4-one in 30 ml of THF was adjusted to 5 using glacial acetic acid, after which 2.2 g (9.8 mmol) of Mavn(oOAc) were added in portions and the reaction mixture was left to stir overnight at CT. Next, the excess Mavn(OAc)z was decomposed by adding a small amount of water, and the reaction solution was dried over Co»CO3. The supernatant was decanted, concentrated in vacuo, and the residue was purified by chromatography (silica gel, gradient elution: with a change from E(Ac) to EFAsC/Meon/mnmn with a ratio of 90:91).

Output: 0.71g (22905 from theory).

MS(EB5I): (MN) -346.

E0.84 (silica gel, EOAc/Meon/mMnH" in the ratio 70:30:3). "

At18 Ethyl ether of 4-methyl-1-piperidin-4-ylpiperazine-2-carboxylic acid - about 70 To a solution of 2.28 g (b,bmmol) of ethyl ether 1-(1-benzylpiperidin-4-yl)-4-methylpiperazine-2 -carboxylic acid with 200 mg of Ra(OH)" was added to 100 ml of EYN and the reaction mixture was hydrogenated for 9.5 hours. at KT and pressure No Z:z» bars. To complete the reaction, 100 mg of Ra(OH) was added again, and the reaction mixture was hydrogenated for the next few hours. After that, the catalyst was separated by vacuum filtration, the filtrate was concentrated, and the residue without purification was used in the next reaction. -1 15 Yield: 1.7g (10095 from theory).

MS(EB5I): (MN) -256. se) Eche 0.21 (silica gel, EUDAs/Meon/mn" in the ratio 60:40:4). Example A19 tert-Butyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid g) 50 s dust

A19a. tert-Butyl ether of 1-(4-(1-benzylpiperidin-4-yl)piperazin-1-yl) acetic acid o To a solution of 74 g (12 mmol) of 1-(1-benzylpiperidin-4-yl)piperazine (which was used in the form of tristrifluoroacetate salt) and acetonitrile, 100 g (709 mmol) of K»CO» were added and the suspension was stirred at room temperature for 1 h. After that, 20 ml (13 mmol) of tert-butyl bromoacetic acid ether was added. Then the reaction mixture was stirred at room temperature for 1 h and dried was mixed with Mo5O. After that, the components that did not dissolve were filtered off, the solvent was evaporated in a vacuum, the residue was mixed with water, the formed precipitate was separated by filtration and dried at 502C in a drying cabinet with air circulation.

Output: ЗОг (6596 from the theory).

MS(EB5I): (MAN) -374.

Ech20,51 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2). because A196. tert-Butyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid

Bg 10956 Ra/С was added to a solution of 30 g (80.3 mmol) of tert-butyl ether (|4-(1-benzylpiperidin-4-yl)piperazin-1-yl|acetic acid in 30 ml of THF and the reaction mixture was hydrogenated at 502С and a pressure of 3 bar to the theoretical absorption of Н 5. After separation of the catalyst by vacuum filtration and removal of the solvent, the target product was obtained, which was used without purification in the next reaction.

Output: 22.3g (98905 from theory).

MS(EB5I): (MN) -284.

Ee0.17 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2).

Example A2O 70 Ethyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid

Ag0a. 4-(4-Ethoxycarbonylmethylpiperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ether

To a cooled to room temperature solution of 4.0 g (13.0 v8 mmol) of 4-piperazin-1-ylpiperidine-1-carboxylic acid tert-butyl ether (which was used in the form of hydrochloride) and 6 g.54 ml (39.233 mmol) of ethyldiisopropylamine in 100 ml of acetonitrile was added a solution of 1.42 ml (13.3 mmol) of ethyl chloroacetic acid in 1 ml of acetonitrile. After removing the cooling bath, Maya was added on the tip of the spatula and the reaction mixture was left to stir overnight at RT. It was then mixed with a saturated Manso solution, carefully extracted with DCM, and the organic phase was dried over Ma»5O). After removal of the desiccant and solvent, the residue without purification was used in the next reaction.

Yield: 4.25g (91905 from theory).

MS(E5I): (MAN) -356. with

GE 20.67 (silica gel, DXM/MesynH in the ratio 9:1). Gee)

A206. (4-piperidin-4-ylpiperazin-1-yl)acetic acid ethyl ester

To a solution of 4.25 g (11.9 bmmol) of tert-butyl ester of 4-(4-ethoxycarbonylmethylpiperazin-1-yl)upiperidine-1-carboxylic acid in 80 ml of DCM, bml of TFOK was added to a solution of 4.25 g (11.9 bmmol) of 4-(4-ethoxycarbonylmethylpiperazin-1-yl)upiperidine-1-carboxylic acid, cooled to room temperature, and the reaction mixture was left to stir overnight at room temperature. Then it was concentrated in a vacuum, the residue was mixed with o-tert-butyl methyl ether, the precipitate was separated by vacuum filtration and the product obtained in Ge! in the form of a tristrifluoroacetate salt.

Output: 6.7g (9495 from theory). Shk

MS(EBZI)(MaN) -256. (22)

E-e0.38 (silica gel, DXM/Meon/MmN" in the ratio 75:25:5). and -

Example A21

Ethyl ether of 14,4Dbipiperidinyl-1-ylacetic acid, also known as Aga. tert-Butyl ether of 1"-ethoxycarbonylmethyl-|(44Dbipiperidinyl-1-carboxylic acid » Analogously to example A 19a with 8.40 g (31.1 mmol) of tert-butyl ether (|4.4LDbipiperidinyl-1-carboxylic acid and C3, 53 ml (31.1 mmol) of ethyl bromoacetic acid obtained the target product.

Yield: 9.4g (8595 from theory).

Sh- MS(E)(M)7-355. so GE e0.64 (silica gel, EUAs/Meon in the ratio 9:1).

A216. Ethyl ether of 14.4-bipiperidinyl-1-ylacetic acid o Similarly to example A206 with 7.50 g (21.2 mmol) of tert-butyl ether

GI 20 of 1-ethoxycarbonylmethyl-I4,4|bipiperidinyl-1-carboxylic acid obtained the target product in the form of a bistrifluoroacetate salt. byu" Output: 10.1g (99965 from theory).

MS(EBI)(M AN) -255.

Ee0.15 (silica gel, DCM). 52 Example A22

HF) Ethyl ether (4-piperazin-1-ylpiperidin-1-yl) acetic acid ime) 60

A22a. 4-(4-benzylpiperazin-1-yl)/piperidine-1-carboxylic acid tert-butyl ether

The pH value of a solution of 66b.7ml (38immol) of 1-benzylpiperazine and 75.bg (333vOmole) of tert-butyl ether of 4-oxopiperidine-1-carboxylic acid was set to 5 with the help of glacial acetic acid. Then be Within 2 hours. while cooling with ice, 100 g (Zv8Omole) of Mavn(OAs) 3 was added and the mixture was left to stir overnight at room temperature. Next, the reaction mixture was basified with a solution of KSO3 (300 g/l), stirred for an hour at room temperature and extracted three times with EtOAc. The organic phase was dried over Mo50O), and the solvent was removed in vacuo.

Output: 114g (8395 from theory).

MS(EBI): (Ma-N) -369.

GE 0.74 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

A226. 1-benzyl-4-piperidin-4-ylpiperazine

Similarly to example A206b, from 40.0 g (111 mmol) of tert-butyl ether of 4-(4-benzylpiperazin-1-yl)upiperidine-1-carboxylic acid, the target product was obtained in the form of 70 tristrifluoroacetate salt.

Yield: 54.8g (82905 from theory).

MS(EB5I): (MN) -260.

Ee0.18 (silica gel, DXM/Sus/Meon/mn" in the ratio 70:15:15:2).

A22c. Ethyl ether (4-(4-benzylpiperazin-1-yl)piperidin-1-yl|!acetic acid

Similarly to example A 19a, the target product was obtained from 51.8 g (8 mmol) of 1-benzyl-4-piperidin-4-ylpiperazine (which was used in the form of tristrifluoroacetate) and 10.3 ml (9 mmol) of ethyl bromoacetic acid.

Output: 25.3g (85905 from theory).

MS(EI): (M) -346.

Ee0.58 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

A22g. (4-piperazin-1-ylpiperidin-1-yl)acetic acid ethyl ester

Similarly to example A196 with 25.3 g (73.3 mmol) of ethyl ether

I(4-(4-benzylpiperazin-1-yl)piperidin-1-yl|ioacetic acid gave the target product. This product contained 5990 methyl ester of (4-piperazin-1-ylpiperidin-1-yl)acetic acid. c

Output: 17.4g (93905 from theory). at

MS(E5I): (MAN) -256 and for methyl ether: (MAN) -242.

E20.15 (silica gel, DCM/Sus/Meon/mN" in the ratio 70:15:15:2).

Example A23 1-2,2,2-trifluoroethyl)-I4 4Dbipiperidinyl me) sch aa o (22)

Ag2Za. tert-Butyl ether of 1-(2,2,2-trifluoroacetyl)-I4,4Dbipiperidinyl-1-carboxylic acid M

Similarly to example A7a, the target product was obtained from 15.0 g (55.9 mmol) of tert-butyl ether of C|4,4Dbipiperidinyl-1-carboxylic acid.

Output: 19.Ohm (93905 from theory).

MS(E5I): (Mother) -387. "

A236. tert-Butyl ether of 1'-(2,2,2-trifluoroethyl)-I4 4|bipiperidinyl-1-carboxylic acid - c Similarly to example A7b with 20.7 g (56.7 mmol) of tert-butyl ether there is 1-(2 ,2,2-trifluoroacetyl)-I4,A4bipiperidinyl-1-carboxylic acid gave the target product. "» Yield: 19.9g (100905 from theory).

MS(EBI)(M AN) -351.

GE e0.78 (silica gel, PE/EUAs in the ratio 1:1) - and A2g3Zv. 1-(2,2,2-trifluoroethyl)-(4,4bipiperidinyl) Analogously to example A206b with 21.4 g (61.1 mmol) of tert-butyl ether 1-(2,2,2-trifluoroethyl)-I4,4Dbipiperidinyl- 1-carboxylic acid gave the target product in the form of (95) bistrifluoroacetate.from 50 Yield: 26.8g (92965 from theory).

MS(EBZI)(MaN) -251. s" Eche 0.17 (silica gel, DCH/MeoN/MH" in the ratio 9:1:0.1).

Example A24

Dimethyl (|3-(4-piperazin-1-yl phenyl)propyl) amine

F) ime) 60 Ag4a. 1-I4-(4-benzylpiperazin-1-yl)phenylthetanone

A solution of 35.3 g (200 mmol) of benzylpiperazine and 13.8 g (100 mmol) of 4-fluoroacetophenone in 34 ml (200 mmol) of ethyldiisopropylamine was refluxed for 2 days. After cooling, the residue was mixed with tert-butyl methyl ether, subjected to vacuum filtration and air-dried. The product without purification was used in the next reaction. b5 Yield: 12.2g (4296 from theory).

MSc(EI!): (M)7-294.

Eche 0.53 (silica gel, PE/EUdAs in the ratio 3:2).

A246. 1-(I4-(4-benzylpiperazin-1-yl)phenyl|-3-dimethylaminopropan-1-one

To a solution of 6.9 g (23.4 mmol) of 1-I4-(4-benzylpiperazin-1-yl)/uphenyl|iethanone and 2.90 g (35.0 mmol) of dimethylamine hydrochloride in T0bml of EYN and 10ml of conc. 1.40 g of paraformaldehyde was added to NSI. Then the reaction mixture for 20 hours. boiled under reflux. After that, the solvent was removed in vacuo and the residue was mixed with acetonitrile. The sediment was separated by vacuum filtration and dried at 302C in a drying cabinet with air circulation.

Yield: 4.4 g (48965 from theory in the form of hydrochloride). 70 MS(E)(M) -351.

Eche 0.35 (silica gel, DCH/EUAc/Sus/mMeon/mMH" in the ratio 60:16:5:5:0.6).

Ag24v. Dimethyl3-(4-piperazin-1-ylphenyl)propylamine

To a solution of 8.00g (20.bmmol) of 1-I4-(4-benzylpiperazin-1-yl)phenyl|-3-dimethylaminopropan-1-one in 6b.7ml of conc.

NSI and Zobml Meon added 2g of 1095 Ra/S. Then the reaction mixture during the Accord. stirred at 75 bar pressure and at a temperature of 5020. After filtration, the filtrate was evaporated to dryness. The residue was mixed with

EUN and EOAs and left to mix for the night. Next, the sediment was subjected to vacuum filtration in a nitrogen atmosphere and dried at 202C in a drying cabinet with air circulation.

Yield: 5.7g (86905 from theory in the form of dihydrochloride).

MS(E!): (M)7-247. mE9.35 DHM/Sus/Meon/ MN" in the ratio 70:15:15:2).

Other amines used in the preparation of the final compounds are commercially available products or were obtained by methods known from the literature.

Preparation of final compounds

Example 1 with (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-( 2-oxo-1,2,4 o,o-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione

E so sch so o. F with ks sn, in « 40 . - s:z» 1a. (4-amino-3-chloro-5-trifluoromethylphenyl)methanol

To a solution of 93.4 g (0.39 mol) of 4-amino-3-chloro-5-trifluoromethylbenzoic acid (described in Aggpeit.-Rogzsp.,

ZA(11A), 1984, pp. 1612-16241 vol. of THF was added to 69.56 g (0.4 Zmola) of KDI and the mixture was stirred for an hour. at -1,395,402s. Next, the reaction mixture was carefully added to a solution of 51.4 g (1.3 bmol) of Mavn in 4500 ml of water at RT in a nitrogen atmosphere while cooling. Then the mixture for 2 hours. stirred at CT, mixed with 500 ml of water and se) ZOOml semi-conc. NSI, stirred for the next hour, and then thoroughly extracted with EUAs. United these org. phases were dried over Ma»5O,) and concentrated in vacuum. The remaining oil was mixed with 5000 ml of PE and stirred while cooling with ice. The precipitate was separated by vacuum filtration, washed with PE and dried. ime) 20 In this way, 29.7 g of the target product were obtained. The mother liquor was re-mixed with PE and cooled. The resulting precipitate was again washed with PE and dried.

In this way, another 21.8 g of the target product was obtained.

Yield: 51.5 g (5995 from theory) of a white solid.

Ee0.73 (silica gel, PE/EUdAs in the ratio 1:1). and 16. 4-amino-3-chloro-5-trifluoromethylbenzaldehyde

HF) A mixture of 17.0 g (754 mmol) of (4-amino-3-chloro-5-trifluoromethylphenyl)methanol, 100 g (1.15 mol) of manganese dioxide, and 30 mL of DCM was left to stir overnight at room temperature. Next, the precipitate was separated by vacuum filtration and the solution was concentrated under vacuum. In this way, the target product was obtained in the form of a white solid. in Output: 16.Ohm (95905 from theory).

MS(E5I): (MAN) -224/226 (SI). 1 c. Diethyl ether (2-(1H-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl|phosphonic acid

A solution of 168.0 g (0.5 mol) of (K)-4-benzyl-3-(2-bromoacetyl)oxazolidin-2-one and 188.0 ml (1.1 mol) of triethyl phosphite was stirred for 1.5 hours. at 602C, while driving off the ethyl bromide that is formed. b5 Then the reaction mixture was evaporated in a vacuum and the obtained residue was purified by chromatography on silica gel. In this way, the target product was obtained in the form of a yellow-brown oil.

Yield: 130g (6595 from theory).

MS(EB5I): (Ma-H) -356. 1g... 1n-3-KE)-3-(4-amino-3-chloro-5-toifluoromethylphenyl)acryloyl|-4-benzyloxazolidin-2-one

3.93 g ( 90.0 mmol) Man (55905 in mineral oil). Next, the reaction mixture was stirred for 30 minutes. during CT, and then within 35 minutes. at 35920. After the gas evolution process was completed, 16.0 g (71.5 mmol) of 4-amino-33-chloro-5-trifluoromethylbenzaldehyde, dissolved in BOml TIF, was added dropwise, and 70 was stirred for the next 12 hours. at CT. Then the reaction solution was mixed with a saturated solution

MNACI, the mixture was carefully extracted with EtOAc and the combined extracts were dried and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel. In this way, the target product was obtained in the form of a yellow oil.

Output: 38.2g (62905 from theory).

MS(EBI): (MAN) -425/427 (SI).

E20.55 (silica gel, PE/E (AcC in the ratio 2:1). d.. 1n-3-I3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionyl|-4-benzyloxazolidin-2-one

A mixture of 23.7 g (55.8 mmol) (Kk)-3-KE)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)acryloyl|-4-benzyloxazolidin-2-one, 400 ml Meon and 5, 0 g of Raney nickel for 2 hours. shaken in a Parr autoclave at RT and a pressure of H 5 C bar. After that, the catalyst was separated by vacuum filtration and the solvent was removed in vacuo. In this way, the target product was obtained in the form of a yellow oil.

Yield: 22.5g (95905 from theory).

MS(EB5I): (MAN) -427/429 (SI). with 1e. tert-Butyl ether (3 (5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-(1H-4-benzyl-2-oxoxazolidin-3-yl)-4-oxobutyric acid

To a cooled to -789C solution of 22.5 g (52.71 mmol) (/2)-3-(3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionyl|-4-benzyloxazolidin-2-one in 105 ml of THF 63.24 ml (63.24 mmol) of sodium bis(trimethylsilyl)amide solution (1-molar in THF) was added dropwise in an argon atmosphere, and the mixture was stirred at -782 C for 2 hours. Then, 38 was added dropwise to the reaction mixture at -782 C. 9 ml (263.5 mmol) of bromoacetic acid tert-butyl ether, after which the reaction mixture was stirred for another 24 hours at -782 C and then heated to RT. After adding 200 ml of a saturated solution of MH/Cl twice and extracting E(Ac in 30 ml portions , combined organic phases were dried over Ma»5O,) and concentrated in a vacuum F)

The resulting residue was purified by chromatography on silica gel. In this way, the target product was obtained in the form of 39 yellow oil. -

Output: 15.6 bg (55905 from theory).

MS(EBI): (MN) -541/543 (SI).

Eche 0.35 (silica gel, PE/EUdAs in the ratio 8:2). « 20 1 g of 4-tert-butyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid - in s To a solution of 2.51 g (57 mmol) of lithium hydroxide hydride in 150 ml of water was added 11 .75 ml (115.1 mmol) H 2505 (3590 in water). This mixture was then added dropwise to an ice-cooled solution of 15.6 g (28.8 mmol) of tert-butyl ether (5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-((K )-4-benzyl-2-oxoxazolidin-3-yl)-4-oxobutyric acid. in 15 bOOml of THF and the reaction mixture was stirred for the next 2 hours. when cooled with ice. Next, 150 ml of saturated sodium sulfite solution was added to -1 reaction mixture and acidified with citric acid solution.

Org. phase was separated, dried and concentrated in vacuo. In this way, 15.6 bg of viscous yellow (se) oil was obtained. The aqueous phase was carefully extracted with EOAc, combined org. phases were washed with water, dried and concentrated in vacuo. In this way, an additional 5.5 g of yellow oil was obtained. The crude product, which still contained N)-A-benzyloxazolidin-2-one, was used without purification in the next reaction. ime) 20 Yield: 21.1 g of crude product. "Fo" MS(EBI): (MAN) -380/382 (SI). 13. tert-Butyl ether (5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4- oxobutyric acid

A mixture of 15.4 g (40.3 mmol) of 4-tert-butyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid, 7.4 g (40.3 mmol) (1-methyl -4-piperidin-4-yl)piperazine, 5.45g (40.mmol) HOBT, 12.94g (40.mmol) (F) TBTU, 11.77ml (85.0mmol) triethylamine and 40b0ml THF were mixed for 12 hours. at CT. Then the mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc and Manso solution. Org. phase was separated, dried and concentrated in vacuo. The resulting residue was purified by chromatography on aluminum oxide. In this way, the target product was obtained in the form of a yellow oil.

Output: 11.Ohm (50905 from theory).

MS(E5I): (MAN) -547/549 (SI).

E-e0.35 (alox; EYUAS/DHM in the ratio 6:4). 1st (5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-(4--4-methylpiperazin-1-yl)piperidin-1-yl|-4-oxobutyric acid

To a solution of 7.0 g (12.mmol) tert-butyl ether

(5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-oxobutyric acid in 375 bml of acetonitrile was added 5 .75 g (38.44 mmol) of MA, 3 ml of anisole and 4.92 ml (38.4 mmol) of trimethylsilyl chloride. The reaction mixture was stirred for 1 hour at 40 2C, 5.75 g (38 v.4 mmol) of MA and 4.92 ml (38 .4 mmol) of trimethylsilyl chloride and stirred for another 2 hours at 40°C.

Then the mixture was concentrated in a vacuum and the crude product was used in the next reaction. 1 k. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione

A mixture of b,3g (12,mmol) (5)-3-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl| -4-oxobutyric acid, 3.16bg (12.b9mmol) Z-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one, 4.6bg (14.5mmol)

TBTU, 1.96 g (14.5 mmol) of HOBT, 9.45 ml (bvmmol) of triethylamine and 10 ml of DMF were mixed for 12 hours. at

CT. Then the reaction mixture was concentrated in vacuo, the residue was partitioned between EtOAc and a saturated solution of 75 Manso". Org. phase was separated, dried and concentrated in vacuo. The residue was purified by silica gel chromatography. The obtained yellow oil was triturated with ether and subjected to vacuum filtration. In this way, the target product was obtained in the form of a white solid.

Yield: 3.8 g (39905 from theory).

MS(EBI): (MAN) -718/20 (SI).

GE e0.22 (silica gel, EUAs/Meon/mn" in the ratio 70:30:3).

Example 2 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-(4,Abipiperidinyl-1-yl)-4-I4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)piperidin-1-yl|Ibutane-1,4-dione

Y She: Kk so

From her! I. sch

KATdtTtlurit y 9 y se ' cha v. 2a. 2-chloro-d-chloromethyl-6-trifluoromethylphenylamine

To a solution of 1.00g (4.44mmol) of (4-amino-3-chloro-5-trifluoromethylphenyl)methanol in 100ml of DCM at RT, 0.94ml (13.00mmol) 5OSI was added and the mixture was stirred for 10 minutes. at CT. Then the reaction mixture was poured onto ice - and the aqueous phase was carefully extracted with DCM. United org. the phases were washed with an ice-cold solution of MnSOO»z, dried over MnSOO», filtered through activated carbon and concentrated in a vacuum. The crude product without additional purification was used in the reaction at the next stage.

Yield: 1.08g (quantitative yield).

MS(E)): M" -243/245/247 (C15). -1 GE e0.81 (silica gel, PE/EUdAs in the ratio 2:1). 26. tert-Butyl ether 4-(4-amino- 3-chloro-5-trifluoromethylphenyl)-3,3-bisethoxycarbonylbutyric acid d) To a solution of 1.20 g (4.4 mmol) of 4-ethyl, 1-tert-butyl ether of 3-ethoxycarbonylsuccinic acid in 5 ml of absolute THF in a nitrogen atmosphere while cooling with ice, 193 µg (4.4 µmol) of Mann (5595 in mineral oil) was added in portions, and the mixture was stirred for an hour at room temperature. Then, 1.1 g (4.43 mmol) of 2-chloro-4-chloromethyl- b-trifluoromethylphenylamine, dissolved in 1 Oml of absolute THF, and the mixture was stirred for 16 h at RT. Then the reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc. The organic phase was dried over Moss and concentrated in vacuo. The crude product without additional purification was used in the reaction at the next stage.

Yield: 2.1g (9895 from theory).

MS(EBI): (MAN) -482/484 (SI). (F) GE e0.48 (silica gel, PE/EUdAs in the ratio 4:1). ka 2c. 4-(4-amino-3-chloro-5-trifluoromethylphenyl)-3,3-bisethoxycarbonylbutyric acid

To a solution of 30,00 (62.25 mmol) tert-butyl ether bo 4-(4-amino-3-chloro-5-trifluoromethylphenyl)-3,3-bisethoxycarbonylbutyric acid in 200 ml of DCM under ice cooling was added 20 ml of TFOC and the mixture was stirred for 1 day at CT. Then the reaction mixture was concentrated in vacuo and the residue was recrystallized from PE. The precipitate was filtered off, washed with PE and dried.

Yield: 23.6 bg (89905 from theory). 65 MS(EBI): (М-Н) -424/426 (SI). 2 years Diethyl ether

2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(2-oxo-2-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1 -yl|et yl)malonic acid

To a solution of 8.00 g (19.Omol) of 4-(4-amino-3-chloro-5--trifluoromethylphenyl)-3,3-bisethoxycarbonylbutyrate

ACIDS, 4.39g (19.00mmol) Z-piperidin-4-yl-3,4-dihydro-THA-quinazolin-2-one, 6.00g (18.0mmol) TBTU and 2.75g (18.0mmol) 3.2 ml (23.0 mmol) of triethylamine was added dropwise to HOBT in 100 ml of THF, and the mixture was stirred for 1 hour. at CT. The solid that formed was filtered off, washed with diethyl ether and dried under vacuum. Yield: 10.45g (87905 from theory). 2d 70 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3Z-yl)ipiperidin-1-yl| Oil on acid

To a solution of 10.00 g (15.65 mmol) of diethyl ether 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-12-oxo-2-(4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)piperidin-1-yl|ethilumalonic acid was added to bbOml of EN with 3.13g (78.25mmol) of Mahon dissolved in 30Oml of water, and the 7/5 mixture was refluxed for 4 hours After that, EUN was evaporated in a vacuum, the reaction mixture was acidified with concentrated HCl to pH 1 and stirred for 1 h at room temperature. The precipitate that formed was filtered, washed with water and dried in a vacuum.

Yield: 8.01g (95905 from theory). 2e. 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-I4,А4bipiperidinyl-1-yl)-4-I4-(2-oxo-1,4-dihydro-2H-quine zolin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione

To a solution of 0.8 mg (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3Z) -yl)ipiperidin-1-yl|Ibutyric acid, 0.28g (1.50mmol) 1-methyl-14,4bipiperidinyl, 0.49g (1.5O0mmol) TBTU and 0.23g (1.50mmol) HOBT 2.Oml of triethylamine was added to 100 ml of THF and the mixture was stirred for 16 hours. at CT. Then, the reaction mixture was concentrated in a vacuum, the residue was mixed with a saturated solution of MnSO 3 , and the mixture was carefully extracted i)

EUAs. United org. the extracts were dried over Mo5O and concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient elution: a mixture of /Meon/mChn with a ratio varying from 94:5:1 to 70:25:5). so zo Yield: 253 mg (24965 from theory).

MS(E5I): (MAN) -703/705 (SI). with

GE 20.66 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). co

Example C 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1 ,4-dihyde o ro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione rch-

Huh! "

F - s and che .-e

I.Y a o ' ik three Da ia ia 3 C se) cha ' Sew (95) 7 50 The product indicated in the title was obtained similarly to example 2e starting from 0.80 g (1.48 mmol) of 2-(4-amino-3 -chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3Z-yl)ipiperidin-1-yl (1.50 mmol) of 1-methyl-4-piperidin-4-ylpiperazine.

Output: bO0Omg (5795 from theory).

MS(E): M"-703/705 (SI).

Ee0.56 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

HF) Example 4 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1,4bipiperidinyl-1'-yl-4-(4-(2-oxo-1,4-dihydro-2H- quinazoline (Z-yl)/piperidin-1-yl|Ibutane-1,4-dione 60 b5 and

F

4 " Ge as F ch.

OS che ' '

The product indicated in the title was obtained similarly to example 2e, starting from 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1, 4-dihydro-2H-quinazolin-3Z-yl)ipiperidin-1-yl|Ibutyric acid and 0.27 g (1.500 mmol) |1,4bipiperidinyl.

Output: 24Omg (245965 from theory).

MS(E5I): (MAN) -689/691 (SI).

E-e0.59 (silica gel, DXM/Sus/Meon/mNz in the ratio 70:15:15:2).

Example 5 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)ipiperidin-1-yl1|-1- (4-pyridin-4-ylpiperazin-1-yl)butan-1,4-dione (22) m.

The product indicated in the title was obtained similarly to example 2e, starting from 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-14-(2-oxo-1 ,4-dihydro-2H-quinazolin-3Z-yl)ipiperidin-1-yl|In oil - - : golic acid and 0.24 g (1.48 mmol) of 1-pyridin-4-ylpiperazine. c Output: 50Ω (5095 from theory). :z» MS(EII!): M"-683/685 (SI).

Eche 0.35 (silica gel, MeOH). 15 Example 6 - 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-ylamino)piperidin-1-yl|-4-(4-(2-oxo- 1,4- dihydro-2H-quinazolin-3-yl)utperidin-1-yl|butane-1,4-dione se) syu 2 g) 50

Fe 1 and 55. and see

F) name) 60 ba. (1-benzylpiperidin-4-yl)-(1-methylpiperidin-4-yl)amine

A solution of 15.0g (78.mmol) of 1-benzylpiperidin-4-ylamine and 10ml (78.8mmol) of 1-methylpiperidin-4-one in ZOOml

THF was acidified with HOAc to pH 5 and stirred for an hour. at CT. Then 19.0 g (90, mol) of Mavn(OAc)z was added and the mixture was stirred for 1 h. Then the mixture was concentrated in a vacuum, because the residue was dissolved in MeonH and precipitated by adding NSI to Meon. The precipitate that formed was filtered off,

washed with Meon and dried under vacuum.

Yield: 21.8g (70905 from theory).

Ee0.30 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 66. Trihydrochloride (1-methylpiperidin-4-yl)piperidin-4-ylamine

A solution of 10.0 g (25.0 mmol) of (1-benzylpiperidin-4-yl)-(1-methylpiperidin-4-yl)damine in 120 ml of Meon was added to a suspension of 5 g of 1O096 Ra/C in 8 ml of water, and the mixture was hydrogenated for 2 hours . at 502C and a pressure of 2 bar. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with

EUN, the formed precipitate was filtered off, washed with EN and ether and dried in a vacuum. 70 Yield: 7.75g (quantitative yield). bv 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-ylamino)piperidin-1-yl1|-4-(4-(2-oxo-1,4- Dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione

The product indicated in the title was obtained similarly to example 2e starting from 0.80 g (1.48 mmol) 75... 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyric acid and 0.24 g (1.4 in 8 mmol) of trihydrochloride (1-methylpiperidin-4-yl)piperidin-4-ylamine.

Output: ZO0Omg (2595 from theory).

MS(E):M 7-717/719 (SI).

Ee0.20 (silica gel, MeOH).

Example 6.1

I4-(1-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-yl|Ibutyryl)piperidin-4-yl)piperazin-1-yl)acetic acid with c i o i - i - k so boAADT THIS ! ; | with yes and che and sh U Ge") and -

The indicated compound was obtained similarly to example 16.4 From 108 mg (0.20 mmol) of 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)piperidin-1-yl|butyric acid and 51 mg (0.20 mmol) of (4-piperidin-4-ylpiperazin-1-yl)acetic acid ethyl ether.

Output: 1bmg (1095 from theory). - with MS(E5I): (MAN) -748/750 (SI). "Example 6.2 -" Methyl ether (1-22-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)piperidin-1-yl butyryl)-(4,Abipiperidinyl-1-yl)acetic acid

V. t s (95) - : f ; with - s» ИЙ o 7 и ' и че з ' и

The indicated compound was obtained similarly to example 16.5 From 216 mg (04 mmol) of 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)piperidin-1-yl|butyric acid and 102 mg (0.2 mmol) of ethyl ether of 14,4D|bipiperidinyl-1-ylacetic acid.

Yield: 22 mg (22965 from theory).

MS(EB5I): (MAN) -761/763 (SI). for E-e0.33 (silica gel, DXM/MesynH in the ratio 9:1).

Example 6.3 (1-22-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolyl-3-yl)ipiperidin- 1-yl|Ibutyryl)-I4,4bipiperidinyl-1-yl)acetic acid! about | '

The specified compound was obtained similarly to example 16.6 from 201 mg (0.2 bmmol) of methyl ether 20. (1-42-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl butyryl)-(4,4Dbipiperidinyl-1-yl)acetic acid.

Yield: 22 mg (22965 from theory).

MS(E5I): (MAN) -761/763 (SI).

Ee0.21 (silica gel, DHM/MesynH in the ratio 9:1). with

Example 7 o

KRO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1,4"-bipiperidinyl-1'-yl-2-oxoethyl|amide 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid.

I am with

DV p

AND

F: She

GI and (22)

And and | and or her- and

Bi Gl from Ii « d, 1 - s is ta. "» (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-M-(15,25)-2-hydroxy-1-methyl-2-phenylethyl)-M-methylpropion amide

Alkylation was carried out according to the general method described in A.S. Muege et al. Sh. Ogu. Spet., 64, -I 1999, vol. 3322-3327), based on 31.72 g (132 mmol) of 2-amino-M-(15,25)-2-hydroxy-1-methyl-2-phenylethyl)-M-methylacetamide monohydrate and 33.g (13.8 mmol) of -o 2-chloro-4-chloromethyl-b-trifluoromethylphenylamine. The crude product was purified by column chromatography (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Output: 10, Ohm (1895 from the theory). t MS(EBI): (MAN) -430/432 (SI). seu GE e0.48 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 76. (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionic acid

Hydrolysis was performed according to the general method described in A.O. Muege et al. (U. Oga. Spet., 64, 1999, pp. 3322-3327), leaving Kk! 10.0 g (23.00 mmol) (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-M-(15.25)-2-hydroxy-1-methyl-2- phenylethyl)-M-methylpropion o amide. The crude product without additional purification was used in the synthesis at the next stage. to 7c. (K)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butoxycarbonylaminopropionic acid

To a solution of 6.5 g (23.O0 mmol) of (K)-2-amino-3-(4-amino-3-chloro-5--trifluoromethylphenyl)propionic acid in 140 ml of 60 THF was added a solution of 3.71 g (350O0 mmol) l10Oml of water. Next, 15.28g (70.Omol) were added

Vos-anhydride and the mixture were stirred for at CT. THF was evaporated under vacuum, the aqueous phase was washed

EUOdAs and acidified with a 10906 solution of citric acid. The aqueous phase was carefully extracted with E(As, the combined organic extracts were dried over Ma»5O); and concentrated in vacuo. The crude product without additional purification was used in the reaction at the next stage. 65 Yield: 2.00g (1595 from theory).

MS(EZ5I): (M-H) -381/383 (SI).

7 years tert-Butyl ether

KRO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-11,4bipiperidinyl-1'-yl-2-oxoethylcarbamic acid

To a solution of 2.00 g (5.22 mmol) of (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butoxycarbonylaminopropionic acid, 0.99 g (5.30 mmol)

To 1.4 Lbipiperidinyl, 1.77 g (5.500 mmol) TBTU and 0.74 g (5550 mmol) HOBT in 150 ml of THF, 1.5 ml (11.00 mmol) of triethylamine was added and the mixture was stirred for 16 hours. at CT. Then the reaction mixture was concentrated in a vacuum, the residue was mixed with a saturated Manso solution, and the mixture was carefully extracted with E(Ac. The combined organic extracts were dried over M950O,y and concentrated in a vacuum. The residue was purified by column chromatography 7/0. (aluminum oxide ( neutral, II activity), DCH/MeonH in the ratio 99:1).

Output: 50Ω (1895 from theory). 7 days (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-1-1,4-bipiperidinyl-1"-ylpropan-1-one dihydrochloride

Add 500 mg (0.75 mmol) of tert-butyl ether to the solution

KRO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-11,4bipiperidinyl-1'-yl-2-oxoethyl I|carbamic acid in 7/5 30 ml of ЕУН at CT, 5 ml of NCI (12-molar in EYUN), the mixture was stirred during Accord. and then concentrated in vacuo. The crude product without additional purification was used in the reaction at the next stage.

Output: ZvOmg (quantitative output).

That. KK)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-1,4"-bipiperidinyl-1'-yl-2-oxoethyl|amide 4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid

To a solution of ZvOmg (0.75 mmol) of dihydrochloride (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-1-(1,4bipiperidinyl-1-ylpropan-y-one) in BbBO0ml of DMF and

To 0.5 bml (4.00 mmol) of triethylamine at 02C was added 18 mg (1.100 mmol) of KDT and the mixture was stirred for 1.5 hours. at 02. Then 242 mg (0.99 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one was added and the reaction mixture was stirred for 1.5 hours. at 10020. After that, DMF was evaporated in vacuo and the residue was purified by column chromatography (silica gel, DCM/Sus/mMeon/lMnNOi in the ratio 70:15:15:2) and then by HPLC.

Output: 14Ω (2095 from theory).

MS(EB5I): (MAN) -704/706 (SI). co

Ee0.58 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). high school

Example 7.1

KRO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-dimethylaminopiperidin-1-yl)-2-oxoethylamide so 4-(2-oxo-1,2,4,5-tetrahydro Fu -1,3-benzdiazepin-3-yl)piperidine-1-carboxylic acid

But she-

F g o - «

And -

I" m

From Shkl -i and i 7 La. Ethyl ether (K)-2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionic acid o Solution 3.5 g (10.97 mmol) (K)-2-amino-3-(4- amino-3-chloro-5-trifluoromethylphenyl)propionic acid in 100 ml

HF 50 EUN and 7 Oml of ethanol NS (11.5 molar) were left to mix overnight at CT. Then it was concentrated in a vacuum, the residue was dissolved in 150 ml of water, mixed with 30 ml of a 1590 solution of KSO3, extracted with 150 ml of EtOAc, the organic phase was separated and dried over NaCl5O). After removal of the desiccant and solvent, the target product was obtained.

Yield: 3.5 g (9295 from theory).

MS(EB5I): (MAN) -311/313 (SI).

Ge) 7.16. Ethyl ether (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2.4,5-tetrahydro-1,3-benzdiazepin-33-yl)ipiperidine -1- o carbonylIiamino)propionic acid

To a cooled to 0 solution of 3.2 g (10.2 mmol) of ethyl ether 60 (vB)-2-amino-3-(4-amino-3-chloro-B-trifluoromethylphenyl)propionic acid and 1.vml (10.3 mmol) 1.8 g (11.0 mmol) of KDT was added to ethyldiisopropylamine in 1500 ml of THF, and the reaction mixture was stirred for 45 minutes. at this temperature, and then, after removing the ice bath, during ЗОхв. After that, 2.5 g (10.2 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one suspended in 5 mL of THF was added. Next, 40 ml of DMF was added to the reaction solution and stirred for 2 hours. at 8020. Then it was concentrated in a vacuum, mixed with 200 ml of E(Ac) and 200 ml of a 1095 solution of citric acid, the organic phase was separated,

it was extracted with 150 ml of ManHSO solution and dried over MOH. After removal of the desiccant and solvent, the target product was obtained.

Output: 5.9g (10095 from theory).

MS(EB5I): (MAN) -582/584 (SI).

GE e0.4 (silica gel, EUAsC). 7.v. (Kc)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-33-yl)ipiperidine -1-carbonylamino)propionic acid 70 Add (10.3 mmol) ethyl ether (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3Z-yl)ipiperidine-1-carbonylamino)propionic acid in bbml of THF was added to a solution of 0.64 g (15 mmol) of lithium hydroxide hydride in 10 ml of water. 100 ml of water and THF were again added to this suspension, and after 5 h. a solution was formed. Then they stirred for an hour. at CT, THF was distilled off in a vacuum, diluted with 100 ml of water, and 1-molar NSI was added dropwise at 75°C with ice cooling until an acidic reaction was obtained. The precipitated substance was filtered, washed with water and dried in air.

Yield: 5.5g (9695 from theory).

MS(EBI): (MAN) -554/556 (SI). 7.1g. KK)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-dimethylaminopiperidin-1-yl)-2-oxoethyl|amide 4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid

To a solution of 400 mg (0.72 mmol) (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3 241 mg (0.75 mmol) of TBTU, 0.21 ml (1.5 mmol) of triethylamine, and 10 mg (0.0 mmol) of dimethylpiperidin-4-ylamine were added to 100 ml of DMF of -benzdiazepin-33-yl)ipiperidine-1-carbonylamino)upropionic acid and the mixture was left to stir overnight at RT. Then the reaction solution was poured into 150 ml of a 15956 solution of K»CO3, after which it was stirred (5) for 10 minutes. at CT, the precipitated substance was separated by vacuum filtration, washed with ZOml of water, and air-dried overnight. The crude product was suspended in isopropanol, allowed to stir overnight at RT, vacuum filtered, and dried at 4026.

Output: Z5Omg (7395 from theory). co

MS(E5I): (MAN) -664/666 (SI). with

Retention time (RHVT): b,Ochv. (method A).

By analogy with C and) (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine- 3Z-yl)ipiperidine-1-F carbonyl(amino)propionic acid and the appropriate amount of amine yielded the following compounds: ik. y- per Mk "re still PI NI z :" (Zh ke ; and the Horse is Gu -i enny E sho shi tia: I: Nishi mm a uprysmavnv ory poyann yn z | I Year in VAT 7 re TOLI |blzhke she 7 Yes, I'm sorry for you

In a similar way З (Кк)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3Z- yl)ipiperidine-1-bo carbonylIamino)propionic acid and the appropriate amount of amine gave the following compounds, while the crude product was purified by chromatography (silica gel, gradient elution: with a change from DCM to Meon/mcn with a ratio of 9:1 for 45Xmin): - | Example Yield /|Mas- Retention time at (95) spectrum RHVT shle, w 79792 |bbhv 70 sala MN (A) "W 719721. 15.27 min psa MI (A) "w 79721 50 min du mei A)

In a similar way З (Кк)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3Z- yl)ipiperidine-1-carbonyl(amino)propionic acid and the appropriate amount of amine yielded the following compounds, while the crude product was directly purified using PCHT: cm

Example Output (22) | Mass spectrum The time of exhaustion at RHVT|YD TSO. KI. "zh 17 676/618 6.2 min as g zo A, peaks KA) and

And kl, pmene |) to her and -

Example 7.10

KRO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)ethylamide 4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid I and Mr. I I | : I am in this (se) I am my I am this" I

A solution of bOOmg (0.72 mmol) of benzyl ether 4-(1-((k)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-114-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-carbonylamino)propionyl)piperidin-4-yl|Ipiperazine-1-carboxylic acid (example 7.4) and 200 mg of nickel

Rhenium in 5 Oml Meon was hydrogenated for 12 hours. at CT and pressure H » 5Opounds/sq. inch. After that, the catalyst (Ф) was filtered off, the solvent was evaporated in vacuo and the residue was purified by RT.

GI Output: 16bOmg (3295 from theory).

MS(E5I): (MAN) -705/707 (SI). in Retention time (RHVT): 5.5 min. (method A).

Example 7.11

H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidine-1-carbonyl(amino)propionyl)-4,4"-bipiperidinyl-1-yl|!ioacetic acid b5 with ; and

What are you in! with a and Fe Shkiv'

Add 250 mg (0.32 mmol) of ethyl ether to the solution

H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidin-1-carbonylamino)propionyl)-4,4-bipiperidinyl-1-yl)acetic acid (Example 7.5) in Bbml of THF was added to a solution of 20.1mg (0.47mmol) of lithium hydroxide hydride in 10ml of water and the reaction mixture stirred for 2 hours. at CT. Then it was mixed with 0.bml of 1-molar NSII, the substance that precipitated was separated by vacuum filtration and dried at 502С. The crude product was purified by RT.

Yield: 85 mg (3595 from theory).

MS(EB5I): (M.N) -762/764 (SI).

Retention time (RHVT): 6b, 2min. (method A).

In a similar way, the following compounds can be obtained: со со сч (22) de - dikh - с - ;» cha is this. (and and

Example 8 (1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-11,4-bipiperidinyl-1'-yl-2-oxoethylamido se» 4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid

F) name) 60 b5 and nn, va. Diethyl ether of 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethylbenzschmalonic acid)

To a freshly prepared solution of 2.55 g (0.11 mol) of sodium in 200 ml of abs. 24.11 g (0.11 mol) of diethyl ether of 2-acetylaminomalonic acid was added to EN in a nitrogen atmosphere, and the mixture was stirred for 15 minutes. at

CT. Next, a solution of 27.00 g (0.11 mol) of 2-chloro-4-chloromethyl-b6-trifluoromethylphenylamine (example 2a) in 100 ml of 1,4-dioxane was quickly added dropwise and the mixture was stirred for 4 hours. at CT. After that, 500 ml of water was added and the mixture was stirred for another 16 hours. The precipitate that formed was filtered off, washed with water and dried under vacuum.

Output: 40 Ohms (84905 from theory). with

Ee0.14 (silica gel, PE/EUdAs in the ratio 2:1). 86. Hydrochloride of 2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionic acid i)

To a solution of 40.0 g (94.16 bmmol) of 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)malonic acid diethyl ether in 1100 ml of AcOH and 150 ml of water was added 50 ml of conc. CARRIERS, after which the reaction mixture was heated to 1402 and kept at this temperature so

From within 4 hours. Then the precipitate that formed was filtered and discarded. The filtrate was concentrated in a vacuum, mixed with 10 ml of EN and stirred for 15 min. at CT. The precipitate that formed was filtered off, washed with EUN and dried in a vacuum. The crude product without additional purification was used in the reaction at the next stage.

Output: 16 bg (5396 from theory). at

MS(EBI): (M-N) -281/283 (SI). - 8 in. Ethyl ether of 2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionic acid 16bg (50.14 mmol) 2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl) hydrochloride ) of propionic acid was dissolved in 350 ml of the CARRIER (12 molar in EUN) and stirred for two hours. at CT. Then the reaction mixture was concentrated under vacuum to a volume of 100 ml and mixed with 200 ml of diethyl ether. The precipitate that formed was filtered off, washed with diethyl ether and dried under vacuum. - s Output: 12.2g (70905 from theory). « MS(E5I): (MAN) -311/313 (SI). -» 8 years. Ethyl ether 3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3Z-yl)upiperidine- 1-Carbonyl|amino)propionic acid - and To a suspension of 8.00 g (23.04 mmol) of ethyl ether of 2-amino-3-(4-amino-3-chloro-5-trifluoromethylphenyl)propionic acid and 16.Oml ( 115.00 mmol) of triethylamine in 100 ml of DMF at 02C was added 4.15 g (23.04 mmol) of KDT and the mixture was stirred for 1.5 hours. at 0 9 Sat. Next, a solution of 5.64 g (23.00 mmol) and 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one in 200 ml of DMF was added, after which the mixture was heated to 1002C and ko 20 was kept at this temperature for 2 hours. Then the reaction mixture was cooled to room temperature, diluted with 1.5/l of water and stirred for the next 10 minutes. The precipitate that formed was filtered off, washed with water and dried under vacuum.

Output: 13.Ohm (9790 from theory).

MS(EB5I): (MAN) -582/584 (SI). vd.

HF) 3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3Z-yl)upiperidine-1-carb t onylIiamino)propionic acid

To a solution of 13.00 g (22.34 mmol) of 3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3) ethyl ether -benzdiazepin-3Z-yl)upiperidine-1-carb 60 onilyamino)propionic acid was added to 100 ml of EN with 45 ml of 1-molar Masson and the mixture was stirred for 16 hours. at CT. After that, EUN was evaporated in a vacuum, 45 ml of 1-molar NS was added and stirred for 15 min. The precipitate that formed was filtered off, washed with water and dried in vacuo at 7526.

Yield: 10.5g (85905 from theory). be MS(EBI): (М-Н) -552/554 (SI). ve. (1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-11,4bipiperidinyl-1'-yl-2-oxoethyl|amide

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid

To the solution 1.00 g (1.8 mmol) 3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine) -3Z-yl)upiperidine-1-carbonilyamino)propionic acid, 0.34g (1.8mmol) 1,4Lbipiperidinyl and 0.64g (2.00mmol) TBTU were added to 150ml of THF, 0.69ml (5.00mmol) of triethylamine and the mixture was stirred for 16 hours. at CT. Next, the reaction mixture was concentrated in a vacuum, the residue was mixed with a saturated solution of MansSoO»3 and the mixture was carefully extracted

EUAs. United org. the extracts were dried over Mo5O and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EIOAcS/Meon/mN with a ratio of 75:25:2.5). 76 Output: Z5Omg (2895 from theory).

MS(EB5I): (MAN) -704/706 (SI).

Ee0.58 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Example 9 (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)ipiperidin-1-ylI|-4-I(4-( 2-oxo-1,2,4 75,o-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione uva c o so da. Ethyl ether 4-amino -3-trifluoromethylbenzoic acid

A solution of 150 g (0.6 bmol) of M-(4-cyano-2-trifluoromethylphenyl)acetamide in Zb0oml of dry EN and 540 ml of 10-molar ethanolic NCI was heated to 7092C in a high-pressure apparatus and kept at this temperature for 2 hours. with 45 min. After cooling the solution, the precipitate that formed was separated by vacuum filtration, washed with EUN, and the filtrate was concentrated in a vacuum. The residue was mixed with water and EN, which were used in portions of 30 Oml, F was intensively stirred, subjected to vacuum filtration and then washed with a mixture of water/EN in the ratio /- |and 1:11. The crude product without purification was used in the next reaction.

Output: 153g (10095 from theory).

GE e0.4 (silica gel, PE/EUAc in the ratio 1:1). « 96. 4-amino-3-trifluoromethylbenzoic acid

To a solution of 100 g (2.5 mol) of Mahon in 250 ml of water at room temperature, a solution of 153 g (0.6 mol) of ethyl ether-c 4-amino-3-trifluoromethylbenzoic acid in 100 ml of EYN was added and the reaction mixture was stirred for 2 hours. at h 4520. Next, the EUN was removed in a vacuum, the remaining aqueous solution was acidified conc. NSI, the precipitated product, was separated by vacuum filtration, washed with water and dried in air.

Yield: 129g (9695 from theory).

MS(E5I): (М-Н) -204.

Sh- Ov. 4-amino-3-bromo-5-trifluoromethylbenzoic acid so To a solution of 21.0 g (102 mmol) of 4-amino-3-trifluoromethylbenzoic acid in 250 ml of acetic acid, a solution of bml (117 mmol) of bromine in 5 ml of acetic acid was slowly added dropwise, after which heated to 602 and kept at this temperature for 2 hours. After cooling, it was mixed with water and the precipitate was separated by vacuum filtration. The residue was dissolved in DCM, the organic phase was alkalized with Mahon's solution, the aqueous phase was separated and acidified with conc. NSI The precipitate was separated by vacuum filtration and dried at room temperature.

Yield: 18g (6296 from theory).

MS(EBI): (M-N) -282/284 (VG).

Ee0.6 (silica gel, PE/EIHUAS/ASON in the ratio 50:50:1). (F) Oh. (4-amino-3-bromo-5-trifluoromethylphenyl)methanol g) 12g (74mmol) of KDI was added to a solution of 18g (63.4mmol) of 4-amino-3-bromo-5-trifluoromethylbenzoic acid in 400ml of THF, and stirred for an hour. at CT, after which it was heated to 40 oC and kept at this temperature for 1 hour. The activated acid was then added dropwise to a solution of 8.0 g (212 mmol) of Mavn in 200 ml of water, while the temperature should not exceed 402C. Then the reaction mixture was stirred for 2.5 hours. at CT, mixed with ZOOml of semi-concentrated NOSI, stirred for an hour. and thoroughly extracted with EtOAc. The organic phase was washed with a 1595% solution of K»CO3 and dried over Na»2O). After removing the desiccant and the solvent, the residue at 502 was dissolved in isopropanol and the precipitate obtained after cooling at 65 was separated by vacuum filtration, dissolved in PE and separated again by vacuum filtration.

Output: 12.5g (7390 from theory).

MS(EI): (M) -269/271 (Vp).

E-e0.9 (silica gel, MeOH).

Unit 4-amino-3-bromo-5-trifluoromethylbenzaldehyde

To a solution of 12.5 g (46.3 mmol) of (4-amino-3-bromo-5-trifluoromethylphenyl)methanol in 150 ml of DCM, 53 g (0.6 mol) of Mpo was added and the reaction mixture was left to stir overnight at room temperature. After that, MPO 5 was separated by vacuum filtration, after which it was washed with DCM, the solvent was removed in vacuo, and the residue was stirred with PE.

The precipitate was separated by vacuum filtration, washed with a small amount of PE and dried.

Yield: 9.5g (77905 from theory).

MS(E5I): (MAN) -268/270 (Ve).

Ee0.6 (silica gel, PE/EUAc in the ratio 2:1). where. 2-(1-(4-amino-3-bromo-5-trifluoromethylphenyl)-meth-(E)-ylidene|succinic acid 1-methyl ester

To a solution of 9.5 g (35.4 mmol) of 4-amino-3-bromo-5-trifluoromethylbenzaldehyde in vOml of THF was added 27.9 g (71.0 mmol) of 2-(tri.phenyl-),»-phosphanilidene) 1-methyl ether succinic acid, after which the reaction mixture was heated to 409C and kept at this temperature for 120 hours. The precipitate was separated by vacuum filtration, the filtrate was concentrated in a vacuum, the residue was mixed with water and EtOAc, the organic phase was separated, it was washed three times with water and extracted three times with a 596% K»CO3 solution. The aqueous phase was acidified conc. NSI, the precipitate formed was separated, washed with water and dried at 602С.

Output: 5.9g (4495 from theory).

MS(E5O): (MN) -382/384 (VH).

Already 1-methyl ester of (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzspanic acid)

To a solution of 5.9 g (1544 mmol) of 2-(/1-(4-amino-3-bromo-5-trifluoromethylphenyl)meth-(E)-ylideneosuccinic acid 1-methyl ether in 5 Oml of degassed MeonN and 5.9 ml of triethylamine in the atmosphere of argon, 130 mg of tetrafluoroborate (33-1,2-bis((2kK,5K)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I) was added and the reaction mixture was hydrogenated for 4 hours at a pressure of 5Olbs/sq. in. After that, the reaction solution was concentrated in a vacuum, the residue was dissolved in 100 ml of EtOAc, washed twice with 2-molar NOS and carefully extracted with a 595% solution of K»CoOz.

The aqueous phase was acidified conc. NSI, E(Ac) was carefully extracted and the organic phase was dried over Ma»53O». After removal of the desiccant and solvent, the target product was obtained. at

Yield: 5.8g (9895 from theory). si

MS(EBI): (M-N)- 382/384 (Vg). - so 93. Methyl ether (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1, 3-Benzdiazepin-3-yl)piper He)idin-1-yl|butyric acid m

To a solution of 5.80 g (15.1 mmol) of 1-methyl ether (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)succinic acid, 4.98 g (15.1 mmol) of TBTU, 2.04 g ( 3.70 g (15.1 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepine-2 -one and the reaction mixture were left to stir overnight at RT. Then the reaction solution was concentrated in a vacuum, mixed with E(Ac) and 20 2090 solution of citric acid, the organic phase was separated, washed with a saturated solution of ManSoO»z - and dried over Ma»zO,. After removing the desiccant and the solvent, the target product was obtained. s Yield: 9.2g (10095 from theory). :z» MS(EB5I): (MAN) -611/613 (B).

Zy. (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piper -1 idin-1-yl butyric acid

To a solution of 9.2 g (15005 mmol) of methyl ether re) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)piper c idin-1-yl| of butyric acid in 7 Oml of THF at CT, a solution of 1.04 g (24.30 mmol) of lithium hydroxide hydride in

ZOml of water and the reaction mixture were stirred for at CT. After that, THF was distilled off in a vacuum, the aqueous solution was acidified with conc. NSI, E(Ac) was carefully extracted, the organic phase was separated and dried over "Fo" Ma"5ZO,. After removing the desiccant and the solvent, the target product was obtained.

Yield: 7.8g (87905 from theory).

MS(E5I): (MAN) -597/599 (Vg).

1-methyl ether can be obtained similarly to the sequence of operations described in examples 3e-9y with 4-amino-3-chloro-5-trifluoromethylbenzaldehyde (see example 16)

F) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid Y ka (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4 -I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid. 60 Uk. (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl1-4-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione

To a solution of 500 mg (0.4 mmol) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)piper b5-idin-1-yl)butyric acid, 289 mg (0.9 mmol) of TBTU, 122 mg (0.9 mmol) of HOBT and 0.35 ml (2.5 mmol) of triethylamine in 40 ml of THF 154 mg (0.84 mmol) of 1-methyl-4-piperidin-4-ylpiperazine was added to 10 mL of DMF and the reaction mixture was left to stir overnight at room temperature. After that, the reaction solution was concentrated in a vacuum, mixed with

EtOAc and saturated Manso solution, the organic phase was separated and dried over NaClO). After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, gradient elution: with a change from DCM to Meon/MtchN in a ratio of 95:5).

Output: 42Zmg (6695 from theory).

MS(EBI): (M.N) -762/764 (Vp).

Retention time (RHVT): 5.9 min. (method A).

By analogy with 70. (3)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzdiazepine-3-yl)piperidin-1-yl|butyric acid, which was used in portions of 500mg, and the corresponding amount of amine, the following compounds were obtained: pe i th rntet. see bad Bk. D i) maschenente in I; Mr. RAV) y o iy N "vi Kk . AND WHAT "a" | in Ia MO te IC av jak zo : h kori u ne yo I : y ia L A sch mya yy shock Shchi i eru par U t i Shk o ee zali te Uzh i 0 z In a similar way, the following compounds can be obtained: 7 s ; » -I se) (95) d) 50 syu"

Ф) име) 60 b5 и т лине я What is ble p T y I !

The arrival of HOURS

GO i and a it i 70 U : Z two it i in, - sch pa

In Zh, A 0. zkiann, this | o zo sk s pk, sch aa a

SHHA -- : y t -- t pl yiv chok y t ch- polyan i (is) zv | | yes and - with in and. : Dey rya ve -Щ I o 1. | Example 9.10, (5)-2-(4-amino-3-trifluoromethylbenzyl)-1-(4-(4-methylpiperazine-1- yl)piperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1, 4-dione t -I E s a

E CHE, d) 50 s» ) " rin c- 1 ' a. ime) in To a solution of 150 mg (0.2 mmol) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1- 14-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine -1-yl|Ibutane-1,4-dione in 20 ml of MeOH was added at 100 mg of 1095 Ra/s and the reaction mixture was hydrogenated for 1 h at RT and at a pressure of 50 psig. The catalyst was then separated by vacuum filtration, the solvent was concentrated in a vacuum, the residue was mixed with a 590 b5 solution of CoCO»z and EOAs, the organic phase was separated and concentrated in a vacuum, the residue was triturated with diisopropyl ether and subjected to vacuum filtration.

Yield: 134mg (10095 from theory).

MS(EBI): (MN) -684.

Retention time (RHVT): 5.5 min. (method A).

Example 10 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-dimethylaminopiperidin-1-yl)-4-I(4-(2-oxo-1,2,4 ,5-tetrahyd ro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione and in 70 there is ' ' 4 -

AND

5 F ka 4 y (I el '

To the solution 130 mg (0.24 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)piperidin-1-yl)butyric acid in 10 ml of DMF was added 80.3 mg (0.25 mmol) of TBTU, 0.21 ml (1.2 mmol) of ethylisopropylamine and 38.5 mg ( 0.Zmmol) of dimethylpiperidin-4-ylamine and the reaction mixture was left to stir overnight at room temperature. Then the reaction solution was poured into 3 ml of a 1595% solution of K»CO3, stirred for 10 minutes. at CT, the precipitated substance was separated by vacuum filtration, washed with 5 ml of water and air-dried over the weekend. After that, the product was purified using HCVT.

Yield: 82 mg (5395 from theory). (ze)

MS(E5I): (M.N) -663/665 (SI). with

Retention time (RHVT): 6b, 1min. (method A).

The following compounds were obtained in a similar way: o (22) i - shi c z -I se) (95) d) 50 syu»

F) name) 60 b5

-, and | / g y - y ay I MO shchi as, B r: v. buck her; zo Ya t, sho 49 ZAI) Ibn still asks; Nenikh, Ix NG A ' in

Neck. b i WE WE s: WE IN h 2 MP t. 0 ia vi HALL min - "17 HA | reto yuyu -| and in ( her "7 pk zashki drinking i I i i i 057706 te TK ХА r ta i yan -sh (So) : "DI M pk Tse shk, Maya I i Y trik Z: os : i r U

PI MI. prin shi t still; IS. ! I am (F.

Because b5

: May

PI si I fa 3 di y | W SHEZ BI SA) I "VE I gu y BI bak I pe : yaz I I -k ek sht BOBI ban shi!

Goa i 53 |BBULBYA vi baka le ; in "DY. i she NI y | y V. . ryk y 3 i Y kv ( in | o zo still her | shk SHE still Ye Ku I Id s | 7 sch i t: iniy shi". a sini ; Me) y y re y | y : PI | Mena, ee still ve "KE y ; Z le SCHO p i yy liy ; ; s ! yy ! r. yiz e : ST - - and eye y. y and 5 "- our nkn T in Sha!

And 1 nn and zr obbni: LA ee all:

Y " i r i I i bo | en OTHER. : b5

( How Z shchi Ha hu HER Z

Example 10.26 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4--4-dimethylaminomethylphenyl)piperidin-1-yl|-4-(4-(2-oxo-1 , 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|Ibutane-1,4-dione with 2 no 4

G

29 т ч ше о

With and

To the solution 130 mg (0.24 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)piper o-idin-1-yl|imibutyric acid was added to 2 ml of DMF with 8 mg (0.25 mmol) of TBTU and 87 μl (0.5 mmol) of ethyldiisopropylamine and stirred for 3 h at RT. After that, 8 mg (0.3 mmol) of dimethyl(4-piperidin-4-ylbenzyl)amine (which was used in the form of hydrochloride) was added and the reaction mixture was left to stir overnight at room temperature. Then, the reaction solution was filtered through a syringe with a filter nozzle and directly purified using HCVT.

Output: 8 Ohms (4595 from theory). in.

MS(EB5I): (MAN) -753/755 (SI).

Retention time (RHVT): b, bhv. (method A).

By analogy with "(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzdiazepin-3-yl)piper From idin-1-yl|butyric acid, which was used in portions of 130 mg, and the appropriate amount of amine (from 1.07 equiv. s of ethyldiisopropylamine in the case of free amines and additionally the required amount of base when using salts " » amine) the following compounds were obtained: p -I se) (95) d) 50 syu»

F) name) 60 b5

? vu ney le h che shi 4 | "2 ii. des: Z and yy -

Yes, yes. nya Mas. 7 - keeping pr - y M nt p psiv yntaki" "my t ! , with goal: y kt»: Zh SD zha til Viv

Kon ooo move in! / in | ev 25. Hits! ichunnn sinya sh-o o

SHHI Pen (0) o V shle s ay z ta zona nonsputya shi m redlany ninia Y i. r z MAYA ek 1 Bo/655 Ibozh zv sya, YN pan 0 She 0-3 y y I 7 ke | | widow y I I t 7 p Z Bi 7 c

Example 10.34 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperids - n-1-yl|-1-piperidin-1-ylbutane-1,4-dione from (95) d) 50 syu»

AND

F) name) 60

To a solution of 100 mg (0.18 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid in 2 ml of DMF was added 2 mg (0.1 mmol) of TBTU and 34 μl (0.2 mmol) of ethyldiisopropylamine and stirred for 30 minutes. at CT. After that, 24 μl (0.24 mmol) of piperidine 65 was added and the reaction mixture was stirred for 4 hours. at CT. Then, the reaction solution was directly purified using HCVT.

Yield: 54 mg (4895 from theory).

MS(EBI): (MAN) -620/622 (SI).

Retention time (RHVT): 8.4 min. (method A).

By analogy with (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzdiazepin-3-yl)piperidin-1-yl|butyric acid, which was used in portions of 100mg, and the corresponding amount of amine, the following compounds were obtained: -I se) (95) d) 50 syu"

F) name) 60 b5

"and and | mik

M KI j vit I GUK Mas; yar spe time uUtaana At TAN. shi sh-- pa | sh

M di What MN Pi What | AND

GK I 47 IY ek" ;

N same lozi t pany mine t-; prnprinu, I t what I am; I I - clery - le ne E so with Psa i re ii Her Kk ek era ia ia o y

T 4; - sya t Y You I ЧИ и Е. 5 . and

Yi Shan SHE sho SHE "

There is MNN siv sv rn i z YaYzLya - x sinna inst in Uk shii shi. poi u shi - ;" and : AHA, . Azh : (Aw -5 "Ma eat shi shi shii, gi:

In : Her El food m) | Z : Goa i PN TA 5 PV ko I5a BEN 0 | Buezhv ' m ДЯ ТЖ eh b YAM lah 60 i ie " y I I ! i M se | (AK b5

Z. that. AGE and this is the gender; VAS K. Sh pTnv an Nu BE» g her No - t Z y

In st. 1 DYN

Pii zh ik MM pak S ' "She en o I. go ZH -E- siny i pish rt En ryany i det net is ; y | i Ж Й Kiya | o

TO T same What she Al ge: V SHY: y y "I and oh ih meku, Z. 1 "| IN CHA Z | with

CHIV Oh, dn TYA be s so

Y A 1 i y y . | I tіt a ts BYAI 0 ubolya rent U y y Her: to her pnrnih Z sile le! ch -y -« of the post office and still guests sha s --a - tiise and ladies nave nih so rtistviyaya and with PD: br. I ze 79 BA Z

Example 10.57 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(2-amino-4,5,7 8-tetrahydrothiazolo|4,5-4|azepin-b-yl) -4-I(4-( -| 2-oxo-1,2,4,5-tetrahydro-13-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione se) (95) d) 50 units

F) name) 60

ZOOmg solution (0.54 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid and 190 mg (0.59 μmol) of TBTU in 0.4 ml (2.27 mmol) of ethyldiisopropylamine and 15 ml of DMF for an hour. stirred at Kt. Then 160 mg (0.6b4mmol) of 65 5,6,7,8-tetrahydro-4H-thiazolo|4,5-4)azepin-2-ylamine (which was used in the form of hydrobromide) was added and the reaction solution was stirred during the following hours. at CT. Next, the reaction mixture was poured into 500 ml

1596 solution of K»CO3, the precipitated product was separated by vacuum filtration and purified by chromatography (silica gel, gradient elution: changing from DCM to DCM/Meon/mn with a ratio of 10:9:1).

Output: 10Ω (2695 from theory).

MS(E5I): (MAN) -704/706 (SI).

Retention time (RHVT): 6b, 1min. (method A).

By analogy with (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzodiazepin-3-yl)piperidin-1-yl|ybutyric acid, which was used in portions of mg, and the appropriate amount of amine (which is 1-yl and 108) and one quinone (which was used as a free amine or in in the form of amine hydrochloride) the following compounds were obtained: ke

Ok

EE in the SAME and EK and ke ti F V (y

Where and KY R PY dechshichte rtotvrsnnyakh x pet! what else is there? her A) ze I Tv be 150 IT Toy m or men

TE s chy y Ga IL |bryav « ryn dk | And, (A : і | that S I p I I in sah | A sh-v so ne A, -k ITBNBAE b5khv « y Shchsti ik, ok - V z TI Nv z l i

PE - 5 M. mch in il ik v sho shrshenya t v sin inn svv dni: v ty DIA GU t ot VE U PM - sili MN NAH so ih tt y t-- ih di sta nanya soku z pam sny sy snklyakaa shik , according to GK Kk I NOYA be

It is from now on, What: Pi veshyaya; and oyu Y av iz SHI NI m) spon veshshishi pa VE and pin Pov 4,

Mobya I EK 552 schi FV. Her last words: "In kosai y - peru ZNAKy TZ Yang y

Both compounds from Examples 10.64 and 10.65 could be isolated from one reaction mixture, since the used 3-piperazin-1-yl-1-azabicyclo|2.2.2|octane contained piperazine as an impurity.

F) Example 10.66 co (1-methylpiperidin-4-yl)amide 4-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepine-3-yl)pyridine-1-ylbutyryl)piperazine-1-sulfonic acid b5 with 1! scha y and x

Fo i ini N g Z | and:

A solution of 5OOmMg (0.90 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid and 320 mg (1.00 mmol) of TBTU in 0.2 ml (1.14 mmol) of ethyldissopropylamine and bOml of THF for an hour. stirred at CT. Then 270 mg (1.033 mmol) of piperazine-1-sulfonic acid (1-methylpiperidin-4-yl)amide and 5 bml of DMF were added. After that, the reaction solution was left to stir overnight at RT. Next, the reaction mixture was diluted with 50 ml of E(Ac), extracted with 30 ml of a 1595% solution of K»CO»z and the organic phase was dried over Ma»5ZO). After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, gradient elution: with a change from DCM to DCM/MeonN/MH" in the ratio 10:9:1).

Output: 17Omg (245965 from theory).

MS(E5I): (MAN) -797/799 (SI). with

Retention time (RHVT): 6.4 min. (method A). at

Example 10.67 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-(5-aminopentyl)-4-oxo-4-I4-(2-oxo-1,2,4,5 -tetrahydro-1,3-6 enzdiazepin-3-yl)/piperidine-1-ilibutyramide

R co

And. with

F y ' I - "7 th (22) : . . v. s y y S mich 7 s |!

I.Y "» To a solution of 260 mg (0.47 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)piper

Mydin-1-ylbutyric acid and 161 mg (000.50 mmol) of TBTU in 0.4 ml (2.500 mmol) of ethyldiisopropylamine and 10 ml of DMF were added to 2 mg (0.3 mmol) of tert-butyl ether (5-aminopentyl)carbamic acid and the reaction mixture was left to stir overnight at RT. Then it was mixed with VOml of a 1595% K»CO»z solution, after which it was mixed for 1 hour. and the precipitated substance was separated by vacuum filtration, which was then washed with water and air-dried. The crude product was dissolved in 20 ml of DCM, mixed with 2 ml of TFC and stirred for 2 hours. at CT. Next, the reaction mixture was neutralized with a 1596 solution of K»SOuz, and the organic phase was separated and concentrated. The crude product obtained in this way was directly purified by RT.

Output: 11Omg (3795 from theory).

MS(EBI): (MN) -637/639 (SI).

Retention time (RHVT): b,Ochv. (method A). o In a similar way with 260 mg (0.47 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)pipercoidin-1-yl|butyric acid and 142 mg (0.bmmol) tert-butyl ether of (2-aminomethylbenzyl)carbamic acid gave the following compound: 60 b5

It's action penya sot and them same as about Ga and flesh V U pila! : 3 Ki e. g I Ka ICH i i ko t inve Biy i: '

Example 10.69 1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2,4,5-tetrahydro-1, 3-Benzdiazepine-3-yl)piperidin-1-yl|butyryl)piperidine-4-carboxylic acid

I study 3 s o

To a solution of 15 mg (0.02 mmol) of methyl ether 1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)pyridin-1-yl!butyryl)ipiperidine-4-carboxylic acid (Example 10.48) in 5 Bml of THF was added 2 mg (0.0 bmmol) of lithium hydroxide hydride, dissolved in a small amount of water, and the reaction mixture within Accord. so was stirred at CT. After that, the solvent was distilled off under vacuum, the residue was dissolved in water and acetonitrile and lyophilized.

Yield: 14mg (9695 from theory). (ze)

MS(E5I): (MAN) -664/666 (SI). F

Retention time (RHVT): 7.2 min. (method A).

By a similar method with 20 mg (0.0 mmol) of methyl ether - (1-4(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-ylbutyryl)piperidin-4-yl)acetic acid (example 10.43) the following compound was obtained:

Sword I NML 9 her SHO SYASHKUVI CHA ' h y a pyv ik - y | Requests. E Z DY EH ZK: NE si i RA Hey how. and t 45. ate vya, uy | In Zh: position TV; -i E ZE 2Й t (95) Example 10.71 7 50 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(8-methyl-8-azabicyclo/|3.2. 1|oct-3-yl)piperazin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl |butane-1,4-dione syu» R i 8 (F) ' Shk g L ka : i u i 6o K I i b5

To the solution 1.04 g (1.68 in 8 mmol)

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piperidin-1-yl|butyric acid, 642 mg (2.0 mmol) of TBTU and 1.64 ml (9.b mmol) of ethyldiisopropylamine in 20 ml of DMF was added to 850 mg (2.4 mmol) of 8-methyl-3-piperazine-1- yl-8-azabicyclo|3.2.1|octane and the reaction mixture was left to stir overnight at room temperature. Then the reaction solution was mixed with the 1596th solution of K»CO»z, after which it was stirred for 1 hour. at CT and separated by vacuum filtration the precipitated substance, which was then washed with 5 Oml of water, dried in air and purified by chromatography (silica gel, gradient elution: with a change from DCM to DCM/Meon/mChN" in the ratio 10:85:5 ).

Output: 1.07g (7790 from theory).

MS(E5I): (MAN) -744/746 (SI).

Retention time (RHVT): 5.4 min. (method A).

Example 10.72 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperides n-1-yl|-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione

E a F mi i o i

I s a same o li i i slya I 10.72a. Benzyl ether 4-(1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzdiazepin-3-yl )piperidin-1-ylbutyryl)piperidin-4-yl)piperazine-1-carboxylic acid

To the solution 390 mg (0.71 mmol) of (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5- tetrahydro-1,3-benzdiazepin-3-yl)piper (Foidin-1-yl)|butyric acid was added to 10 ml of DMF with 241 mg (0.5 mmol) of TBTU, 0.2 ml (3.5 mmol) of ethyldiisopropylamine and 215 mg (0.5 mmol) of 71 mmol) of 4-piperidin-4-ylpiperazine-1-carboxylic acid benzyl ether and the reaction mixture was left to stir overnight at RT. Next, the reaction solution was poured into 8 Oml of a 1595% solution of K»CO»z, stirred for 1 hour. at CT and separated the precipitated substance by vacuum filtration, which was then washed with 5 ml of water and air-dried over the weekend. "

Output: 58 Ohms (9895 from theory).

MS(E5I): (MAN) -838/840 (SI). in p. 10.726. "» (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piperidin-1-" yl|I-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione

To a solution of 250 mg (0.300 mmol) of benzyl ether 4-(1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-|4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl (piperidin-1-ylbutyryl)piperidin-4-yl)piperazine-1-carboxylic acid in 3 ml of MeOH was added to 100 mg of nickel

Ge) Raney and the reaction mixture was stirred for 10 minutes. at CT and H pressure of 5 BOlbs/sq. inch. To complete the reaction, 100 mg of Raney nickel was added again and stirred for the next 1 hour. at CT. After that, the catalyst was separated by vacuum filtration, the solvent was removed under vacuum and the residue was purified

MO 70 with the help of RKHVT.

Yield: 88mg (4295 from theory). s» MS(EB5I): (MAN) -704/706 (SI).

Retention time (RHVT): 5, bhv. (method A).

Example 10.73 25 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1H-imidazol-4-yl)piperidin-1-ylI|-4-(4-(2 -oxo-1,2,4,5th

HF) trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|Ibutan-1,4-dione ime) 60 b5 fe a chu, ii i-i

With GI

-is '

To a solution of b5O0mg (1.18 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid was added to 20O0ml of DMF with 40O0mg (12bmmol) of TBTU and 0.bb5ml (3.7Bmmol) of ethyldiisopropylamine and the resulting mixture was stirred for 3h. at CT. Next, 34 mg (1.52 mmol) of 20. 4-(H-imidazol-4-yl)piperidine (which was used in the form of dihydrochloride) was added and the reaction mixture was left to stir overnight at RT. Then the reaction mixture was concentrated in a vacuum, the residue was mixed with 30 ml of a 1596% CoCO solution, extracted twice with DCM in portions of 15 ml, and the organic phase was dried over M950.4. After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, gradient elution: changing from DCM to DCM/Meon/Sh" in the ratio 20:75:5). high school

Output: 46bOhm (5795 from theory). at

MS(E5I): (MAN) -686/688 (SI).

E-e0.35 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Example 10.74 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperides so n-1-yl|-1-(4-I4-(2,2,2-trifluoroacetyl)phenyl|piperazin-1-yl)butan-1,4-dione

Io ya s chu " o "Schy. i | m.! me and you

AND

! 10.74a. tert-Butyl ether of 4-(4-bromophenyl)piperazine-1-carboxylic acid -I To a suspension of 10.0 g (Zbmmols). 4-(4-bromophenyl)piperazine (which used in the form of hydrochloride) and 15 ml (108 mmol) of triethylamine in 100 ml of THF, Bos anhydride was added in portions, after which the reaction mixture was heated to 602C and kept at this temperature for 10 hours. After cooling, the reaction mixture was poured (95) into water, sediment extracted with EtOAc, the organic phase was washed with water and dried over NaClO). After removing about 50% of the desiccant and solvent, the target product was obtained.

Output: 12.Ohm (9895 from theory). seu Ee0.6 (silica gel, Sus/EOUds in the ratio 2:1). 10.746. tert-Butyl ether of 4-I4-(2,2,2-trifluoroacetyl)phenyl|piperazine-1-carboxylic acid

To a cooled to -782C solution of 2.0 bml (3.3 mmol) of n-butyllithium (1.6-molar in n-hexane) in 40 ml of dry

A solution of 1.02 g (Z. Ommol) of tert-butyl ether of 4-(4-bromophenyl)piperazine-1-carboxylic acid in 20 ml of THF was slowly added dropwise to THF in a nitrogen atmosphere, and the resulting mixture was stirred for 15 minutes. at the indicated temperature. After that, a solution of 043 ml (33,000 mol) of M,M-diethyl-2,2,2-trifluoroacetamide in 100 ml of THF was slowly added dropwise. After completion of this addition operation, the reaction mixture was kept for 2 hours. at -782C, after which it was poured into 10 Oml of water, extracted twice with EtOAc in portions of 5 Oml each, the organic phase was separated by vacuum filtration through Ma»53O, concentrated in a vacuum and purified by chromatography (silica gel, Sus/E(OAc in the ratio of :1).

Yield: 267 mg (2595 from theory).

MSc(EII!): (M) -358.

Ee0.37 (silica gel, Sus/EUAc in the ratio 3:1). because 10.74v. 2,2,2-trifluoro-1-(4-piperazin-1-ylphenyl)ethanone

To a solution of 267 mg (0.75 mmol) of tert-butyl ether of 4-I4-(2,2,2-trifluoroacetyl)phenyl|piperazine-1-carboxylic acid in 3 mL of DCM, cooled to room temperature, 2.0 mL of TFOC was added and the reaction mixture was stirred for 24 hours ., which at the same time heated up to CT. Then the reaction mixture was concentrated in vacuo and the crude product obtained without purification was used in the next reaction.

M3Z (EB5I): (MAN) -259 10.74g. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl )piperidin-1-yl|-1-(4-i4-(2,2,2-trifluoroacetyl)phenyl|piperazin-1-yl).butan-1,4-dione 70 To a solution of 234 mg (0.42 mmol) ( 5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3- yl)piperidin-1-yl|butyric acid, 13 mg (0.42 mmol) of TBTU, 57 mg (0.42 mmol) of HOBT and 0.14 ml (1.0 mmol) of triethylamine in 20 ml of THF and 2 ml of DMF were added to the crude obtained in Example 10.74 the product and the reaction mixture were stirred for 2 hours at room temperature. Then the reaction solution was mixed with a half-saturated solution of MnSO" and extracted with 75 0 ml of EAs. The organic phase was separated by vacuum filtration through MnSO), the filtrate was concentrated. in vacuo and the residue was purified by chromatography (silica gel, Eu6Ac/Meon in the ratio 95:5).

Yield: 246 mg (7395 from theory).

MS(EB5I): (MAN) -793/795 (SI).

Eche 0.27 (silica gel, ЕХАСС).

Example 10.75 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-I4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione - i- 10.75a. Methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)ipiperidin-1-yl|m « 70 acetic acid - with Solution of 3.0 g (8.83 mmol) of 1-methyl ether (5)-2-(4-amino-3-chloro-5- -trifluoromethylbenzyl)succinic acid and 3.05 g (9.bmmol) of TBTU, 1.28g (947mmol) of HOBT in 1.7ml (9.7bmmol) of ethyldisopropylamine and 100ml of DMF were stirred for an hour at Kt. Then 2, 2 g (9.51 mmol)

Z-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one and the reaction solution were left to stir overnight at room temperature.

Next, the reaction mixture was concentrated in a vacuum, the residue was dissolved in DCM, washed with a 10956 solution of -I citric acid and a 15956 solution of K»CO3 and dried over Ma»5O). Then, the desiccant was removed by filtration through activated carbon, and after removing the solvent, the target product was obtained. ee, Output: 4.8g (9895 from theory). (95) MS(E5I): (MAN) -553/555 (SI).

E20.71 (silica gel, DCM/Sus/Meon/mN" in the ratio 70:15:15:2). 10,756 each. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-|I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-yl|m butylic acid

Add 4.8 g (8.6 in 8 mmol) of methyl ether to the solution

B (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) of piperidin-1-ylacetic acid in 28 ml of THF was added to a solution of 558 mg (13.02 mmol) of lithium hydroxide hydride in 12 ml of water and

IF) the reaction mixture was stirred for 7 hours. at CT. Then the reaction mixture was concentrated in a vacuum, the residue was mixed with 100 ml of water, acidified with 1-molar NH! and the resulting precipitate was separated by vacuum filtration. The residue was dissolved in EtOAc, extracted with a 15956 solution of KSO 3 , and the aqueous phase was again acidified with 1 molar NH. The resulting precipitate was separated by vacuum filtration and dried.

Yield: 4.2g (9095 from theory).

MS(E5I): (MAN) -539/541 (SI).

E-e0.09 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.758v. 65 (5)-2-(4-amino-3-chloro-5--trifluoromethylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-ilibutane-1,4-dione

Similarly to example 10.75a with 500mMg (0.933mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)piperidin-1-yl acetic acid and 180 mg (0.98 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave a crude product.

After its processing according to the method described in the given example, it was first purified by chromatography (silica gel, gradient elution: with a change from DCM to DCM/Meon/mn with a ratio of 70:27:3), and then further purified using PCHT.

Output: 120Ω (1895 from theory).

MS(EB5I): (MAN) -704/706 (SI). 70 GE e0.43 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Retention time (RHVT): 5, bhv. (method A).

Example 10.76 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(5 -oxo-3-phen yl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|butane-1,4-dione .- 10.76ba Methyl ether c (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-14-(5-oxo-3-phenyl-4,5-dihydro -1,2,4-triazol-1-yl)piperidin-1-ylbutyric acid c

Similarly to example 10.75a with 3,Og (8.3 mmol) of 1-methyl ether with (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid and 3.55 g (9.45 mmol) 5 -phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one gave the target product. (is)

Output: 2.5g (5095 from theory). chn

MS(EBI): (MAN) -566/568 (SI).

GE e0.67 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.766. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole -1-yl)piperide

MH-1-yl)ybutyric acid with Analogously to example 10.756 with 2.5 g (4.42 mmol) of methyl ether. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole -1-yl)piperide and in-1-yl|butyric acid gave the target product.

Output: 2.5g (5095 from theory).

MS(EBI): (MAN) -552/554 (SI). -I Ee0.14 (silica gel, DCM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.76v. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-( 5-oxo-3-phenyl-4-oz,B-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|butane-1,4-dione

Similarly to example 10.75a with 500 mmol (0.9 mmol) of (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl- 4,5-dihydro-1,2,4-triazol-1-yl)piperid c»yn-1-yl|butyric acid and 180 mg (0.98 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave a crude product . This product, after its processing according to the method described in the specified example, was purified by chromatography (silica gel, gradient elution: with a change from DXM to DXM/MeonN/MH" in the ratio 70:27:3).

Output: Z5Omg (5495 from theory).

MS(EB5I): (MAN) -717/719 (SI). o GE e0.44 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). Retention time (RHVT): 5, bhv. (method A).

Example 10.77 60 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2 -oxo-1,2-dihydroimidazo|4,5-c)quinolin-3-yl)piperidin-1-yl|butane-1,4-dione b5 and ku - and 10.77a. Methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroimidazoi|4,5-s|quinoline- 3-yl)piperids of n-1-ylbutyric acid

Similarly to example 10.75a with 3,Og (8.3 mmol) of 1-methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid and 2.55 g (9.4 mmol)

of s-piperidin-4-yl-1,3-dihydroimidazo|4,5-siquinolin-2-one gave the target product.

Yield: 5.2g (10095 from theory).

MS(EBI): (MAN) -590/592 (SI).

GE 20.66 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10,776 p

And I

(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroimidazoi|4,5-s|quinoline-3- yl)piperides of n-1-ylbutyric acid

Similarly to example 10.756 with 5.2 g (8.81 mmol) methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1 ,2-dihydroimidazoi|4,5-c|quinolin-3-yl)piperides with n-1-yl|butyric acid gave the target product.

Output: 2.75g (5490 from theory). with

MS(EB5I): (MAN) -576/578 (SI). co

E-e0.09 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.77 in. ia (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl1-4-I4-(2-oxo -1,2-dihyde M roimidazo|4,5-c|quinolin-3-yl)piperidin-1-yl|butane-1,4-dione

Similarly to example 10.75a with 5OOmMg (0.87 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2- of dihydroimidazoi|4,5-c|quinolin-3-yl)piperides of n-1-yl|butyric acid and 17Omg (0.9 mmol) of 1-methyl-4-piperidin-4-ylpiperazine, a crude product was obtained. After processing as described in the specified example, the residue was mixed with isopropyl ether and processed in an ultrasonic bath, after which the product was separated by vacuum filtration and dried. . Output: 52 Ohms (8195 from theory). "» MS(E5I): (MAN) -741/743 (SI).

GE e0.40 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Retention time (RHVT): 4.5 min. (method A). -I Example 10.78 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-( 2-oxo-1,2-di-ohydro-4H-thieno|3,4-4|Ipyrimidin-3-yl)piperidine-1-ilibutane-1,4-dione o g) 50 syu" and im

F) name) 60 10.78va. Methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2-dihydro-4H-thienoIII3,4-4| pyrimidine-3-yl)piperidine-1-yl)butyric acid

Similarly to example 10.75a with 3,Og (8.3 mmol) 1-methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)succinic acid and 3.34 g (9.51 mmol)

of C-piperidin-4-yl-3,4-dihydro-1H-thieno|3,4-4-pyrimidin-2-one gave the target product.

Yield: 2.2g (4595 from theory).

MS(E5I): (MAN) -559/561 (SI).

Ee0.56 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.786. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2-dihydro-4H-thienoIII3,4-4|pyrimidine- C3-yl)piper 70 ridin-1-yl)butyric acid

Similarly to example 10.756 with 2.2 g (3.94 mmol) of methyl ether (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1 ,2-dihydro-4H-thienoIII,4-4|pyrimidin-3-yl)piperidin-1-yl|butyric acid gave the target product.

Yield: 1.10g (51905 from theory).

MS(E5I): (MAN) -545/547 (SI).

GE e0.24 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 10.78 in. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo- 1,2-Dihyd ro-4H-thieno|3,4-4|Ipyrimidin-3-yl)piperidin-1-yl|Ibutane-1,4-dione

Similarly to example 10.75a with 500 mg (0.92 mmol) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2-dihydro -4H-thieno

13,4-4-Ipyrimidin-3-yl)piperidin-1-yl|butyric acid and 180 mg (0.98 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave a crude product. This product, after its processing according to the method described in the specified example, was purified by chromatography (silica gel, gradient elution: with a change from DCM to DCM/Meon/MH with a ratio of 70:27:3). at

Output: 10Ω (8195 from theory).

MS(E5I): (MAN) -710/712 (SI).

GE e0.43 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Retention time (RHVT): 5.5 min. (method A). (ze)

Example 10.79 g (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(5-methyl-2,5-diazabicyclo|2.2.1)hept-2-yl)piperidin- 1-yl)-4-(I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione Ge) 2 (22) nn, - "

And I - with ;" -AND

The specified compound was obtained analogously to Example 10.26 from 100 mg (0.18 mmol) of (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperazine-1-yl|butyric acid and 39.mg (0.2 mmol) 2-methyl-5-piperidine-4 -yl-2,5-diazabicyclo|2.2.1|)heptane using triethylamine as a base. Output: 8Zmg (6395 from theory). syu» MS(E5I): (MAN) -730/732 (SI).

Retention time (RHVT): 5, bhv. (method A).

Similarly to the methods described above, the following compounds can be obtained:

F) name) 60 b5

1080 Yi village. and M dynes 170 ay - ; ode and

Example 11 (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-14-(4-methylperhydro-1,4-diazepin-1-yl)/piperidin-1-yl|-4-( 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione with c o 2 c o c c c c c o (22)

And ich- 11a. 4-amino-3,5-bistrifluoromethylbenzaldehyde

A solution of 5 g (19.67 mmol) of 4-amino-3,5-bistrifluoromethylbenzonitrile in 3 ml of formic acid was shaken in 10 equal portions for 20 hours. at 110 °C in high-pressure vessels. After that, individual portions were combined, filtered, washed with formic acid and concentrated in vacuo. The residue was purified -in y and s. and with chromatography (silica gel, PE/EUAc in the ratio 9:1).

Output: 3.8 g (7595 from theory). with MS(E5I): (M-H) -256. 116. 2-(1-(4-amino-3,5-bistrifluoromethylphenyl)-meth-(E)-ylidene|succinic acid 1-methyl ester

To a solution of 4.2 g (16.33 mmol) of 4-amino-3,5-bistrifluoromethylbenzaldehyde in 8 Oml of THF was added 12.79 g of -I (32.bmmol) 1-methyl ester of 2-(triphenyl-5,-phosphanilidene)succinic acid, after which the reaction mixture was heated to 402C and kept at this temperature for 120 hours. Then the reaction mixture was concentrated in a vacuum, the residue was mixed with water and EtOAc, and the organic phase was separated, which was washed with water and extracted three times (95) with a 596% solution of CoCO3 in portions of 8 Oml. The combined aqueous phases were acidified conc. Carriers, yuyu 50, the oily precipitate was extracted twice with EtOAc in portions of 100 ml each and dried over Na»zO,. After removal of the desiccant and solvent, the target product was obtained.

Fe» Yield: 5.9g (9795 from theory).

MS(E) KhM) 7371. 11v. 1-methyl ester of (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)succinic acid

The specified compound was obtained similarly to example Uzh from 5.g of 1-methyl ether o 2-(/1-(4-amino-3,5-bistrifluoromethylphenyl)-meth-(E)-ylidene|succinic acid.

Yield: 5.9g (9795 from theory). about MS(EB5I): (MAN) -374. 11 years Methyl ether bo (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine- 3-yl) piperide of yn-1-yl butyric acid

The specified compound was obtained similarly to example 9z from 4.40 g (11./ummol) of 1-methyl ether (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)succinic acid and 2.89 g (11.7v8 mmol)

Z-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one. 65 Yield: 6.75g (9595 from theory).

MS(EBZI)(M AN) -601.

Eche 0.13 (silica gel, PE/EUdAs in the ratio 1:1). 11 days 85 (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3Z) -yl)piperidin-1-ylbutyric acid

To solution b, 7 g (11.16 mmol) of methyl ether (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-ylbutyric acid in 30 ml of THF at RT, a solution of 0.72 g (16.75 mmol) of lithium hydroxide hydride in 30 ml of water was added and the reaction mixture was stirred for 5 hours. at CT. After that, THF was distilled off in vacuo, the aqueous solution was cooled to 1092, and the pH was adjusted to 1 using conc. NOSI, which was accompanied by precipitation of the product. This precipitate was separated by vacuum filtration and dried at 6520. The dried substance was mixed with 300 mL of isopropyl ether, the mixture was separated by stirring overnight, and the resulting product was separated by vacuum filtration, after which it was washed with diisopropyl ether and dried.

Yield: 5.6 bg (8695 from theory).

MS(EB5I): (MAN) -587. 11th (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4-methylperhydro-1,4-diazepin-1-yl)/piperidin-1-ylI|-4-(4- (2-oxo 20.-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-ilibutane-1,4-dione

To a solution of 400 mg (0.6 in 8 mmol) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid, 241 mg (0.75 mmol) of TBTU and 0.25 ml (1.mmol) of triethylamine in bml of DMF was added to 197 mg (1.00 mmol) of 1-methyl- 4-piperidin-4-ylperhydro-1,4-diazepine and the reaction mixture was left to stir overnight with RT. Then the reaction solution was slowly poured into 150 ml of a 1595 solution of K»CO»z, the product that precipitated was separated by vacuum filtration and air-dried. The obtained crude product was purified by chromatography (silica gel, gradient elution: with a change from DCM to Meon /mN" in the ratio 95:5).

Output: 40 Ohms (7795 from theory).

MS(EB5I): (M.N) -767. and,

B0.2 (silica gel, DCH/MeOH/MH" in the ratio 85:15:1.5). high school

Retention time (RHVT): 5, bhv. (method A).

By analogy with C and, (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzdiazepine-Z-ilutperide b n-1-yl|butyric acid, which was used in portions of 40 mg (in example 11.7 in a portion of 387 mg), and the corresponding amount of amine, the following compounds were obtained: 50 syu"

F) name) 60 b5 i

Ok, y street Shriklad Exit |Mass- Retention time at (m) spectrum RHVT cat, 766 . 5.7 2 men A) with 752 5bhv ram menu |) with 25 . i o "zh 754 6.2 min ky МNN IA) so zo shchi 752 6.0 min sch . - ku, MN A) so t 751 6.8 he F n-z

MI (A) and - t 62 737 6 min lk Pmenu A) « z b 872 what I put, (menu » | yo 7 -I The compound obtained in example 11.7 was used without purification in the next reaction.

Example 11.8 ise) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl )piperidin-1-yl|-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione g) 50 syu» | , " about . name) 60

A solution of 5bOmg (0.6b4mmol) of benzyl ether bo 4-(1-(5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepine-3-yl)piperidin-1-yl|Ibutyryl)piperidin-4-yl)piperazine-1-carboxylic acid (crude product from example 11.7) in 5 Oml

Meon was mixed with 200 mg of 1095 Ra/C and the reaction mixture was hydrogenated for at KT and pressure No Z bar.

After that, the catalyst was separated by vacuum filtration, the solution was concentrated in vacuo, and the residue was purified by chromatography (silica gel, gradient elution: changing from DCM to DCM/Meon/MH with a ratio of 10:85:5).

Output: 23Omg (4995 from theory).

MS(EB5I): (M.N) -738.

Eche 0.27 (silica gel, DXM/MeonN/MN" in the ratio 50:50:5).

In a similar way, the following compounds can be obtained: И ШЙ И "Kat ion schu

Example. still Ho efbue

I siy: shh sk with MM y Y y Y "s

I | ' ; Her I you sera sik et i o lo Zh : shk y vra: BA: y : o -y. Her. lyn Pd ar laundries and y

GI ' - . yo " : NYA ry

OO 4. I am more g. p: m a p

H y ii that syu" Their Eh " another sh Ж t v v v y 1 ! : -shchii shi a pi row m na oi o | od yo ; se How in i-t t ptr dele N son nta t pil iz sleep ik lyk st kis y - zhEpinsup es t sig p n

Example 12

O-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl-2-oxoethyl)amide 4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid b5

Kn, their 1. se, 12a. (4-amino-3,5-bistrifluoromethylphenyl)methanol

To a solution of 7.2 g (28.0 mmol) of 4-amino-3,5-bistrifluoromethylbenzaldehyde (example 1184) in 100 ml of Meon in a nitrogen atmosphere, 1.06 g (28 mmol) of Mavn was added in portions and the reaction mixture was stirred for 2 hours. at

CT. Then the reaction solution was acidified with 1-molar NH, concentrated in a vacuum, the residue was mixed with 150 ml

Water and 150 ml of EtOAc, the organic phase was separated and dried over NaCl5O). After removing the desiccant and solvent, the residue was purified by chromatography (silica gel, PE/E(Ac in the ratio 9:1).

Yield: 5.1g (7095 from theory).

MS(E5I): (M-H) -258.

Eche 0.15 (silica gel, PE/EUdAs in the ratio 9:1). Ha 126. 4-chloromethyl-2,6-bistrifluoromethylphenylamine

To a solution of 5.1 g (19.6 mmol) of (4-amino-3,5-bistrifluoromethylphenyl)methanol in 10 ml of DCM at room temperature, i) 4.35 ml (bOmol) of thionyl chloride was added and the reaction mixture was stirred for at CT. Then the reaction solution was poured onto ice and ice-cold Manso solution, the organic phase was separated and dried over Ma»bSOu.

After removal of the desiccant and solvent, the residue without purification was used in the next reaction. co

Output: 5.4g (9995 from theory).

Eche 0.55 (silica gel, PE/EUdAs in the ratio 4:1). from the 12th century Diethyl ether of 2-acetylamino-2-(4-amino-3,5-bistrifluoromethylbenzyl)malonic acid with

4.34 g (20.0 mmol) of diethyl ether of 2-acetylaminomalonic acid was added to a solution of sodium ethanolate (obtained by the reaction of 0.46 g (20.0 mmol) of sodium with ЕУН) in 5 Оml of dry ЕУН in a nitrogen atmosphere, and the reaction mixture was stirred for 15 minutes. at CT. Then during the coverage a solution of 5.4 g (1945 mmol) of rch-4-chloromethyl-2,6-bistrifluoromethylphenylamine in 10 Oml of 1,4-dioxane was added dropwise, after which the reaction solution was stirred for the next 4 hours. at CT, mixed with 17 l of water and left to stir overnight. The precipitate that formed was filtered off, washed with water and dried in air. "

Output: 5.2g (57905 from theory).

MS(E5I): (MAN) -459, - with Ee0.65 (silica gel, PE/EUdAs in the ratio 2:1). h 12 Monoethyl ether of 2-acetylamino-2-(4-amino-3,5-bistrifluoromethylbenzyl)malonic acid." To a solution of 51 g (11.13 mmol) of diethyl ether 2-acetylamino-2-(4-amino-3,5-bistrifluoromethylbenzyl) of malonic acid in 8 Oml of dry EN, 2.Oml of b-molar Masson's solution was added and the reaction mixture was left to stir overnight at room temperature. Then the reaction mixture was concentrated under vacuum, the residue was dissolved in 1500 ml of water, acidified with 1-molar NH, the aqueous phase was extracted with 150 ml of EtOAc, and the organic phase was dried over NaCl5O). After removal of the desiccant and solvent, the residue without purification was used in the next reaction. (95) Output: 4,Zg (9095 from theory). 7 50 MS(EBI)(MaN) 431.

Ee0.1 (silica gel, PE/EUAs in the ratio 2:1). with" 12d. Ethyl ester of 2-acetylamino-3-(4-amino-3,5-bistrifluoromethylphenyl)propionic acid

A solution of 4.3 g (10 mmol) of 2-acetylamino-2-(4-amino-3,5-bistrifluoromethylbenzyl)malonic acid monoethyl ether in 200 ml of isopropanol and 8 ml of toluene was heated to 1002C and kept at this temperature for 15 hours. Then the reaction mixture was concentrated in

Ge) under vacuum and the residue without purification was used in the next reaction.

Output: 3.8 g (9895 from theory). у GE e0.60 (silica gel, PE/EUdAs in a ratio of 1:1). 12th century Ethyl ether of (K)-2-acetylamino-3-(4-amino-3,5-bistrifluoromethylphenyl)propionic acid 60 4 ml of alcalase 2.4 was added to a solution of 3.65 g (20.5 mmol) of MagHPO dihydrate heated to 372C in 130 ml of water

РО (Momogutez company A/5; located at OK 2880 Vadzmuaetga) and by adding Ma РО dihydrate) the pH value was set to 7.5. Then, at 379C, a solution of 33.8 g (9.84 mmol) of 2-acetylamino-3-(4-amino-3,5-bistrifluoromethylphenyl)propionic acid ethyl ether in 40 ml of acetone was added dropwise with stirring. At the same time, the pH value of the reaction mixture was constantly maintained by adding 1-molar Mahon in the range from 7.4 to 7.6. After completion of this addition operation, the mixture was stirred for 4 hours. at 37 90.

After cooling to room temperature, the reaction mixture was mixed with 30 ml of DCM, 30 ml of 1595 K 2CO3 solution and 200 ml of water. The organic phase was separated, washed with a 790% solution of K»CO3 and dried over Na»3O). After removing the desiccant and solvent, the crude product (2.2 g) was used in the next reaction without purification.

MUZ (EBI) (MaN) "387.

GE e0.60 (silica gel, PE/EUdAs in a ratio of 1:1). 12 years old Ethyl ether of (K)-2-amino-3-(4-amino-3,5-bistrifluoromethylphenyl)propionic acid

A solution of 2.2 g of the raw product obtained at the previous stage was added for 1.5 hours. refluxed in 4-molar NSI. Then the reaction mixture was concentrated in a vacuum, the residue was dissolved in 5 Oml of 70 EUN and 50 Oml of ethanolic NH (11.5-molar) and the reaction mixture was left to stir overnight at room temperature. Then the reaction mixture was again concentrated in a vacuum, the residue was mixed with BOml of a 1595% solution of K»CO»z, extracted with 200 ml of EtOAc and the organic phase was separated, which was concentrated in a vacuum. The obtained crude product (1.8 g) without purification was used in the next reaction.

Ministry of Health (EBI): (MN) 345.

Eche 0.50 (silica gel, DXM/MeoN/MH" in the ratio 90:10:1). 123. Ethyl ether (Kk)-3-(4-amino-3,5-bistrifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) )piperidine-1-carbonyliamino)propionic acid

0.94 g (5.7 mmol) of KDT was added to a solution of 1.8 g of the crude product obtained at the previous stage in 10 ml of THF, cooled to -52 C, and the reaction mixture was stirred at this temperature for 45 minutes, and then, after removing the ice bath, for another 3 minutes. Next, a solution of 1.28 g (5.2 mmol) was added

Z-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one in BOml DMF. After that, the reaction solution was heated to 802C, kept at this temperature for 2 hours, after cooling it was concentrated in a vacuum, the residue was mixed with 150 ml of BEAs and 150 ml of a 1095 solution of citric acid, the organic phase "CM" was separated, it was washed with 150 ml of a saturated solution of MansSoOz and dried over Ma»ZzO). After removal of the desiccant and solvent, the crude product (3.7 g) was used without purification in the next reaction.

MS(EBI)(MAN) 616.

Eche 0.25 (silica gel, EUAcC). 12 and. (B)-3-(4-amino-3,5-bistrifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1 -ka s rbonilyamino)propionic acid

To a solution of 3.7 g of the crude product obtained at the previous stage in 5 bbml of THF, a solution of 04 g (9.5 mmol) of lithium hydroxide hydride in 5 ml of water was added, and the reaction mixture was left to stir overnight at room temperature. b

Then THF was distilled off under vacuum, the residue was mixed with 100 ml of water and acidified with 1-molar NH. The precipitated product was separated by vacuum filtration, washed with 5 ml of water and dried at 602C in an oven. -

Yield: 2.6 g (90965 from theory in terms of the compound from example 12e).

MS(E5I): (M-H) -586.

Retention time (RHVT): 7.1 min. (method A). « 12kK. w-v 70 O-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide c 4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid :z» To a solution of 5OOmMg (0.85 mmol) (Kk)-3-(4- amino-3,5-bistrifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-carbonylamino)propionic acid, 289 mg ( 0.9 mmol) of TBTU and 0.2 in 8 ml (2.0 mmol) of triethylamine in 5 Oml of THF -1 395 was added to 155 mg (0.85 mmol) of 1-methyl-4-piperidin-4-ylpiperazine and the reaction mixture was left to stir overnight at room temperature. Then the reaction mixture was concentrated in a vacuum, the residue was dissolved in 100 ml EAs and 100 ml (Ce) 1096 solution of citric acid, the organic phase was separated and the solvent was distilled off in a vacuum. After that, the residue was purified by chromatography (silica gel, gradient elution: with a change from DCM to

DCM/Meon/mnn with the ratio 10:85:55). ko 50 Output: 57 Ohms (8995 from theory). "c" MS(E5I): (MAN) -753.

Ee0.5 (silica gel, DCH/MeOH/MH" in the ratio 85:15:1.5).

By analogy with (Kk)-3-(4-amino-3,5-bistrifluoromethylphenyl)-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) of piperidine-1-carbonylamino)propionic acid and the corresponding amount of amine, the following compounds were obtained:

F) name) 60 b5 from r

Oh, yes! gives "B in Example Yield of IMas- /|Deterioration of E; at (6) |spectrum |chromatography on reading room 2 PTU 753. dl, (Man (DHM/MeOHN;" in 85:15:1 sch 25 "k 738 0, 5 o loh NI lummeonya 85:15:1,5) o y y 873 sch y

Man so and (22) 35 : m.

The compound obtained in example 12.3 was used without purification in the next reaction.

Example 12.4

KRO-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)ethylamide « 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid - in s;" - And 2

Te) i (95) d) 50 s» '

The indicated compound was obtained similarly to example 11.8 from 450 mg (0.52 mmol) of benzyl ether 4-(1-((k)-3-(4-amino-3,5-bistrifluoromethylphenyl)-2-(C4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperides (F)n-1-carbonylamino)propionyl)piperidin-4-yl|Ipiperazine-1-carboxylic acid (crude product from example 12.3 ).

He output: 200 Ohms (5395 from theory).

MS(EB5I): (MAN) -739. in Ee0.3 (silica gel, DXM/MeoN/MH" in the ratio 50:50:5).

The following compounds can be obtained in a similar way: b5

FF 170 and t -

And du

Mk. iy y i I dey E ku E s ;y u yy 7 5 KZ shvi vet aa lower sho o ant inn yin ipnrishchnya y toy tn ch-k:

Zk keyi , - she zhi | Geo)

Ink t Cl ha - y i y;

И г я и и о я че "- Shose r shocks:" otiti sh a y t p p n Y 112 M kosh | P. 1 c. se» Example 13 (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl ether 4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carboxylic acid

F) ime) 60 b5 t 19 1Za. (5)-3-(K)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxypropionyl|-4-benzyloxazolidin-2-one

To a cooled to -602C solution of 5.1 ml (5.1 mmol, 1-molar in THF) sodium bistrimethylsilylamide in 4 ml

THF in a nitrogen atmosphere for 1 min. a cooled to -60 C solution of 1.33 g (4.1 mmol) (5)-4-benzyl-3-(2-benzyloxyacetyl)oxazolidin-2-one in 15 ml of THF was added dropwise, and the reaction mixture was stirred for 1 hour. at this temperature. Next, the reaction mixture was cooled to -702C and a solution of 2.0 g (8.2 mmol) of 2-chloro-4-chloromethyl-b6-trifluoromethylphenylamine (example 2a) in 1 mL of THF was slowly added dropwise. Then the reaction solution for 1 hour. kept at -702С, after which it was kept for 2 hours. allowed to warm up to CT. Next, it was mixed with 500 ml of a saturated solution of MNACI, 50 ml of E(OAc) was extracted, the organic phase was separated, the aqueous phase was extracted again with 20 ml of EUAs, the combined organic phases were washed with 100 ml of a saturated solution of Masi and a 1-molar solution of KNBZO), and dried over Ma»zO ). After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, PE/EUAc in the ratio 4:1). (at)

Output: 2.1g (9695 from theory).

MS(E5I): (MAN) -533/535.

Eche 0.15 (silica gel, PE/EUdAs in the ratio 4:1). so 136. (k)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxypropionic acid

To a solution cooled to 0, 2.1 g (3.p94 mmol) of (5)-3-I(5)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxypropionyl|-4-benzyloxazolidine-2- onu in BOml co

THF was added to a solution of 0.34 g (8 mmol) of lithium hydroxide hydride and 1.38 ml (1 mmol, 359% in water) of H»O» in 25 ml of water, and the reaction mixture was stirred for 2 hours. at 02C. Then it was mixed with 5 ml of a saturated Me solution

Ma»SO3 and 5 ml of a saturated solution of ManSO3 were mixed for 30 minutes. and then the THF was removed in vacuo. uh-

The aqueous residue was extracted twice with EtOAc in portions of 5 Oml, and the combined organic phases were dried over Mo50o.

After removal of the desiccant and solvent, the crude product was used without purification in the next reaction. 1 Vol. (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxy-1-(4-(4-methylpiperazin-1-yl)/piperidin-1-yl|Ipropan-1-o 40. H o, c To a solution of 1.5 g (4.01 mmol) of (K)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxypropionic acid in 1 BOml of THF was added 1.35 g ( 4.20 mmol) of TBTU, 0.70 ml (5.0 mmol) of triethylamine and 0.75 g (4.01 mmol) of 1-methyl-4-piperidin-4-ylpiperazine and the reaction mixture was left to stir overnight at room temperature. Then the reaction solution concentrated in a vacuum, the residue was mixed with 200 ml of EOAc and 200 ml of a saturated Manso solution, the organic phase was separated and extracted with 100 ml of a 590% citric acid solution. in vacuo and the residue without purification was used in the next reaction.ee, Yield: 1.75g (81905 from theory).(95) MS(E5I): (MAN) -539/541 (CI).

Retention time (RHVT): 5.9 min. (method A). 13 years (K)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-hydroxy-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|Ipropan-1-one

To the suspension 450 mg (0.4 mmol) (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxy-1-(4-(4-methylpiperazin-1-yl)/piperidin-1 0.32 ml (2.5 mmol) of chlorotrimethylsilane was added to 3 ml of acetonitrile, and the reaction mixture was stirred for 7 hours at 802 C. Then it was mixed with 3 ml of EUN and 20 ml of isopropanol , stirred for 30 minutes at room temperature, added 15 ml of MH solution and stirred for 30 minutes. Then the reaction mixture was concentrated in a vacuum, the residue was mixed with 100 ml of 15956 solution of K»CO»3, extracted with 100 ml of EtOAc and the organic phase was separated , which was washed with a 39% solution of Ma 25O3 and dried over Ma»zOd. After removing the desiccant and solvent, the residue without purification was used in the next reaction.

Output: ZO0Omg (8095 from theory).

Retention time (RHVT): Z, 7 min. (method A). 1 Zd. 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carbonyl chloride

To a solution cooled to 02, 2.5 g (10.2 mmol) of 65 Z-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one and 2.bml (14.9 mmol) ethyldiisopropylamine in 7 bml

Bg (12.1 mmol) of phosgene (20 wt.bo in toluene) was added to DCM, and the reaction mixture was stirred for 30 minutes. at this temperature. The reaction mixture was then allowed to warm to RT, concentrated in vacuo to a volume of approximately 50 ml, then filtered through silica gel, which was then washed with 200 ml of DCM/E(OAc (in a 1:1 ratio), and the combined filtrates were again concentrated in vacuo The residue was stirred with isopropyl ether, subjected to vacuum filtration and dried in a vacuum.

Yield: 2.42g (7790 from theory).

GE 0.43 (silica gel, DXM/E (OAc in the ratio 1:1). 1Ze. (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-(4-methylpiperazine) -1-yl)piperidin-1-yl|-2-oxoethyl ether 70 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine-1-carboxylic acid

To a solution cooled to 0 ZOOmg (0.67 mmol) (k)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-hydroxy-1-(4--(4-methylpiperazin-1-yl) 31 mg (0.7 mmol) of Mann (5595 mg in mineral oil) was added to piperidin-1-yl|ipropan-1-one in 30 mL of THF under a nitrogen atmosphere, and the reaction mixture was stirred for 3 h at this temperature. Then, 24 mg (0. vmmol) 75. 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidine-1-carbonyl chloride and the reaction solution, after removing the cooling bath, was stirred for hours at room temperature. Then the reaction mixture was concentrated in vacuo, the residue was mixed with 4 ml of acetonitrile and purified by LCHT-MS.

Output: 88mg (1595 from theory).

MS(EB5I): (M.N) -720/722 (SI).

Retention time (RHVT): b,Ochv. (method A).

Similarly to examples 1Zv, 13g and 1Ze Kk! (Kk)-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-benzyloxypropionic acid and the corresponding amines, the following compounds can be obtained: с (8) со сч со (22) m. ши с ;» -I se) (95) d) 50 syu"

Ф) име) 60 б5 ше 5 шыны SAHNO that Shi cha 75 І (id and ke ve pu sche and 20. 4 ; | I ay and 1 re DK y

And Lee

He left at 30 | | call and sch 35 : ve. I and them - about | "40 tniaadet i - VE i - ;" t and i what TE and i o IEE Same s tik I s | pu ry

F) ko 60 65

Tdnklado 000 (breathe 0033000 chi 70 I and E her neck and tadch zhi; avg zh is " '

Shh g B on

Example 14 (2-I1,4Dbipiperidinyl-1'-yl-1-4-bromo-3-methylbenzyl)-2-oxoethylamide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) /piperidine-1-carboxylic acid in o

Mk and faith so that I as p

FF iy v ' z o : i - 14a. 2-amino-3-(4-bromo-3-methylphenyl)propionic acid ethyl ether hydrochloride

A mixture of 314 g (115 mmol) of M-(diphenylmethylene)glycine ethyl ether, 28.5 g (108 mmol) of (4-bromo-3-methylphenyl)methyl bromide, 3.55 g (11.0 mmol) of tetrabutylammonium bromide, 116 g (5500 mmol) of K»CO3 and « 40O0ml of acetonitrile within 4 hours. boiled under reflux. After that, solid C was filtered off and the mother liquor was evaporated under vacuum. The residue was dissolved in 500 ml of tert-butyl methyl ether, and after adding 200 ml of 1095 NCI, it was left to stir overnight at RT. Next, the organic phase was separated, the aqueous phase was additionally washed twice with tert-butyl methyl ether in portions of 50 ml, after which, under external cooling with ice, it was neutralized with a 1096% solution of Ma»CO3 and carefully extracted with DM.

The combined organic phases were washed twice with water in portions of 500 ml each, dried over MozoO/, and filtered. through activated carbon and concentrated in a vacuum. The obtained oily residue was dissolved in 50 ml

Ge) of anhydrous EN was mixed with a solution of NOI in ether and then diluted with tert-butyl methyl ether, bringing the total volume of the reaction mixture to 5000 ml. After 20 minutes of stirring, a colorless crystalline precipitate fell out, which was separated by filtration through a notch filter and dried in air. ma 70 Yield: 17.6g (4795 from theory).

GE e0.45 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). p" 146. Ethyl ether of 3-(4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionic acid 59 To an ice-cooled suspension of 6b, 45g (20, mol) of ethyl ether hydrochloride

HF) of 2-amino-3-(4-bromo-3-methylphenyl)propionic acid in bbml of DMF was added 3.28 g (20.00 mmol) of KDT and 2.77 ml (20.0 mmol) of triethylamine. Next, the reaction mixture was first stirred for an hour. stirred at 0 2C, and then at for an hour. at CT, after which it was mixed with a suspension of 4.63 g (20.Omol)

Z-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one in Homl DMF. Then the mixture was heated to 802C, kept at 60°C for 1.5 hours, after which it was mixed with 500 ml of water. After some time, the solidified sediment was crushed using a Shga-Tigtakh stirrer (homogenizer), thoroughly washed with water, separated by filtration through a notch filter and dried at 502C in a drying cabinet with air circulation.

Yield: 11.9 g (97905 from theory; product contains 1.0 eq. of DMF).

Ee0.40 (silica gel, DCM/MeoN/MN" in the ratio 9:1:0.1). 65 ranks,

3-(4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonyl|Iamino)propionic acid

To a solution of 10.9 g (20 mmol) of 3-(4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino ethyl ether ) of propionic acid in bbml of EN, bOml of 1-molar Masson was added, and then the mixture was added for 2 hours. boiled under reflux. After cooling, the mixture was diluted with 500 ml of water and acidified with a 2095 solution of citric acid. The precipitate that fell out was separated by filtration through a nutch filter, washed thoroughly with water and dried at 502C in a drying cabinet with air circulation.

Output: 9, bg (9395 from theory).

MS(E5I): (M-H)- 513/515 (Hg).

E-e0.10 (silica gel, DXM/MesynH in the ratio 9:1). 14 years (2-P1,4Zbipiperidinyl-1"-yl-1-4-bromo-3-methylbenzyl)-2-oxoethyl|amide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) /piperidine-1-carboxylic acid

Similarly to example 2e with 515 mg (1.00 mmol) of 3-(4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin- 1-carbonylamino)propionic acid and 177 mg (1.0O0mmol) |1,4Dbipiperidinyl obtained the target product.

Output: 320Ω (4895 from theory).

MS(EBI): (MN) -665/667 (VG).

E0.33 (silica gel, DCM/Meon/mN" in the ratio 9:1:0.1).

In a similar way, with 3-(4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionic acid and the corresponding amount of amine the following compounds were obtained: c (8) in (ze) sch

Fa so (22) m. ley 0 (ener (kyu « l PI - 52 679681 1028. no s pul Man (DHM/MeOH/chi;" in chu co-greening 9:1:0 1 p i p- 142 GT 0, 24 "Nd A (DHM/MeOH/chY, in the ratio of 9101 se) (95) d) 50 seu"

Ф) ime) 60 b5 with as much NeshiVB ! thanks B | 5 BULL 19 And what She ZY: pile of cotton wool: rynv y

And also sf pay hz; "SHY - what is your E shchi in these and for NE I, and your ee and a and She vid che ibbiievni 9). and 1425 o rya n ko y tt y 40 75 y: t t Ko va

Me: SHY I. shi ratios 9). . . in more: Чи s TK Heprochv duv g ke Kn dych wn I ini Z SDM u - y sha i ! semi-vinayutenn U.'

Example 15 (4-(1-(3--4-bromo-3-methylphenyl)-2-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin-1- carbonyl(amino)prop He ionyl)piperidin-4-yl|piperazin-1-yl)acetic acid o et so

F s. so whose rank ' od | To a solution of 8 mg (0.11 mmol) of ethyl ether -(1-(3-(4-bromo-3-methylphenyl)-2-(4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonyl|amino)propioni 14-(1-(3-(4-6 C phenyl)-2-(4-(2 1,4 I 2H-chi) in-Z-il)pi 1 bonyl|amino) ions

I.Y and? 1.00 ml (1.00 mmol) of 1-molar Mahon was added to 1) piperidin-4-yl|piperazine-1-ylacetic acid (Example 14.4) in 4 ml of THF. The reaction mixture was then allowed to stir overnight at RT, after which the solvent was removed in vacuo. A ml of 1-molar NSII was added to the residue and evaporated to dryness again. The residue was dissolved in -I EUN and after filtration, the mother solution was evaporated in a vacuum. The residue was triturated with diisopropyl ether and dried in air after filtration. and, Output: 8Ω (10095 from theory). Retention time (RHVT): 5.9 min. (method A). oo The following compounds were obtained in a similar way from the corresponding ethyl ethers (examples 14.5 and 14.6): d) 50

F) name) 60 b5

I: y y s n uh IExample Exit Mas. Eii (m) spectrum o |(silica gel) or time y in M thesis Iv. ЕХхртТ я 745147 012 2 (sword! KDHM/MeON In "n ratio 9:13 "w 722124 |5.5 min sch ; IM-NI A) 25 o

Example 16 with 2-(4-bromo-3-methylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4-(2-oxo-1,4-dihydro -2H-quinazoline 30 -3-yl)piperidin-1-yl|butane-1,4-dione He so 35 cha m.

F a « oh! E 40 cc; - not dl z» ' 1ba. 1-ethyl, 4-tert-butyl ether of 2-(4-bromo-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid - and : .

Similarly to example 26, from 114 g (41.7 mmol) of 1-ethyl, 4-tert-butyl ether (Ce) of 2-ethoxycarbonylsuccinic acid and 11.0 g (41.7 mmol) of 1-bromo-4-bromomethyl-2-methylbenzene was obtained by target product.

Output: 21.3g (100905 from theory). ko 50 GE e0.64 (silica gel, PE/EUdAs in the ratio 8:2). so 166. Ethyl ether of 2-(4-bromo-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid

Similarly to example 28, the target product was obtained from 21.3 g (41.7 mmol) of 2-(4-bromo-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid 1-ethyl, 4-tert-butyl ether.

Yield: 7.8g (47905 from theory). 59 GE e0.26 (silica gel, PE/EUAs in the ratio 8:2).

GF) 16v. Diethyl ether 7 2-(4-bromo-3-methylbenzyl)-2-(2-oxo-2-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl |iethylmalonic acid

Similarly to example 2g from 7.80g (19.4mmol) of ethyl ether of 2-(4-bromo-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid and 4.50g (194mmol)

of C-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one gave the target product.

Output: 8.30 Ohms (70905 from theory).

MSc(EI!): (M) -613/615 (Vp). 65 GE e0.80 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 16 years 2-(4-bromo-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyric acid

Similarly to example 2d with 8.30 g (13.bmmol) of 2-(4-bromo-3-methylbenzyl)-2-(2-oxo-2-I4-(2-oxo-1,4-dihydro-2H) diethyl ether -quinazolin-3-yl)piperidin-1-yl|ethylumalon

Acids yielded the target product.

Yield: 5.10g (7490 from theory).

MSc(E!): (M) -513/515 (VH).

GE 20.20 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 1 bd. 70. 2-(4-bromo-3-methylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-ylI-4-(4-(2-oxo-1.4-dihydro-2H- quinazoline-3-and l)piperidine-1-ilibutane-1,4-dione

Similarly to the example of the 2nd Kk! 0.51 g (1.00 mmol) 2-(4-bromo-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin- 1-yl|butyric acid. and 0.18 g (1.00 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave the target product.

Output: 25 Ohms (3795 from theory).

MSc(EI!): (M) -678/680 (VH).

Ee0.50 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

In a similar way, with 2-(4-bromo-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin-1-yl|butyric acid and the appropriate amount of amine, the following compounds were obtained: с (8) со сч сч со (22) счи ; tro I (silica gel ii- i, MN zh nch 677679 10.50 aa PMG | (DHM/Suu/MeOHNN" in " du UNDO ShshNN 79:15:15:2 -

K.I s ts 663/665 10.52 ratios 70:15:15:2 zv with more 7427144 10.56 - ІІ (IDHMYSUsMeONchN; In

Ge) from Vinny 7K15:1552 (95) Example 16.4 dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyl)piperidin-4-yl)piperazin-1-yl)acetic acid

F) name) 60 b5

The synthesis was carried out in a Spetzreed ABMU2000 robotic synthesizer (Spetzreed Tsa., located at KPeiipzigaVe 32, SN-4302 Atsavi, Zspueizg).

Mixture (abbreviation "BP" means "starting substance"): and o

BP 1-4 were placed in the appropriate positions, after which they were combined by pipetting with the help of a robot and shaken for 8 hours. at CT. Then the reaction mixtures were evaporated, each of them was mixed with 7 ml of EtOAc, each of the obtained solutions was washed with 1 ml of a 1095% solution of K»CO» and bml of water and the solvent was removed again.

Each of the obtained residues was dissolved in BP 7 and after adding BP 5, it was stirred for two hours. at CT.

Then each reaction mixture was neutralized by adding BP 6 and then evaporated. Each of the obtained residues was dissolved in 1.0 ml of DMF and placed on a titration microplate. The samples were separated using a system for HCVT-MS (Adiyepi Tespoiodiev company, modules and systems for HCVT and LC/MS Adiyepi 1100

Zegiez Modishez apa Zuzietv og NRI S apa I S/M5) and the product was collected in a fraction of a given volume. The final product was dried by lyophilization.

Yield: 4 mg (395 from theory).

MS(EBI): (M-N) -721/723 (Vo) (MAN) -723/725 (Vi) s

Example 16.5

O (1-22-(4-bromo-3-methylbenzyl)-4-oxo-4-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylbutyryl )-I4,4-bipiperidinyl-1-yl)acetic acid so and " ch

F z h y b » Ua ana y ' | "cho"she 2 s |.

I.Y -» The synthesis was carried out in a Spetzreed ABMU2000 robotic synthesizer (Spetzreed Tsa., located at KPeiipzigaVe 32, SN-4302 Atsavi, Zspueizg).

Mixture (abbreviation "BP" means "starting substance"): -I

Fo o m) se» BP 1-4 were placed in the appropriate positions, after which they were combined by pipetting with the help of a robot and shaken for 8 hours. at CT. Then the reaction mixtures were evaporated, each of them was mixed with 7 ml of EtOAc and 1 ml of a 1096% solution of K»CO»z, vigorously shaken, the aqueous phase was separated and discarded. The organic phase was evaporated and dissolved in bml of MeOH. Then a third of this solution was taken and placed on a titration microplate. The samples were separated using a system for HCVT-MS (Adiyepi Tesppoiodiyev company, modules iF) and a system for HCVT and LC/MS Adiyepi 1100 Zegiez Modshiez apa Zuzietv og NRI S apa I S/M5) and the product was collected in a fraction of a given volume. The final product was dried by lyophilization.

Output: UMG (995 from theory). in MS(E)): (M) -735/737 (Vp).

E0.38 (silica gel, DCM/MeoOonN in a ratio of 9:1).

The other two-thirds of the MeonN solution was evaporated and the crude product (195 mg) was used in the next reaction in Example 16.6.

Example 16.6 6E (1-(2-(4-bromo-3-methylbenzyl)-4-oxo-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin- 1-yl|butyl)-(4,4-Dipiperidinyl-1-yl)acetic acid

And so

The synthesis was carried out in a Spetzreed ABMU2000 robotic synthesizer (Spetzreed Tsa., located at KPeiipzigaVe 32, SN-4302 Atsavi, Zspueizg).

Mixture (abbreviation "BP" means "starting substance"):

BP / 195 mg (0.2 bmmol) methyl ether 1:.(1-2-(4-bromo-3-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)piperidin-1-yl|butyryl)-(4,4bipiperidinyl-1-yl)acetic acid,

VR |Bml meon, 2: and 3:

BP 1.00 ml AM NS. and)

AND:

BP 1 was dissolved in BP 2 and then BP 3 was added. The resulting mixture was shaken for 5 hours. at 2090 and then neutralized by adding BP 4. After that, the reaction mixture was evaporated and dissolved in 2 ml of DMF. Shk samples were separated using a system for RHVT-MS (firm Adiepi Tespoiodiyev, modules and systems for RHVI and

LC/MS Adiyepi 1100 Zegiez Modshevz apa Zuzietv og NRI S apa I C/M5) and the product was collected in fractions of the given volume. The final product was dried by lyophilization. Shk

Yield: 22 mg (1195 from theory). (Gee)

MS(EB5I): (MAN) -722/724 (Vk). M

GE e0.22 (silica gel, DXM/MesynH in the ratio 9:1).

Example 17 (1-(4-chloro-3-methylbenzyl)-2-(4-(4-methylpiperazin-1-ylpiperidin-1-yl)|-2-oxoethylamide 4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)/piperidine-1-carboxylic acid "shi c;" -.re) -.(95) d) 50 syu" 17a. 2-amino-3-(4-chloro-3-methylphenyl)propionic acid ethyl ether hydrochloride

Similarly to example 14a, the target product was obtained from 31.4 g (115 mmol) of M-(diphenylmethylene) glycine ethyl ether and 25.2 g (F) (115 mmol) of 4-bromomethyl-1-chloro-2-methylbenzene.

He Yield: 20.4g (64905 from theory).

MS(EB5I): (MAN) -241/243 (SI). in Eche 0.35 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 176. Ethyl ester of 3-(4-chloro-3-methylphenyl)-2-1C4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonylamino)propionic acid

Similarly to example 146 with 5.56 g (20.Omol) of ethyl ether hydrochloride 65 2-amino-3-(4-chloro-3-methylphenyl)propionic acid Y 4.63 (20.Omol)

of C-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one gave the target product.

Yield: 9.50g (95905 from theory).

MS(EBI): (M-N) -497/499 (SI). 17th century 85 3-(4-chloro-3-methylphenyl)-2-(I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionic acid

Similarly to example 148 with 9.50 g (19.Omol) of 3-(4-chloro-3-methylphenyl)-2-1C4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) ethyl ether /piperidine-1-carbonylamino)propionic acid gave the target product.

Yield: 8.90g (99965 from theory).

MS(EBI): (M-N) -469/471 (SI).

E-e0.10 (silica gel, DXM/MesynH in the ratio 9:1). 17 (1-(4-chloro-3-methylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid

Similarly to example 2e with 7Obmg (1.500mmol) 3-(4-chloro-3-methylphenyl)-2-1C4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin-1 -carbonylamino)propionic acid and 275 g (1.50 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave the target product.

Output: 25Ω (2695 from theory).

MS(E5I): (MAN) -636/638 (SI).

Eche 0.17 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1).

In a similar way, with 3-(4-chloro-3-methylphenyl)-2-1C4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonylamino)propionic acid and the corresponding amount amine, the following compounds were obtained: со со сч со (22) and - "shi c;" -I se) (95) d) 50 syu"

F) name) 60 b5

: va

Be what M. "U. and I ptn sne ss PO i i EE EN kip ti ntsne tv y T vie ELE her tya ks. vh a y Y Y what I Y y De s: chiy (ya rya GI A Z y

I che Tent tyny p spishssya zhh - - -- Gn Tl wn U shi slag" BTI BATHS MANEZH NI;

I: 1 ие что вро вив и е е | ho I y y What p poshe Y KO NI POTEN II. ге я я Бе ШИ ' I Е, lona ТОПИВНИДНОТЕННи BUT, сч 178 иж ШЧХ вд c) 58) Shi Щ | at

I and Kk. and, and MN iDkhMIMoYA ZyChEu . и V ak: Y, I and thank you: | and YAM, | kV EN pod sa che lesi; same now what she and -tk se Theme PDylin s ; Well, I'm pi | at. Vozhyaks: I) vh li GU Bi v. пе х TU, ТЯ ШАЭ Й « z | PA | peso NO ZUNAINS IN 1 z tens sovi in i Щ шщ- ее ее у ? : pe SHA Y TI Di VENU Chu. shi NIMY ZO MYOMYA PIKA inolovianviny vva a che on TU tv pd . y: "Mk sy z. what M D-t, " y, cheh Ki vk Y ! k My name is: ana OTOMLYSOVLIAN i

Mshi y: Z. chura y Y t ee y -1 ; And what - her zhk i dvi et Ya. 1 . Example 18 (4) (1'-(3-(4-chloro-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin- 1-CarbonylIamino)propio 50 nyl)-I4A|bipiperidinyl-1-yl)|acetic acid si» 2 -

F t vk

Ф) : ше Чо ет ' и бо Similarly to example 15 with 220 mg (0.28 mmol) of ethyl ether

(1'-(3-(4-chloro-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonylamino)propionyl) - (Х4,4bipiperidinyl-1-ylacetic acid obtained the target product.

Output: 190mg (9995 from theory).

MS(EB5I): (MAN) -679/681 (SI).

Ee0.13 (silica gel, DHM/MesynH in the ratio 9:1).

Example 19 2-(4-chloro-3-methylbenzyl)-1-I(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4- dihydro-2H-quinazoline-

(Z-yl)/piperidin-1-yl|Ibutan-1,4-dione is the name of 19a. 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid 1-ethyl, 4-tert-butyl ester

Similarly to example 26, from 19.5 g (71.00 mmol) of 1-ethyl, 4-tert-butyl ether with 29 2-ethoxycarbonylsuccinic acid and 15.5 g (71.0 mmol) of 4-bromomethyl-1-chloro-2-methylbenzene was obtained Ge) target product.

Yield: 25.7g (88905 from theory).

GE O.74 (silica gel, DCM). 196. Ethyl ether of 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid o

Similarly to example 28, the target product was obtained from 21.3 g (41.7 mmol) of 1-ethyl, 4-tert-butyl ether with 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid.

Yield: 22.2g (10090 from theory). at

GE e0.18 (silica gel, DXM). Gee! 19th century Diethyl ether

Zo 2-(4-chloro-3-methylbenzyl)-2-(2-oxo-2-|4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl| and ethylmalonic acid

Similarly to example 2g from 8.00g (22.4mmol) of 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid ethyl ether and 5.18g (22.4mmol)

of C-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one gave the target product. - 70 Yield: 9.20g (7290 from theory). with MSE): (M) -569/570 (SI). :z" GE e0.64 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 19 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl)butyric acid - 15 Similar to example 2d from 9.20 g (16.2 mmol) of diethyl ether 2-(4-chloro-3-methylbenzyl)-2-12-oxo-2-|4-(2-oxo-1,4-dihydro-2H- of quinazolin-3-yl)piperidin-1-yl|ethylumalonic (Ce) acid, the target product was obtained. yield: 7.20g (95905 from theory).

MS(EBI): (M-N) -468/470 (SI). where 19d "so 2-(4-chloro-3-methylbenzyl)-1-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione

Analogously to example 2e with 47 mg (1.00 mmol) of 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) /piperidin-1-yl|ybutyric acid and 59 mg (1.10 mmol) of 1-ethyl-4-piperidin-4-ylpiperazine tristrifluoroacetate gave the target product. (F; Yield: 280 mg (4395 from theory). co MSc(EI): (M) -648/650 (SI).

Ee0.47 (silica gel, DCM/MeoN/MN" in the ratio 9:1:0.1). In a similar way, C 2-(4-chloro-3-methylbenzyl)-4-oxo-4-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin-1-yl| of butyric acid and the corresponding amount of amine, the following compounds were obtained: b5

70 and | in.

OS

"uk 7 ennkyu (nyu

M s sshishzhkagel t 634/636 10.49 r A IM 0 DXM/Sus/meOVychi" in r I same pi 70:15:15 52 32 162622 |0.54 lk (Men DXM/Sus/MeONlchN" in the ratio 70: 15:15:2 s 635/637 0.50 . (menu dhmsusmeov/h; in si sing; LY - pni 70:15:15:2 so t 6987700 10.54 boF . mode MIG 0 (DHM/MeONn" in the ratio 9:1.1 "sh s i" - And se) (95) with 50 be»

F) name) 60 b5

It is not the fault of the tires that you are a pedestrian

Ha ; drinkers "and tyka la" 95 Io. "how. That J. TOBI MK -Y

ШО ШАЩИК ня, ИК и против и. and S. i i g DASHANO sit M ox: I Y a --i hopilnyastya pininnkna; s int tn tya Vyvnvnnya did not drink nnvinil m plums MORE 3 and AN 1 a: in i no do, drink and drank from them SO:

Brik D She CHI Y Shchy B will throw GUnyvuzh even with dokzhete; We don't have zhen VV PI

I t I y V. and Y klin ze

Z. ! Oh and!

It's your DNA. others t y : E 599 Another gender: psy s ss chu pyt She p "ly sce t u ce rya, pktryiv os ks ss Nevns vk Markets i --

Kyren Alany and Z Zh Sini dNaniu shcha U, and s pttenannany and Mai; And in I In Chn Sany o) 1910 c. eat Du NU. swarm | ryn deno MIRACLE I and r! sha g t not i: Y g. NO) | : co

KN TI FROM THE FRAME приння за и и бай тк |. Znati nty we shishe M ho Jean J o Ne zl. how pi PE LDNZ CHE '

In the middle of the day, Olya, oh, why are you nave" And: and and more; we WHERE ARE YOU, There is a check B - « s Example 19.13. I4-(1-422-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylIbrTutyryl) n "" iperidin-4-yl) piperazine-1-yl acetic acid - and . se) (95) d) 50 syu"

F) name)

Similarly to example 16.4 with 9 mg (0.20 mmol) of /2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)ipiperidin-1-ylbutyric acid and 51 mg (0.20 mmol) of ethyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid gave the target product.

Yield: 27mg (1995 from theory).

MSc(EI!): (M) -679/681 (SI).

Retention time (RHVT): 5.9 min. (method A). 65 Example 19.14

Methyl ether

(1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyl )-(4,4Dbipiperidinyl-1-yl)acetic acid (e, e

Y F | sew and eat; . 4 " I -

IN

Similarly to example 16.5 with 188 mg (0.400 mmol) of 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) /piperidin-1-yl|butyric acid and

102 mg (0.40 mmol) of ethyl ester of 14,ALbipiperidinyl-1-ylacetic acid obtained the target product.

Yield: 27mg (3095 from theory).

MS(E5I): (MAN) -692/694 (SI).

GE e0.36 (silica gel, DXM/MesynN in the ratio 9:1).

Example 19.15 Ha (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl |bsutiryl)-(4 o "Abipiperidinyl-1-yl)u'acetic acid so s s so i (22) and - « si s Analogously to example 16.6 with 184 mg (0.2 bmmol) of methyl ether h" (1-22- (4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyryl)-I4,41 " of bipiperidinyl-1-yl)/acetic acid gave the target product.

Output: ZOmg (1695 from the theory).

MS(E5I): (MAN) -678/680 (SI). - Ee0.21 (silica gel, DHM/MesynH in the ratio 9:1).

Ge) Similarly to example 15, the following compounds were obtained from the corresponding ethyl ethers (examples 19.7-19.9): (95) d) 50 syu"

Ф) име) 60 b5 i-th zh (Priknad Exit Kk

C) Izjectr silicatel). tk 18 1679681 16.05

MANI KEYUOASS/MeONYCHN, in the text of 6:430,4) this is them. that sew yaoshya, -mvygo in - VYSH N U NIK, PI U DN Kya a r g. . There are only a few people who ate her food and 7 of them. and to Shchi and y y I b - y 3o Sha san still en КЖММЕОНАчНИу : о и. And that's it. Y AND SY DEIYASHENNI and cheeks with) E | with half of the village and ten tya t a. pig 0 F se Ve. z sh "zu y -Shsch s I y ! divniy pi , ch- zho; МН 0 eОАСЛМООННЕ У и Ан вч у - syt " 20 Example 20 -in 2-(4-chloro-3-methylbenzyl)-1-I( 4-(1-methylpiperidin-4-yl)piperazin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-6c-enzdiazepin-3-yl) piperidin-1-yl|butane-1,4-dione with

Fo' or d) 50: y i iz I ih

AND

GF) 20a. 2-(4-chloro-3-methylbenzyl)-2-(2-oxo-2-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) diethyl ether )ipiperidin-1-ylylethyl)m alonic acid in Analogous to example 2g from 1.43g (4.00mmol) of 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid ethyl ether and 981mg (4.00mmol) 3 -(1-methylpiperidin-4-yl)-1,3,4,5-tetrahydro-1,3-benzdiazepin-2-one gave the target product.

Yield: 2.10g (9095 from theory).

GE 20.69 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2). 206. b5 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin- 1-yl|butyric acid

Similarly to example 2d with 2.10 g (3.6 mmol) of diethyl ether 2-(4-chloro-3-methylbenzyl)-2-12-oxo-2-I4-(2-oxo-1,2,4,5- of tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-ylethyl)malonic acid gave the target product. This product was used without purification in the next reaction.

Yield: 1.20g (69905 from theory). 20th century 2-(4-chloro-3-methylbenzyl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-I(4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|butane-1,4-dione 70 Similarly to example 2e with 800 mg (1.6 mmol) of 2-(4-chloro-3- methylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butyric acid and CO2 mg (1.65 mmol ) of 1-(1-methylpiperidin-4-yl)/piperazine gave the target product.

Output: 40Ω (3795 from theory).

MSE): (M) -648/650 (SI).

Ee0.50 (silica gel, DXM/Sus/Meon/mN" in the ratio 70:15:15:2).

Example 20.1 2-(4-chloro-3-methylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-ylI-4-I(I4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-6 enzdiazepine-3-yl)piperidin-1-yl|butane-1,4-dione

Ai s » vada o ' so

Similarly to example 2e with 400 mg (0.83 mmol) of 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzdiazepin-3-yl)piperidin-1-yl|butyric acid and 152 mg (0.83 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave the target product. in.

Output: 200Ω (3795 from theory).

MSc(EI): (M) -648/650 (SI).

Ech20,51 (silica gel, DCM/Sus/Meon/mN" in the ratio 70:15:15:2). "

Example 21

I4-(1-(2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole-1 -yl)piperidin-1-yl C with Ibutyryl)piperidin-4-yl)piperazin-1-yl|!acetic acid;» as I with se) and with R I i n chiy, nia: vi m) o I . ; with ai h7

GF) I d where 21a. 2-(4-chloro-3-methylbenzyl)-2-12-oxo-2-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl) diethyl ether )piperidin-1-yl|iethyl)mal 60 enoic acid

Similarly to example 2g from 5.00g (14.Omol) of 2-(4-chloro-3-methylbenzyl)-2-ethoxycarbonylsuccinic acid ethyl ether and 3.42g (14.Omol) of 5-phenyl-2-piperidine-4- yl-2,4-dihydro-1,2,4-triazol-3-one gave the target product.

Yield: 5.50g (6790 from theory). bo B0.50 (silica gel, DCH/MeOH/MH" in the ratio 9:1:0.1).

2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1 -yl)butyric acid

Similarly to example 2d with 5.50 g (9.4 mmol) of diethyl ether 2-(4-chloro-3-methylbenzyl)-2-12-oxo-2-I4-(5-oxo-3-phenyl-4,5- of dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|ethyl)malonic acid gave the target product.

Yield: 2.80g (62905 from theory).

MS(EBI): (M-N) -481/483 (SI). 70,218.

I4-(1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1- yl)piperidin-1-yl|butyl ryl)piperidin-4-yl)piperazin-1-yl|acetic acid

Similarly to example 16.4 with 9 mg (0.20 mmol) of 2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2, 4-triazol-1-yl)piperidin-1-yl|butyric acid 75 and 51 mg (0.200 mmol) of ethyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid gave the target product.

Output: ZMG (296 from the theory).

MS(EBI): (MAN) -692/694 (SI).

Example 21.1

Methyl ether (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole-1- yl)piperidin-1-yl|bsutyrs of 1)-4,4-bipiperidinyl-1-yl)acetic acid I , c (8) : co | high school

E so (22) m. "

Similarly to example 16.5 with 193 mg (0.400 mmol) 49 2-(d-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2 ,4-triazol-1-yl)piperidin-1-ylbutyric acid and 102 mg (04 mmoles) of ethyl ether (|4,4Dbipiperidinyl-1-ylacetic acid) gave the target product. Yield: 14 mg (1595 from theory).

MS(E5I): (MAN) -705/707 (SI).

GE e0.32 (silica gel, DXM/MesynH in the ratio 9:1). and Example 21.2 (Ce) (1-(2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4 -triazol-1-yl)piperidin-1-yl)-4,4"-bipiperidinyl-1-yl)acetic acid d) 50 2bmmol) of methyl ether (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole- 1-yl)piperidin-1-yl esters of 1)-4,4-bipiperidinyl-1-yl)acetic acid gave the target product.

Yield: 11 mg (695 from theory).

MS(EBI): (MN) -691/693 (SI).

Ee0.21 (silica gel, DHM/MesynH in the ratio 9:1).

Example 22 2-(3-bromo-4-chloro-5-methylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo- 1,4-dihydro-2H-hynosolin-3-yl)piperidin-1-yl|butane-1,4-dione

I'm like | | cheek cheek 8 :

That's right

AND

22a. 1-(3-bromo-4-chloro-5-methylphenyl)ethanone

25.0 g (148 mmol) of 1-(4-chloro-3-methylphenyl)ethanone was added dropwise to 59.2 g (444 mmol) of aluminum trichloride. At the same time, the temperature rose to 702C. The mixture was stirred for

REFERENCE at 8090 and then at this temperature 10.7 ml (1700 mmol) of bromine was added dropwise. After that, the reaction solution was stirred for an hour. at 802C, and then poured onto ice. The aqueous phase was extracted with diethyl ether and the combined organic extracts were washed with a saturated solution of ManHsSOOz. The organic phase was dried over NaCl3O), and the solvent was removed in vacuo. The product was purified by column chromatography on silica gel with (toluene).

Output: 14.Ohm (38905 from theory). with

MSc(E!): (M) -246/248/250 (Hg, SI). co

GE e0.28 (silica gel, toluene). 226. 3-bromo-4-chloro-5-methylbenzoic acid Me)

To a solution of 22.8 g (570 mmol) of MaonN in 114 ml of water at 02С, 8.7 ml (171 mmol) of bromine was added dropwise so that the temperature did not exceed 102С. Then, at 102C, 14.0 g (57 mol) of 1-(3-bromo-4-chloro-5-methylphenyl)ethanone was added dropwise to 57 ml of 1,4-dioxane and the mixture was stirred for 2 hours. at CT. Then the reaction mixture was diluted with water and the bromoform formed was separated. The aqueous phase was acidified with half conc. "

NOI, the precipitate was separated by vacuum filtration and then washed with water.

Output: 11.Ohm (78905 from theory). - with MSc(E!): (M) -248/250/252 (Hg, SI). h Melting point: 207-20996. -" 22 c. (3-bromo-4-chloro-5-methylphenyl)methanol

To a solution of 11.0 g (44 mmol) of 3-bromo-4-chloro-5-methylbenzoic acid in 285 ml of THF, 8.1 g (B5 mmol) of KDI was added. After that, the reaction mixture was stirred for an hour. at 402C. Then this solution was added - to a solution of 5.38 g (142 mmol) of Mavn in 47.5 ml of water. Then the mixture was stirred for 10 minutes. at CT, after which it was diluted with ZOO ml of water and acidified with semi-conc. NSI The aqueous phase was extracted with EtOAc, and the organic phase was successively washed with water and a saturated solution of MansCoO3. The organic phase was dried over NaCl, and the solvent was removed in vacuo.

Ge 50 Yield: 9.00 g (8790 from theory).

MS(E5I): (M-H) -233/235/237 (Hg, SI). c» GE e0.62 (silica gel, PE/EUdAs in the ratio 1:1). 22 years 1-bromo-5-bromomethyl-2-chloro-3-methylbenzene

5.2 ml (19 mmol) of phosphorus tribromide was added 22 drops to a solution of 9.00 g (3 mmol) of (3-bromo-4-chloro-5-methylphenyl)methanol in 250 ml of diethyl ether at RT and for an hour. boiled with reverse

HF) refrigerator. Then the reaction mixture was poured into a saturated solution of CaCl3, the organic phase was separated, washed with water and dried over NaCl3O. After removal of the desiccant and solvent, the target product was obtained. where Output: 10.7g (94905 from theory).

MSc(EI): (M) -296/298/300/302 (2Vg, SI). 60 E0.89 (silica gel, PE/E (JuAcC in a ratio of 1:1). 22d. 2-(3-bromo-4-chloro-5-methylbenzyl)-2-ethoxycarbonylamber acid

Similarly to example 26 with 9.86 bg (Zbmmol) of 1-ethyl, 4-tert-butyl ether of 2-ethoxycarbonylsuccinic acid and 10.7g (Zbmmol). 1-bromo-5-bromomethyl-2-chloro-3-methylbenzene gave the target product. because Output: 17.5g (99965 from theory).

MS(E5I): (MAN) -513/515/517 (Vg, SI).

Ee0.57 (silica gel, DCM). 22nd 2-(3-bromo-4-chloro-5-methylbenzyl)-2-ethoxycarbonylsuccinic acid 1-ethyl ether

Similarly to example 28 with 18.0 g. (37mmol) of 2-(3-bromo-4-chloro-5-methylbenzyl)-2-ethoxycarbonylsuccinic acid 1-ethyl, 4-tert-butyl ether gave the target product. The crude product, which still contained TFOC, was used without purification in the next reaction.

MS(E5I): (M-H) -433/435/437 (Hg, SI). 22 Diethyl ether 70. 2-(3-bromo-4-chloro-5-methylbenzyl)-2-(2-oxo-2-I4-(2-oxo-1.4-dihydro-2H-quinazolin-3-yl)piperidin- 1-yl|Iethylumalonic acid

Similarly to example 2g from 18.2g (42mmol) of 2-(3-bromo-4-chloro-5-methylbenzyl)-2-ethoxycarbonylsuccinic acid 1-ethyl ether and 9.6g (42mmol)

of C-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one gave the target product.

Output: 15.Ohm (56905 from theory).

MSc(EI): (M) -647/649/651(Hg, SI).

GE e0.60 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 223. 2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl |butyric acid

Similarly to example 2d with 15.0 g (23 mmol) of 2-(3-bromo-4-chloro-5-methylbenzyl)-2-12-oxo-2-(4-(2-oxo-1,4-dihydro) diethyl ether -2H-quinazolin-3-yl)piperidin-1-ylethyl)umalic acid gave the target product.

Output: 11.8g (93905 from theory). everything

Ee0.20 (silica gel, EUDAs/MeonH/acetic acid in a ratio of 8:2:0.1). at 22. 2-(3-bromo-4-chloro-5-methylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo- 1,4-dihydro-2H-quinazo lin-Z-yl)/piperidin-1-yl|Ibutane-1,4-dione

Similarly to the example of the 2nd Kk! 1.09 g (2.00 mmol) He) 2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)piperidin-1-yl|Butyric acid and 367 mg (2.00 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave the target product.

Output: 77Zmg (5495 from theory). (ze)

MS(E)): (M)7-712/714/716 (Hg, SI). b

GE e0.24 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 3o In a similar way C - 2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin- 1-yl|butyric acid and the corresponding amount of amine, the following compounds were obtained: i. ne) i a 15 ke st syu ay v- : y 5 I i d) 50 | that Ch. (45) And Threads! g | I am in PARADISE Piy KD I nlEya and Gal i m pog trrei o I i t K. tretyu g CHI - yu GO 0000 Mninvidnymny (JAVA)

We eat I am TOPMidnight now in ! 13 of them ate in the hall!

TMYANT / KZHBNYOKYCHN U ;

Example 22.4

I4-(1-(2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)) piperidin-1-yl(butyril)piperidin-4-yl)piperazin-1-yl|!acetic acid oo

Similarly to example 16.4 with 109 mg (0.20 mmol) of 2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)piperidin-1-yl|butyric acid and 51 mg (0.20 mmol) of ethyl ether (4-piperidin-4-ylpiperazin-1-yl)acetic acid gave the target product.

Output: 1Omg (695 from theory).

MS(E5I): (M-H) -755/757/759 (Hg, SI). with

Ee0.21 (silica gel, DHM/MesynH in the ratio 9:1). at

Example 22.5

Methyl ether (1-22-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine) -1-yl|Ibsutiryl) -(S4,4bipiperidinyl-1-yl)acetic acid with sch - ish ' B

Y - s aa y y Z is "

Fe 7 - s sha, I;"

Similarly to example 16.5 with 220 mg (0.400 mmol) of 2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)piperidin-1-yl butyric acid and 102 mg (04 mmol) of ethyl ether (4,4 Dbipiperidinyl-1-ylacetic acid) gave the target product.

Yield: 19mg (1895 from theory). o MS(EBI): (MAN) -770/772/774 (Vg, SI). ma 70 Ru0.36 (silica gel, DCM/MeOH in the ratio 9:1).

Example 22.6 c" (1-(2-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)piperidin-1-yl|butyryl)-(4,4Dbipiperidinyl-1-yl)acetic acid

F) name) 60 b5 and. ' ' -- - rank of them; 70th SF i ch - ' a

Similarly to example 16.6 with 204 mg (0.2 bmmol) of methyl ether (1-22-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4- of dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyryl)-(X4,4bipiperidinyl-1-yl)acetic acid gave the target product.

Yield: 25mg (1295 from theory).

MS(EBI): (M.N) -756/758/760 (Vg, SI).

GE e0.23 (silica gel, DXM/MesynH in the ratio 9:1).

Example 23 (1-(3-bromo-4-chloro-5-methylbenzyl)-2-I4-(4-methylpiperazin-1-yl)piperidin-1-yl-2-oxoethyl)amide 4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid Ha o dk -

More. "

Y cha I so zo | - i , c i Fo i 1 i . 2For. Hydrochloride of ethyl ether of 2-amino-3-(3-bromo-4-chloro-5-methylphenyl)propionic acid « 20 Similarly to example 14a with 6.0 bg (22.2 mmol) of ethyl ether of M-(diphenylmethylene)glycine and 6, The target product was obtained with 300 g of 1-bromo-5-bromomethyl-2-chloro-3-methylbenzene (115 mmol).

Output: 5.82g (7790 from theory). ;" MS(E5I): (MAN) -320/322/324.

Eche 0.70 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 236. Ethyl ether -I 3-(3-bromo-4-chloro-5-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino )propionic acid and, Analogously to example 146 with 5.82 g (16.3 mmol) of ethyl ether hydrochloride 2) 2-amino-3-(3-bromo-4-chloro-5-methylphenyl)propionic acid and 3.77 ( 16.3 mmol)

of C-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one gave the target product. Output: 7.bOg (81905 from theory). 4) Ee0.52 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 23 c. 3-(3-bromo-4-chloro-5-methylphenyl)-2-(I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionic acid

Similarly to example 148 of 7 boh (13,Tmmol) of ethyl ether

F) 3-(3-bromo-4-chloro-5-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionate acids gave the target product.

Output: 6.7Ω (93905 from theory). in MS(E5I): (M-H) -547/549/551 (Hg, SI).

Eche 0.05 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1). 2Zr. 11-(3-bromo-4-chloro-5-methylbenzyl)-2-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethylamide 4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid

Similarly to the example of the 2nd Kk! 1.35 g (2.45 mmol) 65 33-(3-bromo-4-chloro-5-methylphenyl)-2-C4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine -1-carbonylamino)propionic acid and 449 g (2.45 mmol) of 1-methyl-4-piperidin-4-ylpiperazine gave the target product.

Output: 1.10g (63905 from theory).

MS(EBI): (MN) -714/716/718 (Hg, SI).

Eche 0.41 (silica gel, DXM/MeoN/MH" in the ratio 9:1:0.1).

In a similar way, with 3-(3-bromo-4-chloro-5-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propion acid and the corresponding amount of amine, the following compounds were obtained: --y "I KI iy

Convinced: Yours Your advice: 68 es zo VINNY WE be shk, ! And see her (DYMIMONLnuH

I RR PC 6. Ky o i Me VISHIA r. "vii. In, p. ches Cl. i In 1. heh 153 0 IVLLOILYAYUUH What! 7 Te i o KOLIA OD shi still i Z i ani p vich ŽY

Ч кдд хи Ге я. yad va1h (С И) ЕВ Z Что « и и овый У. ия; 40 Example 24 z» 2-(4-chloro-3-trifluoromethylbenzyl)-1-(1-methyl-I4 A4bipiperidinyl-1-yl)-4-I( 4-(2-oxo-1,4-dihydro-2H-quinazoli n-3-yl)/piperidin-1-yl|Ibutan-1,4-dione 1 -i - k (se in syu p - z x - syu" and so on

AK

; t yan

GF) 'ko 24a. 2-(1-(4-chloro-3-trifluoromethylphenyl)meth-(E)-ylideneosuccinic acid 1-methyl ester

20.7 ml (158 mmol) of succinic dimethyl ether was added to a freshly prepared solution of sodium methylate (obtained by dissolving 3.64 g (158 mmol) of sodium in 60 Meon) in 300 ml of Meon, and the reaction mixture was stirred for an hour. at CT. Next, 30 g (144 mmol) of 4-chloro-3-trifluoromethylbenzaldehyde and the reaction solution were added for 2 hours. boiled under reflux. Then the reaction mixture was concentrated in a vacuum, the residue was dissolved in water, acidified with a 20956 solution of citric acid and carefully extracted

EUAs. The organic phase was extracted five times with 200 ml portions of 390 ml solution of MH, the combined aqueous phases were acidified with citric acid solution, carefully extracted with E(OAc) and dried over Ma 2504. After removal of the desiccant and solvent, the target product was obtained in the form of a yellow oil .

Output: 12g (2696 from theory).

E-e0.33 (silica gel, PE/EYUAS/ASON in the ratio 75:25:5). 246. 2-(4-chloro-3-trifluoromethylbenzyl)succinic acid 1-methyl ester

To a solution of 2.0 g (b.2 mmol) of 2-(1-(4-chloro-Z3--rifluoromethylphenyl)meth-(E)-ylideneosuccinic acid 1-methyl ether in 20 ml of Meon, 200 mg of 1095th RUS was added and the reaction mixture was hydrogenated during the period of agreement at KT and pressure No

From the bar. After that, the catalyst was filtered off and the solvent was evaporated under vacuum. The crude product without purification was used in the next reaction.

Yield: 1.85g (92965 from theory). 70 E-e0.38 (silica gel, PE/EYUAS/AsSON in the ratio 75:25:5). 248. 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylbutyric acid methyl ester

A solution of 1.5 g (4.6 mmol) of 2-(4-chloro-3-trifluoromethylbenzyl)succinic acid 1-methyl ether, 1.64 g of 7/5 (5.1 mmol) of TBTU, 0.69 g (5.0 mmol) of HOBT and 1.32 ml (7.5 mmol) of ethyldiisopropylamine in 1000 ml of a THF/water mixture (in a ratio of 9:1) was stirred for 10 min. at CT and then mixed with 1.2g (5.Omol)

Z-heperidin-4-yl-3,4-dihydro-yl-quinazolin-2-one. After that, the reaction mixture was stirred for 2 hours. at

CT was concentrated in a vacuum, the residue was mixed with a saturated solution of MansSo»z, carefully extracted with E(Ac) and the combined organic extracts were dried over M950. After removing the desiccant and the solvent, the target product was obtained, which was used without purification in the next reaction.

Output: 2.2g (8995 from theory).

GE e0.6 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2). 24. 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)ipiperidin-1-yl|Imaslyana sch r; Acid

To a solution of 2.2 g (4, Immol) of methyl ether and) 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin- 3-yl)piperidin-1-ylbutyric acid was added to 200 ml of MeonN with 1 ml of 1-molar Masson solution and the reaction mixture was stirred for

Bhod at 5020. Then it was diluted with 17 Oml of water, extracted twice with tert-butyl methyl ether in portions of 30 ml each, the aqueous phase was mixed with 1 bml of 1-molar HCl, extracted three times with EtOAc in portions of 7 Oml, and the combined organic phases were dried over Ma»5O). After removal of the desiccant and the solvent, the residue was triturated with diisopropyl ether, subjected to vacuum filtration and air-dried. co

Yield: 1.1g (5195 from theory).

GE 20.25 (silica gel, DCM/MeOH/Sus/MH" in the ratio 70:15:15:2). ia with 5 years і- 2-(4-chloro-3-trifluoromethylbenzyl)-1-(1-methyl-I4 4bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin- 3-yl)piperidin-1-yl|butane-1,4-dione

The specified compound was obtained similarly to example 248 from 790 mg (1.5 mmol) of 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)piperidin-1-ylbutyric acid "

Acids and 37Omg (1.bmmol) 1-methyl-|4,4|bipiperidinyl. 8 s Output: 5ZOmg (5195 from theory). h MSc(EI): (M) -687/689 (SI). ," GE e0.6 (silica gel, DCH/MeOH/Sus/MH" in the ratio 70:15:15:2).

Example 24.1 2-(4-chloro-3-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-ylI-4-I(I4-(2-oxo-1,4-dihydro -2H-hi-I nazolin-3-yl)piperidine-1-ilibutan-1,4-dione from (95) d) 50 syu»

F) name) bo n

To a solution of 800 mg (1.53 mmol) of 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin- 280 mg (1.53 mmol) of 1-methyl-4-piperidine-4- illiperazine and the reaction mixture were stirred for 2.5 hours at room temperature. Then the reaction mixture was concentrated in vacuo, the residue was dissolved in DCM, the organic phase was washed twice with saturated Manso solution and dried over MazO)". After removing the desiccant and the solvent, the residue was purified by chromatography (silica gel, MeOnH).

Output: 40 Ohms (3895 from theory).

MSc(EI): (M) -688/690 (SI).

Ee0.25 (silica gel, MeOH).

Example 24.2 1-1,4bipiperidinyl-1'-yl-2-(4-chloro-3-trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-ilibutan-1,4-dione "etc. to" i

Fo sht sia i ' « syu nya i s

The indicated compound was obtained similarly to the example (2441 Kk) 80mg (1.53mmol) of 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H) -quinazolin-3-yl)piperidin-1-ylbutyric acid and 271 mg (1.61 mmol) |1.4Dbipiperidinyl.

Output: 47 Ohms (4695 from theory).

MSc(EI!): (M) -673/675 (SI). at

P.0.28 (silica gel, MEON). high school

Example 24.3

I4-(1-(2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl) |bu me) tiril)piperidin-4-yl)piperazin-1-yl|!acetic acid Ge! ги и- ; 8 « chik chn С. o) - o - y ' t. 0 7 "Sho -I '" (Se) The specified compound was obtained similarly to example 16.4 from 105 mg (0.2 mmol) of 2-(4-chloro-3- trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylbutyric acid and 51 mg (0.2 mmol) of ethyl ether (4-piperidine -4-ylpiperazin-1-yl)acetic acid. c, y pe co Yield: 1 mg (895 from theory). "su MS(EB5I): (MAN) -733/735 (CI).

Retention time (RHVT): 6b, Zhv. (method A).

Example 24.4

Methyl ether (1-(2-(4-chloro-33-trifluoromethylbenzyl)-4-oxo-4-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl) |bsutiryl) (F) -(Х4,4bipiperidinyl-1-yl)acetic acid ime) 60 b5 ko i. nn The specified compound was obtained analogously to example 16.5 from 209 mg (0.4 mmol) of 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-( 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylbutyric acid and 102 mg (0.4 mmol) of ethyl ether (4,4bipiperidinyl-1-ylacetic acid.

Yield: 17mg (1795 from theory). 20 MS(EB5I): (MAN) -746/748 (SI).

EO,44 (silica gel, DCM/MeOOnH in the ratio 9:1).

Example 24.5 (1-(2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl) |butyryl)-(4.4Lbipiperidinyl-1-yl)acetic acid s.c.o. 30 I s.c.

And co. : (22) 35 - : ich-

The indicated compound was obtained similarly to example 16.6 from 198 mg (0.2 mmol) of methyl ether "(1-22-(4-chloro-33-trifluoromethylbenzyl)-4-oxo-4-14-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)piperidin-1-yl|butyryl) - t0 -(X4,4bipiperidinyl-1-yl)acetic acid. s Yield: 19 mg (995 from theory). MS(E5I): (MAN) -732/734 (SI). :z» GE e0.22 (silica gel, DHM/MesynH in the ratio 9:1).

Example 24.6 2-(4-chloro-3-trifluoromethylbenzyl)-1-(1-methyl-I4 A4bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazoles - n-3-yl)piperidine-1-ilibutane-1,4-dione

I s 2 dit ek m) o si g syu" as ; F o 4 u - t 60

The specified compound was obtained similarly to example (2441 from 800 mg (1.533 mmol) 2-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)piperidin-1-ylbutyric acid and 2709 mg (1.53 mmol) of 1-methyl-(4,4-bipiperidinyl).

Output: 320Ω (3095 from theory). 65 MSc(EI): (M) -687/689 (SI).

Ee0.20 (silica gel, MeOH).

The following compounds can also be obtained by the methods described above:

Example about (Structure.u/ 7 7

And to dey se o

Ge) sch

Gee)

Ge) i- « - s z -I (se) (95) mo

Fe» (F) ko bo 65 wires b Y Guz | Mr

Ah

Izkya what she cho sh -----N- tk s Y -h -- t

І ІІ и и ; ze ; li: konk " skit with Y sch

S. Y

And 1. How she

Y I pava ' -v "» there are platinums and Nv : ш- | ' ich with km: ; I schi and ТЖЖ t : pa te nya penny Sho Sho .

Ge) E and SE, and WE about. inranin and Sh 0. ko bo 65

Pirshely Htrum 00000000. ! and "Ke ate:

Ba ; pin oi nn ptn ionni e syery bin ! 30. and Boi Shchi | sch "in uyu and a | F

And the ovals here pashi pai sheozy - shk ghiishche rch-chav! Their a " | "y ;

V and Pryazna,

T ss vaz i -y V y ; « i y V: shk I i shi s ЖК p Z y y y z y y p 7 t a i chi PINY PI i. - sho ssh show o.

And g still och sei tn SCHO y: 29 in sia; : ka senya - soch yo. -- drone skl giv Nah shsh-ooooshvo - p. what . and E 60 b5

Tennia Tsrianya 77700007 more | shk y yu Z I ve y - o sho Y | What I

BA and dv |. i g h i pe z0 o ti, I ; le ee, ac. : сч 7 И Е и и и | and 40 years of the same idea of dreams : - how Sn. | OO G (F) | (g i M i y 60 I ' b5

Parshuti (Structure 00000011 or

Ta95: I h o i i o E nya Y "xx gava sch 29 u nin - a Y.Ya 2. y - p. - a for ish : Z innnnisnnnn : y (o)

TIA in !

Зо І І : и; MORE. mash with u" | is 1 1 i i | he p a ay « sho i I a che iy u i s v : more KO shchi : (F) ko 60 65

Minin zha r!

E and | I'm not with her either

GU and fe regiment Z A s ich y SHY 15 h s i: s pe Play vish t drinking pope mon "» what Beny her y | ; nn o i t s

With housing | STILL study in uk | and

GF) sen a pranny skl zy - pzhisy niny itizhnii t 60 b5

! y X A she How n 70 1. M - iy pychany shk nknnasvnvshish shi kyynisoi, . What | what in: ist 5 CHERRIES) SHA kn writes | t not - : ry. I I y : I zo y | y " y sch shchi | z Osti ppininisinnny ineti inii sn vn lanya - ik ! y, s х шх Z i y - p es sho ШЙ | Shi che

In the 1st edition. "Y - ke so vkshe t cha t ga tyti v zi Zh sana bo 65

Pirivlad ruyuure 20001010 a

S y av that their che t rek in the same

V. | Kai and 45. ! iy in. I. ss! m Irynka Tsnmshy 03 syu» and K /.1. 4 E And why b5

SHY "y ki 70 S. "oh sho What SHY!

And Shi o what and shi a ; not me : y same 4 sho : so zo. more Oh my God

Mon | I eat And I | and NO, quit. m more Ya tsa z oyi shi « ' Ka Yak -o 45. | give SA a Best M, mo 2 Gryklid ryu 00003300 so S " Her. X | Viy ssh i y y 60 65

70 "Y sh yo | In no SA le still I and No, SHY and other SHY | o sha: your SHY HER o week and nni in. 40: n/ 5 more that

I" 9 rn" - | ur "Li I. va. Vi. z "a vo ay ko vo 65 i Y 70 ey ssh shi di sho 1, M Y! 1 r Y Me: EK. ih i y i i Ko: i, Aly :

Using 4-amino-33-chloro-5-methylbenzoic acid as a starting compound, the following compounds can be obtained:

Arrival Knock 0.00. BUT

FO shko de 5) va - y KU - - PRIN sira - ioodshinya siv. . - ts- varieties se. | high school их и шва чи 79. : Psy t ; Я ч я т 50 z che zay V. y y ; c» x g 5 !

F) name) 60 b5

Gnezhnyk Tbtfuyuuni 200000010001171 i o In ban 70 ; with schi 19 ! Pakusa IF; 7 K Dol z Y g z Shcho r.

I and WE! M s z no" They are the mountains of Sh ki z sa: sin y SYA s h i gava | w p. y y shchi Shchi siekaik Zh la sok y so TV | And | Shk I ; soy; about / in an even b5

' KI, y Y y gr rhythm,

With / y. : t t | Щ GU che chai soti : taya What

Y |, Ba: "I rn i ks y 2" i ve | o niya h r a | kolu Z 7 sho Ka zhi Her ze .

F is called A | in me! | A - ! o b she ; pa NO with pini -x 1 Em shk 2iisrh plat . . co 60 65

Example beech 00000001 in y «y | And (Z y : y | vit drkeetoya y trash shop zu sha oi sho pdopa y da ts. pr spur zho pivo rmy r sho sЖ Te | va Я kyu

IV Z! :. ay, A « -I yii ak BU 503 ve S y " o |. | | shk i seni y ne VSH NSH What 65

Example beech 00000001 in y «y | And (Z y : y | vit drkeetoya y trash shop zu sha oi sho pdopa y da ts. pr spur zho pivo rmy r sho sЖ Te | va Я kyu

IV Z! :. ay, A « -I yii ak BU 503 ve S y " o |. | | shk ia seni y ne VSH NSH What 65 pe Х i и E

How 70th : As in 53. Sh shchi p and Her pair Ave ; as !

YOU | . who is this

Ya. shk and

SHE I E | . | r "A | is rn ! unit | 0 - ;» Using 2-chloro-b6-t-rifluoromethylphenol as a starting compound, the following compounds can be obtained, while the phenolic hydroxy function should be blocked, if necessary, with the use of an acceptable protecting group:

Shrskndya GberuyuturaioG S rn. and VN. about; ' as schiche ' JHE Y I seti syagy VN d oyu | ШЯ about you gentlemen: Ж: га я я я s»: Ка: и И (Ф, име) 60 b5

Forshenad btruyutura. 32332346; and Shi Tyu | Grove | go : shi ; d i sny i I " nau I Y uk !

FROM NIDISHCHA ; ix g. - - -- - scourge by : ; Chi M ' o z porozhi sin sh- y What from : » Meshiinanya | h! in F. Ts and non k shchi ! y Ya. yy B zhov Yana y. ra ay applied "in" | - - Rat shi vo. and her; I am 65

Hprnica m | pe ruk i 00000000 mo ey z |. and other things are M I ok | and what i sch what pr 7 i: i o 1 de - 8: shchi t g . The most common ones are: A SHI what | nn with | AK, I'm 65 Sha g yu ha o

I

| I that her inn in nn Su sho! k t - - and o. t h

Pirshelah fairy 111

In "Zh y y o

I Z M v r: sha ssh z tn va s y I per ry; ee She sho and rst nya ak che ! - come to see me

In I shii yuyu A 29 | and gu | and; all this b5

(Birmkkah Ist 007 70 y Yak i» ha shchi and st Ann zhttnt I I I shi 20 orvy and su ru I tk zo| is ; - Zh: v: poet R yad | sch khaka disputable nni rn dya - pe zasy pek bin - is-,

In no: WHERE events p «

Ф4Ф7 Sa her and what ssh IN: sh

PShrylshchi Myriaura 010.

And Shk.

У НИ ШИ kdd ny va 70 1» aa и Я ила - vo ze ss s. -sh - backs NN oon rn kivyonykinnnny porenia ish pory b5 eh be shchi "a 170 | oh what

SHE DYA SE'

R vd goodia.

ES y gne piki ka y NI kerlilya pEsyech --t sahsshny-tya M zhe I yar r o ovo sydrkki Ж chi zv 155 SE zh: shi y Y bk m y ! not pa z » tu - SSLSCHESHIANYichYa t z ra xx san i sho. - А : о : в ЦИ sі sini niv ptn a ZEnA kont, ор о ; DE ay mu 0 Shchy action, and with |. that m with

І І дич 65

Look at that! : and I'm from ska. and

Shisa 20: Not I 7 s I VASH sho and shi o

Sh GU Kk (y chn zi . s "z EE g i v i still sit Ki ; ZK Y o Gdasv; Ken NN i pniv y an entnfinninya snip it nt rn dily wa bo DY st v SHY Sh S

GF) : : Shan Ya ryv g. - g. ko bo b5 yo Y Zhe y t plen yk geni sk livi'st SHELK che ro sens shko ia 5 vv

Se Yi i, i dn shk soya nya t iK

Example 37 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2- oxo-1,4-dihydro-2H-thieno|3,2-4|Ipyrimidin-3-yl)piperidin-1-yl|Ibutane-1,4-dione 15 20 Y I I s 25 : (8) o

Example 37.1 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(5 -oxo-4,5,7 o 30 »8-tetrahydro-2-thia-4,6-diazaazulene-b-yl)piperidin-1-yl|Ibutane-1,4-dione Ga with so (22) 35 and - « 40 s with 45 -1 Example 37.2 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl1 -4-I4-(2-oxo-1,2,4 (se) o-tetrahydrothienoiZ,2-41|-1,3-diazepin-3-yl)piperidin-1-yl|Ibutan-1,4- dion (95) what with m) o i ! i "s

At ov, " about F : because Z where n i;

Example 37.3 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2 -oxo-1,2,4 be,o-tetrahydrothieno|2,3-41|-1,3-diazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione with

Example 37.4 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-( 2-oxo-1,4-dihydro-2H-thieno|2,3-4|Ipyrimidin-3-yl)piperidin-1-yl|Ibutane-1,4-dione

Example 37.5 o (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4,4-difluoro-1,4"-bipiperidinyl-1"-yl)-4-I(4 -(2-oxo-1,2,4,5-t(o)tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione mixed with -I se) (95)

The following examples describe pharmaceutical dosage forms that contain any of the compounds of the general formula (I) as an active ingredient, and their preparation. 4) Example

Capsules with powder for inhalation, which contain Tmg of the active substance

Composition based on 1 capsule with powder for inhalation: - о ю домо 60 Obtaining:

The active substance is crushed to particles of the size necessary for inhalation. The crushed active substance is mixed with lactose until homogeneous. This mixture is packaged in hard gelatin capsules.

Example II 65 Inhalation solution, which contains mg of the active substance, for an inhaler of the Bezritai type?

Composition based on one portion, which is issued in the form of a sprayed stream:

active ingredient 1.0mg benzalkonium chloride 0.002mg disodium edetate 0.007Bmg purified water up to 15.Omcl.

Obtaining:

The active substance and benzalkonium chloride are dissolved in water and packaged in replaceable canisters designed for 70 Regvrit mud inhalers!

Example II

Inhalation solution, which contains 1 mg of the active substance, for an aerosol nebulizer

Composition based on the content of 1 vial: active substance b 1g sodium chloride 0.18g benzalkonium chloride 0.002g purified water up to 20.Oml.

Obtaining:

The active substance, sodium chloride and benzalkonium chloride are dissolved in water.

An example of them

Dosed aerosol with a propellant containing 1 mg of the active substance

Composition based on one portion, which is issued in the form of a sprayed stream: c active substance 1.0 mg Go) lecithin 0.190 propellant up to 50,Omcl.

Obtained: Ge)

The micronized active substance is suspended until homogeneous in a mixture of lecithin and propellant. The obtained SC suspension is packaged in an aerosol can that is under pressure with a dosing valve.

Example M Ge)

Nasal spray containing 1 mg of the active substance Fu

Composition: the active ingredient is 1.0 mg of sodium chloride, 0.9 mg of benzalkonium chloride / 0.025 mg of disodium edetate, and 0.0 mg of purified water up to 0.1 ml. - - Production: "» The active substance and auxiliary substances are dissolved in water and packaged in a suitable container.

An example of MI

Solution for injections, which contains 5 mg of the active substance per bml -I

Composition: se) active substance Bmg

OO glucose 250mg yuyu 50 human serum albumin 1Omg glycofurol 250mg

Fe» water for injections to Bml.

Obtaining:

Glycofurol and glucose are dissolved in water for injections (Vdi), after which human serum albumin is added, then the active substance is dissolved in this solution when heated, the volume is brought to (F. specified above) by adding Vdi and finally packaged in a nitrogen atmosphere in ampoules. Example of MY

Solution for injections, which contains 10 mg of the active substance per 20 ml

Composition: active ingredient 100 mg monopotassium dihydrophosphate (KNoPOd) 12 mg disodium hydrogen phosphate (MagHPO4.2Ng0) 2 mm 65 sodium chloride 180 mg human serum albumin Bomg polysorbate 80 20 mg water for injections up to 1 Oml.

Obtaining:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WDI), after which human serum albumin is added, then the active substance is dissolved in this solution when heated, the volume is brought up to the above indicated volume by adding WDI and finally packaged in ampoules.

Example of MIA 70 Lyophilizate, which contains 1 mg of the active substance

Composition: active substance 1Omg mannitol ZbOmg human serum albumin 20Omg water for injections 2 ml.

Obtaining:

Mannitol is dissolved in water for injections (WDI), after which human serum albumin is added, then the active substance is dissolved in this solution when heated, the volume is brought up to the above by adding WDI, packaged in glasses and finally freeze-dried.

Solvent for lyophilizate: polysorbate 80 (Tween 80) 20 mg mannitol 200 mg with water for injections up to 1 Oml. Gee)

Obtaining:

Polysorbate 80 and mannitol are dissolved in water for injections (WDI) and packaged in ampoules.

Example of IX Ge)

Tablets containing 20 mg of the active ingredient

Composition: Geo) active ingredient 20 mg lactose 120 mg corn starch 40 mg magnesium stearate 2 mg povidone K25 18 mg.

Obtaining: "

The active substance is mixed with lactose and corn starch until homogeneous, then the resulting mixture is granulated using an aqueous solution of povidone, mixed with magnesium stearate and finally pressed on a tablet press. The weight of one tablet is 200 mg. "» Example X

Capsules containing 20 g of the active substance - I Composition: active substance 20mg and corn starch 8Omg

OO highly dispersed silicic acid Bmg kyu 50 magnesium stearate 2, Bmg. c» Obtaining:

The active ingredient is mixed until homogeneous with corn starch and silicic acid, then mixed with magnesium stearate, and finally, the mixture is packaged in a machine for filling capsules into hard gelatin capsules of size Z.

Example XI (F; Candles containing 500 mg of the active substance ko

Composition: active substance Bomg 60 hardened fat (Aderz 5oiidiv) a.5. up to 1700Ω.

Obtaining:

The solidified fat is melted at a temperature of approximately 382C, then the crushed active substance is dispersed in this melted solidified fat until homogeneous, and the resulting mass, after cooling to approximately 3523C, is poured into pre-cooled forms.

An example of HIA

Solution for injections, which contains 1mg of the active substance per Tml

Composition: active substance 1Omg mannitol Bomg human serum albumin 1Omg water for injections up to ml.

Obtaining:

Mannitol is dissolved in water for injections (WDI), after which human serum albumin is added, then the active substance is dissolved in this solution when heated, the volume is brought up to the above by adding WDI, and finally packaged in ampoules in a nitrogen atmosphere.

Claims (1)

The formula of the invention 1. COokKR-antagonists of the general formula 2 y (U i; sch v o I x "-shcha o sch vi o so gu (22) in which A means an oxygen or sulfur atom, a phenylsulfonylimino group or a cyanimino group, - X means an oxygen or sulfur atom , an imino group optionally substituted by a C-Svalky group or a methylene group optionally substituted by a C-Svalky group, Mu means a C-Svalky, Co-Svalkenyl or Co-Svalkynyl group, in which each methylene group can be substituted 1-2 fluorine atoms, and each methyl group can be replaced by 1-3 fluorine atoms, M means a chlorine or bromine atom, an amino-, methylamino- or hydroxy group, - with M means a hydrogen, fluorine, chlorine, bromine or iodine atom, difluoro- or trifluoromethyl group, "» B" means a saturated or monounsaturated or doubly unsaturated 5-7-ene aza-, diaza-, triaza-, oxaza-, " thiaza-, thiadiaza- or 5,5-dioxidotidiazaheterocycle, while the above-mentioned heterocycles are attached through carbon or nitrogen atom, contain one or two carbonyl or thiocarbonyl groups adjacent to at nitrogen atom, may be substituted by one of the nitrogen atoms - an alkyl group and may be substituted by one or two carbon atoms identical or different with substituents selected from alkyl, phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, o pyrazolyl, 1-methylpyrazolyl, imidazolyl and 1-methylimidazolyl groups, and the olefinic double g 20 bond of one of the above unsaturated heterocycles can be condensed with phenyl, naphthyl , pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, M-methylpyrrole, or quinoline ring, with an optionally substituted 1H-quinolin-2-one ring at the nitrogen atom with an alkyl group, or with an imidazole or M -methylimidazole ring, or each of the two olefinic double bonds of one of the above unsaturated heterocycles can be condensed with a phenyl ring m, 22 and /phenyl, pyridinyl, diazinyl, furyl, / thienyl, pyrrolyl, 1,3-oxazolyl, HF! 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, which are contained in K 1, and also condensed with benzene, thiene, pyridine and diazine ring o heterocycles can additionally be one-, two- or trisubstituted in the carbon skeleton by identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, an alkyl group, an alkoxy group, a nitro group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkylsulfonylamino group, a phenyl group, a difluoromethyl group, a trifluoromethyl group, an alkoxycarbonyl group, carboxy group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetyl group, acetylamino group, propionylamino group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, (4-morpholinyl)carbonyl group, (1-pyrrolidinyl)carbonyl group, (1-piperidinyl)carbonyl group, bo (hexahydro-1-azepinyl)carbonyl group, (4-methyl-1-pipe erazinyl) carbonyl group, methylenedioxy group, an aminocarbonylamino group, an alkanoyl group, a cyano group, a difluoromethoxy group, a trifluoromethoxy group, a trifluoromethylthio group, a trifluoromethylsulfinyl group and a trifluoromethylsulfonyl group, B2 means a hydrogen atom, a phenylmethyl group or a Co-C7alkyl group, which can be substituted in the o-position by a cyclohexyl group, a phenyl group, a pyridinyl group, a diazinyl group group, hydroxy group, amino group, alkylamino group, dialkylamino group, carboxy group, alkoxycarbonyl group, aminocarbonyl group, aminocarbonylamino group, acetylamino group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-(1-piperidinyl)-1-piperidinyl group, 4-morpholinyl group, hexahydro-TN-1-azepinyl group, 70. Ibis(2-hydroxyethyl))amino group, 4-alkyl-1-piperazinyl group or 4-( p -hydroxy-Co-STalkyl)-1-piperazinyl group, phenyl or pyridinyl group, while the above mentioned heterocyclic residues and phenyl groups can additionally be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, methyl group, alkoxy group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, C.--Salkylamino group, di(Ci-Salkyl)amino group, acetylamino group, aminocarbonyl group, cyano group, methylsulfonyloxy group, difluoromethoxy group, trifluoromethoxy group, trifluoromethylthio group, trifluoromethylsulfinyl group, trifluoromethylsulfonyl group, amino-Ci-Salkyl group, C.-Salkylamino-C.4-Salkyl group and di(Ci-Salkyl)amino-C1-Salkyl group, VZ means a hydrogen atom or a C 4-Salkyl group optionally substituted by a phenyl or pyridinyl group, while C.i is indicated -Szalkal group can be connected with the one present in B? an alkyl group or a phenyl or pyridyl ring present in K2 and a nitrogen atom to which they are attached, forming a ring, or B2 and BZ together with a nitrogen atom located between them form a residue of the general formula Het (I), o (stenU ), --sh | t SveAI and yavu 000 and tesvv t and - in which Ж means a carbon atom or when ВЕ? represents a free pair of electrons, also means a nitrogen atom, 4 and g, When U represents a carbon atom, mean the number 0, 1 or 2, or 4 and g, when U represents a nitrogen atom, " mean the number 1 or 2, BK "? means a hydrogen atom, amino group, alkylamino group, cycloalkylamino group, 50 dialkylamino group, M-(cycloalkyl)alkylamino group, dicycloalkylamino group, hydroxy group, alkyl group, C c cycloalkyl group, amino-Co-C7 alkyl group, alkylamino-Co-Stalkyl group, dialkylamino- Со-СТалкільну Із» групу, аміноїмінометильну групу, алкілкарбонільну групу, алкілсульфонільну групу, алкілкарбоніламіногрупу, алкілсульфоніламіногрупу, М-алкілкарбоніл-М-алкіламіногрупу, М-алкілсульфоніл-М-алкіламіногрупу, амінокарбоніламіногрупу, алкіламінокарбоніламіногрупу, діалкіламінокарбоніламіногрупу, циклоалкіламінокарбоніламіногрупу, дициклоалкіламінокарбоніламіногрупу, 7 феніламінокарбоніламіногрупу, амінокарбонілалкільну group, alkylaminocarbonylalkyl group, (Te) dialkylaminocarbonylalkyl group, ami a nocarbonylaminoalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group or a carboxyalkyl group, or when U! does not represent a nitrogen atom, also means a carboxy group, an aminomethyl group, an alkylaminomethyl group, or a dialkylaminomethyl group, or co 20 means a phenyl, phenyl-C1-C alkyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl, or phenylcarbonyl group, each of which can be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, an alkyl group, an oxy group, a methylsulfonyloxy group, a difluoromethyl group, a trifluoromethyl group, a hydroxy group, an amino group, an acetylamino group , aminocarbonyl group, aminocarbonylamino group, 59 aminocarbonylaminomethyl group, cyano group, carboxy group, carboxycarbonyl group, carboxyalkyl HF) group, alkoxycarbonylalkyl group, alkanoyl group, o-(dialkylamino)alkanoyl HF group, o-(dialkylamino)alkyl group, (o-(dialkylamino )hydroxyalkyl group, oF-(carboxy)alkanoyl group, difluoromethoxy group, trifluoromethoxy group, trifluoromethylthio group, trifluoromethylsulfinyl group and trifluoromethylsulfonyl group, saturated or mono- or polyunsaturated 4-10-membered azacycloalkyl group, 5-10-membered oxaza-, thiaza-, diaza- or triazacycloalkyl group, 6-10-membered -lene azabicyclo- or diazabicycloalkyl group, 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group, 1-alkyl-4-piperidinylamino group, 1-alkyl-4-piperidinylaminocarbonyl group or 1-alkyl-4-piperidinylaminosulfonyl group , while the above-mentioned mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in the above-mentioned mono- and bicyclic heterocycles can be replaced by a carbonyl or sulfonyl group, in the above-mentioned mono- and bicyclic heterocycles it is not directly connected to a nitrogen atom , oxygen or sulfur, the methylene group can be replaced by one or two fluorine atoms, the above mono- and bicyclic heterocycles, as well as //1-alkyl-4-piperidinylcarbonyl (and 4-alky l-1-piperazinylcarbonyl group can be mono- or polysubstituted in the ring by a C-C7alkyl group and/or monosubstituted in the ring by a benzyl group, alkanoyl group, dialkylamino group, phenylcarbonyl group, pyridinylcarbonyl group, carboxy group, carboxyalkanoyl group, carboxyalkyl group, alkoxycarbonylalkyl group an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group, an alkylsulfonyl group, a cycloalkyl group, or a cycloalkylalkyl group, or optionally substituted in the ring with an alkyl cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl, or oxazacycloalkylcarbonyl, and these fragments contain 3-10 alicyclic substituents ring members, and heteroalicyclic fragments have 4-10 ring members each, and phenyl and pyridinyl residues contained in the above residues, in turn, can be mono-, di- or tri-substituted with identical or different substituents compounds selected from fluorine, chlorine, bromine and iodine atoms, alkyl group, alkoxy group, methylsulfonyloxy group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, acetylamino group, aminocarbonyl group, aminocarbonylamino group, aminocarbonylaminomethyl group, cyano group, carboxyl group, alkoxycarbonyl group, carboxyl an alkoxycarbonylalkyl group, an alkanoyl group, an (o-(dialkylamino)alkanoyl group, an o-(carboxy)alkanoyl group, a difluoromethoxy group, a trifluoromethoxy group, a trifluoromethylthio group, a trifluoromethylsulfinyl group and a trifluoromethylsulfonyl group, BZ means a hydrogen atom, C.-C/alkyl residue, while the unbranched alkyl residue can be substituted in the o-position by He phenyl group, pyridinyl group, diazinyl group, amino group, alkylamino group, o dialkylamino group, 1-pyrrolidinyl group, 1-piperidinyl group, 4-methyl -1-piperazinyl group, 4-morpholinyl group or hexahydro-1IN-1-azepinyl group, alkoxycarbonyl group, cyano group or aminocarbonyl group, or when U! represents a nitrogen atom, also means a free pair of electrons, or, when U" does not represent a nitrogen atom, also means a fluorine atom, or about B and VK? together, when U! represents a carbon atom, mean 4-7--lenne cycloaliphatic ring, in which one or two methylene groups can be replaced by a -MH- or -M(alkyl)y- group and one or two other methylene groups can be replaced by one, respectively two, carbonyl groups, while attached to the nitrogen atom in the above-mentioned K7 group, the hydrogen atom can be replaced by a protective /Ф) Св ТРУПУ, и- 29 and B" can have identical or different values and each of them means a hydrogen atom, a C4-C alkyl group or a dialkylamino group, or, when U! does not represent a nitrogen atom, it also means a fluorine atom, and 28 and BZ can have identical or different values, and each of them means a hydrogen atom or a C.-C.alkyl group, a carboxy group or a C.-C.alkyloxycarbonyl group, while all the above-mentioned alkyl groups and alkoxy groups, as well as alkyl groups present in the other above-mentioned residues /-- with, unless otherwise specified, contain from 1 to 7 carbon atoms and can be unbranched or branched, and each methylene group can be replaced by 1-2 fluorine atoms, and each methyl "» group can be substituted by 1-3 fluorine atoms, all the above-mentioned cycloalkyl groups, as well as the cycloalkyl groups present in the other above-mentioned residues, can contain, unless otherwise specified, from 3 to 10 carbon atoms, and each methylene group can be - and substituted by 1-2 fluorine atoms, and with all the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di-, or tri-substituted by identical or different substituents selected from fluorine, chlorine atoms and bromine, cyano groups and hydroxy groups, (95) their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, as well as hydrates of salts. yuyu 50 2. Compounds of the general formula (I) according to claim 1, in which А, У, М, МУ, Х, В2 and ВЗ have the values specified in claim 1, and "В" means monounsaturated or doubly unsaturated 5-7- membered aza-, diaza-, triaza- or thiazageheterocycle, while the above-mentioned heterocycles are attached through a carbon or nitrogen atom, contain one or two carbonyl groups adjacent to the nitrogen atom, and may be substituted after the carbon atom by phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or HF!1-methylpyrazolyl group, and the olefinic double bond of one of the above unsaturated heterocycles can be condensed with a phenyl, naphthyl, pyridine, diazine, thienyl or quinoline o ring, or with optionally substituted at the nitrogen atom by a methyl group 1H-quinolin-2-one ring, and phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, 60 pyrazolyl or 1-methylpyrazolyl groups, which are contained in B, as well as heterocycles condensed with a benzene, pyridine, and diazine ring, can additionally be mono-, di-, or tri-substituted in the carbon skeleton by identical or different substituents selected from fluorine, chlorine, bromine, and iodine atoms, an alkyl group, an alkoxy group, a nitro group, a difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetylamino group, acetyl group, cyano group, difluoromethoxy group. and b trifluoromethoxy group, at the same time, all the above-mentioned alkyl groups or alkyl groups present in the above-mentioned residues contain, unless otherwise specified, from 1 to 7 carbon atoms and can be branched or unbranched, and each methylene group can be replaced by 1-2 fluorine atoms, and each methyl group may be substituted by 5o001-3 fluorine atoms, and the above-mentioned aromatic and heteroaromatic residues may additionally be mono-, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 3. Compounds of the general formula (I) according to claim 1, in which 70 A, M, M, MU, X, B2 and BZ have the values indicated in claim 1, and B means a monounsaturated 5-7-ene diaza- or triazaheterocycle , while the above heterocycles are attached through a nitrogen atom, contain a carbonyl group adjacent to the nitrogen atom, and can additionally be substituted after the carbon atom by a phenyl group, and the olefinic double bond of one of the above unsaturated heterocycles can be condensed with a phenyl, thienyl or quinoline ring, and phenyl groups contained in B 7, as well as heterocycles condensed with the benzene ring, can additionally be mono-, di-, or tri-substituted in the carbon skeleton by identical or different substituents selected from fluorine, chlorine, bromine, and iodine atoms, methyl group, methoxy group, nitro group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetylamino group, acetyl group, cyano group, difluoromethoxy group and trifluoromethoxy groups, preferably, however, are unsubstituted or monosubstituted by a fluorine, chlorine or bromine atom, a methyl group or a methoxy group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted CM 25 with identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts. 4. Compounds of the general formula (I) according to claim 1, in which A, M, M, MU, X, B2 and VZ have the values specified in claim 1, and in! means 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl, and. 30 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl, c 4-(5-oxo-3-phenyl-4,5-dihydro-1,2, 4-triazol-1-yl)piperidin-1-yl, 4-(2-oxo-1,2-dihydroimidazoi|4,5-c|quinolin-3-yl)/piperidin-1-yl, and. 4-(2-oxo-1,2-dihydro-4H-thieno|3,4-4|Ipyrimidin-3-yl)piperidin-1-yl, Ge»! 4-(2-oxo-1,4-dihydro-2H-thieno|Z,2-4|Ipyrimidin-3-yl)piperidin-1-yl, 35 4-(5-oxo-4,5,7 8- tetrahydro-2-thia-4,6-diazaazulen-b-yl)piperidin-1-yl, - 4-(2-oxo-1,2,4,5-tetrahydrothieno|Z,2-4|-1,3 -diazepin-3-yl)piperidin-1-yl, 4-(2-oxo-1,2,4,5-tetrahydrothieno|2,3-41-1,3-diazepin-3-yl)upiperidin-1- yl or 4-(2-oxo-1,4-dihydro-2H-thieno|2,3-4|Ipyrimidin-3-yl)upiperidin-1-yl group, while the above-mentioned mono- and "bicyclic heterocycles can additionally be monosubstituted in the carbon skeleton by a methoxy group, while the above-mentioned aromatic and heteroaromatic residues may additionally be mono-, di-, or tri-substituted with identical or different substituents selected from fluorine, chlorine, and bromine atoms, cyano groups, and hydroxy groups, their tautomers, and their diastereomers , their enantiomers, their mixtures and their salts. 5. Compounds of the general formula (I) according to claim 1, in which A, U, M, MU, X and B! have the values indicated in claim 1, and - 75 B2 means a hydrogen atom or a phenylmethyl group, or a Co-Stalkyl group, which in the φ-position can be replaced by a phenyl group, Ф by a pyridinyl group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, a carboxy group, ( 95) an alkoxycarbonyl group, an aminocarbonyl group, an aminocarbonylamino group, an acetylamino group, a 50 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group or an ibis(2-hydroxyethyl))amino group, while the above-mentioned heterocyclic residues and phenyl groups can additionally be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine, chlorine, bromine and iodine atoms, methyl group, alkoxy group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, C.-S alkylamino group, di(Si- Szalkyl)amino group, acetylamino group, aminocarbonyl group, cyano group, difluoromethoxy group, trifluoromethoxy group, amino-C.--Szalkyl group, o C.-Salkylamino-C.4-Salkyl group and di(Ci-Salkyl)amino-C1-Salkyl group, where BZ means a hydrogen atom or a C.-Salkyl group, while the indicated C.-Salkyl group can be from combined with the alkyl group present in K2 or with the phenyl or pyridyl ring present in 2 and the nitrogen atom 60 to which they are attached, with the formation of a 5-7-ene ring, or B2 and BZ together with the nitrogen atom located between them, form the remainder of the general formula (1) is a carbon atom, means the number 0 or 1, or 4 and g, when U! represents a nitrogen atom, means the number 1 or 2, V means a hydrogen atom, a hydroxy group, an amino group, an alkylamino group, a C3-Cvcycloalkylamino group, /M-( C.-C cycloalkyl)alkylamino group, dialkylamino group, alkyl group, trifluoromethyl group, C3-Seccycloalkyl group, dialkylamino-C2-Stalkyl group, carboxyalkyl group, alkoxycarbonylalkyl group, alkylsulfonyl group, alkylsulfonylamino group or M-(alkylsulfonyl)alkylamino group, or when U does not represent a nitrogen atom, also means a carboxy group or a dialkylaminomethyl group, or means a phenyl, phenyl-C-C-C alkyl, pyridinyl or diazinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, saturated C or mono- or polyunsaturated 4-7-ene azacycloalkyl group, 5-7-ene oxaza-, diaza- or triazacycloalkyl group, 7-9-ene azabicyclo- or diazabicycloalkyl group, o) 1-alkyl- 4-piperidinylamino group or 1-alkyl-4-piperidinylaminosulfonyl group, while the above mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in in the above mono- and bicyclic heterocycles can be replaced by a carbonyl or co-sulfonyl group, in the above mono- and bicyclic heterocycles not directly connected to a nitrogen, oxygen or sulfur atom, the methylene group can be replaced by one or two fluorine atoms, with the above mono- and bicyclic heterocycles may be substituted by one or two C.i.C.alkyl groups, in which each methylene group may be substituted by 1-2 fluorine atoms, and each methyl group may F) be substituted by 1-3 fluorine atoms, and/or can be substituted by a C3-Swicycloalkyl-C1-Salkyl group, a benzyl group, a C--Salkanoyl group, a di(C-4-Salkyl)amino group, a C--Salkylsulfonyl group, an alkoxycarbonyl group, a benzyloxycarbonyl group, an alkoxycarbonylalkyl group, a carboxy group or a carboxyalkyl group group, B means a hydrogen atom, a C.i.S. alkyl group or an alkoxycarbonyl group, or, when U! represents a "nitrogen" atom, also means a free pair of electrons, or shsh with B and VK? jointly, when U! represents a carbon atom, mean a 5-membered cycloaliphatic ring, in which one or two methylene groups can be replaced by a -МН- or -М(methyl)- group, and one or two other "» methylene groups can be replaced by one, respectively two, carbonyl groups, 29 and B" can have identical or different values and each of them means a hydrogen atom, a C4-Salkyl group or a di(C--Salkyl)amino group and - 28 and KU can have identical or different values, and each of them means a hydrogen atom, a C.i.i.-C alkyl group, a carboxyl group or a C.i.i.-Ci-C alkyloxycarbonyl group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and the above He 20 aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their tautomers, their dias tereomers, their enantiomers, their mixtures and their salts. 6. Compounds of the general formula (I) according to claim 1, in which A, U, M, MU, X and B! have the values indicated in claim 1, and 99 V? means a phenylmethyl group or a Co-Stalkyl group, which can be substituted in the pho -position (F, by a phenyl group, an amino group, an alkylamino group, or a dialkylamino group, while the above-mentioned phenyl km group can be substituted by an amino-C4-Salkyl, C.-Salkylamino-C -S-alkyl or di(C41-Salkyl)amino-C--Salkyl group, in BZ means a hydrogen atom or C.-Salkyl group, in Y 3 together with the nitrogen atom to which they are attached, mean 7-dimethylaminomethyl-1, 2,4,5-tetrahydro-3-benzazepin-3Z-yl or 2-amino-4,5,7 8-tetrahydrothiazolo|4,5-4|azepin-6-yl group, or B2 and BZ together with a nitrogen atom , which is between them, form the remainder of the general formula b5 te (1), y BR x, ! "Is t|stere in which U means a carbon atom, or, when В? represents a free pair of electrons, it also means a nitrogen atom, 4 and g, when U! represents a carbon atom, mean the number 0 or 1, or 4 and g, when U! represents a nitrogen atom, mean the number 1 or 2, B" means a hydrogen atom, phenyl, benzyl or pyridinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, a hydroxy group, a carboxy group, a methyl group, a trifluoromethyl group, an n-propyl group, a phenyl group, a p-tolyl group, a p-trifluoromethylcarbonylphenyl group , p-(3-dimethylaminopropyl)phenyl group, amino group, benzyl group, tert-butylamino group, dimethylamino group, diethylamino group, diethylaminomethyl group, 2-dimethylaminoethyl group, 2-diethylaminoethyl group, 5-aminopentyl group, methoxycarbonyl group, methoxycarbonylmethyl group, perhydroazepine- 1-yl group, 4-methylperhydro-1,4-diazepin-1-yl group, c 29 1-methyl-1-piperidinyl-4-yl group, 4-piperazin-1-yl group, 4-acetylpiperazin-1- yl group, 03 4-cyclopropylmethylpiperazin-1-yl group, pyrrolidin-1-yl group, 4-ethylpiperazin-1-yl group, 4-isopropylpiperazin-1-yl group, piperidin-1-yl group, piperidin-4-yl group, morpholin-4-yl group, 4,4-difluoro-1-piper dyn-1-yl group, 1-methyl-1-azabicyclo|3.2.1oct-4-yl group, 4-methylpiperazin-1-yl group, 4-ethylpiperazin-1-yl group, 1-methylpiperidin-1-yl group . methyl-2,5-diazabicyclo|2.2.1|hept-2-yl group, 1-benzylpiperidin-4-yl group, o 4-benzylpiperazin-1-yl group, 4-dimethylaminomethyl-1-phenyl group, 2,2 ,2-trifluoroethylpiperazin-1-yl F) group, 1-methylsulfonylpiperidin-4-yl group, piperidin-1-ylmethyl group, Z0 1-methylpiperidin-4-ylamino group, methylsulfonylamino group, M-methylsulfonyl-M-methylamino group, - M- (cyclopentyl)methylamino group, 1,1-dioxohex-isothiazolidin-2-yl group, 2-oxoperhydro-1,3-oxazin-3-yl group, cyclohexyl group, 2-oxoimidazolidin-1-yl group, "2- methylimidazol-1-yl group, 4-methylimidazol-1-yl group, 4-thiazol-2-yl group, 2, 4-dimethylimidazol-1-yl group, 4-imidazol-1-yl group, 1,2,4-triazol-1-yl group, C c 1-azabicyclo|2.2.2)oct-3-yl group, 1- methylpiperidin-4-ylmethylsulfonyl group, 1H-imidazol-4-yl "» group, 4-ethoxycarbonylmethylpiperazin-1-yl group, 1-ethoxycarbonylpiperidin-4-yl group, " 4-tert-butoxycarbonylmethylpiperazin-1-yl group, 1- -2,2,2-trifluoroethyl)piperidin-4-yl group, 4-methylsulfonylpiperazin-1-yl group, 2-carboxy-4-methylpiperazin-1-yl group, 3-carboxy-4-methylpiperazin-1-yl group , 2-ethoxycarbonyl-4-methylpiperazin-1-yl group, 3-ethoxycarbonyl-4-methylpiperazin-1-yl group or 4-(2,2,2-trifluoroethyl)piperazin-1-yl group, (Ce) VE? means a hydrogen atom, a methyl group, or when U! is a nitrogen atom, also means a free pair of electrons, or o 4 5 rB : 1 : pi KT Oi Kk? together, when M is a carbon atom, mean 1-methylpiperidine-4-ylidene, cyclohexylidene or imidazolidin-2,4-dione-5-ylidene group, "with each of KZ and B" means a hydrogen atom or a dimethylamino group, and each of the 28th BZ means a hydrogen atom, a carboxy group or an ethoxycarbonyl group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise indicated, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted by identical or F) different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their tautomers, their ca diastereomers, their enantiomers, their mixtures and their salt 7. Compounds of the general formula (I) according to claim 1, in which A means an oxygen atom, a cyanimino group or a phenylsulfonylimino group, X means an oxygen atom, an imino group or a methylene group, MO means an unbranched C.i.sulfyl, Co-sulfenyl or Co-sulfynyl a group in which each methylene group can be replaced by 1-2 fluorine atoms, and the methyl group can be replaced by 1-3 fluorine atoms, 65 M means an amino group or a hydroxy group, M means a hydrogen, chlorine or bromine atom or a trifluoromethyl group, B! means singly unsaturated 5-7-lene diaza- or triazheterocycle, while the above-mentioned heterocycles are attached through a nitrogen atom, contain a carbonyl group adjacent to the nitrogen atom, and can additionally be substituted after the carbon atom by a phenyl group, and the olefinic double bond of one of the above-mentioned unsaturated heterocycles can be condensed with a phenyl, thienyl or quinoline ring, and the phenyl groups contained in B", as well as heterocycles condensed with benzene, can additionally be mono-, di- or tri-substituted in the carbon skeleton with identical or different substituents selected from fluorine atoms , chlorine, bromine and iodine, methyl group, methoxy group, nitro group, difluoromethyl group, trifluoromethyl group, hydroxy group, amino group, alkylamino group, dialkylamino group, acetylamino group, 70 acetyl group, cyano group, difluoromethoxy group and trifluoromethoxy group, preferably, however, are unsubstituted or monosubstituted by a fluorine atom , chlorine or bromine, a methyl group or a methoxy group, B2 means an atom of one or a phenylmethyl group or a Co-Stalkyl group, which can be substituted in the (y) position by a phenyl group, a pyridinyl group, a hydroxy group, an amino group, an alkylamino group, a dialkylamino group, an alkoxycarbonyl group, a carboxy group, an aminocarbonyl group, an aminocarbonylamino group, an acetylamino group, a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group or Ibis-(2-hydroxyethyl))amino group, while the above-mentioned heterocyclic residues and phenyl groups can additionally be mono-, di- or tri-substituted in the carbon skeleton by identical or different substituents selected from fluorine atoms ) .--The climbing group, C.-Salkylamino-C.4-Salkyl group and di(Ci-Salkyl)amino-C1-Salkyl group, BZ means a hydrogen atom or a C1-Salkyl group, while the specified C4-Salkyl group can be connected cm » with present in B? alkyl group or present in B? by a phenyl or pyridyl ring and the nitrogen atom to which they are attached, with the formation of a 5-7-membered ring, or B2 and BZ together with the nitrogen atom located between them form the residue of the general formula E5 (1, со сч х (СЕН ), , Ф "Is cha (СсЕена) в -к г свв " in which - с УЖ means a carbon atom, or when 2? represents a free pair of electrons, it also means a nitrogen atom, "з д и г, when У ! represents a carbon atom, they mean the number 0 or 1, or " 4 and g, when U! represents a nitrogen atom, they mean the number 1 or 2, B means a hydrogen atom, a hydroxy group, an amino group, an alkylamino group, a C3-Cvcycloalkylamino group, - 45 M -(C3-C cycloalkyl)alkylamino group, dialkylamino group, alkyl group, trifluoromethyl group, C3-C8cycloalkyl group, dialkylamino-C0-C7alkyl group, carboxyalkyl group, alkoxycarbonylalkyl (Ce) group, alkylsulfonyl group, alkylsulfonylamino group or M-(alkylsulfonyl)alkylamino group, or, c When U is not a nitrogen atom, it also means a carboxy group or dialkyl inomethyl group or means 20 phenyl, phenyl-C-C-alkyl, pyridinyl or diazinyl group, each of which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethylcarbonyl group, a methyl group or a methoxy group, saturated with" or mono- or polyunsaturated 4-7-lene azacycloalkyl group, 5-7-lene oxaza-, diaza- or triazacycloalkyl group, 7-9-lene azabicyclo- or diazabicycloalkyl group, 1-alkyl-4-piperidinylamino group or 1-alkyl-4- piperidinylaminosulfonyl group, while the above-mentioned mono- and bicyclic heterocycles are attached through a nitrogen or carbon atom, the methylene group in the above-mentioned mono- and bicyclic heterocycles can be replaced by a carbonyl or (F. sulfonyl group, in the above mono- and bicyclic heterocycles is not directly connected to a nitrogen atom, GI of oxygen or sulfur, the methylene group can be replaced by one or two fluorine atoms, the above mono- and bicyclic heterocycles can be replaced by one or two C .i-Salkyl groups, in which each boron Methylene group can be substituted by 1-2 fluorine atoms, and each methyl group can be substituted by 1-3 fluorine atoms, and/or can be substituted by a C3-Cvcycloalkyl-Ci-Salkyl group, benzyl group, C1-C6alkanoyl group, di(C1-C6alkyl)amino group, C1-C6alkylsulfonyl group, alkoxycarbonyl group, benzyloxycarbonyl group, alkoxycarbonylalkyl group, carboxy group or carboxyalkyl group, 65 B means a hydrogen atom, C1-C6alkyl group or alkoxycarbonyl group , or, when U! represents a nitrogen atom, also means a free pair of electrons, or In and VK? together, when U! represents a carbon atom, mean a 5-membered cycloaliphatic ring in which one or two methylene groups can be replaced by a -MH- or -M(methyl)- group, and one or two other methylene groups can be replaced by one , respectively, two carbonyl groups, 29 and B" can have identical or different values and each of them means a hydrogen atom, a C4-Calkyl group or a di(C41-Calkyl)amino group, and B8 and KU can have identical or different values and each of of them means a hydrogen atom, a C1-C6 alkyl group, a carboxy group or a C1-C6 carboxycarbonyl group, while all the above-mentioned alkyl groups or alkyl groups present in the above-mentioned residues contain, unless otherwise specified, from 17 to 7 carbon atoms and can be branched or unbranched, and the above-mentioned aromatic and heteroaromatic residues can additionally be mono-, di- or tri-substituted by identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their tautomers, their enantiomers, their di astereomers, their mixtures and their salts. 8. Compounds of the general formula (I) according to claim 1, in which A means an oxygen atom, X means an oxygen atom, an imino group or a methylene group, Mu means a methyl, ethyl, Co-C.alkenyl or Co-C.alkynyl group, in which the methylene group can be substituted by 1-2 fluorine atoms, and the methyl group can be substituted by 1-3 fluorine atoms, M means an amino group or a hydroxy group, M means a hydrogen, chlorine or bromine atom or a trifluoromethyl group, in! means 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl, 4-(2-oxo-1,4-dihydro-2H-quinazoline -3-yl)piperidin-1-yl, 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl, 4-(2 -oxo-1,2-dihydroimidazoi|4,5-s|quinolin-3-yl)/piperidin-1-yl, c 4-(2-oxo-1,2-dihydro-4H-thieno|3,4- 4|pyrimidin-3-yl)piperidin-1-yl, d) 4-(2-oxo-1,4-dihydro-2H-thieno|Z,2-4|Ipyrimidin-3-yl)piperidin-1-yl , 4-(5-oxo-4,5,7 8-tetrahydro-2-thia-4,6-diazaazulen-b-yl)piperidin-1-yl, 4-(2-oxo-1,2,4, 5-tetrahydrothieno|Z,2-4|-1,3-diazepin-3-yl)piperidin-1-yl, 4-(2-oxo-1,2,4,5-tetrahydrothieno|2,3-41- 1,3-diazepin-3-yl)piperidin-1-yl or i) 4-(2-oxo-1,4-dihydro-2H-thieno|2,3-4Ipyrimidin-3-yl)piperidin-1-yl group, while the above-mentioned mono- and bicyclic heterocycles can additionally be monosubstituted in the carbon skeleton by a methoxy group, 22 means a phenylmethyl group or a Co-Stalkyl group, which can be substituted in the y-position by a phenyl group, an amino group, an alkyl group no group or a dialkylamino group, while the above-mentioned phenyl MeZ group can be replaced by an amino-C--C-alkyl group, a C.-C-alkylamino-C--alkyl group or a M di(C41-C-alkyl)amino-C--alkyl group, BZ means a hydrogen atom or a C.-Szalkyl group, in J 3 together with Kk! by the nitrogen atom to which they are attached mean "7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3Z-yl or 2-amino-4,5,7,8-tetrahydrothiazolo|4,5- d|azepin-b-yl group, or - with B2 and BZ together with the nitrogen atom that is between them, form the residue of the general formula хз» EE (1), В Sen so shchi 1 and "Is , vo un (СЕ, y and sten in which UZh means a carbon atom, or when 2? represents a free pair of electrons, it also means a nitrogen atom, 59 d and g, when U! represents a carbon atom, mean the number 0 or 1, or (Ф; 4 and g, when U! represents a nitrogen atom, means the number 1 or 2, where B" means a hydrogen atom, a phenyl, benzyl, or pyridinyl group, each of which can be replaced by a fluorine, chlorine, or bromine atom, a trifluoromethylcarbonyl group, a methyl group or methoxy group, hydroxy group, carboxy group, methyl group, trifluoromethyl group, n-propyl group, phenyl group, p-tolyl group, p-trifluoromethylcarbonylphenyl group, p-(3-dimethylaminopropyl)phenyl group, amino group, benzyl group, tert-butylamino group, dimethylamino group, diethylamino group, diethylaminomethyl group, 2-dimethylaminoethyl group, 2-diethylaminoethyl group, 5-aminopentyl group, methoxycarbonyl group, 65 methoxycarbonylmethyl group, perhydroazepin-1-yl group, 4-methylperhydro-1,4 -diazepin-1-yl group, 1-methyl-1-piperidinyl-4-yl group, 4-piperazin-1-yl group, 4-acetylpiperazin-1-yl group, 4-cyclopropylmethylpiperazin-1-yl group, pyrrolidin-1-yl group, 4-ethylpiperazin-1-yl group, 4-isopropylpiperazin-1-yl group, piperidin-1-yl group, piperidin-4-yl group, morpholin- 4-yl group, 4,4-difluoro-1-piperidin-1-yl group, 1-methyl-1-azabicyclo|3.2.1oct-4-yl group, 4-methylpiperazin-1-yl group, 4-ethylpiperazin- 1-yl group, 1-methylpiperidin-1-yl group, 4-carboxymethylpiperazin-1-yl group, 1-carboxymethylpiperidin-4-yl group, 4-benzyloxycarbonylpiperazin-1-yl group, 1-ethoxycarbonylmethylpiperidin-4-yl group, azetidin-1-yl group, 5-methyl-2,5-diazabicyclo|2.2.1|Hept-2-yl group, 1-benzylpiperidin-4-yl group, 4-benzylpiperazin-1-yl group, 4-dimethylaminomethyl- 1-phenyl group, 2,2,2-trifluoroethylpiperazin-1-yl group, 7/0 1-methylsulfonylpiperidin-4-yl group, piperidin-1-ylmethyl group, 1-methylpiperidin-4-ylamino group, methylsulfonylamino group, M-methylsulfonyl -M-methylamino group, M-(cyclopentyl)methylamino group, 1,1-dioxo-he-iz othiazolidin-2-yl group, 2-oxoperhydro-1,3-oxazin-3-yl group, cyclohexyl group, 2-oxoimidazolidin-1-yl group, 2-methylimidazol-1-yl group, 4-methylimidazol-1-yl group, 4-thiazol-2-yl group, 2,4-dimethylimidazol-1-yl group, 4-imidazol-1-yl group, 1,2,4-triazol-1-yl group, 1-azabicyclo|2.2. 2|oct-3-yl group, 1-methylpiperidin-4-ylmethylsulfonyl group, 1H-imidazol-4-yl group, 4-ethoxycarbonylmethylpiperazin-1-yl group, 1-ethoxycarbonylpiperidin-4-yl group, 4-tert-butoxycarbonylmethylpiperazine -1-yl group, 1-(2,2,2-trifluoroethyl)piperidin-4-yl group, 4-methylsulfonylpiperazin-1-yl group, 2-carboxy-4-methylpiperazin-1-yl group, 3-carboxy- 4-methylpiperazin-1-yl group, 2-ethoxycarbonyl-4-methylpiperazin-1-yl group, 3-ethoxycarbonyl-4-methylpiperazin-1-yl group or 4-(2,2,2-trifluoroethyl)piperazin-1- ilny group, 2? means a hydrogen atom, a methyl group, or when U! represents a nitrogen atom, also means a free pair of electrons, or B? and B? together, when M! represents a carbon atom, denotes a 1-methylpiperidine-4-ylidene, Ha cyclohexylidene or imidazolidine-2,4-dione-5-ylidene group, each of KZ and B" denotes a hydrogen atom or a dimethylamino group, and each of BZ and EZ denotes a hydrogen atom, a carboxy group or an ethoxycarbonyl group, while all the above-mentioned alkyl groups, as well as alkyl groups present in other residues, contain, unless otherwise specified, from 1 to 7 carbon atoms and can be unbranched or branched, and the above-mentioned 9 aromatic and heteroaromatic residues additionally, they can be mono-, di- or tri-substituted with identical or different substituents selected from fluorine, chlorine and bromine atoms, cyano groups and hydroxy groups, their enantiomers, their diastereomers and their salts. (ze) 9. Compounds of the general formula (I) according to claim 1, selected from the group that includes Fo (in (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazine) -1-yl)piperidin-1-yl-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane -1,4-dione, (2) 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-I4,A4bipiperidinyl-1-yl)-4-I4-(2-oxo -1,4-dihydro-2H-quine zolin-3-yl)piperidin-1-yl|butane-1,4-dione, (3 o) with 2-(4-amino-3-chloro-5-trifluoromethylbenzyl )-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4-dihydro-2"H-quinazolin-3-yl) Piperidin-1-yl|Ibutan-1,4-dione, and (3 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(11,4bipiperidinyl-1"-yl-4-I(4 -(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butan-1,4-dione, Che (5) o 2-(4-amino-3-chloro- 5--trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylI|-1-(4-pyridine n-4-ylpiperazine-1- yl)butane-1,4-dione, o (6) 7 50 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-ylamino)piperidin-1-yl1 |-4-I(I 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butan-1,4-dione, si (7 I4-(1-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylbutyryl)piperidin-4-yl) piperazin-1-yl)|juctic acid, (8) methyl ether Ge! (1-22-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1 -yl butyryl)(4,4Dbipiperidinyl-1-yl)acetic acid, according to (9) (1-22-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl 60 butyryl)-(4 4Dbipiperidinyl-1-yl)acetic acid, (10). (K)-1-(4- amino-3-chloro-5-trifluoromethylbenzyl)-2-(1,4bipiperidinyl-1"-yl-2-oxoethyl|amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine -3-yl)/piperidine-1-carboxylic acid, (11). (Kk)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(4-dimethylaminopiperidin-1-yl)-2 -oxoethyl|amide of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, b5 (12). (K)-1- (4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-pyridin-4-ylpiperazin-1-yl)ethylamide 4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (13). (KO-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-(1"-methyl-4"-bipiperidinyl-1-yl)-2-oxoethyl|amide 4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (14) benzyl ether 500 4-1-(K)-3-4-amino-Z- chloro-5-trifluoromethylphenyl)-2-4C4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-carbonylamino)propionyl)piperidin-4-yl | piperazine-1-carboxylic acid, (15) ethyl ether Г1-(РО-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-carbonylamino)propionyl)-4,4"-bipiperidinyl-1-yl|acetic acid, 70 (16) 4k)-1-(4- amino-3-chloro-5-trifluoromethylbenzyl)-2-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (17) 4k)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-I4-( 1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin- 1-carboxylic acid, (18). (K)-1-(4-ami 4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (19) 4O)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-I4-(5-methyl-2, 5-diazabicyclo|2.2.1|hept-2-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)/piperidine-1-carboxylic acid, (20). (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)ethylamide 4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (21) H1-(PO-3-(4-amino-3-chloro-5-trifluoromethylphenyl)-2 -(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-carbonylamino)propionyl)-4,4"-bipiperidinyl-1-yl |acetic acid, (22). (1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2-11,4bipiperidinyl-1'-yl-2-oxoethylamide and) 4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (23) (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1 -14-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-(4-(2-oxo-1,2,4,5-isotetrahydro-1,3-benzdiazepin-3- yl)ipiperidin-1-yl|Ibutan-1,4-dione, (24) with (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-4-I4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-soyl|I-1-(4-pyridin-4-ylpiperazin-1-yl)butan-1,4-dione , (25) F Zv (Z)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)-1-1,4-bipiperidinyl-1"-yl-4-|4-(2-oxo-1 , 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)upiperidin-1-yl|butane-1,4-dione, (25) (5)-2-(4-amino-3 -bromo-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-(4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutane-1,4-dione, « from (1) 2 with (5)-2-(4-amino-3-bromo-5-trifluoromethylbenzyl)- 1-(1"-methyl-4,4"-bipiperidinyl-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahyde). ro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, "" (28) (5)-2-(4-amino-3-trifluoromethylbenzyl)-1-I (4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) piperidin-1-yl|butane-1,4-dione, - (29) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-dimethylaminopiperidin-1-yl)- 4-(4-(2-oxo-1,2,4,5-tetrahydro-1 ise) ,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, so (30) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(3-dimethylaminopiperidin-1-yl)-4-(4-(2-oxo-1,2,4,5- Tetrahydro-1 co,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, syu (31) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl) -4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-(4-pyrrolidin-1-ylpiperidine) -1-yl)butane-1,4-dione, (32) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methyl-4,4-bipiperidinyl-1 -yl)-4-I(4-(2-oxo-1,2,4,5-tetrahyd (Ph. ro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, t (33) (5)-2-(4-amino-3-chloro-5- trifluoromethylbenzyl)-1-I(4--4-cyclopropylmethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, (34) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-morpholine -4-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4 -dione, (35) 65 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzdiazepin-3-yl)piperidin-1-yl|-1-(4-perhydroazepin-1-ylpiperidin-1-yl)butan-1,4-dione, (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(4-methylperhydro-1,4-diazepin-1-yl)upiperidin-1-yl)-4-(4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutane-1,4-dione, I (87) (5)-2 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(4-isopropylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4 , B-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (38) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl )-1-1,4"-bipiperidinyl-1'-yl-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-ben 70 zdiazepin-3-yl)upiperidin- 1-yl|butane-1,4-dione, (39) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)perhydro- 1,4-diazepin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan- 1,4-dione, (40) 75. (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I3-(4-methylpiperazin-1-yl)azetidin-1-yl|-4-(4-(2- oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (41) (5)-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1 -"(3-pyrrolidin-1-ylazetidin-1-yl)butan-1,4-dione, 20 (42) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I (4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-ylI-1-3-piperidin-1-ylazetidin-1-yl)butane -1,4-dione, (43) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(3-diethylaminoazetidin-1-yl)-4-I(4-(2 -oxo-1,2,4,5-tetrahydro-1,3 ch 25 -benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, (44) (o) (5)- 2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-azetidin-1-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro - 1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (45) c zo (5)-1-(4-(4-acetylpiperazin-1-yl)piperidin- 1-yl|-2-(4-amino-3-chloro-5--trifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5- tetrag hydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, c (46) c (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl) -1-(4-diethylaminomethylpiperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl| butane-1,4-dione, Me) 35 (47) it- (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(4-ethylpiperazin-1-yl)piperidine -1-yl|-4-(4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butan-1,4- dione, (48) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(1-ethylpiperidin-4-yl)piperazin-1-yl|-4-(4- (2-oxo-1,2,4,5-the « 40 trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butane-1,4-dione, from c (49) . (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl )piperidin-1-yl|-1-(3,4,5,6-tetrahydro-2H-4-4-bipyridinyl-1-yl)butan-1,4-dione, (50) 45 (5)-2 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1- -I yl|I-1-(4-pyridin-4-ylpiperazin-1-yl)butan-1,4-dione, (51) and, (5)-2-(4-amino-3-chloro-5 -trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-2)ylI|-1-"3-perhydroazepine -1-ylazetidin-1-yl)butan-1,4-dione, (52 o (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(1-benzylpiperidine-4 -yl)piperazin-1-yl|-4-I(I4-(2-oxo-1,2,4,5- 4)tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane -1,4-dione, (53) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-benzylpiperazin-1-yl)piperidin-1-yl| -4-I(I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (54) F ) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(7-dimethylaminomethyl-1,2,4,5-tetrahyde ro-3-benzazepin-3-yl)-4-|4- ka (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan- 1,4-dione, (55) in (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4--4-dimethylaminomethylphenyl)piperidin-1-ylI-4-I4- (2-oxo-1,2,4,B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (56) (5)-2-(4 -amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|- 1--4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipiperidin-1-yl)butan-1,4-dione, b5 (57) (5)-2-(4- amino-3-chloro-5-trifluoromethylbenzyl)-1-(1-methanesulfonyl-4-4-bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-( 9-methyl-3,9-diazaspiro|5,5)undec-3-yl)-4-14-(2-oxo-1,2,4,5-tet-rahydro-1,3-benzdiazepin-3-yl)piperidine -1-yl|butane-1,4-dione, (59) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-4-piperidin-1-ylmethylpiperidin-1-yl)butan-1,4-dione, (60 ) 70 (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4--2-dimethylaminoethyl)piperidin-1-yl|-4-(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (61) (5)-2-(4-amino-3 -chloro-5-trifluoromethylbenzyl)-M-methyl-M-(2-(1-methylpiperidin-4-yl)ethyl1-4-oxo-4-I4-(2-oxo-1,2, 4,5-tetrahydro -1,3-benzdiazepin-3-yl)piperidin-1-yl|bsuthyramide, (62) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-methyl-M-(1 -methylpiperidin-4-ylmethyl)-4-oxo-4-I(4-(2-oxo-1,2,4,B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|bsutyramide , (63) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenz l)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|-1-piperidin-1-ylbutan-1 ,4-dione, (64) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzdiazepin-3-yl)piperidin-1-yl|I-1--4-propylpiperidin-1-yl)butane-1,4-dione, (65) ch (5)-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-1-(4-benzylpiperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3 -yl)upiperidin-1-yl|butan-1,4-dione, o (66) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-14-(2-diethylaminoethyl) piperidin-1-yl|-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione , so z o (67) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(3-azaspiro|5.5)undec-3-yl)-4-I4-(2-oxo -1,2,4,5-tetrahydro-1,3-c benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, so (68) M-(1-445)-2- (4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl Me)piperidine -1-ylButyryl)piperidin-4-yl)-M-methylmethanesulfonamide, M (69) M-(1-445)-2-(4-amine o-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-ylbutyryl )piperidin-4-yl)umethanesulfonamide, (70) « (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4--cyclopentylmethylamino)piperidin-1-yl)-4- (4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, . (7) and (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-methylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benz diazepin-3-yl)upiperidin-1-yl|butane-1,4-dione, (72) methyl ether -I (1-4(5)-2-(4- amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl |Ibutyryl)piperidin-4-yl)acetic acid, i-o (73) 2) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-hydroxypiperidin-1-yl) (74) 4) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine-3 -yl)piperidin-1-ylI-1-4-trifluoromethylpiperidin-1-yl)butan-1,4-dione, (75) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl) -1-(4-(1,1-dioxo-1,6-isothiazolidin-2-yl)piperidin-1-yl|-4-I4-(2-oK co-1,2,4,5-tetrahydro- 1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutan-1,4-dione, F) (76)(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1 -I4-(2-oxoperhydro-1,3-oxazin-3-yl)piperidin-1-yl)-4-(4 ka -(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan-1,4-dione, (77) methyl ether in 1-( 5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine- 3-yl)piperidin-1-ylbutyryl)piperidine-4-carboxylic acid, (78) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-cyclohexylpiperidine-1- yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, b5 (79) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-tert-butylaminopiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5 -tetrahydro o-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4- I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|I-1-«4-phenylpiperidin-1-yl)butan- 1,4-dione, (81) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzdiazepin-3-yl)piperidin-1-yl|-1-(4-p-tolylpiperidin-1-yl)butane-1,4-dione, (82) 70 8-(5)-2- (4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4- 14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)pyridin-1-yl|Ibutyryl)-1,3,8-triazaspiro|4.5|decane-2 ,4-dione, (83) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)-4- (4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl|Ibutane-1,4-dione, (va) (5)-2 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-amino-4-methylpiperidin-1-yl)-4-(4-(2-oxo-1,2,4,5-tetrahydro - 1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (85) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1- I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin- 1-yl|Ibutane-1,4-dione, (86) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(2-amino-4,5,7,8- tetrahydrothiazolo|4,5-4|azepin-b-yl)-4-I4-(2-oCco-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)ipiperidin-1-yl |Ibutane-1,4-dione, (87) ch (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(2-methylimidazol-1-yl)piperidin-1- yl|-4-I4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/pip eridin-1-yl|butane-1,4-dione, o (88) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylimidazol-1- yl)piperidin-1-yl|-4-I4-(2-oxo-1,2,4,5-the trahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butan-1, 4-dione, so z o (89) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro- 1,3-Benzdiazepin-3-yl)piperidin-1-cyl|-1-(4-thiazol-2-ylpiperazin-1-yl)butan-1,4-dione, so (90) (5)-2 -(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(2,4-dimethylimidazol-1-yl)piperidin-1-yl|-4-(4-(2-oxo-1, 2,4, Me B-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4-dione, M (91) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-1-(4-imidazol-1-ylpiperidin-1-yl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3- yl)piperidin-1-yl|Ibutane-1,4-dione, (92) « (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-z cyl|-1-(4-1,2,4-triazol-1-ylpiperidin-1-yl) )butane-1,4-dione, . (93) and (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(1-azabicyclo|2.2.2)oct-3-yl)piperazin-1-yl| -4-I4-(2-oxo-1,2 "4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (94) -I ( 5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) piperidin-1-yl|-1-piperazin-1-ylbutane-1,4-dione, and, (95) (1-methylpiperidin-4-yl)amide 2) 4-(5)-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)pyridin-1-ylbutyryl) piperazine-1-sulfonic acid, dk (96) 4) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-M-(5-aminopentyl)-4-oxo-4-I4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|butyramide, (97) (5)-2-(4-amino-3- chloro-5-trifluoromethylbenzyl)-M-(3-aminomethylbenzyl)-4-oxo-4-|4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidine -1-yl|butyramide, (F. (98) ka 1-(5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-oxo-4-I(4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzdiazepin-3-yl)pyridin-1-ylbutyryl)piperidine-4-carboxylic acid, in (99) (1-4(5)-2-(4-amino-3-chloro -5-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutyryl)piperidin- 4-yl)acetic acid, (100) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(8-methyl-8-azabicyclo|3.2.1|oct- 3-yl)piperazin-1-yl)-4-(4-(2-65 oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|Ibutan- 1,4-dione, (101) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl )piperidin-1-yl|I-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, (102) (5)-2-(4-amino-3-chloro- 5-trifluoromethylbenzyl)-1-I4-(1H-imidazol-4-yl)piperidin-1-ylI-4-I(I4-(2-oxo-1,2,4,5-tetrahydro-1,3- Benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, (103) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-4-I(4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|-1--4-(4-(2,2,2-trifluoroacetyl)phenyl| piperazin-1-yl)butan-1,4-dione, 70 (104) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazine-1- yl)piperidin-1-yl|-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (105) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(5-oxo -3-phenyl-4,B-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl|butan-1,4-dione, (106) (5)-2-(4-amino -3-chloro-5-trifluoromethylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-14-(2-oxo-1,2-dihyde roimidazo|4,5-c|quinolin-3-yl)piperidin-1-yl|butane-1,4-dione, (107) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl) -1-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,2-dihydro-4H-thieno|3,4-4Ipyrimidin-3- yl)piperidin-1-yl|butane-1,4-dione, (108) (5)-2-(4-amino-3-chloro-5-trifluoromethylbenzyl)-1-I4-(5-methyl-2, 5-diazabicyclo|2.2.1)hept-2-yl)piperidin-1-yl)-4-4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) Piperidin-1-yl|Ibutan-1,4-dione, ch (109) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4-methylperhydro-1,4-diazepine -1-yl)/piperidin-1-yl|-4-(4-(2-oxo)-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl |butan-1,4-dione, (110) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)perhydro-1,4-diazepine -1-yl|-4-(4-(2-oxo cozo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butan-1,4- dione, (117) c (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-methylpiperidin-4-yl)piperazin-1-ylI|-4-(4-( 2-oxo-1,2,4,5-tetso rahydro-1,3-benzdiazepin-3-yl)piperidine-1- yl|butane-1,4-dione, (112) Me (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(1-azabicyclo|2.2.2|oct-3-yl )piperazin-1-yl|-4-(4-(2-oxo-1,2,4M,B-tetrahydro-1,3-benzdiazepin-3-yl)/piperidin-1-yl|butan-1, 4-dione, (113) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4- (2-oxo-1,2,4,5-tet-rahydro-1,3-benzdiazepin-3-yl)piperidin-1-yl|butane-1,4-dione, « (114) in c (5)- 2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-14-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-33-yl)ipiperidin-1-yl. 1-1-(4-perhydroazepin-1-ylpiperidin-1-yl)butan-1,4-dione, "" (115) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-1- 11,4bipiperidinyl-1'-yl-4-I(I4-(2-oxo-1,2,4,5-tetrahydro-1,3-benz diazepin-3-yl)upiperidin-1-yl|butan-1 ,4-dione, -I (116) (5)-2-(4-amino-3,5-bistrifluoromethylbenzyl)-4-I4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzdiazepin-3Z-yl)piperidin-1-yl and, 1-1-(4-piperazin-1-ylpiperidin-1-yl)butan-1,4-dione, oo (117) 50. ХР)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-|4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-oxoethyl)amide ko 4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (118) XO)-1-(4-amino-3,5-bistrifluoromethylbenzyl) )-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepine- 3-yl)/piperidine-1-carboxylic acid, (1193. KK)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-1,4-bipiperidinyl-1'-yl-2-oxoethylamide 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, F) (120). (kK)-1-(4-amino-3,5-bistrifluoromethylbenzyl)-2-oxo-2-(4-piperazin-1-ylpiperidin-1-yl)ethylamide ka 4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzdiazepin-3-yl)/piperidine-1-carboxylic acid, (121) in (K)-1-(4-amino-3-chloro-5-trifluoromethylbenzyl)-2- (4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl ether 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) /piperidine-1-carboxylic acid, (122) 12-P1,4Dbipiperidinyl-1'-yl-1-4-bromo-3-methylbenzyl)-2-oxoethyl|amide 4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (123). (1-(4-bromo-3-methylbenzyl)-2-(1-methyl-(4,4bipiperidinyl-1-yl)-2-oxoethyl|amide 65 4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)/piperidine-1-carboxylic acid, (124). 11-(4-bromo-3-methylbenzyl)-2-14-(4-methylpiperazin-1-yl)piperidin-1-yl| -2-oxoethylamide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (125). 11-(4-bromo-3-methylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethylamide 4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)/piperidine-1-carboxylic acid, (126) ethyl ether TA4-(1-(3-(4-bromo-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)upiperidin-1- carbonylamino)propionyl)piperidin-4-yl|piperazine-1-illuic acid, (127) ethyl ether (1'-(3--4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino )propionyl) 70 I4, Abipiperidinyl-1-yl| acetic acid, (128) ethyl ether ТА4-И4-(3-(4-bromo-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)upiperidine-1-carbonylamino )propionyl)piperazin-1-yl|piperidine-1-ylacetic acid, (129) TA4-(1-(3-(4-bromo-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)upiperidine-1-carbonylamino)propionyl) piperidin-4-yl|piperazine-1-ylacetic acid, (130) (1'-(3--4-bromo-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine-1-carbonylamino)propionyl) -( 4,4-bipiperidinyl-1-yl|acetic acid, (131) tA4-I4-(3-(4-bromo-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)upiperidine-1-carbonylamino)propion l) piperazin-1-yl|piperidine-1-ylacetic acid, (132) 2-(4-bromo-3-methylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-dione)piperidin-1-yl|butane-1,4-dione, (133) i) 2-(4-bromo-3-methylbenzyl)-1-(1"-methyl-I(4,4Dbipiperidinyl-1-yl)-4-I4-(2-oxo-1,4-dihydro -2H-quinazoline-3-yl)piperidin-1-yl|butane-1,4-dione, (134) sozo 1-P "Abipiperidinyl-1"-yl-2-(4-bromo-3-methylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) )piperidin-1-yl Ibutan-1,4-dione, p (135) so 2-(4-bromo-3-methylbenzyl)-1-4-14--3-dimethylaminopropyl)phenyl|piperazin-1-yl)-4-(4-(2-oxo-1,4- dihydro-2H-kinase olin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, Me) (136) it-I4-(1-42-(4-bromo-3-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidin-1-ylbutyryl)piperidin-4-yl)piperazin-1-yl|acetic acid, (137) methyl ether (1-22-(4-bromo-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1 -ylbutyryl)-I4,4 « of bipiperidinyl-1-yl)acetic acid, with (138) . (1-22-(4-bromo-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylIbutyryl)-I4 ,4 and bipiperidinyl-1-yl)acetic acid, (139). 411-(4-chloro-3-methylbenzyl)-2-I(4-(4-methylpiperazin-1-yl)/piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, -And (140). 12-(1,4Zbipiperidinyl-1'-yl-1-(4-chloro-3-methylbenzyl)-2-oxoethyl|amide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) /piperidine-1-carboxylic acid, and, (141). 411-(4-chloro-3-methylbenzyl)-2-I4-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide 2) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (142). (1-(4-chloro-3-methylbenzyl)-2-(1-methyl-I4 А4bipiperidinyl-1-yl)-2-oxoethylamide co 4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)/piperidine-1-carboxylic acid, (143) ethyl ether (1'-(3-(4-chloro-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidin-1 -carbonyl(amino)propionyl)I4,Albipiperidinyl-1-yl|acetic acid, 5B (144) tert-butyl ether tA4-(1-(3-(4-chloro-3-methylphenyl)-2-114-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-carbonyl|amino)propioni F) l)piperidin-4-yl|piperazine-1-ylacetic acid, ka (145). 11-(4-chloro-3-methylbenzyl)-2-oxo-2-I(1-(2,2,2-trifluoroethyl)|(4,4bipiperidinyl-1-ylylethyl)iamide 4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, in (146). (1-(4-chloro-3-methylbenzyl)-2-oxo-2-14-I4-(2,2,2-trifluoroethyl)piperazin-1-yl|Ipiperidin-1-ylethyl)amide 4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (147) (1'-(3-(4-chloro-3-methylphenyl)-2-14-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carbonylamino)propionyl) - (4,4-bipiperidinyl-1-yl|acetic acid, 65 (148) 2-(4-chloro-3-methylbenzyl)-1-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)-4-(4-(2-oxo-1,4-dihydro-2H) -quinazolin-3-yl )piperidin-1-yl|Ibutane-1,4-dione, 2-(4-chloro-3-methylbenzyl)-1-(1-methyl-14,4Dbipiperidinyl-1-yl)-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)piperidin-1-yl|butane-1,4-dione, (150) 1-11,4Dbipiperidinyl-1'-yl-2-(4-chloro-3-methylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-yl Ibutan-1,4-dione, (151) 70 2-(4-chloro-3-methylbenzyl)-1-I4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-(4-(2-oxo-1,4-dihydro-2H) -quinazoline-3-yl)piperidin-1-yl|butane-1,4-dione, (152) 2-(4-chloro-3-methylbenzyl)-1-I4-(1-methylpiperidin-4-yl)piperazin-1-ylI|-4-I(4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, (153) 2-(4-chloro-3-methylbenzyl)-1-I4-(4-methanesulfonylpiperazin-1-yl)piperidin-1-ylI|-4-(4-(2-oxo-1,4-dihydro -2H-quina zolin-3-yl)piperidin-1-yl|butane-1,4-dione, (154) 2-(4-chloro-3-methylbenzyl)-1-I4-(4-isopropylpiperazin-1-yl)piperidin-1-ylI|-4-I(4-(2-oxo-1,4- dihydro-2H-quinazoline -3-yl)piperidin-1-yl|butane-1,4-dione, (155) ethyl ether 1-2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1- yl|IbrTutyryl)-4-(1-methylpiperidin-4-yl)piperazine-2-carboxylic acid, (156) ethyl ether p 1-(1-2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl| Ibrsutiryl)piperidin-4-yl)-4-methylpiperazine-2-carboxylic acid, and) (157) ethyl ether 4-(1-2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine -1-yl|IbrTutyryl)piperidin-4-yl)-1-methylpiperazine-2-carboxylic acid, sodium (158) ethyl ether 4-(2-(4-chloro-3-methylbenzyl)-4-oxo- 4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyryl)-1-(1-methylpiperidin-4-yl)piperazine-2-carbon acids, so (159) 2-(4-chloro-3-methylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|-1-(1- (2,2,2-trifluoroethyl)-Me I4,Albipiperidinyl-1-yl|butane-1,4-dione, i- (160) 2-(4-chloro-3-methylbenzyl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylI|-1-14 -I(4-(2,2,2-trifluoroethyl)piperazin-1-yl|piperidin-1-yl)butan-1,4-dione, (161) " I4-(1-422-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-ylIbGutyryl) pepper with sydin-4-yl)piperazin-1-yl|acetic acid, . (162) methyl ether and (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin- 1-yl|butyryl)-I4,41 bipiperidinyl-1-yl)acetic acid, (163)-I (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyryl)-I4,41 bipiperidinyl-1-yl)acetic acid, and, (164) 2) 1-2-(4 -chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|IbrTutyryl)-4-(1-meth ylpiperidin-4-yl)piperazine-2-carboxylic acid, o (165) 4) 1-(1-2-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|Ibrsutiryl)piperidin-4-yl)-4-methylpiperazine-2-carboxylic acid, (166) 4-(1-2-(4 -chloro-3-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|IbrTutyryl)piperidin-4-yl) -1-methylpiperazine-2-carboxylic acid, (F) (167) ka 2-(4-chloro-3-methylbenzyl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl|- 4-I(4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|Ibutan-1,4- dione, 60 (168) 2-(4-chloro-3-methylbenzyl)-1-(4-(4-methylpiperazin-1-yl)piperidin-1-ylI|-4-I(4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzd iazepin-3-yl)/piperidin-1-yl|Ibutan-1,4-dione, (169) I4-(1-22-(4-chloro) -3-methylbenzyl)-4-oxo-4-14-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl )piperidin-4-yl)piperazin-1-yl)acetic acid, (170) methyl ether (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-I4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl) Piperidin-1-yl esters of 1)-4,4"-bipiperidinyl-1-ylacetic acid, (171) (1-22-(4-chloro-3-methylbenzyl)-4-oxo-4-14-(5 -oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)piperidin-1-yl[butyric acid]-4,4-bipiperidinyl-1-yl acetic acid, (172) 2 -(3-bromo-4-chloro-5-methylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-4-I4-(2-oxo-1,4- dihydro-2H-quinazo lin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, 70 (173) 2-(3-bromo-4-chloro-5-methylbenzyl)-1-(1- methyl-(4,4bipiperidinyl-1-yl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, ( 174) 2-(3-bromo-4-chloro-5-methylbenzyl)-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|-1 -(4-pyridin-4-ylpiperazin-1-yl)butane-1,4-dione, (175) 2-(3-bromo-4-chloro-5-methylbenzyl)-1-14-(1-methylpiperidine) -4-yl)piperazin-1-yl|-4-I4-(2-oxo-1,4-dihydro-2H-quinazo lin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (176) I4-(1-422-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-di hydro-2H-quinazolin-3-yl)piperidin-1-yl|butyric l)piperidin-4-yl)piperazin-1-yl|acetic acid, (177) methyl ether (1-22-(3-bromo-4 -chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|ibutyryl) I4,ALbipiperidinyl-1- (178) (1-22-(3-bromo-4-chloro-5-methylbenzyl)-4-oxo-4-(4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)piperidin-1-yl|butyryl) and) -(X4,4Dbipiperidinyl-1-yl)acetic acid, (179). 41-(3-bromo-4-chloro-5-methylbenzyl)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl|-2-oxoethyl)amide 4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, salt (180). 12-11,4Dbipereridinyl-1'-yl-1-(3-bromo-4-chloro-5-methylbenzyl)-2-oxoethyl|amide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)/piperidine-1-carboxylic acid, c (181). 41-(3-bromo-4-chloro-5-methylbenzyl)-2-14-(1-methylpiperidin-4-yl)piperazin-1-yl|-2-oxoethyl)amide so 4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (182). (1-(3-bromo-4-chloro-5-methylbenzyl)-2-(1-methyl-(4,4bipiperidinyl-1-yl)-2-oxoethyl|amide Me 4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, M (183). (1-(3-bromo-4-chloro-5-methylbenzyl)-2-oxo-2-(4- Pyridin-4-ylpiperazin-1-yl)ethyliamide 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)/piperidine-1-carboxylic acid, (184) 2-(4-chloro- 3-trifluoromethylbenzyl)-1-(1-methyl-I4 4bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-" yl)piperidin-1- yl|butan-1,4-dione, with c (185) 2-(4-chloro-3-trifluoromethylbenzyl)-1-I(4-(4-methylpiperazin-1-yl)piperidin-1-yl|- 4-I4-(2-oxo-1,4-dihydro-2H-quinazo and lin-3-yl)piperidin-1-yl|Ibutane-1,4-dione, (186) 45..1-1 "Abipiperidinyl-1'-yl-2-(4-chloro-3-trifluoromethylbenzyl)-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperide -I in-1-yl|butane-1,4-dione, (187) and, I4-(1-422-(4-chloro-3-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butyrs 2) l)piperidin-4-yl)piperazin-1-yl|acetic acid, (188) methyl ether o (1- 22-(4-chloro-33-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|bsutiryl) 4) I4 ,Albipiperidinyl-1-yl)acetic acid, (189) (1-22-(4-chloro-3Z-trifluoromethylbenzyl)-4-oxo-4-I4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)piperidin-1-yl|bsutiryl)-(4,4Dbipiperidinyl-1-yl)acetic acid, (190). 2-(4-chloro-3-trifluoromethylbenzyl)-1-(1"-methyl- I4 4 F) bipiperidinyl-1-yl)-4-I(4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidin-1-yl|butane-1,4-dione, their enantiomers, their diastereomers and their salts. 10. Compounds according to any of claims 1-9, which are physiologically compatible salts with inorganic or organic acids or bases. 11. Medicinal product containing a compound according to any of claims 1-9 or a physiologically compatible salt according to claim 10, as well as optionally one or more inert carriers and/or diluents. 12. Use of the compound according to any one of claims 1-10 for obtaining a medicinal product intended for emergency and preventive treatment of headaches, primarily migraines, cluster headaches, vasomotor headaches and chronic headaches, respectively. 13. Use of a compound according to any one of claims 1-10 for the preparation of a medicinal product intended for the prophylactic treatment of migraine during the prodromal period or for the emergency and prophylactic treatment of migraine occurring before menstruation or during menstruation. 14. Use of the compound according to any one of claims 1-10 for the preparation of a medicinal product intended for combating non-insulin-dependent diabetes (IND). 15. Use of a compound according to any one of claims 1-10 for the preparation of a medicinal product intended for the treatment of cardiovascular diseases, morphine tolerance, clostridial toxin-induced diseases accompanied by diarrhea, skin diseases, primarily thermal and radiation damage to the skin, including solar erythema, inflammatory diseases, primarily inflammatory diseases of the joints, such as 7/0 arthritis, neurogenic inflammations of the mucous membrane of the oral cavity, inflammatory diseases of the lungs, allergic rhinitis, asthma, diseases caused by excessive expansion of blood vessels and the associated reduced blood supply to tissues, primarily shock or sepsis, or redness of the skin, to relieve pain conditions in general, primarily in neuropathic pain, in neuropathic pain conditions that accompany systemic diseases with toxic damage to the nervous system, as well as in pain conditions caused by inflammatory processes, or for preventive or emergency therapy effect on vasodilation and increased blood flow symptoms of menopausal hot flushes in women with estrogen deficiency, as well as hot flushes in patients suffering from prostate cancer after hormone therapy. 16. The method of obtaining a medicinal product according to claim 11, which differs in that the compound according to any of paragraphs 20.1-10 are not chemically combined with one or more inert carriers and/or diluents. 17. The method for obtaining compounds of the general formula (I) according to any of claims 1-9, which differs in that for obtaining compounds of the general formula (I), in which X means an oxygen atom or a MH group, and B!-K? have the values specified in claim 1, provided that these groups do not contain a free carboxyl function, piperidines of the general formula (PO, s rii В o in which В! has the values specified in claim 1, are subjected to interaction (I) with carbonic acid derivatives of the general formula formulas с содмс Ховсе Ф in which A has the values indicated in claim 1, and C means a nucleofuge group, provided that X is a group and - -MH, or (II) with carbonic acid derivatives of the general formula (M, "E X, sh c z" in which A means an oxygen atom, and both C mean nucleofuge groups, which can have identical or different values, provided that X represents an oxygen atom, and with compounds of the general formula (M , щ M se) (95) d) 50 ni syu» No dz Ф) o in which X denotes an oxygen atom or the group -МН, and |, M, MU, B2 and VZ have the values indicated in claim 1, provided that that 2 and BZ do not contain a free carboxyl function and/or other free primary or secondary aliphatic or amino function or other free hydroxy function, and then, if necessary, the protective group is removed, which was used in the reactions described above, and/or, if necessary, functional groups that were not necessarily used in the precursors are transformed in the compound obtained in this way, and/or if necessary, the compound of the general formula (I) obtained in this way is separated into its stereoisomers, and/ or because the compound of the general formula (I) obtained in this way is converted into its salts, first of all, for pharmaceutical use, it is converted into its physiologically compatible salts. 18. The method for obtaining compounds of general formula (I) according to any of claims 1-9, which differs in that for obtaining compounds of general formula (I), in which X denotes a methylene group, and B !-KZ have the specified in claim 1 value, provided that these groups do not contain a free carboxyl function and/or other free primary or secondary aliphatic amino function, a carboxylic acid of the general formula (MI), o di H t-da in which M, M, MU, B2 and VZ have the values indicated in claim 1, are subjected to combination with piperidine of the general formula (11), in which VE! has the values specified in claim 1, and then, if necessary, the protective group that was used in the reactions described above is cleaved off, and/or if necessary, functional groups that were not necessarily used in the precursors are transformed in the compound obtained in this way, and/or with if necessary, the compound of the general formula (I) obtained in this way is divided into its stereoisomers, and/or the compound of the general formula (I) obtained in this way is converted into its salts, primarily for pharmaceutical use, converted into its physiologically compatible salts. with 19. The method for obtaining compounds of the general formula (I) according to any of claims 1-9, which differs in that for obtaining compounds of the general formula (I), in which X denotes a methylene group, and B 2 and ВZ have the specified in claim 1 Me Sv value, provided that these groups do not contain a free primary or secondary amine, a compound of the general formula M (MI), st - - I» o de - My o se) (95) | | | | Y Y in which M, M, MU, B2 and BZ have the values indicated in claim 1, provided that 22 and BZ do not contain a free primary or o secondary amine, and My means a group that is removed, subjected to coupling with piperidine of the general formula with (1), lotu - in ! ! in which K' has the values indicated in claim 1, and HF) then, if necessary, the protective group used in the reactions described above is cleaved off, and/or 7 if necessary, functional groups, which were not necessarily used in the precursors, are transformed in the compound obtained in this way . 20. The method of obtaining compounds of general formula (I) according to any of claims 1-9, which differs in that for obtaining compounds of general formula (I), in which all residues have the values specified in claim 1, carboxylic acid of general formula b5 (MI, in which all residues have the values specified in claim 1, is subjected to coupling with an amine of the general formula HMR, in which K2 and KZ have the values specified in claim 1, provided that these groups do not contain a free carboxyl function and/or other free a primary or secondary aliphatic amino function, and then, if necessary, the protective group used in the reactions described above is removed, and/or, if necessary, functional groups, which were not necessarily used in the precursors, are transformed into the compound thus obtained, and/or, if necessary, the thus obtained by dividing the compound of the general formula (I) into its stereoisomers, and/or the compound of the general formula (I) obtained in this way is converted into its salts, first of all, for pharmaceutical use, it is converted into its physiologically compatible salts. 21. The method of obtaining compounds of general formula (I) according to any of claims 1-9, which differs in that for (o) obtaining compounds of general formula (I), in which B ! has the values indicated in claim 1, provided that it does not contain a free primary or secondary amine, a compound of the general formula (XI), so zo M c (ze) (o) A i - - c nu o И.Й "» o, , , in which all residues have the values specified in claim 1, and M means a group that is removed, subjected to 15 coupling with an amine of the general formula HME2B, in which B? and BEZ have the values specified in claim 1, provided that - these groups do not contain a free carboxyl group and/or other free primary or secondary aliphatic amino group, and then, if necessary, the protecting group used in the reactions described above is cleaved off, and/or (Ce) if necessary in the one obtained in this way the compounds transform functional groups that were not necessarily used in the precursors, and/or if necessary, the compound of the general formula (I) obtained in this way is separated into its stereoisomers, and/or the compound of the general formula (I) obtained in this way is converted into its salts , primarily for c" pharmaceutical use is translated into its physiologically compatible salts. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 8, 11.06.2007 . State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. name) 60 b5