Title of Invention	"NOVEL CARBOXAMIDES FOR USE AS XA INHIBITORS"
Abstract	Substituted carboxylic acid amides of general formula I Wherein A denotes a group of general formula wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylarnino, di-(C1-3-alkyl)-arnino, aminocarbonyl, C1-3-alkylaminocarbonyl, dHC1-3-alkyl)-aminocarbonyl or C1-3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-4-aikylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsuiphonyl group, with the proviso that in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula wherein m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X* denotes an oxygen or sulphur atom or a -NR6b group, Xs denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(Ct-3-alkyi)-aminocarbonyl or C1-3-a(kylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyt or C1-3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, -NH2, C1-3-alkoxy, a mono-, di- or trifiuoromethoxy group, R2 denotes a hydrogen or fluorine atom, R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, fmidazoiyl, oxazolyl, Isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyI-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyIoxycarbonyI groups, and R4 denotes a hydrogen atom or a C1-3-alkyl group, R3 and R4 together with the carbon atom to which they are bound, denote a tetrahydrofuran-3,3- diyl group, R5 denotes a hydrogen atom, B denotes a group of formula wherein n denotes the number 1 or 2, R7 denotes a hydrogen atom and R8 denotes a fluorine, chlorine, bromine or iodine atom, or a C2-3-alkynyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomners, the diastereomers, the mixtures thereof or the salts thereof.

Title of Invention

"NOVEL CARBOXAMIDES FOR USE AS XA INHIBITORS"

Abstract

Substituted carboxylic acid amides of general formula I Wherein A denotes a group of general formula wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylarnino, di-(C1-3-alkyl)-arnino, aminocarbonyl, C1-3-alkylaminocarbonyl, dHC1-3-alkyl)-aminocarbonyl or C1-3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-4-aikylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsuiphonyl group, with the proviso that in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula wherein m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X* denotes an oxygen or sulphur atom or a -NR6b group, Xs denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(Ct-3-alkyi)-aminocarbonyl or C1-3-a(kylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyt or C1-3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, -NH2, C1-3-alkoxy, a mono-, di- or trifiuoromethoxy group, R2 denotes a hydrogen or fluorine atom, R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, fmidazoiyl, oxazolyl, Isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyI-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyIoxycarbonyI groups, and R4 denotes a hydrogen atom or a C1-3-alkyl group, R3 and R4 together with the carbon atom to which they are bound, denote a tetrahydrofuran-3,3- diyl group, R5 denotes a hydrogen atom, B denotes a group of formula wherein n denotes the number 1 or 2, R7 denotes a hydrogen atom and R8 denotes a fluorine, chlorine, bromine or iodine atom, or a C2-3-alkynyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomners, the diastereomers, the mixtures thereof or the salts thereof.

Full Text	86618pct NOVEL CARBOXAMIDES FOR USE AS XA INHIBITORS The present invention relates to new substituted carboxylic acid amides of general formula (Figure Removed) the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties. The compounds of the above general formula I as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity. The present application thus relates to the new compounds of the above general formula I, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof. In the above general formula in a first embodiment A denotes a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, R63 independently of one another denotes a hydrogen, fluorine, chlorine or bromine atom or a Ci.3-alkyl, hydroxy, amino, C-s-alkylamino, di-(C3-alkyl)- amino, aminocarbonyl, d-s-alkylaminocarbonyl, di-(Ci.3-alkyl)-aminocarbonyl or d-3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C-alkyl, C-M-alkylcarbonyl, C-alkyloxycarbonyl or d-3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, X1 denotes an oxygen atom or a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X4 denotes an oxygen or sulphur atom, a -NR6b or carbonyl group, X5 denotes a carbonyl or sulphonyl group, X6 denotes an oxygen atom, a -NR6b or methylene group, X7 denotes an oxygen or sulphur atom or a -NR6b group, X8 denotes a methylene or carbonyl group, X9 denotes a -NR6b or carbonyl group, X10 denotes a sulphinyl or sulphonyl group and R6a independently of one another denote a hydrogen, fluorine, chlorine or bromine atom or a C.3-alkyl, hydroxy, amino, C.3-alkylamino, di-(C-3-alkyl)- amino, aminocarbonyl, C.3-alkylaminocarbonyl, d-(C.3-alkyl)- aminocarbonyl or C.3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C-alkyl, d-4-alkylcarbonyl, C-alkoxycarbonyl or C3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a C3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2-3-alkenyl, C2-3-alkynyl, nitro, amino, C3-alkoxy, a mono-, di- or trifluoromethoxy group, R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C3-alkyl group, R3 denotes a hydrogen atom, a C2-3-alkenyl or Ca-s-alkynyl group or a straightchain or branched Ce-alkyI group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a Cs-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, Cs-alkylcarbonyloxy, Cs-alkyloxycarbonyloxy, carboxy-d.3-alkyloxy, C5-alkyloxycarbonyl-C3-alkyloxy, Ci-e-alkyloxycarbonylamino, mercapto, C3-alkylsulphanyl, Ci.3-alkylsulphinyl, Ci.3-alkylsulphonyl, C3-alkylcarbonylamino-Ci-3-alkylsulphanyl, Ci.3-alkylcarbonylamino- C-alkylsulphinyl, C3-alkylcarbonylamino-C3-alkylsulphonyl, carboxy, Ci-s-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, Cs-alkylaminocarbonyl, di-alkyl)- aminocarbonyl, Cs-e-cycloalkyleneiminocarbonyl, aminosulphonyl, C3-alkylaminosulphonyl, di-(C3-alkyl)-aminosulphonyl, Cs-ecycloalkyleneiminosulphonyl, amino, C-s-alkylamino, di-(C-3-alkyl)-amino, C-5-alkylcarbonylamino, C-3-alkylsulphonylamino, A/-(C-3-alkylsulphonyl)- C-3-alkylamino, C3.6-cycloalkylcarbonylamino, aminocarbonylamino, C-3-alkylaminocarbonylamino, di-(C-3-alkyl)-aminocarbonylamino, a 4- to 7- membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl, C-M-alkylaminocarbonyl, C3.6-cycloalkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl, C-M-alkoxycarbonyl, C4,6- cycloalkyleneiminocarbonyl group, a phenyl or heteroaryl, phenylcarbonyl-C-i-3-alkyl, phenyl-Ci-3-alkyl or heteroaryl- C-3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino, C-3-alkylamino, di-(C-3-alkyl)-amino, hydroxy, C-alkyloxy, mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C3-alkyloxy, C3-alkyloxycarbonyl- C3-alkyloxy, aminocarbonyl-C3-alkyloxy, C3-alkylaminocarbonyl- C-3-alkyloxy, di-(C3-alkyl)-aminocarbonyl-C3-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-C3-alkoxy, carboxy, Cs-alkyloxycarbonyl or C3-alkyloxycarbonylamino group, a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Cs-alkyI or cycloalkyleneimino-C3-alkyl group wherein in the cyclic moiety a methylene group may be replaced by an -NH- group optionally substituted by a C-alkyl or C3-alkylcarbonyl group or by an oxygen atom and wherein additionally a methylene group adjacent to the -NH-, -N(C3-alkylcarbonyl)- or -N(C3-alkyl)- group may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one -CHa- group is excluded, R4 denotes a hydrogen atom or a Cs-alkyI group or R3 and R4 together with the carbon atom to which they are bound, denote a C3-7-cycloalkyl group, while one of the methylene groups of the C3.7-cycloalkyl group may be replaced by an imino, C-s-alkylimino, acylimino or sulphonylimino group, R5 denotes a hydrogen atom or a C3-alkyl group, B denotes a group of formula (Figure Removed) wherein n denotes the number 1 or 2, R7 denotes a hydrogen atom or a C3-alkyl, hydroxy, C5-alkyloxycarbonyl, carboxy-C3-alkyl, C3-alkyloxycarbonyl-Ci.3-alkyl, amino or C3-alkylamino group and R8 independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a Cs-alkyI group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a Ca-s-alkenyl or C2.3-alkynyl, a hydroxy, C-3-alkoxy, trifluoromethoxy, amino, nitro or nitrile group, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C-i-s-alkyl, phenyl or phenyl-Ci-s-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a Ci.3-alkyl, phenyl, amino- C2-3-alkyl, C3-alkylamino-C2-3-alkyl, di-(C3-alkyl)-amino-C2-3-alkyl, a 4- to 7-membered cycloalkyleneimino-C^s-alkyl or phenyl-C3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a Ci-3-alkyl or phenyl-Ci.3-alkyl group and two or three nitrogen atoms, and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a C3-alkyl, hydroxy, C3-alkyloxy group, amino, C3-alkylamino, di-(C3-alkyl)-amino or Cs-e-cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. Examples of monocyclic heteroaryl groups are the pyridyl, A/-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl, [1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl, imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or [1,2,5]thiadiazolyl group. Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]- isothiazolyl, benzo[of]isothiazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[djisoxazolyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thiadiazolyl, benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, A/-oxy-quinolinyl, isoquinolinyl, quinazolinyl, A/-oxy-quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group. Examples of the Ci-8-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, te/f-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl group. Examples of the Ci-8-alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, terf-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, neo-pentyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy, 1-octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy group. By a group which can be converted in vivo into a carboxy group is meant for example a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C1.6-alkanol, a phenyl-Ci-3-alkanol, a C3.9-cycloalkanol, a CS.Tcycloalkenol, a C3.5-alkenol, a phenyl-C3.5-alkenol, a C3_5-alkynol or phenyl- C3-5-alkynol with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-Ci-3-alkanol or an alcohol of formula R9-CO-0-(R10CR11)-OH, wherein R9 denotes a C1.8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-Ci-3-alkyl group, R10 denotes a hydrogen atom, a C-i-3-alkyl, C5-7-cycloalkyl or phenyl group and R11 denotes a hydrogen atom or a C-i-3-alkyl group. Preferred groups which may be cleaved from a carboxy group in vivo include a Ci-6-alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or a phenyl- Ci-3-alkoxy group such as the benzyloxy group. Those compounds of general formula I wherein R3 contains a group which may be converted in vivo into a carboxy group are prodrugs for those compounds of general formula I wherein R3 contains a carboxy group. A 2nd embodiment of the present invention comprises those compounds of general formula I wherein A denotes a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, R>6 aa independently of one another denote a hydrogen or fluorine atom, a C3-alkyl, hydroxy, amino, Cs-alkylamino, di-(C-3-alkyl)-amino, aminocarbonyl, C3-alkylaminocarbonyl, di-(C3-alkyl)-aminocarbonyl or C3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C-M-alkyl, C4-alkylcarbonyl, C4-alkoxycarbonyl or Cs-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X4 denotes an oxygen or sulphur atom, a -NR6b or carbonyl group, X5 denotes a carbonyl or sulphonyl group, X8 denotes a carbonyl group, X9 denotes a carbonyl group, R6a independently of one another denote a hydrogen or fluorine atom, a Ci-3-alkyl, hydroxy, amino, C3-alkylamino, di-(C3-alkyl)-amino, aminocarbonyl, C3-alkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl or C3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C4-alkyl, C4-alkylcarbonyl, C-M-alkoxycarbonyl or C3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a d.3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2-3-alkenyl, Ca-s-alkynyl, nitro, amino, C3-alkoxy, a mono-, di- or trifluoromethoxy group, R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C3-alkyl group, R3 denotes a C2.3-alkenyl or C2-3-alkynyl group or a straight-chain or branched C6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a Cs-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C5-alkylcarbonyloxy, Cs-alkyloxycarbonyloxy, carboxy-C.3-alkyloxy, C5-alkyloxycarbonyl- C3-alkyloxy, Cs-alkyloxycarbonylamino, mercapto, C3-alkylsulphanyl, Ci-s-alkylsulphinyl, C-3-alkylsulphonyl, C- a-alkylcarbonylamino-Ci-s-alkylsulphanyl, Ci-3-alkylcarbonylamino- C3-alkylsulphinyl, C-alkylcarbonylamino-C-s-alkylsulphonyl, carboxy, C3-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, C3-alkylaminocarbonyl, d-(C3-alkyl)- aminocarbonyl, Cs-e-cycloalkyleneiminocarbonyl, aminosulphonyl, C3-alkylaminosulphonyl, di-(C3-alkyl)-aminosulphonyl, C3.6- cycloalkyleneiminosulphonyl, amino, Ci-s-alkylamino, di-(C3-alkyl)-amino, C5-alkylcarbonylamino, Cs-alkylsulphonylamino, /V-(C3-alkylsulphonyl)- C3-alkylamino, C3-6-cycloalkylcarbonylamino, aminocarbonylamino, C3-alkylaminocarbonylamino, di-(C3-alkyl)-aminocarbonylamino, a 4- to 7- membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl, C4-alkylaminocarbonyl, C3.6-cycloalkylaminocarbonyl, di-(C3-alkyl)-aminocarbonyl, C-M-alkoxycarbonyl, Cecycloalkyleneiminocarbonyl group, a phenyl or heteroaryl, phenylcarbonyl-C3-alkyl, phenyl-C3-alkyl or heteroaryl- Cs-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino, C-s-alkylamino, di-(C3-alkyl)-amino, hydroxy, C4-alkyloxy, mono-, d- or trifluoromethoxy, benzyloxy, carboxy-Ci-3-alkyloxy, Ci.3-alkyloxycarbonyl- C3-alkyloxy, aminocarbonyl-C.3-alkyloxy, C.3-alkylaminocarbonyl- Cs-alkyloxy, d-(C3-alkyl)-aminocarbonyl-C3-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-C3-alkoxy, carboxy, C3-alkyloxycarbonyl or C3-alkyloxycarbonylamino group, a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C3-alkyl or cycloalkyleneimino-C3-alkyl group wherein in the cyclic moiety a methylene group may be replaced by a -NH- group optionally substituted by a C3-alkyl or C3-alkylcarbonyl group or by an oxygen atom and wherein additionally a methylene group adjacent to the -NH-, -N(C3-alkylcarbonyl)- or -N(C3-alkyl)- group may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one -CH2- group is excluded, R4 denotes a hydrogen atom or a C3-alkyl group, R5 denotes a hydrogen atom or a C3-alkyl group, B denotes a group of formula (Figure Removed) wherein n denotes the number 1 or 2, R7 denotes a hydrogen atom, a C3-alkyl, hydroxy, C5-alkyloxycarbonyl, carboxy-C3-alkyl, Ci.3-alkyloxycarbonyl-C1.3-alkyl, amino or C3-alkylamino group and R8 independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C2.3-alkenyl or C2.3-alkynyl, a hydroxy, C3-alkoxy, trifluoromethoxy, amino, nitro or nitrile group, hile, unless otherwise stated, by the term "heteroaryl group" mentioned ereinbefore in the definitions is meant a monocyclic 5- or 6-membered Bteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci-3-alkyl, phenyl or phenyl-C3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C3-alkyl, phenyl, amino- C2-3-alkyl, C3-alkylamino-C2.3-alkyl, di-(C3-alkyl)-amino-C2-3-alkyl, a 4- to 7-membered cycloalkyleneimino-Ci.3-alkyl or phenyl-C3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C3-alkyl or phenyl-Ci-3-alkyl group and two or three nitrogen atoms, and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a C3-alkyl, hydroxy, Cs-alkyloxy group, amino, C3-alkylamino, di-(C3-alkyl)-amino or C3-6-cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 3rd embodiment of the present invention comprises those compounds of general formula I, wherein A denotes a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom, a C-3-alkyl, hydroxy, amino, C-s-alkylamino, di-(C-3-alkyl)-amino, aminocarbonyl, C3-alkylaminocarbonyl, di-(C-3-alkyl)-aminocarbonyl or Ca-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C4-alkylcarbonyl, Calkoxycarbonyl or C3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula (Figure Removed) vherein m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, 6b X2 denotes an oxygen atom or a -NR group, X3 denotes a methylene, carbonyl or sulphonyl group, X4 denotes an oxygen or sulphur atom or a -NR6b group, X5 denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom, a C3-alkyl, hydroxy, amino, C3-alkylamino, di-(C.3-alkyl)-amino, aminocarbonyl, Ci.3-alkylaminocarbonyl, di-(Ci.3-alkyl)-aminocarbonyl or C3-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C4-alkyl, C4-alkylcarbonyl, C-alkoxycarbonyl or C3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a fluorine, chlorine or bromine atom, a C3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, Ci-3-alkoxy, a mono-, di- or trifluoromethoxy group, R2 denotes a hydrogen atom, R3 denotes a straight-chain or branched Ci.6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrite, hydroxy, benzyloxy, a Ci-5-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, Cvs-alkylcarbonyloxy, C-5-alkyloxycarbonyloxy, carboxy- C-3-alkyloxy, Ci.5-alkyloxycarbonyl-C.3-alkyloxy, C8-alkyloxycarbonylamino, d-3-alkylsulphanyl, C1.3-alkylsulphonyl, carboxy, C-3-alkyloxycarbonyl, C3-alkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl, C3.6- cycloalkyleneiminocarbonyl, aminocarbonylamino, C-3-alkylaminocarbonylamino or di-(C-3-alkyl)-aminocarbonylamino group, an aminocarbonyl, C-4-alkylaminocarbonyl, C3-cycloalkylaminocarbonyl or d- (C-3-alkyl)-aminocarbonyl group, a phenyl or heteroaryl, phenyl-Ci-3-alkyl or heteroaryl-C.3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci.3-alkyl, amino, Ci-s-alkylamino, di-(C-3-alkyl)-amino, hydroxy, C-4-alkyloxy, mono-, d- or trifluoromethoxy, carboxy, or C.3-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a -NH- group optionally substituted by a C-i-3-alkyl or C_3-alkylcarbonyl group, or an oxygen atom, R4 denotes a hydrogen atom, R5 denotes a hydrogen atom, B denotes a group of formula (Figure Removed) wherein n denotes the number 1, R7 denotes a hydrogen atom and R8 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, C2-3-alkynyl, or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1.3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C-3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 4th embodiment of the present invention comprises those compounds of general formula I wherein A, R1, R2, R4, R5 and B are defined as described under the 3rd embodiment and R3 denotes a straight-chain or branched Ci_e-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, benzyloxy, a Ci-5-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, C-s-alkylcarbonyloxy, C-s-alkyloxycarbonyloxy, carboxy- C-3-alkyloxy, C-s-alkyloxycarbonyl-C^a-alkyloxy, C-s-alkyloxycarbonylamino, C-3-alkylsulphanyl, C.3-alkylsulphonyl, carboxy, Cs-alkyloxycarbonyl, C-3-alkylaminocarbonyl, d-(C-3-alkyl)-aminocarbonyl, C3-ecycloalkyleneiminocarbonyl, aminocarbonylamino, Ci.s-alkylaminocarbonylamino or di-(C-3-alkyl)-aminocarbonylamino group, an aminocarbonyl, C4-alkylaminocarbonyl, C3-6-cycloalkylaminocarbonyl or di- (C3-alkyl)-aminocarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 5th embodiment of the present invention comprises those compounds of general formula I wherein A, R1, R2, R4, R5 and B are defined as described under the 3rd embodiment and R3 denotes a phenyl or heteroaryl, phenyl-C3-alkyl or heteroaryl-C3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C.3-alkyl, amino, C3-alkylamino, di-(C-3-alkyl)-amino, hydroxy, C-4-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or Ci.3-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a -NH- group optionally substituted by a C3-alkyl or d-3-alkylcarbonyl group, or by an oxygen atom, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C.3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C.3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 6th embodiment of the present invention comprises those compounds of general formula I, wherein A denotes a group of general formula or wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom or a C-3-alkyl group and R6b may be a hydrogen atom or a C.3-alkyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula (Figure Removed) wherein m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X4 an oxygen or sulphur atom or a -NR6b group, X5 denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom or a d-3-alkyl group and R6b independently of one another may be a hydrogen atom or a C-alky! group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R2 denotes a hydrogen atom, R3 denotes a straight-chain or branched C-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C.3-alkylsulphanyl, d-3-alkylsulphonyl, carboxy or C-3-alkyloxycarbonyl group, a phenyl or heteroaryl, phenyl-C.3-alkyl or heteroaryl-C.3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C.3-alkyl, C-4-alkyloxy, mono-, d- or trifluoromethoxy, carboxy, or C.3-alkyloxycarbonyl group, R4 denotes a hydrogen atom, R5 denotes a hydrogen atom and B denotes a group of formula (Figure Removed) wherein n denotes the number 1, R7 denotes a hydrogen atom and R8 denotes a chlorine or bromine atom or the ethynyl group, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 7th embodiment of the present invention comprises those compounds of general formula I, wherein A, R1, R2, R4, R5 and B are defined as described under the 6th embodiment and R3 denotes a straight-chain or branched C-M-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C3-alkylsulphanyl, d-3-alkylsulphonyl, carboxy or C3-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. An 8th embodiment of the present invention comprises those compounds of general formula I, wherein A, R1, R2, R4, R5 and B are defined as described under the 6th embodiment and R3 denotes a phenyl or heteroaryl, phenyl-Ci.3-alkyl or heteroaryl-C3-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, d-3-alkyl, d-4-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or C3-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a -NH- group optionally substituted by a Ci_3-alkyl or C3-alkylcarbonyl group, or by an oxygen atom, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci.3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 9th embodiment of the present invention comprises those compounds of general formula I, wherein A denotes a group of formula (Figure Removed) wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom or a C3-alkyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the fluorine atoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R2 denotes a hydrogen atom, R3 denotes a straight-chain or branched Ci-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a Ci-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a Ci-3-alkylsulphanyl, C3-alkylsulphonyl, carboxy or Ci-3-alkyloxycarbonyl group, a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C2-alkyl or imidazolyl-C2- alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C-s-alkyl groups, C3-alkyloxy groups, carboxy or C3-alkyloxycarbonyl groups, and R4 denotes a hydrogen atom, R5 denotes a hydrogen atom and B denotes a group of formula (Figure Removed) wherein n denotes the number 1, R7 denotes a hydrogen atom and R8 denotes a chlorine or bromine atom or an ethynyl group, while, unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C-3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 10th embodiment of the present invention comprises those compounds of general formula I, wherein A, R1, R2, R4, R5 and B are defined as described under the 9th embodiment and R3 denotes a straight-chain or branched Ci-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a Cs-alkylsulphanyl, C-3-alkylsulphonyl, carboxy or C-3-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. An 11th embodiment of the present invention comprises those compounds of general formula I wherein A, R1, R2, R4, R5 and B are defined as described under the 9th embodiment and denote a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-Ci-2-alkyl or imidazolyl-Ci-2- alkyl group which may optionally be substituted in the heteroaryl moiety by one or two Cs-alkyI groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C.3-alkyloxy groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, carboxy or C-3- alkyloxycarbonyl groups, and unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a Ci-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a Ci.3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C3-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof. A 12th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1,2,3, 4, 5, 6, 7 and 8, wherein the group X1 denotes a methylene group. A 13th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1,2,3, 4, 5, 6, 7 and 8, wherein the group X1 denotes a carbonyl group. A 14th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12 and 13, wherein the group X3 denotes a methylene group. A 15th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12 and 13 wherein the group X3 denotes a carbonyl group. A 16th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12, 13, 14 and 15, wherein the group X4 denotes an oxygen atom. A 17th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14, 15 and 16, wherein the group B denotes the group An 18th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14,15 and 16, wherein the group B denotes the group A 19th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14,15 and 16, wherein the group B denotes the group A 20th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13,14,15, 16, 17,18 and 19, wherein the group R8 denotes a chlorine atom. A 21st embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14,15,16,17,18 and 19, wherein the group R8 denotes a bromine atom. A 22nd embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14, 15, 16,17,18 and 19, wherein the group R8 denotes an ethynyl group. A 23rd embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12,13,14, 15, 16,17,18,19, 20, 21 and 22, which correspond to general formula la (Figure Removed) The following preferred compounds of general formula I will now be mentioned by way of example: (1) 3-chloro-/V-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4- ([1,4]diazepan-1-yl)-benzamide, (2) 4-(4-/V-Boc-piperazin-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)- ethyl]-3-trifluoromethyl-benzamide, (3) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3- trifluoromethyl-benzamide, (4) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin- 1-yl)-3-trifluoromethyl-benzamide, (5) 4-(4-/V-acetyl-piperazin-1 -yl)-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)- ethyl]-3-trifIuoromethyl-benzamide, (6) 4-(azepan-2-on-1 -yl)-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3- methyl-benzamide, (7) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethyl]-3-methyl-benzamide, (8) 4-(azepan-2-on-1 -yl)-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- hydroxy-ethyl]-3-methyl-benzamide, (9) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1 -yl)- benzamide, (1 0) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2- on-1 -yl)-benzamide, (1 1 ) A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3- methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, (1 2) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-A/-methyl- [1 ,4]diazepan-1 -yl)-benzamide, (1 3) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(2-methylpyrrolidin- 1 -yl)-benzamide, (14) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-1 • yl)-benzamide, (1 5) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4- (morpholin-1 -yl)-benzamide, (16) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3- trifluoromethyl-4-(morpholin-1 -yl)-benzamide, (1 7) 4-(azepan-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3- trifluoromethyl-benzamide, (18) 4-(azepan-1 -yl)-3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)- ethyl]-benzamide, (19) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1 yl)-benzamide, (20) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4- ([1 ,4]oxazepan-4-yl)-benzamide, (21 ) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide, (22) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (23) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3- methyI-4-(morpholin-3-on-4-yl)-benzamide, -39- (24) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (25) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)- 2-methoxy-ethyl]-benzamide, (26) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethylJ-3-trifluoromethyl-benzamide, (27) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)- benzamide, (28) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin- 3-on-4-yl)-benzamide, (29) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)- benzamide, (30) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1 yl)-benzamide, (31 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2- on-1 -yl)-benzamide, (32) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2- on-1 -yl)-benzamide, (33) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(A/-methyl-piperazin-1 yl)-3-trifIuoromethyl-benzamide, (34) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (35) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (pyrrolidin-2-on-1-yl)-benzamide, (36) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-4-(pyrrolidin-2-on- 1-yl)-benzamide, (37) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin- 1-yl)-benzamide, (38) 3-chlora-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,4- didehydro-piperidin-1-yl)-benzamide, (39) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide (40) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4- (piperazin-1 -yl)-3-trifIuoromethyl-benzamide, (41 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (morpholin-3-on-4-yl)-3-nitro-benzamide, (42) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(tetrahydropyrimidin- 2-on-1 -yl)-benzamide, (43) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide, (44) 3-chloro-A/-[(1 R)-1-(5-chloro-1 A/-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([1,4]oxazepan-5-on-4-yl)-benzamide, -41 - (45) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([1,4]oxazepan-3-on-4-yl)-benzamide, (46) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1-yl)-benzamide, (47) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (48) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 , 1 -dioxoisothiazolidin- 2-yl)-3-methyl-benzamide, (49) /V-[1 -(5-chloro-1 H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)- benzamide, (50) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methylpiperazin- 1-yl-methyl)-piperidin-1-yl)-benzamide, (51 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin- 2-on-3-yl)-benzamide, (52) 3-chloro-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3- on-4-yl)-benzamide, (53) A/-[(1 R,2S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (54) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin- 1 -yl)-benzamide, (55) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4- (thiomorpholin-3-on-4-yl)-benzamide, (56) A/-[(1 fl)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperidin-2-on-1 -yl)-benzamide, (57) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1 ,3]- oxazinan-2-on-3-yl)-benzamide, (58) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]-oxazinan-2-on-3-yl)-benzamide, (59) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin- 2-on-1-yl)-3-trifluoromethyl-benzamide, (60) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide, (61 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6- didehydro-azepan-2-on-1-yl)-benzamide, (62) 4-(azepan-2-on-1 -yl)-A/-[(1 S)-1 -(5-chloro-6-fluoro-1 H-benzimidazol-2-yl)- ethyl]-3-methyl-benzamide, (63) W-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 ,3-dioxothiomorpholin- 4-yl)-3-methyl-benzamide, (64) W-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1 , 1 ,3-trioxothiomorpholin- 4-yl)-benzamide, (65) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperazin-1 -yl)-benzamide, (66) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperazin-2-on-1-yl)-benzamide, (67) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin- 3-on-4-yl)-benzamide, (68) /V-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([1,3]oxazepan-2-on-3-yl)-3-trifIuoromethyl-benzamide, (69) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin- 2-on-1 -yl)-benzamide, (70) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4- (piperidin-2-on-1 -yl)-benzamide, (71) A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1l1-dioxo- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, (72) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 , 1 -dioxo- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, (73) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 ,1 -dioxo-6-methyl- [1 ejthiadiazinan^-yO-S-methyl-benzamide, (74) /V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo- S-methyl-fl^.ejthiadiazinan^-yO-S-methyl-benzamide, (75) /V-[(1 /?)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (76) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (77) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (78) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (79) A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (80) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (thiomorpholin-3-on-4-yl)-benzamide, (81 ) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (82) 3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro- [1 ,2]oxazin-2-yl)-benzamide, (83) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (1 ,1-dioxo-[1 ,2]thiazinan-2-yl)-benzamide, (84) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo- [1,2]thiazepan-2-yl)-3-methyl-benzamide, (85) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1 -yl)- trifluoromethoxy-benzamide, (86) 3-bromo-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2- on-1 -yl)-benzamide, (87) 3-bromo-/V-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1-yl)-benzamide, (88) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(furan-2-yl)-methyl]-3-methyl-4- (piperidin-2-on-1-yl)-benzamide, (89) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4- ([1,2]oxazinan-2-yl)-benzamide, (90) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (5-oxo-[1,4]oxazepan-4-yl)-benzamide, (91 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxoimidazolidin- 1-yl)-3-methyl-benzamide, (92) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4- dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide, (93) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2- oxo-oxazolidin-3-yl)-benzamide, (94) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4-methyl-2-oxo-oxazolidin-3-yl)-benzamide, (95) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (96) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin- 3-on-4-yl)-benzamide, (97) 3-bromo-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (98) A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo- [1 ,4]diazepan-1-yl)-benzamide, (99) A/-[(1 ft)-1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(thiophen-2-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (1 00) /V-[(1 A?)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1 , 1 -dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide, (101) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide, (1 02) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide> (1 03) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide, (1 04) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (4-(4f?)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, (1 05) 3-chloro-A/-[(1 fi)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4-(4f?)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide, (1 06) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4- (morpholin-3-on-4-yl)-benzamide, (107) A/-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (108) A/-[1-(1SH5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (109) A/-[1 -(5-chloro-1 /V-benzimidazol-2-yl)-1 -pyridin-3-yl-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (110) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1H-1 -methyl-pyrazol-3-yl)- methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, (111) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (5-methyl-morpholin-3-on-4-yl)-benzamide, (112) 3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3- dimethylamino-pyrrolidin-1-yl)-benzannide, (113) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)- 3-trifluoromethyl-benzamide, (114) 3-chloro-A/-[(1R)-1-(5-chIoro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (tetrahydro-pyrimidin-2-on-1-yl)-benzamide, (115) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4- ([1,4]diazepan-1-yl)-benzamide, (116) 3-chloro-A/-[1 -(5-chloro-1 H-indoi-2-yl)-2-methoxy-ethyl]-4-([1,4]diazepan- 1 -yl)-benzamide, (117) A/-[1 -(5-chloro-1 H-indol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3- on-4-yl)-benzamide, (118) 3-bromo-/V-[1 -(5-chloro-1 H-indol-2-yl)-1 -(furan-2-yl)-methyl]-4- ([1,4]oxazepan-5-on-4-yl)-benzamide, (119) A/-[1 -(5-bromo-1 H-indoI-2-yl)-1 -(1 -methyl-1 H-pyrazol-3-yl)-methyl]-3- methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, (120) /V-[1 -(5-chloro-1 H-indol-2-yl)-3-(methyl-sulphonyl)-propyl]-3-methyl-4- (tetrahydropyrimidin-2-on-1-yl)-benzamide, (121) A/-[1-(5-chloro-1 H-indol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(5-methylpyrrolidin- 2-on-1-yl)-benzamide, (122) A/-[1-(5-chloro-1H-indol-2-yl)-1-phenyl-methyl]-4-(piperazin-1-yl)-3- trifluoromethyl-benzamide, (123) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[1 -(5-chloro-1 H-indol-2-yl)-3-(1 Htetrazol- 5-yl)-propyl]-benzamide, (124) A/-[1-(5-bromo-1H-indol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo- [1,2]thiazepan-2-yl)-3-methyl-benzamide, (125) 3-chloro-/V-[1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4- (diazepan-1 -yl)-benzamide, (126) 3-chloro-A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-ethyl]-4- ([1,4]oxazepan-5-on-4-yl)-benzamide, (127) A/-[(1 S)-1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4- (morpholin-S-on^-ylJ-benzamide, (128) A/-[1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (129) 3-bromo-A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(1H-pyrazol-3-yl)- methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, (130) A/-[1 -(7-bromo-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-chloro-4-(4- methyl-piperazin-1-yl)-benzamide, (131) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (132) A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(furan-2-yl)-methyl]-4- (diazepan-1-yl)-3-trifluoromethyl-benzamide, (1 33) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-1 -phenyl-methyl]-3-methyl-4- (1 ,1-dioxo-[1 ,2]thiazepan-2-yl)-benzamide, (1 34) 3-chloro-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (1 35) 3-bromo-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-3-(methyl-sulphanyl)- propyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide, (1 36) 3-chloro-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-hydroxy-ethyl]-4- (piperazin-2-on-1 -yl)-benzamide, (1 37) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperidin-2-on-1-yl)-benzamide, (1 38) A/-[1 -(7-bromo-imidazo[1 ,2a]pyridin-2-yl)-3-methoxy-propyl]-3-chloro-4- (1 ,1-dioxo-[1 (1 39) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-trifluoromethoxy-ethyl]-3- methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide, (1 40) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 41 ) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 42) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-benzyloxycarbonyl-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (1 43) A/-[1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (1 44) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(pyrazin-2-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 45) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(oxazol-2-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (146) A/-[1-(5-chloro-1 H-benzimidazol-2-yl)-1-(1 H-imidazol-4-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamideI (1 47) A/-[1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3- difluoromethoxy-4-(morpholin-3-on-4-yl)-benzamide, (1 48) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -methyl-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 49) A/-[3-(5-chloro-1 H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 50) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(pyrrolidin-1 -yl-carbonyl)-propyl]- 3-methyl-4-(morpholin-3-on-4-yl)-benzamide, (151) /V-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on- 4-yl)-benzamide, ( 1 52) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, ( 1 53) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperidin-2-on-1-yl)-benzamide, (1 54) 3-bromo-A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (1 55) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4- methyl-oxazolidin-2-on-3-yl)-benzamide, (1 56) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,4]oxazepan-5-on-4-yl)-benzamide, (1 57) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (2-methyl-tetrahydropyridazin-1-yl)-benzamide, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, while the compounds 4-(azepan-2-on-1 -yl)-/V-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethyl]-3-methyl-benzamide, (2) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- hydroxy-ethyl]-3-methyl-benzamide, (3) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3- methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, (4) yv-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-3-trifIuoromethyl-benzamide, (5) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (6) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3- methyl-4-(morpholin-3on-4-yl)-benzamide, (7) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (8) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)- 2-methoxy-ethyl]-benzamide, (9) 4-(azepan-2-on-1 -yl)-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethyl]-3-trifluoromethyl-benzamide, (10) A/-[(1 S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide, -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (morpholin-3-on-4-yl)-3-nitro-benzamide, (12) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide, (1 3) 3-chloro-A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([1,4]oxazepan-5-on-4-yl)-benzamide, (14) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1-yl)-benzamide, -53- (1 5) A/-[(1 /?)-! -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (1 6) A/-[(1 f?,2S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (17) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4- (thiomorpholin-3-on-4-yl)-benzamide, (18) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperidin-2-on-1 -yl)-benzamide, (1 9) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]-oxazinan-2-on-3-yl)-benzamide, (20) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin- 2-on-1-yl)-3-trifluoromethyl-benzamide, (21 ) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide, (22) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin- 3-on-4-yl)-benzamide, (23) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([I.Sloxazepan^-on-S-ylJ-S-trifluoromethyl-benzamide, (24) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, (25) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (26) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (27) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (28) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamidef (29) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (thiomorpholin-3-on-4-yl)-benzamide, (30) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (31 ) 3-chloro-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (1 ,1-dioxo-[1 ,2]thiazinan-2-yl)-benzamide, (32) / [1,2]thiazepan-2-yl)-3-methyl-benzamide, (33) 3-bromo-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2- on-1 -yl)-benzamide, (34) 3-bromo-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1 -yl)-benzamide, (35) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(furan-2-yl)-methyl]-3-methyl-4- (piperidin-2-on-1-yl)-benzamide, (36) A/-[(1 R)-1 -(5-chioro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (5-oxo-[1,4]oxazepan-4-yl)-benzamide, (37) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4-methyl-2-oxo-oxazolidin-3-yl)-benzamide, (38) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (39) 3-bromo-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (morpholin-3-on-4-yl)-benzamide, (40) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(thiophen-2-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (41 ) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1 , 1 -dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide, (42) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide, (43) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, (44) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide, (45) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (4_(4/?)-methyl-2-oxo-oxazolidin-3-yl)-benzamidel (46) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide, (47) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4- (morpholin-3-on-4-yl)-benzamide, (48) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 H-pyrazol-3-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide, (49) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 H-1 -methyl-pyrazol-3-yl)- methylj-S-methyl^morpholin-S-on^-ylJ-benzamide, (50) 3-chloro-/V-[(1 fi)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (5-methyl-morpholin-3-on-4-yl)-benzamide, (51 ) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (tetrahydro-pyrimidin-2-on-1-yl)-benzamide, (52) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (53) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide (54) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4- (piperazin-1-yl)-3-trifluoromethyl-benzamide, (55) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (morpholin-3-on-4-yl)-3-nitro-benzamide, (56) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (piperazin-1 -yl)-benzamide, (57) A/-[(1 S)-1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof are particularly preferred. Within the scope of the present application, where applicable, the "isomer", "stereoisomer", "diastereomer", "enantiomer", "chiral", "racemate" or "racemic mixture" are defined as follows. Compounds of the same empirical formula which differ in the nature or arrangement of the bonding of their atoms or their connectivity or the spatial arrangement of the atoms in the molecule are known as "isomers". Isomers which differ in the spatial arrangement of the atoms in the molecule and are not congruent, while having the same type of connectivity of their atoms, are known as "stereoisomers". Stereoisomers which do not behave as image and mirror image to one another are known as "diastereomers", and stereoisomers which behave as an image and mirror image to one another are known as "enantiomers". Where an asymmetric centre or atom is present (also known as a stereocentre or chiral centre), for example in the case of a carbon atom substituted by four different substituents, the molecule has the attribute "chiral", and a pair of enantiomers is possible. An enantiomer may be characterised by the absolute configuration of its stereocentre. The absolute configuration is described by means of the descriptors (R) and (S), which are determined by the application of the sequence rules according to Cahn, Ingold and Prelog , or by describing the rotation of the plane of polarised light as it interacts with the molecule, which is referred to as dextrorotatory or laevorotatory (i.e. accordingly with (+) or (-) as the descriptor). A chiral compound may occur both as an individual enantiomer or as a mixture of the corresponding enantiomers. A mixture which contains equal amounts of both enantiomers of a compound is known as a "racemate" or "racemic mixture". According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods: -58- (a) In order to prepare compounds of general formula (Figure Removed) wherein R3 to R5 are as hereinbefore defined and Z1 denotes the hydrogen atom or a protective group and B1 denotes a group of formula wherein R7 and R8 are as hereinbefore defined: cyclisation of a compound of general formula (Figure Removed) optionally formed in the reaction mixture wherein R3 to R5, R7 and R8 are as hereinbefore defined and Z1 denotes the hydrogen atom or a protective group, after which any protective group used is cleaved. The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide or tetralin, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, for example at temperatures between 0 and 250°C, but preferably between 20 and 100°C, optionally in the presence of a condensation agent such as phosphorus oxychloride, thionyl chloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, A/,A/-dicyclohexylcarbodiimide or optionally also in the presence of a base such as potassium ethoxide or potassium-ferf.-butoxide. The cyclisation may however also be carried out without a solvent and/or condensation agent. Compounds of general formula (IV) may be obtained by acylation of compounds of general formula wherein n, R7 and R8 are as hereinbefore defined, with compounds of general formula (XXV), wherein R3, R4 and R5 are as hereinbefore defined, Q denotes a halogen atom or a hydroxy, Ci^-alkoxy or Ci-4-acyloxy group and Z1 denotes a protective group, according to processes described in (e). (b) In order to prepare a compound of general formula (Figure Removed) wherein R3 to R5 are as hereinbefore defined, Z1 denotes the hydrogen atom or a protective group, for example a Ci-s-alkyloxycarbonyl or benzyloxycarbonyl group, and B1 denotes a group of formula R )7 __ wherein R an dj 0R8 are as hereinbefore defined: i) transition metal-catalysed coupling and cyclisation of a compound of general formula R33 NHR5 wherein R3 denotes a phenyl or heteroaryl group and R4 denotes a hydrogen atom and R5 is as hereinbefore defined, with a compound of general formula (Figure Removed) wherein R8 is as hereinbefore defined and Z1 denotes a protective group, for example an acetyl or methylsulphonyl group, after which the protective group is cleaved. The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, Nmethylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform or tetrachtoromethane, for example at temperatures between 0 and 250°C, but preferably between 20 and 120°C, conveniently in the presence of transition metal catalysts such as bis-(triphenylphosphine)-palladium(ll)- chloride, bis-(tricyclohexylphosphine)-palladium(ll)-chloride, bis-(triethylphosphine)- palladium(ll)-chlorideorbis-(tri-o-tolylphosphine)-palladium(ll)- chloride and optionally in the presence of a transition metal catalyst such as copper(l)-iodide, copper(l)-bromide or copper(l)-acetate and conveniently in the presence of a base such as tetramethylguanidine, tetramethylethylenediamine or A/,A/'-dimethylethylenediamine as well as optionally using an inert gas atmosphere (for example nitrogen or argon). ii) alkylation and subsequent reductive amination of a compound of general formula (Figure Removed) wherein R7 and R8 are as hereinbefore defined and Y denotes a halogen atom, a C^-alkoxy, CM-alkoxyamino or a A/-C-i-4-alkoxy-A/-Ci-4-alkylamino group, with a compound of general formula (Figure Removed) wherein R4 is as hereinbefore defined and M denotes a metal such as for example lithium, sodium or potassium, or a metal such as for example magnesium, cadmium, copper or zinc, with a suitable counter-ion, such as for example chloride, bromide or iodide, or also a combination of two metals, such as for example magnesium and copper, lithium and copper or zinc and copper, with suitable counter-ions, such as for example cyanide, chloride, bromide or iodide, as well as a grouping containing combinations thereof, and subsequent reductive amination of the compounds thus obtained. The alkylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, Nmethylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, diethyl ether, terf.-butyl-methyl-ether or tetrahydrofuran, for example, at temperatures between -100 and +100°C, but preferably between -100 and 30°C, with alkylating reagents such as Grignard reagents, organolithium reagents, Oilman or Knochel cuprates which may be produced by methods known from the literature, optionally using an inert gas atmosphere (nitrogen or argon). The subsequent reductive amination of the ketones formed after alkylation is carried out for example by reaction with ammonia, hydroxylamine, alkoxylamines, primary amines, hydroxyl-alkylamines or alkoxy-alkylamines followed by or accompanied by reduction, for example with hydride donors such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycoldimethylether, diethyleneglycoldimethylether, /V-alkylmorpholine, diethyl ether, fe/t-butylmethylether, tetrahydrofuran, hexane or cyclohexane or by hydrogenation optionally under pressure and conveniently in the presence of a catalyst such as Raney nickel, palladium, palladium charcoal, platinum or platinum oxide, in a solvent or mixture of solvents such as ethyl acetate, ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycol dimethylether, diethyleneglycol dimethylether, /V-Ci-s-alkylmorpholine, diethyl ether, terf.-butyl-methylether, tetrahydrofuran, hexane or cyclohexane. (c) In order to prepare a compound of general formula (Figure Removed) wherein R3 to R5 are as hereinbefore defined, Z1 denotes the hydrogen atom or a protective group, for example a Ci_5-alkyloxycarbonyl or benzyloxycarbonyl group, and B' denotes a group of formula (Figure Removed) wherein R8 is as hereinbefore defined: coupling and subsequent cyclisation of a compound of general formula wherein n and R8 are as hereinbefore defined, with a compound of general formula (Figure Removed) wherein R3 to R5 are as hereinbefore defined, Z1 denotes a protective group, for example a Cs-alkyloxycarbonyl or benzyloxycarbonyl group, and Z4 denotes a nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a tosylate, triflate or mesylate group, after which the protective group Z1 is cleaved by methods known from the literature. The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as water, ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane or A/-ethyldiisopropylamine, A/-Ci.5-alkylmorpholine, A/-Ci-5-alkylpiperidine, A/-Ci-5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, optionally conveniently in the presence of bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium-terf.-butoxide, sodium ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide. (d) In order to prepare a compound of general formula (Figure Removed) wherein A, R1 and R2 are as hereinbefore defined and Q denotes a halogen atom or a hydroxy, Ci^-alkoxy or C-M-acyloxy group: i) nucleophilic substitution of a compound of general formula A'-H , (XIV) wherein A1 denotes a 5- to 7-membered cycloalkyleneimino group as mentioned hereinbefore under the definition of A, at the aromatic group of general formula (Figure Removed) wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile group or a Cs-alkoxycarbonyl group, and subsequent saponification of the nitrile or Cs-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to form a reactive carboxylic acid derivative of general formula XIII. The nucleophilic substitution is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane or A/-ethyldiisopropylamine, /V-Cs-alkylmorpholine, A/-Ci-5-alkylpiperidine, /V-Ci-5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, optionally conveniently in the presence of bases such as potassium carbonate, sodium carbonate, potassium-te/t-butoxide, sodium ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide. ii) transition metal-catalysed coupling reaction of a compound of general formula (Figure Removed) wherein A' denotes a 5- to 7-membered cycloalkyleneimino group as mentioned hereinbefore under the definition of A, at the aromatic group of general formula wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile group or a Ci.5-alkoxycarbonyl group and Z3 denotes a chlorine, bromine or iodine atom or a triflate group, and subsequent saponification of the nitrile or Ci_5-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to form a reactive carboxylic acid derivative of general formula XIII. The reaction is expediently carried out in a solvent or mixture of solvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, te/t-butylmethyl- ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, yV-methylpyrrolidinone, tetralin, dimethyl sulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, conveniently in the presence of transition metal catalysts such as nickel on activated charcoal, palladium charcoal, tetrakis-(triphenylphosphine)- palladium(O), tris-(dibenzylideneacetone)-dipalladium(0), palladium(ll)acetate, palladium(ll)chloride, bis-(triphenylphosphine)-palladium(ll)-chloride, bis- (tricyclohexylphosphine)-palladium(ll)-chloride, bis-(triethylphosphine)- palladium(ll)-chloride, bis-(tri-o-tolylphosphine)-palladium(ll)-chloride, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, trite/ t-butylphosphine, 1,3-bis-(diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)- 1,1'-dinaphthyl, 1,1'-bis-(diphenylphosphino)-ferrocene, xantphos, and conveniently in the presence of a base such as sodium methoxide, sodium ethoxide, sodium-te/t-butoxide, potassium-terf.-butoxide, sodium-terf.- butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, caesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether as well as conveniently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure. iii) Selective oxidation of a cycloalkyleneimino group in compounds of general formula (Figure Removed) wherein A1 denotes a 5- to 7-membered, optionally also substituted, 2-oxo-cycloalkyleneimine group as mentioned hereinbefore under the definition of A, R1 and R2 are as hereinbefore defined and Z2 denotes -68- the carboxyl group, and optionally further reacting to form a reactive carboxylic acid derivative of general formula XIII. The reaction of a compound of general formula XIII obtained for example by the processes described hereinbefore, wherein A1 denotes a cycloalkyleneimino group and Q denotes the hydroxy group, to form the corresponding lactam by oxidation of a methylene group adjacent to the nitrogen is carried out for example with oxidising agents such as potassium permanganate, potassium chromate, potassium dichromate, chromium(VI)oxide, mercury (ll)chloride, selenium(IV)oxide, lead (IV)oxide, lead (ll,IV)oxide, potassium peroxomonosulphate, hydrogen peroxide, sodium hypochlorite, optionally in the presence of a suitable catalyst such as nickel(ll)chloride, cobalt(ll)chloride, ruthenium(lll)chloride, osmium(VIII)oxide, vanadium(IV)oxide and/or in the presence of a crown ether such as 18-crown-6, in a solvent or mixture of solvents such as water, formic acid, acetic acid, ethyl acetate, benzene, pyridine, dichloromethane, chloroform, tetrachloromethane, optionally under 2- phase conditions in the presence of a suitable phase transfer catalyst such as for example tetrabutylammonium chloride, tetrabutylammonium bromide, benzyl-triethyl-ammonium chloride or methyl-trioctyl-ammonium chloride, optionally in the presence of an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogen sulphate, sodium dihydrogen phosphate and/or a base such as sodium hydroxide, potassium hydroxide, ammonia, pyridine, potassium phosphate, dipotassium hydrogen phosphate or sodium acetate at temperatures between -30 and 250°C, but preferably between 0 and 150°C. For example this reaction may be carried out as described by J. H. Markgraf, C. A. Stickney, J. Heterocycl. Chem. 2000, 37(1), 109. iv) transition metal-catalysed coupling reaction of a compound of general formula (Figure Removed) wherein A1 denotes a 5- to 7-membered, optionally substituted 2-oxocycloalkyleneimino group as mentioned hereinbefore under the definition of A, at the aromatic group of general formula wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile group or a C5-alkoxycarbonyl group and Z3 denotes a chlorine, bromine or iodine atom or a triflate group, and subsequent saponification of the nitrile or Ci-s-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to form a reactive carboxylic acid derivative of general formula XII. The reaction is expediently carried out in a solvent or mixture of solvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, fe/t-butylmethyl- ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between -30 and 250°C, but preferably between 0 and 200°C, conveniently in the presence of transition metal catalysts such as tetrakis-(triphenylphosphine)-palladium(0), tris-(dibenzylideneacetone)- dipalladium(O), palladium(ll)acetate, palladium(ll)chloride, bis- (triphenylphosphine)-palladium(ll)-chloride1 bis-(tricyclohexylphosphine)- palladium(ll)-chloride, bis-(triethylphosphine)-palladium(ll)-chloride, bis-(tri-otolylphosphine)- palladium(ll)-chloride, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-fe/t-butylphosphine, 1,3-bis- (diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-1,1'-dinaphthyl, 1,1'- bis-(diphenylphosphino)-ferrocene, xantphos, or for example in the presence of a transition metal catalyst such as copper(l)-iodide, copper(l)-bromide or copper(l)-acetate and conveniently in the presence of a base such as tetramethylguanidine, tetramethylethylenediamine or N,N'- dimethylethylenediamine and conveniently in the presence of a base such as sodium methoxide, sodium ethoxide, sodium-tert.-butoxide, potassium-te/tbutoxide, sodium-fe/f.-butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, caesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether and conveniently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure. v) Acylation/sulphonylation and alkylation of a compound of general formula (Figure Removed) wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile group or a Ci-s-alkoxycarbonyl group, with a compound of general formula (Figure Removed) wherein E denotes a carbonyl, oxycarbonyl, sulphonyl or a sulphamoyl group optionally substituted at the nitrogen atom as mentioned hereinbefore, G denotes a chlorine, bromine or iodine atom or an anhydride, Ci-s-alkoxy or benzotriazoloxy group or E and G together denote an isocyano group and Z4 denotes a nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a tosylate, inflate or mesylate group, and n is a number between 3 and 5, while individual methylene groups according to the description mentioned hereinbefore may additionally be substituted or replaced by heteroatoms, and subsequent intramolecular cyclisation by alkylation of the anilide nitrogen while cleaving the nucleofugic leaving group Z4, followed by saponification of the nitrile or Ci.5-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to form a reactive carboxylic acid derivative of general formula XIII. The acylation/sulphonylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, Nmethylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, A/-ethyl-diisopropylamine, A/-C5-alkylmorpholine, A/-C5-alkylpiperidine, A/-C1.5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, conveniently in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium-terf.-butoxide, sodium methoxide, sodium ethoxide or basic ion exchanger. The subsequent intramolecular alkylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, dimethylsulphoxide, sulpholane, methylene chloride, tetrachloromethane, A/- ethyl-diisopropylamine, A/-C5-alkylmorpholine, A/-C5-alkylpiperidine, A/-C5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, conveniently in the presence of bases such as pyridine, triethylamine, potassium carbonate, sodium carbonate, potassium-te/t-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hexamethyldisilazane or lithium diisopropylamide. vi) carbamoylation / urea formation with a compound of general formula (Figure Removed) wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile group or a Ci.5-alkoxycarbonyl group, and which may be obtained by methods known from the literature from compounds of general formula XVIII, for example by reaction with phosgene in toluene, with a compound of general formula wherein Z4 denotes a nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a tosylate, triflate or mesylate group, and E denotes a hydroxyl, amino or Ci.3-alkylamino function and n is a number between 2 and 4, while individual methylene groups may additionally be substituted according to the description mentioned hereinbefore, and subsequent intramolecular cyclisation by alkylation of the anilide nitrogen while cleaving the nucleofugic leaving group Z4, followed by saponification of the nitrile or C5-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to form a reactive carboxylic acid derivative of general formula XIII. The carbamoylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, A/-ethyl-diisopropylamine, A/-C5-alkylmorpholine, alkylpiperidine, A/-C5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C. The subsequent intramolecular alkylation is carried out for example analogously to the method described under v). vii) cyclisation metathesis of a compound of general formula (Figure Removed) wherein R1 and R2 are defined as described hereinbefore, Z2 denotes a nitrile, Ci_5-alkoxycarbonyl or carboxyl group, E denotes an aminocarbonyl, aminosulphonyl or amino group optionally substituted according to the description mentioned hereinbefore or a carbonyl or sulphonyl group or an oxygen or sulphur atom or a bond, while m and o independently of one another denote identical or different numbers between 1 and 3 which may be obtained by a sequence of alkylation and acylation / sulphonylation / carbamoylation / sulphamoylation with corresponding reagents by the methods already described herein or known from the literature, followed by saponification of the nitrile or C5-alkoxycarbonyl group Z2 and optionally further reaction of the resulting carboxyl group to obtain a reactive carboxylic acid derivative of general formula XIII. The cyclisation by a reaction of metathesis is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, methanol, ethanol, propanol, diethyl ether, fe/t-butyl-methyl-ether, tetrahydrofuran, dioxane, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, pyridine, in the presence of a catalyst such as benzylidene-bis-(tricyclohexylphosphine)- dichloro-ruthenium (1st generation Grubbs catalyst) or benzylidene-[1,3- bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)- ruthenium (2nd generation Grubbs catalyst) for example at temperatures between -30 and 250°C, but preferably between 0 and 150°C, conveniently under an inert gas atmosphere, for example argon. (e) In order to prepare a compound of general formula (Figure Removed) wherein A, B and R1 to R5 are as hereinbefore defined: acylation of a compound of general formula (Figure Removed) wherein B and R3 to R5 are as hereinbefore defined and Z1 denotes the hydrogen atom, with a carboxylic acid or a reactive carboxylic acid derivative of general formula (Figure Removed) wherein A, R1 and R2 are as hereinbefore defined and Q denotes a hydroxy or Ci-4-alkoxy group, a halogen atom or an acyloxy group. The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C. The acylation may, however, also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, /V./V-dicyclohexyl carbodiimide, A/1/V-dicyclohexylcarbodiimide/A/-hydroxysuccinimideor 1-hydroxy-benzotriazole, A/./V-carbonyldiimidazole, O-(benzotriazoM-yl)- A/.A/.A/./V-tetramethyl-uronium tetrafluoroborate/A/-methylmorpholine, O(benzotriazol-1-yl)-N,A/,Af,AMetramethyl-uronium tetrafluoroborate/A/- ethyldiisopropylamine, O-pentafluorophenyl-/V,N,/V',/V'-tetramethyluronium hexafluorophosphate/triethylamine, A/./V-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160°C. Other methods of amide coupling are described for example in P.D. Bailey, I.D. Collier, K.M. Morgan in "Comprehensive Functional Group Interconversions", Vol. 5, page 257ff., Pergamon 1995. (f) In order to prepare a compound of general formula (II), (XXIV), (VII), (VIII), (XI) or (XXIII), wherein A, B and R1 to R7 are as hereinbefore defined and R8 denotes a C2-3-alkynyl group which is linked to the aromatic group via the carbon atom, and which simultaneously carries the triple bond, from a corresponding compound wherein R8 denotes a bromine or iodine atom or the triflate, boric acid or boric acid ester group: transition metal-catalysed coupling reaction of a compound of general formula (Figure Removed) wherein Z5 denotes the hydrogen atom, the methyl group or a protective group such as for example a trimethylsilyl, te/t-butyl-dimethylsilyl, fe/t-butyldiphenylsilyl or triisopropyl group, which can then be cleaved, with a compound of general formula (II), (XXIV), (VII), (VIII), (XI) or (XXIII), wherein A, B and R1 to R7 are as hereinbefore defined and R8 denotes a bromine or iodine atom or the triflate, boric acid or boric acid ester group. The reaction is preferably carried out in a solvent or mixture of solvents such as acetonitrile, diethyl ether, tetrahydrofuran, dioxane, water or dimethylformamide or a mixture of solvents in the presence of a palladium catalyst such as for example bis(triphenylphosphine)-palladium(ll)choride, palladium(ll)-[1,1'-bis- (diphenylphosphino)ferrocene]-chlorideortetrakis-(triphenylphosphine)- palladium(O) in the presence of a base such as triethylamine, AMsopropyldiethylamine, A/,A/-diisopropyl-ethylamine, potassium-fe/t-butoxide, sodium carbonate or caesium carbonate, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-te/t-butylphosphine, 1,3-bis- (diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-1,1I-dinaphthyl, 1,1'- bis-(diphenylphosphino)-ferrocene, xantphos and optionally in the presence of a transition metal compound such as a copper halide such as for example copper(l)iodide and at temperatures between 20 and 120°C, preferably at temperatures between 20 and 90°C under argon or nitrogen atmosphere (cf. also K. Sonogashira, Comprehensive Organic Synthesis, Vol. 3, page 52ff., Pergamon Press, Oxford 1991). Any silyl protective group present such as for example trimethylsilyl is preferably cleaved in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran or dimethylformamide in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide. For cleaving in organic solvents such as for example diethyl ether, tetrahydrofuran, dimethylformamide or dichloromethane it is also possible to use fluoride reagents, such as for example tetrabutylammonium fluoride, lithium fluoride or potassium fluoride, optionally with the addition of a complexing agent such as 18-crown-6-ether. In the reactions described above any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. For example, a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, suitable protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, suitable protecting groups for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group. Other protective groups and their cleaving are described in T.W. Greene, P.G.M. Wuts, "Protecting Groups in Synthesis", Wiley, 1991 and 1999. Any protecting group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar. A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50°C, but preferably at ambient temperature. A methoxy group is expediently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25°C. A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol. A terf.butyl or te/tbutyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether. A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C. An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(l)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70°C. Compounds of general formulae (II), wherein the group B' is represented by a group of general formula (III), and (IV) may be prepared for example analogously to K. Maekawa, J. Ohtani, Agr. Biol. Chem. 1976, 40, 791-799. Moreover the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers. Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above. The enantiomers are preferably separated by column separation on chiral phases or by recrystailisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example. Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. As already mentioned, the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and/or on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor IXa, factor Xla and factor XI la. The compounds listed in the experimental section were investigated for their effect on the inhibition of factor Xa as follows: Method: Enzyme-kinetic measurement with chromogenic substrate. The quantity of pnitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the ICso is calculated, as the concentration which inhibits the factor Xa used by 50 %. Material: Tris(hydroxymethyl)-aminomethane buffer (100 mMol) and sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free Factor Xa (Calbiochem), spec, activity: 217 lU/mg, final concentration: 7 ID/ml for each reaction mixture Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/l (1 KM) for each reaction mixture Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 Procedure: 10 jj.l of a 23.5-times concentrated starting solution of the test substance or solvent (control), 175 jal of TRIS/HSA buffer and 25 nl of a 65.8 U/L Factor Xa working solution are incubated for 10 minutes at 37°C. After the addition of 25 \i\ of S 2765 working solution (2.82 mMol/l) the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37°C. Evaluation: 1. Determining the maximum increase (deltaOD/minutes) over 21 measuring points. 2. Determining the % inhibition based on the solvent control. 3. Plotting a dosage/activity curve (% inhibition vs substance concentration). 4. Determining the ICso by interpolating the X-value (substance concentration) of the dosage/activity curve at Y = 50 % inhibition. All the compounds tested had an IC50 value of less than 100 umol/L The compounds prepared according to the invention are generally well tolerated. In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD, for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic incidents in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin-dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes. The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with PaT receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel). The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories. The Examples which follow are intended to illustrate the invention without restricting its scope: Experimental section As a rule, melting points, IR, UV, 1H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, Rf values were obtained using ready-made silica gel 60 £254 TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The Rf values obtained under the name Alox were determined using ready-made aluminium oxide 60 £254 TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The Rf values obtained under the name Reversed-phase-8 were determined using ready-made RP-8 Paws TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation. The ratios given for the eluants refer to units by volume of the solvent in question. Chromatographic purification was done using silica gel supplied by Messrs Millipore (MATREX™, 35-70 urn). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer. The following abbreviations are used in the descriptions of the tests: Boc terf.-butoxycarbonyl DIPEA A/-ethyl-diisopropylamine DMSO dimethylsulphoxide DMF A/,A/-dimethylformamide sat. saturated h hour(s) i. vac. in vacuo cone. concentrated NMM /V-methyl-morpholine NMP A/-methyl-pyrrolidin-2-one o ortho PfTU O-pentafluorophenyl-A/,A/,A/;,A/'-tetramethyluronium hexafluorophosphate PPA propanephosphonic cycloanhydride quant. quantitative Rf retention factor Rt retention time rac. racemic TBTU O-(benzotriazol-1 -yl)-/V, N, N1, AMetramethyluronium tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran tert. tertiary £ yield over all the steps carried out analogously as described The HPLC/MS data for Examples 35 to 38 were obtained under the following conditions: (a) Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampler, Waters 996 diode array detector The following was used as the mobile phase: A: water with 0.1% trifluoroacetic acid B: acetonitrile with 0.1% trifluoroacetic acid time in min %A %B flow rate in ml/min (Table Removed) The stationary phase used was a Waters column X-Terra™ MS Cis 3.5 urn, 4.6 mm x 50 mm (column temperature: constant at 25°C) The diode array detection took place in a wavelength range from 210-500 nm Range of mass-spectrometry detection: m/z 120 to m/z 950 (b) The HPLC/MS data for the other Examples, if provided, were obtained under the following conditions: HP 1100 with quarternary pump, Gilson G215 Autosampler, HP diode array detector. The mobile phase used was: A: water with 0.1 % TFA B: acetonitrile with 0.08% TFA flow rate in ml/min The stationary phase used was a Waters column X-Terra™ MS C-\|8 2.5 urn, 2.1 mm x 50 mm (column temperature: constant at 25°C) The diode array detection took place in a wavelength range from 210-550 nm Range of mass-spectrometry detection: m/z 120 to m/z 1000. time in min (Table Removed) Example 1 3-chloro-A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)- benzamide (a) 4-(4-A/-acetyl-n ,41diazepan-1 -vl)-3-chloro-benzonitrile 4.67 g (30 mmol) 3-chloro-4-fluoro-benzonitrile and 4.27 g (30 mmol) AMacetyl-[ 1,4]diazepan are stirred in 5.0 ml DIPEA for 6 hours at 90°C. Then the mixture is evaporated down i. vac. and the residue is dissolved in dichloromethane. The organic phase is washed twice with water, dried over sodium sulphate and evaporated down i. vac.. The residue is further reacted without any more purification. Yield: 7.50 g (90 %) Rf value: 0.20 (silica gel; dichloromethane/ethanol = 50:1) (b) 3-chloro-4-(M .41diazepan-1-vl)-benzoic acid The residue obtained in Example 1a (7.50 g, 27.0 mmol) is refluxed for 8 h in 50 ml 25% potassium hydroxide solution. Then the mixture is adjusted to pH 5 with cone, hydrochloric acid. The solid precipitated is filtered off, dried and further reacted without any more purification. Yield: 5.60 g (81%) Rf value: 0.0 (silica gel; dichloromethane/ethanol = 9:1) (c) methyl 3-chloro-4-(n .41diazepan-1-vl)-benzoate The residue obtained in Example 1b (3.00 g, 11.8 mmol) is suspended in 100 ml of methanol and hydrogen chloride is piped in over 1 hour with stirring and heating to reflux temperature. Then the mixture is evaporated down i. vac., the residue is combined with 5% sodium hydrogen carbonate solution and extracted 3 times with dichloromethane. The combined organic phases are dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification. Yield: 2.25 g (71%) Rf value: 0.10 (silica gel; dichloromethane/ethanol = 4:1 + 2% ammonia) Ci3Hi7CIN2O2 (268.75) Mass spectrum: (M+H)+ = 269/271 (chlorine isotope) (d) methvl 4-(4-A/-Boc-n .41diazepan-1-vl)-3-chloro-benzoate The residue obtained in Example 1c (1.00 g, 3.72 mmol) is combined with 0.53 g (3.80 mmol) potassium carbonate in 10 ml dichloromethane and then 0.83 g (3.80 mmol) di-tert. butyl pyrocarbonate are added dropwise. Then the mixture is stirred for 16 hours at ambient temperature. Then it is diluted with dichloromethane, washed twice with water, dried over sodium sulphate and evaporated down i. vac.. Purification by chromatography on silica gel is then carried out (eluant: methylene chloride/ethanol 99:1). Yield: 1.34g(98%) Rf value: 0.50 (silica gel; dichloromethane/ethanol = 50:1) C18H25CIN2O4 (368.86) Mass spectrum: (M+H)* = 369/371 (chlorine isotope) (e) 4-(4-/V-Boc-M .41diazepan-1-vlV3-chloro-benzoic acid 0.60 g (1.63 mmol) methyl 4-(4-A/-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate are dissolved in 10 ml of methanol, combined with 4 ml 2-molar potassium hydroxide solution and stirred for 3 hours at 40°C. Then the mixture is evaporated down i. vac., the residue is diluted with distilled water, acidified with saturated potassium hydrogen sulphate solution and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is further reacted without any more purification. Yield: 0.50 g (87 %) Rf value: 0.05 (silica gel; dichloromethane/ethanol = 50:1) (354.84) (f) 4-(4-A/-Boc-n.41diazeDan-1-vn-3-chloro-A/-r(1S)-1-(5-chloro-1Hbenzimidazol- 2-vl)-ethvn-benzamide 532 mg (1.50 mmol) 4-(4-/V-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acid are suspended in 1 5 ml THF and after the addition of 546 mg (1 .70 mmol) TBTU and 646 mg (5.0 mmol) DIPEA stirred for 30 minutes at ambient temperature. Then 403 mg (1.50 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylaminedihydrochloride are added and the mixture is stirred for a further 16 hours at ambient temperature. It is then evaporated down i. vac., the residue is dissolved in ethyl acetate, the organic phase is washed with 5% sodium hydrogen carbonate solution and water and dried over sodium sulphate. After evaporation i. vac. the residue remaining is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate: 90:10 -> 60:40). Yield: 630 mg (79 %) Rf value: 0.50 (silica gel; dichloromethane/ethanol = 19:1) CaeHaiCbNsOg (532.48) Mass spectrum: (M+H)+ = 532/534/536 (chlorine isotope) (g) 3-chloro-A/-f(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vlVethvn-4- (f 1 .41diazepan-1 -vl)-benzamide A solution of 610 mg (1.15 mmol) 4-(4-A/-Boc-[1,4]diazepan-1-yl)-3-chloro-A/- [(1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethyl]-benzamide in 30 ml dichloromethane is combined with 3 ml TFA and stirred for 3 hours at ambient temperature. Then it is evaporated down i. vac., the residue is taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate solution and water and dried over sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 80:20 -> 50:50). Yield: 380 mg (77 %) Rf value: 0.10 (silica gel; dichloromethane/ethanol = 9:1) (432.36) Mass spectrum: (M+H)+ = 432/434/436 (chlorine isotope) The following compound was prepared analogously: No. 115 structural formula yield mass peak(s) Rf value / Rt value (Figure Removed) (chlorine isotope) 0.13 (silica gel, dichloromethane/ methanol = 9:1) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1 ,4]- diazepan-1 -yl)-benzamide Example 2 4-(4-A/-Boc-piperazin-1 - trifluoromethyl-benzamide -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3- (a) 4-(piperazin-1 -vl)-3-trifluoromethvl-benzoic acid 37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g (66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40 ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water are added and the mixture is refluxed for a further 3.5 hours and kept at ambient temperature for a further 15 hours. Then 43.5 ml of cone, hydrochloric acid are added and the mixture is cooled to 10°C for 30 minutes with stirring. The precipitate obtained is suction filtered, washed with a little water and dried at 40°C in the circulating air dryer for 24 hours. Yield: 20.8 g (quantitative) (b) methyl 4-(piperazin-1 -vl)-3-trifluoromethvl-benzoate 5.00 g (18.2 mmol) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid are stirred 16 hours in 50 ml of methanolic hydrochloric acid. After evaporation of the reaction mixture i. vac. the residue is stirred with isopropanol. The solid is filtered off, washed with diethyl ether and dried at 60°C in the circulating air dryer. Yield: 5.00 g (76%) Ci3H15F3N202 * 2 HCI (288.27 / 361.19) Mass spectrum: (M+H)+ = 289 Rf value: 0.58 (silica gel; cyclohexane/dichloromethane/methanol = 70:15:15 + 2% cone, ammonia solution) (c) methyl 4-(4-A/-Boc-piperazin-1 -vl)-3-trifluoromethvl-benzoate 5.77 g (11.78 mmol) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoate are placed in 100 ml THF and combined with 4.47 g (20.5 mmol) di-tert. butyl pyrocarbonate. After 40 hours stirring at ambient temperature under a nitrogen atmosphere the reaction mixture is evaporated down i. vac., the residue is combined with water and sat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with water, semisaturated and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 9:1 -> 8:1). Yield: 2.60 g (34%) Rf value: 0.52 (silica gel; petroleum ether/ethyl acetate 7:3 + 1% cone, ammonia solution) C18H23F3N204 (388.39) Mass spectrum: (M+H)+ = 389 (d) 4-(4-/V-Boc-piperazin-1 -vl)-3-trifluoromethyl-benzoic acid 2.60 g (6.69 mmol) methyl 4-(4-A/-te/t-butoxylcarbonyl-piperazin-1-yl)-3- trifluoromethyl-benzoate are dissolved in 10 ml of methanol and combined with 12.3 ml (12.3 mmol) 1-molar sodium hydroxide solution. After 15 minutes a further 1 0 ml of methanol are added and the reaction mixture is stirred for 42 hours at ambient temperature. Then the mixture is evaporated down i. vac., the residue is combined with ice and acidified with acetic acid. The precipitate obtained is suction filtered, washed with water and dried in the circulating air dryer at 50°C and in the drying pistol at 40°C over KOH and SiO2. Yield: 2.40 g (96%) Rf value: 0.41 (silica gel; petroleum ether/ethyl acetate = 1:1 +1% acetic acid) C17H2iF3N204 (374.36) Mass spectrum: (M-H)~ = 373 (e) 4-(4-A/-Boc-piperazin-1 -vl)-A/-f(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vOethvn- 3-trifluoromethyl-benzamide Prepared analogously to Example 1f from 4-(4-A/-Boc-piperazin-1-yl)-3- trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1Hbenzimidazol- 2-yl)ethylamine in NMP and subsequent purification by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 50:50). Yield: 57% Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 1:1) Mass spectrum: (M+H)+ = 552/554 (chlorine isotope) Example 3 -chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1 trifluoromethyl-benzamide Prepared analogously to Example 1g from 4-(4-A/-Boc-piperazin-1-yl)-A/-[(1S)-1- (5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide and TFA in dichloromethane. Yield: 73% Rf value: 0.28 (silica gel; dichloromethane/methanol = 90:10 + ammonia solution) C2iH2iCIF3N5O * 2 CF3COOH (679.93 / 451.88) Mass spectrum: (M+H)+ = 452/454 (chlorine isotope) The following were prepared analogously to the sequence described in Examples 2 and 3: No. structural formula yield mass peak(s) Rf value Name (Figure Removed) A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl)-4- (piperazin-1-yl)-3-trifluoromethyl-benzamide structural formula yield mass peak(s) Rf value Name (Figure Removed) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4- (piperazin-1-yl)-3-trifluoromethyl-benzamide Example 5 4-(4-/V-acetyl-piperazin-1 - trifluoromethyl-benzamide -chloro-1H-benzimidazol-2-yl)-ethyl]-3- 220 mg (0.32 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4- (piperazin-1-yl)-3-trifluoromethyl-benzamide-ditrifluoroacetate in 5 ml THF are combined with 0.23 ml (1.65 mmol) TEA, 50 ul (0.70 mmol) acetylchloride are added dropwise with stirring and cooling in the ice bath and stirred for 2 hours at ambient temperature. The reaction mixture is poured into ice water and then extracted with ethyl acetate. The organic phase is washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. The residue is triturated with a solvent mixture of ethyl acetate and diethyl ether, filtered off, washed with diethyl ether and dried in a drying pistol at 50°C . Yield: 0.13 g (81%) Rf value: 0.55 (silica gel; dichloromethane/ethanol = 9:1 + ammonia solution) (493.92) Mass spectrum: (M+H)+ = 494/496 (chlorine isotope) Example 6 4-(azepan-2-on-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methylbenzamide (a) methyl 4-(6-bromo-hexanovl-amino)-3-methvl-benzoate A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification. Yield: 3.30 g (96%) Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 4:1) (342.24) (b) methyl 4-(azepan-2-on-1 -vl)-3-methvl-benzoate 3.20 g (9.35 mmol) of the product obtained in Example 5a is refluxed for 4 hours in a freshly prepared solution of 1 .00 g (43.5 mmol) sodium in 80 ml of methanol. Then the mixture is evaporated down i. vac., the residue is acidified with 2-molar acetic acid and extracted with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulphate. The residue obtained after evaporation i. vac. is further reacted without any more purification. Yield: 1.90 g (contaminated product) Rf value: 0.30 (silica gel; dichloromethane/ethanol = 50:1) Ci5Hi9NO3(261.32) Mass spectrum: (M+H)+ = 262 (c) 4-(azepan-2-on-1 -vl)-3-methvl-benzoic acid 1.90 g of the product obtained in Example 5b in 30 ml of methanol is combined with 10 ml 2-molar sodium hydroxide solution and stirred for 16 hours at ambient temperature. After evaporation i. vac. the residue is combined with water and acidified with cone, hydrochloric acid. The precipitate formed is filtered off and dried. After dissolving in methanol and applying to silica gel the product is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 70:30 -> 50:50). Yield: 0.23 g (10% over 2 steps) Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 1:2) Ci4Hi7NO3 (247.30) Mass spectrum: (M+H)+ = 248 (d) 4-(azepan-2-on-1 -vlVA/-r(1 SM -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-3- methvl-benzamide Prepared analogously to Example 1f from 4-(azepan-2-on-1-yl)-3-methylbenzoic acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2- yl)ethylamine in THF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5 -> 90:10). Yield: 61% Rf value: 0.30 (silica gel; ethyl acetate) C23H25CIN4O2 (424.93) Mass spectrum: (M+H)+ = 425/427 (chlorine isotope) The following compounds were prepared analogously: (Figure Removed) structural formula yield mass peak(s) Rf value Name (Figure Removed) (chlorine isotope) 0.60 (aluminium oxide, CH2CI2/C2H5OH 19:1) 4-(azepan-2-on-1 -yl)-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethyl]-3-methyl-benzamide (Figure Removed) (M+H)+ = 441/443 (chlorine isotope) 0.20 (silica gel, CHzCla/CaHgOH 19:1) 4-(azepan-2-on-1 -yl)-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- hydroxy-ethyl]-3-methyl-benzamide (Figure Removed) (M+H)+ = 397/399 (chlorine isotope) 0.50 (silica gel, CH2CI2 /C2H5OH9:1) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin- 2-on-1 -yl)-benzamide (Figure Removed) (silica gel, CH2CI2 /C2H5OH9:1) A/-[(1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3- methyl-4-(pyrrolidin-2-on-1-yl)-benzamide -98- Example 9 A/-[(1 S>1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1 -yl)- benzamide (a) 4-(pyrrolidin-2-on-1 -vl)-benzoic acid 19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hours together with 25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF. After evaporation i. vac. the residue is combined with 100 ml of water and 50 ml petroleum ether and vigorously stirred for 50 minutes. The precipitate is filtered off, recrystallised from ethanol and dried at 80°C. Yield: 9.36 g (33%) CnHnNOa (205.22) Mass spectrum: (M+H)+ = 206 (b) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-f pvrrolidin-2-on-1 -vl)- benzamide Prepared analogously to Example 1f from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine in THF and subsequent purification by washing the solution of the residue in ethyl acetate with water, dilute sodium hydrogen carbonate solution, water and sat. sodium chloride solution, drying over sodium sulphate and eliminating the solvent!, vac.. Yield: 61% Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1) C2oHi9CIN4O2 (382.85) Mass spectrum: (M+H)+ = 383/385 (chlorine isotope) Example 12 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-A/-methyl- [1,4]diazepan-1-yl)-benzamide (a) 3-chloro-4-(4-A/-methvl-M ,41diazepan-1 -vl)-benzonitrile Prepared analogously to Example 1a from 3-chloro-4-fluoro-benzonitrile and 1- methyl-[1,4]diazepan in DIPEA with subsequent purification by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 98:2 -> 94:6). Yield: 71% Rf value: 0.20 (silica gel; methylene chloride/ethanol = 19:1) C13H16CIN3 (249.75) Mass spectrum: (M+H)+ = 250/252 (chlorine isotope) (b) 3-chloro-4-(4-/V-methvl-M .41diazepan-1-vl)-benzoic acid Prepared analogously to Example Ibfrom 3-chloro-4-(4-methyl-[1,4]diazepan- 1-yl)-benzonitrile in 25% aqueous potassium hydroxide solution. Yield: 99% C13H17CIN2O2 * HCI (268.74 / 305.21) Mass spectrum: (M+H)+ = 269/271 (chlorine isotope) (c) 3-chloro-A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(4-A/-methvlf1.41diazepan- 1-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(4-methyl-[1,4]diazepan-1- yl)-benzoic acid, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 50:50 -> 20:80). Yield: 34% Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1 + 1% ammonia solution) Mass spectrum: (M+H)+ = 446/448/450 (chlorine isotope) Example 13 3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin- 1 -yl)-benzamide ci (a) 3-chloro-4-(2-methvl-pvrrolidin-1-vl)-benzonitrile 5.90 g (37.9 mmol) 3-chloro-4-fluoro-benzonitrile are dissolved in 65 ml DMF under a nitrogen atmosphere and combined with 5.45 g (39.5 mmol) potassium carbonate and 4.2 ml (3.5 g, 39.5 mmol) 2-methyl-pyrrolidine. After stirring for 2.5 days at 90°C the reaction mixture is poured into 400 ml of water and extracted with ethyl acetate. The combined organic phases are washed several times with dilute and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. The residue remaining is further reacted without any more purification. Yield: 7.90 g (94%) Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 9:1 + 0.5% ammonia solution) C12H13CIN2 (220.70) Mass spectrum: (M+H)+ = 221/223 (chlorine isotope) (b) 3-chloro-4-(2-methvl-pvrrolidin-1 -vl)-benzoic acid 8.0 g (40 mmol) of the product obtained in Example 13a are stirred in a mixture of 65 ml 10-molar sodium hydroxide solution and 65 ml of ethanol for 2.75 hours at 90°C. Then the reaction mixture is poured into ice water, combined with cone, hydrochloric acid and volatile organic constituents are evaporated down i. vac.. The aqueous phase remaining is extracted with dichloromethane, combined with ice and adjusted to pH 4.5 with semiconcentrated hydrochloric acid and 2- normal potassium hydrogen sulphate solution. The resulting precipitate is stirred for another 10 minutes, then filtered off, washed with water and dried at 55°C. Yield: 8.30 g (87%) Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate = 6:4 + 1% acetic acid) Ci2Hi4CINO2 (238.72) Mass spectrum: (M+H)+ = 240/242 (chlorine isotope) (c) 3-chloro-A/-rf 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl)-4-(2-methvlpyrrolidin- 1 -vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(2-methyl-pyrrolidin-1-yl)- benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylarnine, TBTU and TEA in DMF, then precipitated by pouring into dilute sodium hydrogen carbonate solution, filtering and washing with water. Then the product is dried at 55°C. Yield: 92% Rt value: 0.66 (silica gel; dichloromethane/ethanol = 9:1) C2iH22Cl2N4O(417.34) Mass spectrum: (M-H)~ = 415/417/419 (chlorine isotope) The following compounds were prepared analogously: No •(Table Removed) Example 21 A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on- 4-yl)-3-trifluoromethyl-benzamide (a) 4-fmorpholin-3-on-4-vl)-3-trifluorornethvl-benzoicacid 1.00 g (3.63 mmol) 4-(morpholin-4-yl)-3-trifluoromethyl-benzbic acid (prepared by synthesis sequence analogously to Example 13a and 13b) is suspended in 40 ml of water and 150 mg (3.75 mmol) sodium hydroxide are added. Then 1.73 g (10.92 mmol) potassium permanganate are added and the mixture is stirred for 1.5 hours at 45°C. Then the reaction mixture is cooled in the ice bath and sodium thiosulphate is added until total decolonisation is obtained. After extraction 3 times with ethyl acetate the combined organic phases are dried over sodium sulphate and evaporated down i. vac.. After application of the residue to silica gel it is purified by chromatography on silica gel (eluant: dichloromethane/methanol 95:5). Yield: 340 mg (32%) C12HioF3NO4 (289.21) Mass spectrum: (M+H)+ = 290 (b) A/'-(2-amino-4-chloro-phenvl)-A/-Boc-(S)-O-methvl-serinamide and N'-(2- amino-5-chloro-Dhenvl)-A/-Boc-(S)-Q-methvl-serinamide 30.0 g (137 mmol) A/-Boc-(S)-O-methyl-serine are dissolved together with 21.9 g (154 mmol) 4-chloro-1 ,2-phenylenediamine in 658 ml THF, and 43.9 ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50 % solution of PPA in ethyl acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice bath the mixture is heated to ambient temperature, poured into water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol = 30:1 -> 9:1). Yield: 33.47 g (72 %) mixture of the two regioisomers Ci5H22CIN3O4 (343.81) Mass spectrum: (M-H)~ = 342/344 (chlorine isotope) Rf value: 0.80 (silica gel; dichloromethane/methanol = 9:1) (c) ( 7ffl-/V-Boc-1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvlamine 26.01 g (75.65 mmol) of the mixture obtained in Example 21 b are dissolved in 1500 ml of toluene and 20.8 ml (364 mmol) acetic acid and 10.0 g molecular sieve, 4A, are added. The reaction mixture is stirred for 5 hours at 60°C. The reaction mixture is filtered, washed again with ethyl acetate and the organic phase is washed with semisat. sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down i. vac.. The residue is stirred with diethyl ether and the crystals formed are suction filtered. The filtrate is evaporated down i. vac. and the residue is purified by three lots of chromatography on silica gel (eluting gradient: dichloromethane/methanol 80:1 -> 50:1). Yield: 1 3.85 g (56%) C15H2oCIN303 (325.79) Mass spectrum: (M+H)+ = 326/328 (chlorine isotope) Rf value: 0.29 (silica gel; dichloromethane/methanol = 30:1) (d) (1f?V1-(5-chloro-1H-benzimidazol-1-vl)-2-methoxv-ethvlamine 0.50 g (1.54 mmol) (1fi)-/v"-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine in 1.5 ml dichloromethane are combined with 1.54 ml (20.0 mmol) TFA and stirred for 2 h at ambient temperature. The mixture is then poured into sat. sodium hydrogen carbonate solution and after thorough mixing the aqueous phase is extracted with dichloromethane and ethyl acetate. The combined organic phases are dried over sodium sulphate and purified by chromatography on silica gel (eluant: dichloromethane/methanol = 9:1 + 1% cone, ammonia solution). Yield: 0.35 g (quant.) C10H12CIN3O (225.68) Mass spectrum: (M-H)~ = 224/226 (chlorine isotope) Rf value: 0.40 (silica gel, dichloromethane/methanol 9:1 + 1% cone, ammonia solution) (e) A/-K1 /?)-1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvn-4- (moroholin-3-on-4-vlV3-trifluoromethvl-benzamide Prepared analogously to Example 1f from 4-(morpholin-3-on-4-yl)-3- trifluoromethyl-benzoic acid, (1 R)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-2-methoxyethylamine, TBTU and NMM in DMF, then precipitation by pouring into water, filtering and drying i. vac.. Yield: 63% Rf value: 0.57 (silica gel; dichloromethane/methanol = 9:1) C22H2oCIF3N404 (496.88) Mass spectrum: (M+H)+ = 497/499 (chlorine isotope) The following compounds were prepared analogously: No. structural formula Yield mass peak(s) Rf value or Rt (Table Removed) Example 22 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21 a), (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF, then pouring into water, extracting with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purifying by chromatography on silica gel (eluting gradient: ethyl acetate/isopropanol/ethanol 9:1:0 -> 9:0:1). Yield: 99% Rf value: 0.13 (silica gel; dichloromethane/isopropanol = 19:1) C22H23CIN4O4 (442.91) Mass spectrum: (M+H)+ = 443/445 (chlorine isotope) The following compounds were prepared analogously: No. (Table Removed) Example 27 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)- benzamide 254 mg (1.15 mmol) 4-(rnorpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21 a) are placed in 5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 ul (3.0 mmol) DIPEA are added. After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1 S)-1- (5-chloro-1/-/-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is filtered through basic aluminium oxide and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol 100:0 -> 90:10), the corresponding fractions are evaporated down i. vac., the residue is dissolved in acetonitrile/water and lyophilised. Yield: 77% Mass spectrum: (M+H)* = 399/401 (chlorine isotope) The following compound is prepared analogously: No. (Table Removed) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin- 3-on-4-yl)-benzamide Example 29 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-A/-methyl- [1 ,4]diazepan-1 -yl)-benzamide (a) 4-fluoro-3-methvl-benzoic acid chloride 14.00 g (90.8 mmol) 4-fluoro-3-methyl-benzoic acid are refluxed for 1 hour together with 50 ml of thionyl chloride and then evaporated down i. vac.. The residue is further reacted without any more purification. Yield: 15.70 g (quantitative) C8H6CIFO (172.59) (b) 4-fluoro-3-methvl-benzamide 15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in 30 ml THF are added dropwise to 300 ml of cone, ammonia solution and then stirred for 2 hours at ambient temperature. The precipitate formed is filtered off, washed with water and dried. Yield: 10.00 g (72%) C8H8FNO(153.16) Rf value: 0.31 (aluminium oxide; dichloromethane/methanol = 50:1) (c) 4-fluoro-3-methvl-benzonitrile 10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirred together with 50 ml phosphorus oxychloride for 4 hours at 60°C and then evaporated down i. vac.. The residue is poured into ice water, the resulting precipitate is filtered off and washed with water. After being taken up in ethyl acetate the organic phase is washed with sat. potassium carbonate solution, dried over sodium sulphate and evaporated down completely i. vac.. Yield: 8.00 g (91%) C8H6FN(135.14) Rf value: 0.84 (silica gel; dichloromethane) (d) 3-methvl-4-(4-A/-methvl-ri .41diazepan-1 -vD-benzonitrile 7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110°C together with 1-A/-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1 ->9:1). Yield: 1.70 g (14%) Ci4H19N3 (229.33) Mass spectrum: (M+H)+ = 230 Rf value: 0.25 (silica gel; dichloromethane/methanol = 9:1) (e) 3-methyl-4-(4-A/-methvl-ri .41diazepan-1-vl)-benzoic acid Prepared analogously to Example 1 b from 3-methyl-4-(4-/V-methyl- [1,4]diazepan-1-yl)-benzonitrile with 25% potassium hydroxide solution by refluxing for 36 hours. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1 -> 9:1). Yield: 14% Ci4H19N202 (248.33) Mass spectrum: (M+H)+ = 249 Rf value: 0.30 (RP-18; methanol/5% aqueous sodium chloride solution = 6:4) (f) 3-methvl-4-(4-A/-methvl-ri.41diazepan-1-vl)-benzoic acid chloride Prepared analogously to Example 29a from 3-methyl-4-(4-A/-methyl- [1,4]diazepan-1-yl)-benzoic acid and thionyl chloride. Yield: quantitative C14H19CIN2O * HCI (266.77 / 303.23) (g) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4-(4-A/-methvl- M .41diazepan-1-vl)-benzamide 489 mg (1.61 mmol) 3-methyl-4-(4-A/-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1Hbenzimidazol- 2-yl)-ethylamine is added dropwise with stirring. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1). The fractions evaporated down are treated with ethereal hydrochloric acid, after total concentration evaporated twice with ethyl acetate and diethyl ether and dried i. vac. at 70°C. Yield: 120mg(16%) C23H28CIN5O * HCI (462.43 / 425.96) Mass spectrum: (M+H)+ = 426/428 (chlorine isotope) Rf value: 0.47 (aluminium oxide; dichloromethane/methanol 19:1) Example 30 A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1 -yl)- benzamide (a) methyl 4-(A/-Boc-piperazin-1 -vl)-3-methvl-benzoate 4.00 g (17.5 mmol) 4-bromo-3-methyl-benzoate methyl are suspended together with 3.92 g (21.0 mmol) A/-Boc-piperazine, 39.2 mg (175 \|jmol) palladium(ll)acetate, 50.7 mg (175 umol) tri-te/t-butyl-phosphoniumtetrafluoroborate and 11.12 g (52.4 mmol) potassium phosphate in 35 ml of toluene and under an argon atmosphere heated to 150°C for 10 minutes in a microwave oven. Then the reaction mixture is poured into water, stirred vigorously and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, applied to silica gel and purified by chromatography on silica gel (eluant: dichloromethane/methanol 80:1). Yield :1.42 g (24%) C18H26N204 (334.42) Mass spectrum: (M+H)+ = 335 Rf value: 0.52 (silica gel; dichloromethane/methanol = 50:1) (b) 4-(A/-Boc-piperazin-1 -vn-3-methvl-benzoic acid 1.42 g (4.24 mmol) of methyl 4-(A/-Boc-piperazin-1-yl)-3-methyl-benzoate are dissolved in 7 ml THF and 9.25 ml of water and 893 mg (21.3 mmol) lithium hydroxide-monohydrate are added. After stirring for 16 hours at ambient temperature the mixture is heated to 45°C for 2 hours. Then another 893 mg (21.3 mmol) lithium hydroxide monohydrate are added and the mixture is stirred for 4 days at ambient temperature. Then it is neutralised with 1 -molar hydrochloric acid and the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac- Yield: 1.29 g (95%) Ci7H24N2O4 (320.39) Mass spectrum: (M+H)+ = 321 Rf value: 0.29 (silica gel; dichloromethane/methanol = 15:1) (c) 4-(A/-Boc-piperazin-1-vl)-/V-r(1S)-1-(5-chloro-1H-benzimidazol-2-vl)- ethvl)-3-methvl-benzamide Prepared analogously to Example 1f from 4-(A/-Boc-piperazin-1-yl)-3-methylbenzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into cone, sodium hydrogen carbonate solution, extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluting gradient: dichloromethane/methanol 50:1 -> 15:1). Yield: 85% Rf value: 0.15 (silica gel; dichloromethane/methanol = 30:1) Mass spectrum: (M+H)'1' = 498/500 (chlorine isotope) (d) A/-K1 SM -f 5-chloro-1 H-benzimidazol-2-vl Vethvn-3-methvl-4-(piperazin-1 - vD-benzamide Prepared analogously to Example 1g from 4-(/V-Boc-piperazin-1-yl)-A/-[(1S)-1- (5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide and TFA in dichloromethane. Yield: quantitative C2iH24CIN5O (397.91) Mass spectrum: (M+H)+ = 398/400 (chlorine isotope) Rf value: 0.14 (silica gel; dichloromethane/methanol = 9:1) The following compound is prepared analogously: No. (Table Removed) Example 31 /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1 - yl)-benzamide (a) methyl 4-(A/-Boc-piperazin-2-on-1 -vl)-3-methvl-benzoate 758 mg (3.31 mmol) methyl 4-bromo-3-methyl-benzoate are suspended together with 796 mg (21.0 mmol) 4-A/-Boc-piperazin-2-one, 31.8 mg (167 copper(l)iodide, 35.1 ul (330 umol) A/,/V'-dimethyl-ethylenediamine and 0.92 g (6.62 mmol) potassium carbonate in 6.6 ml of toluene and under an argon atmosphere heated to 140°C in a microwave oven with stirring for 1.5 hours. Then the reaction mixture is poured into water, stirred vigorously and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, applied to silica gel and purified by chromatography on silica gel (eluant: dichloromethane/methanol 50:1). Yield: 679 mg (59%) Mass spectrum: (M+H)+ = 349 Rf value: 0.25 (silica gel; dichloromethane/methanol = 50:1) (b) 4-(/V-Boc-piperazin-2-on-1 -vl)-3-methvl-benzoic acid 775 mg (2.22 mmol) methyl 4-(/V-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate are dissolved in 3.7 ml THF and 4.9 ml of water as well as 468 mg (1 1 .2 mmol) lithium hydroxide-monohydrate are added. After stirring for 16 hours at ambient temperature the mixture is neutralised with 1 -molar hydrochloric acid and the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac.. Yield: 664 mg (89%) Ci7H22N205 (334.38) Mass spectrum: (M+H)"1" = 335 Rf value: 0.31 (silica gel; dichloromethane/methanol = 15:1) (c) 4-(A/-Boc-piperazin-2-on-1 -vl)-/V-rf 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)- ethvD-3-methvl-benzamide Prepared analogously to Example 1f from 4-(A/-Boc-piperazin-1-yl)-3-methylbenzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into cone, sodium hydrogen carbonate solution, extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluant: dichloromethane/methanol 30:1). Yield: 71% Rf value: 0.30 (silica gel; dichloromethane/methanol = 15:1) C26H3oCIN504(512.01) Mass spectrum: (M+H)* =512/514 (chlorine isotope) (d) A/-F(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4-(piperazin-2- on-1-vn-benzamide Prepared analogously to Example Igfrom 4-(A/-Boc-piperazin-1-yl)-A/-[(1S)-1- (5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide and TFA in dichloromethane. Yield: 36% C2iH22CIN5O2(411.90) Mass spectrum: (M+H)+ = 412/414 (chlorine isotope) Rf value: 0.42 (silica gel; dichloromethane/methanol = 9:1) The following compounds were prepared analogously: No. 66 98 structural formula Yield mass peak(s) Rf value or Rt Name (Table Removed) Example 32 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1 • yl)-benzamide (a) methyl 3-methvl-4-(piperidin-2-on-1 -vl)-benzoate Prepared analogously to Example 31 a from methyl 4-bromo-3-methyl-benzoate and piperidin-2-one in the presence of copper(l)iodide, A/,/V'-dimethylethylenediamine and potassium carbonate in toluene and dioxane under an argon atmosphere. Yield: 34% C14Hi7NO3 (247.30) Mass spectrum: (M+H)+ = 248 Rf value: 0.21 (silica gel; petroleum ether/ethyl acetate = 1:1) (b) 3-methvl-4-(piperidin-2-on-1 -vl)-benzoic acid Prepared analogously to Example 2d from methyl 3-methyl-4-(piperidin-2-on-1- yl)- benzoate and 1 -molar sodium hydroxide solution in methanol. Yield: 83% C3Hi5N03 (233.27) Mass spectrum: (M+H)+ = 234 Rf value: 0.51 (silica gel; ethyl acetate/ethanol = 9:1 + 1% cone, ammonia solution) (c) A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl)-3-methvl-4-(piperidin-2- on-1 -vO-benzamide Prepared analogously to Example 1f from 3-methyl-4-(piperidin-1-yI)-benzoic acid, (1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into ice water, combining with ammonia solution, filtering, taking up in dichloromethane, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc. ammonia solution 19:1) 1:0 -> 9:1). Yield: 32% Rf value: 0.30 (silica gel; ethyl acetate/ethanol = 9:1 + 1% acetic acid) Mass spectrum: (M+H)* =41 1/41 3 (chlorine isotope) The following compounds were prepared analogously: No. (Table Removed) Example 33 A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(/\/-methyl-piperazin-1-yl)-3- trifluoromethyl-benzamide 170 mg (0.24 mmol) /V-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4- (piperazin-1-yl)-3-trifluoromethyl-benzamide are suspended in 2 ml 1,2- dichloroethane and under a nitrogen atmosphere combined with 20 mg (0.67 mmol) paraformaldehyde and 76 mg (0.36 mmol) sodium triacetoxyborohydride. After the addition of 5 ml THF the reaction mixture is stirred for 6 hours at ambient temperature,- then 100 mg (3.33 mmol) of paraformaldehyde and 100 mg (0.47 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for a further 22 hours at ambient temperature. Then it is combined with sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: dichloromethane/(methanol/conc. ammonia solution 19:1) 100:0 -> 92:8). Yield: 70 mg (59%) C23H25CIF3N5O2 (495.94) Mass spectrum: (M+H)+ = 496/498 (chlorine isotope) Rf value: 0.25 (silica gel; dichloromethane/methanol = 9:1 + 1% cone, ammonia solution) Example 34 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl- 4-(morpholin-3-on-4-yl)-benzamide 150 mg (0.32 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3- methylsulphanyl-prop-1-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamideare dissolved in a mixture of 10 ml dichloromethane and 1 ml acetic acid at -15°C and combined with 204 mg (0.89 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for 30 minutes at -15 to -10°C, heated to ambient temperature and stirred for a further 16 hours. Then the reaction mixture is washed twice with 5% sodium hydrogen carbonate solution, dried over sodium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluant: dichloromethane/ethanol 95:5). Yield: 80 mg (50%) C23H25CIN4O5S (505.00) Mass spectrum: (M+H)+ = 505/507 (chlorine isotope) Rf value: 0.45 (silica gel; dichloromethane/ethanol = 9:1) Example 35 -chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (pyrrolidin-2-on-1-yl)-benzamide Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, (1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleaving with TFA analogously to Example 1g. HPLC-MS results: retention time: 3.69 min C22H23CIN4O2S (442.97) Mass spectrum: (M+H)+ = 443/445 (chlorine isotope) The following compound is prepared analogously: No. 36 (Table Removed) Example 39 A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-rnethyl-4-([1,3]oxazepan-2- on-3-yl)-benzamide (a) methyl 4-isocvanato-3-methvl-benzoate 1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroforrnate and refluxed for 5. 5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification. Yield: 1.74 g (quantitative) C10H9NO3(191.19) (b) methyl 4-(A/-r4-chlorobutoxvcarbonvl1-amino)-3-methvl-benzoate 1.74 g (9.08 mmol) 4 methyl -isocyanato-3-methyl-benzoate dissolved in 100 ml of toluene are combined with 1.07 ml (9.11 mmol) 85 %m 4-chloro-butan-1-ol. The mixture is refluxed for 17 hours with stirring. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 17:3 -> 17:4). Yield: 1.19 g (44%) C14H18CINO4 (299.76) Mass spectrum: (M-H)~ = 298/300 (chlorine isotope) Rf value: 0.45 (silica gel; petroleum ether/ethyl acetate = 80:20) (c) methyl 3-methvl-4-(M ,31oxazepan-2-on-3-yl)-benzoate 300 mg (1.00 mmol) methyl 4-(A/-[4-chlorobutoxycarbonyl]-amino)-3-methyl- 125- benzoate are dissolved in 10 ml DMF combined with 168 mg (1.50 mmol) potassium-terf.-butoxide and stirred for 3 hours at 60°C. The reaction mixture is mixed with water and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. Then the residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2). Yield: 160mg(61%) Rf value: 0.26 (silica gel; petroleum ether/ethyl acetate 3:2) C14H17NO4 (263.30) Mass spectrum: (M+H)+ = 264 (d) 3-methvl-4-(f 1.31oxazepan-2-on-3-vl)-benzoic acid 150 mg (0.57 mmol) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate are suspended in 1 ml of ethanol and combined with 0.26 ml (0.87 mmol) 8% aqueous lithium hydroxide solution. The mixture is stirred for 3 hours at ambient temperature and then evaporated down i. vac.. The aqueous residue is extracted twice with ethyl acetate, then acidified and extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. Yield: 122 mg (86%) C13H15NO4 (249.27) Mass spectrum: (M+H)+ = 250 Rf value: 0.14 (silica gel; dichloromethane/methanol = 95:5) (e) A/-K1 S)-1-(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4- (M.31oxazepan-2-on-3-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)- benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then acidifying with TFA and purification of the residue by chromatography (preparative HPLC). Yield: 54% C22H23CIN4O3 * 2 CF3COOH (654.96 / 426.90) Mass spectrum: (M+H)"1" (Table Removed) Example 41 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (morpholin-3-on-4-yl)-3-nitro-benzamide (a) methyl 4-(morpholin-3-on-4-vl)-3-nitro-benzoate 1 .00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 jjmol) tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 urnol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95°C for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1 .31 g (quantitative) Mass spectrum: (M+H)"1" = 281 (b) 4-(2-carboxvmethoxv-ethvlamino)-3-nitro-benzoicacid 400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate are dissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol) 1 -molar lithium hydroxide solution. The mixture is stirred for 2 hours at ambient temperature. Then it is evaporated down i. vac., the residue is diluted with water, cooled in the ice bath and acidified with 2-molar hydrochloric acid. After 10 minutes cooling in the ice bath the precipitate formed is filtered off, washed with water until neutral and dried at 50°C in the drying cupboard. Yield: 290 mg (72 %) CiiHi2N2O7 (284.23) Mass spectrum: IvT = 284 Rf value: 0.59 (Reversed phase 8; methanol/5% sodium chloride solution = 6:4) (c) 4-(morpholin-3-on-4-vl)-3-nitro-benzoic acid-chloride 290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid in 100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionyl chloride and 2 drops of DMF and refluxed for one day. After evaporation of the solution i. vac. it is evaporated with toluene and the residue is further reacted without any more purification. Yield: 290 mg (quant.) (284.66) (d) /V-rn S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methvlsulphanvl-Dropvl1-4- (morpholin-3-on-4-vl)-3-nitro-benzamide 237 mg (0.93 mmol) of (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3- methylsulphanyl-propylamine are dissolved with 0.257 ml TEA in 10 ml THF and a solution of 290 mg (1 .02 mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid chloride in 10 ml THF is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and then evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0 -> 95:5). Yield: 34% (503.97) Mass spectrum: (M-H)"= 502/504 (chlorine isotope) Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1) Example 42 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(tetrahydropyrimidin- 2-on-1 -yl)-benzamide ci (a) 4-(3-Boc-amino-proDvl-amino)-3-chloro-benzonitrile 3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with 2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4- fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature under a nitrogen atmosphere, heated to 105°C for 20 minutes and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. The residue is further reacted without any more purification. Yield: 5.50 g (89 %) C15H2oN3O2 (309.80) Mass spectrum: (M+H)* = 310/312 (chlorine isotope) Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 2:1) (b) 4-(3-arnino-propvlamino)-3-chloro-benzonitrile 4.50 g (14.5 mmol) 4-(3-Boc-amino-propylamino)-3-chloro-benzonitrile are dissolved in 50 ml dioxane and combined with 200 ml 6-molar hydrochloric acid. The mixture is stirred for 2 hours at ambient temperature, then washed with ether and the aqueous phase is poured into 125 ml ice-cooled cone, ammonia solution. Then the mixture is extracted with ethyl acetate, the combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. The residue is further reacted without any more purification. Yield :1.40 g (46%) C10H12CIN3 (209.68) Mass spectrum: (M+H)+ =210/212 (chlorine isotope) Rf value: 0.30 (silica gel; dichloromethane/methanol = 9:1 + 1% cone, ammonia solution) (c) 3-chloro-4-(tetrahvdro-pvrimidin-2-on-1-vl)-benzonitrile A solution of 349 mg (2.15 mmol) A/,/V'-carbonyl-diimidazole in 3 ml NMP is combined with 450 mg (2.15 mmol) 4-(3-amino-propyIamino)-3-chlorobenzonitrile at ambient temperature with stirring and once fully dissolved heated for one hour to 145°C and for 1.5 hours to 155°C. The reaction mixture is washed with water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. Then the residue is purified by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc. ammonia solution 19:1) = 100:0 -> 95:5). Yield: 260 mg (51%) Rf value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 + 1% cone, ammonia solution) CnHioCIN3O (235.68) Mass spectrum: (M+H)* = 236/238 (chlorine isotope) (d) 3-chloro-4-(tetrahvdro-pvrimidin-2-on-1 -vl)-benzoic acid 350 mg (1.49 mmol) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile are suspended in 5 ml of ethanol and combined with 2.0 ml of 10-molar aqueous sodium hydroxide solution. The mixture is stirred for one hour at 100°C and then evaporated down i. vac.. The aqueous residue is combined with ice, acidified with acetic acid and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. The aqueous phase is acidified with 6-molar hydrochloric acid, extracted 5 times with ethyl acetate, the combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.. Yield: 340 mg (90%) CiiHnCIN203 (254.68) Mass spectrum: (M+H)+ = 255/257 (chlorine isotope) Rf value: 0.35 (silica gel; dichloromethane/methanol = 9:1 + 1% acetic acid) (e) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-ftetrahvdro- Dvn'midin-2-on-1 -vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on- 1-yl)-benzoic acid, (1S)-1-(5-chloro-1/V-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding cone, ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1) = 98:2 90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70°C. Yield: 32% C2oHi9Cl2N5O2 (432.31) Mass spectrum: (M+H)+ = 432/434/436 (chlorine isotope) Rf value: 0.40 (silica gel; dichloromethane/methanol = 9:1 + 1% acetic acid) The following compound is prepared analogously: No. structural formula Yield mass peak(s) Rf value or Rt Name No. structural formula Yield mass peak(s) Rf value or Rt Name 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (tetrahydro-pyrimidin-2-on-1-yl)-benzamide Example 46: 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 fY-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1 -yl)-benzamide (a) methyl 3-chloro-4-(5-chloro-pentanovl-amino)-benzoate A solution of 696 ul (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chlorobenzoate in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50°C and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15). Yield: 300 mg (14.6%) 80% product Ci3H15CI2NO3(304.18) Mass spectrum: (M+H)+ = 304/306/308 (chlorine isotope) Rt value: 3.29 min (b) methyl 3-chloro-4-(piperidin-2-on-1 -vl)-benzoate 300 mg (0.79 mmol) of the product obtained in Example 46a is dissolved in 10 ml DMF and combined with 180 mg (1.60 mmol) potassium-fe/t-butoxide and heated to 60°C for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue obtained is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2). Yield:159mg(75%) C13H14CIN03 (267.71) Mass spectrum: (M+H)+ = 268/270 (chlorine isotope) Rf value: 0.18 (silica gel; dichloromethane/isopropanol = 49:1) (c) 3-chloro-4-(piperidin-2-on-1 -vl)-benzoic acid Prepared analogously to Example 39d from methyl 3-chloro-4-(piperidin-2-on-1- yl)-benzoate and 8% lithium hydroxide solution in ethanol. Yield: 36% Ci2H12CINO3 (247.30) Mass spectrum: (M+H)+ = 252/254 (chlorine isotope) Rf value: 0.27 (silica gel; dichloromethane/ethanol = 9:1) (d) 3-chloro-A/-K1 /?)-1 -(5-chloro-1 H-benzimidazol-2-vn-2-methoxv-ethvn-4- (pjperidin-2-on-1 -vlV-benzamide Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)- benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2- methoxy-ethylamine in DMF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5 -> 90:10). Yield: 70% Mass spectrum: (M-H)~ = 459/461/463 (chlorine isotope) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) The following compound is prepared analogously: No. (Table Removed) Example 47 A/-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide (a) A/'-(2-amino-4-bromo-phenvl)-A/-Boc-(S)-serinamide and A/'-(2-amino-5- bromo-phenvn-A/-Boc-(S)-serinamide 5.49 g (26.7 mmol) (S)-A/-Boc-serine are dissolved with 5.00 g (26.7 mmol) 4- bromo-1,2-phenylenediamine in 125 ml THF and a solution of 5.52 g (26.7 mmol) A/,A/'-dicyclohexylcarbodiimide in 20 ml THF is added dropwise while cooling with ice. The reaction mixture is stirred for 16 hours at ambient temperature. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 98:2). Yield: 4.76 g (48 %) mixture of the two regioisomers C14H2oBrN3O4 (374.24) Mass spectrum: (M+H)* = 374/376 (bromine isotope) (b) ( 7f?WV-Boc-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvlamine 3.00 g (8.02 mmol) of the mixture obtained in 47a are dissolved in 30 ml acetic acid and stirred for 2 hours at 50°C. The reaction mixture is added dropwise to a 10% sodium hydroxide solution and extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down i. vac. and the residue is recrystallised from methanol. Yield :1. 96 g (69%) Ci4Hi8BrN3O3 (356.22) Rf value: 0.59 (silica gel; petroleum ether/ethyl acetate = 1:1) (c) f 7ffl-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvlamine 2.00 g (5.62 mmol) (7R)-A/-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16 hours at ambient temperature. The reaction mixture is evaporated down and the resulting precipitate is filtered off. Yield: 1.1 1g (67%) C9Hi0BrN3O * HCI (292.57 / 256.10) Mass spectrum: (M+H)+ = 256/258 (bromine isotope) (d) A/-K1 f?)-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvn-3-methvl-4- (morpholin-3-on-4-vl)-benzamide Prepared analogously to Example Iffrom 3-methyl-4-(morpholin-3-on-4-yl)- benzoicacid, (1f?)-1-(5-bromo-1/-/-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC. Yield: 52% C2iH2iBrN4O4 * CF3COOH (587.35 / 473.32) Mass spectrum: (M+H)* = 473/475 (bromine isotope) Rf value: 0.33 (silica gel; dichloromethane/methanol = 19:1) The following compounds were prepared analogously: No. (Table Removed) Example 48 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,1 -dioxo-isothiazolidin-2- yl)-3-methyl-benzamide (a) methyl 4-(3-chloro-propvl-sulphonvl-amino)-3-rnethvl-benzoate 100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 ul (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. The residue is further reacted without any more purification. Yield: 170 mg (92%) C12Hi6CINO4S (305.78) Mass spectrum: (M+H)* = 306/308 (chlorine isotope) Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 8:2) (b) methyl 4-(1.1-dioxo-isothiazolidin-2-vl)-3-methvl-benzoate 370 mg (0.85 mmol) 70% methyl 4-(3-chloropropane-sulphonylamino)-3-methylbenzoate dissolved in 26 ml DMF are combined with 275 mg (2.45 mmol) potassium-te/t-butoxide and stirred for 16 hours at ambient temperature. The reaction mixture is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2). Yield: 177mg(47%) Ci2Hi5NO4S (269.32) Mass spectrum: (M+H)+ = 270 Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 7:3) (c) 4-(1.1-dioxo-isothiazolidin-2-vl)-3-methvl-benzoic acid 170 mg (0.63 mmol) methyl 4-(1,1-dioxo-isothiazolidin-2yl)-3-methyl-benzoate are stirred in 2 ml of ethanol at ambient temperature for 3 hours with 0.6 ml of 2-molar sodium hydroxide solution. Then the reaction solution is evaporated down i. vac., combined with water and 0.6 ml 2-molar hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is further reacted without any more purification. Yield:148mg(92%) CnHi3N04S (255.30) Mass spectrum: (M-H)" = 254 retention time: 2.23 min (d) N-\( 1SM -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(1.1 -dioxoisothiazolidin- 2-vl)-3-methvl-benzamide Prepared analogously to Example 1f from 4-(1,1-dioxo-isothiazolidin-2yl)-3- methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent extraction with ethyl acetate, drying over magnesium sulphate, activated charcoal and silica gel followed by purification on silica gel (eluant: dichloromethane/isopropanol 95:5). Yield: 37 % C2oH2iCIN4O3S (432.93) Mass spectrum: (M+H)+ = 433/435 (chlorine isotope) Rf value: 0.32 (silica gel; dichloromethane/isopropanol = 19:1) The following compounds were prepared analogously: No. (Table Removed) Example 54 3-amino-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4- (morpholin-3-on-4-yl)-benzamide 65 mg (0.13 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3- methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin(ll)chloridedihydrate and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for 2 hours. The reaction solution is combined with ice water, stirred for 10 minutes and then the precipitate formed is filtered off. After drying for 3 days the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/- ethanoM 00:0 -> 91:9). Yield: 5 mg (8.2 %) C22H24CIN5O3S (473.99) Mass spectrum: (M+H)+ = 474/476 (chlorine isotope) Rf value: 0.48 (silica gel; dichloromethane/ethanol = 9:1) Example 61 -chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydroazepan- 2-on-1 -yl)-benzamide (a) methyl 3-methvl-4-(pent-4-en-1 -ovl-amino)-benzoate Prepared analogously to Example 46a from methyl 4-amino-3-methyl-benzoate and 4-pentene-1-acid-chloride in THF with TEA. Yield: 46% C14Hi7NO3 (247.30) Mass spectrum: (M+H)+ =248 Rt value: 2.88 min (b) methyl 4-(allvl-pent-4-en-1 -ovl-amino)-3-methvl-benzoate 1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate dissolved in 5 ml DMF are combined with 500 mg (4.37 mmol) potassium-te/tbutoxide and at 40°C 350 ul (489 mg, 4.04 mmol) allylbromide are slowly added with stirring. Then the mixture is heated to 70°C for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1). Yield: 58% Ci7H2iNO3 (287.36) Mass spectrum: (M+H)+ = 288 Rf value: 0.46 (petroleum ether/ethyl acetate = 9:1) (c) methyl 4-(4.5-didehvdro-azepan-2-on-1 -vl)-3-methvl-benzoate 150 mg (0.52 mmol) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate are dissolved in 110 ml degassed dichloromethane and rinsed for 30 minutes with argon. Then 88 mg (104 pmol) benzylidene-[1,3-bis(2,4)6-trimethylphenyl)- 2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium(2nd generation Grubbs Catalyst) are added and the mixture is refluxed for 4.5 hours. Then it is evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2). Yield: 83 mg (61 %) Rf value: 0.22 (silica gel, petroleum ether/ethyl acetate 3:2) C15Hi7N03 (259.31) Mass spectrum: (M+H)"1" = 260 (d) 4-(4.5-didehvdro-azepan-2-on-1 -vl)-3-methvl-benzoic acid Prepared analogously to Example 39d from methyl 4-(4,5-didehydro-azepan-2- on-1-yl)-3-methyl-benzoate and 8% lithium hydroxide solution in ethanol. Yield: 51% Rf value: 0.05 (silica gel; dichloromethane/methanol = 19:1) Ci4Hi5NO3 (245.28) Mass spectrum: (M+H)* = 246 (e) A/-K1SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(4.5-didehvdroazepan- 2-on-1-vl)-3-methvl-benzamide Prepared analogously to Example 1f from 4-(4,5-didehydro-azepan-2-on-1-yl)- 3-methyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2- yl)-ethylamine in DMF and subsequent purification by preparative HPLC. Yield: 32% Rf value: 0.44 (silica gel; dichloromethane/methanol = 19:1) C23H23CIN402 * CF3COOH (536.94/422.91) Mass spectrum: (M+H)+ = 423/425 (chlorine isotope) Example 63 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4- yl)-3-methyl-benzamide 204 mg (0.48 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl- 4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at -15°C and combined with 1 10 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at -15 to -10°C, heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1) = 1:0 -> 4:1). Yield: 1 00 mg (47%) Mass spectrum: (M+H)"1" = 445/447 (chlorine isotope) Rf value: 0.15 (silica gel; ethyl acetate/ethanol = 4:1 + 1% cone, ammonia solution) The following compound is prepared analogously: No. (Figure Removed) Example 69 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1- yl)-benzamide (a) methyl 4-(5-chloro-pentanovl-amino)-3-methoxv-benzoate Prepared analogously to Example 6a from methyl 4-amino-3-methoxy-benzoate and 5-chloro-pentanoic acid chloride in THF with TEA. Yield: 99% Ci4Hi8CIN04 (299.76) Mass spectrum: (M+H)+ = 300/302 (chlorine isotope) Rt value: 3.14min (b) methyl 3-methoxv-4-(piperidin-2-on-1 -yl)-benzoate 2.25 g (7.51 mmol) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate dissolved in 60 ml DMF are combined with 1.26 g (11.2 mmol) potassium-terf.- butoxide and stirred for 2.5 hours at 60°C. Then the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue obtained is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 3:2 -> 0:1). Yield: 0.99 g (50%) Rt value: 2.56 min Ci4Hi7NO4 (263.30) Mass spectrum: (M+H)+ = 264 (c) 3-methoxv-4-(piperidin-2-on-1 -vl)-benzoic acid Prepared analogously to Example 39d from methyl 3-methoxy-4-(piperidin-2-on- 1-yl)-benzoate and lithium hydroxide in ethanol. Yield: 95% Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 1:2) Ci3Hi5N04 (249.27) Mass spectrum: (M+H)+ = 250 (d) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvll-3-methoxv-4-(piperidin- 2-on-1 -vl)-benzamide Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)- benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2- yl)ethylamine in DMF and subsequent purification by preparative HPLC. Yield: 75% Rt value: 2.35 min C22H23CIN403 * CF3COOH (540.93 / 426.90) Mass spectrum: (M+H)+ = 427/429 (chlorine isotope) The following compounds were prepared analogously: No. structural formula Yield mass peak(s) Rf value or Rt 70 (Figure Removed) Example 73 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,1 -dioxo-6-methyl- [l^.eithiadiazinan^-yO-S-methyl-benzamide (a) methyl 4-(1 .1-dioxo-6-methvl-n .2.61-thiadiazinan-2-vl)-3-methvl-benzoate 400 mg (1.41 mmol) methyl 4-(1,1-dioxo-[1,2I6]-thiadiazinan-2-yl)-3-methylbenzoate dissolved in 4 ml DMF at 40°C are combined with 240 mg (2.14 mmol) potassium-terf.-butoxide and 96 pi (1.54 mmol) methyl iodide and stirred for 5 hours at 40°C. The reaction solution is evaporated down i. vac., combined with water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. Yield: 220 mg (52 %) Ci3Hi8N2O4S (298.36) Mass spectrum: (M+H)+ = 299 Rf value: 0.44 (silica gel; petroleum ether/ethyl acetate = 3:2) (b) 4-(1 .1-dioxo-6-methvl-M .2.61thiadiazinan-2-vn-3-methvl-benzoic acid Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-3-methyl- [1,2,6]thiadiazinan-2-yl)-3-nnethyl-benzoate and lithium hydroxide in ethanol. Yield: (81 %) Mass spectrum: (M+H)+ = 285 Rf value: 0.07 (silica gel; dichloromethane/methanol = 19:1) (c) A/-K1 S)-1-(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(1 .1-dioxo-6-methvln. 2.61thiadiazinan-2-vl)-3-methvl-benzamide Prepared analogously to Example 1f from 4-(1,1-dioxo-3-methyl- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid, (1 S)-1-(5-chloro-1 Hbenzimidazol- 2-yl)-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC. Yield: 55 % C21H24CIN503S * CF3COOH (576.00 / 461.97) Mass spectrum: (M+H)+ = 462/464 (chlorine isotope) Rt value: 2.50 min The following compound is prepared analogously: No. 74 (Table Removed) Examole 75 -bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide (a) N'-(2-amino-4-bromo-phenvl)-A/-Boc-(S)-O-methvl-serinamide and N'- (2-amino-5-bromo-phenvl)-A/-Boc-(S)-O-methvl-serinamide 2.50 g (6.24 mmol) of the dicyclohexylammonium salt of /v-Boc-(S)-O-methylserine are dissolved in 20 ml 5 % citric acid, the aqueous phase is extracted 2x with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50 % solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.. Yield: 2.38 g (98 %) mixture of the two regioisomers Ci5H22BrN3O4 (388.26) Mass spectrum: (M+H)* = 388/390 (bromine isotope) Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol = 9:1) (b) (?R)-A/-Boc-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-methoxv-ethvlamine 2.38 g (6.13 mmol) of the mixture obtained in 75a are dissolved in 150 ml of toluene and 1 .84 ml (30.7 mmol) acetic acid and 4.00 g molecular sieve, 3A, are added. The reaction mixture is stirred for 3 hours at 55°C and then cooled for 1 5 minutes in the ice bath. The reaction mixture is filtered and poured into a mixture of 500 ml each of water and ethyl acetate. After vigorous mixing the organic phase is separated off, washed with sat. sodium chloride solution, dn'ed over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0 - > 97:3). Yield: 1. 40 g (62%) Ci5H2oBrN3O3 (370.24) Mass spectrum: (M+H)+ = 370/372 (bromine isotope) Rf value: 0.81 (silica gel; dichloromethane/ethanol = 9:1) (c) (1 R)-1 -(5-bromo-1 H-benzimidazole-1 -vlV-2-methoxv-ethvlamine Prepared analogously to Example 1g from (1/?)-/V-Boc-1-(5-bromo-1/-/- benzimidazol-2-yl)-2-methoxy-ethylamine and TFA in dichloromethane. Yield: 51 % Ci0Hi2BrN3O(270.13) Mass spectrum: (M+H)+ = 270/272 (bromine isotope) Rf value: 0.20 (silica gel, dichloromethane/ethanol 9:1 ) (d) A/-T(1 R)-1 -f 5-bromo-1 H-benzimidazol-2-vl V-2-methoxv-ethvn-3-methvl-4- (morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid, (1 ft)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel. Yield: quant. Mass spectrum: (M+H)+ = 487/489 (bromine isotope) Rf value: 0.56 (silica gel; dichloromethane/ethanol = 9:1) Example 76 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3-methyl- 4-(morpholin-3-on-4-yl)-benzamide (a) ethvl(2S)-2-(benzvloxvcarbonvl-amino)-4-cvano-butvrate 5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)- 4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are added and the mixture is stirred for 10 minutes at ambient temperature. Then 50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed with semisaturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down i. vac- Yield: 3.20 g (98 %) Ci5Hi8N204 (290.32) Mass spectrum: (M+NH4)+ =308 Rf value: 0.80 (silica gel; dichloromethane/ethanol = 9:1) (b) ethyl (2S)-2-(benzvloxvcarbonvl-amino)-4-(1H-tetrazol-5-vlVbutvrate 3.20 g (11.0 mmol) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate are dissolved in 40 ml of toluene and 1.08 g (16.5 mmol) sodium azide and 2.28 g (16.5 mmol) triethylamine-hydrochloride are added. The reaction mixture is heated to 85°C for 24 hours, cooled to ambient temperature and extracted with water. The combined aqueous phases are acidified to pH 2 with semiconc. hydrochloric acid, the resulting precipitate is suction filtered, washed with water and dried at 50°C. Yield: 2.90 g (79 %) Ci5Hi9N504 (333.34) Mass spectrum: (M+H)+ = 334 Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1) (c) (2S)-2-(benzvloxvcarbonvl-amino)-4-(1H-tetrazol-5-vl)-butvricacid Prepared analogously to Example 30b from ethyl (2S)-2-(benzyloxycarbonylamino)- 4-(1/-/-tetrazol-5-yl)-butyrate and lithium hydroxide in a mixture of solvents from water and THF. Yield: quant. C13Hi5N5O4 (305.29) Mass spectrum: (M+H)+ = 306 Rf value: 0.30 (silica gel; dichloromethane/ethanol = 4:1) (d) A/'-(2-amino-4-chloro-Dhenvl)-(2S)-2-(benzvloxvcarbonvl-amino)-4-(1Htetrazol- 5-vl)-butvric acid amide and A/-(2-amino-5-chloro-phenvlH2S)-2- (benzvloxvcarbonvl-amino)-4-(1 /-/-tetrazol-5-vn-butvric acid amide Prepared analogously to Example 47a from (2S)-2-(benzyloxycarbonyl-amino)- 4-(1H-tetrazol-5-yl)-butyric acid and 4-chloro-1,2-phenylenediamine with DCC in THF. Yield: quant., mixture of the two regioisomers, slightly contaminated Ci9H2oCIN7O3 (429.86) Rf value: 0.20 (silica gel; dichloromethane/ethanol = 9:1) (e) (1 S)-A/-(benzvloxvcarbonvl)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-(1 Htetrazol- 5-vn-propvlamine Prepared analogously to Example 47b from the product obtained in Example 76d and acetic acid. Yield: quant. C19Hi8CIN7O2 * CH3COOH (471 .90 / 41 1 .85) Rf value: 0.25 (silica gel; dichloromethane/ethanol/conc. ammonia = 4:1:0.1) (f) (1 SM -(5-chloro-1 H-benzimidazol-2-vl)-3-(1 H-tetrazol-5-vlV-propvlamine 2.10 g (4.45 mmol) (fS)-A/-(benzyloxycarbonyl)-1-(5-chloro-1/-/-benzimidazol-2- yl)-3-(1/-/-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient temperature. Then 20 ml of methanol are added, the mixture is stirred for a further 30 minutes at ambient temperature and the reaction mixture is evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane / (ethanol / cone, ammonia 95:5) = 70/30 -> 60:40). Yield: 690 mg (56 %) CnHi2CIN7 (277.71) Mass spectrum: (M+H)+ = 278/280 (chlorine isotope) Rf value: 0.15 (silica gel; dichloromethane/ethanol = 3:2 + 1% cone, ammonia) (g) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2- methvl-4-(morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid, (1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)- propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel. Yield: 33 % C23H23CIN8O3 (494.93) Mass spectrum: (M+H)+ = 495/497 (chlorine isotope) Rf value: 0.20 (silica gel; dichloromethane/ethanol = 4:1) Example 77 A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzannide (a) /V'-(2-amino-4-chloro-phenvlH2S)-2-(Boc-amino)-3-methoxv-propionic acid amide and /V-(2-amino-5-chloro-phenvlH2S)-2-(Boc-amino)-3- methoxv-propionic acid amide 4.90 g (21.0 mmol) (2S)-2-(Boc-amino)-3-methoxy-propionic acid are dissolved in 20 ml THF and combined with 13.57 g (42.0 mmol) TBTU and 5.76 ml (52.5 mmol) triethylamine and stirred for 30 minutes at ambient temperature. Then 3.00 g (21.0 mmol) 4-chloro-1,2-phenylenediamine in 20 ml THF are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is evaporated down i. vac., poured into water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 99:1). Yield: 5.60 g (75%) mixture of the two regioisomers Ci6H24CIN3O3 (357.83) Mass spectrum: (M+H)+ = 358/360 (chlorine isotope) Rf value: 0.26 (silica gel; dichloromethane/methanol = 99:1) (b) ( 1 S)-/V-Boc-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propylamine Prepared analogously to Example 47b from the product obtained in Example 77a and acetic acid. Yield: 96% Ci6H22CIN3O3 (339.82) Mass spectrum: (M+H)+ = 340/342 (chlorine isotope) Rf value: 0.80 (silica gel; dichloromethane/methanol = 19:1) (c) ( 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propylamine Prepared analogously to Example 1g from (1S)-A/-Boc-1-(5-chloro-1Hbenzimidazol- 2-yl)-3-methoxy-propylamine and TFA in dichloromethane. Yield: 31 % CnH14CIN30 (239.70) Mass spectrum: (M+H)+ = 240/242 (chlorine isotope) Rf value: 0.10 (silica gel; dichloromethane/ethanol = 9:1) (d) N-\C\ S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propyl1-3-methvl-4- (morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid, (1 S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel. Yield: 59 % C23H25CIN4O4 (456.92) Mass spectrum: (M+H)+ = 457/459 (chlorine isotope) Rf value: 0.51 (silica gel; dichloromethane/ethanol = 9:1) The following compound is prepared analogously: No. (Table Removed) Example 82 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro- [1,2]oxazin-2-yl)-benzamide (a) methvl 3-chloro-4-nitroso-benzoate 8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of cone, sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with 14 g sodium carbonate. The solution obtained is combined with a suspension of 2.78 g (15.0 mmol) methyl 4-amino-3-chloro-benzoate in 300 ml of water and stirred for 16 hours at ambient temperature. The reaction mixture is suction filtered, the filter cake is washed with water, dried in the air and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1). Yield: 1.00 g (33%) C8H6CINO3 (199.59) Mass spectrum: (M+H)+ = 199/201 (chlorine isotope) Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate = 4:1) (b) methyl 3-chloro-4-(3.6-dihvdro-ri .21oxazin-2-vl)-benzoate 1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10 ml chloroform and a freshly prepared solution of 1.10 g (20.3 mmol) butadiene in 6 ml chloroform is added dropwise with stirring at 0°G. The reaction mixture is stirred for 30 minutes at 0-10°C and for 16 hours at ambient temperature, evaporated down i. vac. and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 19:1). Yield: 1.00 g (79%) Ci2Hi2CIN03 (253.68) Mass spectrum: (M+H)* = 254/256 (chlorine isotope) Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate = 4:1) (c) 3-chloro-4-(3.6-dihvdro-n .21oxazin-2-vl)-benzoic acid Prepared analogously to Example 2d from methyl 3-chloro-4-(3,6-dihydro- [1,2]oxazin-2-yl)-benzoate and sodium hydroxide in a solvent mixture of water and ethanol. Yield: 90% CnHioClN03 (239.66) Mass spectrum: (M-H)' = 238/240 Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 4:1) (d) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(3.6-dihvdro- 159- M.21oxazin-2-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2- yl)-benzoic acid, (1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF. Yield: 88 % C2oHi8Cl2N4O2(417.29) Mass spectrum: (M+H)+ =417/419/421 (chlorine isotope) Rf value: 0.35 (silica gel; petroleum ether/ethyl acetate = 1:1) Example 83 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1 - dioxo-[1,2]thiazinan-2-yl)-benzamide (a) 2-chloro-A/-(4-chlorbutvl-sulphonvl)-4-methvl-aniline 1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine, combined with 2.67 g (10.5 mmol) 75%m 4-chlorobutyl-sulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with 6-molar hydrochloric acid, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate = 9:1 -> 7:3). Yield:1.27 g (40%) CiiHi5CI2NO2S (296.21) Mass spectrum: (M+H)+ = 296/298/300 (chlorine isotope) Rf value: 0.42 (silica gel; petroleum ether/ethyl acetate = 4:1) (b) 3-chloro-4-(1 .1-dioxo-n .21thiazinan-2-vn-toluene 1 .27 g (4.29 mmol) 2-chloro-A/-(4-chlorbutyl-sulphonyl)-4-methyl-aniline are stirred together with 722 mg (6.43 mmol) potassium-fe/t-butoxide in 50 ml DMF for 1 6 hours at 60°C. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 3:2). Yield: 850 mg (76 %) CnH14CIN02S (259.75) Mass spectrum: (M+H)+ = 260/262 (chlorine isotope) Rf value: 0.27 (silica gel; petroleum ether/ethyl acetate = 4:1) (c) 3-chloro-4-(1 .1-dioxo-M ,21thiazinan-2-vl)-benzoic acid 250 mg (0.96 mmol) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene are suspended in 10 ml of water and combined with 456 mg (2.89 mmol) potassium permanganate and 39 mg (0.98 mmol) sodium hydroxide. The reaction mixture is refluxed for 4 hours. After cooling to ambient temperature sodium thiosulphate is added to decolorise the mixture which is then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol = 19:1). Yield: 50 mg (18%) CnH12CINO4S (289.74) Mass spectrum: (M+H)+ = 290/292 Rt value: 2.50 min (d) 3-chloro-A/-ff 1 R)-1 -(5-chloro-1 H-benzirnidazol-2-vl)-2-methoxv-ethvl1-4- (1 .1-dioxo-n .21thiazinan-2-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(1 ,2-dioxo-[1 ,2]thiazinan- 2-yl)-benzoic acid, (1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxyethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC. Yield: 34 % C2iH22CI2N4O4S (497.40) Mass spectrum: (M+H)+ Rt value: 2.53 min = 497/499/501 (chlorine isotope) Example 84 A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo- [1,2]thiazepan-2-yl)-3-methyl-benzamide (a) methyl 4-(5-chloropentvl-sulphonvl-amino)-3-methvl-benzoate Prepared analogously to Example 83a from methyl 4-amino-3-methyl-benzoate and 5-chloropentyl-sulphonic acid chloride in pyridine. Yield: 43 % Ci4H2oCIN04S (333.83) Mass spectrum: (M+H)+ = 334/336 (chlorine isotope) Rf value: 0.72 (silica gel; petroleum ether/ethyl acetate = 7:3) (b) methyl 4-(1.1-dioxo-M .21thiazepan-2-vl)-3-methvl-benzoate Prepared analogously to Example 83b from methyl 4-(5-chloropentyl-sulphonylamino)- 3-methyl-benzoate and potassium-fe/t-butoxide in DMF. Yield: 19% C14Hi9NO4S (297.37) Mass spectrum: (M+H)"* = 298 Rt value: 0.30 (silica gel; petroleum ether/ethyl acetate = 4:1) (c) 4-f 1.1-dioxo-n .21thiazepan-2-vl)-3-methvl-benzoic acid Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-[1,2]thiazepan- 2-yl)-3-methyl-benzoate and lithium hydroxide in a solvent mixture of water and ethanol. Yield: 60 % Ci3Hi7NO4S (283.34) Mass spectrum: (M+H)+ = 284 Rt value: 2.60 min (d) A/-rnm-1-(5-chloro-1H-benzimidazol-2-vl)-2-methoxv-ethvn-4-f1.1-dioxo- M.21thiazepan-2-vl)-3-methvl-benzamide Prepared analogously to Example 1f from 4-(1,2-dioxo-[1,2]thiazepan-2-yl)-3- methyl-benzoic acid, (1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxyethylamine, TBTU and NMM in DMF with subsequent purification by chromatography on silica gel. Yield: 75 % C23H27CIN4O4S (491.00) Mass spectrum: (M+H)* = 491/493 (chlorine isotope) Rt value: 2.60 min Example 89 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)- benzamide 209 mg (0.50 mmol) 3-chloro-/V-[(7S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]- 4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide together with 100 mg 10% palladium charcoal in 5 ml of ethyl acetate for 7 minutes are hydrogenated at ambient temperature at 5 bar under a hydrogen atmosphere. Then the mixture is suction filtered, the filtrate is evaporated down i. vac. and evaporated again with ether. Yield: 200 mg (95 %) C2oH2oCI2N4O2(419.30) Mass spectrum: (M+H)+ =419/421/423 (chlorine isotope) Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 1:1) Example 90 A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo- [1,4Joxazepan-4-yl)-benzamide (a) ethyl 3-(2-benzvloxv-ethoxv)-propionate 8.53 ml (60.0 mmol) benzyloxy-ethanol are combined with 13 mg (0.57 mmol) sodium in 40 ml THF, then when it has dissolved 5.95 ml (54.7 mmol) ethyl acrylate are added under an argon atmosphere and stirred for 20 hours at ambient temperature. After neutralising with 0.6 ml 1-molar hydrochloric acid the reaction mixture is evaporated down i. vac., the residue is taken up in sat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 4:1). Yield: 3.73 g (25 %) C14H2o04 (252.31) Mass spectrum: (M+H)+ = 253 Rf value: 0.48 (silica gel; petroleum ether/ethyl acetate = 4:1) (b) ethvl 3-(2-hvdroxv-ethoxv)-propionate 3.73 g (14.8 mmol) ethyl 3-(2-benzyloxy-ethoxy)-propionate are hydrogenated together with 665 mg 10% palladium charcoal in 70 ml of ethanol for 44 minutes at ambient temperature under a hydrogen atmosphere at 3 bar. Then the mixture is suction filtered and the filtrate is evaporated down i. vac.. Yield: 2.26 g (94 %) C7Hi4O4(162.18) Mass spectrum: (M+H)+ =163 (c) ethvl 3-(2-chloro-ethoxv)-propionate 2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspended in 5 ml (68.5 mmol) thionyl chloride and 20 (jl (0.27 mmol) DMF are added. The reaction mixture is refluxed for 4 hours and then evaporated down i. vac.. The product is further reacted without any more purification. Yield: quant. C7H13O3 (180.63) Mass spectrum: (M+H)* = 181/183 (chlorine isotope) (d) 3-(2-chloro-ethoxv)-propionic acid 2.00 g (11.1 mmol) ethyl 3-(2-chloro-ethoxy)-propionate are suspended in 8 ml of ethanol and 4.96 ml (16.6 mmol) of 8% lithium hydroxide solution are added. The mixture is stirred for 4 hours at ambient temperature, then evaporated down i. vac., acidified with 2-molar hydrochloric acid, combined with diethyl ether and dried over sodium sulphate. Then it is filtered off and evaporated down i. vac.. Yield: 1.51 g (89%) C5H9CIO3 (152.58) Mass spectrum: (M-H)"= 151/153 (chlorine isotope) (e) 3-(2-chloro-ethoxv)-propionic acid-chloride Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionic acid and thionyl chloride with DMF. Yield: 91 % C5H8Cl2O2(171.02) (f) methvl 4-f3-(2-chloro-ethoxv)-propionvl-amino1-3-methvl-benzoate 1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloroethoxy)- propionic acid-chloride in 25 ml THF is added dropwise and the mixture is stirred for a further 2.5 hours at ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate = 7:3 -> 6:4). Yield: 1.25 g (41 %) Ci4H18CINO4 (299.75) Mass spectrum: (M+H)+ = 300/302 (chlorine isotope) Rf value: 0.15 (silica gel; petroleum ether/ethyl acetate = 7:3) (g) methyl 3-methvl-4-(5-oxo-n .41oxazepan-4-vl)-benzoate 900 mg (3.00 mmol) 4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate methyl are stirred in 40 ml DMF together with 520 mg (4.63 mmol) potassium terf.-butoxide and 12 mg (80 umol) sodium iodide for 3 hours at 60°C. After evaporation i. vac. the residue is combined with water, extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 11:9). Yield: 310 mg (39 %) C14H17NO4 (263.29) Mass spectrum: (M+H)+ = 264 (h) 3-methvl-4-(5-oxo-ri .41oxazepan-4-vl)-benzoic acid Prepared analogously to Example 39d from methyl 3-methyl-4-(5-oxo- [1,4]oxazepan-4-yl)-benzoate and lithium hydroxide in a solvent mixture of water and ethanol. Yield: 69 % C13Hi5N04 (249.26) Mass spectrum: (M+H)+ = 250 Rt value: 2.06 min (i) A/-K1 R)-1 -(5-chloro-1 H-benzimidazol-2-vl V2-methoxv-ethvn-3-methvl-4- (5-oxo-n.41oxazepan-4-vn-benzamide Prepared analogously to Example 1f from 3-methyl-4-(5-oxo-[1,4]oxazepan-4- yl)-benzoic acid, (1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC. Yield: 83 % C23H25CIN4O4 (456.92) Mass spectrum: (M+H)+ = 457/459 (chlorine isotope) Rt value: 2.23 min Example 91 )-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4,4-dirnethyl-2-oxoimidazolidin- 1-yl)-3-methyl-benzamide (a) methyl 4-(3-M .1 -dimethvl-2-hvdroxv-ethvn-ureido)-3-rnethvl-benzoate 5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolved in 100 ml THF and a solution of 2.86 ml (30.0 mmol) 2-amino-2-methyl-propan-1-ol in 25 ml THF is added dropwise. The mixture is stirred for 2 hours at ambient temperature and then evaporated down i. vac.. The residue is further reacted without any more purification. Yield: 8.40 g (quant.) Mass spectrum: (M-H)" = 279 Rf value: 0.20 (silica gel; dichloromethane/ethanol = 19:1) (b) methyl 4-(4.4-dimethvl-2-oxo-imidazolidin-1-vl)-3-methvl-benzoate 7.00 g (25.0 mmol) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]-ureido)-3-methylbenzoate are dissolved in 400 ml THF at 0°C and combined with 6.73 g (60.0 mmol) potassium-ferf.-butoxide. After stirring for 15 minutes at 0°C a solution of 5.72 g (30.0 mmol) p-toluenesulphonic acid in 50 ml THF is added dropwise. After another 10 minutes stirring at 0°C 300 ml of water are added, the mixture is neutralised with 1 -molar hydrochloric acid and the THF is removed i. vac.. The residue is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.. Then the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol = 100:0 -> 97:3). Yield: 2.50 g (38 %) Mass spectrum: (M+H)"1" = 263 Rf value: 0.30 (silica gel; dichloromethane/ethanol = 19:1) (c) 4-f4.4-dimethvl-2-oxo-imidazolidin-1-vn-3-methvl-benzoicacid 2.70 g (10.3 mmol) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methylbenzoate are suspended in 75 ml of methanol and combined with a solution of 1.68 g (30.0 mmol) potassium hydroxide in 10 ml of water. It is stirred for 3 hours at ambient temperature and then evaporated down i. vac.. The aqueous residue is diluted with water, acidified with 1-molar hydrochloric acid and the precipitate obtained is suction filtered, washed with water and dried. Yield: 2.30 g (90%) Ci3Hi6N203 (248.28) Mass spectrum: (M+H)+ = 249 Rf value: 0.50 (silica gel; dichloromethane/methanol = 9:1) (d) A/-K1 S)-1 -(5-chloro-1 H-benzirnidazol-2-vl)-ethvl1-3-rnethvl-4- (ri.31oxazepan-2-on-3-vl)-penzamide Prepared analogously to Example 1f from 4-(4,4-dimethyl-2-oxo-imidazolidin-1- yl)-3-methyl-benzoic acid, (1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on silica gel. Yield: 59 % C22H24CIN502 (425.91) Mass spectrum: (M+H)+ = 426/428 (chlorine isotope) Rf value: 0.40 (silica gel; dichloromethane/methanol = 9:1) The following compound is prepared analogously: No. structural formula Yield mass peak(s) Rf value Name (Table Removed) Example 93 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxooxazolidin- 3-yl)-benzamide ci (a) 3-chloro-4-(2-hvdroxv-1-methvl-ethvlamino)-benzonitrile 4.00g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60°C in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. Yield: 5.20 g (96 %) C10HnCIN2O (210.66) Mass spectrum: (M+H)+ = 211/213 (chlorine isotope) Rf value: 0.27 (silica gel; dichloromethane/methanol = 19:1) (b) 3-chloro-4-(2-hvdroxv-1 -methvl-ethvlamino)-benzoic acid 5.20 g (24.7 mmol) 3-ch!oro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile are refluxed for 6 hours in 50 ml of cone, hydrochloric acid with stirring. Then the mixture is evaporated down i. vac., made basic with cone, ammonia solution and extracted with ethyl acetate. After acidification of the aqueous phase with acetic acid the mixture is extracted with ethyl acetate, the combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. Yield: 5.00 g (88 %) C10H12CIN03 (229.66) Mass spectrum: (M+H)+ = 230/232 (chlorine isotope) Rf value: 0.44 (silica gel; dichloromethane/methanol = 9:1) (c) ethvl 3-chloro-4-(2-hvdroxv-1 -methvl-ethvlaminoVbenzoate 5.00 g (21.8 mmol) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoic acid are stirred for 16 hours in 100 ml sat. ethanolic hydrochloric acid at ambient temperature and then evaporated down i. vac.. The residue is combined with water and cone, ammonia solution and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. The residue is purified by chromatography on silica gel (eluant: dichloromethane / methanol = 50:1). Yield: 3.40 g (61 %) C12H16CINO3 (257.71) Mass spectrum: (M+H)+ = 258/260 (chlorine isotope) Rf value: 0.34 (silica gel; dichloromethane/methanol = 19:1) (d) ethvl 3-chloro-4-(4-methvl-2-oxo-oxazolidin-3-vl)-benzoate 0.50 g (1.94 mmol) ethyl 3 -chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are placed in 30 ml THF together with 0.22 g (2.20 mmol) triethylamine and 1.10 ml (2.08 mmol) 20% phosgene solution in toluene is added with stirring at ambient temperature. The mixture is stirred for 1 hour at ambient temperature, then 1 ml of water is added and the mixture is stirred for another 10 minutes. The mixture is then evaporated down i. vac., combined with water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. Yield: 0.54 g (98 %) Ci3Hi4CIN04 (283.71) Mass spectrum: (M+H)+ = 284/286 (chlorine isotope) Rf value: 0.71 (silica gel; dichloromethane/methanol = 19:1) (e) 3-chloro-4-f4-methvl-2-oxo-oxazolidin-3-vl)-benzoicacid 0.90 g (3.17 mmol) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate are stirred for 1 hour in 50 ml of methanol with 10 ml 1-molar aqueous lithium hydroxide solution at ambient temperature. The mixture is then evaporated down to 20 ml i. vac., acidified with cone, hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.. The residue is crystallised from a little diethyl ether and suction filtered. Yield: 0.45 g (56 %) CnH10CINO4 (255.65) Mass spectrum: (M+H)+ = 256/258 (chlorine isotope) Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1) (f) 3-chloro-/V-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(4-methvl-2- oxo-oxazolidin-3-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-(4-methyl-2-oxo-oxazolidin- 3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on aluminium oxide. Yield: 45 % C2oHi8CI2N403 (433.29) Mass spectrum: (M+H)+ = 433/435/437 (chlorine isotope) Rf value: 0.65 (silica gel; dichloromethane/methanol = 9:1) The following compounds were prepared analogously: (Table Removed) Example 95 N-[\ -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4-(morpholin-3- on-4-yl)-benzamide (a) A/'-(2-amino-4-chloro-phenvl)-A/-Boc-phenvl-glvcinamide and A/'-(2- amino-5-chloro-phenvl)-A/-Boc-phenvl-glvcinamide Prepared analogously to Example 47a from A/-Boc-phenyl-glycine, 4-chloro-1,2- phenylenediamine and DCC in THF. Yield: quant, mixture of the two regioisomers C19H22CIN303 (375.85) Mass spectrum: (M+H)+ = 376/378 (chlorine isotope) Rf value: 0.41 (silica gel; dichloromethane/ethanol = 19:1) (b) A/-acetvl-1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -phenvl-methvlamine 3.65 g (9.71 mmol) of the mixture obtained in 95a are dissolved in 8 ml acetic acid and refluxed for 6 hours with stirring. The reaction mixture is evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol = 100:0 -> 94:6). Yield: 1.34 g (46%) Ci6Hi4CIN3O (299.76) Mass spectrum: (M+H)+ = 300/302 (chlorine isotope) Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1) (c) 1 -(5-chloro-1 /-/-benzimidazol-2-vlV-1 -phenvl-methvlamine 1.34 g (4.47 mmol) A/-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenylmethylamine in 9 ml of ethanol are combined with 18 ml of cone, hydrochloric acid and heated to 50°C for 2 days. The reaction mixture is evaporated down i. vac. and twice taken up in ethanol and evaporated down again. Yield: 1.26 g (96%) C14Hi2CIN3 * HCI (294.18 / 257.72) Mass spectrum: (M+H)* = 258/260 (chlorine isotope) (d) A/-M -(5-chloro-1 H-benzimidazol-2-vn-1 -phenvl-methvn-3-methvl-4- (morDholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid, 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU andDIPEAinTHF. Yield: 89 % C26H23CIN403 (474.94) Mass spectrum: (M+H)+ = 475/477 (chlorine isotope) Rf value: 0.68 (silica gel; dichloromethane/ethanol = 9:1) The following compound is prepared analogously: No. structural formula Yield mass peak(s) Rf value or Rt Name (Table Removed) Example 96 /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on- 4-yl)-benzamide (a) A/'-(2-amino-4-chloro-phenvlH2S)-2-(Boc-amino)-butvric acid amide and A/'-(2-amino-5-chloro-phenvl)-(2S)-2-(Boc-amino)-butvricacid amide Prepared analogously to Example 47a from (2S)-2-(Boc-amino)-butyric acid, 4- chloro-1,2-phenylenediamine and DCC in THF. Yield: 89 % mixture of the two regioisomers Mass spectrum: (M+H)+ = 328/330 (chlorine isotope) Rf value: 0.63 (silica gel; dichloromethane/ethanol = 19:1) (b) (1 SV/V-Boc-1 -f 5-chloro-1 H-benzimidazol-2-vl)-propylamine Prepared analogously to Example 47b from the mixture obtained in 95a and acetic acid and purification of the residue by chromatography on silica gel. Yield: 94 % C15H2oCIN3O2 (309.79) Mass spectrum: (M+H)* =310/312 (chlorine isotope) Rf value: 0.63 (silica gel; dichloromethane/ethanol = 19:1) (c) (1 S)-1 -(5-chloro-1 H-benzimidazol-2-vlV-1 -phenvl-methvlamine Prepared analogously to Example 75cfrom (1S)-A/-Boc-1-(5-chloro-1Hbenzimidazol- 2-yl)-propylamine and trifluoroacetic acid in dichloromethane. Yield: quant. Ci0Hi2CIN3 * 2 CF3COOH (437.72 / 209.68) Mass spectrum: (M+Hf =210/212 (chlorine isotope) (d) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-propyl1-3-methvl-4-(morpholin- 3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF. Yield: 17% C22H23CIN403 (426.90) Mass spectrum: (M+H)"1" = 427/429 (chlorine isotope) Rf value: 0.45 (silica gel; dichloromethane/ethanol = 9:1) The following compounds were prepared analogously: No. structural formula Yield mass peak(s) Rf value or Rt (Table Removed) Example 106 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4- (morpholin-3-on-4-yl)-benzamide (a) ethvl4-r(2-chloro-ethoxv)-acetvl-amino1-3-fluoro-benzoate Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoate with TEA in THF. Yield: 44 % C13Hi5CIFN04 (303.71) Mass spectrum: (M+H)+ = 304/306 (chlorine isotope) Rf value: 0.29 (silica gel; dichloromethane) (b) 4-(2-carboxvmethoxv-ethvlamino)-3-fluoro-benzoicacid 580 mg (1.91 mmol) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate in 6 ml dioxane are combined with 3.82 ml (7.64 mmol) 2-molar potassium hydroxide solution and 2 ml of water. Then the mixture is heated to 70°C for 2 h, then diluted with water and acidified with 6-molar hydrochloric acid. After the addition of dichloromethane the precipitate formed is suction filtered and dried in the drying cupboard at 50°C. Yield: 390 mg (79 %) CnH12FNO5 (257.22) Mass spectrum: (M+H)+ = 258 Rf value: 0.66 (reversed phase RP-8; methanol/5% NaCI solution = 6:4) (c) 3-fluoro-4-(morpholin-3-on-4-vl)-benzoic acid-chloride Prepared analogously to Example 41 c from 4-(2-carboxymethoxy-ethylamino)- 3-fluoro-benzoic acid and thionylchoride in dichloromethane with DMF. Yield: quant. CnH9CIFN03 (257.65) (d) A/-K1 KV1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvn-3-fluoro-4- (morpholin-3-on-4-vn-benzamide Prepared analogously to Example 41 d from 3-fluoro-4-(morpholin-3-on-4-yl)- benzoic acid-chloride and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine with TEA in THF. Yield: 47 % C2iH2oCIFN4O4 (446.86) Mass spectrum: (M+H)+ = 447/449 (chlorine isotope) Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1) Example 109 A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(pyridin-3-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide (a) A/'-(2-amino-4-chloro-phenvn-2-(Boc-amino)-2-(pyridin-3-vl)-aceticacid amide and A/'-(2-amino-5-chloro-phenvl)-2-(Boc-amino)-2-(pyridin-3-vl)- acetic acid amide 1.00 g (3.96 mmol) /V-Boc-amino-2-(pyridin-3-yl)-acetic acid are placed together with 0.59 g (4.16 mmol) 4-chloro-1,2-phenylenediamine at 0°C in 20 ml THF and 2.92 ml (4.96 mmol) 50% PPA solution in ethyl acetate and 1.24 ml ( 8.92 mmol) TEA are added. After stirring for 30 min at 0°C the mixture is stirred for 5 h at ambient temperature stirred and then evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane / ethanol = 10:0 -> 9:1). Yield: 1.32 g (88 %) mixture of the two regioisomers Mass spectrum: (M+H)+ = 377/379 (chlorine isotope) Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1) (b) /V-Boc-1 -(5-chloro-1 /-/-benzimidazol-2-vn-1 -(pvridin-3-vl)-methvlamine Prepared analogously to Example 47b from the product obtained in Example 111aand acetic acid. Yield: 81 % C18H19CIN4O2 (358.82) Mass spectrum: (M+H)"1" = 359/361 (chlorine isotope) Rf value: 0.51 (silica gel; dichloromethane/ethanol = 9:1) (c) 1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -(pyridin-3-vl)-methvlamine Prepared analogously to Example 1g from A/-Boc-1-(5-chloro-1H-benzimidazol- 2-yl)-1-(pyridin-3-yl)-methylamine and trifluoroacetic acid in dichloromethane. Yield: 66 % Ci3HnCIN4 (258.71) Mass spectrum: (M+H)* = 259/261 (chlorine isotope) Rf value: 0.62 (silica gel; dichloromethane/ethanol = 9:1) (d) A/-F1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -(pvridin-3-vl)-methvl1-3-methvl-4- (morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid and 1-(5-chloro-1/-/-benzimidazol-2-yl)-1-(pyridin-3-yl)- methylamine with TBTU and DIPEA in THF. Yield: 84 % (475.93) Mass spectrum: (M+H)+ = 476/478 (chlorine isotope) Rf value: 0.31 (silica gel; dichloromethane/ethanol = 9:1) Example 110 A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 -methyl-pyrazol-3-yl)-methyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide (a) methyl ethoxvcarbonvl-methoxvimino-(1-methvl-pvrazol-3-vl)-acetate 5.00 g (20.7 mmol) ethoxycarbonyl-methoxyimino-(pyrazol-3-yl)-acetic acid are placed in 20 ml DMF together with 5.73 g (41.5 mmol) potassium carbonate at ambient temperature, stirred until the development of gas has ended, then 2.58 ml (41.5 mmol) of methyl iodide are added and the mixture is stirred for 2 h at 50°C. After evaporation of the reaction mixture i. vac. the residue is combined with water and ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether / ethyl acetate = 80:20 -> 65:35). Yield: 2.61 g (26 %) in admixture with regioisomers CnHisNaOs (269.25) Mass spectrum: (M+H)+ = 270 Rf value: 0.25 (silica gel; petroleum ether/ethyl acetate = 1:1) (b) methyl 2-amino-2-(1 -methvl-pyrazol-3-vl)-acetate 2.61 g (9.69 mmol) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3- yl)-acetate are hydrogenated in 60 ml of ethanol with 1.1 g 5% palladium charcoal for 1 6 h at 50°C under 3.4 bars pressure in a hydrogen atmosphere. Then the mixture is suction filtered and the filtrate is evaporated down completely i. vac.. Yield: 1 .90 g (quant), slightly contaminated C7HiiN302 (169.18) Mass spectrum: (M+H)"1" =170 Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1) (c) methyl /V-Boc-2-amino-2-(1 -methvl-pyrazol-3-vl)-acetate Prepared analogously to Example 1d from methyl 2-amino-2-(1-methyl-pyrazol- 3-yl)-acetate and di-tert. butyl pyrocarbonate with TEA in dichloromethane. Yield: 81 % Ci2Hi9N304 (269.30) Mass spectrum: (M+H)* = 270 (d) A/-Boc-2-amino-2-(1 -methvl-pvrazol-3-vl)-acetic acid 1.16 g (4.31 mmol) methyl A/-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in 16 ml THF are combined with 10 ml of water and 10 ml of 1 -molar lithium hydroxide solution are added. After stirring at ambient temperature for 2 h the mixture is evaporated down i. vac., the residue is combined with water, filtered and the filtrate is adjusted to pH 5with potassium hydrogen sulphate solution. After total evaporation i. vac. the residue is treated with dichloromethane and a little ethanol, suction filtered and the filtrate is evaporated down completely i. vac.. Yield: 0.92 g (84 %) Mass spectrum: (M+H)* =256 Rf value: 0.15 (silica gel; dichloromethane/ethanol = 8:2) (e) A/'-(2-amino-4-chloro-phenvl)-2-(Boc-amino)-2-(1-methvl-pvrazol-3-vl)- acetic acid amide and A/-(2-amino-5-chloro-phenvl)-2-(Boc-arnino)-2-(1- methvl-pvrazol-3-vl)-acetic acid amide Prepared analogously to Example 111a from A/-Boc-2-amino-2-(1-methylpyrazol- 3-yl)-acetic acid and 4-chloro-1,2-phenylenediamine with PPA in ethyl acetate and NMM in dichloromethane. Yield: 55 % mixture of the two regioisomers C17H22CIN5O3 (379.84) Rf value: 0.61 (silica gel; dichloromethane/ethanol = 9:1) (f) A/-Boc-1-(5-chloro-1H-benzimidazol-2-vl)-1-(1-methvl-Dvrazol-3-vnmethvlamine Prepared analogously to Example 47b from the product obtained in Example 112eand acetic acid. Yield: 81 % Ci7H2oCIN502(361.83) Mass spectrum: (M+H)+ = 362/364 (chlorine isotope) Rf value: 0.60 (silica gel; dichloromethane/ethanol = 9:1) (g) 1 -(5-chloro-1 /-/-benzimidazol-2-vl)-1 -(1 -methvl-pvrazol-3-vl)-methvlamine Prepared analogously to Example Igfrom A/-Boc-1-(5-chloro-1H-benzimidazol- 2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine and trifluoroacetic acid in dichloromethane. Yield: 77 % C12Hi2CIN5(261.71) Mass spectrum: (M-NH3+H)+ = 245/247 (chlorine isotope) Rf value: 0.30 (silica gel; dichloromethane/ethanol/conc. ammonia solution = 9:1:0.1) (h) A/-ri-(5-chloro-1H-benzimidazol-2-vn-1-(1-methvl-pvrazol-3-vl)-methvn-3- methvl-4-(morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)- methylamine with TBTU and DIPEA in THF. Yield: 38 % .93) Mass spectrum: (M+H)"1" = 479/481 (chlorine isotope) Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1 ) Example 1 1 1 3-chloro-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5- methyl-morpholin-3-on-4-yl)-benzamide (a) ethvl4-f2-(fe/t.-butoxvcarbonvl-methoxv)-1-methvl-ethvlamino1-3-chlorobenzoate 1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetate are added and the mixture is stirred for a further 16 h at ambient temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate = 95:5 -> 80:20) Yield: 230 mg (14%) C18H26CINO5(371.86) Mass spectrum: (M+H)+ = 372/374 (chlorine isotope) Rf value: 0.65 (silica gel; petroleum ether/ethyl acetate = 7:3) (b) ethyl 3-chloro-4-f2-(hvdroxvcarbonvl-methoxv)-1-methvl-ethvlamino1- benzoate Prepared analogously to Example 1g from ethyl 4-[2-(te/f-butoxycarbonylmethoxy)- 1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in dichloromethane. Yield: 87 % Ci4Hi8CINO5(315.75) Mass spectrum: (M+H)+ =316/318 Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1) (c) ethyl 3-chloro-4-(5-methyl-morpholin-3-on-4-vl)-benzoate Prepared analogously to Example 41 c from ethyl 3-chloro-4-[2- (hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate and thionyl chloride with DMF in dichloromethane. Yield: 69 % (contaminated) Ci4H16CIN04 (297.73) Mass spectrum: (M+H)+ = 298/300 (chlorine isotope) Rf value: 0.40 (silica gel; dichloromethane/ethanol = 19:1) (d) 3-chloro-4-(5-methvl-morpholin-3-on-4-vl)-benzoicacid Prepared analogously to Example 31 b from ethyl 3-chloro-4-(5-methylmorpholin- 3-on-4-yl)-benzoate with lithium hydroxide in THF and water. Yield: 91 % Ci2H12CIN04 (269.68) Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1) (e) 3-chloro-A/-r(1/?)-1-(5-chloro-1H-benzimidazol-2-vlV2-methoxv-ethvn-4- (5-methvl-morpholin-3-on-4-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(5-methyl-morpholin-3-on- 4-yl)-benzoic acid and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine with TBTU and TEA in DMF. Yield: 28 % (477.34) Mass spectrum: (M-H)" = 475/477/479 (chlorine isotope) Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1) Example 112 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylaminopyrrolidin- 1 -yl)-benzamide (a) 3-chloro-4-(3-dimethvlamino-pyrrolidin-1-vl)-benzonitrile 0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231 mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with stirring and under an argon atmosphere. After stirring at ambient temperature for 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate after thorough mixing. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.. Yield: 1.11 g (92 %) Ci3H16CIN3 (249.74) Mass spectrum: (M+H)+ = 250/252 (chlorine isotope) Rf value: 0.42 (silica gel; petroleum ether/ethyl acetate = 1:1) (b) 3-chloro-4-(3-dimethvlamino-pyrrolidin-1 -vl)-benzoic acid Prepared analogously to Example 13bfrom 3-chloro-4-(3-dimethylaminopyrrolidin- 1-yl)-benzonitrile with 10-molar sodium hydroxide solution and ethanol. Yield: 27 % Ci3Hi7CIN202 (268.74) Mass spectrum: (M+H)+ = 269/271 (chlorine isotope) (c) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(3- dimethvlamino-pvrrolidin-1-vl)-benzamide Prepared analogously to Example 1f from 3-chloro-4-(3-dimethylaminopyrrolidin- 1-yl)-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)- ethylamine with TBTU and TEA in DMF. Yield: 74 %, slightly contaminated C22H25CI2N5O (446.37) Mass spectrum: (M+H)+ = 446/448/450 (chlorine isotope) Rf value: 0.65 (silica gel; dichloromethane/methanol = 8:2 + 0.5% cone, ammonia solution) Example 113 A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3- trifluoromethyl-benzamide (a) 4-(pvrazolidin-3-on-1-vl)-3-trifluoromethvl-benzonitrile 1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirred together with 1.35 g (12.0 mmol) potassium-ferf.-butoxide in 4 ml DMSO at ambient temperature under an argon atmosphere for 35 min and then 1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at ambient temperature for 68 h the reaction mixture is poured into semisat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down completely i. vac.. Yield: 0.58 g (43 %) CnHsFaNaO (255.20) Mass spectrum: (M+H)"1" = 256 Rf value: 0.15 (silica gel; dichloromethane + 0.5% cone, ammonia solution) (b) 4-(pvrazolidin-3-on-1 -vl)-3-trifluoromethvl-benzoic acid Prepared analogously to Example 13bfrom 3-chloro-4-(3-dimethylaminopyrrolidin- 1-yl)-benzonitrile with 10-molar sodium hydroxide solution and ethanol. Yield: 56 % CnHgFgNzOa (274.20) Rf value: 0.60 (silica gel; dichloromethane/ethanol = 8:2 + 0.5% acetic acid) (c) A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(pvrazolidin-3-on-1 • vh-3-trifluoromethvl-benzamide Prepared analogously to Example 1f from the 4-(pyrazolidin-3-on-1-yl)-3- trifluoromethyl-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)- ethylamine with TBTU and TEA in DMF. Yield: 12 %, contaminated C2oHi7CIF3N502 * 2 CF3COOH (679.88/451.83) Mass spectrum: (M+Hf = 452/454 (chlorine isotope) Rf value: 0.58 (silica gel; dichloromethane/methanol = 8:2 + 0.5% cone. ammonia solution) Example 127 -chloro-imidazo[1 ,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide (a) (1 S)-A/-Boc-1 -(7-chloro-imidazof 1.2alpyridin-2-vl)-3-methvl-butvlamine 1.68 g (6.37 mmol) tert.-butyl [1-(2-chloro-acetyl)-3-methyl-butyl]-carbamate in 15 ml of methanol are combined with 819 mg (6.37 mmol) 2-amino-4-chloropyridine at ambient temperature with stirring and the mixture is refluxed for 3 days. After evaporation i. vac. the residue is combined with 5% sodium hydrogen carbonate solution and stirred for 20 h at ambient temperature. Then it is extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and evaporated down completely i. vac.. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol = 100:0 -> 94:6). Yield:180mg(8%) Ci7H24CIN3O2 (337.85) Mass spectrum: (M+H)+ = 338/340 (chlorine isotope) Rf value: 0.61 (silica gel; dichloromethane/ethanol = 9:1) (b) (1S)-1-(7-chloro-imidazori.2a1pvridin-2-vn-3-methvl-butvlamine Prepared analogously to Example Igfrom (1S)-A/-Boc-1-(7-chloroimidazo[ 1,2a]pyridin-2-yl)-3-methyl-butylamine with trifluoroacetic acid in dichloromethane. Yield: quant. C12H16CIN3 * 2 CF3C02H (465.78 / 237.73) Mass spectrum: (M+H)"1" = 238/240 (chlorine isotope) (c) A/-K1 S)-1 -(5-chloro-imidazon .2alpvridin-2-vl)-3-methvl-butvl1-3-methvl-4- (morpholin-3-on-4-vn-benzamide Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)- benzoic acid and (1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methylbutylamine with TBTU and DIPEA in THF. Yield: quant. Mass spectrum: (M+H)+ = 455/457 (chlorine isotope) Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1) The Examples that follow describe the preparation of some pharmaceutical formulations which contain as-active substance any desired compound of general formula I: Example I Dry ampoule containing 75 mg of active substance per 10 ml Composition: Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation: Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water. Example II Dry ampoule containing 35 mg of active substance per 2 ml NOT FURNISHED UPON FILING Example IV Tablet containing 350 mg of active substance Composition: (1) Active substance 350.0 mg (2) Lactose 136.0mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm. Example V Capsules containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine. Example VI Capsules containing 350 mg of active substance Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation: (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing. This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine. Example VII Suppositories containing 100 mg of active substance 1 suppository contains: Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg Preparation: The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40°C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds. WE CLAIM 1. Substituted carboxylic acid amides of general formula I (Formula Removed) wherein A denotes a group of general formula (Formula Removed) wherein m denotes the number 1 or 2, R8a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alky!)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C1-3-aikylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula wherein (Formula Removed) m denotes the number 1 or 2, X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR8b group, X denotes a methylene, carbonyl or sulphonyl group, X4 denotes an oxygen or sulphur atom or a —NR6b group, Xs denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyI or C1-.-alkylcarbonylamino group and R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, -NH2, C1-3-alkoxy, a mono-, di- or trifluoromethoxy group, R2 denotes a hydrogen or fluorine atom, R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-3-alkyIoxycarbonyl group, a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridtnyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted In the heteroary! moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and R4 denotes a hydrogen atom or a C1-3-alkyI group, R3 and R4 together with the carbon atom to which they are bound, denote a tetrahydrofuran-3,3- diyl group, R5 denotes a hydrogen atom, B denotes a group of formula (Formula Removed) wherein n denotes the number 1 or 2, R7 denotes a hydrogen atom and R8 denotes a fluorine, chlorine, bromine or iodine atom, or a C2-3-alkynyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomners, the diastereomers, the mixtures thereof or the salts thereof. 2. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein A, R1, R2, R4, R5 and B are defined as in claim 1 and R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be whofly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsuIphonyl, carboxy or C1-3-alkyIoxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 3. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein A, R1, R2, R4, R5 are defined as in claim 1 and R3 denotes a phenyl, furanyl, thiophenyl, pyrroiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyi, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 4. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein A denotes a group of general formula (Formula Removed) wherein m denotes the number 1 or 2, R6a independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl group and R6b may be a hydrogen atom or a C1-3-alkyl group, with the proviso that in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula (Formula Removed) wherein m denotes the number 1 or 2, X1 denotes a methylene, -NR66-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group, X3 denotes a methylene, carbonyl or sulphonyl group, X4 an oxygen or sulphur atom or a -NR6b group, X5 denotes a carbonyl or sulphonyl group, R6a independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl group and R6b independently of one another may be a hydrogen atom or a C1-3-alkyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R2 denotes a hydrogen atom, R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and R4 denotes a hydrogen atom, R5 denotes a hydrogen atom and B denotes a group of formula (Formula Removed) wherein n denotes the number 1, R7 denotes a hydrogen atom and R8 denotes a chlorine or bromine atom or the ethynyl group, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 5. Substituted carboxylic acid amides of general formula I as claimed in claim 4, wherein A, R1, R2, R4, R5 and B are defined as in claim 4 and R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 6. Substituted carboxy lie acid amides of general formula I as claimed in claim 4, wherein A,R1,R2,R4,R5and B are defined as in claim 4 and R3 denotes a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imldazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 7. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein A denotes a group of formula (Formula Removed) wherein m denotes the number 1 or 2, R63 independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl group, with the proviso that in the above-mentioned substituted 5- to 7-membered cyclic groups A the fluorine atoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R2 denotes a hydrogen atom, R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, Ci-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyi, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidtnyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and R4 denotes a hydrogen atom, R denotes a hydrogen atom and B denotes a group of formula (Formula Removed) wherein n denotes the number 1, R7 denotes a hydrogen atom and R8 denotes a chlorine or bromine atom or an ethynyl group, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 8. Substituted carboxylic acid amides of general formula I as claimed in claim 7, wherein A, R1, R2, R4, R5 and B are defined as in claim 7 and R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsu!phanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof. 9. Substituted carboxylic acid amides of general formula I as claimed in claim 7, wherein A, R1, R2, R4, R5 and B are defined as in claim 7 and R3 denotes a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazoiyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heleroaryl moiety by one or two C1-3-alkyl groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C1-3-alkyloxy groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, carboxy or C1-3-alkyioxycarbonyl groups, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and or the salts thereof. 10. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 5 or 6, wherein the group X1 denotes a methylene group. 11. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6, wherein the group X1 denotes a carbonyl group. 12. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6, 10 or 11, wherein the group X denotes a methylene group. 13. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6,10 or 11, wherein the group X3 denotes a carbonyl group. 14. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6, or 10 to 13, wherein the group X4 denotes an oxygen atom. 15. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 14, wherein the group B denotes the group (Formula Removed) 16. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 14, wherein the group B denotes the group (Formula Removed) 17. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 14, wherein the group B denotes the group (Formula Removed) 18. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17, wherein the group R8 denotes a chlorine atom. 19. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17, wherein the group R8 denotes a bromine atom. 20. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17, wherein the group R8 denotes an ethynyl group. 21. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 20, which correspond to general formula Ia (Formula Removed) 22. The following compounds of general formula I as claimed in claim 1 (Formula Removed) (1) 4-(azepan-2-on-1 -yl)-N-[{1R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyI]-3-methyl-benzamide, (2) 4-{azepan-2-on-1 -yl)-N-[(1 R)-1-(5-ch!oro-1 H-benzimid azol-2-yl)-2-hydraxy-ethyl]-3-methyl-benzamide, (3) N-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, (4) N-[(1 R)-1-(5-chloro-1H-benzimidazoI-2-yl)-2-methoxy-elhyl]-4-(morpholin-3-on-4-y))-3-trifluoromethyl-benzamide, (5) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide, (6) N-[(1 S)-1 {5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyi-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, (7) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morphoiin-3-on-4-yl)-benzamide, (8) 4-(azepan-2-on-1 -y!)-3-chloro-N-[(1R)-1 -{5-chloro-1 H-benzimidazol-2-yl) 2-methoxy-ethyl]-benzamide, (9) 4-(azepan-2-on-1-yl)-N-[{1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2- methoxy-ethyl]-3-trifluoromethyl-benzamide, (10) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide (11) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl-4-(morphoIin-3-on-4-yl)-3-nitro-benzamide, (12) N-[( 1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,33oxazepan-2-on-3-yl)-benzamlde, (13} 3-chloro-N-[(1R)-1-{5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{[1,4]oxazepan-5-on-4-yl)-benzamide, (14) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl3-4-(piperidin-2-on-1-yl) benzamlde, (15) N-[(1R)-1 -{5-bromo-1 H-benzimidazol-2-y[)-2-hydroxy-ethyl3-3-methyl-4-(moipholin-3-on-4-yl)-benzamide, (16) N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide, (17) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yI)-ethy!]-3-methyl-4-(thtomarpholin-3-on-4-yl)-benzamide, (18) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, (19) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide, (20) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin- 2-on-1-yl)-3-trifluoromethyl-benzamide, (21) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-eihyl]-4-{1, 1 -dioxo-(1,2]thiazinan-2-yl)-3-methyl-benzamide, (22) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyI-4-(morpholin-3-on-4-yl)-benzamide, (23) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1 ,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide, (24) N-[(1 R)-1 -(5-chioro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{1,1-dioxo-[1,2,8}thiadiazinan-2-yl)-3-methyl-benzamide, (25) N-[(1R)-1-(5-bromo-1H-benzimidazo!-2-y!)-2-methoxy-ethyl]-3-methy!-4-(morpholin-3-on-4-yl)-benzamide, (26) N-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyI]-3-methyl-4-(morpholin-3-on-4-y!)-benzamide, (27) N-[(1S)-1 -{5-chlcro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholm-3-on-4-yl)-benzamide, (28) -N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsuIphany!-ethyl]-3- methyl-4-(rnorpholin-3-on-4-yl)-benzamnide, (29) N-[(1 R)-1 -{5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- (thiomorphoIin-3-on-4-yl)-benzamide, (30) 3-chloro-N-\|(1R)-1 -(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, (31) 3-cbloro-N-{(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1 -dioxo-[1,2]thiazinan-2-yl)-benzamide, 32) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide, 33) 3-bromo-N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyI]-4-(piperidin-2-on-1-yl)-benzamide, 34) 3-bromo-N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{piperidin-2-on-1-yl)-benzamide or (35) N-[1-(5-chloro-1H-benzim!dazo!-2-yl)-1-(furan-2-yll)-methy!]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof, 23. Physiologically acceptable salts of the compounds as claimed in claims 1 to 22.

Full Text

86618pct
NOVEL CARBOXAMIDES FOR USE AS XA INHIBITORS
The present invention relates to new substituted carboxylic acid amides of
general formula
(Figure Removed)
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof, particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases, which have valuable properties.
The compounds of the above general formula I as well as the tautomers, the
enantiomers, the diastereomers, the mixtures thereof and the salts thereof,
particularly the physiologically acceptable salts thereof with inorganic or organic
acids or bases, and their stereoisomers have valuable pharmacological
properties, particularly an antithrombotic activity and a factor Xa-inhibiting
activity.
The present application thus relates to the new compounds of the above
general formula I, the preparation thereof, the pharmaceutical compositions
containing the pharmacologically effective compounds, the preparation and use
thereof.
In the above general formula in a first embodiment
A denotes a group of general formula
(Figure Removed)
wherein
m denotes the number 1 or 2,
R63 independently of one another denotes a hydrogen, fluorine, chlorine or
bromine atom or a Ci.3-alkyl, hydroxy, amino, C-s-alkylamino, di-(C3-alkyl)-
amino, aminocarbonyl, d-s-alkylaminocarbonyl, di-(Ci.3-alkyl)-aminocarbonyl or
d-3-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C-alkyl,
C-M-alkylcarbonyl, C-alkyloxycarbonyl or d-3-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered groups A the
heteroatoms optionally introduced as substituents are not separated from
another heteroatom by precisely one carbon atom, or
a group of general formula
(Figure Removed)
wherein
m denotes the number 1 or 2,
X1 denotes an oxygen atom or a methylene, -NR6b-, carbonyl or sulphonyl
group,
X2 denotes an oxygen atom or a -NR6b group,
X3 denotes a methylene, carbonyl or sulphonyl group,
X4 denotes an oxygen or sulphur atom, a -NR6b or carbonyl group,
X5 denotes a carbonyl or sulphonyl group,
X6 denotes an oxygen atom, a -NR6b or methylene group,
X7 denotes an oxygen or sulphur atom or a -NR6b group,
X8 denotes a methylene or carbonyl group,
X9 denotes a -NR6b or carbonyl group,
X10 denotes a sulphinyl or sulphonyl group and
R6a independently of one another denote a hydrogen, fluorine, chlorine or
bromine atom or a C.3-alkyl, hydroxy, amino, C.3-alkylamino, di-(C-3-alkyl)-
amino, aminocarbonyl, C.3-alkylaminocarbonyl, d-(C.3-alkyl)-
aminocarbonyl or C.3-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C-alkyl,
d-4-alkylcarbonyl, C-alkoxycarbonyl or C3-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered groups A the
heteroatoms optionally introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a C3-alkyl group
wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
a C2-3-alkenyl, C2-3-alkynyl, nitro, amino, C3-alkoxy, a mono-, di- or
trifluoromethoxy group,
R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C3-alkyl group,
R3 denotes a hydrogen atom, a C2-3-alkenyl or Ca-s-alkynyl group or a straightchain
or branched Ce-alkyI group wherein the hydrogen atoms may be wholly
or partly replaced by fluorine atoms, and which is optionally substituted by a
nitrile, hydroxy, a Cs-alkyloxy group wherein the hydrogen atoms may be
wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy,
benzyloxy, Cs-alkylcarbonyloxy, Cs-alkyloxycarbonyloxy, carboxy-d.3-alkyloxy,
C5-alkyloxycarbonyl-C3-alkyloxy, Ci-e-alkyloxycarbonylamino, mercapto,
C3-alkylsulphanyl, Ci.3-alkylsulphinyl, Ci.3-alkylsulphonyl,
C3-alkylcarbonylamino-Ci-3-alkylsulphanyl, Ci.3-alkylcarbonylamino-
C-alkylsulphinyl, C3-alkylcarbonylamino-C3-alkylsulphonyl, carboxy,
Ci-s-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,
benzyloxycarbonyl, aminocarbonyl, Cs-alkylaminocarbonyl, di-alkyl)-
aminocarbonyl, Cs-e-cycloalkyleneiminocarbonyl, aminosulphonyl,
C3-alkylaminosulphonyl, di-(C3-alkyl)-aminosulphonyl, Cs-ecycloalkyleneiminosulphonyl,
amino, C-s-alkylamino, di-(C-3-alkyl)-amino,
C-5-alkylcarbonylamino, C-3-alkylsulphonylamino, A/-(C-3-alkylsulphonyl)-
C-3-alkylamino, C3.6-cycloalkylcarbonylamino, aminocarbonylamino,
C-3-alkylaminocarbonylamino, di-(C-3-alkyl)-aminocarbonylamino, a 4- to 7-
membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,
phenylcarbonylamino or guanidino group,
a carboxy, aminocarbonyl, C-M-alkylaminocarbonyl, C3.6-cycloalkylaminocarbonyl,
di-(C1.3-alkyl)-aminocarbonyl, C-M-alkoxycarbonyl, C4,6-
cycloalkyleneiminocarbonyl group,
a phenyl or heteroaryl, phenylcarbonyl-C-i-3-alkyl, phenyl-Ci-3-alkyl or heteroaryl-
C-3-alkyl group which is optionally mono- or polysubstituted in the phenyl or
heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino,
C-3-alkylamino, di-(C-3-alkyl)-amino, hydroxy, C-alkyloxy, mono-, di- or
trifluoromethoxy, benzyloxy, carboxy-C3-alkyloxy, C3-alkyloxycarbonyl-
C3-alkyloxy, aminocarbonyl-C3-alkyloxy, C3-alkylaminocarbonyl-
C-3-alkyloxy, di-(C3-alkyl)-aminocarbonyl-C3-alkyloxy, a 4- to 7-membered
cycloalkyleneiminocarbonyl-C3-alkoxy, carboxy, Cs-alkyloxycarbonyl or
C3-alkyloxycarbonylamino group,
a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-Cs-alkyI or
cycloalkyleneimino-C3-alkyl group wherein in the cyclic moiety a methylene
group may be replaced by an -NH- group optionally substituted by a C-alkyl or
C3-alkylcarbonyl group or by an oxygen atom and wherein additionally a
methylene group adjacent to the -NH-, -N(C3-alkylcarbonyl)- or -N(C3-alkyl)-
group may be replaced in each case by a carbonyl or sulphonyl group, with the
proviso that a cycloalkyleneimino group as hereinbefore defined wherein two
nitrogen atoms are separated from one another by precisely one -CHa- group is
excluded,
R4 denotes a hydrogen atom or a Cs-alkyI group or
R3 and R4 together with the carbon atom to which they are bound, denote a
C3-7-cycloalkyl group, while
one of the methylene groups of the C3.7-cycloalkyl group may be replaced
by an imino, C-s-alkylimino, acylimino or sulphonylimino group,
R5 denotes a hydrogen atom or a C3-alkyl group,
B denotes a group of formula
(Figure Removed)
wherein
n denotes the number 1 or 2,
R7 denotes a hydrogen atom or a C3-alkyl, hydroxy, C5-alkyloxycarbonyl,
carboxy-C3-alkyl, C3-alkyloxycarbonyl-Ci.3-alkyl, amino or C3-alkylamino
group and
R8 independently of one another denote a hydrogen, fluorine, chlorine,
bromine or iodine atom, a Cs-alkyI group wherein the hydrogen atoms may
be wholly or partly replaced by fluorine atoms, a Ca-s-alkenyl or C2.3-alkynyl,
a hydroxy, C-3-alkoxy, trifluoromethoxy, amino, nitro or nitrile group,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C-i-s-alkyl, phenyl or phenyl-Ci-s-alkyl group, an oxygen or
sulphur atom or
an imino group optionally substituted by a Ci.3-alkyl, phenyl, amino-
C2-3-alkyl, C3-alkylamino-C2-3-alkyl, di-(C3-alkyl)-amino-C2-3-alkyl, a 4- to
7-membered cycloalkyleneimino-C^s-alkyl or phenyl-C3-alkyl group or an
oxygen or sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a Ci-3-alkyl or phenyl-Ci.3-alkyl
group and two or three nitrogen atoms,
and moreover a phenyl ring optionally substituted by a fluorine, chlorine or
bromine atom, a C3-alkyl, hydroxy, C3-alkyloxy group, amino, C3-alkylamino,
di-(C3-alkyl)-amino or Cs-e-cycloalkyleneimino group may be fused to the
above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms
and the bond is effected via a nitrogen atom or a carbon atom of the
heterocyclic moiety or a fused-on phenyl ring,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
Examples of monocyclic heteroaryl groups are the pyridyl, A/-oxy-pyridyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl, [1,3,5]triazinyl,
[1,2,4]triazinyl, pyrrolyl, imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl,
furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, furazanyl,
thiophenyl, thiazolyl, isothiazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or
[1,2,5]thiadiazolyl group.
Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl,
benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]-
isothiazolyl, benzo[of]isothiazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[djisoxazolyl,
benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thiadiazolyl,
benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl,
quinolinyl, A/-oxy-quinolinyl, isoquinolinyl, quinazolinyl, A/-oxy-quinazolinyl,
quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.
Examples of the Ci-8-alkyl groups mentioned hereinbefore in the definitions are
the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, te/f-butyl, 1-pentyl,
2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl,
3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl group.
Examples of the Ci-8-alkyloxy groups mentioned hereinbefore in the definitions
are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy,
terf-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, neo-pentyloxy, 1-hexyloxy,
2-hexyloxy, 3-hexyloxy, 1-heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy,
1-octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy group.
By a group which can be converted in vivo into a carboxy group is meant for
example a carboxy group esterified with an alcohol wherein the alcohol moiety
is preferably a C1.6-alkanol, a phenyl-Ci-3-alkanol, a C3.9-cycloalkanol, a CS.Tcycloalkenol,
a C3.5-alkenol, a phenyl-C3.5-alkenol, a C3_5-alkynol or phenyl-
C3-5-alkynol with the proviso that no bond to the oxygen atom starts from a
carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-Ci-3-alkanol
or an alcohol of formula
R9-CO-0-(R10CR11)-OH,
wherein
R9 denotes a C1.8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-Ci-3-alkyl group,
R10 denotes a hydrogen atom, a C-i-3-alkyl, C5-7-cycloalkyl or phenyl group
and
R11 denotes a hydrogen atom or a C-i-3-alkyl group.
Preferred groups which may be cleaved from a carboxy group in vivo include a
Ci-6-alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy,
n-butyloxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or a phenyl-
Ci-3-alkoxy group such as the benzyloxy group.
Those compounds of general formula I wherein R3 contains a group which may
be converted in vivo into a carboxy group are prodrugs for those compounds of
general formula I wherein R3 contains a carboxy group.
A 2nd embodiment of the present invention comprises those compounds of
general formula I wherein
A denotes a group of general formula
(Figure Removed)
wherein m denotes the number 1 or 2,
R>6 aa independently of one another denote a hydrogen or fluorine atom, a
C3-alkyl, hydroxy, amino, Cs-alkylamino, di-(C-3-alkyl)-amino, aminocarbonyl,
C3-alkylaminocarbonyl, di-(C3-alkyl)-aminocarbonyl or
C3-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C-M-alkyl,
C4-alkylcarbonyl, C4-alkoxycarbonyl or Cs-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered groups A the
heteroatoms optionally introduced as substituents are not separated from
another heteroatom by precisely one carbon atom, or
a group of general formula
(Figure Removed)
wherein
m denotes the number 1 or 2,
X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group,
X2 denotes an oxygen atom or a -NR6b group,
X3 denotes a methylene, carbonyl or sulphonyl group,
X4 denotes an oxygen or sulphur atom, a -NR6b or carbonyl group,
X5 denotes a carbonyl or sulphonyl group,
X8 denotes a carbonyl group,
X9 denotes a carbonyl group,
R6a independently of one another denote a hydrogen or fluorine atom, a
Ci-3-alkyl, hydroxy, amino, C3-alkylamino, di-(C3-alkyl)-amino,
aminocarbonyl, C3-alkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl or
C3-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C4-alkyl,
C4-alkylcarbonyl, C-M-alkoxycarbonyl or C3-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A
the heteroatoms introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a d.3-alkyl group
wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
a C2-3-alkenyl, Ca-s-alkynyl, nitro, amino, C3-alkoxy, a mono-, di- or
trifluoromethoxy group,
R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C3-alkyl group,
R3 denotes a C2.3-alkenyl or C2-3-alkynyl group or a straight-chain or branched
C6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced
by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a
Cs-alkyloxy group wherein the hydrogen atoms may be wholly or partly
replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C5-alkylcarbonyloxy,
Cs-alkyloxycarbonyloxy, carboxy-C.3-alkyloxy, C5-alkyloxycarbonyl-
C3-alkyloxy, Cs-alkyloxycarbonylamino, mercapto,
C3-alkylsulphanyl, Ci-s-alkylsulphinyl, C-3-alkylsulphonyl,
C- a-alkylcarbonylamino-Ci-s-alkylsulphanyl, Ci-3-alkylcarbonylamino-
C3-alkylsulphinyl, C-alkylcarbonylamino-C-s-alkylsulphonyl, carboxy,
C3-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,
benzyloxycarbonyl, aminocarbonyl, C3-alkylaminocarbonyl, d-(C3-alkyl)-
aminocarbonyl, Cs-e-cycloalkyleneiminocarbonyl, aminosulphonyl,
C3-alkylaminosulphonyl, di-(C3-alkyl)-aminosulphonyl, C3.6-
cycloalkyleneiminosulphonyl, amino, Ci-s-alkylamino, di-(C3-alkyl)-amino,
C5-alkylcarbonylamino, Cs-alkylsulphonylamino, /V-(C3-alkylsulphonyl)-
C3-alkylamino, C3-6-cycloalkylcarbonylamino, aminocarbonylamino,
C3-alkylaminocarbonylamino, di-(C3-alkyl)-aminocarbonylamino, a 4- to 7-
membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino,
phenylcarbonylamino or guanidino group,
a carboxy, aminocarbonyl, C4-alkylaminocarbonyl, C3.6-cycloalkylaminocarbonyl,
di-(C3-alkyl)-aminocarbonyl, C-M-alkoxycarbonyl, Cecycloalkyleneiminocarbonyl
group,
a phenyl or heteroaryl, phenylcarbonyl-C3-alkyl, phenyl-C3-alkyl or heteroaryl-
Cs-alkyl group which is optionally mono- or polysubstituted in the phenyl or
heteroaryl moiety by fluorine, chlorine or bromine atoms, Ci-3-alkyl, amino,
C-s-alkylamino, di-(C3-alkyl)-amino, hydroxy, C4-alkyloxy, mono-, d- or
trifluoromethoxy, benzyloxy, carboxy-Ci-3-alkyloxy, Ci.3-alkyloxycarbonyl-
C3-alkyloxy, aminocarbonyl-C.3-alkyloxy, C.3-alkylaminocarbonyl-
Cs-alkyloxy, d-(C3-alkyl)-aminocarbonyl-C3-alkyloxy, a 4- to 7-membered
cycloalkyleneiminocarbonyl-C3-alkoxy, carboxy, C3-alkyloxycarbonyl or
C3-alkyloxycarbonylamino group,
a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C3-alkyl or
cycloalkyleneimino-C3-alkyl group wherein in the cyclic moiety a methylene
group may be replaced by a -NH- group optionally substituted by a C3-alkyl or
C3-alkylcarbonyl group or by an oxygen atom and wherein additionally a
methylene group adjacent to the -NH-, -N(C3-alkylcarbonyl)- or -N(C3-alkyl)-
group may be replaced in each case by a carbonyl or sulphonyl group, with the
proviso that a cycloalkyleneimino group as hereinbefore defined wherein two
nitrogen atoms are separated from one another by precisely one -CH2- group is
excluded,
R4 denotes a hydrogen atom or a C3-alkyl group,
R5 denotes a hydrogen atom or a C3-alkyl group,
B denotes a group of formula
(Figure Removed)
wherein
n denotes the number 1 or 2,
R7 denotes a hydrogen atom, a C3-alkyl, hydroxy, C5-alkyloxycarbonyl,
carboxy-C3-alkyl, Ci.3-alkyloxycarbonyl-C1.3-alkyl, amino or C3-alkylamino
group and
R8 independently of one another denote a hydrogen, fluorine, chlorine,
bromine or iodine atom, a C3-alkyl group wherein the hydrogen atoms may
be wholly or partly replaced by fluorine atoms, a C2.3-alkenyl or C2.3-alkynyl,
a hydroxy, C3-alkoxy, trifluoromethoxy, amino, nitro or nitrile group,
hile, unless otherwise stated, by the term "heteroaryl group" mentioned
ereinbefore in the definitions is meant a monocyclic 5- or 6-membered
Bteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a Ci-3-alkyl, phenyl or phenyl-C3-alkyl group, an oxygen or
sulphur atom or
an imino group optionally substituted by a C3-alkyl, phenyl, amino-
C2-3-alkyl, C3-alkylamino-C2.3-alkyl, di-(C3-alkyl)-amino-C2-3-alkyl, a 4- to
7-membered cycloalkyleneimino-Ci.3-alkyl or phenyl-C3-alkyl group or an
oxygen or sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C3-alkyl or phenyl-Ci-3-alkyl
group and two or three nitrogen atoms,
and moreover a phenyl ring optionally substituted by a fluorine, chlorine or
bromine atom, a C3-alkyl, hydroxy, Cs-alkyloxy group, amino,
C3-alkylamino, di-(C3-alkyl)-amino or C3-6-cycloalkyleneimino group may
be fused to the above-mentioned monocyclic heteroaryl groups via two
adjacent carbon atoms
and the bond is effected via a nitrogen atom or a carbon atom of the
heterocyclic moiety or a fused-on phenyl ring,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 3rd embodiment of the present invention comprises those compounds of
general formula I, wherein
A denotes a group of general formula
(Figure Removed)
wherein m denotes the number 1 or 2,
R6a independently of one another denote a hydrogen or fluorine atom, a
C-3-alkyl, hydroxy, amino, C-s-alkylamino, di-(C-3-alkyl)-amino, aminocarbonyl,
C3-alkylaminocarbonyl, di-(C-3-alkyl)-aminocarbonyl or
Ca-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a
C4-alkylcarbonyl, Calkoxycarbonyl or C3-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered groups A the
heteroatoms optionally introduced as substituents are not separated from
another heteroatom by precisely one carbon atom, or
a group of general formula
(Figure Removed)
vherein
m denotes the number 1 or 2,
X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group,
6b X2 denotes an oxygen atom or a -NR group,
X3 denotes a methylene, carbonyl or sulphonyl group,
X4 denotes an oxygen or sulphur atom or a -NR6b group,
X5 denotes a carbonyl or sulphonyl group,
R6a independently of one another denote a hydrogen or fluorine atom, a
C3-alkyl, hydroxy, amino, C3-alkylamino, di-(C.3-alkyl)-amino,
aminocarbonyl, Ci.3-alkylaminocarbonyl, di-(Ci.3-alkyl)-aminocarbonyl or
C3-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C4-alkyl,
C4-alkylcarbonyl, C-alkoxycarbonyl or C3-alkylsulphonyl group, with the
proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A
the heteroatoms introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a fluorine, chlorine or bromine atom, a C3-alkyl group wherein the
hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro,
Ci-3-alkoxy, a mono-, di- or trifluoromethoxy group,
R2 denotes a hydrogen atom,
R3 denotes a straight-chain or branched Ci.6-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a nitrite, hydroxy, benzyloxy, a Ci-5-alkyloxy group
wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
an allyloxy, Cvs-alkylcarbonyloxy, C-5-alkyloxycarbonyloxy, carboxy-
C-3-alkyloxy, Ci.5-alkyloxycarbonyl-C.3-alkyloxy, C8-alkyloxycarbonylamino,
d-3-alkylsulphanyl, C1.3-alkylsulphonyl, carboxy, C-3-alkyloxycarbonyl,
C3-alkylaminocarbonyl, di-(C1.3-alkyl)-aminocarbonyl, C3.6-
cycloalkyleneiminocarbonyl, aminocarbonylamino,
C-3-alkylaminocarbonylamino or di-(C-3-alkyl)-aminocarbonylamino group,
an aminocarbonyl, C-4-alkylaminocarbonyl, C3-cycloalkylaminocarbonyl or d-
(C-3-alkyl)-aminocarbonyl group,
a phenyl or heteroaryl, phenyl-Ci-3-alkyl or heteroaryl-C.3-alkyl group which is
optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by
fluorine, chlorine or bromine atoms, Ci.3-alkyl, amino, Ci-s-alkylamino,
di-(C-3-alkyl)-amino, hydroxy, C-4-alkyloxy, mono-, d- or trifluoromethoxy,
carboxy, or C.3-alkyloxycarbonyl group,
a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene
group may be replaced by a -NH- group optionally substituted by a C-i-3-alkyl or
C_3-alkylcarbonyl group, or an oxygen atom,
R4 denotes a hydrogen atom,
R5 denotes a hydrogen atom,
B denotes a group of formula
(Figure Removed)
wherein
n denotes the number 1,
R7 denotes a hydrogen atom and
R8 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl,
C2-3-alkynyl, or methoxy group, wherein the hydrogen atoms may be wholly
or partly replaced by fluorine atoms,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C1.3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C-3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C-3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 4th embodiment of the present invention comprises those compounds of
general formula I wherein
A, R1, R2, R4, R5 and B are defined as described under the 3rd embodiment and
R3 denotes a straight-chain or branched Ci_e-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a nitrile, hydroxy, benzyloxy, a Ci-5-alkyloxy group
wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
an allyloxy, C-s-alkylcarbonyloxy, C-s-alkyloxycarbonyloxy, carboxy-
C-3-alkyloxy, C-s-alkyloxycarbonyl-C^a-alkyloxy, C-s-alkyloxycarbonylamino,
C-3-alkylsulphanyl, C.3-alkylsulphonyl, carboxy, Cs-alkyloxycarbonyl,
C-3-alkylaminocarbonyl, d-(C-3-alkyl)-aminocarbonyl, C3-ecycloalkyleneiminocarbonyl,
aminocarbonylamino, Ci.s-alkylaminocarbonylamino
or di-(C-3-alkyl)-aminocarbonylamino group,
an aminocarbonyl, C4-alkylaminocarbonyl, C3-6-cycloalkylaminocarbonyl or di-
(C3-alkyl)-aminocarbonyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 5th embodiment of the present invention comprises those compounds of
general formula I wherein
A, R1, R2, R4, R5 and B are defined as described under the 3rd embodiment and
R3 denotes a phenyl or heteroaryl, phenyl-C3-alkyl or heteroaryl-C3-alkyl
group which is optionally mono- or polysubstituted in the phenyl or heteroaryl
moiety by fluorine, chlorine or bromine atoms, C.3-alkyl, amino, C3-alkylamino,
di-(C-3-alkyl)-amino, hydroxy, C-4-alkyloxy, mono-, di- or trifluoromethoxy,
carboxy, or Ci.3-alkyloxycarbonyl group,
a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene
group may be replaced by a -NH- group optionally substituted by a C3-alkyl or
d-3-alkylcarbonyl group, or by an oxygen atom,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C.3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C.3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl groups contained in the foregoing definitions which have more
than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups,
for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 6th embodiment of the present invention comprises those compounds of
general formula I, wherein
A denotes a group of general formula
or
wherein m denotes the number 1 or 2,
R6a independently of one another denote a hydrogen or fluorine atom or a
C-3-alkyl group and
R6b may be a hydrogen atom or a C.3-alkyl group, with the proviso that
in the above-mentioned substituted 5- to 7-membered groups A the
heteroatoms optionally introduced as substituents are not separated from
another heteroatom by precisely one carbon atom, or
a group of general formula
(Figure Removed)
wherein
m denotes the number 1 or 2,
X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group,
X2 denotes an oxygen atom or a -NR6b group,
X3 denotes a methylene, carbonyl or sulphonyl group,
X4 an oxygen or sulphur atom or a -NR6b group,
X5 denotes a carbonyl or sulphonyl group,
R6a independently of one another denote a hydrogen or fluorine atom or a
d-3-alkyl group and
R6b independently of one another may be a hydrogen atom or a C-alky!
group, with the proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A
the heteroatoms introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the
hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro
group,
R2 denotes a hydrogen atom,
R3 denotes a straight-chain or branched C-4-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a hydroxy, a C-4-alkyloxy group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, a C.3-alkylsulphanyl,
d-3-alkylsulphonyl, carboxy or C-3-alkyloxycarbonyl group,
a phenyl or heteroaryl, phenyl-C.3-alkyl or heteroaryl-C.3-alkyl group which is
optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by
fluorine, chlorine or bromine atoms, C.3-alkyl, C-4-alkyloxy, mono-, d- or
trifluoromethoxy, carboxy, or C.3-alkyloxycarbonyl group,
R4 denotes a hydrogen atom,
R5 denotes a hydrogen atom and
B denotes a group of formula
(Figure Removed)
wherein
n denotes the number 1,
R7 denotes a hydrogen atom and
R8 denotes a chlorine or bromine atom or the ethynyl group,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C-3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C-3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl groups contained in the foregoing definitions which have more
than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups,
for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 7th embodiment of the present invention comprises those compounds of
general formula I, wherein
A, R1, R2, R4, R5 and B are defined as described under the 6th embodiment and
R3 denotes a straight-chain or branched C-M-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a hydroxy, a C4-alkyloxy group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, a C3-alkylsulphanyl,
d-3-alkylsulphonyl, carboxy or C3-alkyloxycarbonyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
An 8th embodiment of the present invention comprises those compounds of
general formula I, wherein
A, R1, R2, R4, R5 and B are defined as described under the 6th embodiment and
R3 denotes a phenyl or heteroaryl, phenyl-Ci.3-alkyl or heteroaryl-C3-alkyl
group which is optionally mono- or polysubstituted in the phenyl or heteroaryl
moiety by fluorine, chlorine or bromine atoms, d-3-alkyl, d-4-alkyloxy, mono-,
di- or trifluoromethoxy, carboxy, or C3-alkyloxycarbonyl group,
a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene
group may be replaced by a -NH- group optionally substituted by a Ci_3-alkyl or
C3-alkylcarbonyl group, or by an oxygen atom,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a Ci.3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl groups contained in the foregoing definitions which have more
than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups,
for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 9th embodiment of the present invention comprises those compounds of
general formula I, wherein
A denotes a group of formula
(Figure Removed)
wherein
m denotes the number 1 or 2,
R6a independently of one another denote a hydrogen or fluorine atom or a
C3-alkyl group, with the proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A
the fluorine atoms introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the
hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro
group,
R2 denotes a hydrogen atom,
R3 denotes a straight-chain or branched Ci-4-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a hydroxy, a Ci-4-alkyloxy group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, a Ci-3-alkylsulphanyl,
C3-alkylsulphonyl, carboxy or Ci-3-alkyloxycarbonyl group,
a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C2-alkyl or imidazolyl-C2-
alkyl group which may optionally be substituted in the heteroaryl moiety by one
or two C-s-alkyl groups, C3-alkyloxy groups, carboxy or C3-alkyloxycarbonyl
groups, and
R4 denotes a hydrogen atom,
R5 denotes a hydrogen atom and
B denotes a group of formula
(Figure Removed)
wherein
n denotes the number 1,
R7 denotes a hydrogen atom and
R8 denotes a chlorine or bromine atom or an ethynyl group,
while, unless otherwise stated, by the term "heteroaryl group" mentioned
hereinbefore in the definitions is meant a monocyclic 5- or 6-membered
heteroaryl group, while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a C-3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C-3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C-3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl groups contained in the foregoing definitions which have more
than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups,
for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 10th embodiment of the present invention comprises those compounds of
general formula I, wherein
A, R1, R2, R4, R5 and B are defined as described under the 9th embodiment and
R3 denotes a straight-chain or branched Ci-4-alkyl group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, and which is
optionally substituted by a hydroxy, a C-alkyloxy group wherein the hydrogen
atoms may be wholly or partly replaced by fluorine atoms, a Cs-alkylsulphanyl,
C-3-alkylsulphonyl, carboxy or C-3-alkyloxycarbonyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions
which have more than two carbon atoms may, unless otherwise stated, be
straight-chain or branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
An 11th embodiment of the present invention comprises those compounds of
general formula I wherein
A, R1, R2, R4, R5 and B are defined as described under the 9th embodiment and
denote a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-Ci-2-alkyl or imidazolyl-Ci-2-
alkyl group which may optionally be substituted in the heteroaryl moiety by one
or two Cs-alkyI groups, wherein the hydrogen atoms may be wholly or partly
replaced by fluorine atoms, C.3-alkyloxy groups, wherein the hydrogen atoms
may be wholly or partly replaced by fluorine atoms, carboxy or C-3-
alkyloxycarbonyl groups, and
unless otherwise stated, by the term "heteroaryl group" mentioned hereinbefore
in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group,
while
the 6-membered heteroaryl group contains one, two or three nitrogen atoms
and
the 5-membered heteroaryl group contains an imino group optionally
substituted by a Ci-3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a Ci.3-alkyl group or an oxygen or
sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C3-alkyl group and two or three
nitrogen atoms,
and the bond is effected via a nitrogen atom or via a carbon atom,
while the alkyl groups contained in the foregoing definitions which have more
than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups,
for example the dialkylamino groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the
foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof.
A 12th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1,2,3, 4, 5, 6, 7 and 8,
wherein the group X1 denotes a methylene group.
A 13th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1,2,3, 4, 5, 6, 7 and 8,
wherein the group X1 denotes a carbonyl group.
A 14th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12 and
13, wherein the group X3 denotes a methylene group.
A 15th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12 and
13 wherein the group X3 denotes a carbonyl group.
A 16th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8,12, 13,
14 and 15, wherein the group X4 denotes an oxygen atom.
A 17th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14, 15 and 16, wherein the group B denotes the group
An 18th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14,15 and 16, wherein the group B denotes the group
A 19th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14,15 and 16, wherein the group B denotes the group
A 20th embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12,13,14,15, 16, 17,18 and 19, wherein the group R8 denotes a chlorine
atom.
A 21st embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14,15,16,17,18 and 19, wherein the group R8 denotes a bromine
atom.
A 22nd embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14, 15, 16,17,18 and 19, wherein the group R8 denotes an ethynyl
group.
A 23rd embodiment of the present invention comprises those compounds of
general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,10,
11,12,13,14, 15, 16,17,18,19, 20, 21 and 22, which correspond to general
formula la
(Figure Removed)
The following preferred compounds of general formula I will now be mentioned
by way of example:
(1) 3-chloro-/V-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-
([1,4]diazepan-1-yl)-benzamide,
(2) 4-(4-/V-Boc-piperazin-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-
ethyl]-3-trifluoromethyl-benzamide,
(3) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-
trifluoromethyl-benzamide,
(4) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin-
1-yl)-3-trifluoromethyl-benzamide,
(5) 4-(4-/V-acetyl-piperazin-1 -yl)-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-
ethyl]-3-trifIuoromethyl-benzamide,
(6) 4-(azepan-2-on-1 -yl)-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-
methyl-benzamide,
(7) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethyl]-3-methyl-benzamide,
(8) 4-(azepan-2-on-1 -yl)-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
hydroxy-ethyl]-3-methyl-benzamide,
(9) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1 -yl)-
benzamide,
(1 0) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-
on-1 -yl)-benzamide,
(1 1 ) A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-
methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,
(1 2) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-A/-methyl-
[1 ,4]diazepan-1 -yl)-benzamide,
(1 3) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(2-methylpyrrolidin-
1 -yl)-benzamide,
(14) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-1 •
yl)-benzamide,
(1 5) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4-
(morpholin-1 -yl)-benzamide,
(16) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-
trifluoromethyl-4-(morpholin-1 -yl)-benzamide,
(1 7) 4-(azepan-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-
trifluoromethyl-benzamide,
(18) 4-(azepan-1 -yl)-3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-
ethyl]-benzamide,
(19) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1
yl)-benzamide,
(20) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-
([1 ,4]oxazepan-4-yl)-benzamide,
(21 ) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide,
(22) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(23) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-
methyI-4-(morpholin-3-on-4-yl)-benzamide,
-39-
(24) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(25) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-
2-methoxy-ethyl]-benzamide,
(26) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethylJ-3-trifluoromethyl-benzamide,
(27) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-
benzamide,
(28) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-
3-on-4-yl)-benzamide,
(29) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-
benzamide,
(30) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1
yl)-benzamide,
(31 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-
on-1 -yl)-benzamide,
(32) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-
on-1 -yl)-benzamide,
(33) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(A/-methyl-piperazin-1
yl)-3-trifIuoromethyl-benzamide,
(34) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(35) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(pyrrolidin-2-on-1-yl)-benzamide,
(36) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-4-(pyrrolidin-2-on-
1-yl)-benzamide,
(37) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-
1-yl)-benzamide,
(38) 3-chlora-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,4-
didehydro-piperidin-1-yl)-benzamide,
(39) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide
(40) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-
(piperazin-1 -yl)-3-trifIuoromethyl-benzamide,
(41 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(morpholin-3-on-4-yl)-3-nitro-benzamide,
(42) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(tetrahydropyrimidin-
2-on-1 -yl)-benzamide,
(43) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide,
(44) 3-chloro-A/-[(1 R)-1-(5-chloro-1 A/-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
([1,4]oxazepan-5-on-4-yl)-benzamide,
-41 -
(45) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
([1,4]oxazepan-3-on-4-yl)-benzamide,
(46) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(piperidin-2-on-1-yl)-benzamide,
(47) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(48) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 , 1 -dioxoisothiazolidin-
2-yl)-3-methyl-benzamide,
(49) /V-[1 -(5-chloro-1 H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-
benzamide,
(50) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methylpiperazin-
1-yl-methyl)-piperidin-1-yl)-benzamide,
(51 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin-
2-on-3-yl)-benzamide,
(52) 3-chloro-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-
on-4-yl)-benzamide,
(53) A/-[(1 R,2S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(54) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-
1 -yl)-benzamide,
(55) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-
(thiomorpholin-3-on-4-yl)-benzamide,
(56) A/-[(1 fl)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperidin-2-on-1 -yl)-benzamide,
(57) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1 ,3]-
oxazinan-2-on-3-yl)-benzamide,
(58) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,3]-oxazinan-2-on-3-yl)-benzamide,
(59) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-
2-on-1-yl)-3-trifluoromethyl-benzamide,
(60) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo-
[1,2]thiazinan-2-yl)-3-methyl-benzamide,
(61 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-
didehydro-azepan-2-on-1-yl)-benzamide,
(62) 4-(azepan-2-on-1 -yl)-A/-[(1 S)-1 -(5-chloro-6-fluoro-1 H-benzimidazol-2-yl)-
ethyl]-3-methyl-benzamide,
(63) W-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 ,3-dioxothiomorpholin-
4-yl)-3-methyl-benzamide,
(64) W-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1 , 1 ,3-trioxothiomorpholin-
4-yl)-benzamide,
(65) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperazin-1 -yl)-benzamide,
(66) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperazin-2-on-1-yl)-benzamide,
(67) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-
3-on-4-yl)-benzamide,
(68) /V-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
([1,3]oxazepan-2-on-3-yl)-3-trifIuoromethyl-benzamide,
(69) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-
2-on-1 -yl)-benzamide,
(70) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4-
(piperidin-2-on-1 -yl)-benzamide,
(71) A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1l1-dioxo-
[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,
(72) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 , 1 -dioxo-
[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,
(73) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1 ,1 -dioxo-6-methyl-
[1 ejthiadiazinan^-yO-S-methyl-benzamide,
(74) /V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo-
S-methyl-fl^.ejthiadiazinan^-yO-S-methyl-benzamide,
(75) /V-[(1 /?)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(76) /V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(77) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(78) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(79) A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(80) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(thiomorpholin-3-on-4-yl)-benzamide,
(81 ) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(82) 3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-
[1 ,2]oxazin-2-yl)-benzamide,
(83) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(1 ,1-dioxo-[1 ,2]thiazinan-2-yl)-benzamide,
(84) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo-
[1,2]thiazepan-2-yl)-3-methyl-benzamide,
(85) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1 -yl)-
trifluoromethoxy-benzamide,
(86) 3-bromo-A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-
on-1 -yl)-benzamide,
(87) 3-bromo-/V-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(piperidin-2-on-1-yl)-benzamide,
(88) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(furan-2-yl)-methyl]-3-methyl-4-
(piperidin-2-on-1-yl)-benzamide,
(89) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-
([1,2]oxazinan-2-yl)-benzamide,
(90) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(5-oxo-[1,4]oxazepan-4-yl)-benzamide,
(91 ) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxoimidazolidin-
1-yl)-3-methyl-benzamide,
(92) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-
dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide,
(93) 3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-
oxo-oxazolidin-3-yl)-benzamide,
(94) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide,
(95) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(96) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-
3-on-4-yl)-benzamide,
(97) 3-bromo-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(98) A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo-
[1 ,4]diazepan-1-yl)-benzamide,
(99) A/-[(1 ft)-1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(thiophen-2-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(1 00) /V-[(1 A?)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1 , 1 -dioxo-
[1,2]thiazinan-2-yl)-3-methyl-benzamide,
(101) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide,
(1 02) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide>
(1 03) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide,
(1 04) A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(4-(4f?)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,
(1 05) 3-chloro-A/-[(1 fi)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4-(4f?)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide,
(1 06) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-
(morpholin-3-on-4-yl)-benzamide,
(107) A/-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(108) A/-[1-(1SH5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(109) A/-[1 -(5-chloro-1 /V-benzimidazol-2-yl)-1 -pyridin-3-yl-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(110) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1H-1 -methyl-pyrazol-3-yl)-
methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,
(111) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(5-methyl-morpholin-3-on-4-yl)-benzamide,
(112) 3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3-
dimethylamino-pyrrolidin-1-yl)-benzannide,
(113) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-
3-trifluoromethyl-benzamide,
(114) 3-chloro-A/-[(1R)-1-(5-chIoro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(tetrahydro-pyrimidin-2-on-1-yl)-benzamide,
(115) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-
([1,4]diazepan-1-yl)-benzamide,
(116) 3-chloro-A/-[1 -(5-chloro-1 H-indoi-2-yl)-2-methoxy-ethyl]-4-([1,4]diazepan-
1 -yl)-benzamide,
(117) A/-[1 -(5-chloro-1 H-indol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-
on-4-yl)-benzamide,
(118) 3-bromo-/V-[1 -(5-chloro-1 H-indol-2-yl)-1 -(furan-2-yl)-methyl]-4-
([1,4]oxazepan-5-on-4-yl)-benzamide,
(119) A/-[1 -(5-bromo-1 H-indoI-2-yl)-1 -(1 -methyl-1 H-pyrazol-3-yl)-methyl]-3-
methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide,
(120) /V-[1 -(5-chloro-1 H-indol-2-yl)-3-(methyl-sulphonyl)-propyl]-3-methyl-4-
(tetrahydropyrimidin-2-on-1-yl)-benzamide,
(121) A/-[1-(5-chloro-1 H-indol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(5-methylpyrrolidin-
2-on-1-yl)-benzamide,
(122) A/-[1-(5-chloro-1H-indol-2-yl)-1-phenyl-methyl]-4-(piperazin-1-yl)-3-
trifluoromethyl-benzamide,
(123) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[1 -(5-chloro-1 H-indol-2-yl)-3-(1 Htetrazol-
5-yl)-propyl]-benzamide,
(124) A/-[1-(5-bromo-1H-indol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-
[1,2]thiazepan-2-yl)-3-methyl-benzamide,
(125) 3-chloro-/V-[1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-
(diazepan-1 -yl)-benzamide,
(126) 3-chloro-A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-ethyl]-4-
([1,4]oxazepan-5-on-4-yl)-benzamide,
(127) A/-[(1 S)-1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-
(morpholin-S-on^-ylJ-benzamide,
(128) A/-[1 -(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(129) 3-bromo-A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(1H-pyrazol-3-yl)-
methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide,
(130) A/-[1 -(7-bromo-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-chloro-4-(4-
methyl-piperazin-1-yl)-benzamide,
(131) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(132) A/-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(furan-2-yl)-methyl]-4-
(diazepan-1-yl)-3-trifluoromethyl-benzamide,
(1 33) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-1 -phenyl-methyl]-3-methyl-4-
(1 ,1-dioxo-[1 ,2]thiazepan-2-yl)-benzamide,
(1 34) 3-chloro-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(1 35) 3-bromo-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-3-(methyl-sulphanyl)-
propyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide,
(1 36) 3-chloro-A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-hydroxy-ethyl]-4-
(piperazin-2-on-1 -yl)-benzamide,
(1 37) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperidin-2-on-1-yl)-benzamide,
(1 38) A/-[1 -(7-bromo-imidazo[1 ,2a]pyridin-2-yl)-3-methoxy-propyl]-3-chloro-4-
(1 ,1-dioxo-[1
(1 39) A/-[1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-2-trifluoromethoxy-ethyl]-3-
methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide,
(1 40) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 41 ) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 42) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-benzyloxycarbonyl-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(1 43) A/-[1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(1 44) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(pyrazin-2-yl)-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 45) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(oxazol-2-yl)-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(146) A/-[1-(5-chloro-1 H-benzimidazol-2-yl)-1-(1 H-imidazol-4-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamideI
(1 47) A/-[1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-
difluoromethoxy-4-(morpholin-3-on-4-yl)-benzamide,
(1 48) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -methyl-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 49) A/-[3-(5-chloro-1 H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 50) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(pyrrolidin-1 -yl-carbonyl)-propyl]-
3-methyl-4-(morpholin-3-on-4-yl)-benzamide,
(151) /V-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-
4-yl)-benzamide,
( 1 52) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
( 1 53) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperidin-2-on-1-yl)-benzamide,
(1 54) 3-bromo-A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(1 55) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-
methyl-oxazolidin-2-on-3-yl)-benzamide,
(1 56) A/-[1 -(5-ethynyl-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,4]oxazepan-5-on-4-yl)-benzamide,
(1 57) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(2-methyl-tetrahydropyridazin-1-yl)-benzamide,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof, while the compounds
4-(azepan-2-on-1 -yl)-/V-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethyl]-3-methyl-benzamide,
(2) 4-(azepan-2-on-1 -yl)-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
hydroxy-ethyl]-3-methyl-benzamide,
(3) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-
methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,
(4) yv-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-3-trifIuoromethyl-benzamide,
(5) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(6) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-
methyl-4-(morpholin-3on-4-yl)-benzamide,
(7) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(8) 4-(azepan-2-on-1 -yl)-3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-
2-methoxy-ethyl]-benzamide,
(9) 4-(azepan-2-on-1 -yl)-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethyl]-3-trifluoromethyl-benzamide,
(10) A/-[(1 S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide,
-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(morpholin-3-on-4-yl)-3-nitro-benzamide,
(12) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide,
(1 3) 3-chloro-A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
([1,4]oxazepan-5-on-4-yl)-benzamide,
(14) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(piperidin-2-on-1-yl)-benzamide,
-53-
(1 5) A/-[(1 /?)-! -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(1 6) A/-[(1 f?,2S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(17) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-
(thiomorpholin-3-on-4-yl)-benzamide,
(18) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperidin-2-on-1 -yl)-benzamide,
(1 9) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,3]-oxazinan-2-on-3-yl)-benzamide,
(20) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-
2-on-1-yl)-3-trifluoromethyl-benzamide,
(21 ) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo-
[1,2]thiazinan-2-yl)-3-methyl-benzamide,
(22) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-
3-on-4-yl)-benzamide,
(23) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
([I.Sloxazepan^-on-S-ylJ-S-trifluoromethyl-benzamide,
(24) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1 , 1 -dioxo-
[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide,
(25) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(26) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(27) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(28) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamidef
(29) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(thiomorpholin-3-on-4-yl)-benzamide,
(30) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(31 ) 3-chloro-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(1 ,1-dioxo-[1 ,2]thiazinan-2-yl)-benzamide,
(32) /
[1,2]thiazepan-2-yl)-3-methyl-benzamide,
(33) 3-bromo-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-
on-1 -yl)-benzamide,
(34) 3-bromo-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(piperidin-2-on-1 -yl)-benzamide,
(35) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(furan-2-yl)-methyl]-3-methyl-4-
(piperidin-2-on-1-yl)-benzamide,
(36) A/-[(1 R)-1 -(5-chioro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(5-oxo-[1,4]oxazepan-4-yl)-benzamide,
(37) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide,
(38) /V-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(39) 3-bromo-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(morpholin-3-on-4-yl)-benzamide,
(40) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(thiophen-2-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(41 ) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1 , 1 -dioxo-
[1,2]thiazinan-2-yl)-3-methyl-benzamide,
(42) A/-[(1 R)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide,
(43) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide,
(44) 3-chloro-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide,
(45) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(4_(4/?)-methyl-2-oxo-oxazolidin-3-yl)-benzamidel
(46) 3-chloro-A/-[(1 /?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide,
(47) A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-
(morpholin-3-on-4-yl)-benzamide,
(48) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 H-pyrazol-3-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide,
(49) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 H-1 -methyl-pyrazol-3-yl)-
methylj-S-methyl^morpholin-S-on^-ylJ-benzamide,
(50) 3-chloro-/V-[(1 fi)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(5-methyl-morpholin-3-on-4-yl)-benzamide,
(51 ) 3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(tetrahydro-pyrimidin-2-on-1-yl)-benzamide,
(52) A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(53) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-
([1,3]oxazepan-2-on-3-yl)-benzamide
(54) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-
(piperazin-1-yl)-3-trifluoromethyl-benzamide,
(55) A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(morpholin-3-on-4-yl)-3-nitro-benzamide,
(56) A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(piperazin-1 -yl)-benzamide,
(57) A/-[(1 S)-1 -(7-chloro-imidazo[1 ,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the
salts thereof are particularly preferred.
Within the scope of the present application, where applicable, the "isomer",
"stereoisomer", "diastereomer", "enantiomer", "chiral", "racemate" or "racemic
mixture" are defined as follows. Compounds of the same empirical formula
which differ in the nature or arrangement of the bonding of their atoms or their
connectivity or the spatial arrangement of the atoms in the molecule are known
as "isomers". Isomers which differ in the spatial arrangement of the atoms in
the molecule and are not congruent, while having the same type of connectivity
of their atoms, are known as "stereoisomers". Stereoisomers which do not
behave as image and mirror image to one another are known as
"diastereomers", and stereoisomers which behave as an image and mirror
image to one another are known as "enantiomers". Where an asymmetric
centre or atom is present (also known as a stereocentre or chiral centre), for
example in the case of a carbon atom substituted by four different substituents,
the molecule has the attribute "chiral", and a pair of enantiomers is possible. An
enantiomer may be characterised by the absolute configuration of its
stereocentre. The absolute configuration is described by means of the
descriptors (R) and (S), which are determined by the application of the
sequence rules according to Cahn, Ingold and Prelog , or by describing the
rotation of the plane of polarised light as it interacts with the molecule, which is
referred to as dextrorotatory or laevorotatory (i.e. accordingly with (+) or (-) as
the descriptor). A chiral compound may occur both as an individual enantiomer
or as a mixture of the corresponding enantiomers. A mixture which contains
equal amounts of both enantiomers of a compound is known as a "racemate" or
"racemic mixture".
According to the invention the compounds of general formula I are obtained by
methods known per se, for example by the following methods:
-58-
(a) In order to prepare compounds of general formula
(Figure Removed)
wherein R3 to R5 are as hereinbefore defined and Z1 denotes the hydrogen
atom or a protective group and B1 denotes a group of formula
wherein R7 and R8 are as hereinbefore defined:
cyclisation of a compound of general formula
(Figure Removed)
optionally formed in the reaction mixture
wherein
R3 to R5, R7 and R8 are as hereinbefore defined and Z1 denotes the hydrogen
atom or a protective group, after which any protective group used is cleaved.
The cyclisation is conveniently carried out in a solvent or mixture of solvents
such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene,
toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether,
sulpholane, dimethylformamide or tetralin, dimethylsulphoxide, methylene
chloride, chloroform, tetrachloromethane, for example at temperatures between
0 and 250°C, but preferably between 20 and 100°C, optionally in the presence
of a condensation agent such as phosphorus oxychloride, thionyl chloride,
sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic
acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic
anhydride, A/,A/-dicyclohexylcarbodiimide or optionally also in the presence of a
base such as potassium ethoxide or potassium-ferf.-butoxide. The cyclisation
may however also be carried out without a solvent and/or condensation agent.
Compounds of general formula (IV) may be obtained by acylation of compounds
of general formula
wherein n, R7 and R8 are as hereinbefore defined, with compounds of general
formula
(XXV),
wherein R3, R4 and R5 are as hereinbefore defined, Q denotes a halogen atom
or a hydroxy, Ci^-alkoxy or Ci-4-acyloxy group and Z1 denotes a protective
group, according to processes described in (e).
(b) In order to prepare a compound of general formula
(Figure Removed)
wherein R3 to R5 are as hereinbefore defined, Z1 denotes the hydrogen atom or
a protective group, for example a Ci-s-alkyloxycarbonyl or benzyloxycarbonyl
group, and B1 denotes a group of formula
R
)7 __ wherein R an dj 0R8 are as hereinbefore defined:
i) transition metal-catalysed coupling and cyclisation of a compound
of general formula
R33
NHR5
wherein R3 denotes a phenyl or heteroaryl group and R4 denotes a
hydrogen atom and R5 is as hereinbefore defined, with a compound of
general formula
(Figure Removed)
wherein R8 is as hereinbefore defined and Z1 denotes a protective group,
for example an acetyl or methylsulphonyl group, after which the
protective group is cleaved.
The reaction sequence is conveniently carried out in a solvent or mixture of
solvents such as ethanol, isopropanol, glacial acetic acid, benzene,
chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,
diethyleneglycoldimethylether, sulpholane, dimethylformamide, Nmethylpyrrolidinone,
tetralin, dimethylsulphoxide, methylene chloride,
chloroform or tetrachtoromethane, for example at temperatures between 0 and
250°C, but preferably between 20 and 120°C, conveniently in the presence of
transition metal catalysts such as bis-(triphenylphosphine)-palladium(ll)-
chloride, bis-(tricyclohexylphosphine)-palladium(ll)-chloride, bis-(triethylphosphine)-
palladium(ll)-chlorideorbis-(tri-o-tolylphosphine)-palladium(ll)-
chloride and optionally in the presence of a transition metal catalyst such as
copper(l)-iodide, copper(l)-bromide or copper(l)-acetate and conveniently in the
presence of a base such as tetramethylguanidine, tetramethylethylenediamine
or A/,A/'-dimethylethylenediamine as well as optionally using an inert gas
atmosphere (for example nitrogen or argon).
ii) alkylation and subsequent reductive amination of a compound of
general formula
(Figure Removed)
wherein R7 and R8 are as hereinbefore defined and Y denotes a halogen
atom, a C^-alkoxy, CM-alkoxyamino or a A/-C-i-4-alkoxy-A/-Ci-4-alkylamino
group, with a compound of general formula
(Figure Removed)
wherein R4 is as hereinbefore defined and M denotes a metal such as for
example lithium, sodium or potassium, or a metal such as for example
magnesium, cadmium, copper or zinc, with a suitable counter-ion, such
as for example chloride, bromide or iodide, or also a combination of two
metals, such as for example magnesium and copper, lithium and copper
or zinc and copper, with suitable counter-ions, such as for example
cyanide, chloride, bromide or iodide, as well as a grouping containing
combinations thereof, and subsequent reductive amination of the
compounds thus obtained.
The alkylation is conveniently carried out in a solvent or mixture of solvents
such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether,
diethyleneglycoldimethylether, sulpholane, dimethylformamide, Nmethylpyrrolidinone,
tetralin, dimethylsulphoxide, methylene chloride,
chloroform, tetrachloromethane, diethyl ether, terf.-butyl-methyl-ether or
tetrahydrofuran, for example, at temperatures between -100 and +100°C, but
preferably between -100 and 30°C, with alkylating reagents such as Grignard
reagents, organolithium reagents, Oilman or Knochel cuprates which may be
produced by methods known from the literature, optionally using an inert gas
atmosphere (nitrogen or argon). The subsequent reductive amination of the
ketones formed after alkylation is carried out for example by reaction with
ammonia, hydroxylamine, alkoxylamines, primary amines, hydroxyl-alkylamines
or alkoxy-alkylamines followed by or accompanied by reduction, for example
with hydride donors such as sodium borohydride, lithium aluminium hydride,
sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminium
hydride in a solvent or mixture of solvents such as ethanol, isopropanol,
benzene, toluene, pyridine, ethyleneglycoldimethylether,
diethyleneglycoldimethylether, /V-alkylmorpholine, diethyl ether, fe/t-butylmethylether,
tetrahydrofuran, hexane or cyclohexane or by hydrogenation
optionally under pressure and conveniently in the presence of a catalyst such
as Raney nickel, palladium, palladium charcoal, platinum or platinum oxide, in a
solvent or mixture of solvents such as ethyl acetate, ethanol, isopropanol,
benzene, toluene, pyridine, ethyleneglycol dimethylether, diethyleneglycol
dimethylether, /V-Ci-s-alkylmorpholine, diethyl ether, terf.-butyl-methylether,
tetrahydrofuran, hexane or cyclohexane.
(c) In order to prepare a compound of general formula
(Figure Removed)
wherein R3 to R5 are as hereinbefore defined, Z1 denotes the hydrogen atom or
a protective group, for example a Ci_5-alkyloxycarbonyl or benzyloxycarbonyl
group, and B' denotes a group of formula
(Figure Removed)
wherein R8 is as hereinbefore defined:
coupling and subsequent cyclisation of a compound of general formula
wherein n and R8 are as hereinbefore defined, with a compound of general
formula
(Figure Removed)
wherein R3 to R5 are as hereinbefore defined, Z1 denotes a protective group, for
example a Cs-alkyloxycarbonyl or benzyloxycarbonyl group, and Z4 denotes a
nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a
tosylate, triflate or mesylate group, after which the protective group Z1 is
cleaved by methods known from the literature.
The reaction sequence is conveniently carried out in a solvent or mixture of
solvents such as water, ethanol, isopropanol, benzene, chlorobenzene, toluene,
xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether,
dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide,
sulpholane, methylene chloride, chloroform, tetrachloromethane or A/-ethyldiisopropylamine,
A/-Ci.5-alkylmorpholine, A/-Ci-5-alkylpiperidine,
A/-Ci-5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures
between -30 and 250°C, but preferably between 0 and 150°C, optionally
conveniently in the presence of bases such as potassium carbonate, sodium
carbonate, sodium hydrogen carbonate, potassium-terf.-butoxide, sodium
ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide.
(d) In order to prepare a compound of general formula
(Figure Removed)
wherein A, R1 and R2 are as hereinbefore defined and Q denotes a halogen
atom or a hydroxy, Ci^-alkoxy or C-M-acyloxy group:
i) nucleophilic substitution of a compound of general formula
A'-H , (XIV)
wherein A1 denotes a 5- to 7-membered cycloalkyleneimino group as
mentioned hereinbefore under the definition of A, at the aromatic group
of general formula
(Figure Removed)
wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile
group or a Cs-alkoxycarbonyl group, and subsequent saponification of
the nitrile or Cs-alkoxycarbonyl group Z2 and optionally further reaction
of the resulting carboxyl group to form a reactive carboxylic acid
derivative of general formula XIII.
The nucleophilic substitution is conveniently carried out in a solvent or mixture
of solvents such as ethanol, isopropanol, benzene, chlorobenzene, toluene,
xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether,
dimethylformamide, A/-methylpyrrolidinone, tetralin, dimethylsulphoxide,
sulpholane, methylene chloride, chloroform, tetrachloromethane or A/-ethyldiisopropylamine,
/V-Cs-alkylmorpholine, A/-Ci-5-alkylpiperidine,
/V-Ci-5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures
between -30 and 250°C, but preferably between 0 and 150°C, optionally
conveniently in the presence of bases such as potassium carbonate, sodium
carbonate, potassium-te/t-butoxide, sodium ethoxide, potassium
hexamethyldisilazane, sodium hydride or lithium diisopropylamide.
ii) transition metal-catalysed coupling reaction of a compound of
general formula
(Figure Removed)
wherein A' denotes a 5- to 7-membered cycloalkyleneimino group as
mentioned hereinbefore under the definition of A, at the aromatic group
of general formula
wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile
group or a Ci.5-alkoxycarbonyl group and Z3 denotes a chlorine, bromine
or iodine atom or a triflate group, and subsequent saponification of the
nitrile or Ci_5-alkoxycarbonyl group Z2 and optionally further reaction of
the resulting carboxyl group to form a reactive carboxylic acid derivative
of general formula XIII.
The reaction is expediently carried out in a solvent or mixture of solvents such
as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, te/t-butylmethyl-
ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether,
sulpholane, dimethylformamide, yV-methylpyrrolidinone, tetralin, dimethyl
sulphoxide, methylene chloride, chloroform or tetrachloromethane, for example
at temperatures between -30 and 250°C, but preferably between 0 and 150°C,
conveniently in the presence of transition metal catalysts such as nickel on
activated charcoal, palladium charcoal, tetrakis-(triphenylphosphine)-
palladium(O), tris-(dibenzylideneacetone)-dipalladium(0), palladium(ll)acetate,
palladium(ll)chloride, bis-(triphenylphosphine)-palladium(ll)-chloride, bis-
(tricyclohexylphosphine)-palladium(ll)-chloride, bis-(triethylphosphine)-
palladium(ll)-chloride, bis-(tri-o-tolylphosphine)-palladium(ll)-chloride, optionally
in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, trite/
t-butylphosphine, 1,3-bis-(diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-
1,1'-dinaphthyl, 1,1'-bis-(diphenylphosphino)-ferrocene, xantphos,
and conveniently in the presence of a base such as sodium methoxide, sodium
ethoxide, sodium-te/t-butoxide, potassium-terf.-butoxide, sodium-terf.-
butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium
diisopropylamide, potassium carbonate, rubidium carbonate, caesium
carbonate, potassium phosphate, sodium hydride, optionally in the presence of
a complexing agent such as 18-crown-6-ether as well as conveniently using an
inert gas atmosphere (for example nitrogen or argon) and optionally under
pressure.
iii) Selective oxidation of a cycloalkyleneimino group in compounds of
general formula
(Figure Removed)
wherein A1 denotes a 5- to 7-membered, optionally also substituted,
2-oxo-cycloalkyleneimine group as mentioned hereinbefore under the
definition of A, R1 and R2 are as hereinbefore defined and Z2 denotes
-68-
the carboxyl group, and optionally further reacting to form a reactive
carboxylic acid derivative of general formula XIII.
The reaction of a compound of general formula XIII obtained for example by the
processes described hereinbefore, wherein A1 denotes a cycloalkyleneimino
group and Q denotes the hydroxy group, to form the corresponding lactam by
oxidation of a methylene group adjacent to the nitrogen is carried out for
example with oxidising agents such as potassium permanganate, potassium
chromate, potassium dichromate, chromium(VI)oxide, mercury (ll)chloride,
selenium(IV)oxide, lead (IV)oxide, lead (ll,IV)oxide, potassium
peroxomonosulphate, hydrogen peroxide, sodium hypochlorite, optionally in the
presence of a suitable catalyst such as nickel(ll)chloride, cobalt(ll)chloride,
ruthenium(lll)chloride, osmium(VIII)oxide, vanadium(IV)oxide and/or in the
presence of a crown ether such as 18-crown-6, in a solvent or mixture of
solvents such as water, formic acid, acetic acid, ethyl acetate, benzene,
pyridine, dichloromethane, chloroform, tetrachloromethane, optionally under 2-
phase conditions in the presence of a suitable phase transfer catalyst such as
for example tetrabutylammonium chloride, tetrabutylammonium bromide,
benzyl-triethyl-ammonium chloride or methyl-trioctyl-ammonium chloride,
optionally in the presence of an acid such as acetic acid, hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogen sulphate,
sodium dihydrogen phosphate and/or a base such as sodium hydroxide,
potassium hydroxide, ammonia, pyridine, potassium phosphate, dipotassium
hydrogen phosphate or sodium acetate at temperatures between -30 and
250°C, but preferably between 0 and 150°C. For example this reaction may be
carried out as described by J. H. Markgraf, C. A. Stickney, J. Heterocycl. Chem.
2000, 37(1), 109.
iv) transition metal-catalysed coupling reaction of a compound of
general formula
(Figure Removed)
wherein A1 denotes a 5- to 7-membered, optionally substituted 2-oxocycloalkyleneimino
group as mentioned hereinbefore under the definition
of A, at the aromatic group of general formula
wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile
group or a C5-alkoxycarbonyl group and Z3 denotes a chlorine, bromine
or iodine atom or a triflate group, and subsequent saponification of the
nitrile or Ci-s-alkoxycarbonyl group Z2 and optionally further reaction of
the resulting carboxyl group to form a reactive carboxylic acid derivative
of general formula XII.
The reaction is expediently carried out in a solvent or mixture of solvents such
as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, fe/t-butylmethyl-
ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether,
sulpholane, dimethylformamide, A/-methylpyrrolidinone, tetralin,
dimethylsulphoxide, methylene chloride, chloroform or tetrachloromethane, for
example at temperatures between -30 and 250°C, but preferably between 0 and
200°C, conveniently in the presence of transition metal catalysts such as
tetrakis-(triphenylphosphine)-palladium(0), tris-(dibenzylideneacetone)-
dipalladium(O), palladium(ll)acetate, palladium(ll)chloride, bis-
(triphenylphosphine)-palladium(ll)-chloride1 bis-(tricyclohexylphosphine)-
palladium(ll)-chloride, bis-(triethylphosphine)-palladium(ll)-chloride, bis-(tri-otolylphosphine)-
palladium(ll)-chloride, optionally in the presence of ligands such
as triphenylphosphine, tri-o-tolylphosphine, tri-fe/t-butylphosphine, 1,3-bis-
(diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-1,1'-dinaphthyl, 1,1'-
bis-(diphenylphosphino)-ferrocene, xantphos, or for example in the presence of
a transition metal catalyst such as copper(l)-iodide, copper(l)-bromide or
copper(l)-acetate and conveniently in the presence of a base such as
tetramethylguanidine, tetramethylethylenediamine or N,N'-
dimethylethylenediamine and conveniently in the presence of a base such as
sodium methoxide, sodium ethoxide, sodium-tert.-butoxide, potassium-te/tbutoxide,
sodium-fe/f.-butyldimethyl-silanoate, potassium hexamethyldisilazane,
lithium diisopropylamide, potassium carbonate, rubidium carbonate, caesium
carbonate, potassium phosphate, sodium hydride, optionally in the presence of
a complexing agent such as 18-crown-6-ether and conveniently using an inert
gas atmosphere (for example nitrogen or argon) and optionally under pressure.
v) Acylation/sulphonylation and alkylation of a compound of general
formula
(Figure Removed)
wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile
group or a Ci-s-alkoxycarbonyl group, with a compound of general
formula
(Figure Removed)

wherein E denotes a carbonyl, oxycarbonyl, sulphonyl or a sulphamoyl
group optionally substituted at the nitrogen atom as mentioned
hereinbefore, G denotes a chlorine, bromine or iodine atom or an
anhydride, Ci-s-alkoxy or benzotriazoloxy group or E and G together
denote an isocyano group and Z4 denotes a nucleofugic leaving group,
for example a chlorine, bromine or iodine atom, a tosylate, inflate or
mesylate group, and n is a number between 3 and 5, while individual
methylene groups according to the description mentioned hereinbefore
may additionally be substituted or replaced by heteroatoms, and
subsequent intramolecular cyclisation by alkylation of the anilide nitrogen
while cleaving the nucleofugic leaving group Z4, followed by
saponification of the nitrile or Ci.5-alkoxycarbonyl group Z2 and optionally
further reaction of the resulting carboxyl group to form a reactive
carboxylic acid derivative of general formula XIII.
The acylation/sulphonylation is conveniently carried out in a solvent or mixture
of solvents such as benzene, chlorobenzene, toluene, xylene,
glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, Nmethylpyrrolidinone,
tetralin, dimethylsulphoxide, sulpholane, methylene
chloride, chloroform, tetrachloromethane, A/-ethyl-diisopropylamine,
A/-C5-alkylmorpholine, A/-C5-alkylpiperidine, A/-C1.5-alkylpyrrolidine,
triethylamine, pyridine, for example at temperatures between -30 and 250°C,
but preferably between 0 and 150°C, conveniently in the presence of bases
such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate,
sodium carbonate, potassium-terf.-butoxide, sodium methoxide, sodium
ethoxide or basic ion exchanger.
The subsequent intramolecular alkylation is conveniently carried out in a solvent
or mixture of solvents such as benzene, chlorobenzene, toluene, xylene,
glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide,
dimethylsulphoxide, sulpholane, methylene chloride, tetrachloromethane, A/-
ethyl-diisopropylamine, A/-C5-alkylmorpholine, A/-C5-alkylpiperidine,
A/-C5-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures
between -30 and 250°C, but preferably between 0 and 150°C, conveniently in
the presence of bases such as pyridine, triethylamine, potassium carbonate,
sodium carbonate, potassium-te/t-butoxide, sodium methoxide, sodium
ethoxide, sodium hydride, potassium hexamethyldisilazane or lithium
diisopropylamide.
vi) carbamoylation / urea formation with a compound of general
formula
(Figure Removed)
wherein R1 and R2 are as hereinbefore defined and Z2 denotes the nitrile
group or a Ci.5-alkoxycarbonyl group, and which may be obtained by
methods known from the literature from compounds of general formula
XVIII, for example by reaction with phosgene in toluene, with a
compound of general formula
wherein Z4 denotes a nucleofugic leaving group, for example a chlorine,
bromine or iodine atom, a tosylate, triflate or mesylate group, and E
denotes a hydroxyl, amino or Ci.3-alkylamino function and n is a number
between 2 and 4, while individual methylene groups may additionally be
substituted according to the description mentioned hereinbefore, and
subsequent intramolecular cyclisation by alkylation of the anilide nitrogen
while cleaving the nucleofugic leaving group Z4, followed by
saponification of the nitrile or C5-alkoxycarbonyl group Z2 and optionally
further reaction of the resulting carboxyl group to form a reactive
carboxylic acid derivative of general formula XIII.
The carbamoylation is conveniently carried out in a solvent or mixture of
solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether,
diethyleneglycoldimethylether, dimethylformamide, A/-methylpyrrolidinone,
tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform,
tetrachloromethane, A/-ethyl-diisopropylamine, A/-C5-alkylmorpholine,
alkylpiperidine, A/-C5-alkylpyrrolidine, triethylamine, pyridine, for example at
temperatures between -30 and 250°C, but preferably between 0 and 150°C.
The subsequent intramolecular alkylation is carried out for example analogously
to the method described under v).
vii) cyclisation metathesis of a compound of general formula
(Figure Removed)
wherein R1 and R2 are defined as described hereinbefore, Z2 denotes a
nitrile, Ci_5-alkoxycarbonyl or carboxyl group, E denotes an
aminocarbonyl, aminosulphonyl or amino group optionally substituted
according to the description mentioned hereinbefore or a carbonyl or
sulphonyl group or an oxygen or sulphur atom or a bond, while m and o
independently of one another denote identical or different numbers
between 1 and 3 which may be obtained by a sequence of alkylation and
acylation / sulphonylation / carbamoylation / sulphamoylation with
corresponding reagents by the methods already described herein or
known from the literature, followed by saponification of the nitrile or
C5-alkoxycarbonyl group Z2 and optionally further reaction of the
resulting carboxyl group to obtain a reactive carboxylic acid derivative of
general formula XIII.
The cyclisation by a reaction of metathesis is conveniently carried out in a
solvent or mixture of solvents such as benzene, chlorobenzene, toluene,
xylene, methanol, ethanol, propanol, diethyl ether, fe/t-butyl-methyl-ether,
tetrahydrofuran, dioxane, glycoldimethylether, diethyleneglycoldimethylether,
dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide,
sulpholane, methylene chloride, chloroform, tetrachloromethane, pyridine, in the
presence of a catalyst such as benzylidene-bis-(tricyclohexylphosphine)-
dichloro-ruthenium (1st generation Grubbs catalyst) or benzylidene-[1,3-
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-
ruthenium (2nd generation Grubbs catalyst) for example at
temperatures between -30 and 250°C, but preferably between 0 and 150°C,
conveniently under an inert gas atmosphere, for example argon.
(e) In order to prepare a compound of general formula
(Figure Removed)
wherein A, B and R1 to R5 are as hereinbefore defined:
acylation of a compound of general formula
(Figure Removed)
wherein B and R3 to R5 are as hereinbefore defined and Z1 denotes the
hydrogen atom,
with a carboxylic acid or a reactive carboxylic acid derivative of general formula
(Figure Removed)
wherein A, R1 and R2 are as hereinbefore defined and Q denotes a hydroxy or
Ci-4-alkoxy group, a halogen atom or an acyloxy group.
The acylation is conveniently carried out with a corresponding halide or
anhydride in a solvent such as methylene chloride, chloroform, carbon
tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile,
dimethylformamide, sodium hydroxide solution or sulpholane, optionally in the
presence of an inorganic or organic base at temperatures between -20 and
200°C, but preferably at temperatures between -10 and 160°C.
The acylation may, however, also be carried out with the free acid, optionally in
the presence of an acid-activating agent or a dehydrating agent, e.g. in the
presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane,
hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic
acid, phosphorus trichloride, phosphorus pentoxide, /V./V-dicyclohexyl
carbodiimide, A/1/V-dicyclohexylcarbodiimide/A/-hydroxysuccinimideor
1-hydroxy-benzotriazole, A/./V-carbonyldiimidazole, O-(benzotriazoM-yl)-
A/.A/.A/./V-tetramethyl-uronium tetrafluoroborate/A/-methylmorpholine,
O(benzotriazol-1-yl)-N,A/,Af,AMetramethyl-uronium tetrafluoroborate/A/-
ethyldiisopropylamine, O-pentafluorophenyl-/V,N,/V',/V'-tetramethyluronium
hexafluorophosphate/triethylamine, A/./V-thionyldiimidazole or
triphenylphosphine/carbon tetrachloride, at temperatures between -20 and
200°C, but preferably at temperatures between -10 and 160°C.
Other methods of amide coupling are described for example in P.D. Bailey, I.D.
Collier, K.M. Morgan in "Comprehensive Functional Group Interconversions",
Vol. 5, page 257ff., Pergamon 1995.
(f) In order to prepare a compound of general formula (II), (XXIV), (VII),
(VIII), (XI) or (XXIII), wherein A, B and R1 to R7 are as hereinbefore
defined and R8 denotes a C2-3-alkynyl group which is linked to the
aromatic group via the carbon atom, and which simultaneously carries
the triple bond, from a corresponding compound wherein R8 denotes a
bromine or iodine atom or the triflate, boric acid or boric acid ester group:
transition metal-catalysed coupling reaction of a compound of general formula
(Figure Removed)
wherein Z5 denotes the hydrogen atom, the methyl group or a protective group
such as for example a trimethylsilyl, te/t-butyl-dimethylsilyl, fe/t-butyldiphenylsilyl
or triisopropyl group, which can then be cleaved,
with a compound of general formula (II), (XXIV), (VII), (VIII), (XI) or (XXIII),
wherein A, B and R1 to R7 are as hereinbefore defined and R8 denotes a
bromine or iodine atom or the triflate, boric acid or boric acid ester group.
The reaction is preferably carried out in a solvent or mixture of solvents such as
acetonitrile, diethyl ether, tetrahydrofuran, dioxane, water or dimethylformamide
or a mixture of solvents in the presence of a palladium catalyst such as for
example bis(triphenylphosphine)-palladium(ll)choride, palladium(ll)-[1,1'-bis-
(diphenylphosphino)ferrocene]-chlorideortetrakis-(triphenylphosphine)-
palladium(O) in the presence of a base such as triethylamine, AMsopropyldiethylamine,
A/,A/-diisopropyl-ethylamine, potassium-fe/t-butoxide, sodium
carbonate or caesium carbonate, optionally in the presence of ligands such as
triphenylphosphine, tri-o-tolylphosphine, tri-te/t-butylphosphine, 1,3-bis-
(diphenylphosphino)-propane, 2,2'-bis-(diphenylphosphino)-1,1I-dinaphthyl, 1,1'-
bis-(diphenylphosphino)-ferrocene, xantphos and optionally in the presence of a
transition metal compound such as a copper halide such as for example
copper(l)iodide and at temperatures between 20 and 120°C, preferably at
temperatures between 20 and 90°C under argon or nitrogen atmosphere (cf.
also K. Sonogashira, Comprehensive Organic Synthesis, Vol. 3, page 52ff.,
Pergamon Press, Oxford 1991).
Any silyl protective group present such as for example trimethylsilyl is preferably
cleaved in a solvent or mixture of solvents such as water, methanol, ethanol,
isopropanol, acetone, dioxane, tetrahydrofuran or dimethylformamide in the
presence of a base such as lithium hydroxide, sodium hydroxide, potassium
carbonate or sodium methoxide. For cleaving in organic solvents such as for
example diethyl ether, tetrahydrofuran, dimethylformamide or dichloromethane
it is also possible to use fluoride reagents, such as for example
tetrabutylammonium fluoride, lithium fluoride or potassium fluoride, optionally
with the addition of a complexing agent such as 18-crown-6-ether.
In the reactions described above any reactive groups present such as hydroxy,
carboxy, amino, alkylamino or imino groups may be protected during the
reaction by conventional protecting groups which are cleaved again after the
reaction. For example, a suitable protecting group for a hydroxy group may be
the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or
tetrahydropyranyl group,
suitable protecting groups for a carboxyl group might be the trimethylsilyl,
methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group,
suitable protecting groups for an amino, alkylamino or imino group might be the
acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl,
benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and
additionally, for the amino group, the phthalyl group.
Other protective groups and their cleaving are described in T.W. Greene,
P.G.M. Wuts, "Protecting Groups in Synthesis", Wiley, 1991 and 1999.
Any protecting group used may optionally subsequently be cleaved for example
by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,
tetrahydrofuran/water or dioxane/water, in the presence of an acid such as
trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an
alkali metal base such as lithium hydroxide, sodium hydroxide or potassium
hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at
temperatures between 0 and 100°C, preferably at temperatures between 10
and 50°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved
hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst
such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl
acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid,
optionally with the addition of an acid such as hydrochloric acid at temperatures
between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen
pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising
agent such as cerium(IV)ammonium nitrate in a solvent such as methylene
chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and
50°C, but preferably at ambient temperature.
A methoxy group is expediently cleaved in the presence of boron tribromide in a
solvent such as methylene chloride at temperatures between -35 and -25°C.
A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the
presence of anisol.
A terf.butyl or te/tbutyloxycarbonyl group is preferably cleaved by treating with
an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a
solvent such as methylene chloride, dioxane or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary
amine such as methylamine, ethylamine or n-butylamine in a solvent such as
methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures
between 20 and 50°C.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of
tetrakis-(triphenylphosphine)-palladium(0), preferably in a solvent such as
tetrahydrofuran and preferably in the presence of an excess of a base such as
morpholine or 1,3-dimedone at temperatures between 0 and 100°C, preferably
at ambient temperature and under an inert gas, or by treating with a catalytic
amount of tris-(triphenylphosphine)-rhodium(l)chloride in a solvent such as
aqueous ethanol and optionally in the presence of a base such as
1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70°C.
Compounds of general formulae (II), wherein the group B' is represented by a
group of general formula (III), and (IV) may be prepared for example
analogously to K. Maekawa, J. Ohtani, Agr. Biol. Chem. 1976, 40, 791-799.
Moreover the compounds of general formula I obtained may be resolved into
their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained which occur
as racemates may be separated by methods known per se (cf. Allinger N. L.
and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)
into their optical antipodes and compounds of general formula I with at least 2
asymmetric carbon atoms may be resolved into their diastereomers on the
basis of their physical-chemical differences using methods known per se, e.g.
by chromatography and/or fractional crystallisation, and, if these compounds
are obtained in racemic form, they may subsequently be resolved into the
enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral
phases or by recrystailisation from an optically active solvent or by reacting with
an optically active substance which forms salts or derivatives such as e.g.
esters or amides with the racemic compound, particularly acids and the
activated derivatives or alcohols thereof, and separating the diastereomeric
mixture of salts or derivatives thus obtained, e.g. on the basis of their
differences in solubility, whilst the free antipodes may be released from the pure
diastereomeric salts or derivatives by the action of suitable agents. Optically
active acids in common use are e.g. the D- and L-forms of tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid,
camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically
active alcohol may be for example (+) or (-)-menthol and an optically active acyl
group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example.
Furthermore, the compounds of formula I may be converted into the salts
thereof, particularly for pharmaceutical use into the physiologically acceptable
salts with inorganic or organic acids. Acids which may be used for this purpose
include for example hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid,
citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain a carboxy group, they may
subsequently, if desired, be converted into the salts thereof with inorganic or
organic bases, particularly for pharmaceutical use into the physiologically
acceptable salts thereof. Suitable bases for this purpose include for example
sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
As already mentioned, the compounds of general formula I as well as the
tautomers, the enantiomers, the diastereomers and the physiologically
acceptable salts thereof have valuable pharmacological properties, particularly
an antithrombotic activity, which is preferably based on an effect on thrombin or
factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on
a prolonging effect on the aPTT time and/or on an inhibiting effect on related
serine proteases such as e.g. urokinase, factor Vila, factor IXa, factor Xla and
factor XI la.
The compounds listed in the experimental section were investigated for their
effect on the inhibition of factor Xa as follows:
Method:
Enzyme-kinetic measurement with chromogenic substrate. The quantity of pnitroaniline
(pNA) released from the colourless chromogenic substrate by
human factor Xa is determined photometrically at 405 nm. It is proportional to
the activity of the enzyme used. The inhibition of the enzyme activity by the test
substance (in relation to the solvent control) is determined at various
concentrations of test substance and from this the ICso is calculated, as the
concentration which inhibits the factor Xa used by 50 %.
Material:
Tris(hydroxymethyl)-aminomethane buffer (100 mMol) and sodium chloride (150
mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free
Factor Xa (Calbiochem), spec, activity: 217 lU/mg, final concentration: 7 ID/ml
for each reaction mixture
Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/l (1 KM) for each
reaction mixture
Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003,
0.001
Procedure:
10 jj.l of a 23.5-times concentrated starting solution of the test substance or
solvent (control), 175 jal of TRIS/HSA buffer and 25 nl of a 65.8 U/L Factor Xa
working solution are incubated for 10 minutes at 37°C. After the addition of
25 \i\ of S 2765 working solution (2.82 mMol/l) the sample is measured in a
photometer (SpectraMax 250) at 405 nm for 600 seconds at 37°C.
Evaluation:
1. Determining the maximum increase (deltaOD/minutes) over 21 measuring
points.
2. Determining the % inhibition based on the solvent control.
3. Plotting a dosage/activity curve (% inhibition vs substance concentration).
4. Determining the ICso by interpolating the X-value (substance concentration)
of the dosage/activity curve at Y = 50 % inhibition.
All the compounds tested had an IC50 value of less than 100 umol/L
The compounds prepared according to the invention are generally well
tolerated.
In view of their pharmacological properties the new compounds and the
physiologically acceptable salts thereof are suitable for the prevention and
treatment of venous and arterial thrombotic diseases, such as for example the
prevention and treatment of deep leg vein thrombosis, for preventing
reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in
peripheral arterial diseases, and for preventing and treating pulmonary
embolism, disseminated intravascular coagulation and severe sepsis, for
preventing and treating DVT in patients with exacerbation of COPD, for treating
ulcerative colitis, for treating and preventing coronary thrombosis, for
preventing stroke and the occlusion of shunts. In addition, the compounds
according to the invention are suitable for antithrombotic support in thrombolytic
treatment, such as for example with alteplase, reteplase, tenecteplase,
staphylokinase or streptokinase, for preventing long-term restenosis after
PT(C)A, for the prevention and treatment of ischaemic incidents in patients with
all forms of coronary heart disease, for preventing metastasis and the growth of
tumours and inflammatory processes, e.g. in the treatment of pulmonary
fibrosis, for preventing and treating rheumatoid arthritis, for preventing and
treating fibrin-dependent tissue adhesions and/or the formation of scar tissue
and for promoting wound healing processes. The new compounds and the
physiologically acceptable salts thereof may be used therapeutically in
conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such
as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban,
roxifiban), with physiological activators and inhibitors of the clotting system and
the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with
inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with PaT
receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor
antagonists/synthetase inhibitors (e.g. terbogrel).
The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg,
preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg,
preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times
a day.
For this purpose, the compounds of formula I prepared according to the
invention may be formulated, optionally together with other active substances,
with one or more inert conventional carriers and/or diluents, e.g. with corn
starch, lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,
water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol,
cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat
or suitable mixtures thereof, to produce conventional galenic preparations such
as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are intended to illustrate the invention without
restricting its scope:
Experimental section
As a rule, melting points, IR, UV, 1H-NMR and/or mass spectra have been
obtained for the compounds prepared. Unless otherwise stated, Rf values were
obtained using ready-made silica gel 60 £254 TLC plates (E. Merck, Darmstadt,
Item no. 1.05714) without chamber saturation. The Rf values obtained under the
name Alox were determined using ready-made aluminium oxide 60 £254 TLC
plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The
Rf values obtained under the name Reversed-phase-8 were determined using
ready-made RP-8 Paws TLC plates (E. Merck, Darmstadt, Item no. 1.15684)
without chamber saturation. The ratios given for the eluants refer to units by
volume of the solvent in question. Chromatographic purification was done using
silica gel supplied by Messrs Millipore (MATREX™, 35-70 urn). If the
configuration is not specified in detail, it is unclear whether the compound in
question is a pure stereoisomer or a mixture of enantiomer and diastereomer.
The following abbreviations are used in the descriptions of the tests:
Boc terf.-butoxycarbonyl
DIPEA A/-ethyl-diisopropylamine
DMSO dimethylsulphoxide
DMF A/,A/-dimethylformamide
sat. saturated
h hour(s)
i. vac. in vacuo
cone. concentrated
NMM /V-methyl-morpholine
NMP A/-methyl-pyrrolidin-2-one
o ortho
PfTU O-pentafluorophenyl-A/,A/,A/;,A/'-tetramethyluronium
hexafluorophosphate
PPA propanephosphonic cycloanhydride
quant. quantitative
Rf retention factor
Rt retention time
rac. racemic
TBTU O-(benzotriazol-1 -yl)-/V, N, N1, AMetramethyluronium
tetrafluoroborate
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
tert. tertiary
£ yield over all the steps carried out analogously as described
The HPLC/MS data for Examples 35 to 38 were obtained under the following
conditions:
(a) Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampler, Waters
996 diode array detector
The following was used as the mobile phase:
A: water with 0.1% trifluoroacetic acid
B: acetonitrile with 0.1% trifluoroacetic acid
time in min %A %B flow rate in ml/min
(Table Removed)
The stationary phase used was a Waters column X-Terra™ MS Cis 3.5 urn, 4.6
mm x 50 mm (column temperature: constant at 25°C)
The diode array detection took place in a wavelength range from 210-500 nm
Range of mass-spectrometry detection: m/z 120 to m/z 950
(b) The HPLC/MS data for the other Examples, if provided, were obtained
under the following conditions:
HP 1100 with quarternary pump, Gilson G215 Autosampler, HP diode array
detector.
The mobile phase used was:
A: water with 0.1 % TFA
B: acetonitrile with 0.08% TFA
flow rate in ml/min
The stationary phase used was a Waters column X-Terra™ MS C-|8 2.5 urn, 2.1
mm x 50 mm (column temperature: constant at 25°C)
The diode array detection took place in a wavelength range from 210-550 nm
Range of mass-spectrometry detection: m/z 120 to m/z 1000.
time in min
(Table Removed)
Example 1
3-chloro-A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-
benzamide
(a) 4-(4-A/-acetyl-n ,41diazepan-1 -vl)-3-chloro-benzonitrile
4.67 g (30 mmol) 3-chloro-4-fluoro-benzonitrile and 4.27 g (30 mmol) AMacetyl-[
1,4]diazepan are stirred in 5.0 ml DIPEA for 6 hours at 90°C. Then the
mixture is evaporated down i. vac. and the residue is dissolved in
dichloromethane. The organic phase is washed twice with water, dried over
sodium sulphate and evaporated down i. vac.. The residue is further reacted
without any more purification.
Yield: 7.50 g (90 %)
Rf value: 0.20 (silica gel; dichloromethane/ethanol = 50:1)
(b) 3-chloro-4-(M .41diazepan-1-vl)-benzoic acid
The residue obtained in Example 1a (7.50 g, 27.0 mmol) is refluxed for 8 h in 50
ml 25% potassium hydroxide solution. Then the mixture is adjusted to pH 5 with
cone, hydrochloric acid. The solid precipitated is filtered off, dried and further
reacted without any more purification.
Yield: 5.60 g (81%)
Rf value: 0.0 (silica gel; dichloromethane/ethanol = 9:1)
(c) methyl 3-chloro-4-(n .41diazepan-1-vl)-benzoate
The residue obtained in Example 1b (3.00 g, 11.8 mmol) is suspended in 100
ml of methanol and hydrogen chloride is piped in over 1 hour with stirring and
heating to reflux temperature. Then the mixture is evaporated down i. vac., the
residue is combined with 5% sodium hydrogen carbonate solution and extracted
3 times with dichloromethane. The combined organic phases are dried over
sodium sulphate. The residue remaining after evaporation i. vac. is further
reacted without any more purification.
Yield: 2.25 g (71%)
Rf value: 0.10 (silica gel; dichloromethane/ethanol = 4:1 + 2% ammonia)
Ci3Hi7CIN2O2 (268.75)
Mass spectrum: (M+H)+ = 269/271 (chlorine isotope)
(d) methvl 4-(4-A/-Boc-n .41diazepan-1-vl)-3-chloro-benzoate
The residue obtained in Example 1c (1.00 g, 3.72 mmol) is combined with 0.53
g (3.80 mmol) potassium carbonate in 10 ml dichloromethane and then 0.83 g
(3.80 mmol) di-tert. butyl pyrocarbonate are added dropwise. Then the mixture
is stirred for 16 hours at ambient temperature. Then it is diluted with
dichloromethane, washed twice with water, dried over sodium sulphate and
evaporated down i. vac.. Purification by chromatography on silica gel is then
carried out (eluant: methylene chloride/ethanol 99:1).
Yield: 1.34g(98%)
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 50:1)
C18H25CIN2O4 (368.86)
Mass spectrum: (M+H)* = 369/371 (chlorine isotope)
(e) 4-(4-/V-Boc-M .41diazepan-1-vlV3-chloro-benzoic acid
0.60 g (1.63 mmol) methyl 4-(4-A/-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate
are dissolved in 10 ml of methanol, combined with 4 ml 2-molar potassium
hydroxide solution and stirred for 3 hours at 40°C. Then the mixture is
evaporated down i. vac., the residue is diluted with distilled water, acidified with
saturated potassium hydrogen sulphate solution and extracted 3 times with
ethyl acetate. The combined organic phases are dried over sodium sulphate
and concentrated by evaporation. The residue is further reacted without any
more purification.
Yield: 0.50 g (87 %)
Rf value: 0.05 (silica gel; dichloromethane/ethanol = 50:1)
(354.84)
(f) 4-(4-A/-Boc-n.41diazeDan-1-vn-3-chloro-A/-r(1S)-1-(5-chloro-1Hbenzimidazol-
2-vl)-ethvn-benzamide
532 mg (1.50 mmol) 4-(4-/V-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acid are
suspended in 1 5 ml THF and after the addition of 546 mg (1 .70 mmol) TBTU
and 646 mg (5.0 mmol) DIPEA stirred for 30 minutes at ambient temperature.
Then 403 mg (1.50 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylaminedihydrochloride
are added and the mixture is stirred for a further 16 hours at
ambient temperature. It is then evaporated down i. vac., the residue is dissolved
in ethyl acetate, the organic phase is washed with 5% sodium hydrogen
carbonate solution and water and dried over sodium sulphate. After evaporation
i. vac. the residue remaining is purified by chromatography on silica gel (eluting
gradient: petroleum ether/ethyl acetate: 90:10 -> 60:40).
Yield: 630 mg (79 %)
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 19:1)
CaeHaiCbNsOg (532.48)
Mass spectrum: (M+H)+ = 532/534/536 (chlorine isotope)
(g) 3-chloro-A/-f(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vlVethvn-4-
(f 1 .41diazepan-1 -vl)-benzamide
A solution of 610 mg (1.15 mmol) 4-(4-A/-Boc-[1,4]diazepan-1-yl)-3-chloro-A/-
[(1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethyl]-benzamide in 30 ml
dichloromethane is combined with 3 ml TFA and stirred for 3 hours at ambient
temperature. Then it is evaporated down i. vac., the residue is taken up in ethyl
acetate, washed with 5% sodium hydrogen carbonate solution and water and
dried over sodium sulphate. After evaporation i. vac. the residue is purified by
chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate
80:20 -> 50:50).
Yield: 380 mg (77 %)
Rf value: 0.10 (silica gel; dichloromethane/ethanol = 9:1)
(432.36)
Mass spectrum: (M+H)+ = 432/434/436 (chlorine isotope)
The following compound was prepared analogously:
No.
115
structural formula yield mass peak(s) Rf value / Rt value
(Figure Removed)
(chlorine
isotope)
0.13
(silica gel,
dichloromethane/
methanol = 9:1)
A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1 ,4]-
diazepan-1 -yl)-benzamide
Example 2
4-(4-A/-Boc-piperazin-1 -
trifluoromethyl-benzamide
-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-
(a) 4-(piperazin-1 -vl)-3-trifluoromethvl-benzoic acid
37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g
(66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40 ml of ethanol.
Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water
are added and the mixture is refluxed for a further 3.5 hours and kept at
ambient temperature for a further 15 hours. Then 43.5 ml of cone, hydrochloric
acid are added and the mixture is cooled to 10°C for 30 minutes with stirring.
The precipitate obtained is suction filtered, washed with a little water and dried
at 40°C in the circulating air dryer for 24 hours.
Yield: 20.8 g (quantitative)
(b) methyl 4-(piperazin-1 -vl)-3-trifluoromethvl-benzoate
5.00 g (18.2 mmol) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid are stirred
16 hours in 50 ml of methanolic hydrochloric acid. After evaporation of the
reaction mixture i. vac. the residue is stirred with isopropanol. The solid is
filtered off, washed with diethyl ether and dried at 60°C in the circulating air
dryer.
Yield: 5.00 g (76%)
Ci3H15F3N202 * 2 HCI (288.27 / 361.19)
Mass spectrum: (M+H)+ = 289
Rf value: 0.58 (silica gel; cyclohexane/dichloromethane/methanol = 70:15:15 +
2% cone, ammonia solution)
(c) methyl 4-(4-A/-Boc-piperazin-1 -vl)-3-trifluoromethvl-benzoate
5.77 g (11.78 mmol) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoate are
placed in 100 ml THF and combined with 4.47 g (20.5 mmol) di-tert. butyl
pyrocarbonate. After 40 hours stirring at ambient temperature under a nitrogen
atmosphere the reaction mixture is evaporated down i. vac., the residue is
combined with water and sat. sodium chloride solution and extracted with ethyl
acetate. The combined organic phases are washed with water, semisaturated
and sat. sodium chloride solution, dried over magnesium sulphate and
evaporated down i. vac.. The residue is purified by chromatography on silica gel
(eluting gradient: petroleum ether/ethyl acetate 9:1 -> 8:1).
Yield: 2.60 g (34%)
Rf value: 0.52 (silica gel; petroleum ether/ethyl acetate 7:3 + 1% cone, ammonia
solution)
C18H23F3N204 (388.39)
Mass spectrum: (M+H)+ = 389
(d) 4-(4-/V-Boc-piperazin-1 -vl)-3-trifluoromethyl-benzoic acid
2.60 g (6.69 mmol) methyl 4-(4-A/-te/t-butoxylcarbonyl-piperazin-1-yl)-3-
trifluoromethyl-benzoate are dissolved in 10 ml of methanol and combined with
12.3 ml (12.3 mmol) 1-molar sodium hydroxide solution. After 15 minutes a
further 1 0 ml of methanol are added and the reaction mixture is stirred for 42
hours at ambient temperature. Then the mixture is evaporated down i. vac., the
residue is combined with ice and acidified with acetic acid. The precipitate
obtained is suction filtered, washed with water and dried in the circulating air
dryer at 50°C and in the drying pistol at 40°C over KOH and SiO2.
Yield: 2.40 g (96%)
Rf value: 0.41 (silica gel; petroleum ether/ethyl acetate = 1:1 +1% acetic acid)
C17H2iF3N204 (374.36)
Mass spectrum: (M-H)~ = 373
(e) 4-(4-A/-Boc-piperazin-1 -vl)-A/-f(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vOethvn-
3-trifluoromethyl-benzamide
Prepared analogously to Example 1f from 4-(4-A/-Boc-piperazin-1-yl)-3-
trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1Hbenzimidazol-
2-yl)ethylamine in NMP and subsequent purification by
chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 50:50).
Yield: 57%
Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 1:1)
Mass spectrum: (M+H)+ = 552/554 (chlorine isotope)
Example 3
-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1
trifluoromethyl-benzamide
Prepared analogously to Example 1g from 4-(4-A/-Boc-piperazin-1-yl)-A/-[(1S)-1-
(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide and TFA in
dichloromethane.
Yield: 73%
Rf value: 0.28 (silica gel; dichloromethane/methanol = 90:10 + ammonia
solution)
C2iH2iCIF3N5O * 2 CF3COOH (679.93 / 451.88)
Mass spectrum: (M+H)+ = 452/454 (chlorine isotope)
The following were prepared analogously to the sequence described in
Examples 2 and 3:
No.
structural formula yield mass peak(s) Rf value
Name
(Figure Removed)
A/-[(1 R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-
(piperazin-1-yl)-3-trifluoromethyl-benzamide
structural formula yield mass peak(s) Rf value
Name
(Figure Removed)
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-
(piperazin-1-yl)-3-trifluoromethyl-benzamide
Example 5
4-(4-/V-acetyl-piperazin-1 -
trifluoromethyl-benzamide
-chloro-1H-benzimidazol-2-yl)-ethyl]-3-
220 mg (0.32 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-
(piperazin-1-yl)-3-trifluoromethyl-benzamide-ditrifluoroacetate in 5 ml THF are
combined with 0.23 ml (1.65 mmol) TEA, 50 ul (0.70 mmol) acetylchloride are
added dropwise with stirring and cooling in the ice bath and stirred for 2 hours
at ambient temperature. The reaction mixture is poured into ice water and then
extracted with ethyl acetate. The organic phase is washed with water and sat.
sodium chloride solution, dried over sodium sulphate and evaporated down i.
vac.. The residue is triturated with a solvent mixture of ethyl acetate and diethyl
ether, filtered off, washed with diethyl ether and dried in a drying pistol at 50°C .
Yield: 0.13 g (81%)
Rf value: 0.55 (silica gel; dichloromethane/ethanol = 9:1 + ammonia solution)
(493.92)
Mass spectrum: (M+H)+ = 494/496 (chlorine isotope)
Example 6
4-(azepan-2-on-1 -yl)-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methylbenzamide
(a) methyl 4-(6-bromo-hexanovl-amino)-3-methvl-benzoate
A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is
slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol)
methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16
hours stirring at ambient temperature the mixture is evaporated down i. vac., the
residue is dissolved in dichloromethane, washed twice with water and dried
over sodium sulphate. The residue remaining after evaporation i. vac. is further
reacted without any more purification.
Yield: 3.30 g (96%)
Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 4:1)
(342.24)
(b) methyl 4-(azepan-2-on-1 -vl)-3-methvl-benzoate
3.20 g (9.35 mmol) of the product obtained in Example 5a is refluxed for 4 hours
in a freshly prepared solution of 1 .00 g (43.5 mmol) sodium in 80 ml of
methanol. Then the mixture is evaporated down i. vac., the residue is acidified
with 2-molar acetic acid and extracted with ethyl acetate. The combined organic
phases are washed with water and dried over sodium sulphate. The residue
obtained after evaporation i. vac. is further reacted without any more
purification.
Yield: 1.90 g (contaminated product)
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 50:1)
Ci5Hi9NO3(261.32)
Mass spectrum: (M+H)+ = 262
(c) 4-(azepan-2-on-1 -vl)-3-methvl-benzoic acid
1.90 g of the product obtained in Example 5b in 30 ml of methanol is combined
with 10 ml 2-molar sodium hydroxide solution and stirred for 16 hours at
ambient temperature. After evaporation i. vac. the residue is combined with
water and acidified with cone, hydrochloric acid. The precipitate formed is
filtered off and dried. After dissolving in methanol and applying to silica gel the
product is purified by chromatography on silica gel (eluting gradient: petroleum
ether/ethyl acetate 70:30 -> 50:50).
Yield: 0.23 g (10% over 2 steps)
Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 1:2)
Ci4Hi7NO3 (247.30)
Mass spectrum: (M+H)+ = 248
(d) 4-(azepan-2-on-1 -vlVA/-r(1 SM -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-3-
methvl-benzamide
Prepared analogously to Example 1f from 4-(azepan-2-on-1-yl)-3-methylbenzoic
acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-
yl)ethylamine in THF and subsequent purification by chromatography on silica
gel (eluting gradient: ethyl acetate/ethanol 95:5 -> 90:10).
Yield: 61%
Rf value: 0.30 (silica gel; ethyl acetate)
C23H25CIN4O2 (424.93)
Mass spectrum: (M+H)+ = 425/427 (chlorine isotope)
The following compounds were prepared analogously:
(Figure Removed)
structural formula yield mass
peak(s)
Rf value
Name
(Figure Removed)
(chlorine
isotope)
0.60
(aluminium oxide,
CH2CI2/C2H5OH
19:1)
4-(azepan-2-on-1 -yl)-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethyl]-3-methyl-benzamide
(Figure Removed)
(M+H)+ =
441/443
(chlorine
isotope)
0.20
(silica gel,
CHzCla/CaHgOH
19:1)
4-(azepan-2-on-1 -yl)-A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
hydroxy-ethyl]-3-methyl-benzamide
(Figure Removed)
(M+H)+ =
397/399
(chlorine
isotope)
0.50
(silica gel, CH2CI2
/C2H5OH9:1)
/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-
2-on-1 -yl)-benzamide
(Figure Removed)
(silica gel, CH2CI2
/C2H5OH9:1)
A/-[(1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-
methyl-4-(pyrrolidin-2-on-1-yl)-benzamide
-98-
Example 9
A/-[(1 S>1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1 -yl)-
benzamide
(a) 4-(pyrrolidin-2-on-1 -vl)-benzoic acid
19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hours together with
25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF. After evaporation i.
vac. the residue is combined with 100 ml of water and 50 ml petroleum ether
and vigorously stirred for 50 minutes. The precipitate is filtered off, recrystallised
from ethanol and dried at 80°C.
Yield: 9.36 g (33%)
CnHnNOa (205.22)
Mass spectrum: (M+H)+ = 206
(b) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-f pvrrolidin-2-on-1 -vl)-
benzamide
Prepared analogously to Example 1f from 4-(pyrrolidin-2-on-1-yl)-benzoic acid,
TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine in THF
and subsequent purification by washing the solution of the residue in ethyl
acetate with water, dilute sodium hydrogen carbonate solution, water and sat.
sodium chloride solution, drying over sodium sulphate and eliminating the
solvent!, vac..
Yield: 61%
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1)
C2oHi9CIN4O2 (382.85)
Mass spectrum: (M+H)+ = 383/385 (chlorine isotope)
Example 12
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-A/-methyl-
[1,4]diazepan-1-yl)-benzamide
(a) 3-chloro-4-(4-A/-methvl-M ,41diazepan-1 -vl)-benzonitrile
Prepared analogously to Example 1a from 3-chloro-4-fluoro-benzonitrile and 1-
methyl-[1,4]diazepan in DIPEA with subsequent purification by chromatography
on silica gel (eluting gradient: dichloromethane/ethanol 98:2 -> 94:6).
Yield: 71%
Rf value: 0.20 (silica gel; methylene chloride/ethanol = 19:1)
C13H16CIN3 (249.75)
Mass spectrum: (M+H)+ = 250/252 (chlorine isotope)
(b) 3-chloro-4-(4-/V-methvl-M .41diazepan-1-vl)-benzoic acid
Prepared analogously to Example Ibfrom 3-chloro-4-(4-methyl-[1,4]diazepan-
1-yl)-benzonitrile in 25% aqueous potassium hydroxide solution.
Yield: 99%
C13H17CIN2O2 * HCI (268.74 / 305.21)
Mass spectrum: (M+H)+ = 269/271 (chlorine isotope)
(c) 3-chloro-A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(4-A/-methvlf1.41diazepan-
1-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(4-methyl-[1,4]diazepan-1-
yl)-benzoic acid, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and
DIPEA in THF with subsequent purification by chromatography on silica gel
(eluting gradient: petroleum ether/ethyl acetate 50:50 -> 20:80).
Yield: 34%
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1 + 1% ammonia
solution)
Mass spectrum: (M+H)+ = 446/448/450 (chlorine isotope)
Example 13
3-chloro-/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin-
1 -yl)-benzamide
ci
(a) 3-chloro-4-(2-methvl-pvrrolidin-1-vl)-benzonitrile
5.90 g (37.9 mmol) 3-chloro-4-fluoro-benzonitrile are dissolved in 65 ml DMF
under a nitrogen atmosphere and combined with 5.45 g (39.5 mmol) potassium
carbonate and 4.2 ml (3.5 g, 39.5 mmol) 2-methyl-pyrrolidine. After stirring for
2.5 days at 90°C the reaction mixture is poured into 400 ml of water and
extracted with ethyl acetate. The combined organic phases are washed several
times with dilute and sat. sodium chloride solution, dried over magnesium
sulphate and evaporated down i. vac.. The residue remaining is further reacted
without any more purification.
Yield: 7.90 g (94%)
Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 9:1 + 0.5% ammonia
solution)
C12H13CIN2 (220.70)
Mass spectrum: (M+H)+ = 221/223 (chlorine isotope)
(b) 3-chloro-4-(2-methvl-pvrrolidin-1 -vl)-benzoic acid
8.0 g (40 mmol) of the product obtained in Example 13a are stirred in a mixture
of 65 ml 10-molar sodium hydroxide solution and 65 ml of ethanol for 2.75 hours
at 90°C. Then the reaction mixture is poured into ice water, combined with cone,
hydrochloric acid and volatile organic constituents are evaporated down i. vac..
The aqueous phase remaining is extracted with dichloromethane, combined
with ice and adjusted to pH 4.5 with semiconcentrated hydrochloric acid and 2-
normal potassium hydrogen sulphate solution. The resulting precipitate is stirred
for another 10 minutes, then filtered off, washed with water and dried at 55°C.
Yield: 8.30 g (87%)
Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate = 6:4 + 1% acetic acid)
Ci2Hi4CINO2 (238.72)
Mass spectrum: (M+H)+ = 240/242 (chlorine isotope)
(c) 3-chloro-A/-rf 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl)-4-(2-methvlpyrrolidin-
1 -vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(2-methyl-pyrrolidin-1-yl)-
benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylarnine, TBTU and
TEA in DMF, then precipitated by pouring into dilute sodium hydrogen
carbonate solution, filtering and washing with water. Then the product is dried at
55°C.
Yield: 92%
Rt value: 0.66 (silica gel; dichloromethane/ethanol = 9:1)
C2iH22Cl2N4O(417.34)
Mass spectrum: (M-H)~ = 415/417/419 (chlorine isotope)
The following compounds were prepared analogously:
No
•(Table Removed)
Example 21
A/-[(1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-
4-yl)-3-trifluoromethyl-benzamide
(a) 4-fmorpholin-3-on-4-vl)-3-trifluorornethvl-benzoicacid
1.00 g (3.63 mmol) 4-(morpholin-4-yl)-3-trifluoromethyl-benzbic acid (prepared
by synthesis sequence analogously to Example 13a and 13b) is suspended in
40 ml of water and 150 mg (3.75 mmol) sodium hydroxide are added. Then 1.73
g (10.92 mmol) potassium permanganate are added and the mixture is stirred
for 1.5 hours at 45°C. Then the reaction mixture is cooled in the ice bath and
sodium thiosulphate is added until total decolonisation is obtained. After
extraction 3 times with ethyl acetate the combined organic phases are dried
over sodium sulphate and evaporated down i. vac.. After application of the
residue to silica gel it is purified by chromatography on silica gel (eluant:
dichloromethane/methanol 95:5).
Yield: 340 mg (32%)
C12HioF3NO4 (289.21)
Mass spectrum: (M+H)+ = 290
(b) A/'-(2-amino-4-chloro-phenvl)-A/-Boc-(S)-O-methvl-serinamide and N'-(2-
amino-5-chloro-Dhenvl)-A/-Boc-(S)-Q-methvl-serinamide
30.0 g (137 mmol) A/-Boc-(S)-O-methyl-serine are dissolved together with 21.9
g (154 mmol) 4-chloro-1 ,2-phenylenediamine in 658 ml THF, and 43.9 ml (316
mmol) triethylamine and 103 ml (173 mmol) of a 50 % solution of PPA in ethyl
acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice
bath the mixture is heated to ambient temperature, poured into water and the
aqueous phase is extracted with ethyl acetate. The combined organic phases
are washed with sat. sodium carbonate solution and water, dried over sodium
sulphate and evaporated down i. vac.. The residue is purified by
chromatography on silica gel (eluting gradient: dichloromethane/methanol =
30:1 -> 9:1).
Yield: 33.47 g (72 %) mixture of the two regioisomers
Ci5H22CIN3O4 (343.81)
Mass spectrum: (M-H)~ = 342/344 (chlorine isotope)
Rf value: 0.80 (silica gel; dichloromethane/methanol = 9:1)
(c) ( 7ffl-/V-Boc-1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvlamine
26.01 g (75.65 mmol) of the mixture obtained in Example 21 b are dissolved in
1500 ml of toluene and 20.8 ml (364 mmol) acetic acid and 10.0 g molecular
sieve, 4A, are added. The reaction mixture is stirred for 5 hours at 60°C. The
reaction mixture is filtered, washed again with ethyl acetate and the organic
phase is washed with semisat. sodium hydrogen carbonate solution, dried over
sodium sulphate and evaporated down i. vac.. The residue is stirred with diethyl
ether and the crystals formed are suction filtered. The filtrate is evaporated
down i. vac. and the residue is purified by three lots of chromatography on silica
gel (eluting gradient: dichloromethane/methanol 80:1 -> 50:1).
Yield: 1 3.85 g (56%)
C15H2oCIN303 (325.79)
Mass spectrum: (M+H)+ = 326/328 (chlorine isotope)
Rf value: 0.29 (silica gel; dichloromethane/methanol = 30:1)
(d) (1f?V1-(5-chloro-1H-benzimidazol-1-vl)-2-methoxv-ethvlamine
0.50 g (1.54 mmol) (1fi)-/v"-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine
in 1.5 ml dichloromethane are combined with 1.54 ml (20.0 mmol)
TFA and stirred for 2 h at ambient temperature. The mixture is then poured into
sat. sodium hydrogen carbonate solution and after thorough mixing the aqueous
phase is extracted with dichloromethane and ethyl acetate. The combined
organic phases are dried over sodium sulphate and purified by chromatography
on silica gel (eluant: dichloromethane/methanol = 9:1 + 1% cone, ammonia
solution).
Yield: 0.35 g (quant.)
C10H12CIN3O (225.68)
Mass spectrum: (M-H)~ = 224/226 (chlorine isotope)
Rf value: 0.40 (silica gel, dichloromethane/methanol 9:1 + 1% cone, ammonia
solution)
(e) A/-K1 /?)-1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvn-4-
(moroholin-3-on-4-vlV3-trifluoromethvl-benzamide
Prepared analogously to Example 1f from 4-(morpholin-3-on-4-yl)-3-
trifluoromethyl-benzoic acid, (1 R)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-2-methoxyethylamine,
TBTU and NMM in DMF, then precipitation by pouring into water,
filtering and drying i. vac..
Yield: 63%
Rf value: 0.57 (silica gel; dichloromethane/methanol = 9:1)
C22H2oCIF3N404 (496.88)
Mass spectrum: (M+H)+ = 497/499 (chlorine isotope)
The following compounds were prepared analogously:
No. structural formula Yield mass peak(s) Rf value or Rt
(Table Removed)
Example 22
-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d
and 21 a), (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU
and NMM in DMF, then pouring into water, extracting with ethyl acetate, drying
over sodium sulphate, evaporation i. vac. and purifying by chromatography on
silica gel (eluting gradient: ethyl acetate/isopropanol/ethanol 9:1:0 -> 9:0:1).
Yield: 99%
Rf value: 0.13 (silica gel; dichloromethane/isopropanol = 19:1)
C22H23CIN4O4 (442.91)
Mass spectrum: (M+H)+ = 443/445 (chlorine isotope)
The following compounds were prepared analogously:
No.
(Table Removed)
Example 27
-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-
benzamide
254 mg (1.15 mmol) 4-(rnorpholin-3-on-4-yl)-benzoic acid (prepared by
synthesis sequence analogously to Example 30a, 2d and 21 a) are placed in 5
ml DMF and 428 mg (1.0 mmol) PfTU and 514 ul (3.0 mmol) DIPEA are added.
After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1 S)-1-
(5-chloro-1/-/-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the
mixture is stirred for 16 hours at ambient temperature. Then the reaction
mixture is filtered through basic aluminium oxide and evaporated down i. vac..
The residue is purified by chromatography on silica gel (eluting gradient:
dichloromethane/methanol 100:0 -> 90:10), the corresponding fractions are
evaporated down i. vac., the residue is dissolved in acetonitrile/water and
lyophilised.
Yield: 77%
Mass spectrum: (M+H)* = 399/401 (chlorine isotope)
The following compound is prepared analogously:
No.
(Table Removed)
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-
3-on-4-yl)-benzamide
Example 29
-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-A/-methyl-
[1 ,4]diazepan-1 -yl)-benzamide
(a) 4-fluoro-3-methvl-benzoic acid chloride
14.00 g (90.8 mmol) 4-fluoro-3-methyl-benzoic acid are refluxed for 1 hour
together with 50 ml of thionyl chloride and then evaporated down i. vac.. The
residue is further reacted without any more purification.
Yield: 15.70 g (quantitative)
C8H6CIFO (172.59)
(b) 4-fluoro-3-methvl-benzamide
15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in 30 ml
THF are added dropwise to 300 ml of cone, ammonia solution and then stirred
for 2 hours at ambient temperature. The precipitate formed is filtered off,
washed with water and dried.
Yield: 10.00 g (72%)
C8H8FNO(153.16)
Rf value: 0.31 (aluminium oxide; dichloromethane/methanol = 50:1)
(c) 4-fluoro-3-methvl-benzonitrile
10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirred together
with 50 ml phosphorus oxychloride for 4 hours at 60°C and then evaporated
down i. vac.. The residue is poured into ice water, the resulting precipitate is
filtered off and washed with water. After being taken up in ethyl acetate the
organic phase is washed with sat. potassium carbonate solution, dried over
sodium sulphate and evaporated down completely i. vac..
Yield: 8.00 g (91%)
C8H6FN(135.14)
Rf value: 0.84 (silica gel; dichloromethane)
(d) 3-methvl-4-(4-A/-methvl-ri .41diazepan-1 -vD-benzonitrile
7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110°C together
with 1-A/-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac.
the residue is separated on aluminium oxide (eluant: dichloromethane) and the
corresponding fractions are again purified on silica gel (eluting gradient:
dichloromethane/methanol 100:1 ->9:1).
Yield: 1.70 g (14%)
Ci4H19N3 (229.33)
Mass spectrum: (M+H)+ = 230
Rf value: 0.25 (silica gel; dichloromethane/methanol = 9:1)
(e) 3-methyl-4-(4-A/-methvl-ri .41diazepan-1-vl)-benzoic acid
Prepared analogously to Example 1 b from 3-methyl-4-(4-/V-methyl-
[1,4]diazepan-1-yl)-benzonitrile with 25% potassium hydroxide solution by
refluxing for 36 hours. After evaporation i. vac. the residue is separated on
aluminium oxide (eluant: dichloromethane) and the corresponding fractions are
again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1 ->
9:1).
Yield: 14%
Ci4H19N202 (248.33)
Mass spectrum: (M+H)+ = 249
Rf value: 0.30 (RP-18; methanol/5% aqueous sodium chloride solution = 6:4)
(f) 3-methvl-4-(4-A/-methvl-ri.41diazepan-1-vl)-benzoic acid chloride
Prepared analogously to Example 29a from 3-methyl-4-(4-A/-methyl-
[1,4]diazepan-1-yl)-benzoic acid and thionyl chloride.
Yield: quantitative
C14H19CIN2O * HCI (266.77 / 303.23)
(g) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4-(4-A/-methvl-
M .41diazepan-1-vl)-benzamide
489 mg (1.61 mmol) 3-methyl-4-(4-A/-methyl-[1,4]diazepan-1-yl)-benzoic acid
chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at
ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1Hbenzimidazol-
2-yl)-ethylamine is added dropwise with stirring. After 16 hours
stirring at ambient temperature the mixture is evaporated down i. vac., the
residue is combined with water and extracted with ethyl acetate. The combined
organic phases are washed with sat. sodium chloride solution, dried over
sodium sulphate and evaporated down i. vac.. The residue is purified by
chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1).
The fractions evaporated down are treated with ethereal hydrochloric acid, after
total concentration evaporated twice with ethyl acetate and diethyl ether and
dried i. vac. at 70°C.
Yield: 120mg(16%)
C23H28CIN5O * HCI (462.43 / 425.96)
Mass spectrum: (M+H)+ = 426/428 (chlorine isotope)
Rf value: 0.47 (aluminium oxide; dichloromethane/methanol 19:1)
Example 30
A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1 -yl)-
benzamide
(a) methyl 4-(A/-Boc-piperazin-1 -vl)-3-methvl-benzoate
4.00 g (17.5 mmol) 4-bromo-3-methyl-benzoate methyl are suspended together
with 3.92 g (21.0 mmol) A/-Boc-piperazine, 39.2 mg (175 |jmol)
palladium(ll)acetate, 50.7 mg (175 umol) tri-te/t-butyl-phosphoniumtetrafluoroborate
and 11.12 g (52.4 mmol) potassium phosphate in 35 ml of
toluene and under an argon atmosphere heated to 150°C for 10 minutes in a
microwave oven. Then the reaction mixture is poured into water, stirred
vigorously and extracted 3 times with ethyl acetate. The combined organic
phases are dried over sodium sulphate, applied to silica gel and purified by
chromatography on silica gel (eluant: dichloromethane/methanol 80:1).
Yield :1.42 g (24%)
C18H26N204 (334.42)
Mass spectrum: (M+H)+ = 335
Rf value: 0.52 (silica gel; dichloromethane/methanol = 50:1)
(b) 4-(A/-Boc-piperazin-1 -vn-3-methvl-benzoic acid
1.42 g (4.24 mmol) of methyl 4-(A/-Boc-piperazin-1-yl)-3-methyl-benzoate are
dissolved in 7 ml THF and 9.25 ml of water and 893 mg (21.3 mmol) lithium
hydroxide-monohydrate are added. After stirring for 16 hours at ambient
temperature the mixture is heated to 45°C for 2 hours. Then another 893 mg
(21.3 mmol) lithium hydroxide monohydrate are added and the mixture is stirred
for 4 days at ambient temperature. Then it is neutralised with 1 -molar
hydrochloric acid and the reaction mixture is extracted with ethyl acetate. The
combined organic phases are dried over sodium sulphate and evaporated down
completely i. vac-
Yield: 1.29 g (95%)
Ci7H24N2O4 (320.39)
Mass spectrum: (M+H)+ = 321
Rf value: 0.29 (silica gel; dichloromethane/methanol = 15:1)
(c) 4-(A/-Boc-piperazin-1-vl)-/V-r(1S)-1-(5-chloro-1H-benzimidazol-2-vl)-
ethvl)-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(A/-Boc-piperazin-1-yl)-3-methylbenzoic
acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and
NMM in DMF, then stirring into cone, sodium hydrogen carbonate solution,
extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac.
and purification of the residue by chromatography on silica gel (eluting gradient:
dichloromethane/methanol 50:1 -> 15:1).
Yield: 85%
Rf value: 0.15 (silica gel; dichloromethane/methanol = 30:1)
Mass spectrum: (M+H)'1' = 498/500 (chlorine isotope)
(d) A/-K1 SM -f 5-chloro-1 H-benzimidazol-2-vl Vethvn-3-methvl-4-(piperazin-1 -
vD-benzamide
Prepared analogously to Example 1g from 4-(/V-Boc-piperazin-1-yl)-A/-[(1S)-1-
(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide and TFA in
dichloromethane.
Yield: quantitative
C2iH24CIN5O (397.91)
Mass spectrum: (M+H)+ = 398/400 (chlorine isotope)
Rf value: 0.14 (silica gel; dichloromethane/methanol = 9:1)
The following compound is prepared analogously:
No.
(Table Removed)
Example 31
/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1 -
yl)-benzamide
(a) methyl 4-(A/-Boc-piperazin-2-on-1 -vl)-3-methvl-benzoate
758 mg (3.31 mmol) methyl 4-bromo-3-methyl-benzoate are suspended
together with 796 mg (21.0 mmol) 4-A/-Boc-piperazin-2-one, 31.8 mg (167
copper(l)iodide, 35.1 ul (330 umol) A/,/V'-dimethyl-ethylenediamine and 0.92 g
(6.62 mmol) potassium carbonate in 6.6 ml of toluene and under an argon
atmosphere heated to 140°C in a microwave oven with stirring for 1.5 hours.
Then the reaction mixture is poured into water, stirred vigorously and extracted
3 times with ethyl acetate. The combined organic phases are dried over sodium
sulphate, applied to silica gel and purified by chromatography on silica gel
(eluant: dichloromethane/methanol 50:1).
Yield: 679 mg (59%)
Mass spectrum: (M+H)+ = 349
Rf value: 0.25 (silica gel; dichloromethane/methanol = 50:1)
(b) 4-(/V-Boc-piperazin-2-on-1 -vl)-3-methvl-benzoic acid
775 mg (2.22 mmol) methyl 4-(/V-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate
are dissolved in 3.7 ml THF and 4.9 ml of water as well as 468 mg (1 1 .2 mmol)
lithium hydroxide-monohydrate are added. After stirring for 16 hours at ambient
temperature the mixture is neutralised with 1 -molar hydrochloric acid and the
reaction mixture is extracted with ethyl acetate. The combined organic phases
are dried over sodium sulphate and evaporated down completely i. vac..
Yield: 664 mg (89%)
Ci7H22N205 (334.38)
Mass spectrum: (M+H)"1" = 335
Rf value: 0.31 (silica gel; dichloromethane/methanol = 15:1)
(c) 4-(A/-Boc-piperazin-2-on-1 -vl)-/V-rf 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-
ethvD-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(A/-Boc-piperazin-1-yl)-3-methylbenzoic
acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and
NMM in DMF, then stirring into cone, sodium hydrogen carbonate solution,
extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac.
and purification of the residue by chromatography on silica gel (eluant:
dichloromethane/methanol 30:1).
Yield: 71%
Rf value: 0.30 (silica gel; dichloromethane/methanol = 15:1)
C26H3oCIN504(512.01)
Mass spectrum: (M+H)* =512/514 (chlorine isotope)
(d) A/-F(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4-(piperazin-2-
on-1-vn-benzamide
Prepared analogously to Example Igfrom 4-(A/-Boc-piperazin-1-yl)-A/-[(1S)-1-
(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide and TFA in
dichloromethane.
Yield: 36%
C2iH22CIN5O2(411.90)
Mass spectrum: (M+H)+ = 412/414 (chlorine isotope)
Rf value: 0.42 (silica gel; dichloromethane/methanol = 9:1)
The following compounds were prepared analogously:
No.
66
98
structural formula Yield mass peak(s) Rf value or Rt
Name
(Table Removed)
Example 32
-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1 •
yl)-benzamide
(a) methyl 3-methvl-4-(piperidin-2-on-1 -vl)-benzoate
Prepared analogously to Example 31 a from methyl 4-bromo-3-methyl-benzoate
and piperidin-2-one in the presence of copper(l)iodide, A/,/V'-dimethylethylenediamine
and potassium carbonate in toluene and dioxane under an
argon atmosphere.
Yield: 34%
C14Hi7NO3 (247.30)
Mass spectrum: (M+H)+ = 248
Rf value: 0.21 (silica gel; petroleum ether/ethyl acetate = 1:1)
(b) 3-methvl-4-(piperidin-2-on-1 -vl)-benzoic acid
Prepared analogously to Example 2d from methyl 3-methyl-4-(piperidin-2-on-1-
yl)- benzoate and 1 -molar sodium hydroxide solution in methanol.
Yield: 83%
C3Hi5N03 (233.27)
Mass spectrum: (M+H)+ = 234
Rf value: 0.51 (silica gel; ethyl acetate/ethanol = 9:1 + 1% cone, ammonia
solution)
(c) A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl)-3-methvl-4-(piperidin-2-
on-1 -vO-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(piperidin-1-yI)-benzoic
acid, (1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethylamine, TBTU and NMM in
DMF, then stirring into ice water, combining with ammonia solution, filtering,
taking up in dichloromethane, evaporation i. vac. and purification of the residue
by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc.
ammonia solution 19:1) 1:0 -> 9:1).
Yield: 32%
Rf value: 0.30 (silica gel; ethyl acetate/ethanol = 9:1 + 1% acetic acid)
Mass spectrum: (M+H)* =41 1/41 3 (chlorine isotope)
The following compounds were prepared analogously:
No.
(Table Removed)
Example 33
A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(/\/-methyl-piperazin-1-yl)-3-
trifluoromethyl-benzamide
170 mg (0.24 mmol) /V-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-
(piperazin-1-yl)-3-trifluoromethyl-benzamide are suspended in 2 ml 1,2-
dichloroethane and under a nitrogen atmosphere combined with 20 mg (0.67
mmol) paraformaldehyde and 76 mg (0.36 mmol) sodium triacetoxyborohydride.
After the addition of 5 ml THF the reaction mixture is stirred for 6 hours at
ambient temperature,- then 100 mg (3.33 mmol) of paraformaldehyde and 100
mg (0.47 mmol) sodium triacetoxyborohydride are added and the mixture is
stirred for a further 22 hours at ambient temperature. Then it is combined with
sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The
combined organic phases are dried over magnesium sulphate, evaporated
down i. vac. and purified by chromatography on silica gel (eluting gradient:
dichloromethane/(methanol/conc. ammonia solution 19:1) 100:0 -> 92:8).
Yield: 70 mg (59%)
C23H25CIF3N5O2 (495.94)
Mass spectrum: (M+H)+ = 496/498 (chlorine isotope)
Rf value: 0.25 (silica gel; dichloromethane/methanol = 9:1 + 1% cone, ammonia
solution)
Example 34
-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl-
4-(morpholin-3-on-4-yl)-benzamide
150 mg (0.32 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-
methylsulphanyl-prop-1-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamideare
dissolved in a mixture of 10 ml dichloromethane and 1 ml acetic acid at -15°C
and combined with 204 mg (0.89 mmol) 3-chloroperbenzoic acid. The mixture is
then stirred for 30 minutes at -15 to -10°C, heated to ambient temperature and
stirred for a further 16 hours. Then the reaction mixture is washed twice with 5%
sodium hydrogen carbonate solution, dried over sodium sulphate, evaporated
down i. vac. and purified by chromatography on silica gel (eluant:
dichloromethane/ethanol 95:5).
Yield: 80 mg (50%)
C23H25CIN4O5S (505.00)
Mass spectrum: (M+H)+ = 505/507 (chlorine isotope)
Rf value: 0.45 (silica gel; dichloromethane/ethanol = 9:1)
Example 35
-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(pyrrolidin-2-on-1-yl)-benzamide
Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid,
(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU
and TEA in DMSO at ambient temperature and subsequent Boc cleaving with
TFA analogously to Example 1g.
HPLC-MS results:
retention time: 3.69 min
C22H23CIN4O2S (442.97)
Mass spectrum: (M+H)+ = 443/445 (chlorine isotope)
The following compound is prepared analogously:
No.
36
(Table Removed)
Example 39
A/-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-rnethyl-4-([1,3]oxazepan-2-
on-3-yl)-benzamide
(a) methyl 4-isocvanato-3-methvl-benzoate
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml
dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroforrnate and
refluxed for 5. 5 hours with stirring. Then the mixture is evaporated down i. vac.
and the residue is further reacted without any more purification.
Yield: 1.74 g (quantitative)
C10H9NO3(191.19)
(b) methyl 4-(A/-r4-chlorobutoxvcarbonvl1-amino)-3-methvl-benzoate
1.74 g (9.08 mmol) 4 methyl -isocyanato-3-methyl-benzoate dissolved in 100 ml
of toluene are combined with 1.07 ml (9.11 mmol) 85 %m 4-chloro-butan-1-ol.
The mixture is refluxed for 17 hours with stirring. After evaporation i. vac. the
residue is purified by chromatography on silica gel (eluting gradient: petroleum
ether/ethyl acetate 17:3 -> 17:4).
Yield: 1.19 g (44%)
C14H18CINO4 (299.76)
Mass spectrum: (M-H)~ = 298/300 (chlorine isotope)
Rf value: 0.45 (silica gel; petroleum ether/ethyl acetate = 80:20)
(c) methyl 3-methvl-4-(M ,31oxazepan-2-on-3-yl)-benzoate
300 mg (1.00 mmol) methyl 4-(A/-[4-chlorobutoxycarbonyl]-amino)-3-methyl-
125-
benzoate are dissolved in 10 ml DMF combined with 168 mg (1.50 mmol)
potassium-terf.-butoxide and stirred for 3 hours at 60°C. The reaction mixture is
mixed with water and extracted 3 times with ethyl acetate. The combined
organic phases are dried over sodium sulphate and evaporated down i. vac..
Then the residue is purified by chromatography on silica gel (eluant: petroleum
ether/ethyl acetate 3:2).
Yield: 160mg(61%)
Rf value: 0.26 (silica gel; petroleum ether/ethyl acetate 3:2)
C14H17NO4 (263.30)
Mass spectrum: (M+H)+ = 264
(d) 3-methvl-4-(f 1.31oxazepan-2-on-3-vl)-benzoic acid
150 mg (0.57 mmol) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate are
suspended in 1 ml of ethanol and combined with 0.26 ml (0.87 mmol) 8%
aqueous lithium hydroxide solution. The mixture is stirred for 3 hours at ambient
temperature and then evaporated down i. vac.. The aqueous residue is
extracted twice with ethyl acetate, then acidified and extracted twice more with
ethyl acetate. The combined organic phases are dried over sodium sulphate
and evaporated down i. vac..
Yield: 122 mg (86%)
C13H15NO4 (249.27)
Mass spectrum: (M+H)+ = 250
Rf value: 0.14 (silica gel; dichloromethane/methanol = 95:5)
(e) A/-K1 S)-1-(5-chloro-1 H-benzimidazol-2-vl)-ethvn-3-methvl-4-
(M.31oxazepan-2-on-3-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-
benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and
NMM in DMF, then acidifying with TFA and purification of the residue by
chromatography (preparative HPLC).
Yield: 54%
C22H23CIN4O3 * 2 CF3COOH (654.96 / 426.90)
Mass spectrum: (M+H)"1"
(Table Removed)
Example 41
-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(morpholin-3-on-4-yl)-3-nitro-benzamide
(a) methyl 4-(morpholin-3-on-4-vl)-3-nitro-benzoate
1 .00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml
dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen
atmosphere and 36.6 mg (40 jjmol) tris-(dibenzylideneacetone)-dipalladium(0),
67.1 mg (116 urnol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are
added. Under a nitrogen atmosphere and with stirring, the reaction mixture is
heated to 95°C for 16 hours. Then it is filtered, the solution is evaporated down
i. vac. and evaporated with ether. The residue is further reacted without any
more purification. Yield: 1 .31 g (quantitative)
Mass spectrum: (M+H)"1" = 281
(b) 4-(2-carboxvmethoxv-ethvlamino)-3-nitro-benzoicacid
400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate are
dissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol) 1 -molar
lithium hydroxide solution. The mixture is stirred for 2 hours at ambient
temperature. Then it is evaporated down i. vac., the residue is diluted with
water, cooled in the ice bath and acidified with 2-molar hydrochloric acid. After
10 minutes cooling in the ice bath the precipitate formed is filtered off, washed
with water until neutral and dried at 50°C in the drying cupboard.
Yield: 290 mg (72 %)
CiiHi2N2O7 (284.23)
Mass spectrum: IvT = 284
Rf value: 0.59 (Reversed phase 8; methanol/5% sodium chloride solution = 6:4)
(c) 4-(morpholin-3-on-4-vl)-3-nitro-benzoic acid-chloride
290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid in
100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionyl
chloride and 2 drops of DMF and refluxed for one day. After evaporation of the
solution i. vac. it is evaporated with toluene and the residue is further reacted
without any more purification.
Yield: 290 mg (quant.)
(284.66)
(d) /V-rn S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methvlsulphanvl-Dropvl1-4-
(morpholin-3-on-4-vl)-3-nitro-benzamide
237 mg (0.93 mmol) of (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-
methylsulphanyl-propylamine are dissolved with 0.257 ml TEA in 10 ml THF
and a solution of 290 mg (1 .02 mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic
acid chloride in 10 ml THF is added dropwise. The reaction mixture is stirred for
16 hours at ambient temperature and then evaporated down i. vac.. The residue
is purified by chromatography on silica gel (eluting gradient:
dichloromethane/ethanol 100:0 -> 95:5).
Yield: 34%
(503.97)
Mass spectrum: (M-H)"= 502/504 (chlorine isotope)
Rf value: 0.46 (silica gel; dichloromethane/ethanol = 9:1)
Example 42
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(tetrahydropyrimidin-
2-on-1 -yl)-benzamide
ci
(a) 4-(3-Boc-amino-proDvl-amino)-3-chloro-benzonitrile
3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with
2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4-
fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature
under a nitrogen atmosphere, heated to 105°C for 20 minutes and extracted
with ethyl acetate. The combined organic phases are washed with water and
sat. sodium chloride solution, dried over magnesium sulphate and evaporated
down i. vac.. The residue is further reacted without any more purification.
Yield: 5.50 g (89 %)
C15H2oN3O2 (309.80)
Mass spectrum: (M+H)* = 310/312 (chlorine isotope)
Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 2:1)
(b) 4-(3-arnino-propvlamino)-3-chloro-benzonitrile
4.50 g (14.5 mmol) 4-(3-Boc-amino-propylamino)-3-chloro-benzonitrile are
dissolved in 50 ml dioxane and combined with 200 ml 6-molar hydrochloric acid.
The mixture is stirred for 2 hours at ambient temperature, then washed with
ether and the aqueous phase is poured into 125 ml ice-cooled cone, ammonia
solution. Then the mixture is extracted with ethyl acetate, the combined organic
phases are washed with water and sat. sodium chloride solution, dried over
magnesium sulphate and evaporated down i. vac.. The residue is further
reacted without any more purification.
Yield :1.40 g (46%)
C10H12CIN3 (209.68)
Mass spectrum: (M+H)+ =210/212 (chlorine isotope)
Rf value: 0.30 (silica gel; dichloromethane/methanol = 9:1 + 1% cone, ammonia
solution)
(c) 3-chloro-4-(tetrahvdro-pvrimidin-2-on-1-vl)-benzonitrile
A solution of 349 mg (2.15 mmol) A/,/V'-carbonyl-diimidazole in 3 ml NMP is
combined with 450 mg (2.15 mmol) 4-(3-amino-propyIamino)-3-chlorobenzonitrile
at ambient temperature with stirring and once fully dissolved heated
for one hour to 145°C and for 1.5 hours to 155°C. The reaction mixture is
washed with water and extracted with ethyl acetate. The combined organic
phases are washed with water and sat. sodium chloride solution, dried over
magnesium sulphate and evaporated down i. vac.. Then the residue is purified
by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc.
ammonia solution 19:1) = 100:0 -> 95:5).
Yield: 260 mg (51%)
Rf value: 0.40 (silica gel; ethyl acetate/ethanol 9:1 + 1% cone, ammonia
solution)
CnHioCIN3O (235.68)
Mass spectrum: (M+H)* = 236/238 (chlorine isotope)
(d) 3-chloro-4-(tetrahvdro-pvrimidin-2-on-1 -vl)-benzoic acid
350 mg (1.49 mmol) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile are
suspended in 5 ml of ethanol and combined with 2.0 ml of 10-molar aqueous
sodium hydroxide solution. The mixture is stirred for one hour at 100°C and
then evaporated down i. vac.. The aqueous residue is combined with ice,
acidified with acetic acid and extracted with ethyl acetate. The combined
organic phases are washed with water and sat. sodium chloride solution, dried
over magnesium sulphate and evaporated down i. vac.. The aqueous phase is
acidified with 6-molar hydrochloric acid, extracted 5 times with ethyl acetate, the
combined organic phases are washed with sat. sodium chloride solution, dried
over magnesium sulphate and evaporated down i. vac..
Yield: 340 mg (90%)
CiiHnCIN203 (254.68)
Mass spectrum: (M+H)+ = 255/257 (chlorine isotope)
Rf value: 0.35 (silica gel; dichloromethane/methanol = 9:1 + 1% acetic acid)
(e) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-ftetrahvdro-
Dvn'midin-2-on-1 -vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-
1-yl)-benzoic acid, (1S)-1-(5-chloro-1/V-benzimidazol-2-yl)-ethylamine, TBTU
and NMM in DMF, then pouring into ice water, adding cone, ammonia solution,
filtering, washing with water and purifying by chromatography on silica gel
(eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1) = 98:2 90:10) with subsequent filtration through activated charcoal, trituration with
ether and drying in the drying pistol at 70°C.
Yield: 32%
C2oHi9Cl2N5O2 (432.31)
Mass spectrum: (M+H)+ = 432/434/436 (chlorine isotope)
Rf value: 0.40 (silica gel; dichloromethane/methanol = 9:1 + 1% acetic acid)
The following compound is prepared analogously:
No.
structural formula Yield mass peak(s) Rf value or Rt
Name
No. structural formula Yield mass peak(s) Rf value or Rt
Name
3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(tetrahydro-pyrimidin-2-on-1-yl)-benzamide
Example 46:
3-chloro-A/-[(1 f?)-1 -(5-chloro-1 fY-benzimidazol-2-yl)-2-methoxy-ethyl]-4-
(piperidin-2-on-1 -yl)-benzamide
(a) methyl 3-chloro-4-(5-chloro-pentanovl-amino)-benzoate
A solution of 696 ul (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml
THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chlorobenzoate
in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring
for 16 hours at ambient temperature, for 3 hours at 50°C and for 3 hours at
reflux temperature the mixture is poured into water and extracted with ethyl
acetate. After the organic phases have been dried over sodium sulphate the
mixture is evaporated down i. vac. and the residue remaining is purified by
chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15).
Yield: 300 mg (14.6%) 80% product
Ci3H15CI2NO3(304.18)
Mass spectrum: (M+H)+ = 304/306/308 (chlorine isotope)
Rt value: 3.29 min
(b) methyl 3-chloro-4-(piperidin-2-on-1 -vl)-benzoate
300 mg (0.79 mmol) of the product obtained in Example 46a is dissolved in 10
ml DMF and combined with 180 mg (1.60 mmol) potassium-fe/t-butoxide and
heated to 60°C for 3 hours. Then the reaction mixture is poured into water and
extracted with ethyl acetate. The combined organic phases are dried over
sodium sulphate, evaporated down i. vac. and the residue obtained is purified
by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2).
Yield:159mg(75%)
C13H14CIN03 (267.71)
Mass spectrum: (M+H)+ = 268/270 (chlorine isotope)
Rf value: 0.18 (silica gel; dichloromethane/isopropanol = 49:1)
(c) 3-chloro-4-(piperidin-2-on-1 -vl)-benzoic acid
Prepared analogously to Example 39d from methyl 3-chloro-4-(piperidin-2-on-1-
yl)-benzoate and 8% lithium hydroxide solution in ethanol.
Yield: 36%
Ci2H12CINO3 (247.30)
Mass spectrum: (M+H)+ = 252/254 (chlorine isotope)
Rf value: 0.27 (silica gel; dichloromethane/ethanol = 9:1)
(d) 3-chloro-A/-K1 /?)-1 -(5-chloro-1 H-benzimidazol-2-vn-2-methoxv-ethvn-4-
(pjperidin-2-on-1 -vlV-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)-
benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-
methoxy-ethylamine in DMF and subsequent purification by chromatography on
silica gel (eluting gradient: ethyl acetate/ethanol 95:5 -> 90:10).
Yield: 70%
Mass spectrum: (M-H)~ = 459/461/463 (chlorine isotope)
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1)
The following compound is prepared analogously:
No.
(Table Removed)
Example 47
A/-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide
(a) A/'-(2-amino-4-bromo-phenvl)-A/-Boc-(S)-serinamide and A/'-(2-amino-5-
bromo-phenvn-A/-Boc-(S)-serinamide
5.49 g (26.7 mmol) (S)-A/-Boc-serine are dissolved with 5.00 g (26.7 mmol) 4-
bromo-1,2-phenylenediamine in 125 ml THF and a solution of 5.52 g (26.7
mmol) A/,A/'-dicyclohexylcarbodiimide in 20 ml THF is added dropwise while
cooling with ice. The reaction mixture is stirred for 16 hours at ambient
temperature. After evaporation i. vac. the residue is purified by chromatography
on silica gel (eluant: dichloromethane/methanol 98:2).
Yield: 4.76 g (48 %) mixture of the two regioisomers
C14H2oBrN3O4 (374.24)
Mass spectrum: (M+H)* = 374/376 (bromine isotope)
(b) ( 7f?WV-Boc-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvlamine
3.00 g (8.02 mmol) of the mixture obtained in 47a are dissolved in 30 ml acetic
acid and stirred for 2 hours at 50°C. The reaction mixture is added dropwise to
a 10% sodium hydroxide solution and extracted 3 times with ethyl acetate. The
combined organic phases are dried over magnesium sulphate and evaporated
down i. vac. and the residue is recrystallised from methanol.
Yield :1. 96 g (69%)
Ci4Hi8BrN3O3 (356.22)
Rf value: 0.59 (silica gel; petroleum ether/ethyl acetate = 1:1)
(c) f 7ffl-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvlamine
2.00 g (5.62 mmol) (7R)-A/-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxyethylamine
in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar
hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16
hours at ambient temperature. The reaction mixture is evaporated down and the
resulting precipitate is filtered off.
Yield: 1.1 1g (67%)
C9Hi0BrN3O * HCI (292.57 / 256.10)
Mass spectrum: (M+H)+ = 256/258 (bromine isotope)
(d) A/-K1 f?)-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-hvdroxv-ethvn-3-methvl-4-
(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example Iffrom 3-methyl-4-(morpholin-3-on-4-yl)-
benzoicacid, (1f?)-1-(5-bromo-1/-/-benzimidazol-2-yl)-2-hydroxy-ethylamine,
TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Yield: 52%
C2iH2iBrN4O4 * CF3COOH (587.35 / 473.32)
Mass spectrum: (M+H)* = 473/475 (bromine isotope)
Rf value: 0.33 (silica gel; dichloromethane/methanol = 19:1)
The following compounds were prepared analogously:
No.
(Table Removed)
Example 48
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,1 -dioxo-isothiazolidin-2-
yl)-3-methyl-benzamide
(a) methyl 4-(3-chloro-propvl-sulphonvl-amino)-3-rnethvl-benzoate
100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of
pyridine are combined with 82 ul (0.67 mmol) 3-chloropropanesulphonic acid
chloride and stirred for 16 hours at ambient temperature. The reaction solution
is combined with water and ethyl acetate and then the aqueous phase is again
extracted with ethyl acetate. The combined organic phases are dried over
sodium sulphate and evaporated down i. vac.. The residue is further reacted
without any more purification.
Yield: 170 mg (92%)
C12Hi6CINO4S (305.78)
Mass spectrum: (M+H)* = 306/308 (chlorine isotope)
Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 8:2)
(b) methyl 4-(1.1-dioxo-isothiazolidin-2-vl)-3-methvl-benzoate
370 mg (0.85 mmol) 70% methyl 4-(3-chloropropane-sulphonylamino)-3-methylbenzoate
dissolved in 26 ml DMF are combined with 275 mg (2.45 mmol)
potassium-te/t-butoxide and stirred for 16 hours at ambient temperature. The
reaction mixture is combined with water and extracted with ethyl acetate. The
combined organic phases are dried over sodium sulphate, evaporated down i.
vac. and the residue is purified by chromatography on silica gel (eluant:
dichloromethane/isopropanol 98:2).
Yield: 177mg(47%)
Ci2Hi5NO4S (269.32)
Mass spectrum: (M+H)+ = 270
Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 7:3)
(c) 4-(1.1-dioxo-isothiazolidin-2-vl)-3-methvl-benzoic acid
170 mg (0.63 mmol) methyl 4-(1,1-dioxo-isothiazolidin-2yl)-3-methyl-benzoate
are stirred in 2 ml of ethanol at ambient temperature for 3 hours with 0.6 ml of
2-molar sodium hydroxide solution. Then the reaction solution is evaporated
down i. vac., combined with water and 0.6 ml 2-molar hydrochloric acid and
extracted with ethyl acetate. The combined organic phases are dried over
sodium sulphate, evaporated down i. vac. and the residue is further reacted
without any more purification.
Yield:148mg(92%)
CnHi3N04S (255.30)
Mass spectrum: (M-H)" = 254
retention time: 2.23 min
(d) N-\( 1SM -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(1.1 -dioxoisothiazolidin-
2-vl)-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(1,1-dioxo-isothiazolidin-2yl)-3-
methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU
and NMM in DMF with subsequent extraction with ethyl acetate, drying over
magnesium sulphate, activated charcoal and silica gel followed by purification
on silica gel (eluant: dichloromethane/isopropanol 95:5).
Yield: 37 %
C2oH2iCIN4O3S (432.93)
Mass spectrum: (M+H)+ = 433/435 (chlorine isotope)
Rf value: 0.32 (silica gel; dichloromethane/isopropanol = 19:1)
The following compounds were prepared analogously:
No.
(Table Removed)
Example 54
3-amino-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-
(morpholin-3-on-4-yl)-benzamide
65 mg (0.13 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-
methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in
2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin(ll)chloridedihydrate
and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for
2 hours. The reaction solution is combined with ice water, stirred for 10 minutes
and then the precipitate formed is filtered off. After drying for 3 days the residue
is purified by chromatography on silica gel (eluting gradient: dichloromethane/-
ethanoM 00:0 -> 91:9).
Yield: 5 mg (8.2 %)
C22H24CIN5O3S (473.99)
Mass spectrum: (M+H)+ = 474/476 (chlorine isotope)

Rf value: 0.48 (silica gel; dichloromethane/ethanol = 9:1)
Example 61
-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydroazepan-
2-on-1 -yl)-benzamide
(a) methyl 3-methvl-4-(pent-4-en-1 -ovl-amino)-benzoate
Prepared analogously to Example 46a from methyl 4-amino-3-methyl-benzoate
and 4-pentene-1-acid-chloride in THF with TEA.
Yield: 46%
C14Hi7NO3 (247.30)
Mass spectrum: (M+H)+ =248
Rt value: 2.88 min
(b) methyl 4-(allvl-pent-4-en-1 -ovl-amino)-3-methvl-benzoate
1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate
dissolved in 5 ml DMF are combined with 500 mg (4.37 mmol) potassium-te/tbutoxide
and at 40°C 350 ul (489 mg, 4.04 mmol) allylbromide are slowly added
with stirring. Then the mixture is heated to 70°C for 3 hours. Then the reaction
mixture is poured into water and extracted with ethyl acetate. The combined
organic phases are dried over sodium sulphate, evaporated down i. vac., the
residue is applied to silica gel and purified by chromatography on silica gel
(eluant: petroleum ether/ethyl acetate 9:1).
Yield: 58%
Ci7H2iNO3 (287.36)
Mass spectrum: (M+H)+ = 288
Rf value: 0.46 (petroleum ether/ethyl acetate = 9:1)
(c) methyl 4-(4.5-didehvdro-azepan-2-on-1 -vl)-3-methvl-benzoate
150 mg (0.52 mmol) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate
are dissolved in 110 ml degassed dichloromethane and rinsed for 30 minutes
with argon. Then 88 mg (104 pmol) benzylidene-[1,3-bis(2,4)6-trimethylphenyl)-
2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium(2nd
generation Grubbs Catalyst) are added and the mixture is refluxed for 4.5
hours. Then it is evaporated down i. vac., the residue is applied to silica gel and
purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate
3:2).
Yield: 83 mg (61 %)
Rf value: 0.22 (silica gel, petroleum ether/ethyl acetate 3:2)
C15Hi7N03 (259.31)
Mass spectrum: (M+H)"1" = 260
(d) 4-(4.5-didehvdro-azepan-2-on-1 -vl)-3-methvl-benzoic acid
Prepared analogously to Example 39d from methyl 4-(4,5-didehydro-azepan-2-
on-1-yl)-3-methyl-benzoate and 8% lithium hydroxide solution in ethanol.
Yield: 51%
Rf value: 0.05 (silica gel; dichloromethane/methanol = 19:1)
Ci4Hi5NO3 (245.28)
Mass spectrum: (M+H)* = 246
(e) A/-K1SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(4.5-didehvdroazepan-
2-on-1-vl)-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(4,5-didehydro-azepan-2-on-1-yl)-
3-methyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-
yl)-ethylamine in DMF and subsequent purification by preparative HPLC.
Yield: 32%
Rf value: 0.44 (silica gel; dichloromethane/methanol = 19:1)
C23H23CIN402 * CF3COOH (536.94/422.91)
Mass spectrum: (M+H)+ = 423/425 (chlorine isotope)
Example 63
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4-
yl)-3-methyl-benzamide
204 mg (0.48 mmol) A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-
4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml
dichloromethane and 1.2 ml acetic acid at -15°C and combined with 1 10 mg
(0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at
-15 to -10°C, heated to ambient temperature and stirred for a further 3 hours.
Then the reaction mixture is combined with semi-concentrated sodium
hydrogen carbonate solution and extracted with a solvent mixture
dichloromethane/methanol 19:1. The combined organic phases are washed
with water, dried over magnesium sulphate, evaporated down i. vac. and
purified by chromatography on silica gel (eluting gradient: ethyl
acetate/(ethanol/conc. ammonia solution 19:1) = 1:0 -> 4:1).
Yield: 1 00 mg (47%)
Mass spectrum: (M+H)"1" = 445/447 (chlorine isotope)
Rf value: 0.15 (silica gel; ethyl acetate/ethanol = 4:1 + 1% cone, ammonia
solution)
The following compound is prepared analogously:
No.
(Figure Removed)
Example 69
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-
yl)-benzamide
(a) methyl 4-(5-chloro-pentanovl-amino)-3-methoxv-benzoate
Prepared analogously to Example 6a from methyl 4-amino-3-methoxy-benzoate
and 5-chloro-pentanoic acid chloride in THF with TEA.
Yield: 99%
Ci4Hi8CIN04 (299.76)
Mass spectrum: (M+H)+ = 300/302 (chlorine isotope)
Rt value: 3.14min
(b) methyl 3-methoxv-4-(piperidin-2-on-1 -yl)-benzoate
2.25 g (7.51 mmol) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate
dissolved in 60 ml DMF are combined with 1.26 g (11.2 mmol) potassium-terf.-
butoxide and stirred for 2.5 hours at 60°C. Then the mixture is evaporated down
i. vac., the residue is combined with water and extracted with ethyl acetate. The
combined organic phases are dried over sodium sulphate, evaporated down i.
vac. and the residue obtained is purified by chromatography on silica gel
(eluting gradient: petroleum ether/ethyl acetate 3:2 -> 0:1).
Yield: 0.99 g (50%)
Rt value: 2.56 min
Ci4Hi7NO4 (263.30)
Mass spectrum: (M+H)+ = 264
(c) 3-methoxv-4-(piperidin-2-on-1 -vl)-benzoic acid
Prepared analogously to Example 39d from methyl 3-methoxy-4-(piperidin-2-on-
1-yl)-benzoate and lithium hydroxide in ethanol.
Yield: 95%
Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate = 1:2)
Ci3Hi5N04 (249.27)
Mass spectrum: (M+H)+ = 250
(d) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvll-3-methoxv-4-(piperidin-
2-on-1 -vl)-benzamide
Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)-
benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-
yl)ethylamine in DMF and subsequent purification by preparative HPLC.
Yield: 75%
Rt value: 2.35 min
C22H23CIN403 * CF3COOH (540.93 / 426.90)
Mass spectrum: (M+H)+ = 427/429 (chlorine isotope)
The following compounds were prepared analogously:
No. structural formula Yield mass peak(s) Rf value or Rt
70
(Figure Removed)
Example 73
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(1,1 -dioxo-6-methyl-
[l^.eithiadiazinan^-yO-S-methyl-benzamide
(a) methyl 4-(1 .1-dioxo-6-methvl-n .2.61-thiadiazinan-2-vl)-3-methvl-benzoate
400 mg (1.41 mmol) methyl 4-(1,1-dioxo-[1,2I6]-thiadiazinan-2-yl)-3-methylbenzoate
dissolved in 4 ml DMF at 40°C are combined with 240 mg (2.14
mmol) potassium-terf.-butoxide and 96 pi (1.54 mmol) methyl iodide and stirred
for 5 hours at 40°C. The reaction solution is evaporated down i. vac., combined
with water and the aqueous phase is extracted with ethyl acetate. The
combined organic phases are dried over sodium sulphate and evaporated down
i. vac..
Yield: 220 mg (52 %)
Ci3Hi8N2O4S (298.36)
Mass spectrum: (M+H)+ = 299
Rf value: 0.44 (silica gel; petroleum ether/ethyl acetate = 3:2)
(b) 4-(1 .1-dioxo-6-methvl-M .2.61thiadiazinan-2-vn-3-methvl-benzoic acid
Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-3-methyl-
[1,2,6]thiadiazinan-2-yl)-3-nnethyl-benzoate and lithium hydroxide in ethanol.
Yield: (81 %)
Mass spectrum: (M+H)+ = 285
Rf value: 0.07 (silica gel; dichloromethane/methanol = 19:1)
(c) A/-K1 S)-1-(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(1 .1-dioxo-6-methvln.
2.61thiadiazinan-2-vl)-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(1,1-dioxo-3-methyl-
[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid, (1 S)-1-(5-chloro-1 Hbenzimidazol-
2-yl)-ethylamine, TBTU and NMM in DMF with subsequent
purification by preparative HPLC.
Yield: 55 %
C21H24CIN503S * CF3COOH (576.00 / 461.97)
Mass spectrum: (M+H)+ = 462/464 (chlorine isotope)
Rt value: 2.50 min
The following compound is prepared analogously:
No.
74
(Table Removed)
Examole 75
-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide
(a) N'-(2-amino-4-bromo-phenvl)-A/-Boc-(S)-O-methvl-serinamide and N'-
(2-amino-5-bromo-phenvl)-A/-Boc-(S)-O-methvl-serinamide
2.50 g (6.24 mmol) of the dicyclohexylammonium salt of /v-Boc-(S)-O-methylserine
are dissolved in 20 ml 5 % citric acid, the aqueous phase is extracted 2x
with 20 ml of ethyl acetate, the combined organic phases are dried over sodium
sulphate and freed from solvent i. vac. The residue is dissolved together with
1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml
(14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50 % solution of PPA in
ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in
the ice bath the mixture is heated to ambient temperature and stirred for 23
hours at ambient temperature. The reaction mixture is poured into 100 ml of
water and the aqueous phase is extracted with ethyl acetate. The combined
organic phases are extracted with sat. sodium carbonate solution and water,
dried over sodium sulphate and evaporated down i. vac..
Yield: 2.38 g (98 %) mixture of the two regioisomers
Ci5H22BrN3O4 (388.26)
Mass spectrum: (M+H)* = 388/390 (bromine isotope)
Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol = 9:1)
(b) (?R)-A/-Boc-1 -(5-bromo-1 H-benzimidazol-2-vl)-2-methoxv-ethvlamine
2.38 g (6.13 mmol) of the mixture obtained in 75a are dissolved in 150 ml of
toluene and 1 .84 ml (30.7 mmol) acetic acid and 4.00 g molecular sieve, 3A, are
added. The reaction mixture is stirred for 3 hours at 55°C and then cooled for
1 5 minutes in the ice bath. The reaction mixture is filtered and poured into a
mixture of 500 ml each of water and ethyl acetate. After vigorous mixing the
organic phase is separated off, washed with sat. sodium chloride solution, dn'ed
over sodium sulphate and evaporated down i. vac.. The residue is purified by
chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0 -
> 97:3).
Yield: 1. 40 g (62%)
Ci5H2oBrN3O3 (370.24)
Mass spectrum: (M+H)+ = 370/372 (bromine isotope)
Rf value: 0.81 (silica gel; dichloromethane/ethanol = 9:1)
(c) (1 R)-1 -(5-bromo-1 H-benzimidazole-1 -vlV-2-methoxv-ethvlamine
Prepared analogously to Example 1g from (1/?)-/V-Boc-1-(5-bromo-1/-/-
benzimidazol-2-yl)-2-methoxy-ethylamine and TFA in dichloromethane.
Yield: 51 %
Ci0Hi2BrN3O(270.13)
Mass spectrum: (M+H)+ = 270/272 (bromine isotope)
Rf value: 0.20 (silica gel, dichloromethane/ethanol 9:1 )
(d) A/-T(1 R)-1 -f 5-bromo-1 H-benzimidazol-2-vl V-2-methoxv-ethvn-3-methvl-4-
(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid, (1 ft)-1 -(5-bromo-1 H-benzimidazol-2-yl)-2-methoxy-ethylamine,
TBTU and DIPEA in THF with subsequent purification by chromatography on
silica gel.
Yield: quant.
Mass spectrum: (M+H)+ = 487/489 (bromine isotope)
Rf value: 0.56 (silica gel; dichloromethane/ethanol = 9:1)
Example 76
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyl]-3-methyl-
4-(morpholin-3-on-4-yl)-benzamide
(a) ethvl(2S)-2-(benzvloxvcarbonvl-amino)-4-cvano-butvrate
5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-
4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then
extracted with ethyl acetate. The combined organic phases are dried over
sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in
70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are
added and the mixture is stirred for 10 minutes at ambient temperature. Then
50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the
reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed
with semisaturated sodium hydrogen carbonate solution and water, dried over
sodium sulphate and evaporated down i. vac-
Yield: 3.20 g (98 %)
Ci5Hi8N204 (290.32)
Mass spectrum: (M+NH4)+ =308
Rf value: 0.80 (silica gel; dichloromethane/ethanol = 9:1)
(b) ethyl (2S)-2-(benzvloxvcarbonvl-amino)-4-(1H-tetrazol-5-vlVbutvrate
3.20 g (11.0 mmol) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate
are dissolved in 40 ml of toluene and 1.08 g (16.5 mmol) sodium azide and 2.28
g (16.5 mmol) triethylamine-hydrochloride are added. The reaction mixture is
heated to 85°C for 24 hours, cooled to ambient temperature and extracted with
water. The combined aqueous phases are acidified to pH 2 with semiconc.
hydrochloric acid, the resulting precipitate is suction filtered, washed with water
and dried at 50°C.
Yield: 2.90 g (79 %)
Ci5Hi9N504 (333.34)
Mass spectrum: (M+H)+ = 334
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1)
(c) (2S)-2-(benzvloxvcarbonvl-amino)-4-(1H-tetrazol-5-vl)-butvricacid
Prepared analogously to Example 30b from ethyl (2S)-2-(benzyloxycarbonylamino)-
4-(1/-/-tetrazol-5-yl)-butyrate and lithium hydroxide in a mixture of
solvents from water and THF.
Yield: quant.
C13Hi5N5O4 (305.29)
Mass spectrum: (M+H)+ = 306
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 4:1)
(d) A/'-(2-amino-4-chloro-Dhenvl)-(2S)-2-(benzvloxvcarbonvl-amino)-4-(1Htetrazol-
5-vl)-butvric acid amide and A/-(2-amino-5-chloro-phenvlH2S)-2-
(benzvloxvcarbonvl-amino)-4-(1 /-/-tetrazol-5-vn-butvric acid amide
Prepared analogously to Example 47a from (2S)-2-(benzyloxycarbonyl-amino)-
4-(1H-tetrazol-5-yl)-butyric acid and 4-chloro-1,2-phenylenediamine with DCC in
THF.
Yield: quant., mixture of the two regioisomers, slightly contaminated
Ci9H2oCIN7O3 (429.86)
Rf value: 0.20 (silica gel; dichloromethane/ethanol = 9:1)
(e) (1 S)-A/-(benzvloxvcarbonvl)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-(1 Htetrazol-
5-vn-propvlamine
Prepared analogously to Example 47b from the product obtained in Example
76d and acetic acid.
Yield: quant.
C19Hi8CIN7O2 * CH3COOH (471 .90 / 41 1 .85)
Rf value: 0.25 (silica gel; dichloromethane/ethanol/conc. ammonia = 4:1:0.1)
(f) (1 SM -(5-chloro-1 H-benzimidazol-2-vl)-3-(1 H-tetrazol-5-vlV-propvlamine
2.10 g (4.45 mmol) (fS)-A/-(benzyloxycarbonyl)-1-(5-chloro-1/-/-benzimidazol-2-
yl)-3-(1/-/-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with
1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient
temperature. Then 20 ml of methanol are added, the mixture is stirred for a
further 30 minutes at ambient temperature and the reaction mixture is
evaporated down completely i. vac.. The residue is purified by chromatography
on silica gel (eluting gradient: dichloromethane / (ethanol / cone, ammonia 95:5)
= 70/30 -> 60:40).
Yield: 690 mg (56 %)
CnHi2CIN7 (277.71)
Mass spectrum: (M+H)+ = 278/280 (chlorine isotope)
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 3:2 + 1% cone, ammonia)
(g) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-
methvl-4-(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid, (1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-
propylamine, TBTU and DIPEA in THF with subsequent purification by
chromatography on silica gel.
Yield: 33 %
C23H23CIN8O3 (494.93)
Mass spectrum: (M+H)+ = 495/497 (chlorine isotope)
Rf value: 0.20 (silica gel; dichloromethane/ethanol = 4:1)
Example 77
A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzannide
(a) /V'-(2-amino-4-chloro-phenvlH2S)-2-(Boc-amino)-3-methoxv-propionic
acid amide and /V-(2-amino-5-chloro-phenvlH2S)-2-(Boc-amino)-3-
methoxv-propionic acid amide
4.90 g (21.0 mmol) (2S)-2-(Boc-amino)-3-methoxy-propionic acid are dissolved
in 20 ml THF and combined with 13.57 g (42.0 mmol) TBTU and 5.76 ml (52.5
mmol) triethylamine and stirred for 30 minutes at ambient temperature. Then
3.00 g (21.0 mmol) 4-chloro-1,2-phenylenediamine in 20 ml THF are added and
the mixture is stirred for 16 hours at ambient temperature. Then the reaction
mixture is evaporated down i. vac., poured into water and extracted with ethyl
acetate. The combined organic phases are washed with sat. sodium hydrogen
carbonate solution, dried over sodium sulphate and evaporated down i. vac..
The residue is purified by chromatography on silica gel (eluant:
dichloromethane/methanol 99:1).
Yield: 5.60 g (75%) mixture of the two regioisomers
Ci6H24CIN3O3 (357.83)
Mass spectrum: (M+H)+ = 358/360 (chlorine isotope)
Rf value: 0.26 (silica gel; dichloromethane/methanol = 99:1)
(b) ( 1 S)-/V-Boc-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propylamine
Prepared analogously to Example 47b from the product obtained in Example
77a and acetic acid.
Yield: 96%
Ci6H22CIN3O3 (339.82)
Mass spectrum: (M+H)+ = 340/342 (chlorine isotope)
Rf value: 0.80 (silica gel; dichloromethane/methanol = 19:1)
(c) ( 1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propylamine
Prepared analogously to Example 1g from (1S)-A/-Boc-1-(5-chloro-1Hbenzimidazol-
2-yl)-3-methoxy-propylamine and TFA in dichloromethane.
Yield: 31 %
CnH14CIN30 (239.70)
Mass spectrum: (M+H)+ = 240/242 (chlorine isotope)
Rf value: 0.10 (silica gel; dichloromethane/ethanol = 9:1)
(d) N-\C\ S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-3-methoxv-propyl1-3-methvl-4-
(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid, (1 S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine,
TBTU and DIPEA in THF with subsequent purification by chromatography on
silica gel.
Yield: 59 %
C23H25CIN4O4 (456.92)
Mass spectrum: (M+H)+ = 457/459 (chlorine isotope)
Rf value: 0.51 (silica gel; dichloromethane/ethanol = 9:1)
The following compound is prepared analogously:
No.
(Table Removed)
Example 82
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-
[1,2]oxazin-2-yl)-benzamide
(a) methvl 3-chloro-4-nitroso-benzoate
8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of cone,
sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under
a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with
14 g sodium carbonate. The solution obtained is combined with a suspension
of 2.78 g (15.0 mmol) methyl 4-amino-3-chloro-benzoate in 300 ml of water and
stirred for 16 hours at ambient temperature. The reaction mixture is suction
filtered, the filter cake is washed with water, dried in the air and purified by
chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).
Yield: 1.00 g (33%)
C8H6CINO3 (199.59)
Mass spectrum: (M+H)+ = 199/201 (chlorine isotope)
Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate = 4:1)
(b) methyl 3-chloro-4-(3.6-dihvdro-ri .21oxazin-2-vl)-benzoate
1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10 ml
chloroform and a freshly prepared solution of 1.10 g (20.3 mmol) butadiene in 6
ml chloroform is added dropwise with stirring at 0°G. The reaction mixture is
stirred for 30 minutes at 0-10°C and for 16 hours at ambient temperature,
evaporated down i. vac. and purified by chromatography on silica gel (eluant:
petroleum ether/ethyl acetate = 19:1).
Yield: 1.00 g (79%)
Ci2Hi2CIN03 (253.68)
Mass spectrum: (M+H)* = 254/256 (chlorine isotope)
Rf value: 0.50 (silica gel; petroleum ether/ethyl acetate = 4:1)
(c) 3-chloro-4-(3.6-dihvdro-n .21oxazin-2-vl)-benzoic acid
Prepared analogously to Example 2d from methyl 3-chloro-4-(3,6-dihydro-
[1,2]oxazin-2-yl)-benzoate and sodium hydroxide in a solvent mixture of water
and ethanol.
Yield: 90%
CnHioClN03 (239.66)
Mass spectrum: (M-H)' = 238/240
Rf value: 0.20 (silica gel; petroleum ether/ethyl acetate = 4:1)
(d) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(3.6-dihvdro-
159-
M.21oxazin-2-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-
yl)-benzoic acid, (1S)-1-(5-chloro-1/-/-benzimidazol-2-yl)-ethylamine, TBTU and
NMM in DMF.
Yield: 88 %
C2oHi8Cl2N4O2(417.29)
Mass spectrum: (M+H)+ =417/419/421 (chlorine isotope)
Rf value: 0.35 (silica gel; petroleum ether/ethyl acetate = 1:1)
Example 83
3-chloro-A/-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1 -
dioxo-[1,2]thiazinan-2-yl)-benzamide
(a) 2-chloro-A/-(4-chlorbutvl-sulphonvl)-4-methvl-aniline
1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine,
combined with 2.67 g (10.5 mmol) 75%m 4-chlorobutyl-sulphonic acid chloride
and stirred for 16 hours at ambient temperature. The reaction mixture is poured
into water and extracted with ethyl acetate. The combined organic phases are
washed with 6-molar hydrochloric acid, dried over sodium sulphate and
evaporated down i. vac.. The residue is purified by chromatography on silica gel
(eluting gradient: petroleum ether/ethyl acetate = 9:1 -> 7:3).
Yield:1.27 g (40%)
CiiHi5CI2NO2S (296.21)
Mass spectrum: (M+H)+ = 296/298/300 (chlorine isotope)
Rf value: 0.42 (silica gel; petroleum ether/ethyl acetate = 4:1)
(b) 3-chloro-4-(1 .1-dioxo-n .21thiazinan-2-vn-toluene
1 .27 g (4.29 mmol) 2-chloro-A/-(4-chlorbutyl-sulphonyl)-4-methyl-aniline are
stirred together with 722 mg (6.43 mmol) potassium-fe/t-butoxide in 50 ml DMF
for 1 6 hours at 60°C. Then the reaction mixture is poured into water and
extracted with ethyl acetate. The combined organic phases are dried over
sodium sulphate and evaporated down i. vac.. The residue is purified by
chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 3:2).
Yield: 850 mg (76 %)
CnH14CIN02S (259.75)
Mass spectrum: (M+H)+ = 260/262 (chlorine isotope)
Rf value: 0.27 (silica gel; petroleum ether/ethyl acetate = 4:1)
(c) 3-chloro-4-(1 .1-dioxo-M ,21thiazinan-2-vl)-benzoic acid
250 mg (0.96 mmol) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene are
suspended in 10 ml of water and combined with 456 mg (2.89 mmol) potassium
permanganate and 39 mg (0.98 mmol) sodium hydroxide. The reaction mixture
is refluxed for 4 hours. After cooling to ambient temperature sodium
thiosulphate is added to decolorise the mixture which is then extracted with
ethyl acetate. The combined organic phases are dried over sodium sulphate
and evaporated down i. vac.. The residue is purified by chromatography on
silica gel (eluant: dichloromethane/methanol = 19:1).
Yield: 50 mg (18%)
CnH12CINO4S (289.74)
Mass spectrum: (M+H)+ = 290/292
Rt value: 2.50 min
(d) 3-chloro-A/-ff 1 R)-1 -(5-chloro-1 H-benzirnidazol-2-vl)-2-methoxv-ethvl1-4-
(1 .1-dioxo-n .21thiazinan-2-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(1 ,2-dioxo-[1 ,2]thiazinan-
2-yl)-benzoic acid, (1 f?)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxyethylamine,
TBTU and NMM in DMF with subsequent purification by preparative
HPLC.
Yield: 34 %
C2iH22CI2N4O4S (497.40)
Mass spectrum: (M+H)+
Rt value: 2.53 min
= 497/499/501 (chlorine isotope)
Example 84
A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-
[1,2]thiazepan-2-yl)-3-methyl-benzamide
(a) methyl 4-(5-chloropentvl-sulphonvl-amino)-3-methvl-benzoate
Prepared analogously to Example 83a from methyl 4-amino-3-methyl-benzoate
and 5-chloropentyl-sulphonic acid chloride in pyridine.
Yield: 43 %
Ci4H2oCIN04S (333.83)
Mass spectrum: (M+H)+ = 334/336 (chlorine isotope)
Rf value: 0.72 (silica gel; petroleum ether/ethyl acetate = 7:3)
(b) methyl 4-(1.1-dioxo-M .21thiazepan-2-vl)-3-methvl-benzoate
Prepared analogously to Example 83b from methyl 4-(5-chloropentyl-sulphonylamino)-
3-methyl-benzoate and potassium-fe/t-butoxide in DMF.
Yield: 19%
C14Hi9NO4S (297.37)
Mass spectrum: (M+H)"* = 298
Rt value: 0.30 (silica gel; petroleum ether/ethyl acetate = 4:1)
(c) 4-f 1.1-dioxo-n .21thiazepan-2-vl)-3-methvl-benzoic acid
Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-[1,2]thiazepan-
2-yl)-3-methyl-benzoate and lithium hydroxide in a solvent mixture of water and
ethanol.
Yield: 60 %
Ci3Hi7NO4S (283.34)
Mass spectrum: (M+H)+ = 284
Rt value: 2.60 min
(d) A/-rnm-1-(5-chloro-1H-benzimidazol-2-vl)-2-methoxv-ethvn-4-f1.1-dioxo-
M.21thiazepan-2-vl)-3-methvl-benzamide
Prepared analogously to Example 1f from 4-(1,2-dioxo-[1,2]thiazepan-2-yl)-3-
methyl-benzoic acid, (1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxyethylamine,
TBTU and NMM in DMF with subsequent purification by
chromatography on silica gel.
Yield: 75 %
C23H27CIN4O4S (491.00)
Mass spectrum: (M+H)* = 491/493 (chlorine isotope)
Rt value: 2.60 min
Example 89
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)-
benzamide
209 mg (0.50 mmol) 3-chloro-/V-[(7S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-
4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide together with 100 mg 10% palladium
charcoal in 5 ml of ethyl acetate for 7 minutes are hydrogenated at ambient
temperature at 5 bar under a hydrogen atmosphere. Then the mixture is suction
filtered, the filtrate is evaporated down i. vac. and evaporated again with ether.
Yield: 200 mg (95 %)
C2oH2oCI2N4O2(419.30)
Mass spectrum: (M+H)+ =419/421/423 (chlorine isotope)
Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate = 1:1)
Example 90
A/-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-
[1,4Joxazepan-4-yl)-benzamide
(a) ethyl 3-(2-benzvloxv-ethoxv)-propionate
8.53 ml (60.0 mmol) benzyloxy-ethanol are combined with 13 mg (0.57 mmol)
sodium in 40 ml THF, then when it has dissolved 5.95 ml (54.7 mmol) ethyl
acrylate are added under an argon atmosphere and stirred for 20 hours at
ambient temperature. After neutralising with 0.6 ml 1-molar hydrochloric acid
the reaction mixture is evaporated down i. vac., the residue is taken up in sat.
sodium chloride solution and extracted with ethyl acetate. The combined
organic phases are washed with sat. sodium chloride solution, dried over
sodium sulphate and evaporated down i. vac.. The residue is purified by
chromatography on silica gel (eluant: petroleum ether/ethyl acetate = 4:1).
Yield: 3.73 g (25 %)
C14H2o04 (252.31)
Mass spectrum: (M+H)+ = 253
Rf value: 0.48 (silica gel; petroleum ether/ethyl acetate = 4:1)
(b) ethvl 3-(2-hvdroxv-ethoxv)-propionate
3.73 g (14.8 mmol) ethyl 3-(2-benzyloxy-ethoxy)-propionate are hydrogenated
together with 665 mg 10% palladium charcoal in 70 ml of ethanol for 44 minutes
at ambient temperature under a hydrogen atmosphere at 3 bar. Then the
mixture is suction filtered and the filtrate is evaporated down i. vac..
Yield: 2.26 g (94 %)
C7Hi4O4(162.18)
Mass spectrum: (M+H)+ =163
(c) ethvl 3-(2-chloro-ethoxv)-propionate
2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspended in 5
ml (68.5 mmol) thionyl chloride and 20 (jl (0.27 mmol) DMF are added. The
reaction mixture is refluxed for 4 hours and then evaporated down i. vac.. The
product is further reacted without any more purification.
Yield: quant.
C7H13O3 (180.63)
Mass spectrum: (M+H)* = 181/183 (chlorine isotope)
(d) 3-(2-chloro-ethoxv)-propionic acid
2.00 g (11.1 mmol) ethyl 3-(2-chloro-ethoxy)-propionate are suspended in 8 ml
of ethanol and 4.96 ml (16.6 mmol) of 8% lithium hydroxide solution are added.
The mixture is stirred for 4 hours at ambient temperature, then evaporated
down i. vac., acidified with 2-molar hydrochloric acid, combined with diethyl
ether and dried over sodium sulphate. Then it is filtered off and evaporated
down i. vac..
Yield: 1.51 g (89%)
C5H9CIO3 (152.58)
Mass spectrum: (M-H)"= 151/153 (chlorine isotope)
(e) 3-(2-chloro-ethoxv)-propionic acid-chloride
Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionic acid
and thionyl chloride with DMF.
Yield: 91 %
C5H8Cl2O2(171.02)
(f) methvl 4-f3-(2-chloro-ethoxv)-propionvl-amino1-3-methvl-benzoate
1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are
combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at
ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloroethoxy)-
propionic acid-chloride in 25 ml THF is added dropwise and the mixture
is stirred for a further 2.5 hours at ambient temperature. Then water is added
and the mixture is extracted with ethyl acetate. The combined organic phases
are dried over sodium sulphate and evaporated down completely i. vac.. The
residue is purified by chromatography on silica gel (eluting gradient: petroleum
ether/ethyl acetate = 7:3 -> 6:4).
Yield: 1.25 g (41 %)
Ci4H18CINO4 (299.75)
Mass spectrum: (M+H)+ = 300/302 (chlorine isotope)
Rf value: 0.15 (silica gel; petroleum ether/ethyl acetate = 7:3)
(g) methyl 3-methvl-4-(5-oxo-n .41oxazepan-4-vl)-benzoate
900 mg (3.00 mmol) 4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate
methyl are stirred in 40 ml DMF together with 520 mg (4.63 mmol) potassium
terf.-butoxide and 12 mg (80 umol) sodium iodide for 3 hours at 60°C. After
evaporation i. vac. the residue is combined with water, extracted with ethyl
acetate and the combined organic phases are dried over sodium sulphate and
evaporated down i. vac.. The residue is purified by chromatography on silica gel
(eluant: petroleum ether/ethyl acetate = 11:9).
Yield: 310 mg (39 %)
C14H17NO4 (263.29)
Mass spectrum: (M+H)+ = 264
(h) 3-methvl-4-(5-oxo-ri .41oxazepan-4-vl)-benzoic acid
Prepared analogously to Example 39d from methyl 3-methyl-4-(5-oxo-
[1,4]oxazepan-4-yl)-benzoate and lithium hydroxide in a solvent mixture of
water and ethanol.
Yield: 69 %
C13Hi5N04 (249.26)
Mass spectrum: (M+H)+ = 250
Rt value: 2.06 min
(i) A/-K1 R)-1 -(5-chloro-1 H-benzimidazol-2-vl V2-methoxv-ethvn-3-methvl-4-
(5-oxo-n.41oxazepan-4-vn-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(5-oxo-[1,4]oxazepan-4-
yl)-benzoic acid, (1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethylamine,
TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Yield: 83 %
C23H25CIN4O4 (456.92)
Mass spectrum: (M+H)+ = 457/459 (chlorine isotope)
Rt value: 2.23 min
Example 91
)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4,4-dirnethyl-2-oxoimidazolidin-
1-yl)-3-methyl-benzamide
(a) methyl 4-(3-M .1 -dimethvl-2-hvdroxv-ethvn-ureido)-3-rnethvl-benzoate
5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolved in 100
ml THF and a solution of 2.86 ml (30.0 mmol) 2-amino-2-methyl-propan-1-ol in
25 ml THF is added dropwise. The mixture is stirred for 2 hours at ambient
temperature and then evaporated down i. vac.. The residue is further reacted
without any more purification.
Yield: 8.40 g (quant.)
Mass spectrum: (M-H)" = 279
Rf value: 0.20 (silica gel; dichloromethane/ethanol = 19:1)
(b) methyl 4-(4.4-dimethvl-2-oxo-imidazolidin-1-vl)-3-methvl-benzoate
7.00 g (25.0 mmol) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]-ureido)-3-methylbenzoate
are dissolved in 400 ml THF at 0°C and combined with 6.73 g (60.0
mmol) potassium-ferf.-butoxide. After stirring for 15 minutes at 0°C a solution of
5.72 g (30.0 mmol) p-toluenesulphonic acid in 50 ml THF is added dropwise.
After another 10 minutes stirring at 0°C 300 ml of water are added, the mixture
is neutralised with 1 -molar hydrochloric acid and the THF is removed i. vac..
The residue is extracted with dichloromethane. The combined organic phases
are dried over sodium sulphate and evaporated down i. vac.. Then the residue
is purified by chromatography on silica gel (eluting gradient:
dichloromethane/ethanol = 100:0 -> 97:3).
Yield: 2.50 g (38 %)
Mass spectrum: (M+H)"1" = 263
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 19:1)
(c) 4-f4.4-dimethvl-2-oxo-imidazolidin-1-vn-3-methvl-benzoicacid
2.70 g (10.3 mmol) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methylbenzoate
are suspended in 75 ml of methanol and combined with a solution of
1.68 g (30.0 mmol) potassium hydroxide in 10 ml of water. It is stirred for 3
hours at ambient temperature and then evaporated down i. vac.. The aqueous
residue is diluted with water, acidified with 1-molar hydrochloric acid and the
precipitate obtained is suction filtered, washed with water and dried.
Yield: 2.30 g (90%)
Ci3Hi6N203 (248.28)
Mass spectrum: (M+H)+ = 249
Rf value: 0.50 (silica gel; dichloromethane/methanol = 9:1)
(d) A/-K1 S)-1 -(5-chloro-1 H-benzirnidazol-2-vl)-ethvl1-3-rnethvl-4-
(ri.31oxazepan-2-on-3-vl)-penzamide
Prepared analogously to Example 1f from 4-(4,4-dimethyl-2-oxo-imidazolidin-1-
yl)-3-methyl-benzoic acid, (1 S)-1 -(5-chloro-1 /-/-benzimidazol-2-yl)-ethylamine,
TBTU and DIPEA in THF and purification of the residue by chromatography on
silica gel.
Yield: 59 %
C22H24CIN502 (425.91)
Mass spectrum: (M+H)+ = 426/428 (chlorine isotope)
Rf value: 0.40 (silica gel; dichloromethane/methanol = 9:1)
The following compound is prepared analogously:
No. structural formula Yield mass peak(s) Rf value
Name
(Table Removed)
Example 93
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxooxazolidin-
3-yl)-benzamide
ci
(a) 3-chloro-4-(2-hvdroxv-1-methvl-ethvlamino)-benzonitrile
4.00g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60°C in 20 ml
DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours.
Then the reaction mixture is poured into water and extracted with ethyl acetate.
The combined organic phases are washed with water and sat. sodium chloride
solution, dried over sodium sulphate and evaporated down i. vac..
Yield: 5.20 g (96 %)
C10HnCIN2O (210.66)
Mass spectrum: (M+H)+ = 211/213 (chlorine isotope)
Rf value: 0.27 (silica gel; dichloromethane/methanol = 19:1)
(b) 3-chloro-4-(2-hvdroxv-1 -methvl-ethvlamino)-benzoic acid
5.20 g (24.7 mmol) 3-ch!oro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile are
refluxed for 6 hours in 50 ml of cone, hydrochloric acid with stirring. Then the

mixture is evaporated down i. vac., made basic with cone, ammonia solution
and extracted with ethyl acetate. After acidification of the aqueous phase with
acetic acid the mixture is extracted with ethyl acetate, the combined organic
phases are washed with water and sat. sodium chloride solution, dried over
sodium sulphate and evaporated down i. vac..
Yield: 5.00 g (88 %)
C10H12CIN03 (229.66)
Mass spectrum: (M+H)+ = 230/232 (chlorine isotope)
Rf value: 0.44 (silica gel; dichloromethane/methanol = 9:1)
(c) ethvl 3-chloro-4-(2-hvdroxv-1 -methvl-ethvlaminoVbenzoate
5.00 g (21.8 mmol) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoic acid
are stirred for 16 hours in 100 ml sat. ethanolic hydrochloric acid at ambient
temperature and then evaporated down i. vac.. The residue is combined with
water and cone, ammonia solution and extracted with ethyl acetate. The
combined organic phases are washed with water and sat. sodium chloride
solution, dried over sodium sulphate and evaporated down i. vac.. The residue
is purified by chromatography on silica gel (eluant: dichloromethane / methanol
= 50:1).
Yield: 3.40 g (61 %)
C12H16CINO3 (257.71)
Mass spectrum: (M+H)+ = 258/260 (chlorine isotope)
Rf value: 0.34 (silica gel; dichloromethane/methanol = 19:1)
(d) ethvl 3-chloro-4-(4-methvl-2-oxo-oxazolidin-3-vl)-benzoate
0.50 g (1.94 mmol) ethyl 3 -chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate
are placed in 30 ml THF together with 0.22 g (2.20 mmol) triethylamine and
1.10 ml (2.08 mmol) 20% phosgene solution in toluene is added with stirring at
ambient temperature. The mixture is stirred for 1 hour at ambient temperature,
then 1 ml of water is added and the mixture is stirred for another 10 minutes.
The mixture is then evaporated down i. vac., combined with water and extracted
with ethyl acetate. The combined organic phases are washed with water and
sat. sodium chloride solution, dried over sodium sulphate and evaporated down
i. vac..
Yield: 0.54 g (98 %)
Ci3Hi4CIN04 (283.71)
Mass spectrum: (M+H)+ = 284/286 (chlorine isotope)
Rf value: 0.71 (silica gel; dichloromethane/methanol = 19:1)
(e) 3-chloro-4-f4-methvl-2-oxo-oxazolidin-3-vl)-benzoicacid
0.90 g (3.17 mmol) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate
are stirred for 1 hour in 50 ml of methanol with 10 ml 1-molar aqueous lithium
hydroxide solution at ambient temperature. The mixture is then evaporated
down to 20 ml i. vac., acidified with cone, hydrochloric acid and extracted with
ethyl acetate. The combined organic phases are washed with sat. sodium
chloride solution, dried over sodium sulphate and evaporated down i. vac.. The
residue is crystallised from a little diethyl ether and suction filtered.
Yield: 0.45 g (56 %)
CnH10CINO4 (255.65)
Mass spectrum: (M+H)+ = 256/258 (chlorine isotope)
Rf value: 0.26 (silica gel; dichloromethane/methanol = 9:1)
(f) 3-chloro-/V-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvl1-4-(4-methvl-2-
oxo-oxazolidin-3-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-(4-methyl-2-oxo-oxazolidin-
3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU
and DIPEA in THF and purification of the residue by chromatography on
aluminium oxide.
Yield: 45 %
C2oHi8CI2N403 (433.29)
Mass spectrum: (M+H)+ = 433/435/437 (chlorine isotope)
Rf value: 0.65 (silica gel; dichloromethane/methanol = 9:1)
The following compounds were prepared analogously:
(Table Removed)
Example 95
N-[\ -(5-chloro-1 H-benzimidazol-2-yl)-1 -phenyl-methyl]-3-methyl-4-(morpholin-3-
on-4-yl)-benzamide
(a) A/'-(2-amino-4-chloro-phenvl)-A/-Boc-phenvl-glvcinamide and A/'-(2-
amino-5-chloro-phenvl)-A/-Boc-phenvl-glvcinamide
Prepared analogously to Example 47a from A/-Boc-phenyl-glycine, 4-chloro-1,2-
phenylenediamine and DCC in THF.
Yield: quant, mixture of the two regioisomers
C19H22CIN303 (375.85)
Mass spectrum: (M+H)+ = 376/378 (chlorine isotope)
Rf value: 0.41 (silica gel; dichloromethane/ethanol = 19:1)
(b) A/-acetvl-1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -phenvl-methvlamine
3.65 g (9.71 mmol) of the mixture obtained in 95a are dissolved in 8 ml acetic
acid and refluxed for 6 hours with stirring. The reaction mixture is evaporated
down i. vac. and the residue is purified by chromatography on silica gel (eluting
gradient: dichloromethane/ethanol = 100:0 -> 94:6).
Yield: 1.34 g (46%)
Ci6Hi4CIN3O (299.76)
Mass spectrum: (M+H)+ = 300/302 (chlorine isotope)
Rf value: 0.19 (silica gel; dichloromethane/ethanol = 19:1)
(c) 1 -(5-chloro-1 /-/-benzimidazol-2-vlV-1 -phenvl-methvlamine
1.34 g (4.47 mmol) A/-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenylmethylamine
in 9 ml of ethanol are combined with 18 ml of cone, hydrochloric
acid and heated to 50°C for 2 days. The reaction mixture is evaporated down i.
vac. and twice taken up in ethanol and evaporated down again.
Yield: 1.26 g (96%)
C14Hi2CIN3 * HCI (294.18 / 257.72)
Mass spectrum: (M+H)* = 258/260 (chlorine isotope)
(d) A/-M -(5-chloro-1 H-benzimidazol-2-vn-1 -phenvl-methvn-3-methvl-4-
(morDholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid, 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU
andDIPEAinTHF.
Yield: 89 %
C26H23CIN403 (474.94)
Mass spectrum: (M+H)+ = 475/477 (chlorine isotope)
Rf value: 0.68 (silica gel; dichloromethane/ethanol = 9:1)
The following compound is prepared analogously:
No. structural formula Yield mass peak(s) Rf value or Rt
Name
(Table Removed)
Example 96
/V-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-
4-yl)-benzamide
(a) A/'-(2-amino-4-chloro-phenvlH2S)-2-(Boc-amino)-butvric acid amide and
A/'-(2-amino-5-chloro-phenvl)-(2S)-2-(Boc-amino)-butvricacid amide
Prepared analogously to Example 47a from (2S)-2-(Boc-amino)-butyric acid, 4-
chloro-1,2-phenylenediamine and DCC in THF.
Yield: 89 % mixture of the two regioisomers
Mass spectrum: (M+H)+ = 328/330 (chlorine isotope)
Rf value: 0.63 (silica gel; dichloromethane/ethanol = 19:1)
(b) (1 SV/V-Boc-1 -f 5-chloro-1 H-benzimidazol-2-vl)-propylamine
Prepared analogously to Example 47b from the mixture obtained in 95a and
acetic acid and purification of the residue by chromatography on silica gel.
Yield: 94 %
C15H2oCIN3O2 (309.79)
Mass spectrum: (M+H)* =310/312 (chlorine isotope)
Rf value: 0.63 (silica gel; dichloromethane/ethanol = 19:1)
(c) (1 S)-1 -(5-chloro-1 H-benzimidazol-2-vlV-1 -phenvl-methvlamine
Prepared analogously to Example 75cfrom (1S)-A/-Boc-1-(5-chloro-1Hbenzimidazol-
2-yl)-propylamine and trifluoroacetic acid in dichloromethane.
Yield: quant.
Ci0Hi2CIN3 * 2 CF3COOH (437.72 / 209.68)
Mass spectrum: (M+Hf =210/212 (chlorine isotope)
(d) A/-K1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-propyl1-3-methvl-4-(morpholin-
3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and
DIPEA in THF.
Yield: 17%
C22H23CIN403 (426.90)
Mass spectrum: (M+H)"1" = 427/429 (chlorine isotope)
Rf value: 0.45 (silica gel; dichloromethane/ethanol = 9:1)
The following compounds were prepared analogously:
No. structural formula Yield mass peak(s) Rf value or Rt
(Table Removed)
Example 106
-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-
(morpholin-3-on-4-yl)-benzamide
(a) ethvl4-r(2-chloro-ethoxv)-acetvl-amino1-3-fluoro-benzoate
Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride
and ethyl 4-amino-3-fluoro-benzoate with TEA in THF.
Yield: 44 %
C13Hi5CIFN04 (303.71)
Mass spectrum: (M+H)+ = 304/306 (chlorine isotope)
Rf value: 0.29 (silica gel; dichloromethane)
(b) 4-(2-carboxvmethoxv-ethvlamino)-3-fluoro-benzoicacid
580 mg (1.91 mmol) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate
in 6 ml dioxane are combined with 3.82 ml (7.64 mmol) 2-molar potassium
hydroxide solution and 2 ml of water. Then the mixture is heated to 70°C for 2 h,
then diluted with water and acidified with 6-molar hydrochloric acid. After the
addition of dichloromethane the precipitate formed is suction filtered and dried
in the drying cupboard at 50°C.
Yield: 390 mg (79 %)
CnH12FNO5 (257.22)
Mass spectrum: (M+H)+ = 258
Rf value: 0.66 (reversed phase RP-8; methanol/5% NaCI solution = 6:4)
(c) 3-fluoro-4-(morpholin-3-on-4-vl)-benzoic acid-chloride
Prepared analogously to Example 41 c from 4-(2-carboxymethoxy-ethylamino)-
3-fluoro-benzoic acid and thionylchoride in dichloromethane with DMF.
Yield: quant.
CnH9CIFN03 (257.65)
(d) A/-K1 KV1 -(5-chloro-1 H-benzimidazol-2-vl)-2-methoxv-ethvn-3-fluoro-4-
(morpholin-3-on-4-vn-benzamide
Prepared analogously to Example 41 d from 3-fluoro-4-(morpholin-3-on-4-yl)-
benzoic acid-chloride and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine
with TEA in THF.
Yield: 47 %
C2iH2oCIFN4O4 (446.86)
Mass spectrum: (M+H)+ = 447/449 (chlorine isotope)
Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1)
Example 109
A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(pyridin-3-yl)-methyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide
(a) A/'-(2-amino-4-chloro-phenvn-2-(Boc-amino)-2-(pyridin-3-vl)-aceticacid
amide and A/'-(2-amino-5-chloro-phenvl)-2-(Boc-amino)-2-(pyridin-3-vl)-
acetic acid amide
1.00 g (3.96 mmol) /V-Boc-amino-2-(pyridin-3-yl)-acetic acid are placed together
with 0.59 g (4.16 mmol) 4-chloro-1,2-phenylenediamine at 0°C in 20 ml THF
and 2.92 ml (4.96 mmol) 50% PPA solution in ethyl acetate and 1.24 ml ( 8.92
mmol) TEA are added. After stirring for 30 min at 0°C the mixture is stirred for 5
h at ambient temperature stirred and then evaporated down completely i. vac..
The residue is purified by chromatography on silica gel (eluting gradient:
dichloromethane / ethanol = 10:0 -> 9:1).
Yield: 1.32 g (88 %) mixture of the two regioisomers
Mass spectrum: (M+H)+ = 377/379 (chlorine isotope)
Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1)
(b) /V-Boc-1 -(5-chloro-1 /-/-benzimidazol-2-vn-1 -(pvridin-3-vl)-methvlamine
Prepared analogously to Example 47b from the product obtained in Example
111aand acetic acid.
Yield: 81 %
C18H19CIN4O2 (358.82)
Mass spectrum: (M+H)"1" = 359/361 (chlorine isotope)
Rf value: 0.51 (silica gel; dichloromethane/ethanol = 9:1)
(c) 1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -(pyridin-3-vl)-methvlamine
Prepared analogously to Example 1g from A/-Boc-1-(5-chloro-1H-benzimidazol-
2-yl)-1-(pyridin-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.
Yield: 66 %
Ci3HnCIN4 (258.71)
Mass spectrum: (M+H)* = 259/261 (chlorine isotope)
Rf value: 0.62 (silica gel; dichloromethane/ethanol = 9:1)
(d) A/-F1 -(5-chloro-1 H-benzimidazol-2-vl)-1 -(pvridin-3-vl)-methvl1-3-methvl-4-
(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid and 1-(5-chloro-1/-/-benzimidazol-2-yl)-1-(pyridin-3-yl)-
methylamine with TBTU and DIPEA in THF.
Yield: 84 %
(475.93)
Mass spectrum: (M+H)+ = 476/478 (chlorine isotope)
Rf value: 0.31 (silica gel; dichloromethane/ethanol = 9:1)
Example 110
A/-[1 -(5-chloro-1 H-benzimidazol-2-yl)-1 -(1 -methyl-pyrazol-3-yl)-methyl]-3-
methyl-4-(morpholin-3-on-4-yl)-benzamide
(a) methyl ethoxvcarbonvl-methoxvimino-(1-methvl-pvrazol-3-vl)-acetate
5.00 g (20.7 mmol) ethoxycarbonyl-methoxyimino-(pyrazol-3-yl)-acetic acid are
placed in 20 ml DMF together with 5.73 g (41.5 mmol) potassium carbonate at
ambient temperature, stirred until the development of gas has ended, then 2.58
ml (41.5 mmol) of methyl iodide are added and the mixture is stirred for 2 h at
50°C. After evaporation of the reaction mixture i. vac. the residue is combined
with water and ethyl acetate, the organic phase is washed with water, dried over
magnesium sulphate and evaporated down completely i. vac.. The residue is
purified by chromatography on silica gel (eluting gradient: petroleum ether /
ethyl acetate = 80:20 -> 65:35).
Yield: 2.61 g (26 %) in admixture with regioisomers
CnHisNaOs (269.25)
Mass spectrum: (M+H)+ = 270
Rf value: 0.25 (silica gel; petroleum ether/ethyl acetate = 1:1)
(b) methyl 2-amino-2-(1 -methvl-pyrazol-3-vl)-acetate
2.61 g (9.69 mmol) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-
yl)-acetate are hydrogenated in 60 ml of ethanol with 1.1 g 5% palladium
charcoal for 1 6 h at 50°C under 3.4 bars pressure in a hydrogen atmosphere.
Then the mixture is suction filtered and the filtrate is evaporated down
completely i. vac..
Yield: 1 .90 g (quant), slightly contaminated
C7HiiN302 (169.18)
Mass spectrum: (M+H)"1" =170
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1)
(c) methyl /V-Boc-2-amino-2-(1 -methvl-pyrazol-3-vl)-acetate
Prepared analogously to Example 1d from methyl 2-amino-2-(1-methyl-pyrazol-
3-yl)-acetate and di-tert. butyl pyrocarbonate with TEA in dichloromethane.
Yield: 81 %
Ci2Hi9N304 (269.30)
Mass spectrum: (M+H)* = 270
(d) A/-Boc-2-amino-2-(1 -methvl-pvrazol-3-vl)-acetic acid
1.16 g (4.31 mmol) methyl A/-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in
16 ml THF are combined with 10 ml of water and 10 ml of 1 -molar lithium
hydroxide solution are added. After stirring at ambient temperature for 2 h the
mixture is evaporated down i. vac., the residue is combined with water, filtered
and the filtrate is adjusted to pH 5with potassium hydrogen sulphate solution.
After total evaporation i. vac. the residue is treated with dichloromethane and a
little ethanol, suction filtered and the filtrate is evaporated down completely i.
vac..
Yield: 0.92 g (84 %)
Mass spectrum: (M+H)* =256
Rf value: 0.15 (silica gel; dichloromethane/ethanol = 8:2)
(e) A/'-(2-amino-4-chloro-phenvl)-2-(Boc-amino)-2-(1-methvl-pvrazol-3-vl)-
acetic acid amide and A/-(2-amino-5-chloro-phenvl)-2-(Boc-arnino)-2-(1-
methvl-pvrazol-3-vl)-acetic acid amide
Prepared analogously to Example 111a from A/-Boc-2-amino-2-(1-methylpyrazol-
3-yl)-acetic acid and 4-chloro-1,2-phenylenediamine with PPA in ethyl
acetate and NMM in dichloromethane.
Yield: 55 % mixture of the two regioisomers
C17H22CIN5O3 (379.84)
Rf value: 0.61 (silica gel; dichloromethane/ethanol = 9:1)
(f) A/-Boc-1-(5-chloro-1H-benzimidazol-2-vl)-1-(1-methvl-Dvrazol-3-vnmethvlamine
Prepared analogously to Example 47b from the product obtained in Example
112eand acetic acid.
Yield: 81 %
Ci7H2oCIN502(361.83)
Mass spectrum: (M+H)+ = 362/364 (chlorine isotope)
Rf value: 0.60 (silica gel; dichloromethane/ethanol = 9:1)
(g) 1 -(5-chloro-1 /-/-benzimidazol-2-vl)-1 -(1 -methvl-pvrazol-3-vl)-methvlamine
Prepared analogously to Example Igfrom A/-Boc-1-(5-chloro-1H-benzimidazol-
2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine and trifluoroacetic acid in
dichloromethane.
Yield: 77 %
C12Hi2CIN5(261.71)
Mass spectrum: (M-NH3+H)+ = 245/247 (chlorine isotope)
Rf value: 0.30 (silica gel; dichloromethane/ethanol/conc. ammonia solution =
9:1:0.1)
(h) A/-ri-(5-chloro-1H-benzimidazol-2-vn-1-(1-methvl-pvrazol-3-vl)-methvn-3-
methvl-4-(morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-
methylamine with TBTU and DIPEA in THF.
Yield: 38 %
.93)
Mass spectrum: (M+H)"1" = 479/481 (chlorine isotope)
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1 )
Example 1 1 1
3-chloro-/V-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-
methyl-morpholin-3-on-4-yl)-benzamide
(a) ethvl4-f2-(fe/t.-butoxvcarbonvl-methoxv)-1-methvl-ethvlamino1-3-chlorobenzoate
1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate
are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride
dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl
bromoacetate are added and the mixture is stirred for a further 16 h at ambient
temperature. Then the reaction mixture is poured into water and extracted with
ethyl acetate. The combined organic phases are washed with water and sat.
sodium chloride solution, dried over sodium sulphate and evaporated down
completely i. vac.. The residue is purified by chromatography on silica gel
(eluting gradient: petroleum ether/ethyl acetate = 95:5 -> 80:20)
Yield: 230 mg (14%)
C18H26CINO5(371.86)
Mass spectrum: (M+H)+ = 372/374 (chlorine isotope)
Rf value: 0.65 (silica gel; petroleum ether/ethyl acetate = 7:3)
(b) ethyl 3-chloro-4-f2-(hvdroxvcarbonvl-methoxv)-1-methvl-ethvlamino1-
benzoate
Prepared analogously to Example 1g from ethyl 4-[2-(te/f-butoxycarbonylmethoxy)-
1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in
dichloromethane.
Yield: 87 %
Ci4Hi8CINO5(315.75)
Mass spectrum: (M+H)+ =316/318
Rf value: 0.40 (silica gel; dichloromethane/ethanol = 9:1)
(c) ethyl 3-chloro-4-(5-methyl-morpholin-3-on-4-vl)-benzoate
Prepared analogously to Example 41 c from ethyl 3-chloro-4-[2-
(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate and thionyl chloride
with DMF in dichloromethane.
Yield: 69 % (contaminated)
Ci4H16CIN04 (297.73)
Mass spectrum: (M+H)+ = 298/300 (chlorine isotope)
Rf value: 0.40 (silica gel; dichloromethane/ethanol = 19:1)
(d) 3-chloro-4-(5-methvl-morpholin-3-on-4-vl)-benzoicacid
Prepared analogously to Example 31 b from ethyl 3-chloro-4-(5-methylmorpholin-
3-on-4-yl)-benzoate with lithium hydroxide in THF and water.
Yield: 91 %
Ci2H12CIN04 (269.68)
Rf value: 0.30 (silica gel; dichloromethane/ethanol = 9:1)
(e) 3-chloro-A/-r(1/?)-1-(5-chloro-1H-benzimidazol-2-vlV2-methoxv-ethvn-4-
(5-methvl-morpholin-3-on-4-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(5-methyl-morpholin-3-on-
4-yl)-benzoic acid and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethylamine
with TBTU and TEA in DMF.
Yield: 28 %
(477.34)
Mass spectrum: (M-H)" = 475/477/479 (chlorine isotope)
Rf value: 0.50 (silica gel; dichloromethane/ethanol = 9:1)
Example 112
3-chloro-A/-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylaminopyrrolidin-
1 -yl)-benzamide
(a) 3-chloro-4-(3-dimethvlamino-pyrrolidin-1-vl)-benzonitrile
0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g,
5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231
mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with
stirring and under an argon atmosphere. After stirring at ambient temperature
for 3.5 h the reaction mixture is poured into water and extracted with ethyl
acetate after thorough mixing. The combined organic phases are washed with
sat. sodium chloride solution, dried over magnesium sulphate and evaporated
down completely i. vac..
Yield: 1.11 g (92 %)
Ci3H16CIN3 (249.74)
Mass spectrum: (M+H)+ = 250/252 (chlorine isotope)
Rf value: 0.42 (silica gel; petroleum ether/ethyl acetate = 1:1)
(b) 3-chloro-4-(3-dimethvlamino-pyrrolidin-1 -vl)-benzoic acid
Prepared analogously to Example 13bfrom 3-chloro-4-(3-dimethylaminopyrrolidin-
1-yl)-benzonitrile with 10-molar sodium hydroxide solution and
ethanol.
Yield: 27 %
Ci3Hi7CIN202 (268.74)
Mass spectrum: (M+H)+ = 269/271 (chlorine isotope)
(c) 3-chloro-A/-r(1 S)-1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(3-
dimethvlamino-pvrrolidin-1-vl)-benzamide
Prepared analogously to Example 1f from 3-chloro-4-(3-dimethylaminopyrrolidin-
1-yl)-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-
ethylamine with TBTU and TEA in DMF.
Yield: 74 %, slightly contaminated
C22H25CI2N5O (446.37)
Mass spectrum: (M+H)+ = 446/448/450 (chlorine isotope)
Rf value: 0.65 (silica gel; dichloromethane/methanol = 8:2 + 0.5% cone,
ammonia solution)
Example 113
A/-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-
trifluoromethyl-benzamide
(a) 4-(pvrazolidin-3-on-1-vl)-3-trifluoromethvl-benzonitrile
1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirred together
with 1.35 g (12.0 mmol) potassium-ferf.-butoxide in 4 ml DMSO at ambient
temperature under an argon atmosphere for 35 min and then 1.00 g (8.16
mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at
ambient temperature for 68 h the reaction mixture is poured into semisat.
sodium chloride solution and extracted with ethyl acetate. The combined
organic phases are dried over magnesium sulphate and evaporated down
completely i. vac..
Yield: 0.58 g (43 %)
CnHsFaNaO (255.20)
Mass spectrum: (M+H)"1" = 256
Rf value: 0.15 (silica gel; dichloromethane + 0.5% cone, ammonia solution)
(b) 4-(pvrazolidin-3-on-1 -vl)-3-trifluoromethvl-benzoic acid
Prepared analogously to Example 13bfrom 3-chloro-4-(3-dimethylaminopyrrolidin-
1-yl)-benzonitrile with 10-molar sodium hydroxide solution and
ethanol.
Yield: 56 %
CnHgFgNzOa (274.20)
Rf value: 0.60 (silica gel; dichloromethane/ethanol = 8:2 + 0.5% acetic acid)
(c) A/-r(1 SV1 -(5-chloro-1 H-benzimidazol-2-vl)-ethvn-4-(pvrazolidin-3-on-1 •
vh-3-trifluoromethvl-benzamide
Prepared analogously to Example 1f from the 4-(pyrazolidin-3-on-1-yl)-3-
trifluoromethyl-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-
ethylamine with TBTU and TEA in DMF.
Yield: 12 %, contaminated
C2oHi7CIF3N502 * 2 CF3COOH (679.88/451.83)
Mass spectrum: (M+Hf = 452/454 (chlorine isotope)
Rf value: 0.58 (silica gel; dichloromethane/methanol = 8:2 + 0.5% cone.
ammonia solution)
Example 127
-chloro-imidazo[1 ,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide
(a) (1 S)-A/-Boc-1 -(7-chloro-imidazof 1.2alpyridin-2-vl)-3-methvl-butvlamine
1.68 g (6.37 mmol) tert.-butyl [1-(2-chloro-acetyl)-3-methyl-butyl]-carbamate in
15 ml of methanol are combined with 819 mg (6.37 mmol) 2-amino-4-chloropyridine
at ambient temperature with stirring and the mixture is refluxed for 3
days. After evaporation i. vac. the residue is combined with 5% sodium
hydrogen carbonate solution and stirred for 20 h at ambient temperature. Then
it is extracted with dichloromethane, the combined organic phases are dried
over sodium sulphate and evaporated down completely i. vac.. The residue is
purified by chromatography on silica gel (eluting gradient:
dichloromethane/ethanol = 100:0 -> 94:6).
Yield:180mg(8%)
Ci7H24CIN3O2 (337.85)
Mass spectrum: (M+H)+ = 338/340 (chlorine isotope)
Rf value: 0.61 (silica gel; dichloromethane/ethanol = 9:1)
(b) (1S)-1-(7-chloro-imidazori.2a1pvridin-2-vn-3-methvl-butvlamine
Prepared analogously to Example Igfrom (1S)-A/-Boc-1-(7-chloroimidazo[
1,2a]pyridin-2-yl)-3-methyl-butylamine with trifluoroacetic acid in
dichloromethane.
Yield: quant.
C12H16CIN3 * 2 CF3C02H (465.78 / 237.73)
Mass spectrum: (M+H)"1" = 238/240 (chlorine isotope)
(c) A/-K1 S)-1 -(5-chloro-imidazon .2alpvridin-2-vl)-3-methvl-butvl1-3-methvl-4-
(morpholin-3-on-4-vn-benzamide
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-
benzoic acid and (1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methylbutylamine
with TBTU and DIPEA in THF.
Yield: quant.
Mass spectrum: (M+H)+ = 455/457 (chlorine isotope)
Rf value: 0.54 (silica gel; dichloromethane/ethanol = 9:1)
The Examples that follow describe the preparation of some pharmaceutical
formulations which contain as-active substance any desired compound of
general formula I:
Example I
Dry ampoule containing 75 mg of active substance per 10 ml
Composition:
Active substance 75.0 mg
Mannitol 50.0 mg
water for injections ad 10.0 ml
Preparation:
Active substance and mannitol are dissolved in water. After packaging the
solution is freeze-dried. To produce the solution ready for use for injections, the
product is dissolved in water.
Example II
Dry ampoule containing 35 mg of active substance per 2 ml
NOT FURNISHED UPON FILING
Example IV
Tablet containing 350 mg of active substance
Composition:
(1) Active substance 350.0 mg
(2) Lactose 136.0mg
(3) Maize starch 80.0 mg
(4) Polyvinylpyrrolidone 30.0 mg
(5) Magnesium stearate 4.0 mg
600.0 mg
Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous solution of
(4). (5) is added to the dried granulated material. From this mixture tablets are
pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
Example V
Capsules containing 50 mg of active substance
Composition:
(1) Active substance 50.0 mg
(2) Dried maize starch 58.0 mg
(3) Powdered lactose 50.0 mg
(4) Magnesium stearate 2.0 mg
160.0mg
Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4)
with vigorous mixing.
This powder mixture is packed into size 3 hard gelatine capsules in a capsule
filling machine.
Example VI
Capsules containing 350 mg of active substance
Composition:
(1) Active substance 350.0 mg
(2) Dried maize starch 46.0 mg
(3) Powdered lactose 30.0 mg
(4) Magnesium stearate 4.0 mg
430.0 mg
Preparation:
(1) is triturated with (3). This trituration is added to the mixture of (2) and (4)
with vigorous mixing.
This powder mixture is packed into size 0 hard gelatine capsules in a capsule
filling machine.
Example VII
Suppositories containing 100 mg of active substance
1 suppository contains:
Active substance 100.0 mg
Polyethyleneglycol (M.W. 1500) 600.0 mg
Polyethyleneglycol (M.W. 6000) 460.0 mg
Polyethylenesorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
The polyethyleneglycol is melted together with polyethylenesorbitan
monostearate. At 40°C the ground active substance is homogeneously
dispersed in the melt. It is cooled to 38°C and poured into slightly chilled
suppository moulds.

WE CLAIM
1. Substituted carboxylic acid amides of general formula I
(Formula Removed)
wherein
A denotes a group of general formula
(Formula Removed)
wherein m denotes the number 1 or 2,
R8a independently of one another denote a hydrogen or fluorine atom, a C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alky!)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl or C1-3-aikylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsulphonyl group, with the proviso that
in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula
wherein
(Formula Removed)
m denotes the number 1 or 2,
X1 denotes a methylene, -NR6b-, carbonyl or sulphonyl group,
X2 denotes an oxygen atom or a -NR8b group,
X denotes a methylene, carbonyl or sulphonyl group,
X4 denotes an oxygen or sulphur atom or a —NR6b group,
Xs denotes a carbonyl or sulphonyl group,
R6a independently of one another denote a hydrogen or fluorine atom, a

C1-3-alkyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyI or C1-.-alkylcarbonylamino group and
R6b independently of one another may be a hydrogen atom, a C1-4-alkyl, C1-4-alkylcarbonyl, C1-4-alkoxycarbonyl or C1-3-alkylsulphonyl group, with the proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom,
R1 denotes a fluorine, chlorine or bromine atom, a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, -NH2, C1-3-alkoxy, a mono-, di- or trifluoromethoxy group,
R2 denotes a hydrogen or fluorine atom,
R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-3-alkyIoxycarbonyl group,
a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridtnyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted In the heteroary! moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and
R4 denotes a hydrogen atom or a C1-3-alkyI group,
R3 and R4 together with the carbon atom to which they are bound, denote a tetrahydrofuran-3,3- diyl group,
R5 denotes a hydrogen atom,
B denotes a group of formula

(Formula Removed)
wherein
n denotes the number 1 or 2,
R7 denotes a hydrogen atom and
R8 denotes a fluorine, chlorine, bromine or iodine atom, or a C2-3-alkynyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomners, the diastereomers, the mixtures thereof or the salts thereof.
2. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein A, R1, R2, R4, R5 and B are defined as in claim 1 and
R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be whofly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsuIphonyl, carboxy or C1-3-alkyIoxycarbonyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing

definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
3. Substituted carboxylic acid amides of general formula I as claimed in claim 1,
wherein
A, R1, R2, R4, R5 are defined as in claim 1 and
R3 denotes a phenyl, furanyl, thiophenyl, pyrroiyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyi, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups,
while the alkyl groups contained in the foregoing definitions which have more than
two carbon atoms may, unless otherwise stated, be straight-chain or branched and the
alkyl groups in the previously mentioned dialkylated groups, may be identical or
different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
4. Substituted carboxylic acid amides of general formula I as claimed in claim 1,
wherein
A denotes a group of general formula
(Formula Removed)
wherein m denotes the number 1 or 2,
R6a independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl
group and
R6b may be a hydrogen atom or a C1-3-alkyl group, with the proviso that

in the above-mentioned substituted 6- to 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of general formula
(Formula Removed)
wherein
m denotes the number 1 or 2,
X1 denotes a methylene, -NR66-, carbonyl or sulphonyl group, X2 denotes an oxygen atom or a -NR6b group,
X3 denotes a methylene, carbonyl or sulphonyl group,
X4 an oxygen or sulphur atom or a -NR6b group,
X5 denotes a carbonyl or sulphonyl group,
R6a independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl group and
R6b independently of one another may be a hydrogen atom or a C1-3-alkyl group, with the proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A
the heteroatoms introduced as substituents are not separated from
another heteroatom by precisely one carbon atom,
R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the
hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro
group,
R2 denotes a hydrogen atom,
R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group,
a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and R4 denotes a hydrogen atom, R5 denotes a hydrogen atom and B denotes a group of formula
(Formula Removed)
wherein
n denotes the number 1,
R7 denotes a hydrogen atom and
R8 denotes a chlorine or bromine atom or the ethynyl group,
while the alkyl groups contained in the foregoing definitions which have more than two
carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl
groups in the previously mentioned dialkylated groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
5. Substituted carboxylic acid amides of general formula I as claimed in claim 4, wherein
A, R1, R2, R4, R5 and B are defined as in claim 4 and
R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group,
while the alkyl and alkoxy groups contained in the above-mentioned definitions which
have more than two carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned dialkylated groups, may be
identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
6. Substituted carboxy lie acid amides of general formula I as claimed in claim 4, wherein A,R1,R2,R4,R5and B are defined as in claim 4 and
R3 denotes a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imldazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups,
while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
7. Substituted carboxylic acid amides of general formula I as claimed in claim 1, wherein
A denotes a group of formula
(Formula Removed)
wherein m denotes the number 1 or 2,
R63 independently of one another denote a hydrogen or fluorine atom or a C1-3-alkyl group, with the proviso that
in the above-mentioned substituted 5- to 7-membered cyclic groups A the fluorine atoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom,
R1 denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group,
R2 denotes a hydrogen atom,
R3 denotes a straight-chain or branched C1-4-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsulphanyl, Ci-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group,
a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyi, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidtnyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C1-3-alkyl groups, C1-3-alkyloxy groups, carboxy or C1-3-alkyloxycarbonyl groups, and

R4 denotes a hydrogen atom, R denotes a hydrogen atom and B denotes a group of formula
(Formula Removed)
wherein
n denotes the number 1, R7 denotes a hydrogen atom and
R8 denotes a chlorine or bromine atom or an ethynyl group,
while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof.
8. Substituted carboxylic acid amides of general formula I as claimed in claim 7, wherein A, R1, R2, R4, R5 and B are defined as in claim 7 and
R3 denotes a straight-chain or branched C1-4-alky! group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C1-4-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C1-3-alkylsu!phanyl, C1-3-alkylsulphonyl, carboxy or C1-3-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts
thereof.
9. Substituted carboxylic acid amides of general formula I as claimed in claim 7, wherein
A, R1, R2, R4, R5 and B are defined as in claim 7 and
R3 denotes a phenyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazoiyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C1-2-alkyl or imidazolyl-C1-2-alkyl group which may optionally be substituted in the heleroaryl moiety by one or two C1-3-alkyl groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C1-3-alkyloxy groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms,
carboxy or C1-3-alkyioxycarbonyl groups,
while the alkyl groups contained in the foregoing definitions which have more than two
carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl
groups in the previously mentioned dialkylated groups, may be identical or different,
and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing
definitions may be wholly or partly replaced by fluorine atoms,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof and or the salts
thereof.
10. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 5 or 6, wherein the group X1 denotes a methylene group.
11. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6, wherein the group X1 denotes a carbonyl group.
12. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to
6, 10 or 11, wherein the group X denotes a methylene group.
13. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6,10 or 11, wherein the group X3 denotes a carbonyl group.
14. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 6, or 10 to 13, wherein the group X4 denotes an oxygen atom.
15. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 14, wherein the group B denotes the group
(Formula Removed)
16. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to
14, wherein the group B denotes the group
(Formula Removed)
17. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to
14, wherein the group B denotes the group
(Formula Removed)
18. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17,
wherein the group R8 denotes a chlorine atom.
19. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17, wherein the group R8 denotes a bromine atom.
20. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 17, wherein the group R8 denotes an ethynyl group.
21. Substituted carboxylic acid amides of general formula I as claimed in one of claims 1 to 20, which correspond to general formula Ia
(Formula Removed)
22. The following compounds of general formula I as claimed in claim 1
(Formula Removed)
(1) 4-(azepan-2-on-1 -yl)-N-[{1R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyI]-3-methyl-benzamide,
(2) 4-{azepan-2-on-1 -yl)-N-[(1 R)-1-(5-ch!oro-1 H-benzimid azol-2-yl)-2-hydraxy-ethyl]-3-methyl-benzamide,
(3) N-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide,
(4) N-[(1 R)-1-(5-chloro-1H-benzimidazoI-2-yl)-2-methoxy-elhyl]-4-(morpholin-3-on-4-y))-3-trifluoromethyl-benzamide,
(5) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(morpholin-3-on-4-yl)-benzamide,
(6) N-[(1 S)-1 {5-chloro-1 H-benzimidazol-2-yl)-3-methylsulphanyi-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,
(7) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morphoiin-3-on-4-yl)-benzamide,
(8) 4-(azepan-2-on-1 -y!)-3-chloro-N-[(1R)-1 -{5-chloro-1 H-benzimidazol-2-yl) 2-methoxy-ethyl]-benzamide,
(9) 4-(azepan-2-on-1-yl)-N-[{1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-
methoxy-ethyl]-3-trifluoromethyl-benzamide,
(10) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide
(11) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl-4-(morphoIin-3-on-4-yl)-3-nitro-benzamide,
(12) N-[( 1 R)- 1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
([1,33oxazepan-2-on-3-yl)-benzamlde,
(13} 3-chloro-N-[(1R)-1-{5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{[1,4]oxazepan-5-on-4-yl)-benzamide,
(14) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl3-4-(piperidin-2-on-1-yl) benzamlde,
(15) N-[(1R)-1 -{5-bromo-1 H-benzimidazol-2-y[)-2-hydroxy-ethyl3-3-methyl-4-(moipholin-3-on-4-yl)-benzamide,
(16) N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide,
(17) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yI)-ethy!]-3-methyl-4-(thtomarpholin-3-on-4-yl)-benzamide,
(18) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,
(19) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide,
(20) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-
2-on-1-yl)-3-trifluoromethyl-benzamide,
(21) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-eihyl]-4-{1, 1 -dioxo-(1,2]thiazinan-2-yl)-3-methyl-benzamide,
(22) N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-butyl]-3-methyI-4-(morpholin-3-on-4-yl)-benzamide,
(23) N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1 ,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide,
(24) N-[(1 R)-1 -(5-chioro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{1,1-dioxo-[1,2,8}thiadiazinan-2-yl)-3-methyl-benzamide,
(25) N-[(1R)-1-(5-bromo-1H-benzimidazo!-2-y!)-2-methoxy-ethyl]-3-methy!-4-(morpholin-3-on-4-yl)-benzamide,
(26) N-[(1 S)-1-(5-chloro-1 H-benzimidazol-2-yl)-3-(1 H-tetrazol-5-yl)-propyI]-3-methyl-4-(morpholin-3-on-4-y!)-benzamide,
(27) N-[(1S)-1 -{5-chlcro-1 H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholm-3-on-4-yl)-benzamide,
(28) -N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsuIphany!-ethyl]-3-
methyl-4-(rnorpholin-3-on-4-yl)-benzamnide,
(29) N-[(1 R)-1 -{5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-
(thiomorphoIin-3-on-4-yl)-benzamide,
(30) 3-chloro-N-|(1R)-1 -(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide,
(31) 3-cbloro-N-{(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1 -dioxo-[1,2]thiazinan-2-yl)-benzamide,
32) N-[(1R)-1-(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide,
33) 3-bromo-N-[(1 S)-1 -(5-chloro-1 H-benzimidazol-2-yl)-ethyI]-4-(piperidin-2-on-1-yl)-benzamide,
34) 3-bromo-N-[(1 R)-1 -(5-chloro-1 H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-{piperidin-2-on-1-yl)-benzamide or

(35) N-[1-(5-chloro-1H-benzim!dazo!-2-yl)-1-(furan-2-yll)-methy!]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide,
the tautomers, the enantiomers, the diastereomers, the mixtures thereof or the salts thereof,
23. Physiologically acceptable salts of the compounds as claimed in claims 1 to 22.

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Patent Number

272537

Indian Patent Application Number

4542/DELNP/2006

PG Journal Number

15/2016

Publication Date

08-Apr-2016

Grant Date

07-Apr-2016

Date of Filing

07-Aug-2006

Name of Patentee

BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Applicant Address

BINGER STRASSE 173, 55216 INGELHEIM, GERMANY

Inventors:

#	Inventor's Name	Inventor's Address
1	KAI GERLACH	MONDSTRASSE 18/1, BIBERACH 88400, GERMANY
2	ROLAND PFAU	Pfluggasse 15, 88400 Biberach
3	HENNING PRIEPKE	BIRKENHARDERSTR. 11, WARTHAUSEN 88447, GERMANY
4	WOLFGANG WIENEN	KIRSCHENWEG 27, BIBERACH 88400, GERMANY
5	ANNETTE MARIA SCHULER-METZ	HOLZGASSE 7, ULM 89081, GERMANY
6	GEORG DAHMANN	BAHNHOFSTRASSE 14, ATTENWEILER 88448, GERMANY
7	HERBERT NAR	HEXENWEG 19, OCHSENHAUSEN 88416, GERMANY
8	SANDRA RUTH HANDSCHUH	SCHUSTERGASSE 3, WARTHAUSEN 88447, GERMANY
9	NORBERT HAUEL	MARDERWEG 12, SCHEMMERHOFEN 88433, GERMANY
10	IRIS KAUFFMANN-HEFNER	OELBACHSTRASSE 10/1, ATTENWEILER 88448, GERMANY

PCT International Classification Number

C07D 403/12

PCT International Application Number

PCT/EP2005/001796

PCT International Filing date

2005-02-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10 2004 060 984.5	2004-12-18	Germany
2	10 2004 009 835.2	2004-02-28	Germany