HRP20050364A2 - Selected cgrp antagonists, method for production and use thereof as medicament - Google Patents

Abstract

The present invention relates to CGRP antagonists of the general formula wherein A, U, V, W, X and R 1 to R 3 as defined in claim 1, their tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and their salts as well as salt hydrates, in particular their physiologically acceptable salts with inorganic and organic acids, pharmaceutical compositions containing these compounds, their use and preparation processes.

Description

The presented invention relates to CGRP antagonists of the general formula

[image] , (I)

their tautomers, diastereomers, enantiomers, hydrates, combinations and their salts as well as hydrates of salts, especially their physiologically acceptable salts with inorganic or organic acids, pharmaceutical preparations containing these compounds, their use and the process of their preparation.

In the general formula (I) shown above in the first form

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

X denotes an oxygen or sulfur atom, an imino group which can be substituted with a C1-6-alkyl group or a methylene group which can be substituted with a C1-6-alkyl group,

U denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms.

V denotes a chlorine or bromine atom, amino, methylamino or hydroxy group,

W denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a difluoro- or trifluoromethyl group,

R1 denotes a saturated mono- or di-unsaturated 5- to 7-membered aza, diaz, triaz, oxaz, thiaz or S,S-dioxido-thiadiaz heterocyclic group,

in which the aforementioned heterocyclic rings are linked by a carbon or nitrogen atom,

contain one or two carbonyl or thiocarbonyl groups adjacent to the nitrogen atom,

can be substituted at the position of one nitrogen atom by an alkyl group,

may be substituted at one or two carbon atoms by an alkyl group, phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl , imidazolyl or 1-methylimidazolyl group, wherein the substituents can be the same or different, and

while the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings can be attached to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, N-methylpyrrole or quinoline ring on a 1H-quinoline-2 one the ring can be substituted in place of the nitrogen atom with an alkyl group or on the imidazole or N-methylimidazole ring, or two olefinic bonds of one of the above-mentioned unsaturated heterocyclic rings can each be connected to a phenyl ring,

while phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in R1 as well as benzo-, thieno-, pyrido- and diazino-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or trisubstituted with fluorine, chlorine, bromine or iodine atoms, with alkyl, alkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, difluoromethyl, trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino, alkylamino, dialkylamino, acetyl, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro- 1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, alkanoyl, cyano, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, wherein the substituents may be the same or different to read.

R2 denotes a hydrogen atom,

phenylmethyl group or C2-7-alkyl group which can be substituted in position with cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(ω-hydroxy- C2-7-alkyl)-1-piperazinyl group,

phenyl or pyridinyl group,

while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or tri-substituted in the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di -(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, methylsulfonyloxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di -(C1-3-alkyl)-amino-C1-3-alkyl groups and substituents can be the same or different,

R3 denotes a hydrogen atom or a C1-3-alkyl group possibly substituted with a phenyl or pyridinyl group,

while the C1-3-alkyl group can be connected to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 or a nitrogen atom with which they can be connected to form a ring, or

R2 and R3 together with the nitrogen atom they contain denote a group of the general formula

[image] , (II)

where

Y1 denotes a carbon atom or, if R5 is a pair of free electrons, it can also denote a nitrogen atom,

q and r, if Y1 is a carbon atom, represent the numbers 0, 1 or 2, or

q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2,

R4 denotes a hydrogen atom, amino, alkylamino, cycloalkylamino, dialkylamino, N-(cycloalkyl)-alkylamino, dicycloalkylamino, hydroxy, alkyl, cycloalkyl, amino-C2-7-alkyl, alkylamino-C2-7-alkyl, dialkylamino-C2-7 -alkyl, aminoiminomethyl, alkylcarbonyl, alkylsulfonyl, alkylcarbonylamino, alkylsulfonylamino, N-alkylcarbonyl-N-alkylamino, N-alkylsulfonyl-N-alkylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, cycloalkylaminocarbonylamino, dicycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl , an alkoxycarbonylalkyl or carboxyalkyl group,

or, if Y1 does not represent a nitrogen atom, carboxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl group,

phenyl, phenyl-C1-3-alkyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group, each of which can be mono-, di- or trisubstituted in the carbon skeleton with a fluorine, chlorine, bromine or iodine atom, with alkyl, alkoxy, methylsulfonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, -(dialkylamino)alkyl, ω- (dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group, whereby the substituents may be the same or different,

saturated or mono- or polyunsaturated 4- to 10-membered azacycloalkyl groups, 5- to 10-membered oxaza-, thiaza-, diaza- or triazacycloalkyl groups, 6- to 10-membered azabicyclo- or diazabicycloalkyl groups, 1-alkyl-4 -piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl, 1-alkyl-4-piperidinylamino, 1-alkyl-4-piperidinylaminocarbonyl or 1-alkyl-4-piperidinylaminosulfonyl groups

while the above-mentioned mono- and bicyclic rings are bonded through carbon or nitrogen atoms,

the methylene group in the above-mentioned mono- and bicyclic rings can be replaced by a carbonyl or sulfonyl group,

in the above-mentioned mono- and bicyclic rings, any methylene group that is not directly connected to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms,

The above-mentioned mono- and bicyclic rings as well as 1-alkyl-4-piperidinylcarbonyl- and 4-alkyl-1-piperazinylcarbonyl groups in the ring can be mono- or polysubstituted with a C1-7-alkyl group and/or

monosubstituted with a benzyl, alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl or cycloalkylalkyl group, or substituted with a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group, possibly alkyl-substituted in the ring ,

while the alicyclic moieties contained in these substituents each contain 3 to 10 ring members and the heterocyclic moieties each contain 4 to 10 ring members and

phenyl and pyridinyl groups contained in the above-mentioned groups can be mono-, di- or trisubstituted with a fluorine, chlorine, bromine or iodine atom, with alkyl, alkoxy, methylsulfonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl , cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group, whereby the substituents may be the same or different,

R5 denotes a hydrogen atom,

C1-4-alkyl group, while unbranched alkyl group can be substituted in position ω with phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl group,

an alkoxycarbonyl, cyano or aminocarbonyl group or also, if Y1 represents a nitrogen atom, a pair of free electrons.

or, if Y1 does not denote a nitrogen atom, also a fluorine atom, or

R4 and R5 together, if Y1 represents a carbon atom, represent a 4- to 7-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH- or -N(alkyl)- group and one or two additional methylene groups may be replaced with carbonyl groups,

while the hydrogen atom attached to the nitrogen atom within the above-mentioned R4 group can be replaced with a protective group,

R6 and R7, which may be the same or different, in both cases represent a hydrogen atom, a C1-3-alkyl or dialkylamino group or, if Y1 does not represent a nitrogen atom, a chlorine atom and

R8 and R9 can be the same or different, in both they denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group,

whereas, unless otherwise specified, all of the above alkyl and alkoxy groups as well as alkyl groups present within other specified groups contain 1 to 7 carbon atoms and may be straight or branched, while each methylene group may be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms,

all the aforementioned cycloalkyl groups as well as cycloalkyl groups present within other specified groups, unless otherwise stated, may contain 3 to 10 carbon atoms, while each methylene group may be substituted with up to 2 fluorine atoms,

all the above-mentioned aromatic and heteroaromatic groups can additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different and

protecting groups mentioned in the previous and subsequent definitions mean protecting groups known from peptide chemistry, in particular

phenylalkoxycarbonyl group with 1 to 3 carbon atoms in the alkoxy part possibly substituted in the phenyl nucleus with a halogen atom, with a nitro or phenyl group or with one or two methoxy groups,

for example, benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-biphenylyl-α,α-dimethyl -benzyloxycarbonyl or 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,

Alkoxycarbonyl group with a total of 1 to 5 carbon atoms in the alkyl part,

for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert.butyloxycarbonyl group,

allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group or

formyl, acetyl or trifluoroacetyl group.

Another form of the presented invention contains compounds of the general formula (I), where

A, U, V, W, X, R 2 and R 3 are defined as mentioned in the first embodiment above and

R1 denotes a mono- or di-unsaturated 5- to 7-membered aza, diaza, triaz or thiaz heterocyclic group,

in which the above-mentioned heterocyclic rings are connected through carbon or nitrogen atoms,

contain one or two carbonyl groups adjacent to the nitrogen atom,

may be substituted on the carbon atom with a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl group and

the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings can be connected to a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl ring or to a 1H-quinolin-2-one ring optionally substituted on a nitrogen atom with a methyl group,

while phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups contained in R1 as well as benzo-, pyrido- and diazino-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or trisubstituted with fluorine, chlorine, bromine or iodine atoms, with an alkyl, alkoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents can be the same or different,

while the aforementioned alkyl groups or alkyl groups contained in the aforementioned groups, unless otherwise specified, contain 1 to 7 carbon atoms and may be branched or unbranched, wherein each methylene group may be substituted with up to 2 fluoro atoms and each methyl group can be substituted with up to 3 fluorine atoms, i

the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, or with cyano or hydroxy groups and the substituents may be the same or different.

The third form of the presented invention contains compounds of the general formula (I), where

A, U, V, W, X, R 2 and R 3 are defined as mentioned in the first form i

R1 denotes a monounsaturated 5- to 7-membered diaza or triaz heterocyclic group,

while the above-mentioned heterocyclic rings are connected through nitrogen atoms,

contains a carbonyl group adjacent to a nitrogen atom and

can be additionally substituted on the carbon atom with a phenyl group,

and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings may be joined to a phenyl, thienyl or quinoline ring,

wherein the phenyl groups contained in R1 as well as the benzo-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or tri-substituted with fluorine, chlorine, bromine or iodine atoms, with methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents can be the same or different, but are more advantageously unsubstituted or monosubstituted with a fluorine, chlorine or bromine atom or with a methyl or methoxy group,

whereas, unless otherwise stated, the aforementioned alkyl groups or the alkyl groups contained in the other aforementioned groups contain 1 to 7 carbon atoms and may be straight or branched and the aforementioned aromatic and heteroaromatic groups may be additionally mono-, di- or tri-substituted with with fluorine, chlorine or bromine atoms or with cyano or hydroxy groups and the substituents can be the same or different.

The fourth form of the presented invention contains compounds of the general formula (I), where

A, U, V, W, X, R 2 and R 3 are defined as mentioned in the first form i

R1 denotes 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-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, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno [3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin- 1-yl, 4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl, 4-(2-oxo -1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2,4, 5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-1-yl or 4-(2-oxo-1,4-dihydro-2H-thieno[2,3 -d]pyrimidin-3-yl)-piperidin-1-yl group,

while the above-mentioned mono- and bicyclic heterocyclic rings in the carbon skeleton can additionally be monosubstituted with a methoxy group,

while the above mentioned aromatic and heteroaromatic groups can be additionally mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different.

The fifth form of the presented invention contains compounds of the general formula (I), where

A, U, V, W, X and R1 are defined as set forth in the first form i

R2 denotes a hydrogen atom or

a phenylmethyl group or a C2-7-alkyl group which can be substituted in position with phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4morpholinyl, [bis -(2-hydroxyethyl)]amino group

while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or trisubstituted on the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C13-alkyl, C1-3-alkylamino-C13alkyl or di-(C1-3-alkyl)-amino-C1- 3-alkyl groups and substituents can be the same or different,

R3 denotes a hydrogen atom or a C1-3-alkyl group,

while the C1-3-alkyl group may be linked to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 and the nitrogen atom to which it is attached, forming a 5- to 7-membered ring, or

R2 and R3 together with the involved nitrogen atom denote a group of the general formula

[image] , (II)

where

Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom,

q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or

q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2,

R4 denotes a hydrogen atom, amino, alkylamino, C36-cycloalkylamino, N-(C36-cycloalkyl)-alkylamino or dialkylamino, alkyl, trifluoromethyl, C3-6-cycloalkyl, dialkylamino-C2-7-alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkylsulfonyl, alkylsulfonylamino or N-(alkylsulfonyl)-alkylamino group,

or if Y1 does not denote a nitrogen atom, then it denotes a carboxy or dialkylaminomethyl group,

phenyl, phenyl-C13alkyl, pyridinyl or diazinyl group, each of which can be substituted by fluorine, chlorine or bromine atoms or by trifluoromethylcarbonyl, methyl or methoxy group,

saturated or mono- or polyunsaturated 4- to 7-membered azacycloalkyl group, 5- to 7-membered oxase, diaza or triazacycloalkyl group, 7- to 9-membered azabicyclo or diazabicycloalkyl group, 1-alkyl-4-piperidinylamino or 1-alkyl -4-piperidinylaminosulfonyl group,

while the above-mentioned mono- and bicyclic heterocyclic rings are connected through nitrogen or carbon atoms,

the methylene group of the above-mentioned mono- and bicyclic heterocyclic rings can be replaced by a carbonyl or sulfonyl group,

in the above-mentioned mono- and bicyclic heterocyclic rings, each methylene group that is not directly attached to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms,

The aforementioned mono- and bicyclic heterocyclic rings may be substituted with one or two C1-3-alkyl groups where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, and/or

with C3-6-cycloalkyl-C1-3-alkyl, benzyl, C1-4-alkanoyl, di-(C13-alkyl)-amino or C1-3-alkylsulfonyl, with an alkoxycarbonyl, benzyloxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,

R5 denotes a hydrogen atom, a C1-3-alkyl or alkoxycarbonyl group or

if Y1 denotes a nitrogen atom, it may also denote a pair of free electrons, or

R4 and R5 together, if Y1 represents a carbon atom, represent a 5- to 6-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH or -N(methyl) group and a further one or two methylene groups may be replaced by carbonyl groups,

R6 and R7, which may be the same or different, in each case denote a hydrogen atom or a C1-3-alkyl or di-(C1-3-alkyl)-amino group and

R8 and R9, which may be the same or different, in any case denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group,

whereas, unless otherwise indicated, all the aforementioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the aforementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different.

The sixth form of the presented invention contains compounds of the general formula (I), where

A, U, V, W, X and R1 are defined as set forth in the first form i

R2 denotes a phenylmethyl group or a C2-7-alkyl group which may be substituted at the ω position with a phenyl, amino, alkylamino or dialkylamino group,

while the aforementioned phenyl group may be substituted with an amino-C1-3-alkyl, C1-3-alkylamino-C13alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or

R3 denotes a hydrogen atom or a C1-3-alkyl group,

R2 and R3 together with the nitrogen atom to which they are attached denote 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl or 2-amino-4,5,7,8-tetrahydro-thiazolo[ 4,5-d]azepin-6-yl- group or

R 2 and R 3 together with the nitrogen atom that is contained in it denote a group of the general formula

[image] , (II)

where

Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom,

q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or

q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2,

R4 denotes a hydrogen atom,

phenyl, benzyl or pyridinyl group which in any case can be substituted with fluorine, chlorine or bromine atoms, with trifluoromethylcarbonyl, methyl or methoxy group,

hydroxy, carboxy, methyl, trifluoromethyl, n-propyl, phenyl, p-tolyl, p-trifluoromethylcarbonyl-phenyl, p(3dimethylaminopropyl)-phenyl, amino, benzyl, tert-butylamino, dimethylamino, diethylamino, diethylaminomethyl, 2-dimethylaminoethyl, 2 -diethylaminoethyl, 5-aminopentyl, methoxycarbonyl, methoxycarbonylmethyl, perhydro-azepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-1-piperidinyl-4-yl, 4-piperazine -1-yl, 4-acetyl-piperazin-1-yl, 4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl, 4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl , piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-1-piperidin-1-yl, 1-methyl-1-aza-bicyclo[3.2.1]oct-4 -yl or 4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl, 1-methyl-piperidin-1-yl, 4-carboxymethyl-piperazin-1-yl, 1-carboxymethyl-piperidin-4-yl , 4-benzyloxycarbonyl-piperazin-1-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, azetidin-1-yl, 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl, 1 -benzyl-piperidin-4-yl, 4-benzyl-piperazin-1-yl, 4-dimethylaminomethyl-1-phenyl, 2,2,2-tri phlorethyl-piperazin-1-yl, 1-methylsulfonyl-piperidin-4-yl, piperidin-1-yl-methyl, 1-methyl-piperidin-4-yl-amino, methylsulfonylamino, N-methylsulfonyl-N-methylamino, N- (cyclopentyl)-methylamino, 1,1-dioxo-λ6-isothiazolidin-2-yl, 2-oxo-perhydro-1,3-oxazin-3-yl, cyclohexyl, 2-oxo-imidazolidin-1-yl, 2- methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl, 4-thiazol-2-yl, 2,4-dimethyl-imidazol-1-yl, 4-imidazol-1-yl, 1,2, 4triazol-1-yl, 1-aza-bicyclo[2.2.2]oct-3-yl, 1-methyl-piperidin-4-yl-methylsulfonyl, 1H-imidazol-4-yl, 4-ethoxycarbonylmethyl-piperazin-1- yl, 1-ethoxycarbonyl-piperidin-4-yl, 4-tert-butoxycarbonylmethyl-piperazin-1-yl, 1-(2,2,2-trifluoroethyl)-piperidin-4-yl, 4-methylsulfonyl-piperazin-1- yl, 2-carboxy-4-methylpiperazin-1-yl, 3-carboxy-4-methyl-piperazin-1-yl, 2-ethoxycarbonyl-4-methyl-piperazin-1-yl, 3-ethoxycarbonyl-4-methyl- piperazin-1-yl or 4(2,2,2trifluoroethyl)-piperazin-1-yl- group,

R5 represents a hydrogen atom, a methyl group or, if Y1 represents a nitrogen atom, it may also represent a pair of free electrons, or

R4 and R5 together, if Y1 represents a carbon atom, represent a 1-methyl-piperidin-4-ylidene, cyclohexylidene or imidazolidin-2,4-dione-5-ylidene group,

R6 and R7 in each case denote a hydrogen atom or a dimethylamino group and

R8 and R9 in each case denote a hydrogen atom, carboxy or ethoxycarbonyl group,

while, unless otherwise noted, all the above-mentioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different,

while in all the forms mentioned above those compounds where

(i) A represents an oxygen atom, a cyanoimino or a phenylsulfonylimino group,

X denotes an oxygen atom, imino or methylene group,

U denotes an unbranched C1-6-alkyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms,

V denotes an amino or hydroxy group and

W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

are of utmost importance,

those compounds where

(ii) A denotes an oxygen atom,

X denotes an oxygen atom, imino or methylene group,

U denotes an ethyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms,

V denotes an amino or hydroxy group and

W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

are of particularly exceptional importance and

those compounds where

(iii) A denotes an oxygen atom,

X denotes an oxygen atom, imino or methylene group,

U denotes a trifluoromethyl or pentaflorethyl group,

V denotes an amino or hydroxy group and

W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

are of the most pronounced exceptional importance.

The seventh form of the presented invention contains compounds of the general formula (I), where

A denotes an oxygen atom, cyanoimino or phenylsulfonylimino group,

X denotes an oxygen atom, imino or methylene group,

U denotes an unbranched C1-6-alkyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms,

V denotes an amino or hydroxy group,

W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

R1 denotes a monounsaturated 5- to 7-membered diaza or triaz heterocyclic group,

while the above-mentioned heterocyclic rings are connected through nitrogen atoms,

contains a carbonyl group adjacent to a nitrogen atom and

can be additionally substituted on the carbon atom with a phenyl group,

and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings may be joined to a phenyl, thienyl or quinoline ring,

wherein the phenyl groups contained in R1 as well as the benzo-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or tri-substituted with fluorine, chlorine, bromine or iodine atoms, with methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents can be the same or different, but are more advantageously unsubstituted or monosubstituted with a fluorine, chlorine or bromine atom or with a methyl or methoxy group,

R2 denotes a hydrogen atom or

phenylmethyl group or C2-7-alkyl group which can be substituted in position ω with phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or [bis-(2-hydroxyethyl)]amino group,

while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or trisubstituted on the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl )-amino-C1-3-alkyl groups and the substituents can be the same or different,

R3 denotes a hydrogen atom or a C1-3-alkyl group,

while the C1-3-alkyl group may be linked to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 and the nitrogen atom to which it is attached, forming a 5- to 7-membered ring, or

R2 and R3 together with the involved nitrogen atom denote a group of the general formula

[image] , (II)

where

Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom,

q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or

q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2,

R4 denotes a hydrogen atom, hydroxy, amino, alkylamino, C3-6-cycloalkylamino, N-(C3-6-cycloalkyl)-alkylamino or dialkylamino, alkyl, trifluoromethyl, C3-6-cycloalkyl, dialkylamino-C2-7-alkyl, carboxyalkyl , alkoxycarbonylalkyl, alkylsulfonyl, alkylsulfonylamino or N-(alkylsulfonyl)-alkylamino group,

or, if Y1 does not represent a nitrogen atom, it represents a carboxy or dialkylaminomethyl group,

phenyl, phenyl-C1-3-alkyl, pyridinyl or diazinyl group, each of which can be substituted by fluorine, chlorine or bromine atoms or by trifluoromethylcarbonyl, methyl or methoxy group,

saturated or mono- or polyunsaturated 4- to 7-membered azacycloalkyl group, 5- to 7-membered oxase, diaza or triazacycloalkyl group, 7- to 9-membered azabicyclo or diazabicycloalkyl group, 1-alkyl-4-piperidinylamino or 1-alkyl -4-piperidinylaminosulfonyl group,

while the above-mentioned mono- and bicyclic heterocyclic rings are connected through nitrogen or carbon atoms,

the methylene group of the above-mentioned mono- and bicyclic heterocyclic rings can be replaced by a carbonyl or sulfonyl group,

in the above-mentioned mono- and bicyclic heterocyclic rings, each methylene group that is not directly attached to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms,

The aforementioned mono- and bicyclic heterocyclic rings may be substituted with one or two C1-3-alkyl groups where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, and/or

may be substituted with C3-6-cycloalkyl-C1-3-alkyl, benzyl, C1-4-alkanoyl, di-(C13-alkyl)-amino or C1-3-alkylsulfonyl, with alkoxycarbonyl, benzyloxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group,

R5 denotes a hydrogen atom, a C1-3-alkyl or alkoxycarbonyl group or

if Y1 denotes a nitrogen atom, it may also denote a pair of free electrons, or

R4 and R5 together, if Y1 represents a carbon atom, represent a 5- to 6-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH or -N(methyl) group and a further one or two methylene groups may be replaced by carbonyl groups,

R6 and R7, which may be the same or different, in each case denote a hydrogen atom or a C1-3-alkyl or di-(C1-3-alkyl)-amino group and

R8 and R9, which may be the same or different, in any case denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group,

whereas, unless otherwise indicated, all the aforementioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the aforementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different.

The eighth form of the presented invention contains compounds of the general formula (I), where

A denotes an oxygen atom,

X denotes an oxygen atom, imino or methylene group,

U denotes a methyl, ethyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms,

V denotes an amino or hydroxy group,

W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group,

R1 denotes 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-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, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno [3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin- 1-yl, 4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl, 4-(2-oxo -1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2,4, 5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-1-yl or 4-(2-oxo-1,4-dihydro-2H-thieno[2,3 -d]pyrimidin-3-yl)-piperidin-1-yl group,

while the above-mentioned mono- and bicyclic heterocyclic rings in the carbon skeleton can additionally be monosubstituted with a methoxy group,

R2 denotes a phenylmethyl group or a C2-7-alkyl group which can be substituted at position w with a phenyl, amino, alkylamino and dialkylamino group,

while the aforementioned phenyl group may be substituted with an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or

R3 denotes a hydrogen atom or a C1-3-alkyl group,

R2 and R3 together with the nitrogen atom to which they are attached denote 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl or 2-amino-4,5,7,8-tetrahydro-thiazolo[ 4,5-d]azepin-6-yl- group or

R 2 and R 3 together with the nitrogen atom that is contained in it denote a group of the general formula

[image] , (III)

where

Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom,

q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or

q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2,

R4 denotes a hydrogen atom,

a phenyl, benzyl, or pyridinyl group, each of which may be substituted with fluorine, chlorine, or bromine atoms or with a trifluoromethylcarbonyl, methyl, or methoxy group,

hydroxy, carboxy, methyl, trifluoromethyl, n-propyl, phenyl, p-tolyl, p-trifluoromethylcarbonyl-phenyl, p-(3-dimethylaminopropyl)-phenyl, amino, benzyl, tert-butylamino, dimethylamino, diethylamino, diethylaminomethyl, 2- dimethylaminoethyl, 2-diethylaminoethyl, 5-aminopentyl, methoxycarbonyl, methoxycarbonylmethyl, perhydro-azepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-1-piperidinyl-4-yl, 4-piperazin-1-yl, 4-acetyl-piperazin-1-yl, 4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl, 4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin- 1-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, 4,4difluoro-1-piperidin-1-yl, 1-methyl-1-aza-bicyclo[3.2.1]oct- 4-yl, 4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl, 1-methyl-piperidin-1-yl, 4-carboxymethyl-piperazin-1-yl, 1-carboxymethyl-piperidin-4- yl, 4-benzyloxycarbonyl-piperazin-1-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, azetidin-1-yl, 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl, 1-benzyl-piperidin-4-yl, 4-benzyl-piperazin-1-yl, 4-dimethylaminomethyl-1-phenyl, 2,2,2-trifluoro rethyl-piperazin-1-yl, 1-methylsulfonyl-piperidin-4-yl, piperidin-1-yl-methyl, 1-methyl-piperidin-4-yl-amino, methylsulfonylamino, N-methylsulfonyl-N-methylamino, N- (cyclopentyl)-methylamino, 1,1-dioxo-λ6-isothiazolidin-2-yl, 2-oxo-perhydro-1,3-oxazin-3-yl, cyclohexyl, 2-oxo-imidazolidin-1-yl, 2- methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl, 4-thiazol-2-yl, 2,4-dimethyl-imidazol-1-yl, 4-imidazol-1-yl, 1,2, 4triazol-1-yl, 1-aza-bicyclo[2.2.2]oct-3-yl, 1-methyl-piperidin-4-yl-methylsulfonyl, 1H-imidazol-4-yl, 4-ethoxycarbonylmethyl-piperazin-1- yl, 1-ethoxycarbonyl-piperidin-4-yl, 4-tert-butoxycarbonylmethyl-piperazin-1-yl, 1-(2,2,2-trifluoroethyl)-piperidin-4-yl, 4-methylsulfonyl-piperazin-1- yl, 2-carboxy-4-methyl-piperazin-1-yl, 3-carboxy-4-methyl-piperazin-1-yl, 2-ethoxycarbonyl-4-methyl-piperazin-1-yl, 3-ethoxycarbonyl-4- methyl-piperazin-1-yl or 4-(2,2,2trifluoroethyl)-piperazin-1-yl group,

R5 represents a hydrogen atom, a methyl group or, if Y1 represents a nitrogen atom, it may also represent a pair of free electrons, or

R4 and R5 together, if Y1 represents a carbon atom, represent a 1-methyl-piperidin-4-ylidene, cyclohexylidene or imidazolidin-2,4-dione-5-ylidene group,

R6 and R7 in each case denote a hydrogen atom or a dimethylamino group and

R8 and R9 in each case denote a hydrogen atom, carboxy or ethoxycarbonyl group,

while, unless otherwise noted, all the above-mentioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different,

The following compounds are mentioned as examples of particularly preferred compounds of the general formula (I):

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their enantiomers, diastereomers and salts, while compounds

(14) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(15) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-(4-azetidin-1-yl-piperidin-1-yl)-2-oxo-ethyl]-amide,

(16) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-2-oxo -ethyl}-amide,

(17) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide,

(18) [1'-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetic acid,

(19) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[1(4-amino-3-chloro-5 -trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide,

(20) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(21) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butane-1,4-dione,

(22) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(23) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(24) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(25) (S)-2-(4-amino-3-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(26) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-dimethylamino-piperidin-1yl)-4-[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(27) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(28) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(29) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(30) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-morpholin-4-yl-piperidin-1-yl)-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(31) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3benzodiazepine-3 -yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(32) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3yl)-piperidin-1-yl]-butane-1,4-dione,

(33) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-isopropyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1yl]-butane-1,4-dione,

(34) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(35) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepine- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(36) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(37) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(3-pyrrolidin-1-yl-azetidin-1-yl)-butane-1,4-dione,

(38) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(3-piperidin-1-yl-azetidin-1-yl)-butane-1,4-dione,

(39) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-azetidin-1-yl-piperidin-1-yl)-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(40) (S)-1-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(41) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-diethylaminomethyl-piperidin-1-yl)-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(42) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(43) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-ethyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(44) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(3,4,5,6-tetrahydro-2H-4,4'-bipyridinyl-1-yl)-butane-1,4-dione,

(45) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3benzodiazepine-3 -yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butan-1,4-dione,

(46) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(3-perhydro-azepin-1-yl-azetidin-1-yl)-butane-1,4-dione,

(47) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(48) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(49) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl) -4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(50) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-dimethylaminomethyl-phenyl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(51) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-{4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-piperidin-1-yl}-butan-1 ,4-dione,

(52) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methanesulfonyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(53) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(9-methyl-3,9-diaza-spiro[5.5]undec-3-yl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(54) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperidin-1-yl-methyl-piperidin-1-yl)-butane-1,4-dione,

(55) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-dimethylamino-ethyl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(56) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-methyl-N-[2-(1-methyl-piperidin-4-yl)-ethyl]-4 -oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(57) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-methyl-N-(1-methyl-piperidin-4-ylmethyl)-4-oxo-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(58) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(59) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(cyclopentyl-methyl-amino)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(60) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1,1-dioxo-1,6-isothiazolidin-2-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(61) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo-perhydro-1,3-oxazin-3-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(62) methyl 1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidine-4-carboxylate,

(63) 8-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5- tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-1,3,8-triaza-spiro[4.5]decane-2,4-dione,

(64) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo-imidazolidin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(65) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(66) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d] azepin-6-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4 -dion,

(67) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-methyl-imidazol-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(68) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-imidazol-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(69) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-thiazol-2-yl-piperazin-1-yl)-butane-1,4-dione,

(70) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2,4-dimethyl-imidazol-1-yl)-piperidin-1-yl] -4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(71) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-imidazol-1-yl-piperidin-1-yl)-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(72) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-1,2,4-triazol-1-yl-piperidin-1-yl)-butane-1,4-dione,

(73) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(74) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-(5-amino-pentyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(75) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-(3-aminomethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(76) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl) )-piperazin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butan-1 ,4-dione,

(77) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(78) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(79) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(80) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butane-1,4-dione,

(81) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(82) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(83) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2 -yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane -1,4-dione,

(84) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(85) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepine- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(86) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(87) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(88) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(89) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(90) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(91) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(92) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(93) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(94) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide,

(95) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide,

(96) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-(R)-1-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl ester,

(97) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(4-bromo-3-methyl-benzyl)-2-( 1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,

(98) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2-[ 4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(99) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2-[ 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(100) 2-(4-bromo-3-methyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(101) 1-[1,4']Bipiperidinyl-1'-yl-2-(4-bromo-3-methyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(102) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(4-chloro-3-methyl-benzyl)-2-[4 -(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(103) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-chloro-3-methyl-benzyl)-2-[ 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(104) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(4-chloro-3-methyl-benzyl)-2-( 1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,

(105) 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(106) 2-(4-chloro-3-methyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(107) 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(108) 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(109) 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(110) 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(111) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(3-bromo-4-chloro-5-methyl-benzyl)- 2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(112) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(3-bromo-4-chloro-5-methyl-benzyl) -2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(113) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(3-bromo-4-chloro-5-methyl-benzyl) -2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,

(114) 2-(4-chloro-3-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

their enantiomers, diastereomers and salts of particular importance, and compounds

(1) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1yl]-butane-1,4-dione,

(2) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(3) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(4) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(5) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butan-1,4-dione,

(6) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide,

(7) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-amide,

(8) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide,

(9) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,

(10) ethyl [1'-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5- tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetate,

(11) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(12) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(13) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-(4-azetidin-1-yl-piperidin-1-yl)-2-oxo-ethyl]-amide,

(14) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-2-oxo -ethyl}-amide,

(15) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide,

(16) [1'-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetic acid,

(17) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[1(4-amino-3-chloro-5 -trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide,

(18) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(19) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butane-1,4-dione,

(20) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(21) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(22) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(23) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(24) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(25) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(26) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3benzodiazepine-3 -yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(27) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3yl)-piperidin-1-yl]-butane-1,4-dione,

(28) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(29) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepine- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(30) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(31) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-azetidin-1-yl-piperidin-1-yl)-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(32) (S)-1-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(33) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-diethylaminomethyl-piperidin-1-yl)-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(34) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(35) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-ethyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(36) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(3,4,5,6-tetrahydro-2H-4,4'-bipyridinyl-1-yl)-butane-1,4-dione,

(37) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3benzodiazepine-3 -yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butan-1,4-dione,

(38) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(39) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methanesulfonyl-4,4'-bipiperidinyl-1-yl)-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(40) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(9-methyl-3,9-diaza-spiro[5.5]undec-3-yl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(41) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperidin-1-yl-methyl-piperidin-1-yl)-butane-1,4-dione,

(42) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-dimethylamino-ethyl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(43) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-methyl-N-[2-(1-methyl-piperidin-4-yl)-ethyl]-4 -oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(44) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-methyl-N-(1-methyl-piperidin-4-ylmethyl)-4-oxo-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide,

(45) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-4-[4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(46) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo-perhydro-1,3-oxazin-3-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(47) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo-imidazolidin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(48) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(49) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-methyl-imidazol-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(50) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-imidazol-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(51) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2,4-dimethyl-imidazol-1-yl)-piperidin-1-yl] -4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(52) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-imidazol-1-yl-piperidin-1-yl)-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(53) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-1,2,4-triazol-1-yl-piperidin-1-yl)-butane-1,4-dione,

(54) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(55) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl )-piperazin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butan-1 ,4-dione,

(56) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(57) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(58) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(59) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butane-1,4-dione,

(60) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(61) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(62) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2 -yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane -1,4-dione,

(63) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(64) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepine- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(65) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(66) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione ,

(67) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(68) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(69) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione,

(70) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione,

(71) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(72) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(73) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide,

(74) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino- 3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide,

(75) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-(R)-1-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl ester,

(76) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(4-bromo-3-methyl-benzyl)-2-( 1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide,

(77) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2-[ 4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(78) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2-[ 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(79) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(4-chloro-3-methyl-benzyl)-2-[4 -(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(80) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-chloro-3-methyl-benzyl)-2-[ 4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

(81) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(3-bromo-4-chloro-5-methyl-benzyl)- 2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide,

(82) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(3-bromo-4-chloro-5-methyl-benzyl) -2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide,

their enantiomers, stereomers and salts are of utmost importance.

Compounds of the general formula (I) are also prepared by otherwise known procedures. The following procedures proved to be particularly satisfactory in the preparation of compounds of the general formula (I) according to the invention:

(a) In order to prepare compounds of the general formula (I) where X represents an oxygen atom or an NH group and R1 to R3 are as already defined, provided that these groups R2 and R3 do not contain the action of any free carboxylic acids:

Reactive piperidines of the general formula

[image] , (III)

where R1 is as previously defined herein,

(i) with carbonic acid derivatives of the general formula

[image] , (IV)

where A is as hereinbefore defined and G denotes a nucleofuge group, preferably a phenoxy, 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy or 2,5-dioxopyrrolidin-1-yloxy group, provided that X represents an NH group, or

(ii) with carbonic acid derivatives of the general formula

[image] , (IV)

where denotes an oxygen atom and G denotes a nucleofuge group which may be the same or different, preferably a chlorine atom or a p-nitrophenoxy or trichloromethoxy group, provided that X denotes an oxygen atom,

and with compounds of the general formula

[image] , (V)

where X represents an oxygen atom or an .NH group and U, V, W, R 2 and R 3 are as previously defined, provided that R 2 and R 3 do not contain any free carboxylic acids and/or any other free primary or secondary aliphatic amino effect or any other free hydroxy effect.

The basic two-step reaction is normally carried out as a one-pot procedure, in which, preferably, in the first step, one of the two components (III) or (V) is reacted with equimolar amounts of a carbonic acid derivative of the general formula (IV) in a suitable solvent at a lower temperature, then finally equimolar amounts of the second component (II) or (V) are added and the reaction is completed at high temperature. Reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonate) of a tertiary base, for example, triethylamine, N-ethyldiisopropylamine, pyridine, 1,5-diaza-bicyclo- [4.3.0]-non-5-ene, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[5.4.0]-undec-7-ene. The solvents used, which should be anhydrous, can be, for example, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, while if bis-(trichloromethyl)- carbonate using as the carbonyl component anhydrous chlorohydrocarbons, for example dichloromethane, 1,2dichloroethane or trichlorethylenes are preferred. Temperatures for the first step of the reaction are between -30°C and +25°C, preferably -5°C and +10°C, and for the second step between +15°C and the boiling temperature of the solvent used, preferably between +20°C and +70°C (see also: H. A. Staab and W. Rohr, "Synthesen mit heterocyclischen Amidn (Azoliden)", Neuere Methoden der Präparativen Organischen Chemie, Volume V, p. 53-93, Verlag Chemie, Weinheim/Bergstr., 1967 ; P. Majer and R. S. Randad, J. Org. Chem. 59, pp. 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, Tetrahedron Letters 24 (42 ), 4569-4572 (1983)); S.R. Sandler and W. Karo in "Organic Functional Group Preparations", Vol. II, S. 223-245, Academis Press, New York 1971).

(b) In order to prepare compounds of general formula (I) where X denotes a methylene group and R1 to R3 are as previously defined, provided that these groups do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects :

Coupling of a carboxylic acid of the general formula

[image] , (VI)

where U, V, W, R2 and R3 are as previously defined, with piperidine of the general formula

[image] , (III)

where R1 has the meaning given above.

Coupling is preferably carried out using procedures known in peptide chemistry (see e.g. HoubenWeyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as dicyclohexylcarbodiimides (DCC), diisopropyl carbodiimides (DIC) or ethyl-(3dimethylaminopropyl )-carbodiimides, O-(1Hbenzotriazol-1-yl)- N,NN',N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction can be accelerated. Coupling is normally carried out with equimolar amounts of coupling substances and reagents in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and +30°C, preferably -20 and +25°C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig's base) is preferably used as an additional auxiliary base.

The so-called anhydrous process is used as a subsequent coupling method for the synthesis of compounds of general formula (I) (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, p. 5859; M. Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pp. 21-27). Vaughan's variant of the mixed anhydrous process (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)) is preferred, in which mixed carboxylic acid anhydrides of the general formula (VI) which will be combined and monoisobutyl carbonate are obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and coupling with amines is carried out by the "one-pot" process, using the above-mentioned solvents and at temperatures between -20 and +25°C, preferably 0°C and +25°C.

(c) In order to prepare compounds of general formula (I) where X represents a methylene group and R 2 and R 3 are as previously defined, provided that these groups do not contain any free primary or secondary amines:

joining of compounds of the general formula

[image] , (VII)

where U, V, W, R 2 and R 3 are as previously defined, provided that R 2 and R 3 do not contain any free primary or secondary amines, and Nu denotes a leaving group, for example a halogen atom, such as chlorine, bromine or iodine, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl part, a phenylsulfonyloxy or naphthylsulfonyloxy group possibly mono-, di- or trisubstituted with chlorine or bromine atoms or with methyl or nitro groups, whereby the substituents may be the same or different, 1H-imidazole -1-yl, and 1H-pyrazol-1-yl possibly substituted with one or two methyl groups on the carbon skeleton, 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 or pyridinyl, dimethylaminyloxy, 2(1H)- oxopyridin-1-yl-oxy, 2,5dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo-triazol-1-yloxy or azide group,

with piperidine of the general formula

[image] , (III)

where R1 is as previously defined.

The reaction is carried out under SchottenBaumann or Einhorn conditions, ie the ingredients react in the presence of at least one equivalent of auxiliary base at temperatures between -50°C and +120°C, preferably -10°C and +30°C, and possibly in the presence of a solvent. The auxiliary bases we use are preferably alkali metals and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate , as well as tertiary amines, e.g. pyridine, 2,4,6trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicyclo[ 5.4.0]undec-7-ene, the solvents we use can be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or their mixtures, if alkalis are used metals or alkaline earth metal hydroxides, carbonates or acetates of alkali metals as auxiliary bases, water can also be added to the reaction mixture as a co-solvent.

(d) In order to prepare the compounds of general formula (I) as defined above:

Coupling of a carboxylic acid of the general formula

[image] , (VIII)

where all groups are as previously defined, with an amine of the general formula HNR2R3, where R2 and R3 are as previously defined, provided that they do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects.

Coupling is preferably carried out using procedures known in peptide chemistry (see e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)- N,N-N',N'-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl -oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction can be accelerated. The coupling is normally carried out with equimolar amounts of the reactants as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at a temperature between -30 and +30°C, preferably -20 and +25°C. If necessary, it is preferable to use N-ethyl-diisopropylamine (DIEA) (Hünig's base) as an additional auxiliary base.

The so-called anhydrous process is used as a subsequent coupling method for the synthesis of compounds of general formula (I) (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, p. 5859; M. Bodanszky, "Principles of Peptide Synthesis", Springer Verlag 1984, p. 2127). Vaughan's variant of the mixed anhydrous process (J.R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)) is preferred, in which mixed carboxylic acid anhydrides of the general formula (VI) which will be combined and monoisobutyl carbonate are obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and coupling with amines is carried out by the "one-pot" process, using the above-mentioned solvents and at temperatures between -20 and +25°C, preferably 0°C and +25°C.

(e) In order to prepare compounds of general formula (I) where R 1 is as previously defined, provided that there are no free primary or secondary amines:

Compound compound of the general formula

[image] , (IX)

where all groups are as previously defined and Nu denotes a leaving group, for example a halogen atom, such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl part, a phenylsulfonyloxy or naphthylsulfonyloxy group, possibly mono-, di- or trisubstituted with chlorine or bromine atoms or with methyl or nitro groups, whereby the substituents can be the same or different, 1H-imidazol-1-yl, and 1H-pyrazol-1-yl possibly substituted with one or two methyl groups on the carbon skeleton , 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 or pyridinyl, dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo- triazol-1-yloxy or azide group,

with an amine of the general formula HNR2R3, where R2 and R3 are as previously defined, provided that they do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects.

The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the ingredients react in the presence of at least one equivalent of auxiliary base at temperatures between -50°C and +120°C, preferably -10°C and +30°C, and possibly in the presence solvents. The auxiliary bases we use are preferably alkali metals and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate , as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2.2.2]octane or 1,8- diazabicyclo[5.4.0]undec-7-ene, the solvents we use can be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or their mixtures, if alkali metals or alkaline earth metal hydroxides, carbonates or acetates of alkali metals are used as auxiliary bases, water can also be added to the reaction mixture as a co-solvent.

The new compound of general formula (I) according to the invention contains one or more chiral centers. If, for example, there are two chiral centers, the compound can appear in the form of two pairs of diastereomeric antipodes. The invention covers the individual isomers as well as their mixtures.

Diastereomers can be separated based on their different physicochemical properties, eg by fractional crystallization from appropriate solvents, high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.

The racemates covered by the general formula (I) can be separated for example by HPLC on suitable chiral stationary phases (eg Chiral AGP, Chiralpak AD). Racemates that have basic or chiline effects can also be resolved by diastereomeric, optically active salts formed by reaction with an optically active acid, for example (+) or (-)-tartaric acid, (+) or (-)-diacetyl tartaric acid , (+) or (-)-monomethyl tartrate or (+) or (-)-camphorsulfonic acid, or with an optically active base, for example (R)-(+)-1-phenylethylamine, (S)-(-) -1-phenylethylamine or (S)-brucine.

According to the conventional isomer separation method, the racemates of the general formula (I) are reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and their resulting crystalline, diastereomeric, optically active salts are separated using their different solubilities. The reaction can be carried out in any type of solvent, if it is sufficiently different in terms of the solubility of the salt. Methanol, ethanol or their mixture are preferably used, for example in a volume ratio of 50:50. Each of the optically active salts is then dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulfonic acid, and in this way the corresponding free compound is obtained in ( +) or (-) form.

The (R) or (S) enantiomers alone or a mixture of two optically active diastereomeric compounds covered by the general formula (I) can also be obtained by carrying out the synthesis described above with the appropriate reaction ingredients in the (R) or (S) configuration.

The starting compounds of the general formula (III) can be obtained, if not known from the literature or if they are not commercially available, according to the process described in WO 98/11128 and DE 199 52 146. The starting compounds of the general formula (IV) are commercially available. Compounds of the general formula (V) can be obtained by methods known to a chemist dealing with peptides from protected phenylalanines and amines of the general formula HNR2R3.

The phenylalanine derivatives required to prepare the optically pure compound of the general formula (V) can be prepared from the compound of the general formula

[image] , (X)

where U, V and W are as previously defined and R denotes an unbranched alkyl group, preferably a methyl or ethyl group, by racemate cleavage.

Racemate resolution can be carried out using enzymatic procedures, whereby only one enantiomer of the racemate is transformed and the resulting mixture is then separated using physicochemical procedures, preferably using chromatographic procedures. A suitable enzyme system for this step contains the enzyme Alkalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd). Compounds of general formula (X) can then be converted to enantiomerically pure compounds of general formula (V) by methods known to the peptide chemist.

If the group X in the compounds of the general formula (V) denotes an oxygen atom, the hydroxycarboxylic acid required for the synthesis of the general formula

[image] , (XI)

where U, V and W are as previously defined,

can be prepared from compounds of the general formula (X), provided that R represents a hydrogen atom.

Provided that V does not denote an amino or methylamino group, compounds of general formula (XI) can be obtained by diazotizing compounds of general formula (X) with a suitable diazotizing reagent, preferably sodium nitrite in an acidic medium. If enantiomerically pure compounds are used, the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, and the configuration is maintained during the reaction.

Another process for obtaining compounds of general formula (XI) where U, V and W are as previously defined involves alkylation of the compound

[image] , (XII)

with appropriately substituted benzyl chlorides, benzyl bromides or benzyl iodides of the general formula (XIII)

[image] , (XIII)

where U, V and W are as previously defined and X denotes a chlorine, bromine or iodine atom, analogous to procedures known in the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165 -2167 [2000]).

The diastereomeric products that are obtained can then be separated by physicochemical procedures, preferably using chromatography procedures. Hydrolytic cleavage of chiral assistants, coupling with amines of the general formula HNR2R3 and cleavage of the penzil protecting group also provides access to enantiomerically pure hydroxycarboxylic acid compounds of the general formula (V).

The starting compounds of the general formula (VI) are obtained, for example, by the reaction of the amine of the general formula HNR2R3 with 2-(Alkoxycarbonylmethyl)-3-aryl-propanonic acid and then by hydrolytic cleavage of the alkyl group. The required 2-(Alkoxycarbonylmethyl)-3-aryl-propanonic acid can be prepared analogously to procedures known from the literature (David A. Evans, Leester D. Wu, John J. M. Wiener, Jeffrey S. Johnson, David H. B. Ripin and Jason S. Tedrow, J. Org.Chem 64, 6411-6417 [1999]; Saul G. Cohen and Aleksander Milovanovic, J. Am. Chem. Soc. 90, 3495-3502 [1968]; Hiroyuki Kawano, Youichi Ishii, Takao Ikariya, Masahiko Saburi , Sadao Yoshikawa, Yasuzo Uchida and Hidenori Kumobayashi, Tetrahedron Letters 28, 1905-1908 [1987]). Carboxylic acids of general formula (VIII) can be prepared from commonly available starting materials according to the procedure described in WO 98/11128.

If they have suitable basic effects, the obtained compounds of general formula (I) can be converted, especially for pharmaceutical use, into their physiologically acceptable salts with inorganic and organic acids. Suitable acids include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, maloic acid, citric acid, tartaric acid or maleic acid.

Moreover, the new compounds of formula (I), if they have a carboxylic acid effect, can be, if necessary, converted into their additional salts with inorganic and organic bases into their physiologically acceptable salts, especially for pharmaceutical use. Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The presented invention relates to racemates if the compounds of the general formula (I) have only one chiral element. However, the applications also include individual diasteremeric pairs of antipodes or their mixtures obtained if there is more than one chiral element in the compounds of general formula (I), as well as individual optically active enantiomers of which the above-mentioned racemates are composed.

Also included in this invention are the compounds according to the invention and their salts, in which one or more hydrogen atoms are replaced by deuterium.

New compounds of the general formula (I) and their physiologically acceptable salts have valuable pharmacological properties, based on their property of selective CGPR-antagonists. Furthermore, the invention relates to pharmaceutical preparations containing these compounds, their use and preparation.

New compounds of the general formula (I) and their physiologically acceptable salts have CGPR-antagonist properties and show good affinity in binding studies to the CGRP receptor. The compounds show CGPR-antagonist properties in pharmacological test systems that will be described later.

The following experiments were performed to demonstrate the affinity of the above-mentioned compounds for human CGRO receptors and their antagonistic properties:

A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor)

_________________________________________________________________________________________________

SK-N-MC cells were cultured in "Dulbecco's modified Eagle medium". The medium was removed from the confluent cultures. Cells were washed twice with PBS buffer (Gibco 041-04190 M), separated by addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml "Balanced Salts Solution" [BSS (in mM): NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, Dglucose 5.5, HEPES 30, pH 7.40] cells were centrifuged twice at 100 x g and resuspended in BSS. After the cell number was determined, the cells were homogenized using an Ultra-Turrax and centrifuged for 10 min at 3000 x g. The supernatant was discarded and the pellet was centrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1% bacitracin, and resuspended (1 ml/ 1000000 cells). The homogenized product is frozen at -80°C. Under these conditions, the membrane preparations are stable for more than 6 weeks.

After dissolution, the homogenized product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with Ultra-Turrax. 230 µl of the homogenized product is incubated for 180 minutes at room temperature with 50 pM 125I-iodotyrosyl-Calcitonin-Gene-Linked Peptide (Amersham) and increasing concentrations of the test substance in a total volume of 250 µl. Incubation is terminated by rapid filtration through GF/B glass fibers treated with polyethyleneimine (0.1%) using a cell harvester. Protein-bound radioactivity is measured with a gamma counter. Non-specific binding is defined as bound radioactivity in the presence of CGRP-alpha during incubation.

Concentration and binding curves are analyzed using computer-aided nonlinear curve comparison.

The compounds mentioned previously show IC50 values of 10000 nM in the described test.

B. CGRP antagonism in SK-N-MC cells

________________________________________________________________________________________________

SK-N-MC cells (1 million cells) are washed twice with 250 µl incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and preincubated for 15 minutes at 37 °C.. After addition of CGRP (10 µl) as an agonist in increasing concentrations (10-11 to 10-6 M), or additional substance in 3 to 4 different concentrations, the mixture is incubated for a further 15 minutes.

Intracellular cAMP was then extracted by adding 20 µl 1M HCl and centrifugation (2000 x g, 4°C, 15 minutes). The supernatant is frozen in liquid nitrogen and stored at -20°C.

The content of cAMPa in the samples is determined using a radioimmunoassay (Messrs. Amersham) and the pA2 values of substances that act antagonistically are determined graphically.

The compound of general formula I shows CGRP-antagonistic properties in the in vitro test model described, at doses between 1012 and 105 M.

With regard to their pharmacological properties, the compounds of general formula I and their salts with physiologically acceptable acids are therefore suitable for the acute treatment and prophylaxis of headaches, especially migraine or cluster headaches, tension headaches and chronic headaches. The compounds according to the invention are also suitable for the prevention of migraine in the prodromal stage or for the prevention and treatment of migraine occurring before or during menstruation.

Moreover, the compounds of general formula I also have a positive effect on the following diseases: non-insulin dependent diabetes mellitus ("NIDDM"), cardiovascular diseases, morphine tolerance, diarrhea caused by clostridial toxin, skin diseases, especially thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases threatened by excessive vasodilatation and consequent reduced tissue blood supply, e.g. shock and sepsis or erythema. In addition, the compounds according to the invention have a general pain-reducing effect, especially in cases of neuropathic pain, such as in complicated regional pain syndrome (CRPS), in neuropathic pain in systemic neurotoxic diseases such as diabetes mellitus, and in pain caused by an inflammatory process. CGRP-antagonists of the presented application have a positive effect as prevention and acute treatment on symptoms of menopausal hot flashes caused by vasodilation and symptoms due to increased blood flow in women with estrogen deficiency and in patients with prostate cancer treated with hormonal therapy, whereby this therapeutic approach differs from hormonal therapy replacement therapy because it has no side effects.

The dose required to achieve an adequate effect is suitably 0.0001 to 3 mg/kg body weight, more preferably 0.01 to 1 mg/kg body weight, when administered intravenously or subcutaneously and 0.01 to 10 mg/kg body weight , preferably 0.1 to 10 mg/kg of body weight when administered by washing, nasal or inhalation, 1 to 3 times a day in any case.

If therapy with CGRP antagonists and/or release inhibitors is given as an adjunct to conventional hormone replacement therapy, it is recommended that the above doses be reduced, and then the dose may be from 1/5 of the lowest dose mentioned above to 1/1 of the highest dose mentioned above.

The compounds prepared according to the invention can be administered either alone or in combination with other active substances for the treatment of migraine, intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, with aerosol forms being particularly suitable for inhalation. Combinations can be given simultaneously or separately.

Categories of active substances that can be used in combination include, for example, antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine-H1 receptor antagonists, antimuscarinic substances, -blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics , non-steroidal anti-inflammatory drugs, corticosteroids, calcium antagonists, 5-HT1B/1D agonists or other anti-migraine substances, which may be formulated together with one or more conventionally known carriers and/or diluents, eg corn starch, lactose, glucose , microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as fat or its suitable mixtures into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, aerosol doses or and suppositories.

Other substances mentioned above which can be used for combinations include for example the non-steroidal anti-inflammatory drugs aceclofenac, acemethacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen , phenylbutazone, piroxicam, sulfasalazine, zomepirak or their pharmaceutically acceptable salts as well as meloxicam and other selective COX2-inhibitors, such as for example rofecoxib and celecoxib.

It is also possible to use ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochlorperazine, dexamethasone, flunarizine, dextropropoxypene, meperidine. , metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitriptyline, lidocaine or diltiazem and other 5-HT1B/1D-agonists such as almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.

The recommended dose of these active substances is 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.

The invention further relates to the use of the compounds according to the invention as valuable adjuncts for the production and purification (using affinity chromatography) of antibodies as well as in RIA and ELISA analyses, after suitable radiolabelling, with for example tritiation of suitable precursors, for example with catalytic hydrogenation with tritium or replacing halogens tritium atom, and as a diagnostic or analytical supplement to neurotransmitter research.

Experimental part

As a rule, IR, 1H-NMR and/or mass spectra were obtained for the prepared compounds. Unless otherwise indicated, Rf values were obtained using ready-made silica-gel TLC plates 60 F254 (E. Merck, Darmstadt, article no. 1.05714) without saturating the cells. Rf values obtained under the name Alox were obtained using ready-made aluminum oxide TLC plates 60 F254 (E. Merck, Darmstadt, article no. 1.05713) without saturating the cells. Ratios given for dilutions refer to units per volume of solvent in question. The units per volume given for NH3 are based on a concentrated solution of NH3 in water.

Unless otherwise indicated, the acids, bases, and salt solutions used to promote the reaction solutions are aqueous solutions of specific concentrations.

For chromatographic purification, silica gel made by Millipore (MATREXTM, 35-70 μm) was used. Alox (E. Merck, Darmstadt, standardized aluminum oxide 90, 63-200 µm, Article no. 1.01097.9050) is used for chromatographic purification.

The HPLC data provided were measured using the parameters described below: Analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond) - C18; 3.5 µm; 4.6 x 75 mm; column temperature: 30°C; flow rate: 0.8 mL/min; injected volume: 5 µL; detection at 254 nm

Procedure A:

[image]

As a rule, the same gradients are used in preparative HPLC purifications as were used to obtain analytical HPLC data.

The products are collected under mass control and the product-containing fractions are collected and freeze-dried under vacuum.

If no detailed configuration information is given, it is not clear whether this is the pure enantiomer or whether partial or complete racemization has occurred.

The following abbreviations are used in the description of the experiments:

abs. absolute

Boc tert.-butoxycarbonyl

CDI N,N'-carbonyldiimidazole

CDT 1,1'-carbonyldi-(1,2,4-triazole)

Cyc cyclohexane

DCM dichloromethane

DMF N,N-dimethylformamide

EtOAc ethyl acetate

EtOH ethanol

semiconc. partially concentrated

HCl hydrochloric acid

HOAc acetic acid

HOBt 1-hydroxybenzotriazole hydrate

i. vac. in vacuo

KOH potassium hydroxide

conc. concentrated

MeOH methanol

NaCl sodium chloride

NaOH sodium hydroxide

org. organic

PE ether petroleum

RT room temperature (eng. room temperature)

TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

TFA trifluoroacetic acid

THF tetrahydrofuran

Instructions for the preparation of the amines we use (starting compounds)

Example A1

2-methyl-5-piperidin-4-yl-2,5-diaza-bicyclo[2.2.1]heptane (Examples 7.9 and 10.79)

[image]

A1a 2-(1-benzyl-piperidin-4-yl)-5-methyl-2,5-diaza-bicyclo[2.2.1]heptane

0.73 mL (12.7 mmol) of acetic acid was added to a solution of 2.38 mL (12.7 mmol) of 1-benzyl-piperidin-4-one and 3.5 g (12.77 mmol) of 2-methyl-2 ,5-diaza-bicyclo[2.2.1]heptane in 100 mL MeOH and the reaction mixture was stirred for 3 hours at RT. 0.99 g (15.0 mmol) of NaBH 3 CN was added under a stream of nitrogen and the reaction mixture was stirred overnight at RT. It is acidified with 7 mL conc. HCl, stirred for 1 hour at RT and evaporated i.vac. The residue was mixed with 200 mL of 15% K2CO3 solution, extracted twice with 200 mL of DCM both times and the combined organic phases were dried over Na2SO4. After the dried part and the solvent were eliminated, the residue was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:85:5).

Product: 2.1 g (58% of theory)

ESI-MS: (M+H)+ = 286

Rf = 0.15 (silica gel, DCM/MeOH/NH3 80:20:2)

A1b 2-methyl-5-piperidin-4-yl-2,5-diaza-bicyclo[2.2.1]heptane

A solution of 2.1 g (7.36 mmol) of 2-(1-benzyl-piperidin-4-yl)-5-methyl-2,5-diaza-bicyclo[2.2.1]heptane in 100 mL of MeOH together with 500 mg 10% Pd/C and hydrogenated at RT and 50 psi H2 for 3 hours. The catalyst was suction filtered and the solvent was eliminated by i.vac. The product was used in further reactions without being purified.

Product: 1.4 g (97% of theory)

ESI-MS: (M+H)+ = 196

Rf = 0.10 (silica gel, DCM/MeOH/NH3 80:20:2)

Example A2

1-cyclopropylmethyl-4-piperidin-4-yl-piperazine (Example 10.4)

[image]

A2a tert. butyl 4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-carboxylate

1.26 g (20.0 mmol) of NaBH3CN was added in 4 batches at RT to a solution of 1.71 g (5.0 mmol) of tert. butyl 4-piperazin-1-yl-piperidine-1-carboxylate and 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde in 100 mL EtOH and the reaction mixture was stirred overnight at RT. The mixture is evaporated i.vac., the residue is taken up in saturated NaHCO3 solution, it is exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After eliminating the dried substance and the solvent, the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:0.5).

Product: 1.36 g (84% of theory)

EI: (M)+ = 323

A2b 1-cyclopropylmethyl-4-piperidin-4-yl-piperazine

5 mL of TFA was added to a solution of 1.36 g (4.2 mmol) of tert. of butyl 4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidine-1-carboxylate in 30 mL of DCM and the reaction mixture was stirred for 4 hours at RT. The reaction solution is evaporated i.vac., and the residue is mixed with diethyl ether, and the precipitate is suction filtered and dried. The product is precipitated as the tris-trifluorooctene salt.

Product: 1.86 g (78% of theory)

EI: (M)+ = 223

Example A3

4-azetidin-1-yl-piperidine (Example 10.15)

[image]

A3a 4-azetidin-1-yl-1-benzyl-piperidine

1.0 mL (17.49 mmol) of acetic acid was added to a solution of 3.0 mL (16.45 mmol) of 1-benzyl-piperidin-4-one and 1.0 g (17.51 mmol) of azetidine in 100 mL of DCM and the reaction mixture is stirred for 1 hour at RT. Within 1 hour, add 6.0 g (39.55 mmol) of NaBH(OAc)3 in 4 batches

while cooling with ice and stirring the reaction mixture overnight at RT. A solution of 15% K2CO3 is added and stirring is continued for another hour. 200 mL EtOAc is added, the organic phase is separated and dried over MgSO4. After the dried substance and the solvent have been eliminated, the residue is purified by chromatography (silica gel, gradient: DCM to MeOH/NH3 9:1).

Product: 3.2 g (84% of theory)

EI: (M)+ = 230

Rf = 0.57 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A3b 4-azetidin-1-yl-piperidine

A solution of 3.2 g (13.89 mmol) of 4-azetidin-1-yl-1-benzyl-piperidine in 50 mL of MeOH was combined with 500 mg of 10% Pd/C and hydrogenated for 7.5 h at RT and 3 bar H2 . The catalyst is suction filtered and the solvent is eliminated i.vac. The product is used in further reactions without purification.

Product: 1.9 g (98% of theory)

ESI-MS: (M+H)+ = 141

Rf = 0.19 (silica gel, DCM/MeOH/NH3 70:25:5)

Example A4

1-azetidin-3-yl-perhydro-azepine (Example 10.22)

[image]

A4a 1-(1-Benzhydryl-azetidin-3-yl)-perhydro-azepine

In a nitrogen atmosphere, 31.7 g (320 mmol) of perhydroazepine was added to a solution of 31.7 g (100 mmol) of 1,1-dibenzyl-azetidin-3-yl methanesulfonate in 200 mL of DMF and the reaction mixture was stirred for 7 days at 50 °C. The reaction solution is mixed with 1 L of water, the aqueous phase is extracted twice with EtOAc, the combined organic phases are washed twice and dried over Na2SO4. After the dried substance and the solvent have been eliminated, the residue is purified twice by chromatography (silica gel, first column: DCM/MeOH/NH3 19:1:0.025 and second column: tert-butylmethylether).

Product: 22.2 g (69% of theory)

Rf = 0.82 (silica gel, DCM/MeOH/NH3 19:1:0.025)

A4b 1-azetidin-3-yl-perhydro-azepine

5 g of 10% Pd/C was added to a solution of 22.0 g (68.6 mmol) of 1-(1-benzhydryl-azetidin-3-yl)-perhydro-azepine in 400 mL of MeOH and 69 mL of 2 N HCl and the reaction was the mixture is hydrogenated for 3 hours at 45°C until the theoretical acceptance of H2 is reached. After filtration, the solvent is eliminated by i.vac. and the product, which is obtained as bis-hydrochloride, is used further without purification.

Product: 15.5 g (100% theoretical)

melting point: 205-220°C

Rf = 0.08 (silica gel, DCM/MeOH/NH3 9:1:0.1)

Example A5

1-benzyl-4-piperidin-4-yl-piperazine (Example 10.24)

[image]

A5a tert. butyl 4-(4-benzyl-piperazin-1-yl)-piperidine-1-carboxylate

A solution of 66.7 mL (381 mmol) of 1-benzyl-piperazine and 75.8 g (380 mmol) of tert. butyl 4-oxo-piperidine-1-carboxylate in 1 L THF was adjusted to pH 5 with glacial acetic acid and then 100 g (448 mmol) of NaBH(OAc)3 was added in series over 2 h while cooling with ice and the reaction mixture was stirred overnight at RT. The reaction mixture was carefully basified with 2.2 M K2CO3 solution, stirred for 1 hour, extracted generously with EtOAc and the combined organic phases were dried over Na2SO4. After the dried substance and solvent were eliminated, the residue was further used without purification.

Product: 114 g (83% of theory)

ESI-MS: (M+Na) + = 382

Rf = 0.74 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A5b 1-Benzyl-4-piperidin-4-yl-piperazine

20 mL of TFA was added to a solution of 5 g (13.91 mmol) of tert. of butyl 4-(4-benzyl-piperazin-1-yl)-piperidine-1-carboxylate in 200 mL DCM and the reaction mixture was stirred overnight at RT. The reaction mixture is evaporated i.vac., the residue is mixed with 200 mL of 15% K2CO3 solution, extracted 3 times with 100 mL of DCM and each time the combined organic phases are dried over MgSO4. After the dried substance and the solvent have been eliminated, the desired product is obtained, which is further used without purification.

Product: 2.9 g (80% of theory)

ESI-MS: (M+H)+ = 260

Rf = 0.58 (silica gel, DCM/MeOH/NH3 70:25:5)

Example A6

Dimethyl-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylmethyl)-amine (Example 10.25)

[image]

A6a 1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoroethanone

11.7 mL (23.4 mmol) of a 2 M dimethylamine solution in THF was added to a solution of 4.5 g (16.59 mmol) of 3-(2,2,2-trifluoroacetyl)-2,3,4,5 -tetrahydro-1H-3-benzazepine-7-carbaldehyde in 150 mL THF and the solution was adjusted to pH 5 using glacial acetic acid. After 30 min, 4.62 g (21.79 mmol) of NaBH(OAc)3 were added and the reaction mixture was stirred overnight at RT. The reaction solution is cautiously mixed with saturated NaHCO3 solution, stirred for 30 min, generously extracted with EtOAc, the organic phases are separated and dried over Na2SO4. After the dried substance and the solvent have been eliminated, the desired product is obtained, which is further used without purification.

Product: 4.5 g (90% of theory)

ESI-MS: (M+H)+ = 301

Rf = 0.76 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A6b dimethyl-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylmethyl)-amine

50 mL of water and 8.5 g (61.51 mmol) of K2CO3 are added to a solution of 4.5 g (14.98 mmol) of 1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepine-3 -yl)-2,2,2-trifluoroethanone in 50 mL of MeOH and the reaction mixture was stirred for 72 hours at RT. The reaction mixture was evaporated i.vac., the residue was mixed with DCM, filtered to remove insoluble contents and evaporated i.vac. The resulting product is obtained in the form of a light brown oil.

Product: 2.9 g (95% of theory)

ESI-MS: (M+H)+ = 205

Rf = 0.39 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

Example A7

1-piperidin-4-yl-4-(2,2,2-trifluoroethyl)-piperazine (Example 10.27)

[image]

A7a 1-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2,2,2-trifluoroethanone

A solution of 8.21 mL (57.83 mmol) of trifluoroacetic anhydride in 40 mL of DCM was added dropwise to a solution, cooled to 0°C, of 15.0 g (57.83 mmol) of 1-(1-benzyl-piperidine- 4-yl)-piperazine and 20.1 mL (145 mmol) of triethylamine in 200 DCM and the reaction mixture was stirred for 5 hours at RT. Water is added, the organic phases are separated and dried over Na2SO4. After the dried substance and solvent have been eliminated, the crude product is further used without purification.

Product: 8.3 g (40% of theory)

EI: (M)+ = 205

Rf = 0.48 (silica gel, DCM/MeOH/NH3 90:10:1)

A7b 1-(1-benzyl-piperidin-4-yl)-4-(2,2,2-trifluoro-ethyl)-piperazine

0.53 g (14.07 mmol) of NaBH4 was added to a solution of 1.0 g (2.81 mmol) of 1-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-2, of 2,2-trifluoroethanone in 9 mL of 1,4-dioxane and 1 mL of THF and then to this suspension was added a solution of 1.08 mL (14.07 mmol) of TFA in 10 mL of 1,4-dioxane dropwise in 10 min. The reaction solution was allowed to flow for 5 hours, after cooling it was separated with water and evaporated i.vac. The obtained residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5).

Product: 0.41 g (43% of theory)

ESI-MS: (M+H)+ = 342

Rf = 0.45 (silica gel, EtOAc/MeOH/NH3 80:20:2)

A7c 1-piperidin-4-yl-4-(2,2,2-trifluoro-ethyl)-piperazine

50 mg of 10% Pd/C was added to a solution of 0.41 g (1.20 mmol) of 1-(1-benzyl-piperidin-4-yl)-4-(2,2,2-trifluoro-ethyl)-piperazine in 30 mL MeOH and the reaction mixture is hydrogenated for 2.5 hours at RT and 3 bar H2. To complete the reaction, add the tip of a teaspoon of Pd(OH)2 and continue the hydrogenation for another 1.5 hours. After the catalyst is removed by suction filtration, the solvent is eliminated and the desired product is obtained.

Product: 0.28 g (94% of theory)

ESI-MS: (M+H)+ = 252

Rf = 0.05 (silica gel, EtOAc/MeOH/NH3 70:30:3)

Example A8

Methyl-[2-(1-methyl-piperidin-4-yl)-ethyl]-amine (Example 10.32)

[image]

A8a (N,N-dimethyl-2-(1-methyl-piperidin-4-yl)-acetamide

A solution of 9.3 g (50 mmol) of ethyl N-methylpiperidinyl-4-acetate in 50 mL of a 40% aqueous solution of methylamine was stirred for 15 hours at 80°C in a bomb tube. The solvent is eliminated by i.vac. and the residue was dissolved in EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.

Product: 4.7 g (55% of theory)

Rf = 0.53 (silica gel, DCM/MeOH 21:1)

A8b methyl-[2-(1-methyl-piperidin-4-yl)-ethyl]-amine

3.1 g (20 mmol) of N,N-dimethyl-2-(1-methyl-piperidin-4-yl)-acetamide in 40 mL of THF was added dropwise to a solution of 1.1 g (30 mmol) of lithium aluminum hydride in 50 mL of diethyl ether. The mixture was boiled without loss of steam and then stirred overnight at RT. After adding water, 6 N NaOH and more water, the solution is stirred for 30 min. After filtration, the solvent is eliminated by i.vac. The residue is dissolved in diethyl ether, dried over MgSO4 and the solvent is eliminated i.vac.

Product: 2.5 g (80% of theory)

Rf = 0.29 (Alox, DCM/MeOH 21:1)

Example A9

Cyclopentyl-methyl-piperidin-4-yl-amine (Example 10.41)

[image]

A9a (1-Benzyl-piperidin-4-yl)-cyclopentyl-methyl-amine

6.0 mL (105 mmol) of glacial acetic acid is added to a solution of 6.5 g (31.8 mmol) of (1-benzyl-piperidin-4-yl)-methyl-amine and 2.7 g (32.0 mmol) of cyclopentanone in 200 mL of THF and the reaction mixture is heated to 55°C for 10 min. After cooling to 15°C, 10.6 g (50.0 mmol) of NaBH(OAc)3 was added to the mixture and stirred for a further 5 hours at RT. 100 mL of water is carefully added and the pH is made alkaline using Na2CO3, the mixture is extracted liberally with diethyl ether, the combined organic phases are washed with water and evaporated i.vac. After elimination of the solvent, the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 9:1:0.3).

Product: 5.0 g (58% of theory)

EI: (M)+ = 272

Rf = 0.6 (silica gel, EtOAc/MeOH/NH3 9:1:0.3)

A9b cyclopentyl-methyl-piperidin-4-yl-amine

1.0 g of 10% Pd/C was added to a solution of 5.0 g (18.35 mmol) of (1-benzyl-piperidin-4-yl)-cyclopentyl-methyl-amine in 100 mL of MeOH and the reaction mixture was hydrogenated for 3 hours at RT and 5 bars of H2. After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 3.0 g (90% of theory)

Rf = 0.05 (silica gel, EtOAc/MeOH/NH3 9:1:0.4)

Example A10

4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-piperidine (Example 10.46)

[image]

A10a 1-benzyl-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-piperidine

3-chloro-propane-1-sulfonyl chloride was added dropwise at RT to a solution of 19.0 g (100 mmol) of 1-benzyl-piperidin-4-ylamine and 27.2 g (197 mmol) of K2CO3 in 200 mL of acetonitrile. The reaction solution was left to stand overnight. After filtration, the solvent was slowly drained off. The residue was taken up in 120 mL of EtOH and mixed with 6.2 g (111 mmol) of KOH. The mixture was boiled without loss of steam for 1 hour and, after cooling, acidified with HCl. The precipitate was suction filtered and dried.

Product: 15.4 g (46% of theory)

melting point: 255-257°C

A10b 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-piperidine

Analogous to example 17d, the product is prepared from 16.5 g (56.1 mmol) of 1-benzyl-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-piperidine.

Product: 8.5 g (74% of theory)

melting point: 89-92°C

Rf = 0.13 (silica gel, DCM/MeOH 8:2)

Example A11

tert-butyl-piperidin-4-yl-amine (Example 10.50)

[image]

A11a (1-benzyl-piperidin-4-yl)-tert-butyl-amine

In an argon atmosphere, a solution of 8.6 mL (78 mmol) TiCl4 in 100 mL toluene is added dropwise to the solution, cooled to 0°C, 24.1 mL (130 mmol) 1-benzyl-piperidin-4-one and 55 mL (519 mmol) of tert-butylamine in 200 mL of toluene so that the internal temperature does not exceed 15°C. The reaction mixture is stirred overnight at RT, the formed precipitate is suction filtered and the remaining solution after the addition of 65 mg of platinum oxide is hydrogenated until the theoretical H2 uptake is achieved. After the hydrogenation is complete, 160 mL of 2 N NaOH solution is added to the suspension, it is filtered, the organic phase is separated, the aqueous solution is extracted three times with toluene and the combined organic phases are dried over Na2SO4. After the dried substance and the solvent have been eliminated, the product is further used without purification.

Product: 13.9 g (43% of theory)

A11b tert-butyl-piperidin-4-yl-amine

1.5 g of 10% Pd/C is added to a solution of 13.9 g (56.0 mmol) of (1-benzyl-piperidin-4-yl)-tert-butyl-amine in 140 mL of MeOH and the reaction mixture is hydrogenated at RT while does not reach the theoretical acceptance of H2 (2h). After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 8.3 g (95% of theory)

Example A12

4-(2-methyl-imidazol-1-yl)-piperidine (Example 10.58)

[image]

A12a tert. butyl 4-(2-methyl-imidazol-1-yl)-piperidine-1-carboxylate

Under a nitrogen atmosphere, 1.0 g (22.92 mmol) of NaH (55% in mineral oil) was added batchwise to a solution of 2.0 g (21.92 mmol) of 2-methyl-1H-imidazole in 20 mL of DMF at RT within 20 min and the reaction mixture is stirred for 30 min at that temperature. A solution of 4.0 g (14.32 mmol) tert is added slowly. of butyl 4-methanesulfonyloxy-piperidine-1-carboxylate in 50 mL of DMF drop by drop and the reaction mixture is then stirred for 2.5 h at 100°C. The mixture is evaporated i.vac., the residue is placed in 150 mL of DCM, the organic phase is washed twice with 50 mL of water and both times dried over MgSO4. After the dried substance and the solvent have been eliminated, the product is further used without purification.

Product: 0.65 g (17% of theory)

ESI-MS: (M+H)+ = 266

Rf = 0.56 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A12b 4-(2-methyl-imidazol-1-yl)-piperidine

Solution 650 mg (2.45 mmol) tert. butyl 4-(2-methyl-imidazol-1-yl)-piperidine-1-carboxylate is dissolved in 10 mL of 4 M HCl in 1,4-dioxane and the reaction mixture is stirred for 2 hours at RT. The mixture is evaporated i.vac., the residue is mixed with diisopropylether and a little isopropanol, the precipitate is separated by suction filtration and dried in a dryer with circulating air. The desired product is obtained in the form of dihydrochloride.

Product: 430 mg (74% of theory)

ESI-MS: (M+H)+ = 166

Rf = 0.54 (silica gel, DCM/MeOH/NH3 75:25:5)

Example A13

4-(2,4-dimethyl-imidazol-1-yl)-piperidine (Example 10.61)

[image]

A13a tert. butyl 4-(2,4-dimethyl-imidazol-1-yl)-piperidine-1-carboxylate

It is prepared analogously 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 4-methanesulfonyloxy-piperidine-1-carboxylate.

Product: 0.45 g (11% of theory)

ESI-MS: (M+H)+ = 280

Rf = 0.51 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A13b 4-(2,4-dimethyl-imidazol-1-yl)-piperidine

It is prepared analogously to Example A12b from 450 mg (1.61 mmol) of tert. butyl 4-(2,4-dimethyl-imidazol-1-yl)-piperidine-1-carboxylate. The desired product is obtained as the dihydrochloride.

Product: 300 mg (74% of theory)

ESI-MS: (M+H)+ = 180

Rf = 0.63 (silica gel, DCM/MeOH/NH3 75:25:5)

Example A14

Piperazine-1-sulfonic acid-(1-methyl-piperidin-4-yl)-amide (Example 10.66)

[image]

A14a 4-benzyl-piperazine-1-sulfonic acid -(1-methyl-piperidin-4-yl)-amide

1.89 g (11.0 mmol) of 1,3,2-benzodioxathiol-2,2-dioxide is added to a solution of 1.0 g (8.76 mmol) of 1-methyl-piperidin-4-ylamine and 1.25 mL (9.0 mmol) of triethylamine in 50 mL of DCM cooled to 0°C, the cooling bath is removed, and the reaction mixture is stirred overnight at RT. The mixture is evaporated i.vac., the residue is mixed with diethyl ether/diisopropyl ether, filtered and the crude product is dried. In a nitrogen atmosphere, this raw product (2.5 g) and 3.16 g (17.4 mmol) of 1-benzyl-piperazine are dissolved in 100 mL of 1,4-dioxane and the reaction mixture is boiled without loss of steam for 2 hours. The mixture is evaporated i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 90:10:1).

Product: 1.1 g (36% of theory)

ESI-MS: (M+H) + = 353

Rf = 0.50 (silica gel, DCM/MeOH/NH3 80:20:1)

A14b Piperazine-1-sulfonic acid-(1-methyl-piperidin-4-yl)-amide

500 mg of 10% Pd/C is added to a solution of 1.1 g (3.12 mmol) of 4-benzyl-piperazine-1-sulfonic acid-(1-methyl-piperidin-4-yl)-amide in 100 mL of MeOH. the mixture is hydrogenated at RT until the theoretical acceptance of H2 is reached (2.5h). After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 0.82 g (100% theoretical)

ESI-MS: (M+H)+ = 263

Rf = 0.05 (silica gel, EtOAc/MeOH/NH3 90:10:1)

Example A15

ethyl 1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate

[image]

A15a 1-tert-butyl, 3-ethyl 4-(1-methyl-piperidin-4-yl)-piperazine-1,3-dicarboxylate

A solution of 1.0 g (3.87 mmol) of 1-tert-butyl, 3-ethyl piperazine-1,3-dicarboxylate and 0.45 mL (3.87 mmol) of 1-methyl-piperidin-4-one in 25 mL THF was adjusted to a pH of between 5 and 6 using glacial acetic acid and then 1.0 g (4.48 mmol) of NaBH(OAc) 3 was added batchwise and the reaction mixture was stirred overnight at RT. To complete the reaction, another 1 mL (8.6 mmol) of 1-methyl-piperidin-4-one and 0.2 g (0.9 mmol) of NaBH(OAc)3 3 were added and the reaction mixture was stirred for another 2 h at RT. Excess NaBH(OAc)3 is destroyed by adding a little water, the mixture is saturated with K2CO3 and mixed. K2CO3 is filtered, the organic phases are evaporated and purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).

Product: 0.78 g (57% of theory)

ESI-MS: (M+H) + = 356

Rf = 0.46 (silica gel, EtOAc/MeOH/NH3 80:20:2)

A15b Ethyl 1-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate

2.0 mL of TFA was added to a solution of 0.78 g (2.20 mmol) of 1-tert-butyl, 3-ethyl 4-(1-methyl-piperidin-4-yl)-piperazine-1,3-dicarboxylate in 30 mL of DCM while cooling with ice and the reaction mixture was stirred for 3 h at RT. The mixture is evaporated i.vac. and the product, which is obtained as the tris-trifluoroacetate salt, is further reacted without any purification.

Product: quantitative

EI: (M)+ = 255

Rf = 0.11 (silica gel, EtOAc/MeOH/NH3 70:30:3)

Example A16

ethyl 4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate

[image]

A16a 1-tert-butyl, 3-ethyl 4-benzyl-piperazine-1,3-dicarboxylate

A solution of 5.0 mL (42.10 mmol) of benzyl bromide in 50 mL of THF was added dropwise to a solution of 10.69 g (41.39 mmol) of 1-tert-butyl, 3-ethyl piperazine-1,3-dicarboxylate and 7 .32 mL (42 mmol) of ethyl diisopropylamine in 150 mL of THF, and the reaction mixture was stirred for 2 h at RT and the reaction mixture was boiled without loss of steam for 3 h. In order to complete it, a further 0.5 mL (4.21 mmol) of benzyl bromide is added and the reaction mixture is boiled without losing steam for a further 3 hours. After cooling, the reaction solution is filtered, the filtrate is evaporated i.vac. and the residue was purified by chromatography (silica gel, cyc/EtOAc 8:2).

Product: 13.04 g (90% of theory)

ESI-MS: (M+H) + = 349

Rf = 0.51 (silica gel, cyc/EtOAc 8:2)

A16b ethyl 1-benzyl-piperazine-2-carboxylate

35 mL of TFA was added to a solution of 13.04 g (37.42 mmol) of 1-tert-butyl, 3-ethyl 4-benzyl-piperazine-1,3-dicarboxylate in 200 mL of DCM while cooling with ice and the reaction mixture was stirred for 5 h at RT. The mixture is evaporated i.vac. and the product, which is obtained as the bis-trifluoroacetate salt, is reacted further without any purification.

Product: quantitative

ESI-MS: (M+H) + = 249

A16c ethyl 1-benzyl-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate

4.0 g (17.93 mmol) of NaBH(OAc)3 was added to a solution of 8.15 g (17.11 mmol) of ethyl 1-benzyl-piperazine-2-carboxylate (used as the bis-trifluoroacetate salt) and 2.05 mL (17.22 mmol) of 1-methyl- of piperidin-4-one in 200 mL of THF and the reaction mixture was stirred overnight at RT. The mixture is evaporated i.vac. and the residue was purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 50:50:2).

Product: 5.91 g (100% theoretical)

ESI-MS: (M+H) + = 346

Rf = 0.53 (silica gel, EtOAc/MeOH/NH3 80:20:2)

A16d Ethyl 4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate

0.5 g of Pd(OH)2 is added to a solution of 5.91 g (17.11 mmol) of ethyl 1-benzyl-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate in 150 mL of EtOH and the reaction mixture is hydrogenated for 3 ,5 h at RT and 3 bar H2. After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 4.44 g (100% theoretical)

ESI-MS: (M+H)+ = 256

Rf = 0.24 (silica gel, EtOAc/MeOH/NH3 70:30:3)

Example A17

ethyl 1-methyl-4-piperidin-4-yl-piperazine-2-carboxylate

[image]

A17a 1-tert-butyl, 3-ethyl 4-methyl-piperazine-1,3-dicarboxylate

At RT, a solution of 1.25 mL (19.90 mmol) of iodomethane in 20 mL of THF was slowly added dropwise to a solution of 5.04 g (19.51 mmol) of 1-tert-butyl, 3-ethyl piperazine-1,3-dicarboxylate and 3.4 mL (19.52 mmol) ethyldiisopropylamine in 100 mL THF, the reaction mixture is stirred for 20 min and then heated to 60°C for 3 h. In order to complete the reaction, a further 0.2 mL (3.18 mmol) of iodomethane was added to the mixture and heated to 75°C for another 3 h. After cooling, the mixture is filtered to remove insoluble ingredients, the filtrate is evaporated i.vac. and the residue was purified by chromatography (silica gel, EtOAc).

Product: 4.2 g (79% of theory)

ESI-MS: (M+H)+ = 273

Rf = 0.58 (silica gel, EtOAc)

A17b ethyl 1-methyl-piperazine-2-carboxylate

20 mL of TFA was added to a solution of 4.20 g (15.42 mmol) of 1-tert-butyl, 3-ethyl 4-methyl-piperazine-1,3-dicarboxylate in 80 mL of DCM while cooling with ice and the reaction mixture was stirred for 1 h at RT. The mixture is evaporated i.vac. and the product, which is obtained as the bis-trifluoroacetate salt, is reacted further without any purification.

Product: quantitative

ESI-MS: (M+H) + = 173

Rf = 0.16 (silica gel, EtOAc/MeOH/NH3 70:30:3)

A17c ethyl 4-(1-benzyl-piperidin-4-yl)-1-methyl-piperazine-2-carboxylate

4.5 g (20.17 mmol) of NaBH(OAc)3 was added to a batch solution of 6.17 g (15.41 mmol) of ethyl 1-methyl-piperazine-2-carboxylate (used as the bis-trifluoroacetate salt) and 3.77 mL (19.93 mmol) of 1-benzyl -piperidin-4-one in 80 mL of THF and the reaction mixture was stirred for 2 h at RT. Excess NaBH(OAc)3 is destroyed by adding amlo water, the mixture is evaporated i.vac. and the residue was purified by chromatography (silica gel, gradient: EtOAc/MeOH/NH3 90:10:1 to EtOAc/MeOH/NH3 80:20:2).

Product: quantitative

ESI-MS: (M+H) + = 345

Rf = 0.41 (silica gel, EtOAc/MeOH/NH3 80:20:2)

A17d Ethyl 1-methyl-4-piperidin-4-yl-piperazine-2-carboxylate

1 g of 10% Pd/C is added to a solution of the crude product from A17c in 200 mL EtOH and the reaction mixture is hydrogenated for 17.5 h at RT and 3 bar H2. After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 5.32 g (100% theoretical, based on A17a)

ESI-MS: (M+H)+ = 256

Rf = 0.1 (silica gel, EtOAc/MeOH/NH3 50:50:5)

Example A18

ethyl 4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate

[image]

A18a Ethyl 1-benzyl-4-methyl-piperazine-2-carboxylate

A solution of 1.4 mL (22.29 mmol) of iodomethane in 50 mL of THF was slowly added dropwise to a solution of 10.3 g (21.64 mmol) of ethyl 1-benzyl-piperazine-2-carboxylate (see Example A16b, used as the bis-trifluoroacetate salt) and 12 mL (68.89 mmol) of ethyldiisopropylamine in 200 mL of THF and the reaction mixture was stirred overnight at RT. In order to complete the reaction, a further 0.2 mL (3.18 mmol) of iodomethane was added to the mixture and the mixture was stirred for a further 2 h at RT. The formed precipitate is filtered, the filtrate is evaporated i.vac. and the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 90:10:1).

Product: 4.1 g (72% of theory)

ESI-MS: (M+Na)+ = 285

Rf = 0.83 (silica gel, EtOAc/MeOH/NH3 90:10:1)

A18b ethyl 4-methyl-piperazine-2-carboxylate

450 mg of 10% Pd/C was added to a solution of 4.1 g (15.63 mmol) of ethyl 1-benzyl-4-methyl-piperazine-2-carboxylate in 100 mL of EtOH and the reaction mixture was hydrogenated for 11 h at RT and 5 bar H2. To complete the reaction, 450 mg of Pd(OH)2 is added and the reaction mixture is hydrogenated for a further 2.5 hours at 50°C and 3 bar H2. The catalyst was removed by suction filtration, the filtrate was evaporated and the residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 80:20:2).

Product: 2.18 g (81% of theory)

ESI-MS: (M+H) + = 173

Rf = 0.56 (silica gel, EtOAc/MeOH/NH3 80:20:2)

A18c ethyl 1-(1-benzyl-piperidin-4-yl)-4-methyl-piperazine-2-carboxylate

A solution of 1.58 g (9.17 mmol) ethyl 4-methyl-piperazine-2-carboxylate and 1.68 mL (9.2 mmol) 1-benzyl-piperidin-4-one in 30 mL THF was adjusted to pH 5 with glacial acetic acid and then added serially 2.2 g (9.86 mmol) of NaBH(OAc)3 and the reaction mixture is stirred overnight at RT. Excess NaBH(OAc)3 is destroyed by adding a little water and the reaction mixture is dried over K2CO3. The supernatant solution was decanted, evaporated i.vac. and the residue was purified by chromatography (silica gel, gradient: EtOAc to EtOAc/MeOH/NH3 90:9:1).

Product: 0.71 g (22% of theory)

ESI-MS: (M+H) + = 346

Rf = 0.84 (silica gel, EtOAc/MeOH/NH3 70:30:3)

A18d Ethyl 4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate

200 mg of Pd(OH)2 is added to a solution of 2.28 g (6.6 mmol) of ethyl 1-(1-benzyl-piperidin-4-yl)-4-methyl-piperazine-2-carboxylate in 100 mL of EtOH and the reaction mixture is hydrogenated 9 ,5 hours at RT and at 3 bar H2. In order to complete the reaction, a further 100 mg of Pd(OH)2 is added and the reaction mixture is hydrogenated for a further 6 hours. The catalyst is suction filtered, the filtrate is evaporated and the residue is further reacted without any purification.

Product: 1.7 g (100% theoretical)

ESI-MS: (M+H)+ = 256

Rf = 0.21 (silica gel, EtOAc/MeOH/NH3 60:40:4)

Example A19

tert-butyl (4-piperidin-4-yl-piperazin-1-yl)-acetate

[image]

A19a tert. butyl [4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-acetate

100 g (709 mmol) of K2CO3 was added to a solution of 74 g (123 mmol) of 1-(1-benzyl-piperidin-4-yl)-piperazine (used as the tris-trifluoroacetate salt) in 1 L of acetonitrile and the suspension was stirred for 10 min. at RT. Then 20 mL (133 mmol) of tert. of butyl bromoacetate. The reaction mixture was stirred for 3 h at RT and mixed with MgSO 4 to dry. Insoluble solids are removed by filtration, the solvent is evaporated i.vac., the residue is mixed with water, the formed precipitate is suction filtered and dried at 50°C in a dryer with circulating air.

Product: 30 g (65% of theory)

ESI-MS: (M+H)+ = 374

Rf = 0.51 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

A19b tert. butyl (4-piperidin-4-yl-piperazin-1-yl)-acetate

6 g of 10% Pd/C is added to a solution of 30 g (80.3 mmol) of tert. butyl [4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-acetate in 300 mL of THFi and the reaction mixture is hydrogenated at 50°C and 3 bar H2 until the theoretical acceptance of H2 is achieved. After the catalyst was removed by suction filtration and the solvent was eliminated, the desired product was obtained, which was further used without purification.

Product: 22.3 g (98% of theory)

ESI-MS: (M+H) + = 284

Rf = 0.17 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

Example A20

ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate

[image]

A20a tert. butyl 4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidine-1-carboxylate

A solution of 1.42 mL (13.3 mmol) of ethyl chloroacetate in 10 mL of acetonitrile was added to a solution of 4.0 g (13.08 mmol) of tert. butyl 4-piperazin-1-yl-piperidin-1-carboxylate (used as hydrochloride) and 6.54 mL (39.23 mmol) ethyldiisopropylamine in 50 mL acetonitrile, and cooled to 0°C. After the cooling bath was removed, a teaspoonful of NaI was added and the reaction mixture was stirred overnight at RT. The mixture was mixed with saturated NaHCO3 solution, extracted generously with DMC and the organic phase was dried over Na2SO4. After the dried substance and the solvent have been eliminated, the residue is further reacted without purification.

Product: 4.25 g (91% of theory)

ESI-MS: (M+H) + = 356

Rf = 0.67 (silica gel, DCM/MeOH 9:1)

A20b Ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate

6 mL of TFA was added to a solution of 4.25 g (11.96 mmol) of tert. butyl 4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-carboxylate in 80 mL of DCM, cooled to 0°C, and the reaction mixture was stirred overnight at RT. After the mixture was evaporated i.vac., the residue was mixed with tert-butylmethylether, the precipitate was suction filtered and the product, which was obtained as a tris-trifluoroacetate salt, was dried.

Product: 6.7 g (94% of theory)

ESI-MS: (M+H)+ = 256

Rf = 0.38 (silica gel, DCM/MeOH/NH3 75:25:5)

Example A21

ethyl [4,4']bipiperidinyl-1-yl-acetate

[image]

A21a tert. butyl 1'-ethoxycarbonylmethyl-[4,4']bipiperidinyl-1-carboxylate

The product was obtained analogously to Example A19a from 8.40 g (31.1 mmol) of tert. butyl [4,4']bipiperidinyl-1-carboxylate and 3.53 mL (31.1 mmol) of ethyl bromoacetate.

Product: 9.4 g (85% of theory)

EI-MS: (M)+ = 355

Rf = 0.64 (silica gel, EtOAc/MeOH 9:1)

A21b Ethyl [4,4']bipiperidinyl-1-yl-acetate

The product was obtained as a bis-trifluoroacetate salt analogously to Example 20b from 7.50 g (21.2 mmol) of tert. butyl 1'-ethoxycarbonylmethyl-[4,4']bipiperidinyl-1-carboxylate.

Product: 10.1 g (99% theoretical)

ESI-MS: (M+H)+ = 255

Rf = 0.15 (silica gel, DCM)

Example A22

ethyl (4-piperazin-1-yl-piperidin-1-yl)-acetate

[image]

A22a tert. butyl 4-(4-benzyl-piperazin-1-yl)-piperidine-1-carboxylate

A solution of 66.7 mL (381 mmol) of 1-benzylpiperazine and 75.6 g (380 mmol) of tert. butyl 4-oxo-piperidine-1-carboxylate adjusted to pH 5 with glacial acetic acid. While the mixture was cooled with ice, 100 g (380 mmol) of NaBH(OAc) 3 was added over 2 hours and the mixture was stirred overnight at RT. The reaction mixture was basified with K2CO3 solution (300 g/L), stirred for 1 hour at RT and extracted 3 times with EtOAc. The organic phases were dried over MgSO4, and the solvent was eliminated i.vac.

Product: 114 g (83% of theory)

ESI-MS: (M+H)+ = 369

Rf = 0.74 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

A22b 1-Benzyl-4-piperidin-4-yl-piperazine

The product was obtained as a salt of tris-trifluoroacetate analogously to Example 20b from 40.0 g (111 mmol) of tert. butyl 4-(4-benzyl-piperazin-1-yl)-piperidine-1-carboxylate.

Product: 54.8 g (82% of theory)

ESI-MS: (M+H)+ = 260

Rf = 0.18 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

A22c Ethyl [4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-acetate

The product was obtained analogously to Example A19a from 51.8 g (86 mmol) of 1-benzyl-4-piperidin-4-yl-piperazine (used as a tris-trifluoroacetate salt) and 10.3 mL (91 mmol) of ethyl bromoacetate.

Product: 25.3 g (85% of theory)

EI-MS: (M)+ = 346

Rf = 0.58 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

A22d Ethyl (4-piperazin-1-yl-piperidin-1-yl)-acetate

The product was obtained analogously to Example A19b from 25.3 g (73.3 mmol) of ethyl [4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-acetate. The product contains 59% methyl (4-piperazin-1-yl-piperidin-1-yl)-acetate.

Product: 17.4 g (93% of theory)

ESI-MS: (M+H)+ = 256 and for methyl ester: (M+H)+ = 242

Rf = 0.15 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example A23

1-(2,2,2-trifluoroethyl)-[4,4']bipiperidinyl

[image]

A23a tert. butyl 1'-(2,2,2-trifluoroacetyl)-[4,4']bipiperidinyl-1-carboxylate

The product was obtained analogously to Example A7a from 15.0 g (55.9 mmol) of tert. butyl [4,4']bipiperidinyl-1-carboxylate.

Product: 19.0 g (93% of theory)

ESI-MS: (M+Na)+ = 387

A23b tert. butyl 1'-(2,2,2-trifluoro-ethyl)-[4,4']bipiperidinyl-1-carboxylate

The product was obtained analogously to Example A7b from 20.7 g (56.7 mmol) of tert. butyl 1'-(2,2,2-trifluoroacetyl)-[4,4']bipiperidinyl-1-carboxylate.

Product: 19.9 g (100% theoretical)

ESI-MS: (M+H) + = 351

Rf = 0.78 (silica gel, PE/EtOAc 1:1)

A23c 1-(2,2,2-trifluoroethyl)-[4,4']bipiperidinyl

The product was obtained as a bis-trifluoroacetate salt analogously to Example A20b from 21.4 g (61.1 mmol) of tert. butyl 1'-(2,2,2-trifluoro-ethyl)-[4,4']bipiperidinyl-1-carboxylate.

Product: 26.8 g (92% of theory)

ESI-MS: (M+H)+ = 251

Rf = 0.17 (silica gel, DCM/MeOH/NH3 9:1:0.1)

Example A24

dimethyl-[3-(4-piperazin-1-yl-phenyl)-propyl]-amine

[image]

A24a 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone

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 boiled without loss of steam for 2 days. After cooling, the residue was mixed with tert-butyl methyl ether, suction filtered and dried in air. The product reacts further without purification.

Product: 12.2 g (42% of theory)

EI-MS: (M)+ = 294

Rf = 0.53 (silica gel, PE/EtOAc 3:2)

A24b 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-3-dimethylamino-propan-1-one

1.40 g of paraformaldehyde is added to a solution of 6.9 g (23.4 mmol) of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-ethanone and 2.90 g (35.1 mmol) of dimethylamine hydrochloride in 100 mL of EtOH and 10 mL of conc. . HCl. The reaction mixture was boiled without loss of steam for 20 hours. The solvent was evaporated i.vac., and the residue was mixed with acetonitrile. The precipitate was suction filtered and dried at 30°C in a dryer with circulating air.

Product: 4.4 g (48% of theory, as hydrochloride)

EI-MS: (M)+ = 351

Rf = 0.35 (silica gel, DCM/EtOAc/cyc/MeOH/NH3 60:16:5:5:0.6)

A24c dimethyl-[3-(4-piperazin-1-yl-phenyl)-propyl]-amine

2 g of 10% Pd/C was added to a solution of 8.00 g (20.6 mmol) of 1-[4-(4-benzyl-piperazin-1-yl)-phenyl]-3-dimethylamino-propan-1-one in 6.7 mL of conc. HCl and 300 mL of MeOH. The reaction mixture was stirred for 3 h at 3 bar H2 and 50°C. After filtration, the filtrate is evaporated to dryness. The residue was combined with EtOH and EtOAc and stirred overnight. Precipitated suction filter Product: 5.7 g (86% of theory, as bis-hydrochloride)

EI-MS: (M)+ = 247

Rf = 0.35 (DCM/cyc/MeOH/NH3 70:15:15:2)

flush with nitrogen and dry at 20°C in a dryer with circulating air.

Other amines used in the preparation of the final compounds are either commercially available or prepared by procedures known from the literature.

Preparation of end joints

Example 1

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

1a (4-amino-3-chloro-5-trifluoromethyl-phenyl)-methanol

69.56 g (0.43 mol) of CDI was added to a solution of 93.4 g (0.39 mol) of 4-amino-3-chloro-5-trifluoromethyl-benzoic acid (as described in Arzneim.-Forsch. 1984, 34(11A), 1612-1624 ) in 1 L of THF and the mixture was stirred for 1 h at 40°C. The reaction mixture was then cautiously added to a solution of 51.4 g (1.36 mol) NaBH4 in 450 mL of water at RT under a nitrogen atmosphere and with cooling. The mixture is stirred for 2 h at RT, mixed with 500 mL of water and 300 mL of semiconc. HCl, stirred for an additional 1 hour and then extracted liberally with EtOAc. The combined organic phases are dried over Na2SO4 and evaporated i.vac. The remaining oil is mixed with 500 mL of PE and stirred while cooling with ice. The precipitate is suction filtered, washed with PE and dried. 29.7 g of the desired product is obtained.

The resulting liquid is evaporated again, mixed with PE and cooled. The resulting precipitate is washed again with PE and dried. A further 21.8 g of the desired product is obtained.

Product: 51.5 g (59% theoretical) white solid

Rf = 0.73 (silica-gel: PE/EtOAc = 1:1)

1b 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde

A mixture of 17.0 g (75.4 mmol) (4-amino-3-chloro-5-trifluoromethyl-phenyl)-methanol, 100 g (1.15 mol) manganese dioxide and 300 mL DCM was stirred overnight at RT. The precipitate is suction filtered and the solution is evaporated i.vac. The desired product is obtained as a white solid.

Product: 16.0 g (95% of theory)

ESI-MS: (M+H)+ = 224/226 (Cl)

1c diethyl [2-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-2-oxo-ethyl]-phosphonate

A solution of 168.0 g (0.56 mol) (R)-4-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one and 188.6 mL (1.1 mol) of triethylphosphite was stirred for 1.5 h at 60°C, while the formed ethyl bromide is poured off. The reaction mixture is concentrated by evaporation i.vac. and the remaining residue is purified by chromatography on silica gel. The desired product is obtained in the form of a yellow-brown oil.

Product: 130 g (65% of theory)

ESI-MS: (M+H) + = 356

1d (R)-3-[(E)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acryloyl]-4-benzyl-oxazolidin-2-one

In a nitrogen atmosphere, 3.93 g (90.0 mmol) of NaH (55% in mineral oil) was added serially to a solution of 31.98 g (90.0 mmol) of diethyl [2-((R)-4-benzyl-2-oxo-oxazolidin-3-yl) -2-oxo-ethyl]-phosphonate in 400 mL THF. The reaction mixture was stirred for 30 min at RT and for a further 35 min at 35°C. After gas production stops, 16.0 g (71.5 mmol) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde, dissolved in 50 mL of THF, is added dropwise and stirred for a further 12 h at RT. The reaction solution was combined with saturated NH 4 Cl solution, the mixture was extracted liberally with EtOAc and the combined extracts were dried and evaporated i.vac. The remaining residue is purified by chromatography on silica gel. The desired product is obtained in the form of a yellow oil.

Product: 38.2 g (62% of theory)

ESI-MS: (M+H)+ = 425/427 (Cl)

Rf = 0.55 (silica-gel: PE/EtOAc = 2:1)

1e (R)-3-[3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionyl]-4-benzyl-oxazolidin-2-one

Mixture 23.7 g (55.8 mmol) (R)-3-[(E)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acryloyl]-4-benzyl-oxazolidin-2-one, 400 mL MeOH and 5.0 g Raney nickel are shaken for 2 h at RT and 3 bar H2 in a Parr autoclave. The catalyst was suction filtered and the solvent removed by i.vac. The desired product is obtained in the form of a yellow oil.

Product: 22.5 g (95% of theory)

ESI-MS: (M+H) + = 427/429 (Cl)

1f tert.-butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-4 -oxo-butanoate

In an atmosphere of argon, 63.24 mL (63.24 mmol) of a solution of sodium bis(trimethylsilyl)-amide (1 M in THF) was added dropwise to a solution of 22.5 g (52.71 mmol) of (R)-3-[3-(4-amino-3 -chloro-5-trifluoromethyl-phenyl)-propionyl]-4-benzyl-oxazolidin-2-one in 105 mL of THF that was cooled to –78°C and the mixture was stirred for 2 h at –78°C. 38.9 mL (263.5 mmol) of tert-butyl bromoacetate was added dropwise to the reaction mixture at -78°C, and this was stirred for a further 24 h at -78°C and then warmed to RT. After the addition of 200 mL of saturated NH4Cl solution, the mixture is extracted twice with 300 mL of EtOAc, the combined organic phases are dried over Na2SO4 and evaporated i.vac. The remaining residue is purified by chromatography on silica gel. The desired product is obtained in the form of a yellow oil.

Product: 15.6 g (55% of theory)

ESI-MS: (M+H) + = 541/543 (Cl)

Rf = 0.35 (silica gel, PE/EtOAc = 8:2)

1g 4-tert.-butyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate

11.75 ml (115.1 mmol) of H2O2 (35% in water) was added to a solution of 2.51 g (57.6 mmol) of lithium hydroxide hydrate in 150 mL of water. The mixture was then added dropwise to an ice solution of 15.6 g (28.8 mmol) tert.-butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-((R)-4- of benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-butanoate in 600 mL of THF and the reaction mixture was stirred for a further 2 hours while cooling with ice. 150 mL of saturated sodium sulfite solution is added to the reaction mixture and acidified with citric acid solution. Org. phase is separated, dried and evaporated i.vac. 15.6 g of viscous yellow oil is obtained.

The aqueous phase is extracted liberally with EtOAc, the combined organic phases are washed with water, dried and evaporated i.vac. A further 5.5 g of yellow oil is obtained.

The crude product, still containing (R)-4-benzyl-oxazolidin-2-one, is reacted further without purification.

Product: 21.1 g of raw product

ESI-MS: (M+H)+ = 380/382 (Cl)

1g tert. butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo -butanoate

A mixture of 15.4 g (40.3 mmol) of 4-tert. butyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate, 7.4 g (40.3 mmol) (1-methyl-4-piperidin-4-yl)-piperazine, 5.45 g ( 40.3 mmol) HOBt, 12.94 g (40.3 mmol) TBTU, 11.77 mL (85.0 mmol) triethylamine and 400 mL THF were stirred for 12 h at RT. The mixture is then evaporated and the remaining residue is partitioned between EtOAc and NaHCO3 solution. Org. the phase is separated, dried and evaporated. The obtained residue is purified by chromatography on aluminum oxide. The desired product is obtained in the form of a yellow oil.

Product: 11.0 g (50% of theory)

ESI-MS: (M+H) + = 547/549 (Cl)

Rf = 0.35 (Alox; EtOAc/CH2Cl2 = 6:4)

1h (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo - butanoic acid

5.75 g (38.4 mmol) of NaI, 3 mL of anisole and 4.92 mL (38.4 mmol) of trimethylsilyl chloride were added to a solution of 7.0 g (12.8 mmol) of tert. butyl (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo -butanoate in 375 mL of acetonitrile. The reaction mixture was stirred for 90 min at 40°C, mixed with a further 5.75 g (38.4 mmol) of NaI and 4.92 mL (38.4 mmol) of trimethylsilyl chloride and stirred for a further 2 h at 40°C. The mixture is evaporated i.vac. still reacts as a crude product.

1i (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

Mixture 6.3 g (12.8 mmol) (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1- yl]-4-oxo-butanoic acid, 3.16 g (12.9 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one, 4.66 g (14.5 mmol) TBTU, 1.96 g (14.5 mmol) HOBt, 9.45 mL (68 mmol) triethylamine and 300 mL DMF were stirred for 12 h at RT. The reaction mixture was evaporated i.vac., the residue was partitioned between a solution of EtOAc and NaHCO3. Org. the phase is separated, dried and evaporated. The resulting residue is purified by chromatography on silica gel. The resulting yellow oil is triturated with ether and suction filtered. The desired product is obtained as a white solid.

Product: 3.8 g (39% of theory)

ESI-MS: (M+H)+ = 718/20 (Cl)

Rf = 0.22 (silica gel, EtOAc/MeOH/conc. aqueous NH3 = 70:30:3)

Example 2

2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

2a 2-chloro-4-chloromethyl-6-trifluoromethyl-phenylamine

0.94 mL (13.00 mmol) of SOCl2 was added at RT to a solution of 1.00 g (4.43 mmol) of (4-amino-3-chloro-5-trifluoromethyl-phenyl)-methanol in 50 mL of DCM and the mixture was stirred for 3 h at RT. The reaction mixture was poured onto ice, and the aqueous phase was extracted liberally with DCM. The combined organic phases are washed with ice-cold NaHCO3 solution, dried over Na2SO4, filtered through activated carbon and evaporated i.vac. The crude product is used in subsequent reaction steps without further purification.

Product: 1.08 g (quantitative product)

EI-MS: M+ = 243/245/247 (Cl2)

Rf = 0.81 (silica gel, PE/EtOAc = 2:1)

2b tert.butyl 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butyrate

193 mg (4.43 mmol) of NaH (55% in mineral oil) was added to a batch solution of 1.20 g (4.43 mmol) of 1-tert.-butyl-4-ethyl 3-ethoxycarbonyl-succinate in 50 mL of abs. THF under a nitrogen atmosphere and while cooling with ice, the reaction mixture was stirred for 1 h at RT. 1.1 g (4.43 mmol) of 2-chloro-4-chloromethyl-6-trifluoromethyl-phenylamine, dissolved in 10 mL abs. THF, was added dropwise to the mixture and stirred for 16 h at RT. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc. Org. phase is dried over MgSO4 and evaporated i.vac. The crude product is used in the next reaction step without further purification.

Product: 2.1 g (98% of theory)

ESI-MS: (M+H)+ = 482/484 (Cl)

Rf = 0.48 (silica gel, PE/EtOAc = 4:1)

2c 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid

20 mL of TFA was added to a solution of 30.0 g (62.25 mmol) of tert.butyl 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoate in 200 mL of DCM while cooling with ice. and the mixture was stirred for 16 h at RT. The reaction mixture is evaporated and the residue is crystallized from PE. The precipitate is filtered off, washed with PE and dried.

Product: 23.6 g (89% product)

ESI-MS: (M-H)- = 424/426 (Cl)

2d diethyl 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) )-piperidin-1-yl]-ethyl}-malonate

3.2 mL (23.0 mmol) of triethylamine was added dropwise to a solution of 8.00 g (19.0 mmol) of 4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoic acid, 4.39 g (19.0 mmol) 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, 6.00 g (18.0 mmol) TBTU and 2.75 g (18.0 mmol) HOBT in 100 mL THF and the mixture was stirred for 16 h at RT. The formed solid is filtered off, washed with diethyl ether and dried i.vac.

Product: 10.45 g (87% of theory)

2e 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butanoic acid

3.13 g (78.25 mmol) of NaOH, dissolved in 300 mL of water, was added to a solution of 10.00 g (15.65 mmol) of diethyl 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-{2-oxo-2 -[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate in 600 mL of EtOH and the mixture was boiled without loss of steam for 4 h. EtOH is evaporated i.vac., the reaction mixture is acidified to pH 1 with conc. HCl and 1 h at RT. The formed precipitate is filtered off, washed with water and dried i.vac.

Product: 8.01 g (95% of theory)

2f 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

2.0 mL of triethylamine was added to a solution of 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid, 0.28 g (1.50 mmol) 1-methyl-[4,4']bipiperidinyl, 0.49 g (1.50 mmol) TBTU and 0.23 g (1.50 mmol ) HOBT in 100 mL THF and the mixture was stirred for 16 h at RT. The reaction mixture is evaporated i.vac. the residue was mixed with saturated NaHCO 3 solution and the mixture was extracted copiously with EtOAc. Merged org. extracts are dried over MgSO4 and evaporated i.vac. The residue is purified by column chromatography (silica gel, gradient: EtOAc/MeOH/NH3 94/5/1 to 70/25/5).

Product: 253 mg (24% of theory)

ESI-MS: (M+H) + = 703/705 (Cl)

Rf = 0.66 (silica gel, DCM/cyc/MeOH/NH3 70/15/15/2)

Example 3

2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

The product is obtained analogously to Example 2f, starting with 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 0.30 g (1.50 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 600 mg (57% of theory)

EI-MS: M+ = 703/705 (Cl)

Rf = 0.56 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 4

2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

The product is obtained analogously to Example 2f, starting with 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 0.27 g (1.50 mmol) [1,4']bipiperidinyl.

Product: 240 mg (24% of theory)

ESI-MS: (M+H) + = 689/691 (Cl)

Rf = 0.59 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 5

2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]- 1-(4-pyridin-4-yl-piperazin-1-yl)-butane-1,4-dione

[image]

The product is obtained analogously to Example 2f starting with 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 0.24 g (1.48 mmol) of 1-pyridin-4-yl-piperazine.

Product: 500 mg (50% of theory)

EI-MS: M + = 683/685 (Cl)

Rf = 0.35 (silica gel, MeOH)

Example 6

2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-ylamino)-piperidin-1-yl]-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

6a (1-benzyl-piperidin-4-yl)-(1-methyl-piperidin-4-yl)-amine

A solution of 15.0 g (78.8 mmol) of 1-benzyl-piperidin-4-ylamine and 10 mL (78.8 mmol) of 1-methyl-piperidin-4-one in 300 mL of THF was acidified with HOAc to pH 5 and stirred for 1 h at RT. 19.0 g (90.0 mmol) of NaBH(OAc)3 was added and the mixture was stirred for 16 h. The mixture was evaporated i.vac., the residue was dissolved in MeOH and precipitated by addition of HCl in MeOH. The formed precipitate is filtered off, washed with MeOH and dried i.vac.

Product: 21.8 g (70% of theory)

Rf = 0.30 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

6b (1-Methyl-piperidin-4-yl)-piperidin-4-yl-amine-trihydrochloride

A solution of 10.0 g (25.3 mmol) of (1-benzyl-piperidin-4-yl)-(1-methyl-piperidin-4-yl)-amine in 120 mL of MeOH was added to a solution of 5 g of 10% Pd/C in 80 mL of water. and the mixture is hydrogenated for 2 h at 50 °C and 3 bar H2. The reaction mixture is filtered and the filtrate is evaporated i.vac. The residue is mixed with EtOH, the formed precipitate is filtered off, washed with EtOH and ether and dried i.vac.

Product: 7.75 g (quantitative product)

6c 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-ylamino)-piperidin-1-yl]-4-[4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The product is obtained analogously to Example 2f, starting with 0.80 g (1.48 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 0.24 g (1.48 mmol) of (1-methyl-piperidin-4-yl)-piperidin-4-yl-amine trihydrochloride.

Product: 300 mg (25% of theory)

EI-MS: M + = 717/719 (Cl)

Rf = 0.20 (silica gel, MeOH)

Example 6.1

[4-(1-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

Prepared analogously to Example 16.4 from 108 mg (0.20 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.

Product: 16 mg (10% of theory)

ESI-MS: (M+H)+ = 748/750(Cl)

Example 6.2

Methyl (1'-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate

[image]

Prepared analogously to Example 16.5 from 216 mg (0.4 mmol) of 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 102 mg (0.2 mmol) of ethyl [4,4']bipiperidinyl-1-yl-acetate.

Product: 22 mg (22% of theory)

ESI-MS: (M+H)+ = 761/763(Cl)

Rf = 0.33 (silica gel, DCM/MeOH 9:1)

Example 6.3

(1'-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid

[image]

Prepared analogously to Example 16.6 from 201 mg (0.26 mmol) methyl (1'-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate.

Product: 22 mg (22% of theory)

ESI-MS: (M+H)+ = 761/763(Cl)

Rf = 0.21 (silica gel, DCM/MeOH 9:1)

Example 7

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide

[image]

7a (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-N-((1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl) -N-methyl-propionamide

Alkylation is carried out according to the general procedure described by A. G. Myers et al. (J. Org. Chem. 1999, 64, 3322-3327.) starting with 31.72 g (132 mmol) of 2-amino-N-((1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl )-N-methyl-acetamide monohydrate and 33.8 g (138 mmol) of 2-chloro-4-chloromethyl-6-trifluoromethyl-phenylamine. The crude product is purified by column chromatography (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2).

Product: 10.0 g (18% of theory)

ESI-MS: (M+H)+ = 430/432 (Cl)

Rf = 0.48 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

7b (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid

Hydrolysis is carried out according to the general procedure described by A. G. Myers et al. (J. Org. Chem. 1999, 64, 3322-3327.) starting with 10.0 g (23.0 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)- N-((1S,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide. The crude product is used in the next step of the synthesis without further purification.

7c (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butoxycarbonylamino-propionic acid

A solution of 3.71 g (35.0 mmol) of NaHCO3 in 100 mL of water is added to a solution of 6.5 g (23.0 mmol) of (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 140 mL of THF. 15.28 g (70.0 mmol) of Boc anhydride was added to the mixture and stirred for 3 h at RT. THF is evaporated i.vac., the aqueous phase is washed with EtOAc and acidified with 10% citric acid solution. The aqueous phase is extracted liberally with EtOAc, the combined org. extracts are dried over Na2SO4 and evaporated i.vac. The crude product is used in the next step of the synthesis without further purification.

Product: 2.00 g (15% of theory)

ESI-MS: (M-H)- = 381/383 (Cl)

7d tert.-butyl [(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]- carbamate

1.53 mL (11.00 mmol) of triethylamine was added to a solution of 2.00 g (5.22 mmol) of (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butoxycarbonylamino-propionic acid, 0.99 g (5.30 mmol) [1,4']bipiperidinyl, 1.77 g (5.50 mmol) TBTU and 0.74 g (5.50 mmol) HOBt in 150 mL THF and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated i.vac., the residue was mixed with saturated NaHCO 3 solution and the mixture was extracted liberally with EtOAc. Merged org. extracts are dried over MgSO4 and evaporated i.vac. The residue is purified by column chromatography (alumina (neutral, activity III), DCM/MeOH 99:1).

Product: 500 mg (18% of theory)

7e (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1,4']bipiperidinyl-1'-yl-propan-1-one-dihydrochloride

5 mL of HCl (12 M in EtOH) was added at RT to a solution of 500 mg (0.75 mmol) of tert. butyl [(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[1,4']bipiperidinyl-1'-yl-2-oxo-ethyl]-carbamate in 50 mL EtOH and the mixture was stirred for 3 h and then evaporated i.vac. The crude product is used in the next reaction step without further purification.

Product: 380 mg (quantitative product)

7f 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3- chloro-5-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide

180 mg (1.10 mmol) CDT is added at 0 °C to a solution of 380 mg (0.75 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-[1 ,4']bipiperidinyl-1'-yl-propan-1-one-dihydrochloride in 50 mL of DMF and 0.56 mL (4.00 mmol) of triethylamine and the mixture was stirred for 1.5 h at 0 °C. 242 mg (0.99 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one were added and the reaction mixture was stirred for 1.5 h at 100 °C. DMF is evaporated i.vac. and the residue was purified by column chromatography (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2) followed by HPLC.

Product: 140 mg (20% of theory)

ESI-MS: (M+H) + = 704/706 (Cl)

Rf = 0.58 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 7.1

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-amide

[image]

7.1a ethyl (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate

A solution of 3.5 g (10.97 mmol) of (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 100 mL of EtOH and 70 mL of ethanolic HCl (11.5 M) is mixed overnight at RT. The mixture is evaporated i.vac., the residue is placed in 150 mL of water, mixed with 30 mL of 15% K2CO3 solution, extracted with 150 mL of EtOAc, the organic phase is separated and dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 3.5 g (92% of theory)

ESI-MS: (M+H)+ = 311/313 (Cl)

7.1b ethyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionate

1.8 g (11.0 mmol) of CDT was added to a solution of 3.2 g (10.2 mmol) of ethyl (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate and 1.8 mL (10.3 mmol ) of ethyldiisopropylamine in 150 mL of THF cooled to 0°C and the mixture was stirred for 45 min at that temperature and for a further 30 min after removing the ice bath. Then 2.5 g (10.2 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one suspended in 50 mL of THF was added. 40 mL of DMF was added to the reaction solution and it was stirred for 2 h at 80°C. It is evaporated i.vac., mixed with 200 mL EtOAc and 200 mL 10% citric acid solution, the organic phase is separated, extracted with 150 mL NaHCO3 solution and dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 5.9 g (100% theoretical)

ESI-MS: (M+H) + = 582/584 (Cl)

Rf = 0.4 (silica gel, EtOAc)

7.1c (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine -3-yl)-piperidine-1-carbonyl]-amino}-propionic acid

Suspension 6.0 g (10.31 mmol) ethyl (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro) -1,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionate in 50 mL of THF is added to a solution of 0.64 g (15 mmol) of lithium hydroxide hydrate in 100 mL of water. A further 100 mL of water and 100 mL of THF are added to the suspension, and after 5 min a solution is formed. It is stirred for 1 h at RT, THf is removed i.vac., it is diluted with 100 mL of water and while cooling with ice, 1 M HCl is added drop by drop until an acidic reaction is obtained. The precipitated substance is filtered, washed with water and air-dried.

Product: 5.5 g (96% of theory)

ESI-MS: (M+H)+ = 554/556 (Cl)

7.1d 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-amide

241 mg (0.75 mmol) TBTU, 0.21 mL (1.5 mmol) triethylamine and 103 mg (0.8 mmol) dimethyl-piperidin-4-yl-amine were added to a solution of 400 mg (0.72 mmol) (R)-3-(4-amino -3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl] -amino}-propionic acid in 10 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution is poured into 150 mL of 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance is suction filtered, washed with 30 mL of water and air-dried overnight. The crude product is suspended in isopropanol, stirred overnight at RT, suction filtered and dried at 40°C.

Product: 350 mg (73% of theory)

ESI-MS: (M+H) + = 664/666 (Cl)

Retention time (HPLC): 6.0 min (Procedure A)

The following compounds were prepared analogously from (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionic acid and corresponding amounts of amine:

[image]

[image]

The following compounds were prepared analogously from (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionic acid and the appropriate amount of amine, the crude product is purified by chromatography (silica gel, gradient: DCM to MeOH/NH3 9:1 within 45 min ):

[image]

The following compounds were prepared analogously from (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionic acid and appropriate amounts of amine, while the crude product is purified directly by HPLC:

[image]

Example 7.10

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide

[image]

Solution 600 mg (0.72 mmol) benzyl 4-[1-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazine-1-carboxylate (Example 7.4) and 200 mg Raney nickel in 50 mL MeOH was hydrogenated for 12 h at RT and 50 psi H2. The catalyst was filtered off, the solvent was evaporated i.vac. and the residue purified by HPLC.

Product: 160 mg (32% of theory)

ESI-MS: (M+H) + = 705/707 (Cl)

Retention time (HPLC): 5.5 min (procedure A)

Example 7.11

[1'-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetic acid

[image]

A solution of 20.1 mg (0.47 mmol) of lithium hydroxide hydrate in 10 mL of water was added to a solution of 250 mg (0.32 mmol) of ethyl [1'-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-4,4' -bipiperidinyl-1-yl]-acetate (Example 7.5) in 5 mL of THF and the reaction mixture was stirred for 2 h at RT. 0.5 mL of 1 M HCl was added, the precipitated substance was filtered off and dried at 50°C. The crude product is purified by HPLC.

Product: 85 mg (35% of theory)

ESI-MS: (M+H) + = 762/764 (Cl)

Retention time (HPLC): 6.2 min (procedure A)

The following Examples can be prepared analogously:

[image]

Example 8

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[1-(4-amino-3-chloro-5-trifluoromethyl) -benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide

[image]

8a diethyl 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-malonate

24.11 g (0.11 mol) of diethyl 2-acetylamino-malonate was added to a freshly prepared solution of 2.55 g (0.11 mol) of sodium in 200 mL of abs. EtOH under a nitrogen atmosphere and the mixture was stirred for 15 min at RT. A solution of 27.00 g (0.11 mol) of 2-chloro-4-chloromethyl-6-trifluoromethyl-phenylamine (Example 2a) in 100 mL of 1,4-dioxane was quickly added dropwise and the mixture was stirred for 4 h at RT. 500 mL of water was added and the mixture was stirred for a further 16 h. The formed precipitate is filtered off, washed with water and dried i.vac.

Product: 40.0 g (84% of theory)

Rf = 0.14 (silica gel, PE/EtOAc = 2/1)

8b 2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid hydrochloride

50 mL conc. HCl was added to a solution of 40.0 g (94.16 mmol) of diethyl 2-acetylamino-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-malonate in 110 mL of AcOH and 150 mL of water and the reaction mixture was heated for 4 h at 140°C. The formed precipitate is filtered off and thrown away. The filtrate was evaporated i.vac., mixed with 100 mL EtOH and dried i.vac. The crude product is used in the next reaction step without further purification.

Product: 16 g (53% of theory)

ESI-MS: (M-H)- = 281/283 (Cl)

8c ethyl 2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate

16 g (50.14 mmol) of 2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid hydrochloride was dissolved in 350 mL of HCl (12 M EtOH) and stirred for 5 h at RT. The reaction mixture was evaporated to 100 mL i.vac. and mixed with 200 mL of diethyl ether. The formed precipitate is filtered off, washed with diethyl ether and dried i.vac.

Product: 12.2 g (70% of theory)

ESI-MS: (M+H)+ = 311/313 (Cl)

8d ethyl 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl) )-piperidine-1-carbonyl]-amino}-propionate

4.15 g (23.04 mmol) CDT was added at 0°C to a suspension of 8.00 g (23.04 mmol) ethyl 2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionate and 16.0 mL (115.00 mmol ) of triethylamine in 100 mL of DMF and the reaction mixture was stirred for 1.5 h at 0°C. A solution of 5.64 g (23.00 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one in 200 mL of DMF was added and the mixture was heated for 2 h at 100°C . The reaction mixture was cooled to RT, diluted with 1.5 L of water and stirred for another 10 min. The formed precipitate is filtered off, washed with water and dried i.vac.

Product: 13.0 g (97% of theory)

ESI-MS: (M+H) + = 582/584 (Cl)

8e 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl) -piperidine-1-carbonyl]-amino}-propionic acid

45 mL of 1 M NaOH was added to a solution of 13.00 g (22.34 mmol) of ethyl 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionate in 100 mL of EtOH and the mixture was stirred for 16 h at RT. EtOH was evaporated i.vac., 45 mL of 1M HCl was added and the mixture was stirred for 15 min. The formed precipitate is filtered off, washed with water and dried i.vac. at 75°C.

Product: 10.5 g (85% of theory)

ESI-MS: (M-H)- = 552/554 (Cl)

8f 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[1-(4-amino-3-chloro-5- trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide

0.69 mL (5.00 mmol) of triethylamine was added to a solution of 1.00 g (1.81 mmol) of 3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid, 0.34 g (1.81 mmol) [1,4']bipiperidinyl and 0.64 g (2.00 mmol ) TBTU in 150 mL THF and the mixture was stirred for 16 h at RT. The reaction mixture was evaporated i.vac., the residue was mixed with saturated NaHCO3 solution and the mixture was extracted copiously with EtOAc. Merged org. extracts are dried over MgSO4 and evaporated i.vac. The residue is purified by column chromatography (silica gel, EtOAc/MeOH/NH3 = 75:25:2.5).

Product: 350 mg (28% of theory)

ESI-MS: (M+H) + = 704/706 (Cl)

Rf = 0.58 (silica gel, DCM/cyc/MeOH/NH3 = 70/15/15/2)

Example 9

(S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

9a ethyl 4-amino-3-trifluoromethyl-benzoate

A solution of 150 g (0.66 mol) of N-(4-cyano-2-trifluoromethyl-phenyl)-acetamide in 360 mL of dry EtOH and 540 mL of 10 M ethanolic HCL is heated for 2 h 45 min at 70°C in a pressure apparatus. After the solution has cooled, the formed precipitate is suction filtered, washed with EtOH and the filtrate is evaporated i.vac. The residue is mixed with 300 mL of water and the same amount of EtOH, vigorously shaken, suction filtered and washed with water/EtOH 1:1. The crude product reacts further without further purification.

Product: 153 g (100% theoretical)

Rf = 0.4 (silica gel, PE/EtOAc 1:1)

9b 4-amino-3-trifluoromethyl-benzoic acid

At RT, a solution of 153 g (0.66 mol) of ethyl 4-amino-3-trifluoromethyl-benzoate in 350 mL of EtOH was added to a solution of 100 g (2.5 mol) of NaOH in 250 mL of water and the reaction mixture was stirred for 2 h at 45°C. EtOH was removed i.vac., the remaining aqueous solution was acidified with conc. HCl, the precipitated product was suction filtered, washed with water and air dried.

Product: 129 g (96% of theory)

ESI-MS: (M-H)- = 204

9c 4-amino-3-bromo-5-trifluoromethyl-benzoic acid

A solution of 6 mL (117 mmol) of bromine in 50 mL of acetic acid was slowly added dropwise to a solution of 21.0 g (102 mmol) of 4-amino-3-trifluoromethyl-benzoic acid in 250 mL of acetic acid and heated at 60°C for 2 h. After cooling, it was mixed with 1 L of water, and the precipitate was suction filtered. The residue was dissolved in DCM, the organic phase was alkalized with NaOH solution, the aqueous phase was separated and acidified with conc. HCl. The precipitate was suction filtered and dried at 60°C.

Product: 18 g (62% of theory)

ESI-MS: (M-H)- = 282/284 (Br)

Rf = 0.6 (silica gel, PE/EtOAc/AcOH 50:50:1)

9d (4-amino-3-bromo-5-trifluoromethyl-phenyl)-methanol

12 g (74 mmol) of CDI was added to a solution of 18 g (63.4 mmol) of 4-amino-3-bromo-5-trifluoromethyl-benzoic acid in 400 mL of THF, stirred for 1 h at RT and heated for 1 h at 40°C. The activated acid was then added drop by drop to a solution of 8.0 g (212 mmol) of NaBH4 in 200 mL of water, whereby the temperature should not be above 40°C. The reaction mixture was stirred for 2.5 h at RT, mixed with 300 mL semizinc. HCl, was stirred for 1 h and extracted copiously with EtOAc. The organic phase was washed with K2CO3 solution and dried over Na2SO4. After the dried substance and solvent were removed, the residue was dissolved at 50°C in isopropanol; after cooling, the precipitate was suction-filtered, placed in PE and suction-filtered again.

Product: 12.5 g (73% of theory)

EI: (M)+ = 269/271 (Br)

Rf = 0.9 (silica gel, MeOH)

9e 4-amino-3-bromo-5-trifluoromethyl-benzaldehyde

53 g (0.61 mol) MnO2 was added to a solution of 12.5 g (46.3 mmol) (4-amino-3-bromo-5-trifluoromethyl-phenyl)-methanol in 150 mL DCM and the reaction mixture was stirred overnight at RT. MnO2 was suction filtered, washed with DCM, the solvent was removed i.vac. and the rest was mixed with PE. The precipitate was suction filtered, washed with a little PE and dried.

Product: 9.5 g (77% of theory)

ESI-MS: (M+H) + = 268/270 (Br)

Rf = 0.6 (silica gel, PE/EtOAc 2:1)

9f 1-methyl 2-[1-(4-amino-3-bromo-5-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate

27.9 g (71.0 mmol) of 1-methyl 2-(triphenyl-λ5-phosphanilidene)-succinate was added to a solution of 9.5 g (35.4 mmol) of 4-amino-3-bromo-5-trifluoromethyl-benzaldehyde in 80 mL of THF and the reaction mixture was heated for 120 h at 40°C. The precipitate was suction filtered, the filtrate was evaporated i.vac., the residue was mixed with water and EtOAc, the organic phase was separated, washed 3 times with water and extracted three times with a 5% K2CO3 solution. The aqueous phase is acidified with conc. HCl, the formed precipitate was separated, washed with water and dried at 60°C.

Product: 5.9 g (44% of theory)

ESI-MS: (M+H) + = 382/384 (Br)

9g 1-methyl (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-succinate

In an argon atmosphere, 130 mg of (+)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene (cyclooctadiene)rhodium(I)tetrafluoroborate was added to a solution of 5.9 g (15.44 mmol) of 1-methyl 2- [1-(4-amino-3-bromo-5-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate in 50 mL degassed MeOH and 5.9 mL triethylamine and the reaction mixture was hydrogenated for 4 h at 50 psi H2 . Then the reaction solution was evaporated i.vac., the residue was dissolved in 100 mL of EtOAc, washed twice with 2 M HCl and abundantly extracted with a solution of 5% K2CO3. The aqueous phase is acidified with conc. HCl, extracted generously with EtOAc and the organic phase dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 5.8 g (98% theoretical)

ESI-MS: (M-H)- = 382/384 (Br)

9h methyl (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoate

3.70 g (15.1 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one was added to a solution of 5.80 g (15.1 mmol) of 1-methyl (S)-2 -(4-amino-3-bromo-5-trifluoromethyl-benzyl)-succinate, 4.98 g (15.1 mmol) TBTU, 2.04 g (15.1 mmol) HOBt and 4.87 mL (35 mmol) triethylamine in 200 mL THF and the reaction mixture is stirred overnight at RT. The reaction solution was evaporated i.vac., mixed with EtOAc and 20% citric acid solution, the organic phase was separated, washed with saturated NaHCO3 solution and dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 9.2 g (100% theoretical)

ESI-MS: (M+H)+ = 611/613 (Br)

9i (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid

A solution of 1.04 g (24.30 mmol) of lithium hydroxide hydrate in 30 mL of water was added at RT to a solution of 9.2 g (15.05 mmol) of methyl (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4- oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoate in 70 mL of THF and the reaction mixture was stirred 3 h at RT. THF was removed i.vac., the aqueous solution was acidified with conc. HCl, extracted liberally with EtOAc, the organic phase was separated and dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 7.8 g (87% of theory)

ESI-MS: (M+H) + = 597/599 (Br)

Analogous to the sequence described from 9f to 9i, it was possible to obtain 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and (S)-2-(4-amino- 3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1- yl]-butanoic acid from 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde (see Example 1b).

9k (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

154 mg (0.84 mmol) of 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 500 mg (0.84 mmol) of (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)- 4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid, 289 mg (0.9 mmol ) TBTU, 122 mg (0.9 mmol) HOBt and 0.35 mL (2.5 mmol) triethylamine in 40 mL THF and 5 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated i.vac., mixed with EtOAc and saturated NaHCO3 solution, the organic phase was separated and dried over Na2SO4. After removing the dried substance and the solvent, the residue was purified by chromatography (silica gel, gradient: DCM to MeOH/NH3 95:5).

Product: 423 mg (66% of theory)

ESI-MS: (M+H) + = 762/764 (Br)

Retention time (HPLC): 5.9 min (procedure A)

The following compounds were prepared analogously from, in each case, 500 mg of (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image]

The following Examples can be prepared analogously:

[image]

Example 9.10

(S)-2-(4-amino-3-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

100 mg of 10% Pd/C was added to a solution of 150 mg (0.2 mmol) of (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazine- 1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]- butane-1,4-dione in 20 mL MeOH and the reaction mixture was hydrogenized for 3 h at 50 psi H2 and at RT. The catalyst was suction filtered, the solvent evaporated i.vac., the residue was mixed with a solution of 5% K2CO3 and EtOAc, the organic phase was separated and evaporated i.vac. The residue was triturated with diisopropyl ether and suction filtered.

Product: 134 mg (100% theoretical)

ESI-MS: (M+H) + = 684

Retention time (HPLC): 5.5 min (procedure A)

Example 10

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-dimethylamino-piperidin-1-yl)-4-[4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

80.3 mg (0.25 mmol) TBTU, 0.21 mL (1.2 mmol) ethyldiisopropylamine and 38.5 mg (0.3 mmol) dimethyl-piperidin-4-yl-amine were added to a solution of 130 mg (0.24 mmol) (S)-2-(4-amino) -3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1 -yl]-butanoic acid in 10 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution is poured into 80 mL of a 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance is suction filtered, washed with 5 mL of water and air-dried over the weekend. The product is purified by chromatography using HPLC.

Product: 82 mg (53% of theory)

ESI-MS: (M+H) + = 663/665 (Cl)

Retention time (HPLC): 6.1 min (procedure A)

The following compounds are prepared analogously:

[image]

[image] [image]

Example 10.26

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-dimethylaminomethyl-phenyl)-piperidin-1-yl]-4-[4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

80 mg (0.25 mmol) TBTU and 87 µL (0.5 mmol) ethyldiisopropylamine were added to a solution of 130 mg (0.24 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo- 4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid in 2 mL DMF and the mixture was stirred for 30 min at RT. Then 80 mg (0.31 mmol) of dimethyl-(4-piperidin-4-yl-benzyl)-amine (used as hydrochloride) was added and the reaction mixture was stirred overnight at RT. The reaction solution was filtered through an injection filter and purified directly by chromatography using HPLC.

Product: 80 mg (45% of theory)

ESI-MS: (M+H) + = 753/755 (Cl)

Retention time (HPLC): 6.6 min (procedure A)

The following compounds were prepared analogously from, in each case, 130 mg of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and appropriate amounts of amines (with 1.07 eq. of ethyldiisopropylamine in the case of free amines and an additional amount of bases which is required when amine salts are used):

[image]

[image]

Example 10.34

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-1-piperidin-1-yl-butane-1,4-dione

[image]

62 mg (0.19 mmol) TBTU and 34 µL (0.2 mmol) ethyldiisopropylamine were added to a solution of 100 mg (0.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo- 4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid in 2 mL DMF and this was stirred for 30 min at RT. Then 24 µL (0.24 mmol) of piperidine was added and the reaction mixture was stirred for 64 h at RT. The reaction solution is purified directly by chromatography using HPLC.

Product: 54 mg (48% of theory)

ESI-MS: (M+H)+ = 620/622 (Cl)

Retention time (HPLC): 8.4 min (procedure A)

The following compounds were prepared analogously from, in each case, 100 mg of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image] [image]

Example 10.57

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6 -yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Solution 300 mg (0.54 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 190 mg (0.59 mmol) TBTU in 0.4 mL (2.27 mmol) ethyldiisopropylamine and 15 mL DMF were stirred for 1 h at RT. Then 160 mg (0.64 mmol) of 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine (used as hydrobromide) was added and the reaction solution was stirred for a further 3 h at RT. The reaction mixture is poured into 50 mL of a 15% K2CO3 solution, the precipitated product is suction filtered and purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:9:1).

Product: 100 mg (26% of theory)

ESI-MS: (M+H) + = 704/706 (Cl)

Retention time (HPLC): 6.1 min (procedure A)

The following compounds were prepared analogously from, in each case, 300 mg of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and appropriate amounts of amines (used as free amines or amine hydrochloride):

[image]

[image]

The compounds of Examples 10.64 and 10.65 can both be isolated from the reaction mixture if the 3-piperazin-1-yl-1-aza-bicyclo[2.2.2]octane used was contaminated with piperazine.

Example 10.66

4-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperazine-1-sulfonic acid (1-methyl-piperidin-4-yl)-amide

[image]

Solution 500 mg (0.90 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 320 mg (1.00 mmol) TBTU in 0.2 mL (1.14 mmol) ethyldiisopropylamine and 50 mL THF were stirred for 1 h at RT. Then 270 mg (1.03 mmol) of piperazine-1-sulfonic acid-(1-methyl-piperidin-4-yl)-amide and 5 mL of DMF were added. The reaction mixture was stirred overnight at RT. The reaction mixture was diluted with 50 mL of EtOAc, extracted with 30 mL of 15% K2CO3 solution and the organic phase was dried over Na2SO4. After removing the dried substance and the solvent, the residue was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:9:1).

Product: 170 mg (24% of theory)

ESI-MS: (M+H) + = 797/799 (Cl)

Retention time (HPLC): 6.4 min (procedure A)

Example 10.67

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-(5-amino-pentyl)-4-oxo-4-[4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide

[image]

61 mg (0.3 mmol) of tert-butyl (5-amino-pentyl)-carbamate was added to a solution of 260 mg (0.47 mmol) of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4 -oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 161 mg (0.50 mmol) TBTU in 0.43 mL (2.50 mmol) ethyldiisopropylamine and 10 mL DMF and the reaction mixture was stirred overnight at RT. 80 mL of 15% K2CO3 solution was added, the resulting mixture was stirred for 10 min, the precipitated substance was suction filtered; then it was washed with water and air-dried. The crude product was dissolved in 20 mL of DCM, mixed with 2 mL of TFA and stirred for 2 h at RT. The reaction mixture was neutralized with a 15% K2CO3 solution, the organic phase was separated and evaporated. The thus obtained crude product was directly purified with HPLC.

Product: 110 mg (37% of theory)

ESI-MS: (M+H) + = 637/639 (Cl)

Retention time (HPLC): 6.0 min (Procedure A)

The following compound was prepared analogously from 260 mg (0.47 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 142 mg (0.6 mmol) of tert. butyl (2-aminomethyl-benzyl)-carbamate:

[image]

Example 10.69

1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidine-4-carboxylic acid

[image]

2 mg (0.05 mmol) of lithium hydroxide hydrate, dissolved in a little water, was added to a solution of 15 mg (0.02 mmol) of methyl 1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)- 4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidine-4-carboxylate (Example 10.48) in 5 mL of THF and the reaction mixture was stirred for 3 h at RT. The solvent is eliminated i.vac., the residue is placed in water and acetonitrile and lyophilized.

Product: 14 mg (96% of theory)

ESI-MS: (M+H) + = 664/666 (Cl)

Retention time (HPLC): 7.2 min (procedure A)

The following compound was prepared analogously from 20 mg (0.03 mmol) methyl (1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-acetate (Example 10.43):

[image]

Example 10.71

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazine -1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4- part

[image]

850 mg (2.4 mmol) of 8-methyl-3-piperazin-1-yl-8-aza-bicyclo[3.2.1]acetate was added to a solution of 1.04 g (1.88 mmol) of (S)-2-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl ]-butanoic acid, 642 mg (2.0 mmol) TBTU and 1.64 mL (9.6 mmol) ethyldiisopropylamine in 20 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution is mixed with a 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance is suction filtered, washed with 50 mL of water and dried in air and purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10 :85:5).

Product: 1.07 g (77% of theory)

ESI-MS: (M+H) + = 744/746 (Cl)

Retention time (HPLC): 5.4 min (procedure A)

Example 10.72

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione

[image]

10.72a benzyl 4-(1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazine-1-carboxylate

241 mg (0.75 mmol) TBTU, 0.62 mL (3.6 mmol) ethyldiisopropylamine and 215 mg (0.71 mmol) benzyl 4-piperidin-4-yl-piperazine-1-carboxylate were added to a solution of 390 mg (0.71 mmol) (S)-2 -(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl) )-piperidin-1-yl]-butanoic acid in 10 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution is poured into 80 mL of 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance is suction filtered, washed with 5 mL of water and dried in air over the weekend.

Product: 580 mg (98% of theory)

ESI-MS: (M+H) + = 838/840 (Cl)

10.72b (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine- 3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione

100 mg of Raney nickel was added to a solution of 250 mg (0.30 mmol) of benzyl 4-(1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazine-1-carboxylate in 30 mL MeOH and the reaction mixture was stirred for 5 h at RT and 50 psi H2. In order to complete the reaction, another 100 mg of Raney nickel is added and the mixture is stirred for a further 10 h at RT. The catalyst is suction filtered, the solvent is eliminated i.vac. and the residue is purified by HPLC.

Product: 88 mg (42% of theory)

ESI-MS: (M+H) + = 704/706 (Cl)

Retention time (HPLC): 5.6 min (procedure A)

Example 10.73

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1H-imidazol-4-yl)-piperidin-1-yl]-4-[4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

400 mg (1.25 mmol) TBTU and 0.65 mL (3.73 mmol) ethyldiisopropylamine were added to a solution of 650 mg (1.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo- 4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid in 20 mL DMF and this was stirred for 30 min at RT. Then 340 mg (1.52 mmol) of 4-(1H-imidazol-4-yl)-piperidine (used as bis-hydrochloride) was added and the reaction mixture was stirred overnight at RT. It is evaporated, mixed with 30 mL of 15% K2CO3 solution, extracted twice, both times with 15 mL of DCMa and the organic phase is dried with MgSO4. After removing the dried substance and the solvent, the residue is purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 20:75:5).

Product: 460 mg (57% of theory)

ESI-MS: (M+H) + = 686/688 (Cl)

Rf = 0.35 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 10.74

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-1-{4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazin-1-yl}-butane-1,4-dione

[image]

10.74a tert. butyl 4-(4-bromo-phenyl)-piperazine-1-carboxylate

Boc-anhydride is added serially to a suspension of 10.0 g (36 mmol) of 4-(4-bromo-phenyl)-piperazine (used as hydrochloride) and 15 mL (108 mmol) of triethylamine in 150 mL of THF and the reaction mixture is heated for 3 h at 60 °C. After cooling, it is poured into water, the precipitate is extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4. After removing the dried substance and the solvent, the desired product is obtained.

Product: 12.0 g (98% of theory)

Rf = 0.6 (silica gel, cyc/EtOAc 2:1)

10.74b tert. butyl 4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazine-1-carboxylate

In a nitrogen atmosphere, a solution of 1.02 g (3.0 mmol) tert. butyl 4-(4-bromo-phenyl)-piperazine-1-carboxylate in 20 mL THF was slowly added dropwise to a solution of 2.06 mL (3.3 mmol) n-butyllithium (1.6 M in n-hexanes) in 40 mL dry THF cooled at -78°C and this was then stirred for 15 min at that temperature. Then a solution of 0.43 mL (3.0 mmol) of N,N-diethyl-2,2,2-trifluoroacetamide in 10 mL of THF was slowly added dropwise. When all additions are complete, the reaction mixture is placed for 2 h at -78°C, then poured into 100 mL of water, extracted twice with 50 mL of EtOAc both times, the organic phase is suction filtered through Na2SO4, evaporated i.vac. and purified by chromatography (silica gel, cyc/EtOAc 3:1).

Product: 267 mg (25% of theory)

EI: (M)+ = 358

Rf = 0.37 (silica gel, cyc/EtOAc 3:1)

10.74c 2,2,2-trifluoro-1-(4-piperazin-1-yl-phenyl)-ethanone

2.0 mL of TFA was added to a solution of 267 mg (0.75 mmol) of tert. butyl 4-[4-(2,2,2-trifluoroacetyl)-phenyl]-piperazine-1-carboxylate in 30 mL of DCM cooled to 0°C and the reaction mixture was stirred for 24 h while warming to RT. It is evaporated i.vac.; the crude product reacts further without purification.

ESI-MS: (M+H)+ = 259

10.74d (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine- 3-yl)-piperidin-1-yl]-1-{4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazin-1-yl}-butane-1,4-dione

The crude product obtained in 10.74c was added to a solution of 234 mg (0.42 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid, 136 mg (0.42 mmol) TBTU, 57 mg (0.42 mmol) HOBt and 0.14 mL (1.0 mmol) of triethylamine in 20 mL of THF and 2 mL of DMF and the reaction mixture was stirred for 2 h at RT. The reaction solution was mixed with half-saturated NaHCO 3 solution and extracted with 30 mL of EtOAc. The organic phase is suction filtered through Na2SO4, the filtrate is evaporated i.vac. and the residue was purified by chromatography (silica gel, EtOAc/MeOH 95:5).

Product: 246 mg (73% of theory)

ESI-MS: (M+H) + = 793/795 (Cl)

Rf = 0.27 (silica gel, EtOAc)

Example 10.75

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

10.75a methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoate

A solution of 3.0 g (8.83 mmol) 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.05 g (9.5 mmol) TBTU, 1.28 g (9.47 mmol) HOBt in 1.7 mL (9.76 mmol) of ethyldiisopropylamine and 100 mL of DMF were mixed for 1 h at RT. Then 2.2 g (9.51 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one were added and the reaction solution was stirred overnight at RT. The reaction mixture is evaporated i.vac., the residue is placed in DCM, washed with 10% citric acid solution and 15% K2CO3 solution and dried over Na2SO4. The dried substance is removed by filtering through activated carbon; after removing the solvent, the desired product is obtained.

Product: 4.8 g (98% of theory)

ESI-MS: (M+H) + = 553/555 (Cl)

Rf = 0.71 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.75b (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-yl]-butanoic acid

A solution of 558 mg (13.02 mmol) of lithium hydroxide hydrate in 12 mL of water was added to a solution of 4.8 g (8.68 mmol) of methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo- 4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoate in 28 mL of THF and the reaction solution was stirred for 7 h at RT. It is evaporated i.vac., mixed with 100 mL of water, acidified with 1 M HCl and the formed precipitate is suction filtered. The residue was dissolved in EtOAc, extracted with 15% K2CO3 solution and the aqueous phase reacidified with 1 M HCl. The formed precipitate is suction filtered and dried.

Product: 4.2 g (90% of theory)

ESI-MS: (M+H) + = 539/541 (Cl)

Rf = 0.09 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.75c (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4- [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The crude product was obtained analogously to 10.75a from 500 mg (0.93 mmol) of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 180 mg (0.98 mmol) of 1-methyl-4-piperidin-4-yl-piperazine. After it was done as described, it was purified first by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 70:27:3) and then by HPLC.

Product: 120 mg (18% of theory)

ESI-MS: (M+H) + = 704/706 (Cl)

Rf = 0.43 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Retention time (HPLC): 5.6 min (procedure A)

Example 10.76

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

10.76a methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1 ,2,4-triazol-1-yl)-piperidin-1-yl]-butanoate

The desired product is obtained analogously to 10.75a from 3.0 g (8.31 mmol) of 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.55 g (9.45 mmol) of 5-phenyl -2-piperidin-4-yl-2,4-dihydro-1,2,4-triazol-3-one.

Product: 2.5 g (50% of theory)

ESI-MS: (M+H) + = 566/568 (Cl)

Rf = 0.67 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.76b (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1, 2,4-triazol-1-yl)-piperidin-1-yl]-butanoic acid

The desired product is obtained analogously to 10.75b from 2.5 g (4.42 mmol) methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(5-oxo -3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butanoate.

Product: 2.5 g (50% of theory)

ESI-MS: (M+H)+ = 552/554 (Cl)

Rf = 0.14 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.76c (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4- [4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butane-1,4-dione

The crude product was obtained analogously to 10.75a from 500 mg (0.91 mmol) of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(5-oxo- 3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butanoic acid and 180 mg (0.98 mmol) 1-methyl-4-piperidin-4-yl - piperazine. After doing as described, it was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 70:27:3).

Product: 350 mg (54% of theory)

ESI-MS: (M+H) + = 717/719 (Cl)

Rf = 0.44 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Retention time (HPLC): 5.6 min (procedure A)

Example 10.77

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

10.77a methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-imidazo[4,5 -c]quinolin-3-yl)-piperidin-1-yl]-butanoate

The desired product is obtained analogously to 10.75a from 3.0 g (8.31 mmol) of 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 2.55 g (9.40 mmol) of 3-piperidine -4-yl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one.

Product: 5.2 g (100% theoretical)

ESI-MS: (M+H) + = 590/592 (Cl)

Rf = 0.66 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.77b (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-imidazo[4,5- c]quinolin-3-yl)-piperidin-1-yl]-butanoic acid

The desired product is obtained analogously to 10.75b from 5.2 g (8.81 mmol) methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo -1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butanoate.

Product: 2.75 g (54% of theory)

ESI-MS: (M+H) + = 576/578 (Cl)

Rf = 0.09 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.77c (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4- [4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The crude product was obtained analogously to 10.75a from 500 mg (0.87 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo- 1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butanoic acid and 170 mg (0.93 mmol) 1-methyl-4-piperidin-4-yl-piperazine . After this was done as described, the residue was mixed with diisopropylether and processed in an ultrasonic bath, the product was suction filtered and dried.

Product: 520 mg (81% of theory)

ESI-MS: (M+H)+ = 741/743 (Cl)

Rf = 0.40 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Retention time (HPLC): 4.5 min (procedure A)

Example 10.78

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

10.78a methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-4H-thieno[3 ,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butanoate

The desired product is obtained analogously to 10.75a from 3.0 g (8.31 mmol) of 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and 3.34 g (9.51 mmol) of 3-piperidine -4-yl-3,4-dihydro-1H-thieno[3,4-d]pyrimidin-2-one.

Product: 2.2 g (45% of theory)

ESI-MS: (M+H) + = 559/561 (Cl)

Rf = 0.56 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.78b (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-4H-thieno[3, 4-d]pyrimidin-3-yl)-piperidin-1-yl]-butanoic acid

The desired product is obtained analogously to 10.75b from 2.2 g (3.94 mmol) methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo -1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butanoate.

Product: 1.10 g (51% of theory)

ESI-MS: (M+H)+ = 545/547 (Cl)

Rf = 0.24 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

10.78c (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4- [4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The crude product was obtained analogously to 10.75a from 500 mg (0.92 mmol) of (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo- 1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidin-1-yl]-butanoic acid and 180 mg (0.98 mmol) 1-methyl-4-piperidin-4-yl - piperazine. After doing as described, it was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 70:27:3).

Product: 100 mg (81% of theory)

ESI-MS: (M+H)+ = 710/712 (Cl)

Rf = 0.43 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Retention time (HPLC): 5.5 min (procedure A)

Example 10.79

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl) -piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butan-1, 4-dione

[image]

Prepared analogously to Example 10.26 from 100 mg (0.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 39.1 mg (0.2 mmol) of 2-methyl-5-piperidin-4-yl-2,5- of diaza-bicyclo[2.2.1]heptane using triethylamine as base.

Product: 83 mg (63% of theory)

ESI-MS: (M+H) + = 730/732 (Cl)

Retention time (HPLC): 5.6 min (procedure A)

The following compounds can be prepared analogously to the described procedures:

[image]

Example 11

(S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl ]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

11a 4-amino-3,5-bis-trifluoromethyl-benzaldehyde

A solution of 5 g (19.67 mmol) of 4-amino-3,5-bis-trifluoromethyl-benzonitrile in 30 mL of formic acid was shaken in 10 equal samples in containers under pressure for 20 h at 110°C. Individual samples are pooled, filtered, washed with formic acid and evaporated i.vac. The residue was purified by chromatography (silica gel, PE/EtOAc 9:1).

Product: 3.8 g (75% of theory)

ESI-MS: (M-H)- = 256

11b 1-methyl 2-[1-(4-amino-3,5-bis-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate

12.79 g (32.6 mmol) of 1-methyl 2-(triphenyl-λ5-phosphanilidene)-succinate was added to a solution of 4.2 g (16.33 mmol) of 4-amino-3,5-bis-trifluoromethyl-benzaldehyde in 80 mL of THF and the reaction mixture heats for 120 h at 40°C. It is evaporated i.vac., the residue is mixed with water and EtOAc, the organic phase is separated, washed with water and extracted three times, each time with 80 mL of 5% K2CO3 solution. The combined aqueous phases were acidified with conc. HCl, the oily precipitate was extracted twice, both times with 100 mL EtOAc and dried over Na2SO4. After the dried material and solvent were removed, the desired product was obtained.

Product: 5.9 g (97% of theory)

EI: (M)+ = 371

11c 1-methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-succinate

Prepared analogously to Example 9g from 5.9 g of 1-methyl 2-[1-(4-amino-3,5-bis-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate.

Product: 5.9 g (97% of theory)

ESI-MS: (M+H)+ = 374

11d methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoate

Prepared analogously to Example 9h from 4.40 g (11.79 mmol) of 1-methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-succinate and 2.89 g (11.78 mmol) of 3-piperidine-4- yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one.

Product: 6.75 g (95% of theory)

ESI-MS: (M+H)+ = 601

Rf = 0.13 (silica gel, PE/EtOAc 1:1)

11e (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid

A solution of 0.72 g (16.75 mmol) of lithium hydroxide hydrate in 30 mL of water was added to a solution of 6.7 g (11.16 mmol) of methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo- 4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoate in 50 mL THF at RT and the reaction mixture was stirred 5 h at RT. THF was removed i.vac., the aqueous solution was cooled to 10°C and adjusted to pH 1 using conc. HCl, during which the product was precipitated. It is then suction filtered and dried at 65°C. The dry substance is mixed with 300 mL of diisopropylether, stirred overnight, suction filtered, washed with diisopropylether and dried.

Product: 5.6 g (86% of theory)

ESI-MS: (M+H)+ = 587

11f (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1- yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

197 mg (1.0 mmol) of 1-methyl-4-piperidin-4-yl-perhydro-1,4-diazepine was added to a solution of 400 mg (0.68 mmol) of (S)-2-(4-amino-3,5-bis -trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid , 241 mg (0.75 mmol) TBTU and 0.25 mL (1.8 mmol) triethylamine in 5 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution is slowly poured into 150 mL of 15% K2CO3 solution, the precipitated product is suction filtered and dried in air. The crude product is purified by chromatography (silica gel, gradient: DCM to MeOH/NH3 95:5).

Product: 400 mg (77% of theory)

ESI-MS: (M+H)+ = 767

Rf = 0.2 (silica gel, DCM/MeOH/NH3 85:15:1.5)

Retention time (HPLC): 5.6 min (procedure A)

The following compounds were prepared analogously from, in each case, 400 mg (Example 11.7: 387 mg) of (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image]

Example 11.7 is further reacted without purification.

Example 11.8

(S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1-yl)-butane-1,4-dione

[image]

Solution 560 mg (0.64 mmol) benzyl 4-(1-{(S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo- 1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazine-1-carboxylate (crude product from Example 11.7) in 50 mL MeOH was mixed with 200 mg 10% Pd/C and the reaction mixture was hydrogenated for 3 h at RT and 3 bar H2. The catalyst was suction filtered, the solution was evaporated i.vac. and the residue was purified by chromatography (silica gel, gradient: DCM to DCM/MeOH/NH3 10:85:5).

Product: 230 mg (49% of theory)

ESI-MS: (M+H)+ = 738

Rf = 0.27 (silica gel, DCM/MeOH/NH3 50:50:5)

The following compounds can be prepared analogously:

[image]

Example 12

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3,5 -bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

[image]

12a (4-amino-3,5-bis-trifluoromethyl-phenyl)-methanol

In a nitrogen atmosphere, 1.06 g (28 mmol) of NaBH4 was added to a batch solution of 7.2 g (28.0 mmol) of 4-amino-3,5-bis-trifluoromethyl-benzaldehyde (Example 11a) in 100 mL of MeOH and the reaction mixture was stirred for 2 h at RT . The reaction solution is acidified with 1 M HCl, evaporated i.vac., the residue is mixed with 150 mL of water and 150 mL of EtOAc, the organic phase is separated and dried over Na2SO4. After the dried substance and the solvent have been removed, the residue is purified by chromatography (silica gel, PE/EtOAc 9:1).

Product: 5.1 g (70% of theory)

ESI-MS: (M-H)- = 258

Rf = 0.15 (silica gel, PE/EtOAc 9:1)

12b 4-chloromethyl-2,6-bis-trifluoromethyl-phenylamine

4.35 mL (60 mmol) of thionyl chloride was added to a solution of 5.1 g (19.68 mmol) of (4-amino-3,5-bis-trifluoromethyl-phenyl)-methanol in 80 mL of DCM at RT and the reaction mixture was stirred for 3 h at RT. The reaction solution is poured into ice and an ice-cold NaHCO3 solution, the organic phase is separated and dried over Na2SO4. After the dried substance and the solvent have been removed, the residue reacts further without purification.

Product: 5.4 g (99% theoretical)

Rf = 0.55 (silica gel, PE/EtOAc 4:1)

12c diethyl 2-acetylamino-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-malonate

In a nitrogen atmosphere, 4.34 g (20.0 mmol) of diethyl 2-acetylamino-malonate was added to a solution of sodium ethoxide (prepared by the reaction of 0.46 g (20.0 mmol) of sodium with EtOH) in 50 mL of dry EtOH and the reaction mixture was stirred for 15 min at RT. A solution of 5.4 g (19.45 mmol) of 4-chloromethyl-2,6-bis-trifluoromethyl-phenylamine in 100 mL of 1,4-dioxane is added dropwise within 5 min, the reaction solution is stirred for a further 4 hours at RT, mixed with 1 L of water and stir overnight. The formed precipitate is filtered off, washed with water and dried in air.

Product: 5.2 g (57% of theory)

ESI-MS: (M+H)+ = 459

Rf = 0.65 (silica gel, PE/EtOAc 2:1)

12d monoethyl 2-acetylamino-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-malonate

2.0 mL of 6 M NaOH solution was added to a solution of 5.1 g (11.13 mmol) of diethyl 2-acetylamino-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-malonate in 80 mL of dry EtOH and the reaction mixture was stirred over nights at RT. It is evaporated i.vac., the residue is mixed with 150 mL of water, acidified with 1 M HCl, the aqueous phase is extracted with 150 mL of ETOAc, and the organic phase is dried over Na2SO4. After the dried substance and the solvent have been removed, the residue reacts further without purification.

Product: 4.3 g (90% of theory)

ESI-MS: (M+H)+ = 431

Rf = 0.1 (silica gel, PE/EtOAc 2:1)

12e ethyl 2-acetylamino-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-propionate

A solution of 4.3 g (10.0 mmol) of monoethyl 2-acetylamino-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-malonate in 200 mL of isopropanol and 80 mL of toluene is heated at 100°C for 15 h. Evaporate i.vac. and the residue reacts further without purification.

Product: 3.8 g (98% of theory)

Rf = 0.60 (silica gel, PE/EtOAc 1:1)

12f ethyl (R)-2-acetylamino-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-propionate

4 mL of Alkalase 2.4 L FG (Novozymes A/S; DK 2880 Bagsvaerd) was added to a solution of 3.65 g (20.5 mmol) of Na2HPO4 dihydrate in 130 mL of water heated to 37°C and the pH was adjusted to 7.5 by adding NaH2PO4 dihydrate. Then a solution of 3.8 g (9.84 mmol) of ethyl 2-acetylamino-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-propionate in 40 mL of acetone was added drop by drop at 37°C with stirring. The pH of the mixture was constantly maintained in the range of 7.4 to 7.6 by adding 1 M NaOH. After the addition was complete, the mixture was stirred for 4 h at 37°C. After cooling to RT, the reaction mixture is mixed with 300 mL of DCM, 300 mL of 15% K2CO3 solution and 200 mL of water. The organic phase is separated, washed with a 7% K2CO3 solution and dried over Na2SO4. After the dried substance and solvent were removed, the crude product (2.2 g) reacted further without purification.

ESI-MS: (M+H) + 387

Rf = 0.60 (silica gel, PE/EtOAc 1:1)

12g ethyl (R)-2-amino-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-propionate

A solution of 2.2 g of the crude product mentioned above is boiled without loss of steam in 4 M HCl for 1.5 h. It is evaporated i.vac., the residue is mixed with 50 mL of EtOH and 50 mL of ethanolic HCl (11.5 M) and the reaction mixture is stirred overnight at RT. Evaporate again i.vac., mix with 50 mL 15% K2CO3 solution, extract with 200 mL EtOAc, separate the organic phase and evaporate i.vac. The crude product (1.8 g) is further reacted without purification.

ESI-MS: (M+H) + 345

Rf = 0.50 (silica gel, DCM/MeOH/NH3 90:10:1)

12h ethyl (R)-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidine-1-carbonyl]-amino}-propionate

0.94 g (5.7 mmol) of CDT was added to a solution of 1.8 g of the above-mentioned crude product in 50 mL of THF cooled to -5°C and the reaction mixture was stirred for 45 min at this temperature and for a further 30 min after removing the ice bath. A solution of 1.28 g (5.2 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one in 50 mL of DMF was added. The reaction mixture is heated at 80°C for 2 h, after cooling it is evaporated i.vac., the residue is mixed with 150 mL EtOAc and 150 mL 10% citric acid solution, the organic phase is separated and dried over Na2SO4. After the dried substance and solvent were removed, the crude product (3.7 g) reacted further without purification.

ESI-MS: (M+H)+ 616

Rf = 0.25 (silica gel, EtOAc)

12i (R)-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine- 3-yl)-piperidine-1-carbonyl]-amino}-propionic acid

A solution of 0.4 g (9.5 mmol) of lithium hydroxide hydrate in 50 mL of water was added to a solution of 3.7 g of the above-mentioned crude product and the reaction mixture was stirred overnight at RT. THF is removed i.vac., mixed with 100 mL of water and acidified with 1 M HCl. The precipitated product is suction filtered, washed with 50 mL of water and dried in a drying cabinet at 60 °C.

Product: 2.6 g (90% of theory based on 12f)

ESI-MS: (M-H)- = 586

Retention time (HPLC): 7.1 min (procedure A)

12k 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3, 5-bis-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

155 mg (0.85 mmol) of 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 500 mg (0.85 mmol) of (R)-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)- 2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid, 289 mg (0.9 mmol ) TBTU and 0.28 mL (2.0 mmol) triethylamine in 50 mL THF and the reaction mixture was stirred overnight at RT. Evaporate i.vac., the residue is mixed with 100 mL EtOAc and 100 mL 10% citric acid solution, the organic phase is separated and the solvent is evaporated i.vac.. The residue is purified by chromatography (silica gel, gradient: DCM to DCM /MeOH/NH3 10:85:5).

Product: 570 mg (89% of theory)

ESI-MS: (M+H)+ = 753

Rf = 0.5 (silica gel, DCM/MeOH/NH3 85:15:1.5)

The following compounds were prepared analogously from (R)-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionic acid and corresponding amounts of amine:

[image]

[image]

Example 12.3 is reacted further without purification.

Example 12.4

4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid -[(R)-1-(4-amino-3,5 -bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide

[image]

Prepared analogously to Example 11.8 from 450 mg (0.52 mmol) benzyl 4-[1-((R)-3-(4-amino-3,5-bis-trifluoromethyl-phenyl)-2-{[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazine-1-carboxylate (crude product from Example 12.3).

Product: 200 mg (53% of theory)

ESI-MS: (M+H)+ = 739

Rf = 0.3 (silica gel, DCM/MeOH/NH3 50:50:5)

The following compounds can be prepared analogously:

[image]

Example 13

(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo- ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylate

[image]

13a (S)-3-[(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionyl]-4-benzyl-oxazolidin-2-one

In a nitrogen atmosphere, a solution of 1.33 g (4.1 mmol) (S)-4-benzyl-3-(2-benzyloxy-acetyl)-oxazolidin-2-one in 15 mL of THF, cooled to -60°C, was added dropwise within 10 min dissolve 5.1 mL (5.1 mmol, 1 M in THF) of sodium-bis-trimethylsilylamide in 4 mL of THF cooled to -60°C and the reaction mixture is stirred for 1 h at this temperature. It is then cooled to -70°C and a solution of 2.0 g (8.2 mmol) of 2-chloro-4-chloromethyl-6-trifluoromethyl-phenylamine (Example 2a) in 15 mL of THF is slowly added drop by drop. The resulting solution is kept for 1 h at -70°C, and then left to warm to RT for 2 h. 50 mL saturated NH4Cl solution is added, the mixture is extracted with 50 mL EtOAc, the organic phase is separated, the aqueous phase is extracted again with 50 mL EtOAc, the combined organic phases are washed with 100 mL saturated NaCl and 1 M KHSO4 and dried over Na2SO4. After the dried substance and the solvent have been removed, the residue is purified by chromatography (silica gel, PE/EtOAc 4:1).

Product: 2.1 g (96% of theory)

ESI-MS: (M+H) + = 533/535

Rf = 0.15 (silica gel, PE/EtOAc 4:1)

13b (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid

A solution of 0.34 g (8.0 mmol) of lithium hydroxide hydrate and 1.38 mL (16 mmol, 35% in water) of H2O2 in 25 mL of water is added to a solution, cooled to 0°C, of 2.1 g (3.94 mmol) of (S)-3-[ (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionyl]-4-benzyl-oxazolidin-2-one in 50 mL of THF and the reaction mixture was stirred for 2 h at 0°C. 5 mL of saturated Na2SO3 solution and 5 mL of saturated NaHCO3 solution were added, the mixture was stirred for a further 30 min and then the THF was removed i.vac. The aqueous residue is extracted twice with 50 mL of EtOAc in both cases and the combined organic phases are dried over MgSO4. After the dried substance and solvent have been removed, the crude product reacts further without purification.

13c (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl] -propan-1-one

1.35 g (4.20 mmol) TBTU, 0.70 mL (5.0 mmol) triethylamine and 0.75 g (4.01 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 1.5 g (4.01 mmol) (R)-3- (4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid in 50 mL of THF and the reaction mixture was stirred overnight at RT. The reaction solution is evaporated i.vac., the residue is mixed with 200 mL EtOAc and 200 mL saturated NaHCO3 solution, the organic phase is separated and extracted with 100 mL 5% citric acid solution. The citric acid extract is basified with K2CO3 and extracted twice with 100 mL EtOAc in both cases. The combined organic phases are evaporated i.vac. and the residue reacts further without purification.

Product: 1.75 g (81% of theory)

ESI-MS: (M+H) + = 539/541 (Cl)

Retention time (HPLC): 5.9 min (procedure A)

13d (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl] -propan-1-one

0.32 mL (2.5 mmol) of chloro-trimethyl-silane is added to a suspension of 450 mg (0.84 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-1-[4 -(4-methyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one and 380 mg (2.5 mmol) of NaI in 30 mL of acetonitrile and the reaction mixture was stirred for 7 h at 80°C. 30 mL of EtOH and 20 mL of isopropanol were added and the mixture was stirred for 30 min at RT, then 15 mL of NH3 solution was added and the mixture was stirred for another 30 min. It is evaporated i.vac., the residue is mixed with 100 mL of 15% K2CO3 solution, extracted with 100 mL of EtOAc, the organic phase is separated, washed with 3% Na2SO3 solution and dried over Na2SO4. After the dried substance and the solvent have been removed, the residue reacts further without purification.

Product: 300 mg (80% of theory)

Retention time (HPLC): 3.7 min (procedure A)

13e 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl chloride

6 g (12.1 mmol) of phosgene (20 wt.% in toluene) was added to a solution cooled to 0°C 2.5 g (10.2 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3 -benzodiazepine-2-one and 2.6 mL (14.9 mmol) of ethyldiisopropylamine in 75 mL of DCM and the reaction mixture was stirred for 30 min at this temperature. It was allowed to warm to RT, evaporated i.vac. to about 50 mL and filtered through silica gel, washed with 200 mL DCM/EtOAc (1:1) and the combined filtrates were re-evaporated i.vac.. The residue was mixed with diisopropylether, suction filtered and dried i.vac.

Product: 2.42 g (77% of theory)

Rf = 0.43 (silica gel, DCM/EtOAc 1:1)

13f (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo -ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylate

In a nitrogen atmosphere, 31 mg (0.7 mmol) NaH (55% in mineral oil) was added to a solution cooled to 0°C, 300 mg (0.67 mmol) (R)-3-(4-amino-3-chloro-5- trifluoromethyl-phenyl)-2-hydroxy-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-propan-1-one in 30 mL of THF and the reaction mixture was stirred for 30 min at this temperature. Then 246 mg (0.8 mmol) of 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl chloride is added serially and after removing the bath for cooling the solution is stirred for 3 h at RT. Evaporate i.vac., the residue is mixed with 4 mL of acetonitrile and purified using HPLC-MS.

Product: 88 mg (15% of theory)

ESI-MS: (M+H) + = 720/722 (Cl)

Retention time (HPLC): 6.0 min (Procedure A)

The following compounds can be prepared analogously from (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid and the corresponding amines analogously to Example 13c, 13d and 13f:

[image] [image]

Example 14

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipiperidinyl-1'-yl-1-(4-bromo -3-methyl-benzyl)-2-oxo-ethyl]-amide

[image]

14a ethyl 2-amino-3-(4-bromo-3-methyl-phenyl)-propionate hydrochloride

A mixture of 31.4 g (115 mmol) N-(diphenylmethylene)-glycine ethyl ester, 28.5 g (108 mmol) (4-bromo-3-methylphenyl)-methylbromide, 3.55 g (11.0 mmol) tetrabutylammonium bromide, 116 g (550 mmol) K2CO3 and 400 mL of acetonitrile is boiled without loss of steam for 4 h. The solid is filtered off, and the resulting liquid is concentrated by evaporation in a vacuum. The residue is placed in 500 mL of tert-butylmethylether and after the addition of 200 mL of 10% HCl, it is stirred overnight at RT. The organic phase is separated, the aqueous phase is washed twice with 50 mL of tert-butylmethylether and then neutralized with a 10% Na2CO3 solution while cooling from the outside with ice, and is generously extracted with DCM. The combined organic phases are washed two more times with 50 mL of water, dried over MgSO4, filtered through activated carbon and evaporated i.vac. The oily residue is dissolved in 50 mL of anhydrous EtOH, mixed with ethereal HCl solution and diluted with tert-butyl methyl ether to a total volume of 500 mL. After 20 minutes of mixing, a colorless crystalline precipitate forms, which is suction filtered and dried in air.

Product: 17.6 g (47% of theory)

Rf = 0.45 (silica gel, DCM/MeOH/NH3 9:1:0.1)

14b ethyl 3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino }-propionate

3.28 g (20.0 mmol) of CDT and 2.77 mL (20.0 mmol) of triethylamine were added to an ice-cold suspension of 6.45 g (20.0 mmol) of ethyl 2-amino-3-(4-bromo-3-methyl-phenyl)-propionate hydrochloride in 50 mL DMF. The reaction mixture is stirred for 1 h at 0 °C and 1 h at Rt, then it is mixed with a suspension of 4.63 g (20.0 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one in 50 mL DMF. The mixture is heated for 1.5 hours at 80°C and then mixed in 500 mL of water. The precipitate that solidifies after some time is ground using an Ultra-Turrax mixer, washed thoroughly with water, suction filtered and dried at 50°C in a dryer with circulating air.

Product: 11.9 g (97% theoretical; contains 1.0 eq. DMF)

Rf = 0.40 (silica gel, DCM/MeOH/NH3 9:1:0.1)

14c 3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino} -propionic acid

60 mL of 1 M NaOH is added to a solution of 10.9 g (20 mmol) of ethyl 3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidine-1-carbonyl]-amino}-propionate in 60 mL of EtOH and the mixture was boiled without loss of steam for 2 h. After cooling, it is diluted with 50 mL of water and acidified with a 20% solution of citric acid. The obtained precipitate is suction filtered, thoroughly washed with water and dried at 50°C in a dryer with circulating air.

Product: 9.6 g (93% of theory)

ESI-MS: (M-H)- = 513/515 (Br)

Rf = 0.10 (silica gel, DCM/MeOH 9:1)

14d 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[2-[1,4']bipiperidinyl-1'-yl-1-(4- bromo-3-methyl-benzyl)-2-oxo-ethyl]-amide

The product is obtained analogously to Example 2f from 515 mg (1.00 mmol) of 3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-carbonyl]-amino}-propionic acid and 177 mg (1.00 mmol) of [1,4']bipiperidinyl.

Product: 320 mg (48% of theory)

ESI-MS: (M+H)+ = 665/667 (Br)

Rf = 0.33 (silica gel, DCM/MeOH/NH3 9:1:0.1)

The following compounds were prepared analogously from 3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- carbonyl]-amino}-propionic acid and corresponding amounts of amine:

[image]

[image]

Example 15

{4-[1-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetic acid

[image]

1.0 mL (1.00 mmol) of 1 M NaOH was added to a solution of 80 mg (0.11 mmol) of ethyl {4-[1-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetate (Example 14.4) in 4 mL of THF. The reaction mixture was stirred overnight at RT and the solvent was removed i.vac. 1 mL of 1 M HCl was added to the residue and evaporated again to dryness. The residue is taken up in EtOH and after filtration the resulting liquid is concentrated by evaporation i.vac. The residue is triturated with diisopropyl ether and dried in air after filtration.

Product: 80 mg (100% theoretical)

Retention time (HPLC): 5.9 min (procedure A)

The following compounds were prepared analogously from individual ethyl esters (Examples 14.5 and 14.6):

[image]

[image]

Example 16

2-(4-bromo-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

16a 4-tert-butyl, 1-ethyl 2-(4-bromo-3-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product is prepared analogously to Example 2b from 11.4 g (41.7 mmol) of 4-tert-butyl, 1-ethyl 2-ethoxycarbonyl-succinate and 11.0 g (41.7 mmol) of 1-bromo-4-bromomethyl-2-methyl-benzene.

Product: 21.3 g (100% theoretical)

Rf = 0.64 (silica gel, PE/EtOAc 8:2)

16b ethyl 2-(4-bromo-3-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product was prepared analogously to Example 2c from 21.3 g (41.7 mmol) of 4-tert-butyl, 1-ethyl 2-(4-bromo-3-methyl-benzyl)-2-ethoxycarbonyl-succinate.

Product: 7.8 g (47% of theory)

Rf = 0.26 (silica gel, PE/EtOAc 8:2)

16c diethyl 2-(4-bromo-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-ethyl}-malonate

The product is prepared analogously to Example 2d from 7.80 g (19.4 mmol) of ethyl 2-(4-bromo-3-methyl-benzyl)-2-ethoxycarbonyl-succinate and 4.50 g (19.4 mmol) of 3-piperidin-4-yl-3, 4-dihydro-1H-quinazolin-2-one.

Product: 8.30 g (70% of theory)

EI-MS: (M)+ = 613/615 (Br)

Rf = 0.80 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

16d 2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] - butanoic acid

The product is prepared analogously to Example 2e from 8.30 g (13.5 mmol) diethyl 2-(4-bromo-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate.

Product: 5.10 g (74% of theory)

EI-MS: (M)+ = 513/515 (Br)

Rf = 0.20 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

16e 2-(4-bromo-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The product is prepared analogously to Example 2f from 0.51 g (1.00 mmol) of 2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)-piperidin-1-yl]-butanoic acid and 0.18 g (1.00 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 250 mg (37% of theory)

EI-MS: (M)+ = 678/680 (Br)

Rf = 0.50 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

The following compounds were prepared analogously from 2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image]

Example 16.4

[4-(1-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

The synthesis was carried out using a Chemspeed ASW2000 synthesis robot (Chemspeed Ltd., Rheinstraße 32, CH-4302 Augst, Switzerland).

Mixture:

AGV 1: 102 mg (0.20 mmol) 2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) )-piperidin-1-yl]-butanoic acid in 3 mL THF;

AGV 2: 51 mg (0.20 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate in 2 mL of THF;

AGV 3: 64 mg (0.20 mmol) TBTU in 2 mL DMF;

AGV 4: 0.14 mL (1.00 mmol) triethylamine;

AGV 5: 1.00 mL 4 M NaOH;

AGV 6: 1.00 mL 4 M HCl;

AGV 7: 6 mL THF.

AGVs 1 to 4 were placed properly, then pipetted together with a robot and shaken for 8 h at RT. The reaction mixtures were concentrated by evaporation, mixed with 7 mL of EtOAc, the resulting solutions were each washed with 10 mL of 10% K2CO3 solution and 6 mL of water and then freed from the solvent again. The residues were each dissolved in AGV 7 and after the addition of AGV 5 each was stirred for 6 h at RT. The reaction mixtures were each neutralized by adding AGV 6, then concentrated by evaporation. The resulting residue was dissolved in 1.9 mL of DMF and placed on a microtiter plate. The samples were separated using an HPLC-MS apparatus (Agilent Technologies, Agilent 1100 Series Modules and Systems for HPLC and LC/MS), and the product was collected under mass control. The final product is dry frozen.

Product: 4 mg (3% of theory).

ESI-MS: (M-H)- = 721/723 (Br)

(M+H)+ = 723/725 (Br)

Example 16.5

methyl (1'-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate

[image]

The synthesis was carried out using a Chemspeed ASW2000 synthesis robot (Chemspeed Ltd., Rheinstraße 32, CH-4302 Augst, Switzerland).

Mixture:

AGV 1: 206 mg (0.40 mmol) 2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) )-piperidin-1-yl]-butanoic acid in 3 mL THF;

AGV 2: 102 mg (0.40 mmol) ethyl [4,4']bipiperidinyl-1-yl-acetate in 4 mL THF;

AGV 3: 128 mg (0.40 mmol) TBTU in 4 mL DMF;

AGV 4: 0.14 mL (1.00 mmol) triethylamine;

AGVs 1 to 4 were placed properly, then pipetted together with a robot and shaken for 8 h at RT. The reaction mixtures were concentrated by evaporation, mixed with 7 mL EtOAc and 6 mL 10% K2CO3 solution, shaken vigorously, the aqueous phase was separated and discarded. The organic phase was concentrated by evaporation and dissolved in 6 mL of MeOH. A third of this solution was taken and placed on a microtiter plate. The samples were separated using an HPLC-MS apparatus (Agilent Technologies, Agilent 1100 Series Modules and Systems for HPLC and LC/MS), and the product was collected under mass control. The final product is dry frozen.

Product: 9 mg (9% of theory).

EI-MS: (M)+ = 735/737 (Br)

Rf = 0.38 (silica gel, DCM/MeOH 9:1)

The remaining 2/3 of the MeOH solution was concentrated by evaporation and the crude product (195 mg) was further reacted in Example 16.6.

Example 16.6

(1'-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid

[image]

The synthesis was carried out using a Chemspeed ASW2000 synthesis robot (Chemspeed Ltd., Rheinstraße 32, CH-4302 Augst, Switzerland).

Mixture:

AGV 1: 195 mg (0.26 mmol) methyl (1'-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate;

AGV 2: 5 mL MeOH

AGV 3: 1.00 mL 4 M NaOH;

AGV 4: 1.00 mL 4 M HCl;

AGV 1 was dissolved in AGV 2 and then AGV 3 was added. The mixture was stirred for 5 h at 20 °C and then neutralized with AGV 4. The reaction mixture was concentrated by evaporation and dissolved in 2 mL of DMF. The samples were separated using an HPLC-MS apparatus (Agilent Technologies, Agilent 1100 Series Modules and Systems for HPLC and LC/MS), and the product was collected under mass control. The final product is dry frozen.

Product: 22 mg (11% of theory).

ESI-MS: (M+H)+ = 722/724 (Br)

Rf = 0.22 (silica gel, DCM/MeOH 9:1)

Example 17

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(4-chloro-3-methyl-benzyl)-2-[4-(4 -methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

[image]

17a ethyl 2-amino-3-(4-chloro-3-methyl-phenyl)-propionate hydrochloride

The product is prepared analogously to Example 14a from 31.4 g (115 mmol) of N-(diphenylmethylene)-glycine ethyl ester and 25.2 g (115 mmol) of 4-bromomethyl-1-chloro-2-methyl-benzene.

Product: 20.4 g (64% of theory)

ESI-MS: (M+H)+ = 241/243 (Cl)

Rf = 0.35 (silica gel, DCM/MeOH/NH3 9:1:0.1)

17b ethyl 3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino }-propionate

The product is obtained analogously to Example 14b from 5.56 g (20.0 mmol) of ethyl 2-amino-3-(4-chloro-3-methyl-phenyl)-propionate hydrochloride and 4.63 (20.0 mmol) of 3-piperidin-4-yl-3, 4-dihydro-1H-quinazolin-2-one.

Product: 9.50 g (95% of theory)

ESI-MS: (M-H)- = 497/499 (Cl)

17c 3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino} -propionic acid

The product is obtained analogously to Example 14c from 9.50 g (19.0 mmol) ethyl 3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidine-1-carbonyl]-amino}-propionate.

Product: 8.90 g (99% theoretical)

ESI-MS: (M-H)- = 469/471 (Cl)

Rf = 0.10 (silica gel, DCM/MeOH 9:1)

17d 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(4-chloro-3-methyl-benzyl)-2-[4-( 4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

The product was prepared analogously to Example 2f from 706 mg (1.50 mmol) of 3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-carbonyl]-amino}-propionic acid and 275 g (1.50 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 250 mg (26% of theory)

ESI-MS: (M+H) + = 636/638 (Cl)

Rf = 0.17 (silica gel, DCM/MeOH/NH3 9:1:0.1)

The following compounds were prepared analogously from 3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- carbonyl]-amino}-propionic acid and corresponding amounts of amine:

[image]

[image]

Example 18

[1'-(3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl ]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetic acid

[image]

The product was prepared analogously to Example 15 from 220 mg (0.28 mmol) ethyl [1'-(3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetate.

Product: 190 mg (99% of theory)

ESI-MS: (M+H) + = 679/681 (Cl)

Rf = 0.13 (silica gel, DCM/MeOH 9:1)

Example 19

2-(4-chloro-3-methyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

19a 4-tert-butyl, 1-ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product is prepared analogously to Example 2b from 19.5 g (71.0 mmol) of 4-tert-butyl, 1-ethyl 2-ethoxycarbonyl-succinate and 15.5 g (71.0 mmol) of 4-bromomethyl-1-chloro-2-methyl-benzene.

Product: 25.7 g (88% of theory)

Rf = 0.74 (silica gel, DCM)

19b ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product was prepared analogously to Example 2c from 21.3 g (41.7 mmol) of 4-tert-butyl, 1-ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate.

Product: 22.2 g (100% theoretical)

Rf = 0.18 (silica gel, DCM)

19c diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-ethyl}-malonate

The product is prepared analogously to Example 2d from 8.00 g (22.4 mmol) of ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate and 5.18 g (22.4 mmol) of 3-piperidin-4-yl-3, 4-dihydro-1H-quinazolin-2-one.

Product: 9.20 g (72% of theory)

EI-MS: (M) + = 569/570 (Cl)

Rf = 0.64 (silica gel, DCM/MeOH/NH3 9:1:0.1)

19d 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] - butanoic acid

The product was prepared analogously to Example 2e from 9.20 g (16.2 mmol) diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate.

Product: 7.20 g (95% of theory)

ESI-MS: (M-H)- = 468/470 (Cl)

19e 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The product is prepared analogously to Example 2f from 470 mg (1.00 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)-piperidin-1-yl]-butanoic acid and 593 mg (1.10 mmol) of 1-ethyl-4-piperidin-4-yl-piperazine tris-trifluoroacetate.

Product: 280 mg (43% of theory)

EI-MS: (M) + = 648/650 (Cl)

Rf = 0.47 (silica gel, DCM/MeOH/NH3 9:1:0.1)

The following compounds were prepared analogously from 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image]

Example 19.13

[4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

The product is obtained analogously to Example 16.4 from 94 mg (0.20 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.

Product: 27 mg (19% of theory)

EI-MS: (M) + = 679/681 (Cl)

Retention time (HPLC): 5.9 min (procedure A)

Example 19.14

methyl (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate

[image]

The product is obtained analogously to Example 16.5 from 188 mg (0.40 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline) -3-yl)-piperidin-1-yl]-butanoic acid and 102 mg (0.40 mmol) of ethyl [4,4']bipiperidinyl-1-yl-acetate.

Product: 27 mg (30% of theory)

ESI-MS: (M+H)+ = 692/694 (Cl)

Rf = 0.36 (silica gel, DCM/MeOH 9:1)

Example 19.15

(1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid

[image]

The product is obtained analogously to Example 16.6 from 184 mg (0.26 mmol) methyl (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate.

Product: 30 mg (16% of theory)

ESI-MS: (M+H) + = 678/680 (Cl)

Rf = 0.21 (silica gel, DCM/MeOH 9:1)

The following compounds were prepared from individual ethyl esters (Examples 19.7 to 19.9) analogously to Example 15:

[image]

[image]

Example 20

2-(4-chloro-3-methyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

20a diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3 -yl)-piperidin-1-yl]-ethyl}-malonate

The product is prepared analogously to Example 2d from 1.43 g (4.00 mmol) ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate and 981 mg (4.00 mmol) 3-(1-methyl-piperidine-4 -yl)-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one.

Product: 2.10 g (90% of theory)

Rf = 0.69 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

20b 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)- piperidin-1-yl]-butanoic acid

The product is prepared analogously to Example 2e from 2.10 g (3.60 mmol) diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-ethyl}-malonate. The product reacts further without purification.

Product: 1.20 g (69 % of theory)

20c 2-(4-chloro-3-methyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

The product is prepared analogously to Example 2f from 800 mg (1.65 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro) -1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 302 mg (1.65 mmol) of 1-(1-methyl-piperidin-4-yl)-piperazine.

Product: 400 mg (37% of theory)

EI-MS: (M) + = 648/650 (Cl)

Rf = 0.50 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 20.1

2-(4-chloro-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

The product is prepared analogously to Example 2f from 400 mg (0.83 mmol) 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro) -1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butanoic acid and 152 mg (0.83 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 200 mg (37% of theory)

EI-MS: (M) + = 648/650 (Cl)

Rf = 0.51 (silica gel, DCM/cyc/MeOH/NH3 70:15:15:2)

Example 21

[4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4 -triazol-1-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

21a diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole) -1-yl)-piperidin-1-yl]-ethyl}-malonate

The product is prepared analogously to Example 2d from 5.00 g (14.0 mmol) ethyl 2-(4-chloro-3-methyl-benzyl)-2-ethoxycarbonyl-succinate and 3.42 g (14.0 mmol) 5-phenyl-2-piperidine-4- yl-2,4-dihydro-1,2,4-triazol-3-one.

Product: 5.50 g (67 % of theory)

Rf = 0.50 (silica gel, DCM/MeOH/NH3 9:1:0.1)

21b 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl) )-piperidin-1-yl]-butanoic acid

The product is prepared analogously to Example 2e from 5.50 g (9.43 mmol) diethyl 2-(4-chloro-3-methyl-benzyl)-2-{2-oxo-2-[4-(5-oxo-3-phenyl-4 ,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-ethyl}-malonate.

Product: 2.80 g (62 % of theory)

ESI-MS: (M-H)- = 481/483 (Cl)

21c [4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2, 4-triazol-1-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

The product is obtained analogously to Example 16.4 from 96 mg (0.20 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro -1,2,4-triazol-1-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.

Product: 3 mg (2% of theory)

ESI-MS: (M+H)+ = 692/694 (Cl)

Example 21.1

methyl (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4- triazol-1-yl)-piperidin-1-yl]-butyryl}-4,4'-bipiperidinyl-1-yl)-acetate

[image]

The product is obtained analogously to Example 16.5 from 193 mg (0.40 mmol) of 2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro -1,2,4-triazol-1-yl)-piperidin-1-yl]-butanoic acid and 102 mg (0.40 mmol) of ethyl [4,4']bipiperidinyl-1-yl-acetate.

Product: 14 mg (15% of theory)

ESI-MS: (M+H) + = 705/707 (Cl)

Rf = 0.32 (silica gel, DCM/MeOH 9:1)

Example 21.2

(1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazole -1-yl)-piperidin-1-yl]-butyryl}-4,4'-bipiperidinyl-1-yl)-acetic acid

[image]

The product is obtained analogously to Example 16.6 from 187 mg (0.26 mmol) methyl (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl) -4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butyryl}-4,4'-bipiperidinyl-1-yl)-acetate.

Product: 11 mg (6% of theory)

ESI-MS: (M+H)+ = 691/693 (Cl)

Rf = 0.21 (silica gel, DCM/MeOH 9:1)

Example 22

2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

22a 1-(3-bromo-4-chloro-5-methyl-phenyl)-ethanone

25.0 g (148 mmol) of 1-(4-chloro-3-methyl-phenyl)-ethanone was added dropwise to 59.2 g (444 mmol) of aluminum trichloride. The temperature rises to 70°C. The mixture was stirred for 30 min at 80 °C and then 10.7 mL (170 mmol) of bromine was added drop by drop at this temperature. The reaction mixture was stirred for 1 h at 80°C and then placed in ice. The aqueous phase was extracted with diethyl ether, and the combined organic extracts were washed with saturated NaHCO3 solution. The organic phase is dried over Na2SO4, and the solvent is removed i.vac. Purification is carried out by chromatography on silica gel (toluene).

Product: 14.0 g (38% of theory)

EI-MS: (M)+ = 246/248/250 (Br, Cl)

Rf = 0.28 (silica gel, toluene)

22b 3-bromo-4-chloro-5-methyl-benzene acid

8.7 mL (171 mmol) of bromine is added dropwise at 0°C to a solution of 22.8 g (570 mmol) of NaOH in 114 mL of water so that the temperature does not exceed 10°C. At a temperature of 10°C, 14.0 g (57.0 mmol) of 1-(3-bromo-4-chloro-5-methyl-phenyl)-ethanone was added dropwise to 57 mL of 1,4-dioxane and the mixture was stirred for 2 h at RT. The reaction mixture is diluted with water and the resulting bromine is separated. The aqueous phase is acidified semiconc. HCl, the precipitate is suction filtered and washed with water.

Product: 11.0 g (78 % of theory)

EI-MS: (M)+ = 248/250/252 (Br, Cl)

melting point: 207-209°C

22c (3-bromo-4-chloro-5-methyl-phenyl)-methanol

8.1 g (50 mmol) of CDI was added to a solution of 11.0 g (44 mmol) of 3-bromo-4-chloro-5-methyl-benzene acid in 285 mL of THF at RT. The reaction mixture was stirred for 1 h at 40°C. This solution was added to a solution of 5.38 g (142 mmol) of NaBH4 in 47.5 mL of water. The mixture is stirred for 3 h at RT, then diluted with 300 mL of water and acidified with semiconc. HCl. The aqueous phase is extracted with EtOAc and the organic phase is washed with water and then with saturated NaHCO3 solution. The organic phase is dried over Na2SO4 and the solvent is removed i.vac.

Product: 9.00 g (87% of theory)

ESI-MS: (M-H)- = 233/235/237 (Br, Cl)

Rf = 0.62 (silica gel, PE/EtOAc 1:1)

22d 1-bromo-5-bromomethyl-2-chloro-3-methyl-benzene

5.2 mL (19 mmol) phosphorus tribromide is added dropwise to a solution of 9.00 g (38 mmol) (3-bromo-4-chloro-5-methyl-phenyl)-methanol in 250 mL diethyl ether at RT and boiled without loss of steam 1 h. The reaction mixture is added to a saturated solution of NaHCO3, the organic phase is separated, washed with water and dried over Na2SO4. After the dried substance and the solvent were removed, the desired product was obtained.

Product: 10.7 g (94% of theory)

EI-MS: (M)+ = 296/298/300/302 (2Br, Cl)

Rf = 0.89 (silica gel, PE/EtOAc 1:1)

22e 4-tert-butyl, 1-ethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product is prepared analogously to Example 2b from 9.86 g (36 mmol) of 4-tert-butyl, 1-ethyl 2-ethoxycarbonyl-succinate and 10.7 g (36 mmol) of 1-bromo-5-bromomethyl-2-chloro-3-methyl- benzene.

Product: 17.5 g (99% theoretical)

ESI-MS: (M+H) + = 513/515/517 (Br, Cl)

Rf = 0.57 (silica gel, DCM)

22f 1-ethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-ethoxycarbonyl-succinate

The product was prepared analogously to Example 2c from 18.0 g (37 mmol) of 4-tert-butyl, 1-ethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-ethoxycarbonyl-succinate. The crude product still containing TFA is reacted further without purification.

ESI-MS: (M-H)- = 433/435/437 (Br, Cl)

22g diethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) )-piperidin-1-yl]-ethyl}-malonate

The product is prepared analogously to Example 2d from 18.2 g (42 mmol) of 1-ethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-ethoxycarbonyl-succinate and 9.60 g (42 mmol) of 3-piperidine- 4-yl-3,4-dihydro-1H-quinazolin-2-one.

Product: 15.0 g (56% of theory)

EI-MS: (M)+ = 647/649/651(Br, Cl)

Rf = 0.60 (silica gel, DCM/MeOH/NH3 9:1:0.1)

22h 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butanoic acid

The product is prepared analogously to Example 2e from 15.0 g (23 mmol) diethyl 2-(3-bromo-4-chloro-5-methyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate.

Product: 11.8 g (93% of theory)

Rf = 0.20 (silica gel, EtOAc/MeOH/acetic acid 8:2:0.1)

22i 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

The product was prepared analogously to Example 2f from 1.09 g (2.00 mmol) of 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 367 mg (2.00 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 773 mg (54% of theory)

EI-MS: (M)+ = 712/714/716 (Br, Cl)

Rf = 0.24 (silica gel, DCM/MeOH/NH3 9:1:0.1)

The following compounds were prepared analogously from 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-yl]-butanoic acid and corresponding amounts of amine:

[image]

[image]

Example 22.4

[4-(1-{2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

The product is obtained analogously to Example 16.4 from 109 mg (0.20 mmol) of 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.

Product: 10 mg (6% of theory)

ESI-MS: (M-H)- = 755/757/759 (Br, Cl)

Rf = 0.21 (silica gel, DCM/MeOH 9:1)

Example 22.5

methyl (1'-{2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate

[image]

The product is obtained analogously to Example 16.5 from 220 mg (0.40 mmol) of 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 102 mg (0.40 mmol) of ethyl [4,4']bipiperidinyl-1-yl-acetate.

Product: 19 mg (18% of theory)

ESI-MS: (M+H)+ = 770/772/774 (Br, Cl)

Rf = 0.36 (silica gel, DCM/MeOH 9:1)

Example 22.6

(1'-{2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid

[image]

The product is obtained analogously to Example 16.6 from 204 mg (0.26 mmol) methyl (1'-{2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate.

Product: 25 mg (12% of theory)

ESI-MS: (M+H) + = 756/758/760 (Br, Cl)

Rf = 0.23 (silica gel, DCM/MeOH 9:1)

Example 23

4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(3-bromo-4-chloro-5-methyl-benzyl)-2-[ 4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

[image]

23a ethyl 2-amino-3-(3-bromo-4-chloro-5-methyl-phenyl)-propionate hydrochloride

The product is prepared analogously to Example 14a from 6.06 g (22.2 mmol) of N-(diphenylmethylene)-glycine ethyl ester and 6.30 g (115 mmol) of 1-bromo-5-bromomethyl-2-chloro-3-methyl-benzene.

Product: 5.82 g (77% of theory)

ESI-MS: (M+H) + = 320/322/324

Rf = 0.70 (silica gel, DCM/MeOH/NH3 9:1:0.1)

23b ethyl 3-(3-bromo-4-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- carbonyl]-amino}-propionate

The product is obtained analogously to Example 14b from 5.82 g (16.3 mmol) of ethyl 2-amino-3-(3-bromo-4-chloro-5-methyl-phenyl)-propionate hydrochloride and 3.77 (16.3 mmol) of 3-piperidine-4- yl-3,4-dihydro-1H-quinazolin-2-one.

Product: 7.60 g (81% of theory)

Rf = 0.52 (silica gel, DCM/MeOH/NH3 9:1:0.1)

23c 3-(3-bromo-4-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl ]-amino}-propionic acid

The product is obtained analogously to Example 14c from 7.60 g (13.1 mmol) ethyl 3-(3-bromo-4-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H -quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionate.

Product: 6.70 g (93 % of theory)

ESI-MS: (M-H)- = 547/549/551 (Br, Cl)

Rf = 0.05 (silica gel, DCM/MeOH/NH3 9:1:0.1)

23d 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(3-bromo-4-chloro-5-methyl-benzyl)-2- [4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide

The product was prepared analogously to Example 2f from 1.35 g (2.45 mmol) of 3-(3-bromo-4-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionic acid and 449 g (2.45 mmol) of 1-methyl-4-piperidin-4-yl-piperazine.

Product: 1.10 g (63% of theory)

ESI-MS: (M+H)+ = 714/716/718 (Br, Cl)

Rf = 0.41 (silica gel, DCM/MeOH/NH3 9:1:0.1)

The following compounds were prepared analogously from 3-(3-bromo-4-chloro-5-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carbonyl]-amino}-propionic acid and appropriate amounts of amine:

[image]

[image]

Example 24

2-(4-chloro-3-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

24a 1-methyl 2-[1-(4-chloro-3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate

20.7 mL (158 mmol) of dimethyl succinate was added to a freshly prepared solution of sodium methoxide (prepared by dissolving 3.64 g (158 mmol) of sodium in MeOH) in 300 mL of MeOH and the reaction mixture was stirred for 1 h at RT. Then 30 g (144 mmol) of 4-chloro-3-trifluoromethyl-benzaldehyde is added and the reaction solution is boiled without loss of steam for 6 h. Evaporate i.vac., the residue is taken up in water, acidified with 20% citric acid solution and abundantly extracted with EtOAc. The organic phase is extracted five times, each time with 200 mL of 3% NH3 solution, the combined aqueous solutions are acidified with citric acid solution, extracted liberally with EtOAc and dried over Na2SO4. After the dried substance and the solvent were removed, the desired product was obtained in the form of a yellow oil.

Product: 12 g (26% of theory)

Rf = 0.33 (silica gel, PE/EtOAc/AcOH 75:25:5)

24b 1-methyl 2-(4-chloro-3-trifluoromethyl-benzyl)-succinate

200 mg of 10% Pt/C was added to a solution of 2.0 g (6.2 mmol) of 1-methyl 2-[1-(4-chloro-3-trifluoromethyl-phenyl)-meth-(E)-ylidene]-succinate in 20 mL of MeOH and the reaction mixture is hydrogenated for 3 h at RT and 3 bar H2. The catalyst is filtered off and the solvent is evaporated i.vac. The crude product reacts further without purification.

Product: 1.85 g (92% of theory)

Rf = 0.38 (silica gel, PE/EtOAc/AcOH 75:25:5)

24c methyl 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl ]-butanoate

A solution of 1.5 g (4.6 mmol) 1-methyl 2-(4-chloro-3-trifluoromethyl-benzyl)-succinate, 1.64 g (5.1 mmol) TBTU, 0.69 g (5.0 mmol) HOBt and 1.32 mL (7.5 mmol) ethyldiisopropylamine in 100 mL of a THF/water mixture (9:1) was stirred for 10 min at RT and then mixed with 1.2 g (5.0 mmol) of 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one . The reaction mixture was stirred for 2 h at RT, evaporated i.vac., the residue was mixed with a saturated NaHCO3 solution, abundantly extracted with EtOAc and the combined organic extracts were dried over MgSO4. After the dried substance and the solvent were removed, the desired product was obtained, which further reacts without purification.

Product: 2.2 g (89% of theory)

Rf = 0.6 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

24d 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] - butanoic acid

16 mL of 1 M NaOH solution is added to the solution of 2.2 g (4.1 mmol) of methyl 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butanoate in 20 mL of MeOH and the reaction mixture was stirred for 5 h at 50°C. It is diluted with 170 mL of water, extracted twice with tert-butylmethylether, the aqueous phase is mixed with 16 mL of 1M HCl, extracted three times with 70 mL of EtOAc and the combined organic phases are dried over Na2SO4. After the dried material and solvent were removed, the residue was triturated with diisopropyl ether, suction filtered and air dried.

Product: 1.1 g (51% of theory)

Rf = 0.25 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

24e 2-(4-chloro-3-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

Prepared analogously to Example 24c from 790 mg (1.5 mmol) of 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoic acid and 370 mg (1.6 mmol) of 1-methyl-[4,4']bipiperidinyl.

Product: 530 mg (51% of theory)

EI: (M)+ = 687/689 (Cl)

Rf = 0.6 (silica gel, DCM/MeOH/cyc/NH3 70:15:15:2)

Example 24.1

2-(4-chloro-3-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

280 mg (1.53 mmol) of 1-methyl-4-piperidin-4-yl-piperazine is added to a solution of 800 mg (1.53 mmol) of 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4 -(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid, 544 mg (1.7 mmol) TBTU, 206 mg (1.53 mmol) HOBt and 0.69 mL ( 4.94 mmol) of triethylamine in 100 mL of THF and the reaction mixture was stirred for 2.5 h at RT. Evaporate i.vac.,, the residue is placed in DCM, the organic phase is washed twice with saturated NaHCO3 solution and dried over MgSO4. After the dried substance and the solvent have been removed, the residue is purified by chromatography (silica gel, MeOH).

Product: 400 mg (38% of theory)

EI: (M)+ = 688/690 (Cl)

Rf = 0.25 (silica gel, MeOH)

Example 24.2

1-[1,4']bipiperidinyl-1'-yl-2-(4-chloro-3-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Prepared analogously to Example 24.1 from 800 mg (1.53 mmol) 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoic acid and 271 mg (1.61 mmol) [1,4']bipiperidinyl.

Product: 470 mg (46% of theory)

EI: (M)+ = 673/675 (Cl)

Rf = 0.28 (silica gel, MeOH)

Example 24.3

[4-(1-{2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid

[image]

Prepared analogously to Example 16.4 from 105 mg (0.2 mmol) of 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.2 mmol) of ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate.

Product: 13 mg (8% of theory)

ESI-MS: (M+H) + = 733/735 (Cl)

Retention time (HPLC): 6.3 min (method A)

Example 24.4

methyl (1'-{2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine -1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate

[image]

Prepared analogously to Example 16.5 from 209 mg (0.4 mmol) of 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoic acid and 102 mg (0.4 mmol) of ethyl [4,4']bipiperidinyl-1-yl-acetate.

Product: 17 mg (17% of theory)

ESI-MS: (M+H) + = 746/748 (Cl)

Rf = 0.44 (silica gel, DCM/MeOH 9:1)

Example 24.5

(1'-{2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid

[image]

Prepared analogously to Example 16.6 from 198 mg (0.26 mmol) methyl (1'-{2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate.

Product: 19 mg (9% of theory)

ESI-MS: (M+H)+ = 732/734(Cl)

Rf = 0.22 (silica gel, DCM/MeOH 9:1)

Example 24.6

2-(4-chloro-3-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro -2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Prepared analogously to Example 24.1 from 800 mg (1.53 mmol) 2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3 -yl)-piperidin-1-yl]-butanoic acid and 279 mg (1.53 mmol) of 1-methyl-[4,4']bipiperidinyl.

Product: 320 mg (30% of theory)

EI: (M)+ = 687/689 (Cl)

Rf = 0.20 (silica gel, MeOH)

The following compounds can also be prepared by the procedures described above:

[image] [image]

[image] [image]

[image] [image]

[image] [image]

[image] [image]

[image] [image]

The following compounds can be obtained using 4-amino-3-chloro-5-methyl-benzoic acid as starting material:

[image] [image]

[image] [image]

[image] [image]

The following compounds can be obtained using 2-chloro-6-trifluoromethyl-phenol as starting material, if necessary blocking the phenolic hydroxy effect with a suitable protecting group:

[image] [image]

[image] [image]

[image] [image]

Example 37

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Example 37.1

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Example 37.2

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Example 37.3

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,2,4,5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Example 37.4

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4 -(2-oxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

Example 37.5

(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4,4-difluoro-1,4'-bipiperidinyl-1'-yl)-4-[4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione

[image]

The following examples describe the preparation of pharmaceutical forms containing as active substance any desired compound of the general formula (I):

Examples

Capsules for powder inhalation containing 1 mg of active ingredient

Composition:

1 capsule for powder inhalation contains:

active ingredient 1.0 mg

lactose 20.0 mg

hard gelatin capsule 50.0 mg

71.0 mg

Preparation process:

The active substance is ground to the particle size required for inhaled substances. The crushed active ingredient is homogeneously mixed with lactose. The mixture is transferred into hard gelatin capsules.

Example II

Inhalable solution for Respimat® containing 1 mg of active ingredient

Composition:

1 inhalation contains:

active ingredient 1.0 mg

benzalkonium chloride 0.002 mg

disodium edetate 0.0075 mg

purified water up to 15.0 µl

Preparation process:

The active ingredient and benzalkonium chloride are dissolved in water and transferred to Respimat® cartridges.

Example III

Inhalable nebulizer solution containing 1 mg of active ingredient

Composition:

1 bottle contains:

active ingredient 0.1 g

sodium chloride 0.18 g

benzalkonium chloride 0.002 g

purified water up to 20.0 ml

Preparation process:

The active ingredient, sodium chloride and benzalkonium chloride, dissolve in water.

Example IV

Gas-propelled aerosol containing 1 mg of active ingredient

Composition:

1 inhalation contains:

active ingredient 1.0 mg

lecithin 0.1 %

propellant gas up to 50.0 µl

Preparation process:

The micronized active ingredient is homogeneously suspended in a mixture of lecithin and pressure gas. The suspension is transferred to a pressurized container with a dosing valve.

Example V

Nasal spray containing 1 mg of active ingredient

Composition:

active ingredient 1.0 mg

sodium chloride 0.9 mg

benzalkonium chloride 0.025 mg

disodium edetate 0.05 mg

purified water up to 0.1 ml

Preparation process:

The active ingredient and excipients are dissolved in water and transferred to a suitable container.

Example VI

Solution for injection containing 5 mg of active substance in 5 ml

Composition:

active substance 5 mg

glucose 250 mg

human serum albumin 10 mg

glycofurol 250 mg

water for injections up to 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI, English water for injections); human serum albumin is added; the active ingredient is added with heating; a certain volume is achieved by adding WfI; transfer to ampoules under nitrogen gas.

Example VII

Solution for injection containing 100 mg of active substance in 20 ml

Composition:

active substance 100 mg

monopotassium dihydrogen phosphate

= KH2PO4 12 mg

disodium hydrogen phosphate

= Na2HPO4.2H2O 2 mg

sodium chloride 180 mg

human serum albumin 50 mg

Polysorbate 80 20 mg

water for injections up to 10 ml

Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human serum albumin is added; the active ingredient is added with heating; a certain volume is achieved by adding WfI; transfer to ampoules.

Example VIII

Lyophilisate containing 10 mg of active substance

Composition:

Active substance 10 mg

Mannitol 300 mg

human serum albumin 20 mg

water for injections up to 2 ml

Preparation:

Mannitol dissolves in water for injections (WfI); human serum albumin is added; the active ingredient is dissolved by heating; a certain volume is achieved by adding WfI; transfer to bottles; freeze dry.

Solvent for lyophilisate:

Polysorbate 80 = Tween 80 20 mg

mannitol 200 mg

water for injections up to 10 ml

Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI); transfer to ampoules.

Example IX

Tablets containing 20 mg of active substance

Composition:

active substance 20 mg

lactose 120 mg

corn starch 40 mg

magnesium stearate 2 mg

Povidone K 25 18 mg

Preparation:

The active substance, lactose and corn starch are mixed homogeneously; they are granulated using an aqueous solution of Povidone; mixed with magnesium stearate; it is compressed in a tablet press; tablet weight 200 mg.

Example X

Capsules containing 20 mg of active substance

Composition:

active substance 20 mg

corn starch 80 mg

highly dispersed silica 5 mg

magnesium stearate 2.5 mg

Preparation:

The active substance, corn starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatin capsules in a capsule filling machine.

Example XI

Suppositories containing 50 mg of active substance

Composition:

active substance 50 mg

ointment (Adeps solidus) q.s. up to 1700 mg

Preparation:

Fat melts at around 38°C; the crushed active substance is homogeneously dispersed in the fat; after cooling to about 35°C, it is poured into cooled molds.

Example XII

Solution for injection containing 10 mg of active substance in 1 ml

Composition:

active substance 10 mg

mannitol 50 mg

human serum albumin 10 mg

water for injections up to 1 ml

Preparation:

Mannitol dissolves in water for injections; serum albumin is added; the active ingredient is dissolved by heating; a certain volume is achieved by adding WfI; transfer to ampoules under nitrogen gas.

Claims (17)

1. General formula CGRP antagonists [image] , (I) indicated by that A denotes an oxygen or sulfur atom, a phenylsulfonylimino or cyanimino group, X denotes an oxygen or sulfur atom, an imino group which can be substituted with a C1-6-alkyl group or a methylene group which can be substituted with a C1-6-alkyl group, U denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms. V denotes a chlorine or bromine atom, amino, methylamino or hydroxy group, W denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a difluoro- or trifluoromethyl group, R1 denotes a saturated mono- or di-unsaturated 5- to 7-membered aza, diaz, triaz, oxaz, thiaz or S,S-dioxido-thiadiaz heterocyclic group, in which the aforementioned heterocyclic rings are linked by a carbon or nitrogen atom, contain one or two carbonyl or thiocarbonyl groups adjacent to the nitrogen atom, can be substituted at the position of one nitrogen atom by an alkyl group, may be substituted at one or two carbon atoms by an alkyl group, phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl , imidazolyl or 1-methylimidazolyl group, wherein the substituents can be the same or different, and while the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings can be connected to a phenyl, naphthyl, pyridine, diazine, 1,3oxazole, thienyl, furan, thiazole, pyrrole, Nmethylpyrrole or quinoline ring on 1H-quinoline-2 one ring can be substituted on the place of a nitrogen atom with an alkyl group or on an imidazole or Nmethylimidazole ring or two olefinic bonds of one of the above-mentioned unsaturated heterocyclic rings can each be connected to a phenyl ring, while phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in R1 as well as benzo-, thieno-, pyrido- and diazino-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or trisubstituted with fluorine, chlorine, bromine or iodine atoms, with alkyl, alkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, difluoromethyl, trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino, alkylamino, dialkylamino, acetyl, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro- 1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, alkanoyl, cyano, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl groups, wherein the substituents may be the same or different to read. R2 denotes a hydrogen atom, phenylmethyl group or C2-7-alkyl group which can be substituted in position with cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(ω-hydroxy- C2-7-alkyl)-1-piperazinyl group, phenyl or pyridinyl group, while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or tri-substituted in the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di -(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, methylsulfonyloxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl, trifluoromethylsulfonyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di -(C1-3-alkyl)-amino-C1-3-alkyl groups and substituents can be the same or different, R3 denotes a hydrogen atom or a C1-3-alkyl group possibly substituted with a phenyl or pyridinyl group, while the C1-3-alkyl group can be connected to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 or a nitrogen atom with which they can be connected to form a ring, or R2 and R3 together with the nitrogen atom they contain denote a group of the general formula [image] , (II) where Y1 denotes a carbon atom or, if R5 is a pair of free electrons, it can also denote a nitrogen atom, q and r, if Y1 is a carbon atom, represent the numbers 0, 1 or 2, or q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2, R4 denotes a hydrogen atom, amino, alkylamino, cycloalkylamino, dialkylamino, N-(cycloalkyl)-alkylamino, dicycloalkylamino, hydroxy, alkyl, cycloalkyl, amino-C2-7-alkyl, alkylamino-C2-7-alkyl, dialkylamino-C2-7 -alkyl, aminoiminomethyl, alkylcarbonyl, alkylsulfonyl, alkylcarbonylamino, alkylsulfonylamino, N-alkylcarbonyl-N-alkylamino, N-alkylsulfonyl-N-alkylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, cycloalkylaminocarbonylamino, dicycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl , an alkoxycarbonylalkyl or carboxyalkyl group, or, if Y1 does not represent a nitrogen atom, carboxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl group, phenyl, phenyl-C1-3-alkyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group, each of which can be mono-, di- or trisubstituted in the carbon skeleton with a fluorine, chlorine, bromine or iodine atom, with alkyl, alkoxy, methylsulfonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, -(dialkylamino)alkyl, ω- (dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group, whereby the substituents may be the same or different, saturated or mono- or polyunsaturated 4- to 10-membered azacycloalkyl groups, 5- to 10-membered oxaza-, thiaza-, diaza- or triazacycloalkyl groups, 6- to 10-membered azabicyclo- or diazabicycloalkyl groups, 1-alkyl-4 -piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl, 1-alkyl-4-piperidinylamino, 1-alkyl-4-piperidinylaminocarbonyl or 1-alkyl-4-piperidinylaminosulfonyl groups while the above-mentioned mono- and bicyclic rings are bonded through carbon or nitrogen atoms, the methylene group in the above-mentioned mono- and bicyclic rings can be replaced by a carbonyl or sulfonyl group, in the above-mentioned mono- and bicyclic rings, any methylene group that is not directly connected to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms, The above-mentioned mono- and bicyclic rings as well as 1-alkyl-4-piperidinylcarbonyl- and 4-alkyl-1-piperazinylcarbonyl groups in the ring can be mono- or polysubstituted with a C1-7-alkyl group and/or monosubstituted with a benzyl, alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonyl, cycloalkyl or cycloalkylalkyl group, or substituted with a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group, possibly alkyl-substituted in the ring , while the alicyclic moieties contained in these substituents each contain 3 to 10 ring members and the heterocyclic moieties each contain 4 to 10 ring members and phenyl and pyridinyl groups contained in the above-mentioned groups can be mono-, di- or trisubstituted with a fluorine, chlorine, bromine or iodine atom, with alkyl, alkoxy, methylsulfonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl , cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)-alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl group, whereby the substituents may be the same or different, R5 denotes a hydrogen atom, C1-4-alkyl group, while the unbranched alkyl group can be substituted at position ω with phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl group, an alkoxycarbonyl, cyano or aminocarbonyl group or also, if Y1 represents a nitrogen atom, a pair of free electrons. or, if Y1 does not denote a nitrogen atom, also a fluorine atom, or R4 and R5 together, if Y1 represents a carbon atom, represent a 4- to 7-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH- or -N(alkyl)- group and one or two additional methylene groups may be replaced with carbonyl groups, while the hydrogen atom attached to the nitrogen atom within the aforementioned group R4 can be replaced with a protective group, R6 and R7, which may be the same or different, in both cases represent a hydrogen atom, a C1-3-alkyl or dialkylamino group or, if Y1 does not represent a nitrogen atom, a chlorine atom and R8 and R9 can be the same or different, in both they denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group, whereas, unless otherwise specified, all of the above alkyl and alkoxy groups as well as alkyl groups present within other specified groups contain 1 to 7 carbon atoms and may be straight or branched, while each methylene group may be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms, all the aforementioned cycloalkyl groups as well as cycloalkyl groups present within other specified groups, unless otherwise stated, may contain 3 to 10 carbon atoms, while each methylene group may be substituted with up to 2 fluorine atoms, all the above-mentioned aromatic and heteroaromatic groups can additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different, their tautomers, diastereomers, enantiomers, hydrates, their mixtures and salts, as well as hydrates of salts. 2. Compounds of the general formula (I) according to patent claim 1, characterized in that they are A, U, V, W, X, R2 and R3 as defined in claim 1 and R1 denotes a mono- or di-unsaturated 5- to 7-membered aza, diaza, triaz or thiaz heterocyclic group, in which the above-mentioned heterocyclic rings are connected through carbon or nitrogen atoms, contain one or two carbonyl groups adjacent to the nitrogen atom, may be substituted on the carbon atom with a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1methylpyrazolyl group and the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings can be connected to a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl ring or to a 1H-quinolin-2-one ring optionally substituted on a nitrogen atom with a methyl group, while phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups contained in R1 as well as benzo-, pyrido- and diazino-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or trisubstituted with fluorine, chlorine, bromine or iodine atoms, with an alkyl, alkoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents may be the same or different , while the aforementioned alkyl groups or alkyl groups contained in the aforementioned groups, unless otherwise specified, contain 1 to 7 carbon atoms and may be branched or unbranched, wherein each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, i the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, or with cyano or hydroxy groups and the substituents may be the same or different, their tautomers, diastereomers, enantiomers and mixtures and their salts. 3. Compounds of the general formula (I) according to patent claim 1, characterized in that they are A, U, V, W, X, R2 and R3 defined as in claim 1 i R1 denotes a monounsaturated 5- to 7-membered diaza or triaz heterocyclic group, while the above-mentioned heterocyclic rings are connected through nitrogen atoms, contains a carbonyl group adjacent to a nitrogen atom and can be additionally substituted on the carbon atom with a phenyl group, and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings may be joined to a phenyl, thienyl or quinoline ring, wherein the phenyl groups contained in R1 as well as the benzo-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or tri-substituted with fluorine, chlorine, bromine or iodine atoms, with methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents can be the same or different, but are more advantageously unsubstituted or monosubstituted with a fluorine, chlorine or bromine atom or with a methyl or methoxy group, whereas, unless otherwise stated, the aforementioned alkyl groups or the alkyl groups contained in the other aforementioned groups contain 1 to 7 carbon atoms and may be straight or branched and the aforementioned aromatic and heteroaromatic groups may be additionally mono-, di- or tri-substituted with with fluorine, chlorine or bromine atoms or with cyano or hydroxy groups and the substituents can be the same or different, their tautomers, diastereomers, enantiomers and mixtures and their salts. 4. Compounds of the general formula (I) according to patent claim 1, characterized in that they are A, U, V, W, X, R2 and R3 defined as in claim 1 i R1 denotes 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-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, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1yl, 4-(2-oxo-1,2-dihydro-4H-thieno[3 ,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin-1- yl, 4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl, 4-(2-oxo-1 ,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2,4,5- tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-1-yl or 4-(2-oxo-1,4-dihydro-2H-thieno[2,3-d ]pyrimidin-3-yl)-piperidin-1-yl group, while the above-mentioned mono- and bicyclic heterocyclic rings in the carbon skeleton can additionally be monosubstituted with a methoxy group, while the aforementioned aromatic and heteroaromatic groups may be additionally mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents may be the same or different, their tautomers, diastereomers, enantiomers and mixtures and their salts. 5. Compounds of the general formula (I) according to patent claim 1, characterized in that they are A, U, V, W, X, and R1 defined as in claim 1 i R2 denotes a hydrogen atom or a phenylmethyl group or a C27alkyl group which can be substituted in position with phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1pyrrolidinyl, 1piperidinyl, 4morpholinyl, [bis-(2-hydroxyethyl)]amino group while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or trisubstituted on the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C13-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl)- amino-C1-3-alkyl groups and substituents can be the same or different, R3 denotes a hydrogen atom or a C1-3-alkyl group, while the C1-3-alkyl group may be linked to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 and the nitrogen atom to which it is attached, forming a 5- to 7-membered ring, or R2 and R3 together with the involved nitrogen atom denote a group of the general formula [image] , (II) where Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom, q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2, R4 denotes a hydrogen atom, amino, alkylamino, C36-cycloalkylamino, N-(C3-6-cycloalkyl)-alkylamino or dialkylamino, alkyl, trifluoromethyl, C3-6-cycloalkyl, dialkylamino-C2-7-alkyl, carboxyalkyl, alkoxycarbonylalkyl, alkylsulfonyl , alkylsulfonylamino or N-(alkylsulfonyl)-alkylamino group, or if Y1 does not denote a nitrogen atom, then it denotes a carboxy or dialkylaminomethyl group, phenyl, phenyl-C1-3-alkyl, pyridinyl or diazinyl group, each of which can be substituted by fluorine, chlorine or bromine atoms or by trifluoromethylcarbonyl, methyl or methoxy group, saturated or mono- or polyunsaturated 4- to 7-membered azacycloalkyl group, 5- to 7-membered oxase, diaza or triazacycloalkyl group, 7- to 9-membered azabicyclo or diazabicycloalkyl group, 1-alkyl-4-piperidinylamino or 1-alkyl-4 -piperidinylaminosulfonyl group, while the above-mentioned mono- and bicyclic heterocyclic rings are connected through nitrogen or carbon atoms, the methylene group of the above-mentioned mono- and bicyclic heterocyclic rings can be replaced by a carbonyl or sulfonyl group, in the above-mentioned mono- and bicyclic heterocyclic rings, each methylene group that is not directly attached to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms, The aforementioned mono- and bicyclic heterocyclic rings may be substituted with one or two C1-3-alkyl groups where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, and/or with C3-6-cycloalkyl-C1-3-alkyl, benzyl, C1-4-alkanoyl, di-(C13-alkyl)-amino or C1-3-alkylsulfonyl, with an alkoxycarbonyl, benzyloxycarbonyl, alkoxycarbonylalkyl, carboxy or carboxyalkyl group, R5 denotes a hydrogen atom, a C1-3-alkyl or alkoxycarbonyl group or if Y1 denotes a nitrogen atom, it may also denote a pair of free electrons, or R4 and R5 together, if Y1 denotes a carbon atom, represent a 5- to 6-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH or -N(methyl) group and a further one or two methylene groups may be replaced by carbonyl groups, R6 and R7, which may be the same or different, in each case denote a hydrogen atom or a C1-3-alkyl or di-(C1-3-alkyl)-amino group and R8 and R9, which may be the same or different, in any case denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group, whereas, unless otherwise indicated, all the aforementioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the aforementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different, their tautomers, diastereomers, enantiomers and mixtures and their salts. 6. Compounds of the general formula (I) according to patent claim 1, characterized in that they are A, U, V, W, X and R1 defined as in claim 1 i R2 denotes a phenylmethyl group or a C2-7-alkyl group which may be substituted at position w with a phenyl, amino, alkylamino or dialkylamino group, while the aforementioned phenyl group may be substituted with an amino-C1-3-alkyl, C1-3-alkylamino-C13alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or R3 denotes a hydrogen atom or a C1-3-alkyl group, R2 and R3 together with the nitrogen atom to which they are attached denote 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl or 2-amino-4,5,7,8-tetrahydro-thiazolo[ 4,5-d]azepin-6-yl- group or R 2 and R 3 together with the nitrogen atom that is contained in it denote a group of the general formula [image] , (II) where Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom, q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2, R4 denotes a hydrogen atom, phenyl, benzyl or pyridinyl group which in any case can be substituted with fluorine, chlorine or bromine atoms, with trifluoromethylcarbonyl, methyl or methoxy group, hydroxy, carboxy, methyl, trifluoromethyl, n-propyl, phenyl, p-tolyl, p-trifluoromethylcarbonyl-phenyl, p-(3-dimethylaminopropyl)-phenyl, amino, benzyl, tert-butylamino, dimethylamino, diethylamino, diethylaminomethyl, 2- dimethylaminoethyl, 2-diethylaminoethyl, 5-aminopentyl, methoxycarbonyl, methoxycarbonylmethyl, perhydro-azepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-1-piperidinyl-4-yl, 4-piperazin-1-yl, 4-acetyl-piperazin-1-yl, 4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl, 4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin- 1-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-1-piperidin-1-yl, 1-methyl-1-aza-bicyclo[3.2.1] oct-4-yl or 4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl, 1-methyl-piperidin-1-yl, 4carboxymethyl-piperazin-1-yl, 1-carboxymethyl-piperidin-4- yl, 4-benzyloxycarbonyl-piperazin-1-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, azetidin-1-yl, 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl, 1-benzyl-piperidin-4-yl, 4-benzyl-piperazin-1-yl, 4-dimethylaminomethyl-1-phenyl, 2,2,2-tr iflorethyl-piperazin-1-yl, 1-methylsulfonyl-piperidin-4-yl, piperidin-1-yl-methyl, 1-methyl-piperidin-4-yl-amino, methylsulfonylamino, N-methylsulfonyl-N-methylamino, N- (cyclopentyl)-methylamino, 1,1-dioxo-16-isothiazolidin-2-yl, 2-oxo-perhydro-1,3-oxazin-3-yl, cyclohexyl, 2-oxo-imidazolidin-1-yl, 2- methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl, 4-thiazol-2-yl, 2,4-dimethyl-imidazol-1-yl, 4-imidazol-1-yl, 1,2, 4-triazol-1-yl, 1-aza-bicyclo[2.2.2]oct-3-yl, 1-methyl-piperidin-4-yl-methylsulfonyl, 1H-imidazol-4-yl, 4-ethoxycarbonylmethyl-piperazin- 1-yl, 1-ethoxycarbonyl-piperidin-4-yl, 4-tert-butoxycarbonylmethyl-piperazin-1-yl, 1-(2,2,2trifluoroethyl)-piperidin-4-yl, 4-methylsulfonyl-piperazin-1- yl, 2-carboxy-4-methyl-piperazin-1-yl, 3-carboxy-4-methyl-piperazin-1-yl, 2-ethoxycarbonyl-4-methyl-piperazin-1-yl, 3-ethoxycarbonyl-4-methyl- piperazin-1-yl or 4-(2,2,2trifluoroethyl)-piperazin-1-yl- group, R5 represents a hydrogen atom, a methyl group or, if Y1 represents a nitrogen atom, it may also represent a pair of free electrons, or R4 and R5 together, if Y1 represents a carbon atom, represent a 1-methyl-piperidin-4ylidene, cyclohexylidene or imidazolidin-2,4-dione-5-ylidene group, R6 and R7 in each case denote a hydrogen atom or a dimethylamino group and R8 and R9 in each case denote a hydrogen atom, carboxy or ethoxycarbonyl group, while, unless otherwise noted, all the above-mentioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different, their tautomers, diastereomers, enantiomers and mixtures and their salts. 7. Compounds of the general formula (I) according to claim 1, characterized in that A denotes an oxygen atom, cyanoimino or phenylsulfonylimino group, X denotes an oxygen atom, imino or methylene group, U denotes an unbranched C1-6-alkyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms, V denotes an amino or hydroxy group, W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group, R1 denotes a monounsaturated 5- to 7-membered diaza or triaz heterocyclic group, while the above-mentioned heterocyclic rings are connected through nitrogen atoms, contains a carbonyl group adjacent to a nitrogen atom and can be additionally substituted on the carbon atom with a phenyl group, and wherein the olefinic double bond of one of the aforementioned unsaturated heterocyclic rings may be joined to a phenyl, thienyl or quinoline ring, wherein the phenyl groups contained in R1 as well as the benzo-connected heterocyclic rings in the carbon skeleton can additionally be mono-, di- or tri-substituted with fluorine, chlorine, bromine or iodine atoms, with methyl, methoxy, nitro, difluoromethyl, trifluoromethyl, hydroxy, amino, alkylamino, dialkylamino, acetylamino, acetyl, cyano, difluoromethoxy or trifluoromethoxy group, whereby the substituents can be the same or different, but are more advantageously unsubstituted or monosubstituted with a fluorine, chlorine or bromine atom or with a methyl or methoxy group, R2 denotes a hydrogen atom or a phenylmethyl group or a C2-7-alkyl group which may be substituted at the ω position with phenyl, pyridinyl, hydroxy, amino, alkylamino, dialkylamino, alkoxycarbonyl, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or [ bis-(2-hydroxyethyl)]amino group, while the above-mentioned heterocyclic groups and phenyl groups can additionally be mono-, di- or trisubstituted on the carbon skeleton with fluorine, chlorine, bromine or iodine atoms, with methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl )-amino-C1-3-alkyl groups and the substituents can be the same or different, R3 denotes a hydrogen atom or a C1-3-alkyl group, while the C1-3-alkyl group may be linked to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 and the nitrogen atom to which it is attached, forming a 5- to 7-membered ring, or R2 and R3 together with the involved nitrogen atom denote a group of the general formula [image] , (II) where Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom, q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2, R4 denotes a hydrogen atom, hydroxy, amino, alkylamino, C3-6-cycloalkylamino, N-(C3-6-cycloalkyl)-alkylamino or dialkylamino, alkyl, trifluoromethyl, C3-6-cycloalkyl, dialkylamino-C2-7-alkyl, carboxyalkyl , alkoxycarbonylalkyl, alkylsulfonyl, alkylsulfonylamino or N-(alkylsulfonyl)-alkylamino group, or, if Y1 does not represent a nitrogen atom, it represents a carboxy or dialkylaminomethyl group, phenyl, phenyl-C1-3-alkyl, pyridinyl or diazinyl group, each of which can be substituted by fluorine, chlorine or bromine atoms or by trifluoromethylcarbonyl, methyl or methoxy group, saturated or mono- or polyunsaturated 4- to 7-membered azacycloalkyl group, 5- to 7-membered oxase, diaza or triazacycloalkyl group, 7- to 9-membered azabicyclo or diazabicycloalkyl group, 1-alkyl-4-piperidinylamino or 1-alkyl -4-piperidinylaminosulfonyl group, while the above-mentioned mono- and bicyclic heterocyclic rings are connected through nitrogen or carbon atoms, the methylene group of the above-mentioned mono- and bicyclic heterocyclic rings can be replaced by a carbonyl or sulfonyl group, in the above-mentioned mono- and bicyclic heterocyclic rings, each methylene group that is not directly attached to a nitrogen, oxygen or sulfur atom can be substituted with one or two fluorine atoms, The aforementioned mono- and bicyclic heterocyclic rings may be substituted with one or two C1-3-alkyl groups where each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may be substituted with up to 3 fluorine atoms, and/or may be substituted with C3-6-cycloalkyl-C1-3-alkyl, benzyl, C1-4-alkanoyl, di-(C1-3-alkyl)-amino or C1-3-alkylsulfonyl, with alkoxycarbonyl, benzyloxycarbonyl, alkoxycarbonylalkyl, carboxy or a carboxyalkyl group, R5 denotes a hydrogen atom, a C1-3-alkyl or alkoxycarbonyl group or if Y1 denotes a nitrogen atom, it may also denote a pair of free electrons, or R4 and R5 together, if Y1 denotes a carbon atom, represent a 5- to 6-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an -NH or -N(methyl) group and a further one or two methylene groups may be replaced by carbonyl groups, R6 and R7, which may be the same or different, in each case denote a hydrogen atom or a C1-3-alkyl or di-(C1-3-alkyl)-amino group and R8 and R9, which may be the same or different, in any case denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group, whereas, unless otherwise indicated, all the aforementioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the aforementioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different their tautomers, enantiomers, diastereomers and mixtures and their salts. 8. Compounds of the general formula (I) according to patent claim 1, characterized in that A denotes an oxygen atom, X denotes an oxygen atom, imino or methylene group, U denotes a methyl, ethyl, C2-4-alkenyl or C2-4-alkynyl group where each methylene group can be substituted with up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms, V denotes an amino or hydroxy group, W denotes a hydrogen, chlorine or bromine atom or a trifluoromethyl group, R1 denotes 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-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, 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2-dihydro-4H-thieno [3,4-d]pyrimidin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,4dihydro-2H-thieno[3,2-d]pyrimidin-3-yl)-piperidin- 1-yl, 4-(5-oxo-4,5,7,8-tetrahydro-2-thia-4,6-diaza-azulen-6-yl)-piperidin-1-yl, 4-(2-oxo -1,2,4,5-tetrahydro-thieno[3,2-d]-1,3-diazepin-3-yl)-piperidin-1-yl, 4-(2-oxo-1,2,4, 5-tetrahydro-thieno[2,3-d]-1,3-diazepin-3-yl)-piperidin-1-yl or 4-(2-oxo-1,4-dihydro-2H-thieno[2,3 -d]pyrimidin-3-yl)-piperidin-1-yl group, while the above-mentioned mono- and bicyclic heterocyclic rings in the carbon skeleton can additionally be monosubstituted with a methoxy group, R2 denotes a phenylmethyl group or a C2-7-alkyl group which can be substituted at position w with a phenyl, amino, alkylamino and dialkylamino group, while the aforementioned phenyl group may be substituted with an amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl group, or R3 denotes a hydrogen atom or a C1-3-alkyl group, R2 and R3 together with the nitrogen atom to which they are attached denote 7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl or 2-amino-4,5,7,8-tetrahydro-thiazolo[ 4,5-d]azepin-6-yl- group or R 2 and R 3 together with the nitrogen atom that is contained in it denote a group of the general formula [image] , (III) where Y1 represents a carbon atom or, if R5 represents a pair of free electrons, it can also represent a nitrogen atom, q and r, if Y1 denotes a carbon atom, represent the numbers 0 or 1 or q and r, if Y1 denotes a nitrogen atom, represent the numbers 1 or 2, R4 denotes a hydrogen atom, a phenyl, benzyl, or pyridinyl group, each of which may be substituted with fluorine, chlorine, or bromine atoms or with a trifluoromethylcarbonyl, methyl, or methoxy group, hydroxy, carboxy, methyl, trifluoromethyl, n-propyl, phenyl, p-tolyl, p-trifluoromethylcarbonyl-phenyl, p-(3-dimethylaminopropyl)-phenyl, amino, benzyl, tert-butylamino, dimethylamino, diethylamino, diethylaminomethyl, 2- dimethylaminoethyl, 2-diethylaminoethyl, 5-aminopentyl, methoxycarbonyl, methoxycarbonylmethyl, perhydro-azepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-yl, 1-methyl-1-piperidinyl-4-yl, 4-piperazin-1-yl, 4-acetyl-piperazin-1-yl, 4-cyclopropylmethyl-piperazin-1-yl, pyrrolidin-1-yl, 4-ethyl-piperazin-1-yl, 4-isopropyl-piperazin- 1-yl, piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, 4,4-difluoro-1-piperidin-1-yl, 1-methyl-1-aza-bicyclo[3.2.1] oct-4-yl, 4-methyl-piperazin-1-yl, 4-ethylpiperazin-1-yl, 1-methyl-piperidin-1-yl, 4-carboxymethyl-piperazin-1-yl, 1-carboxymethyl-piperidin- 4-yl, 4-benzyloxycarbonyl-piperazin-1-yl, 1-ethoxycarbonylmethyl-piperidin-4-yl, azetidin-1-yl, 5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2- yl, 1-benzyl-piperidin-4-yl, 4-benzyl-piperazin-1-yl, 4-dimethylaminomethyl-1-phenyl, 2,2,2-trif lorethyl-piperazin-1-yl, 1-methylsulfonyl-piperidin-4-yl, piperidin-1-yl-methyl, 1-methyl-piperidin-4-yl-amino, methylsulfonylamino, N-methylsulfonyl-N-methylamino, N- (cyclopentyl)-methylamino, 1,1-dioxo-16-isothiazolidin-2-yl, 2-oxo-perhydro-1,3-oxazin-3-yl, cyclohexyl, 2-oxo-imidazolidin-1-yl, 2- methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl, 4-thiazol-2-yl, 2,4-dimethyl-imidazol-1-yl, 4-imidazol-1-yl, 1,2, 4triazol-1-yl, 1-aza-bicyclo[2.2.2]oct-3-yl, 1-methyl-piperidin-4-yl-methylsulfonyl, 1H-imidazol-4-yl, 4-ethoxycarbonylmethyl-piperazin-1- yl, 1-ethoxycarbonyl-piperidin-4-yl, 4-tert-butoxycarbonylmethyl-piperazin-1-yl, 1-(2,2,2-trifluoroethyl)-piperidin-4-yl, 4-methylsulfonyl-piperazin-1- yl, 2-carboxy-4-methyl-piperazin-1-yl, 3-carboxy-4-methyl-piperazin-1-yl, 2-ethoxycarbonyl-4-methyl-piperazin-1-yl, 3-ethoxycarbonyl-4- methyl-piperazin-1-yl or 4-(2,2,2-trifluoroethyl)-piperazin-1-yl group, R5 represents a hydrogen atom, a methyl group or, if Y1 represents a nitrogen atom, it may also represent a pair of free electrons, or R4 and R5 together, if Y1 represents a carbon atom, represent a 1-methyl-piperidin-4-ylidene, cyclohexylidene or imidazolidin-2,4-dione-5-ylidene group, R6 and R7 in each case denote a hydrogen atom or a dimethylamino group and R8 and R9 in each case denote a hydrogen atom, carboxy or ethoxycarbonyl group, while, unless otherwise noted, all the above-mentioned alkyl groups as well as the alkyl groups contained within the other groups contain 1 to 7 carbon atoms and may be straight chain or branched and the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or tri-substituted with fluorine, chlorine or bromine atoms, with cyano or hydroxy groups and the substituents can be the same or different, their enantiomers, diastereomers and their salts. 9. Compounds, indicated by the fact that they are compounds of the general formula (I) according to patent claim 1: (1) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4 -methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin- 1-yl]-butane-1,4-dione, (2) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl- 1-yl)-4[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (3) 2-( 4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1 ,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (4) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)- 1-[1,4']bipiperidinyl-1'-yl-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1 ,4-dione, (5) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butane-1,4-dione, (6) 2-(4-amino-3-chloro-5- trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-ylamino)-piperidin-1-yl]-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (7) [4-(1-{2-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin -4-yl)-piperazin-1-yl]-acetic acid, (8) methyl (1'-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[ 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (9) (1'-{2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid, (10) 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1' -yl-2-oxo-ethyl]-amide, (11) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid- [(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-amide, (12) 4 -(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiaz epin-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-pyridine-4- yl-piperazin-1-yl)-ethyl]-amide, (13) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-carboxylic acid-[(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(1'-methyl-4,4'-bipiperidinyl-1-yl)-2-oxo-ethyl ]-amide, (14) benzyl 4-[1-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazine-1-carboxylate, (15) ethyl [1 '-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzodiazepine-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetate, (16) 4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4- (4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (17) 4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-ka carboxylic acid-{(R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]- 2-oxo-ethyl}-amide, (18) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R )-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-(4-azetidin-1-yl-piperidin-1-yl)-2-oxo-ethyl]-amide, (19) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-2-[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-2-oxo-ethyl} -amide, (20) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4 -amino-3-chloro-5-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]-amide, (21) [1'-( R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-carbonyl]-amino}-propionyl)-4,4'-bipiperidinyl-1-yl]-acetic acid, (22) 4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzodiazepine-3-yl)-piperidin-1-car Boxylic acid-[1(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl-1'-yl-2-oxo-ethyl]-amide, (23) (S) -2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (24) (S)-2-(4 -amino-3-bromo-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl ]-1-(4-pyridin-4-yl-piperazin-1-yl)-butan-1,4-dione, (25) (S)-2-(4-amino-3-bromo-5-trifluoromethyl- benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin- 1-yl]-butane-1,4-dione, (26) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidine- 4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]- butane-1,4-dione, (27) (S)-2-(4-amino-3-bromo-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1- yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, ( 28) (S)-2 -(4-amino-3-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (29) (S)-2-(4-amino-3-chloro -5-trifluoromethyl-benzyl)-1-(4-dimethylamino-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-butane-1,4-dione, (30) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(3-dimethylamino- piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4 -dione, (31) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-pyrrolidin-1-yl-piperidin-1-yl)-butane-1,4-dione, (32) (S)-2 -(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(1'-methyl-4,4'-bipiperidinyl-1-yl)-4-[4-(2-oxo-1,2 ,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (33) (S)-2-(4-amino-3-chloro -5-trifluoromethyl-benzyl)-1-[4-(4-cyclopropylmethyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5- tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (34) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)- 1-(4-morpholin-4-yl-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin -1-yl]-butane-1,4-dione, (35) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butan-1,4 -dione, (36) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-perhydro-1,4-diazepin-1-yl) -piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butan-1, 4-dione, (37) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-isopropyl-piperazin-1-yl)-piperidin-1- yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, ( 38) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (39) (S)-2-(4-amino-3- chloro-5-trifluoromethyl-b enyl)-1-[4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepin-1-yl]-4-[4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (40) (S)-2-(4-amino-3-chloro-5-trifluoromethyl -benzyl)-1-[3-(4-methyl-piperazin-1-yl)-azetidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (41) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(3-pyrrolidin-1-yl-azetidin- 1-yl)-butane-1,4-dione, (42) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(3-piperidin-1-yl-azetidin-1-yl)-butan-1,4- dione, (43) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(3-diethylamino-azetidin-1-yl)-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (44) (S)-2-(4-amino -3-chloro-5-trifluoromethyl-benzyl)-1-(4-azetidin-1-yl-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzodiazepine-3-yl)-piperide in-1-yl]-butane-1,4-dione, (45) (S)-1-[4-(4-acetyl-piperazin-1-yl)-piperidin-1-yl]-2-(4 -amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl ]-butane-1,4-dione, (46) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-diethylaminomethyl-piperidin-1-yl)-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (47) (S )-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-( 2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (48) (S)-2-( 4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-ethyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (49) (S)-2-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1- (3,4,5,6-tetrahydro-2H-4,4'-bipyridinyl-1-yl)-butane-1,4-dione, (50) (S)-2-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butan-1,4 -dione, (51) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1, 3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(3-perhydro-azepin-1-yl-azetidin-1-yl)-butane-1,4-dione, (52) (S) -2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2 -oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (53) (S)-2-(4 -amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-benzyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (54) (S)-2-(4-amino-3- chloro-5-trifluoromethyl-benzyl)-1-(7-dimethylaminomethyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-4-[4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (55) (S)-2-(4-amino-3-chloro-5 -trifluoromethyl-benzyl)-1-[4-(4-dimethylaminomethyl-phenyl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzodia zepin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (56) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-{4-[4-(2,2,2- trifluoro-ethyl)-piperazin-1-yl]-piperidin-1-yl}-butane-1,4-dione, (57) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl )-1-(1'-methanesulfonyl-4,4'-bipiperidinyl-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-butane-1,4-dione, (58) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(9-methyl- 3,9-diaza-spiro[5.5]undec-3-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin- 1-yl]-butane-1,4-dione, (59) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-piperidin-1-yl-methyl-piperidin-1-yl)-butan-1, 4-dione, (60) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-dimethylamino-ethyl)-piperidin-1-yl]-4 -[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (61) (S )-2-(4-amino-3-chloro-5-tri fluoromethyl-benzyl)-N-methyl-N-[2-(1-methyl-piperidin-4-yl)-ethyl]-4-oxo-4-[4-(2-oxo-1,2,4,5 -tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide, (62) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N- methyl-N-(1-methyl-piperidin-4-ylmethyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl) -piperidin-1-yl]-butyramide, (63) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4 ,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-piperidin-1-yl-butan-1,4-dione, (64) (S)-2-(4 -amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl ]-1-(4-propyl-piperidin-1-yl)-butane-1,4-dione, (65) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1 -(4-benzyl-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl] -butane-1,4-dione, (66) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-diethylamino-ethyl)-piperidine-1 -yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, ( 67) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(3-aza-spiro[5.5]undec-3-yl)-4-[4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (68) N-(1-{(S) -2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3 -yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-N-methyl-methanesulfonamide, (69) N-(1-{(S)-2-(4-amino-3-chloro) -5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]- butyryl}-piperidin-4-yl)-methanesulfonamide, (70) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(cyclopentyl-methyl-amino)- Piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4 -dione, (71) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-methyl-piperidin-1-yl)-4-[4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (72) methyl (1-{(S)- 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- and 1)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-acetate, (73) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-( 4-hydroxy-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane -1,4-dione, (74) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5- tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-trifluoromethyl-piperidin-1-yl)-butane-1,4-dione, (75) (S)-2 -(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1,1-dioxo-1,6-isothiazolidin-2-yl)-piperidin-1-yl]-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (76) (S)- 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo-perhydro-1,3-oxazin-3-yl)-piperidin-1-yl]-4- [4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (77) methyl 1- {(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidine-4-carboxylate, (78) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzi 1)-1-(4-cyclohexyl-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin- 1-yl]-butane-1,4-dione, (79) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-tert-butylamino-piperidine-1 -yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (80) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine) -3-yl)-piperidin-1-yl]-1-(4-phenyl-piperidin-1-yl)-butane-1,4-dione, (81) (S)-2-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1- (4-p-tolyl-piperidin-1-yl)-butane-1,4-dione, (82) 8-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)- 4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-1,3,8 -triaza-spiro[4.5]decane-2,4-dione, (83) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2-oxo- imidazolidin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl ]-butane-1,4-dione, (84 ) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-amino-4-methyl-piperidin-1-yl)-4-[4-(2-oxo -1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (85) (S)-2-(4-amino -3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (86) (S)-2-(4-amino-3-chloro- 5-trifluoromethyl-benzyl)-1-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (87) (S)-2-(4-amino-3 -chloro-5-trifluoromethyl-benzyl)-1-[4-(2-methyl-imidazol-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4, 5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (88) (S)-2-(4-amino-3-chloro-5- trifluoromethyl-benzyl)-1-[4-(4-methyl-imidazol-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (89) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)- 4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-thiazol-2-yl-piperazin-1-yl)-butane-1,4-dione, (90) (S)-2- (4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(2,4-dimethyl-imidazol-1-yl)-piperidin-1-yl]-4-[4-(2- oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (91) (S)-2-(4- amino-3-chloro-5-trifluoromethyl-benzyl)-1-(4-imidazol-1-yl-piperidin-1-yl)-4-[4-(2-oxo-1,2,4,5-tetrahydro -1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (92) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl )-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-1,2,4 -triazol-1-yl-piperidin-1-yl)-butane-1,4-dione, (93) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[ 4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (94) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4- [4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-piperazin-1-yl-butan-1,4- dione, (95) 4-{(S)-2-(4-amino-3-chloro-5). -trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl} -piperazine-1-sulfonic acid (1-methyl-piperidin-4-yl)-amide, (96) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-(5 -amino-pentyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide, (97) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-N-(3-aminomethyl-benzyl)-4-oxo-4-[4-(2-oxo-1 ,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyramide, (98) 1-{(S)-2-(4-amino-3-chloro- 5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl }-piperidine-4-carboxylic acid, (99) (1-{(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2- Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-acetic acid, (100) (S)- 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl ]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodia zepin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (101) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[ 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1- yl)-butane-1,4-dione, (102) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(1H-imidazol-4-yl) -piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butan-1, 4-dione, (103) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1 ,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-{4-[4-(2,2,2-trifluoro-acetyl)-phenyl]-piperazin-1-yl}-butan-1 ,4-dione, (104) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1 -yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (105) (S) -2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(5 -oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butane-1,4-dione, (106) (S)-2- (4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[ 4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl )-piperidin-1-yl]-butane-1,4-dione, (107) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(4- methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-piperidine -1-yl]-butane-1,4-dione, (108) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-1-[4-(5-methyl-2 ,5-diaza-bicyclo[2.2.1]hept-2-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine -3-yl)-piperidin-1-yl]-butane-1,4-dione, (109) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4 -(4-methyl-perhydro-1,4-diazepin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3- benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (110) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[ 4-(1-methyl-piperidin-4-yl)-perhydro-1,4-diazepin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (111) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1- [4-(1-methyl-piperidin-4-yl)-piperazin- 1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione , (112) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(1-aza-bicyclo[2.2.2]oct-3-yl)-piperazine -1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4- dione, (113) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl] -4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (114) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3- yl)-piperidin-1-yl]-1-(4-perhydro-azepin-1-yl-piperidin-1-yl)-butane-1,4-dione, (115) (S)-2-(4- amino-3,5-bis-trifluoromethyl-benzyl)-1-1,4'-bipiperidinyl-1'-yl-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3 -benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (116) (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4- [4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-1-(4-piperazin-1-yl-piperidin-1 -yl)-butane-1,4-dione, (117) 4-(2-approx so-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3,5-bis-trifluoromethyl- benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (118) 4-(2-oxo-1,2, 4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(4-amino-3,5-bis-trifluoromethyl-benzyl)-2-[ 4-(1-Methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (119) 4-(2-oxo-1,2,4,5-tetrahydro- 1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3,5-bis-trifluoromethyl-benzyl)-2-1,4'-bipiperidinyl- 1'-yl-2-oxo-ethyl]-amide, (120) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylic acid-[(R)-1-(4-amino-3,5-bis-trifluoromethyl-benzyl)-2-oxo-2-(4-piperazin-1-yl-piperidin-1-yl)-ethyl]- amide, (121) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl] -2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidine-1-carboxylate, (122) 4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)- Piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(4-bromo-3-methyl-benzyl)-2-oxo-ethyl]-amide, (123) 4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(4-bromo-3-methyl-benzyl)-2-(1'-methyl- [4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide, (124) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}- amide, (125) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-(4-bromo-3-methyl-benzyl)-2 -[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (126) ethyl {4-[1-(3-(4-bromo- 3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperidine-4- yl]-piperazin-1-yl}-acetate, (127) ethyl [1'-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetate, (128) ethyl {4-[4-( 3-(4-bromo-3-methyl-phenyl)-2-{[4-( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperazin-1-yl]-piperidin-1-yl}-acetate, (129 ) {4-[1-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-Carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetic acid, (130) [1'-(3-(4-bromo-3-methyl-phenyl)- 2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl ]-acetic acid, (131) {4-[4-(3-(4-bromo-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazoline- 3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperazin-1-yl]-piperidin-1-yl}-acetic acid, (132) 2-(4-bromo-3-methyl-benzyl) )-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-yl]-butane-1,4-dione, (133) 2-(4-bromo-3-methyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1 -yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (134) 1-[ 1,4']Bipiperidinyl-1'-yl-2-(4-bromo-3-methyl-benzyl)-4-[4-(2- oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (135) 2-(4-bromo-3-methyl-benzyl)-1 -{4-[4-(3-dimethylamino-propyl)-phenyl]-piperazin-1-yl}-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- Piperidin-1-yl]-butane-1,4-dione, (136) [4-(1-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid, (137) methyl ( 1'-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1 -yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (138) (1'-{2-(4-bromo-3-methyl-benzyl)-4-oxo-4- [4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid, ( 139) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {1-(4-chloro-3-methyl-benzyl)-2-[4- (4-Methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (140) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3- yl)-piperidine-1-carboxylic acid-[2-[1,4']bipiperidinyl-1'-yl-1-(4-chloro-3- methyl-benzyl)-2-oxo-ethyl]-amide, (141) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-{1-( 4-chloro-3-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide, (142) 4-( 2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(4-chloro-3-methyl-benzyl)-2-(1'-methyl-[ 4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide, (143) ethyl [1'-(3-(4-chloro-3-methyl-phenyl)-2-{[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-[4,4']bipiperidinyl-1-yl]-acetate, (144 ) tert-butyl {4-[1-(3-(4-chloro-3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) -piperidin-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-yl}-acetate, (145) 4-(2-oxo-1,4-dihydro-2H-quinazolin- 3-yl)-piperidine-1-carboxylic acid-{1-(4-chloro-3-methyl-benzyl)-2-oxo-2-[1'-(2,2,2-trifluoro-ethyl)-[ 4,4']bipiperidinyl-1-yl]-ethyl}-amide, (146) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carboxylic acid-( 1-(4-chloro-3-methyl-benzyl)-2-oxo-2-{4 -[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-piperidin-1-yl}-ethyl)-amide, (147) [1'-(3-(4-chloro- 3-methyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-[4,4 ']bipiperidinyl-1-yl]-acetic acid, (148) 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-ethyl-piperazin-1-yl)-piperidin-1- yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (149) 2-(4 -chloro-3-methyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazoline -3-yl)-piperidin-1-yl]-butane-1,4-dione, (150) 1-[1,4']Bipiperidinyl-1'-yl-2-(4-chloro-3-methyl- benzyl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (151) 2-(4 -chloro-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (152) 2-(4-chloro-3-methyl-benzyl)-1-[4-(1-methyl -piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butan-1 ,4-dione, (153) 2-(4-chloro-3-methyl- benzyl)-1-[4-(4-methanesulfonyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl )-piperidin-1-yl]-butane-1,4-dione, (154) 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-isopropyl-piperazin-1-yl) -piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (155 ) ethyl 1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-yl]-butyryl}-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate, (156) ethyl 1-(1-{2-(4-chloro-3-methyl-benzyl) )-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-4- methyl-piperazine-2-carboxylate, (157) ethyl 4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-1-methyl-piperazine-2-carboxylate, (158) ethyl 4-{2-(4- chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-1- (1-methyl-piperidin-4-yl)-piperazine-2-carboxylate, (159) 2-(4-chloro-3-methyl-benzyl)- 4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-1-[1'-(2,2,2-trifluoro-ethyl)- [4,4']bipiperidinyl-1-yl]-butane-1,4-dione, (160) 2-(4-chloro-3-methyl-benzyl)-4-[4-(2-oxo-1, 4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-1-{4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-piperidin-1 -yl}-butane-1,4-dione, (161) [4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid, (162) methyl (1'- {2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl] -butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (163) (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4- (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid, (164) 1 -{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl ]-butyryl}-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylic acid, (165) 1-(1-{2-(4-chloro-3-methyl-benzyl)-4 -oxo-4-[4-(2-oxo -1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-4-methyl-piperazine-2-carboxylic acid, (166) 4-( 1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1- yl]-butyryl}-piperidin-4-yl)-1-methyl-piperazine-2-carboxylic acid, (167) 2-(4-chloro-3-methyl-benzyl)-1-[4-(1-methyl -piperidin-4-yl)-piperazin-1-yl]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1- yl]-butane-1,4-dione, (168) 2-(4-chloro-3-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl ]-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepine-3-yl)-piperidin-1-yl]-butane-1,4-dione, (169 ) [4-(1-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2, 4-triazol-1-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid, (170) methyl (1'-{2-(4- chloro-3-methyl-benzyl)-4-oxo-4-[4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1- yl]-butyryl}-4,4'-bipiperidinyl-1-yl)-acetate, (171) (1'-{2-(4-chloro-3-methyl-benzyl)-4-oxo-4-[ 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidin-1-yl]-butyryl}-4,4'-bipiperidinyl-1-yl )-acetic acid, (172) 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]- 4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (173) 2-(3-bromo- 4-chloro-5-methyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H- quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (174) 2-(3-bromo-4-chloro-5-methyl-benzyl)-4-[4-(2 -oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-1-(4-pyridin-4-yl-piperazin-1-yl)-butane-1,4-dione , (175) 2-(3-bromo-4-chloro-5-methyl-benzyl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-4-[4 -(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (176) [4-(1-{2-(3 -bromo-4-chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]- butyryl}-piperidin-4-yl)-piperazin-1-yl]-acetic acid, (177) methyl (1'-{2-(3-bromo-4-chloro-5-methyl-benzyl)-4-oxo -4-[4-(2-oxo-1,4-dihydro- 2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (178) (1'-{2-(3-bromo-4 -chloro-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[ 4,4']bipiperidinyl-1-yl)-acetic acid, (179) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-carboxylic acid{1-( 3-bromo-4-chloro-5-methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-amide, (180 ) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[2-[1,4']bipiperidinyl-1'-yl-1-(3 -bromo-4-chloro-5-methyl-benzyl)-2-oxo-ethyl]-amide, (181) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin- 1-carboxylic acid-{1-(3-bromo-4-chloro-5-methyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2- oxo-ethyl}-amide, (182) 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid-[1-(3-bromo-4-chloro -5-methyl-benzyl)-2-(1'-methyl-[4,4']bipiperidinyl-1-yl)-2-oxo-ethyl]-amide, (183) 4-(2-oxo-1, 4-Dihydro-2H-quinazolin-3-yl)-piperidine-1-carbox silicic acid-[1-(3-bromo-4-chloro-5-methyl-benzyl)-2-oxo-2-(4-pyridin-4-yl-piperazin-1-yl)-ethyl]-amide, ( 184) 2-(4-chloro-3-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (185) 2-(4-chloro-3-trifluoromethyl-benzyl)-1-[4-( 4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]- butane-1,4-dione, (186) 1-[1,4']Bipiperidinyl-1'-yl-2-(4-chloro-3-trifluoromethyl-benzyl)-4-[4-(2-oxo- 1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, (187) [4-(1-{2-(4-chloro-3-trifluoromethyl -benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-piperidin-4-yl)- piperazin-1-yl]-acetic acid, (188) methyl (1'-{2-(4-chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4 -dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetate, (189) (1'-{2-(4- chloro-3-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl ]-butyryl}-[4,4']bipiperidinyl-1-yl)-acetic acid, (190) 2-(4-chloro-3-trifluoromethyl-benzyl)-1-(1'-methyl-[4,4 ']bipiperidinyl-1-yl)-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butane-1,4-dione, their enantiomers, diastereomers and their salts. 10. Physiologically acceptable salts of compounds according to at least one of claims 1 to 9, characterized in that they are salts of inorganic or organic acids or bases of inorganic or organic acids or bases. 11. Pharmaceutical preparations containing a compound according to at least one of claims 1 to 9 or a physiologically acceptable salt according to claim 10, characterized by the fact that they can be together with one or more inert bases and/or diluents. 12. Use of the compound according to at least one of claims 1 to 10 for the preparation of a pharmaceutical preparation, indicated by the fact that it is used for the acute treatment and prophylaxis of headaches, especially migraines or cluster headaches, and tension headaches and chronic headaches. 13. The use of a compound according to at least one of claims 1 to 10 for the preparation of a pharmaceutical preparation, characterized in that it is used for the prophylactic treatment of migraine during the prodromal period or for the acute and prophylactic treatment of migraine occurring before or during menstruation. 14. The use of a compound according to at least one of claims 1 to 10 for the preparation of a pharmaceutical preparation, characterized in that it is used to combat insulin-independent diabetes mellitus. 15. Use of a compound according to at least one of claims 1 to 10 for the preparation of a pharmaceutical preparation, indicated by the fact that it is used for the treatment of cardiovascular diseases, morphine tolerance, diarrhea caused by clostridial toxin, skin diseases, especially thermal and radiation-induced skin damage including sunburns, inflammatory diseases, e.g. especially inflammatory joint diseases such as arthritis, neurogenic inflammatory diseases of the mucous membrane of the oral cavity, inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resulting reduced blood flow, e.g. especially shock and sepsis or erythema, for relief of pain in general, especially in cases of neuropathic pain, neuropathic pain as part of systemic neurotoxic diseases and pain caused by an inflammatory process, or for preventive or therapeutic use for the treatment of symptoms of hot flashes caused by vasodilation and increased blood flow in menopausal women with estrogen deficiency or in hormone of treated patients with prostate cancer. 16. Method for preparing a pharmaceutical preparation according to claim 11, characterized in that the compound according to at least one of claims 1 to 10 is incorporated into one or more inert carriers and/or diluents by non-chemical methods. 17. Process for preparing a compound of the general formula (I) according to at least one of claims 1 to 9, characterized in that (a) to prepare compounds of the general formula (I) where X represents an oxygen atom or an NH group and R1 to R3 are as already defined in claim 1, provided that these groups do not contain the action of any free carboxylic acids: reacting piperidines of the general formula [image] , (III) where R1 is as defined in claim 1, (i) with carbonic acid derivatives of the general formula [image] , (IV) where A is as defined in claim 1 and G represents a nucleofuge group, provided that X represents an NH group, or (ii) with carbonic acid derivatives of the general formula [image] , (IV) where A denotes an oxygen atom and G denotes a nucleofuge group which may be the same or different, provided that X denotes an oxygen atom, and with compounds of the general formula [image] , (V) where X represents an oxygen atom or an .NH group and U, V, W, R2 and R3 as defined in claim 1, provided that R2 and R3 do not contain any free carboxylic acids and/or any other free primary or secondary aliphatic amino effect or any other free hydroxy effect, or (b) to prepare compounds of the general formula (I) where X denotes a methylene group and R1 to R3 are as defined in claim 1, provided that these groups do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects: coupling of a carboxylic acid of the general formula [image] , (VI) where U, V, W, R2 and R3 are as already defined in claim 1, with piperidine of the general formula [image] , (III) where R1 is as defined in claim 1. (c) to prepare compounds of the general formula (I) where X denotes a methylene group and R2 and R3 are as already defined in claim 1, provided that these groups do not contain any free primary or secondary amines: joining of compounds of the general formula [image] , (VII) where U, V, W, R 2 and R 3 are as already defined in claim 1, provided that R 2 and R 3 do not contain any free primary or secondary amines, and Nu denotes a leaving group, with piperidine of the general formula [image] , (III) where R 1 is as already defined in claim 1, or (d) to prepare compounds of general formula (I) as defined in claim 1: coupling of a carboxylic acid of the general formula [image] , (VIII) where all groups are as defined in claim 1, with an amine of the general formula HNR2R3, where R2 and R3 are as already defined in claim 1, provided that they do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects , or (e) to prepare compounds of general formula (I) wherein R 1 is as defined in claim 1, provided that there are no free primary or secondary amines: joining of compounds of the general formula [image] , (IX) where all groups are as defined in claim 1 and Nu denotes the outgoing group, with an amine of the general formula HNR2R3, where R2 and R3 are as defined in claim 1, provided that they do not contain any free carboxylic acids and/or other free primary or secondary aliphatic amino effects, and if necessary, each protecting group used in the reactions described above is cleaved off and (or all precursor functions used in the thus obtained compound are converted and/or if necessary, the thus obtained compound of the general formula (I) is separated into its stereoisomers and/or the thus obtained compound of the general formula (I) is converted into salts, especially for pharmaceutical use into physiologically acceptable salts.