2,3-benzodiazepines

Abstract

What is described are BET protein-inhibitory, in particular BRD4-inhibitory 2,3-benzodiazepines of the general formula (I) ##STR00001##
in which R.sup.1a, R.sup.1b, R.sup.1c, R.sup.2, R.sup.3, R.sup.4, R.sup.5, A and X have the meanings given in the description, intermediates for preparing the compounds according to the invention, pharmaceutical compositions comprising the compounds according to the invention and their prophylactic and therapeutic use for hyperproliferative disorders, in particular for tumor disorders. Also described is the use of BET protein inhibitors for benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for the control of male fertility.

Claims

1. A compound of formula I ##STR00485## in which X represents an oxygen or sulphur atom, and A represents a monocyclic heteroaryl ring which has 5 or 6 ring atoms or represents a phenyl ring, and R.sup.1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represents a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl or C.sub.1-C.sub.6-alkoxycarbonyl radical, or represents a monocyclic heterocyclyl radical which has 3 to 8 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.6-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may optionally be mono- or polysubstituted by halogen, C.sub.1-C.sub.3-alkyl and/or C.sub.1-C.sub.3-alkoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms and which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C.sub.1-C.sub.3-alkyl and C.sub.1-C.sub.3-alkoxy, and R.sup.1b and R.sup.1c independently of one another represent hydrogen, halogen, hydroxy, cyano, nitro and/or represent a C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl radical and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and R.sup.2 represents a C.sub.1-C.sub.3-alkyl or trifluoromethyl or a C.sub.3- or C.sub.4-cycloalkyl radical, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, amino, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, monocyclic heterocyclyl which has 3 to 8 ring atoms and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, or represent C.sub.3-C.sub.10-cycloalkyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or represent monocyclic heteroaryl which has 5 or 6 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or represent monocyclic heterocyclyl which has 3 to 8 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-Cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, or represent phenyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylaminocarbonyl, C.sub.1-C.sub.6-alkylaminosulphonyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-Cycloalkyl and/or a monocyclic heterocyclyl radical which has 3 to 8 ring atoms, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.8-cycloalkyl, phenyl, monocyclic heterocyclyl which has 3 to 8 ring atoms or monocyclic heteroaryl which has 5 or 6 ring atoms, where phenyl, heteroaryl and heterocyclyl may optionally be mono- or disubstituted by halogen, C.sub.1-C.sub.3-alkoxy or C.sub.1-C.sub.3-alkyl, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that, if A represents a phenyl ring and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylamino-carbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, monocyclic heterocyclyl which has 3 to 8 ring atoms and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, R.sup.1a does not represent hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represent a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl or C.sub.1-C.sub.6-alkoxycarbonyl radical, except that the proviso does not encompass those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen, fluorine, chlorine or bromine and R.sup.5 is C.sub.1-C.sub.6-alkoxy which is substituted one or more times by identical or different halogens, and R.sup.1a is halogen, and also not encompass those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen and R.sup.5 is C.sub.1-C.sub.6-alkoxy which is substituted one or more times by identical or different monocyclic heterocyclyl radicals having 3 to 8 ring atoms and/or monocyclic heteroaryl radicals having 5 or 6 ring atoms, it being possible for the stated monocyclic heterocyclyl and heteroaryl radicals in turn to be optionally monosubstituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a is halogen.

2. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or pyridyl ring, and R.sup.1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represents a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl or C.sub.1-C.sub.6-alkoxycarbonyl radical, or represents a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.6-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms and/or by a phenyl radical which for its part may optionally be mono- or polysubstituted by halogen, C.sub.1-C.sub.3-alkyl and/or C.sub.1-C.sub.3-alkoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms and which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, C.sub.1-C.sub.3-alkyl and C.sub.1-C.sub.3-alkoxy, and R.sup.1b and R.sup.1c independently of one another represent hydrogen, halogen, hydroxy, cyano, nitro or represent a C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl radical, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, amino, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, monocyclic heterocyclyl which has 4 to 7 ring atoms, and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, or represent a C.sub.3-C.sub.10-cycloalkyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heteroaryl which has 5 or 6 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heterocyclyl which has 4 to 7 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7 and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylaminocarbonyl, C.sub.1-C.sub.6-alkylaminosulphonyl, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.10-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.5-cycloalkyl, phenyl, monocyclic heterocyclyl having 5 or 6 ring atoms, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that, if A represents a phenyl ring and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkoxy-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylamino, amino-C.sub.1-C.sub.6-alkyl, monocyclic heterocyclyl which has 4 to 7 ring atoms and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, R.sup.1a does not represent hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represent a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylamino-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkyl, N-(heterocyclyl)-C.sub.1-C.sub.6-alkoxy, hydroxy-C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.6-alkoxy, halo-C.sub.1-C.sub.6-alkyl, halo-C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl or C.sub.1-C.sub.6-alkoxycarbonyl radical, and where the proviso does not embrace those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen, fluorine, chlorine or bromine and R.sup.5 is C.sub.1-C.sub.6-alkoxy which is substituted one or more times by identical or different halogens, and R.sup.1a is halogen, and also not those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen and R.sup.5 is C.sub.1-C.sub.6-alkoxy which is substituted one or more times by identical or different monocyclic heterocyclyl radicals having 4 to 7 ring atoms and/or monocyclic heteroaryl radicals having 5 or 6 ring atoms, it being possible for the stated monocyclic heterocyclyl and heteroaryl radicals in turn to be optionally monosubstituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a is halogen.

3. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or pyridyl ring, and R.sup.1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represents a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, C.sub.1-C.sub.3-alkylcarbonylamino, C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylcarbonyl or C.sub.1-C.sub.4-alkoxycarbonyl radical, or represents a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.3-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms and which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, and R.sup.1b represents hydrogen, halogen, hydroxy, cyano, nitro or represents a C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, fluoro-C.sub.1-C.sub.3-alkyl or fluoro-C.sub.1-C.sub.3-alkoxy radical, and R.sup.1c represents hydrogen, fluorine, chlorine, bromine or cyano, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino which may be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, monocyclic heterocyclyl which has 4 to 7 ring atoms, and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, or represent a C.sub.3-C.sub.7-cycloalkyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heteroaryl which has 5 or 6 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heterocyclyl which has 4 to 7 ring atoms and which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylaminocarbonyl, C.sub.1-C.sub.3-alkylaminosulphonyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.8-cycloalkyl or monocyclic heterocyclyl which has 5 or 6 ring atoms, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that, if A represents a phenyl ring and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, monocyclic heterocyclyl which has 4 to 7 ring atoms and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, R.sup.1a does not represent hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represent a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, C.sub.1-C.sub.3-alkylcarbonylamino, C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylcarbonyl or C.sub.1-C.sub.4-alkoxycarbonyl radical, and where the proviso does not embrace those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen, fluorine, chlorine or bromine and R.sup.5 is C.sub.1-C.sub.3-alkoxy which is substituted one or more times by identical or different halogens, and R.sup.1a is halogen, and also not those compounds of the formula (I) in which A is phenyl and R.sup.4 is hydrogen and R.sup.5 is C.sub.1-C.sub.3-alkoxy which is substituted one or more times by identical or different monocyclic heterocyclyl radicals having 4 to 7 ring atoms and/or monocyclic heteroaryl radicals having 5 or 6 ring atoms, it being possible for the stated monocyclic heterocyclyl and heteroaryl radicals in turn to be optionally monosubstituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a is halogen.

4. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or pyridyl ring, and R.sup.1a represents a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.3-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl or methoxy, and R.sup.1b represents hydrogen, halogen, hydroxy, cyano, nitro or represents a C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, fluoro-C.sub.1-C.sub.3-alkyl or fluoro-C.sub.1-C.sub.3-alkoxy radical, and R.sup.1c represents hydrogen, fluorine, chlorine, bromine or cyano, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, or represent C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino which may be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, monocyclic heterocyclyl which has 4 to 7 ring atoms, and/or monocyclic heteroaryl which has 5 or 6 ring atoms, where the monocyclic heterocyclyl and heteroaryl radicals mentioned for their part may optionally be monosubstituted by C.sub.1-C.sub.3-alkyl, or represent a C.sub.3-C.sub.7-cycloalkyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heteroaryl which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent monocyclic heterocyclyl which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represent a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylaminocarbonyl, C.sub.1-C.sub.3-alkylaminosulphonyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.5-cycloalkyl or monocyclic heterocyclyl which has 5 or 6 ring atoms, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof.

5. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or pyridyl ring, and R.sup.1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represents a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, C.sub.1-C.sub.3-alkylcarbonylamino, C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylcarbonyl or C.sub.1-C.sub.4-alkoxycarbonyl radical, or represents a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.3-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, and R.sup.1b represents hydrogen, halogen, hydroxy, cyano, nitro or represents a C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy radical, and R.sup.1c represents hydrogen, fluorine, chlorine, bromine or cyano, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 represents a C.sub.3-C.sub.7-cycloalkyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents monocyclic heteroaryl which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents monocyclic heterocyclyl which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)R.sup.8, S(O).sub.2R.sup.9, NR.sup.6R.sup.7, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylaminocarbonyl, C.sub.1-C.sub.3-alkylaminosulphonyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, R.sup.5 represents hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkylaminosulphonyl, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.8-cycloalkyl or monocyclic heterocyclyl which has 5 or 6 ring atoms, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof.

6. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or pyridyl ring, and R.sup.1a represents hydrogen, halogen, cyano, carboxyl, amino or aminosulphonyl, or represents a C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.2-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylamino, C.sub.1-C.sub.3-alkylcarbonylamino, C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.3-alkylcarbonyl or C.sub.1-C.sub.4-alkoxycarbonyl radical, or represents a monocyclic heterocyclyl radical which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, nitro, hydroxy, amino, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, phenyl, halophenyl, phenyl-C.sub.1-C.sub.3-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a monocyclic heteroaryl radical which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxy, amino, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, NHS(O).sub.2R.sup.9, and/or by a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or by a monocyclic heteroaryl radical which has 5 or 6 ring atoms, and/or by a phenyl radical which for its part may be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and/or a monocyclic heteroaryl radical which has 5 or 6 ring atoms which for its part may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl and/or methoxy, and R.sup.1b represents hydrogen, halogen, hydroxy, cyano, nitro or represents a C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, fluoro-C.sub.1-C.sub.3-alkyl or fluoro-C.sub.1-C.sub.3-alkoxy radical, and R.sup.1c represents hydrogen, fluorine, chlorine, bromine or cyano, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, cyclopropylamino or C.sub.1-C.sub.3-alkylamino, and R.sup.4 represents hydrogen, hydroxy, cyano, nitro, amino, aminocarbonyl, fluorine, chlorine, bromine, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylamino, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-alkylaminocarbonyl or C.sub.1-C.sub.6-alkyl-aminosulphonyl, and R.sup.5 represents a C.sub.3-C.sub.7-cycloalkyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents monocyclic heteroaryl which has 5 or 6 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents monocyclic heterocyclyl which has 4 to 7 ring atoms and may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, oxo, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, C.sub.1-C.sub.3-alkylamino, amino-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkylaminocarbonyl, C.sub.1-C.sub.3-alkylaminosulphonyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkoxy, C.sub.3-C.sub.6-cycloalkyl, and/or a monocyclic heterocyclyl radical which has 4 to 7 ring atoms, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.6-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, fluoro-C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy-C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.5-cycloalkyl or monocyclic heterocyclyl which has 5 or 6 ring atoms, and R.sup.9 represents hydrogen, C.sub.1-C.sub.6-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof.

7. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or 3-pyridyl ring, and R.sup.1a represents hydrogen or chlorine, or represents piperazinyl, pyrrolidinyl, piperidinyl, diazepanyl, oxazinanyl, oxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl or azetidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, nitro, hydroxy, oxo, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, dimethylamino, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, phenyl, fluorophenyl, phenyl-C.sub.1-C.sub.3-alkyl, pyridinyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9 and/or NHS(O).sub.2R.sup.9, or represents tetrazolyl, or represents isoxazolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrrolyl, oxadiazolyl, pyridinyl or pyrimidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxy, amino, cyano, nitro, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, dimethylamino, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, cyclopropyl, pyridinyl, phenyl, fluorophenyl, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, S(O).sub.2NR.sup.6R.sup.7, S(O)R.sup.9, S(O).sub.2R.sup.9, and/or NHS(O).sub.2R.sup.9, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, amino, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl, dimethylamino, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, hydroxy-C.sub.1-C.sub.3-alkyl, cyclopropyl, chlorothienyl, morpholino and/or pyridinyl, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen or bromine, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, methyl, ethyl, methoxy, ethoxy, cyclopropylamino, methylamino or ethylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, amino, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represent difluoromethoxy or trifluoromethoxy, or represent C.sub.1-C.sub.3-alkoxy which may be substituted by pyridinyl, morpholinyl, pyrrolidinyl or piperazinyl, in which pyridinyl and piperazinyl in turn may be optionally be substituted by C.sub.1-C.sub.3-alkyl, or represents cyclopropyl, or represents pyridinyl, pyrazolyl, triazolyl or isoxazolyl, which may be optionally mono- or polysubstituted by identical or different substituents from the group consting of hydroxy and/or methyl, or represents pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazolidinyl, thiomorpholinyl, which may optionally be mono- or polysubstituted by oxo, methyl and/or S(O).sub.2R.sup.9, or represents phenyl optionally substituted by C.sub.1-C.sub.3-alkylaminosulphonyl or fluorine, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that, if A represents a phenyl ring and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, amino, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represent difluoromethoxy or trifluoromethoxy, or represent C.sub.1-C.sub.3-alkoxy which may be substituted by pyridinyl, morpholinyl, pyrrolidinyl or piperazinyl, in which pyridinyl and piperazinyl in turn may be optionally substituted by C.sub.1-C.sub.3-alkyl, R.sup.1a does not represent hydrogen or chlorine, and where the proviso does not encompass those compounds of the formula (I) in which A represents phenyl and R.sup.4 represents hydrogen or chlorine and R.sup.5 represents trifluoromethoxy, and R.sup.1a represents chlorine, and also not those compounds of the formula (I) in which A represents phenyl and R.sup.4 represents hydrogen and R.sup.5 represents C.sub.1-C.sub.3-alkoxy which is substituted by morpholinyl, pyrrolidinyl, piperazinyl or pyridyl, in which the piperazinyl and pyridinyl itself may be substituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a represents chlorine.

8. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl or 3-pyridyl ring, and R.sup.1a represents hydrogen or chlorine, or represents piperazinyl, pyrrolidinyl, piperidinyl, diazepanyl, oxazinanyl, oxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl or azetidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, hydroxy, oxo, C.sub.1-C.sub.3-alkyl, methoxy, hydroxy-C.sub.1-C.sub.3-alkyl, dimethylamino, difluoroethyl, trifluoroethyl, benzyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, and/or S(O).sub.2R.sup.9, or represents tetrazolyl, or represents isoxazolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrrolyl, oxadiazolyl, pyridinyl or pyrimidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxy, cyano, C.sub.1-C.sub.2-alkyl, methoxy, methoxymethyl, trifluoromethyl, cyclopropyl, pyridinyl, phenyl, fluorophenyl and/or C(O)R.sup.8, or represents a phenyl radical which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, methoxy, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, trifluoromethyl, trifluoromethoxy, hydroxy-C.sub.1-C.sub.3-alkyl, cyclopropyl, chlorotheinyl and/or morpholino, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen or bromine, and R.sup.2 represents methyl, ethyl or isopropyl, and R.sup.3 represents cyclopropyl, methyl, ethyl, methoxy, ethoxy, cyclopropylamino, methylamino or ethylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, amino, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represent difluoromethoxy or trifluoromethoxy, or represent C.sub.1-C.sub.3-alkoxy which may be substituted by pyridinyl, morpholinyl, pyrrolidinyl or piperazinyl, in which the pyridinyl and piperazinyl may in turn optionally be substituted by C.sub.1-C.sub.3-alkyl, or represent cyclopropyl, or represent pyridinyl, pyrazolyl, triazolyl or isoxazolyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of hydroxy and/or methyl, or represent pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazolidinyl, thiomorpholinyl, which may optionally be mono- or polysubstituted by methyl, oxo, and/or S(O).sub.2R.sup.9, or represent phenyl optionally substituted by C.sub.1-C.sub.3-alkylaminosulphonyl or fluorine, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl, di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl or fluoropyridyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or an enantiomer, diastereomer, racemate, tautomer, or physiologically acceptable salt thereof, with the proviso that, if A represents a phenyl ring and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, amino, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represent difluoromethoxy or trifluoromethoxy, or represent C.sub.1-C.sub.3-alkoxy which may be substituted by pyridinyl, morpholinyl, pyrrolidinyl or piperazinyl, in which the pyridinyl and piperazinyl may in turn optionally be substituted by C.sub.1-C.sub.3-alkyl, R.sup.1a does not represent hydrogen or chlorine, and where the proviso does not encompass those compounds of the formula (I) in which A represents phenyl and R.sup.4 represents hydrogen or chlorine and R.sup.5 represents trifluoromethoxy, and R.sup.1a represents chlorine, and also not those compounds of the formula (I) in which A represents phenyl and R.sup.4 represents hydrogen and R.sup.5 represents C.sub.1-C.sub.3-alkoxy which is substituted by morpholinyl, pyrrolidinyl, piperazinyl or pyridyl, in which the piperazinyl and pyridinyl itself may be substituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a represents chlorine.

9. Compounds of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl ring, and R.sup.1a represents piperazinyl, pyrrolidinyl, piperidinyl, diazepanyl, oxazinanyl, oxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl or azetidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, hydroxy, oxo, C.sub.1-C.sub.3-alkyl, methoxy, hydroxy-C.sub.1-C.sub.3-alkyl, dimethylamino, difluoroethyl, trifluoroethyl, benzyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, and/or S(O).sub.2R.sup.9, or represents tetrazolyl, or represents isoxazolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, triazolyl, pyrrolyl, oxadiazolyl, pyridinyl or pyrimidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxy, cyano, C.sub.1-C.sub.2-alkyl, methoxy, methoxymethyl, trifluoromethyl, cyclopropyl, pyridinyl, phenyl, fluorophenyl and/or C(O)R.sup.8, or represents a phenyl radical, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, hydroxy, cyano, nitro, carboxyl, C.sub.1-C.sub.3-alkyl, methoxy, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, C.sub.1-C.sub.3-alkylsulphinyl, C.sub.1-C.sub.3-alkylsulphonyl, S(O).sub.2NH.sub.2, C.sub.1-C.sub.3-alkylsulphonylamino, C.sub.1-C.sub.3-alkylaminosulphonyl, C.sub.3-C.sub.6-cycloalkylaminosulphonyl, trifluoromethyl, trifluoromethoxy, hydroxy-C.sub.1-C.sub.3-alkyl, cyclopropyl, chlorothienyl and/or morpholino, R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen, and R.sup.2 represents methyl or ethyl, and R.sup.3 represents methylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or difluoromethoxy or trifluoromethoxy, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl or di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or a tautomer or physiologically acceptable salt thereof, and where the stereocentre, which is represented by the carbon atom of the benzodiazepine skeleton which is bound to R.sup.2, is present either in racemic form or predominantly or completely in the (S) configuration.

10. A compound of formula (I) according to claim 1 in which X represents an oxygen atom, and A represents a phenyl ring, and R.sup.1a represents hydrogen or chlorine, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen, and R.sup.2 represents methyl or ethyl, and R.sup.3 represents methylamino, and R.sup.4 represents cyclopropyl, or represents pyridinyl, pyrazolyl, triazolyl or isoxazolyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of hydroxy and/or methyl, or represents pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, oxazolidinyl or thiomorpholinyl, which may optionally be mono- or polysubstituted by methyl, oxo and/or S(O).sub.2R.sup.9, or represents phenyl which is optionally substituted by C.sub.1-C.sub.3-alkylaminosulphonyl or fluorine, and R.sup.5 represents hydrogen, hydroxy, cyano, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represents difluoromethoxy or trifluoromethoxy, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl or di-C.sub.1-C.sub.3-alkyl-amino-C.sub.1-C.sub.3-alkyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or a tautomer or physiologically acceptable salt thereof, and where the stereocentre, which is represented by the carbon atom of the benzodiazepine skeleton which is bound to R.sup.2, is present either in racemic form or predominantly or completely in the (S) configuration.

11. A compound of formula (I), according to claim 1, in which X represents an oxygen atom, and A represents a phenyl ring, and R.sup.1a represents hydrogen or chlorine, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen, and R.sup.2 represents methyl or ethyl, and R.sup.3 represents methylamino, and R.sup.4 represents hydrogen, chlorine, methoxy or ethoxy, or represents difluoromethoxy or trifluoromethoxy, and R.sup.5 represents cyclopropyl, or represents pyridinyl or pyrazolyl, which may optionally be substituted one or more times by methyl, or represents morpholinyl, piperidinyl, piperazinyl or thiomorpholinyl, which may optionally be mono- or polysubstituted by methyl, oxo and/or S(O).sub.2R.sup.9, or represents phenyl which is substituted by C.sub.1-C.sub.3-alkylaminosulphonyl, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl or di-C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, and R.sup.8 represents hydroxy, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or a tautomer or physiologically acceptable salt thereof, and where the stereocentre, which is represented by the carbon atom of the benzodiazepine skeleton which is bound to R.sup.2, is present either in racemic form or predominantly or completely in the (S) configuration.

12. A compound of formula (I), according to claim 1, in which X represents an oxygen atom, and A represents a phenyl ring, and R.sup.1a represents piperazinyl, pyrrolidinyl, piperidinyl, diazepanyl, oxazinanyl, oxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl or azetidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of fluorine, hydroxy, oxo, C.sub.1-C.sub.3-alkyl, methoxy, hydroxy-C.sub.1-C.sub.3-alkyl, dimethylamino, difluoroethyl, trifluoroethyl, benzyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, C(O)R.sup.8, and/or S(O).sub.2R.sup.9, or represents isoxazolyl or pyrazolyl, which may optionally be substituted one or more times by identical or different C.sub.1-C.sub.2-alkyls, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen, and R.sup.2 represents methyl, and R.sup.3 represents methylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, hydroxy, cyano, chlorine, C.sub.1-C.sub.6-alkyl, methoxy, ethoxy or C.sub.1-C.sub.3-alkylcarbonylamino, or represent difluoromethoxy or trifluoromethoxy, and R.sup.6 and R.sup.7 independently of one another represent hydrogen, C.sub.1-C.sub.3-alkyl, cyclopropyl or di-C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkyl, and R.sup.8 represents hydroxyl, C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.1-C.sub.3-alkyl, trifluoromethyl, pyrrolidinyl, morpholinyl or piperidinyl, and R.sup.9 represents C.sub.1-C.sub.4-alkyl or C.sub.1-C.sub.4-alkoxy, or a tautomer or physiologically acceptable salt thereof, and where the stereocentre, which is represented by the carbon atom of the benzodiazepine skeleton which is bound to R.sup.2, is present either in racemic form or predominantly or completely in the (S) configuration.

13. A compound of formula (I), according to claim 1 in which X represents an oxygen atom, and A represents a phenyl ring, and R.sup.1a represents piperazinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azetidinyl, which may optionally be mono- or polysubstituted by identical or different substituents from the group consisting of hydoxy, oxo, C.sub.1-C.sub.3-alkyl, methoxy, dimethylamino, difluoroethyl, trifluoroethyl, NR.sup.6C(O)R.sup.9, C(O)NR.sup.6R.sup.7, and/or C(O)R.sup.8, and R.sup.1b represents hydrogen, fluorine, bromine or cyano, and R.sup.1c represents hydrogen, and R.sup.2 represents methyl, and R.sup.3 represents methylamino, and R.sup.4 and R.sup.5 independently of one another represent hydrogen, chlorine, methoxy or ethoxy, or represent difluoromethoxy or trifluoromethoxy, and R.sup.6 and R.sup.7 independently of one another represent hydrogen or C.sub.1-C.sub.3-alkyl, and R.sup.8 represents methyl, and R.sup.9 represents methyl, or a tautomer or physiologically acceptable salt thereof, and where the stereocentre, which is represented by the carbon atom of the benzodiazepine skeleton which is bound to R.sup.2, is present either in racemic form or predominantly or completely in the (S) configuration.

14. A compound of formula (I) according to claim 1 in which A represents a phenyl ring and R.sup.4 represents hydrogen or chlorine and R.sup.5 represents trifluoromethoxy and R.sup.1a represents chlorine, and compounds of the formula (I) in which A represents a phenyl ring and R.sup.4 represents hydrogen and R.sup.5 represents C.sub.1-C.sub.3-alkoxy which may be substituted by morpholinyl, pyrrolidinyl, piperazinyl or pyridyl, where the piperazinyl or pyridinyl for its part may be substituted by C.sub.1-C.sub.3-alkyl, and R.sup.1a represents chlorine, or a tautomer or physiologically acceptable salt thereof.

15. A compound of formula (I) according to claim 1, selected from the group consisting of ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-(4-chlorophenyl)-N,4-dimethy-8-(trimethxy)-4,5-dimethyl-8-trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1H-pyrazol-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(2-chloropyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-5-(4-{7,8-dimethoxy-4-methyl-3-[(methylamino)carbonyl]-4,5-dihydro-3H-2,3-benzodiazepin-1-yl}phenyl)thiophen-2-carboxylic acid, ()-4-{7,8-dimethoxy-4-methyl-3-[(methylamino)carbonyl]-4,5-dihydro-3H-2,3-benzodiazepin-1-yl}biphenyl-2-carboxylic acid, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(pyridin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-8-cyclopropyl-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-{4-[(methylamino)sulphonyl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-(4-chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-(4-chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(4-methylpiperazin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(piperidin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-methoxy-N,4-dimethyl-1-(pyridin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7-chloro-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, 7-chloro-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(4-isoxazolyl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(1-methyl-H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(1,3,5-trimethyl-H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(1H-pyrazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3-cyclopropyl-5-ethyl-1H-pyrazol-1-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(5-cyclopropyl-3-ethyl-1H-pyrazol-1-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-1-{4-[3-(methoxymethyl)-5-methyl-1H-pyrazol-1-yl]phenyl}-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-1-{4-[5-(methoxymethyl)-3-methyl-1H-pyrazol-1-yl]phenyl}-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[5-cyclopropyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl]phenyl}-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[3-cyclopropyl-5-(pyridin-2-yl)-1H-pyrazol-1-yl]phenyl}-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(1H-tetrazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[2-(morpholin-4-yl)ethoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[2-(pyrrolidin-1-yl)ethoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxooxazolidin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxooxazolidin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-benzyl-2-oxopiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-2-oxo-1,4-diazepan-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxo-1,3-oxazinan-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxopyrrolidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(3-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(3-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-methyl-5-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (stereoisomer mixture), ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-methyl-3-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (stereoisomer mixture), ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-2-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-2-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-2-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(1-methyl-H-1,2,3-triazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(2,4-dimethylthiazol-5-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(2,4-dimethylthiazol-5-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(2,4-dimethylthiazol-5-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(1,2-dimethyl-H-imidazol-5-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[2-(trifluoromethyl)pyridin-3-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(6-hydroxypyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(6-hydroxypyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[6-(trifluoromethyl)pyridin-3-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1,3,5-trimethyl-H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7,8-dimethoxy-N,4-dimethyl-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(isoxazol-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(1,3,5-trimethyl-H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(1-methyl-H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(1-methyl-1H-pyrazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-fluoro-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-(3-nitrobiphenyl-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(biphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(2,4-dichlorobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-fluorobiphenyl-4-yl)-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-Chlorbiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-(4-methylbiphenyl-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-(4-methoxybiphenyl-4-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(6-methoxypyridin-3-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(methylsulphinyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{2-[(methylsulphonyl)amino]biphenyl-4-yl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[2-(methylsulphonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[(methylsulphonyl)amino]biphenyl-4-yl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{3-[(methylsulphonyl)amino]biphenyl-4-yl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-(2-methylbiphenyl-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(methylsulphonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(2-methoxypyrimidin-5-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-cyano-4-fluorobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(2-methoxypyridin-3-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-carbamoylbiphenyl-4-yl)-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(pyrrolidin-1-ylcarbonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(5-methoxypyridin-3-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(5-methylpyridin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpyridin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(cyclopropylcarbamoyl)biphenyl-4-yl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3-fluoropyridin-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(trifluoromethyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(trifluoromethyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-(3-methoxybiphenyl-4-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(5-chlorothien-2-yl)biphenyl-4-yl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-fluorobiphenyl-4-yl)-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-(2-methoxybiphenyl-4-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[2-(trifluoromethyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(2-chlorobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(2-fluorobiphenyl-4-yl)-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(hydroxymethyl)biphenyl-4-yl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(trifluoromethoxy)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(pyrrolidin-1-ylcarbonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(piperidin-1-ylcarbonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(cyclopropylcarbamoyl)biphenyl-4-yl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(2,4-difluorobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-(4-nitrobiphenyl-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(pyridin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(4-methoxypyridin-3-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-cyanobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-cyanobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[2-(trifluoromethoxy)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(methylsulphonyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(2-cyanobiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(pyrimidin-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[2-(hydroxymethyl)biphenyl-4-yl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-{[2-(dimethylamino)ethyl]carb-amoyl}biphenyl-4-yl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-(3-sulphamoylbiphenyl-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(methylsulphamoyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1-methyl-1H-pyrrol-2-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(6-methylpyridin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(cyclopropylsulphamoyl)biphenyl-4-yl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-fluoro-5-hydroxybiphenyl-4-yl)-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(3-fluoro-5-methylbiphenyl-4-yl)-7,8-dimethoxy-N,4-dimethy-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(methylsulphamoyl)biphenyl-4-yl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(5-fluoropyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-fluoropyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(2-methylpyridin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(2-methoxypyridin-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(5-cyanopyridin-3-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(azetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(azetidin-1-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(azetidin-1-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3-fluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(3-fluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3-fluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-hydroxypiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(4-hydroxypiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(piperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(piperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-acetylpiperazin-1-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(4-acetylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(4-acetylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(trifluoracetyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(3-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-3-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(piperidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(3,3-difluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(azetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-fluoro-3-(morpholin-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethy-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[3-(3,3-difluoroazetidin-1-yl)-4-fluorophenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-fluoro-3-(4-hydroxypiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(5-methyl-3-phenyl-1H-pyrazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(5-methyl-3-phenyl-1H-pyrazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(5-cyclopropyl-3-phenyl-1H-pyrazol-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(5-cyclopropyl-3-phenyl-1H-pyrazol-1-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[3-phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-{4-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-tert-butyl-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-8-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4,8-trimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-bis(difluoromethoxy)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-7,8-diethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7-(difluoromethoxy)-1-[4-(3,5-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7-(difluoromethoxy)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7-(difluoromethoxy)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7-(difluoromethoxy)-8-methoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7-(difluoromethoxy)-8-methoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7-(difluoromethoxy)-8-methoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[3-(4-methylpiperazin-1-yl)propoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-(4-chlorophenyl)-N,4-dimethyl-8-[3-(4-methylpiperazin-1-yl)propoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[3-(morpholin-4-yl)propoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[2-(4-methylpiperazin-1-yl)ethoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-8-[(6-methylpyridin-2-yl)methoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-hydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-[3-(morpholin-4-yl)propoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7-cyano-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-acetamido-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-acetamido-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-acetamido-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-8-(3,5-dimethyl-1H-pyrazol-1-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-(3,5-dimethyl-1H-pyrazol-1-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morphin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-8-methoxy-N,4-dimethyl-1-[4-(3-oxomorphin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(4-methoxypiperidin-1-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7,8-dimethoxy-1-[4-(4-methoxypiperidin-1-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-1-[4-(4-methoxypiperidin-1-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,3-difluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-acetamidopiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3-hydroxyazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3-hydroxy-3-methylazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(3-hydroxy-3-methylazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(3-hydroxy-3-methylazetidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-isopropylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-1-[4-(3-methoxyazetidin-1-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-hydroxy-4-methylpiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(4-hydroxy-4-methylpiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[4-(4-hydroxy-4-methylpiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(methylcarbamoyl)piperidin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(methylcarbamoyl)piperidin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(methylcarbamoyl)piperidin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-tert-butyl (1-{4-[7,8-dimethoxy-4-methyl-3-(methylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepin-1-yl]phenyl}-4-methylpiperidin-4-yl)carbamate, ()-1-{4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(3-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-oxopiperidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-{4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-{4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]phenyl}-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dihydroxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-diethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(piperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-4-ethyl-7, 8-dimethoxy-N-methyl-1-[4-(piperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-4-ethyl-7, 8-dimethoxy-N-methyl-1-[4-(piperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-4-ethyl-7, 8-dimethoxy-N-methyl-1-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-4-ethyl-7, 8-dimethoxy-N-methyl-1-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-1-[4-(3-fluoroazetidin-1-yl)phenyl]-7,8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-acetylpiperazin-1-yl)phenyl]-4-ethyl-7, 8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-4-ethyl-7,8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-1-[4-(4-hydroxypiperidin-1-yl)phenyl]-7, 8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-1-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-N,4-dimethyl-1-[4-(piperazin-1-yl)phenyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-1-[4-(4-hydroxypiperidin-1-yl)phenyl]-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-chloro-N,4-dimethyl-1-{4-[4-(methylsulphonyl)piperazin-1-yl]phenyl}-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-(1,1-dioxidothiomorpholin-4-yl)-1-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-8-(1,1-dioxidothiomorpholin-4-yl)-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-acetylpiperazin-1-yl)phenyl]-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-8-methoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-1-(4-fluorobiphenyl-4-yl)-7,8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]-4-ethyl-7, 8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-isopropyl-7,8-dimethoxy-N-methyl-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(2-oxopyrrolidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(3-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-4-ethyl-7,8-dimethoxy-N-methyl-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methyl-2-oxo-1,4-diazepan-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(2-oxo-1,3-oxazolidin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-(4-chlorophenyl)-N,4-dimethyl-7-(2-oxo-1,3-oxazolidin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(2-oxopiperidin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(3-oxomorpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(pyrrolidin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-7-(1,1-dioxidothiomorpholin-4-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(4-methylpiperazin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-N,4-dimethyl-7-(4-methylpiperazin-1-yl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-N,4-dimethyl-7-(4-methyl-3-oxopiperazin-1-yl)-1-[4-(4-methyl-3-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-7-(4-fluorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(pyridin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-7-(6-hydroxypyridin-3-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-(4-chlorophenyl)-N,4-dimethyl-7-(1-methyl-1H-1,2,3-triazol-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-1-[4-(4-hydroxypiperidin-1-yl)phenyl]-7, 8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)-7, 8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(1,1-dioxido-1,2-thiazolidin-2-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-{7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone, 1-{(4S)-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone, ()-1-{1-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-N,4-dimethyl-8-(trifluoromethoxy)-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)N,4-dimethyl-8-(trifluoromethoxy)-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)N,4-dimethyl-8-(trifluoromethoxy)-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-N,4-dimethyl-1-[4-(4-methyl-1-piperazinyl)phenyl]-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4R)N,4-dimethyl-1-[4-(4-methyl-1-piperazinyl)phenyl]-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)N,4-dimethyl-1-[4-(4-methyl-1-piperazinyl)phenyl]-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[4-(4-hydroxy-1-piperidinyl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-1-[2,4-dibromo-5-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, (4S)-1-[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, ()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(1-oxopropyl)-4,5-dihydro-3H-2,3-benzodiazepine, ()-3-(cyclopropylcarbonyl)-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine, ()-N-cyclopropyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine, ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-carbothioamide, methyl ()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxylate, ethyl ()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxylate, ()-N-ethyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, and (4S)N-ethyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide.

16. A method for the control of male fertility comprising administering to a human or mammal in need thereof an effective amount of a compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer or physiologically acceptable salt thereof.

17. A method for the treatment of a leukaemia, prostate carcinoma, breast carcinoma, melanoma or multiple myeloma responsive to inhibition of BRD4 comprising administering to a human or mammal in need thereof an effective amount of a compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer or physiologically acceptable salt thereof.

18. A pharmaceutical formulation comprising a compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer or physiologically acceptable salt thereof, in combination with an antihyperproliferative, cytostatic or cytotoxic substance selected from abiraterone acetate, acolbifene, actinomycin D (dactinomycin), afatinib, aldesleukin, alendronic acid, alitretinoin, allopurinol, altretamine, aminoglutethimide, aminopterin, amifostine, amrubicin, amsacrine, anastrozole, apatinib, arglabin, arsenic trioxide, arzoxifene, asoprisnil, L-asparaginase, atamestane, atrasentan, axitinib, 5-azacytidine, azathioprine, bendamustine, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bicalutamide, bleomycin sulphate, broxuridine, bortezomib, bosutinib, busulfan, cabazitaxel, calcitonin, camptothecin, capecitabin, carboplatin, carfilzomib, carmustine, cediranib, celmoleukin, chlorambucil, cisplatin, cladribine, clodronic acid, clofarabine, colaspase, crisnatol, crizotinib, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, deslorelin, dexrazoxane, diethylstilbestrol, 2,2-difluorodeoxycytidine, docetaxel, doxifluridine, doxorubicin, dronabinol, dutasteride, edotecarin, eflornithine, enzalutamide, epirubicin, epoetin-alfa, epothilone, eptaplatin, erlotinib, erythro-hydroxynonyladenine, estradiol, estramustine sodium phosphate, ethynylestradiol, etidronic acid, etoposide, everolimus, exatecan, exemestan, fadrozole, fenretinide, filgrastim, finasteride, floxuridine, fluconazole, fludarabine, 5-fluordeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustin, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin, gossypol, granisetron-hydrochloride, hexamethylmelamine, histamine dihydrochloride, histrelin, hydroxyurea, hydroxyprogesterone caproate, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, iniparib, irinotecan, ixabepilone, keyhole limpet haemocyanin, lanreotide, lapatinib, lasofoxifene, lentinan sulphate, lestaurtinib, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolinic acid calcium salt, liposomal MTP-PE, lomustine, lonafarnib, lonidamine, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, 6-mercaptopurine, mesna, methotrexate, miltefosine, minocycline, minodronate, miproxifene, mitomycin C, mitotane, mitoxantrone, nafarelin, nedaplatin, nelarabine, nemorubicin, neratinib, nilotinib, nilutamide, nimustine, nolatrexed, obatoclax, oblimersen, octreotide, olaparib, ondansetron hydrochloride, oxaliplatin, paclitaxel, pamidronate disodium, pazopanib, pegaspargase, pemetrexed, pentostatin, N-phosphonoacetyl-L-aspartate, picibanil, pilocarpine hydrochloride, pirarubicin, plerixafor, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, procarbazine, quazepam, raloxifene, raltitrexed, ranpirnase, refametinib, regorafenib, 13-cis-retinoic acid, rhenium-186 etidronate, rituximab, romidepsin, romurtide, ruxolitinib, salinomycin, sargramostim, satraplatin, semaxatinib, semustine, seocalcitol, sipuleucel-T, sizofiran, sobuzoxane, sorafenib, streptozocin, strontium-89 chloride, sunitinib, batabulin, tamoxifen, tamsulosin, tasonermin, testolactone, teceleukin, temozolomide, temsirolimus, teniposide, testosterone propionate, thalidomide, thymosin alpha 1, thioguanine, thiotepa, thyrotropin, tiazofurin, tiludronic acid, tipifarnib, tirapazamine, canfosfamide, toceranib, topotecan, toremifene, tositumomab, tastuzumab, treosulfan, tretinoin, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, trofosfamide, uridine, valrubicin, valspodar, vandetanib, vapreotid, vatalanib, vemurafinib, verteporfin, vesnarinon, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, zinostatin stimalamer, and zoledronic acid.

19. A pharmaceutical formulation comprising a compound according to claim 1, or an enantiomer, diastereomer, racemate, tautomer or physiologically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Description

PREPARATION OF THE INTERMEDIATES

Example 1A

2,2-Dimethyl-5-[4-(trifluoromethoxy)benzyl]-1,3-dioxane-4,6-dione

(1) ##STR00022##

(2) 25.4 g (134 mmol) of 4-(trifluoromethoxy)benzaldehyde (CAS [659-28-9]), 19.3 g (134 mmol) of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione, CAS [2033-24-1]) and 1.93 g (13.4 mmol) of piperidinium acetate (CAS [4540-33-4]) were dissolved in 500 ml of ethanol and stirred at RT for 30 min. The reaction solution was cooled to 0 C. using an ice bath and stirred for a further 10 min. 12.6 g (200 mmol) of sodium cyanoborhydride were introduced a little at a time, and the reaction was then allowed to warm to RT and stirred for a further 1.5 h. 250 ml of 2M hydrochloric acid were then added carefully and stirring was continued until the evolution of gas had ceased completely (about 30 min) The ethanol was removed on a rotary evaporator and the residue was taken up in 2M hydrochloric acid and extracted repeatedly with dichloromethane. The combined organic phases were dried with sodium sulphate and the solvent was removed on a rotary evaporator. This gave 32.7 g (41% of theory) of crude product as a white solid which was reacted without further purification.

(3) LCMS (Method 1): R.sub.t=1.33 min; m/z=319 (M+H).sup.+

Example 2A

5-(4-Bromobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

(4) ##STR00023##

(5) The compound was prepared analogously to Example 1A from 25.0 g (135 mmol) of 4-bromobenzaldehyde, 19.4 g (135 mmol) of Meldrum's acid, 1.95 g (13.5 mmol) of piperidinium acetate and 12.7 g (202 mmol) of sodium cyanoborohydride. This gave 27.1 g (64% of theory) of the desired product which was reacted further without purification.

(6) LCMS (Method 2): R.sub.t=1.23 min; m/z=313, 315 (Br isotope pattern, M+H).sup.+

Example 3A

5-(4-Methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

(7) ##STR00024##

(8) 30.0 g (220 mmol) of 4-methoxybenzaldehyde were initially charged in 500 ml of water, and 33.3 g (231 mmol) of Meldrum's acid were suspended therein. The mixture was stirred mechanically at an internal temperature of 75 C. for 2 h. During this time, the yellowish emulsion turned into a yellow suspension. After cooling, the reaction mixture was extracted with dichloromethane and the extracts were dried with magnesium sulphate. This dichloromethane solution of the intermediate 5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (.sup.1H-NMR (300 MHz, CDCl.sub.3): =1.78 (s, 6H), 3.90 (s, 3H), 6.98 (d, 2H), 8.23 (d, 2H), 8.37 (s, 1H)) was directly processed further. The solution (800 ml) was cooled to 3 C., and 110 ml of acetic acid were added. 20.8 g (155 mmol) of sodium borohydride were then introduced a little at a time over a period of 60 min (temperature at most 2 C.). The suspension formed was stirred at RT for another 15 min. The reaction mixture was quenched by careful dropwise addition of 300 ml of water and stirred at RT for another about 30 min. The phases were separated and the organic phase washed with sodium bicarbonate solution and water and dried with magnesium sulphate. The solvents were removed on a rotary evaporator. This gave 46.60 g (80% of theory) of the desired product as a yellowish oil which crystallized to give a slightly yellow solid and did not require any further purification.

(9) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.48 (s, 3H), 1.72 (s, 3H), 3.44 (d, 2H), 3.72 (t, 1H), 3.77 (s, 3H), 6.82 (d, 2H), 7.24 (d, 2H).

Example 4A

2,2,5-Trimethyl-5-[4-(trifluoromethoxy)benzyl]-1,3-dioxane-4,6-dione

(10) ##STR00025##

(11) At RT, 32.7 g (103 mmol) of 2,2-dimethyl-5-[4-(trifluoromethoxy)benzyl]-1,3-dioxane-4,6-dione (Example 1A) and 21.3 g (154 mmol) of potassium carbonate were initially charged in 400 ml of DMF, and 72.9 g (514 mmol, 32.0 ml) of iodomethane were slowly added dropwise. The mixture was stirred vigorously at RT for 1.5 h and then added to water. The mixture was extracted 3 with ethyl acetate and the combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the crude product (32.5 g colourless oil) was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 20.0 g (55% of theory) of the desired product as a colourless oil.

(12) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.99 (s, 3H), 1.57 (s, 3H), 1.63 (s, 3H), 3.22 (s, 2H), 7.12 (d, 2H), 7.31 (d, 2H).

Example 5A

5-(4-Bromobenzyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione

(13) ##STR00026##

(14) The compound was prepared analogously to Example 4A from 7.37 g (23.5 mmol) of 5-(4-bromobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Example 2A), 16.7 g (118 mmol) of iodomethane and 4.88 g (35.3 mmol) of potassium carbonate. This gave 8 g of crude product which was directly reacted further.

(15) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.06 (s, 3H), 1.62 (s, 3H), 1.74 (s, 3H), 3.28 (s, 2H), 7.05 (d, 2H), 7.40 (s, 2H).

Example 6A

5-(4-Methoxybenzyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione

(16) ##STR00027##

(17) 548 g (2.08 mol) of 5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Example 3A) were initially charged in 3000 ml of dimethyl sulphoxide, and 295 g (2.08 mol) of iodomethane were added dropwise with stirring at RT. Using an ice bath, the solution was cooled to an internal temperature of about 15 C., and 231 g (2.28 mol) of triethylamine were added dropwise over a period of 30 min (internal temperature 15-22 C.). The mixture was stirred in the ice bath for 30 min and at RT for another 3 h. The mixture was added to dilute sodium chloride solution (2 portions of in each case 12 l water and in each case 500 g of sodium chloride) and extracted with methyl tert-butyl ether. The organic phases were combined, washed with semisaturated sodium chloride solution and dried with magnesium sulphate. The solvents were removed, which gave 497 g (86% of theory) of the desired product as a yellowish wax-like solid. Further purification was possible by crystallization (hexane/isopropanol) or chromatographically.

(18) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.98 (s, 3H), 1.60 (s, 3H), 1.72 (s, 3H), 3.27 (s, 2H), 3.76 (s, 3H), 6.79 (d, 2H), 7.09 (s, 2H).

Example 7A

2-Methyl-3-[4-(trifluoromethoxy)phenyl]propanoic acid

(19) ##STR00028##

(20) 19.0 g (57.2 mmol) of 2,2,5-trimethyl-5-[4-(trifluoromethoxy)benzyl]-1,3-dioxane-4,6-dione (Example 4A) were taken up in 90 ml of dioxane and 35 ml of conc. aqueous hydrochloric acid and heated at 125 C. under reflux for 2 h. The mixture was allowed to cool and the solvents were removed on a rotary evaporator. The residue (19.5 g colourless resin) was heated at 200 C. for 1 h. The crude product obtained was reacted further without further purification.

(21) LCMS (Method 2): R.sub.t=1.21 min; m/z [ES]=247 (MH).sup.

(22) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.12 (s, 3H), 3.06 (s, 2H), 7.21-7.27 (m, 4H).

Example 8A

3-(4-Fluoro-3-methoxyphenyl)-2-methylprop-2-enenoic acid

(23) ##STR00029##

(24) 2.18 g (14.1 mmol) of 4-fluoro-3-methoxybenzaldehyde (CAS [128495-46-5]), 2.45 g (14.1 mmol) of sodium propoxide (CAS [137-40-6]) and 1.84 g (14.1 mmol) of propionic anhydride (CAS [123-62-6]) were stirred together at 150 C. for 3 h. During this time, the suspension, which was initially white, turned into a clear solution. The mixture was cooled, diluted with 2M aqueous sodium hydroxide solution and extracted 2 with diethyl ether. The aqueous phase was acidified with 6M hydrochloric acid (pH about 5) and extracted 3 with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate, and the solvents were removed on a rotary evaporator. This gave 1.70 g (51% of theory) of the product as a yellow solid which was reacted further without further purification.

(25) LCMS (Method 2): R.sub.t=1.06 min; m/z [ES]=209 (MH).sup.

(26) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =2.01 (d, 3H), 3.85 (s, 3H), 7.00-7.03 (m, 1H), 7.19-7.25 (m, 2H), 7.51 (s, 1H).

(27) The following compound was prepared analogously to Example 8A from the appropriate aldehyde:

(28) TABLE-US-00001 No Structure Name Analytical data 9A 0 3-[3-chloro-4- (trifluoromethoxy)- phenyl]-2- methylprop-2- enenoic acid .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.98 (d, 3H), 7.51-7.59 (m, 3H), 7.75 (d, 1H). LCMS (Method 2): R.sub.t = 1.32 min; m/z [ES.sup.] = 279/281 (M H, Cl isotopes).sup.

Example 10A

3-(4-Fluoro-3-methoxyphenyl)-2-methylpropanoic acid

(29) ##STR00031##

(30) 1.55 g (7.34 mmol) of 3-(4-fluoro-3-methoxyphenyl)-2-methylprop-2-enoic acid (Example 8A) were hydrogenated (1 atm hydrogen atmosphere) in the presence of 780 mg of palladium catalyst (10% Pd on activated carbon, 0.73 mmol) in 70 ml of ethyl acetate with vigorous shaking at RT for 1 h. The catalyst was then filtered off and washed with dichloromethane, and the filtrate was concentrated on a rotary evaporator. This gave 1.34 g (60%) of 3-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid as an oily product.

(31) LCMS (Method 2): R.sub.t=1.01 min; m/z [ES]=211 (MH).sup.

(32) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.00 (d, 3H), 2.49-2.66 (m, 2H), 2.84 (dd, 1H), 3.77 (s, 3H), 6.67-6.72 (m, 1H), 6.96 (dd, 1H), 7.04 (dd, 1H).

(33) The following compound was prepared analogously to Example 10A from Example 9A:

(34) TABLE-US-00002 No Structure Name Analytical data 11A 3-[3-chloro-4- (trifluoromethoxy)- phenyl]-2- methylpropanoic acid .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.02 (d, 3H), 2.61-2.71 (m, 2H), 2.82-2.91 (m, 1H), 7.27 (dd, 1H), 7.44 (dd, 1H), 7.50 (d, 1H). LCMS (Method 2): R.sub.t = 1.28 min; m/z [ES.sup.] = 281/283 (M H, Cl isotopes).sup.

Example 12A

2-Methyl-6-(trifluoromethoxy)indan-1-one

(35) ##STR00033##

(36) 17.2 g (69.3 mmol) of crude 2-methyl-3-[4-(trifluoromethoxy)phenyl]propanoic acid (Example 7A) were dissolved in 100 ml of dichloromethane, and 12.1 ml (16.6 g, 166 mmol) of thionyl chloride and 0.16 ml of DMF were added dropwise at RT. The mixture was subsequently heated under reflux for about 30 min until the evaluation of gas had ceased. The solution was allowed to cool and the solvents were removed on a rotary evaporator. The residue (yellow solid) was taken up in 35 ml of dichloromethane and, at RT, added dropwise to a suspension of 10.2 g (76.2 mmol) of anhydrous aluminium chloride in 200 ml of dichloromethane. The dark-red solution was stirred for 30 min and then added to water, and the phases were separated. The aqueous phase was extracted 3 with dichloromethane, washed with water, sat. sodium bicarbonate solution and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed and the residue (10.0 g) was purified by flash chromatography (SiO.sub.2, hexane/dioxane). This gave 5.84 g (14% of theory) of the product as a yellow oil.

(37) LCMS (Method 2): R.sub.t=1.27 min; m/z=231; 272 (M+H).sup.+/(M+ACN+H).sup.+

Example 13A

6-Bromo-2-methylindan-1-one

(38) ##STR00034##

(39) 36 ml of polyphosphoric acid were added to 3.64 g (11.1 mmol) of 5-(4-bromobenzyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione (Example 5A), and the mixture was stirred at 100 C. for 10 h. After cooling, the mixture was added to ice-water and extracted with ethyl acetate. The combined organic phases were washed with sat. sodium bicarbonate solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 812 mg (32% of theory) of the product as a brown oil.

(40) LCMS (Method 1): R.sub.t=1.18 min; m/z=225; 227 (Br isotope pattern, M+H).sup.+ and 266; 268 (Br isotope pattern, M+ACN+H).sup.+

(41) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.31 (d, 3H), 2.68 (dd, 1H), 2.72-2.79 (m, 1H), 3.35 (dd, 1H), 7.34 (d, 1H), 7.68 (dd, 1H), 7.88 (d, 1H).

Example 14A

6-Methoxy-2-methylindan-1-one

(42) ##STR00035##

(43) 628 g (5.39 mol) of polyphosphoric acid (CAS [8017-16-1]) were initially charged and heated to about 100 C. With stirring, 100 g (359 mmol) of 5-(4-methoxybenzyl)-2,2,5-trimethyl-1,3-dioxane-4,6-dione (Example 6A), dissolved in 400 ml of toluene, were then added dropwise over a period of 15 min. The mixture was stirred for about 15 min, the reaction mixture was then added to water (about 3 l) and residual material was transferred using dichloromethane. The mixture was diluted with more dichloromethane and water and the phases were separated. The aqueous phase was re-extracted with dichloromethane and the combined organic phases were repeatedly washed carefully with semisaturated sodium bicarbonate solution and with water and dried with magnesium sulphate. The solvents were removed on a rotary evaporator. This gave 58.2 g (92% of theory) the crude product as a brown oil, which was reacted further without purification. Purification can be carried out by kugelrohr distillation at 140 C., this gave a virtually colourless oil.

(44) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.30 (d, 3H), 2.64 (dd, 1H), 2.70-2.78 (m, 1H), 3.32 (dd, 1H), 3.82 (s, 3H), 7.15-7.21 (m, 2H), 7.33 (d, 1H).

Example 15A

6-Fluoro-5-methoxy-2-methylindan-1-one

(45) ##STR00036##

(46) With ice-bath cooling, 13.5 g (116 mmol, 7.71 ml) of chlorosulphonic acid (CAS [7790-94-5]) were added carefully to 4.10 g (19.3 mmol) of 3-(4-fluoro-3-methoxyphenyl)-2-methylpropanoic acid (Example 10A), and the mixture was stirred in an ice bath for 2 h. The reaction was then terminated by carefully adding, at little at a time, crushed ice. The mixture was extracted with dichloromethane and the combined organic phases were washed with sat. sodium bicarbonate solution and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the brown residue was purified by flash chromatography (SiO.sub.2, dichloromethane/methanol 0-3%). This gave 2.15 g (57% of theory) of the product as a pale-yellow solid.

(47) LCMS (Method 2): R.sub.t=1.01 min; m/z=195 (M+H).sup.+

(48) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.13 (d, 3H), 2.57-2.71 (m, 2H), 3.30 (dd, 1H), 3.90 (s, 3H), 7.29 (d, 1H), 7.37 (d, 1H).

(49) The following indanone was prepared analogously to Example 15A from the appropriate carboxylic acid (Example 11A):

(50) TABLE-US-00003 No Structure Name Analytical data 16A 5-chloro-2-methyl-6- (trifluoromethoxy)- indan-1-one .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.17 (d, 3H), 2.66-2.83 (m, 2H), 3.37 (dd, 1H), 7.66 (s, 1H), 7.94 (d, 1H). LCMS (Method 2): R.sub.t = 1.38 min; m/z = 265/267 (M + H, Cl isotopes).sup.+, 306/308 (M + H + ACN, Cl isotopes).sup.+

Example 17A

3-(4-Chlorophenyl)-2-methyl-5-(trifluoromethoxy)-1H-indene

(51) ##STR00038##

(52) Under argon, 38.1 ml of 4-chlorophenylmagnesium bromide (1M in diethyl ether, 38.1 mmol) were initially charged in 80 ml of THF, and 5.84 g (25.4 mmol) of 2-methyl-6-trifluoromethoxy-indan-1-one (Example 12A), dissolved in 20 ml of THF, were added dropwise at RT. The mixture was stirred at RT for 1 h and then added to sat ammonium chloride solution and extracted 3 with ethyl acetate, the combined organic phases were washed with sat. sodium chloride solution, dried with sodium sulphate and the solvents were removed on a rotary evaporator.

(53) The residue was taken up in 375 ml of dichloromethane, 55 mg of 4-toluenesulphonic acid monohydrate were added and the mixture was stirred at RT for 16 h. The reaction mixture was added to sat. sodium bicarbonate solution and extracted 3 with dichloromethane, the combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 2.42 g (21% of theory) of the product as a colourless resin.

(54) LCMS (Method 1): R.sub.t=1.76 min; m/z=325 (M+H).sup.+

(55) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.09 (s, 3H), 3.53 (s, 2H), 6.93 (s, br, 1H), 7.07-7.12 (m, 1H), 7.38 (d, 2H), 7.50-7.56 (m, 1H), 7.54 (d, 2H).

Example 18A

5-Bromo-3-(4-chlorophenyl)-2-methyl-1H-indene

(56) ##STR00039##

(57) The preparation was carried out analogously to Example 17A from 800 mg (3.55 mmol) of 6-bromo-2-methylindan-1-one (Example 13A), 5.33 ml of 1M 4-chlorophenylmagnesium bromide solution in 8 ml of THF; the elimination of water from the tertiary alcohol formed in this reaction was carried out using 7 mg (0.04 mmol) of 4-toluenesulphonic acid monohydrate. The crude product was directly reacted further.

(58) The following compounds were prepared analogously to Example 17A from the appropriate indanones by reaction with 4-chlorophenylmagnesium bromide and subsequent elimination of water using 4-toluenesulphonic acid:

(59) TABLE-US-00004 No Structure Name Analytical data 21A 0 6-chloro-3-(4- chlorophenyl)-2- methyl-5- (trifluoromethoxy)-1H- indene .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 2.08 (s, 3H), 3.57 (s, 2H), 7.07 (d, 1H), 7.38 (d, 2H), 7.55 (d, 2H), 7.73 (s, 1H). LCMS (Method 2): R.sub.t = 1.81 min; m/z [ES.sup.] = 357/359 (M H, Cl isotopes).sup. 22A 3-(4-chlorophenyl)-5- methoxy-2-methyl-1H- indene .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.11 (s, 3H), 3.40 (s, 2H), 3.78 (s, 3H), 6.72 (dd, 1H), 6.73 (sbr, 1H), 7.32 (d, 1H), 7.33 (d, 2H), 7.44 (d, 2H).

Example 23A

3-(5-Methoxy-2-methyl-1H-inden-3-yl)pyridine

(60) ##STR00042##

(61) 6.28 g (30.6 mmol) of 3-iodopyridine (CAS [1120-90-7]) were initially charged in 30 ml of THF, 24 ml of isopropylmagnesium chloride/lithium chloride complex solution (1.3 M in THF, CAS[807329-97-1]) were added dropwise at 0 C. and the mixture was stirred at 0 C. for 30 min. 2.0 g (11.4 mmol) of 6-methoxy-2-methylindan-1-one (Example 14A) dissolved in 30 ml of THF were then added dropwise at 0 C., and the mixture was stirred at 0 C. for 3 h. The reaction was terminated by addition of 100 ml of sat. ammonium chloride solution and stirred for another 10 min. The mixture was then extracted with ethyl acetate, and the combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was taken up in 60 ml of dichloromethane. 4.8 g (25 mmol) of 4-toluenesulphonic acid were added in 2 portions and the mixture was heated to 35-45 C. for a total of 36 h. With ice-bath cooling, 100 ml of sat. sodium bicarbonate solution were then added, and the mixture was stirred for another 10 min and extracted with dichloromethane. The combined organic phases were washed with water and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 851 mg (30% of theory) of the desired product as a yellow oil.

(62) LCMS (Method 2): R.sub.t=0.98 min; m/z=238 (M+H).sup.+; 279 (M+ACN+H).sup.+

(63) .sup.1H-NMR (600 MHz, CDCl.sub.3): =2.15 (s, 3H), 3.45 (s, 2H), 3.78 (s, 3H), 6.72 (d, 1H), 6.75 (dd, 1H), 7.34 (d, 1H), 7.41 (dd, 1H), 7.73 (dt, 1H), 8.62 (dd, 1H), 8.67 (d, 1H).

Example 24A

5-Methoxy-2-methyl-3-1H-inden-3-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

(64) ##STR00043##

(65) 12.6 g (71.5 mmol) of freshly kugelrohr-distilled 6-methoxy-2-methylindan-1-one (Example 14A) were initially charged in 400 ml of THF, and the mixture was stirred in an ice bath for 10 min. 17.1 g (85.8 mmol) of potassium hexamethyldisilazide (CAS [40949-94-8]) were then added a little at a time (internal temperature at most 5 C.). After a further 10 min in the ice bath, the mixture was cooled to 72 C., and 25.9 g (85.8 mmol) of 1,1,2,2,3,3,4,4,4-nonafluorobutan-1-sulphonyl fluoride (CAS [375-72-4]) were then added quickly. During the addition, the internal temperature temporarily rose to 10 C., and the colour of the solution changed to green-brown. The mixture was stirred at 72 C. for 30 min and at 0 C. for a further 30 min, and the reaction mixture was then added to water and extracted with dichloromethane. The organic phases were washed with water and dried with sodium sulphate and the solvents were removed. The crude product (25 g of an orange oil) was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 16.5 g (45% of theory) of the product as an orange resin.

(66) LCMS (Method 2): R.sub.t=1.69 min; m/z=459 (M+H).sup.+

(67) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =2.09 (s, 3H), 3.47 (s, 2H), 3.73 (s, 3H), 6.68 (d, 1H), 6.82 (dd, 1H), 7.34 (d, 1H).

Example 25A

1-[2-(4-Chlorobenzoyl)-4-(trifluoromethoxy)phenyl]propan-2-one

(68) ##STR00044##

(69) 2.42 g (7.45 mmol) of 3-(4-chlorophenyl)-2-methyl-5-trifluoromethoxy-1H-indene (Example 17A) were initially charged in 14 ml of hexane and 14 ml of acetonitrile, and 34 mg (0.15 mmol) of ruthenium(III) chloride hydrate (CAS [14898-67-0]) were added. The mixture was stirred at 0 C. for 10 min, and 3.19 g (14.9 mmol) of sodium periodate were then introduced a little at a time. The brown suspension was stirred for another 30 min and then added to 4M hydrochloric acid. The mixture was extracted 3 with ethyl acetate, the combined organic phases were washed with sat. sodium chloride solution, dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 2.18 g (52% of theory) of the product as a colourless resin.

(70) LCMS (Method 1): R.sub.t=1. 45 min; m/z=357 (M+H).sup.+

(71) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 3.98 (s, 2H), 7.31-7.33 (m, 1H), 7.46 (d, 1H), 7.50-7.56 (m, 1H), 7.60 (d, 2H), 7.68 (d, 2H).

Example 26A

1-[4-Bromo-2-(4-chlorobenzoyl)phenyl]propan-2-one

(72) ##STR00045##

(73) The preparation was carried out analogously to Example 25A from 1.14 g (3.57 mmol) of 5-bromo-3-(4-chlorophenyl)-2-methyl-1H-indene (Example 18A), 16 mg (0.07 mmol) of ruthenium(III) chloride hydrate and 1.53 g (7.13 mmol) of sodium periodate. This gave 347 mg (28% of theory) of the desired product as an orange oil.

(74) LCMS (Method 1): R.sub.t=1.41 min; m/z=351; 353; 355 (BrCl isotope pattern, M+H).sup.+

(75) .sup.1H-NMR (400 MHz, CDCl.sub.3): =2.18 (s, 3H), 3.96 (s, 2H), 7.14 (d, 1H), 7.45-7.50 (m, 3H), 7.61 (dd, 1H), 7.76 (d, 2H).

Example 27A

1-[4-Methoxy-2-(pyridin-3-ylcarbonyl)phenyl]propan-2-one

(76) ##STR00046##

(77) 844 mg (3.56 mmol) of 3-(5-methoxy-2-methyl-1H-inden-3-yl)pyridine (Example 23A) were initially charged in 15 ml of dimethoxyethane and 5 ml of water, and 4.5 ml (0.36 mmol) of osmium tetroxide solution (CAS [20816-12-0], 2.5% in tert-butanol) were added. 1.52 g (7.11 mmol) of sodium periodate (CAS [7790-28-5]) were then added a little at a time, and the mixture was stirred at RT for 3 h. The reaction mixture was filtered through a few centimeters of silica gel 60, the silica gel washed with ethyl acetate and the filtrate washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator. This gave 439 mg of a brown residue as a crude product (about 45% of theory) which was directly reacted further.

(78) LCMS (Method 2): R.sub.t=0.90 min; m/z=270 (M+H).sup.+

(79) The following compounds were prepared analogously to Example 25A from the corresponding 1H-indenes:

(80) TABLE-US-00005 No Structure Name Analytical data 28A 1-[5-chloro-2-(4- chlorobenzoyl)-4- (trifluoromethoxy)- phenyl]propan-2-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.06 (s, 3H), 3.99 (s, 2H), 7.54 (d, 1H), 7.60 (d, 2H), 7.69 (d, 2H), 7.72 (s, 1H). LCMS (Method 2): R.sub.t = 1.52 min; m/z = 391/393 (M + H, Cl isotopes).sup.+ 29A 1-[2-(4-chlorobenzoyl)- 4-methoxyphenyl]- propan-2-one .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.15 (s, 3H), 3.89 (s, 2H), 3.78 (s, 3H), 6.89 (d, 1H), 7.02 (dd, 1H), 7.18 (d, 1H), 7.44 (d, 2H), 7.77 (d, 2H).

Example 30A

1-(4-Chlorophenyl)-4-methyl-8-(trifluoromethoxy)-5H-2,3-benzodiazepine

(81) ##STR00049##

(82) 2.18 g (6.11 mmol) of 1-[2-(4-chlorobenzyl)-4-trifluoromethoxyphenyl]propan-2-one (Example 25A) were initially charged in 25 ml of ethanol, and 920 mg (18.3 mmol) of hydrazine hydrate were added. The mixture was stirred at RT for 30 min, and the reaction mixture was then added to water and extracted 3 with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 1.53 g (65% of theory) of the product as a pale-yellow solid.

(83) LCMS (Method 1): R.sub.t=1.44 min; m/z=353 (M+H).sup.+

(84) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =2.05 (s, 3H), 2.89 (d, 1H), 3.61 (d, 1H), 7.20 (s, br, 1H), 7.49-7.54 (m, 4H), 7.59-7.66 (m, 2H).

Example 31A

8-Bromo-1-(4-chlorophenyl)-4-methyl-5H-2,3-benzodiazepine

(85) ##STR00050##

(86) The preparation was carried out analogously to Example 30A from 340 mg (967 mol) of 1-[4-bromo-2-(4-chlorobenzoyl)phenyl]propan-2-one (Example 26A) and 702 mg (14.0 mmol) of hydrazine hydrate in 34 ml of ethanol. This gave 376 mg of the crude product as an orange oil which was directly reacted further without purification.

(87) LCMS (Method 1): R.sub.t=1.41 min; m/z=347; 349; 351 (BrCl isotope pattern, M+H).sup.+

(88) .sup.1H-NMR (300 MHz, CDCl.sub.3): =2.15 (s, 3H), 3.01 (d, 1H), 3.35 (d, 1H), 7.19 (d, 1H), 7.41 (d, 2H), 7.45 (d, 1H), 7.60 (d, 2H), 7.66 (dd, 1H).

Example 32A

8-Methoxy-4-methyl-1-(pyridin-3-yl)-5H-2,3-benzodiazepine

(89) ##STR00051##

(90) The preparation was carried out analogously to Example 30A from 430 mg (1.60 mmol) of crude 1-[4-methoxy-2-(pyridin-3-ylcarbonyl)phenyl]propan-2-one (Example 27A) and 888 mg (17.7 mmol) of hydrazine hydrate in 43 ml of ethanol. This gave 408 mg of the crude product as a brown resin which was directly reacted further without purification.

(91) LCMS (Method 2): R.sub.t=0.79 min; m/z=266 (M+H).sup.+

(92) The following compounds were prepared analogously to Example 30A from the appropriate diketones:

(93) TABLE-US-00006 No Structure Name Analytical data 33A 7-chloro-1-(4- chlorophenyl)-4- methyl-8- (trifluoromethoxy)-5H- 2,3-benzodiazepine .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 2.07 (s, 3H), 2.89 (d, 1H), 3.62 (d, 1H), 7.39 (d, 1H), 7.49-7.55 (m, 4H), 7.94 (s, 1H). LCMS (Method 1): R.sub.t = 1.51 min; m/z = 387/389/391 (M + H, Cl isotopes).sup.+ 34A 1-(4-chlorophenyl)-8- methoxy-4-methyl-5H- 2,3-benzodiazepine .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.12 (s, 3H), 3.00 (dd, 1H), 3.27 (dd, 1H), 3.72 (s, 3H), 6.78 (d, 1H), 7.08 (dd, 1H), 7.18 (d, 1H), 7.37 (d, 2H), 7.63 (d, 2H). LCMS (Method 3): R.sub.t = 1.03 min; m/z = 284; 286 (Cl isotope pattern, M + H).sup.+

Example 35A

()-1-(4-Chlorophenyl)-4-methyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine

(94) ##STR00054##

(95) At RT, 1.53 g (4.34 mmol) of 1-(4-chlorophenyl)-4-methyl-8-(trifluoromethoxy)-5H-2,3-benzodiazepine (Example 30A) were initially charged in 160 ml of methanol, 2.5 ml of 2M hydrochloric acid were added and 1.36 g (21.7 mmol) of sodium cyanoborohydride were introduced. The mixture was stirred at RT for 1 h and then made alkaline using 2M aqueous sodium hydroxide solution (pH about 8). Most of the methanol was removed on a rotary evaporator and the residue was partitioned between water and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sat. sodium chloride solution, dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 1.00 g (61% of theory) of the product as a yellow crystallizing resin.

(96) LCMS (Method 2): R.sub.t=1.50 min; m/z=355 (M+H).sup.+

(97) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.10 (d, 3H), 2.75 (dd, 1H), 2.99 (dd, 1H), 3.76-3.83 (m, 1H), 6.84 (s, br, 1H), 7.21-7.24 (m, 1H), 7.32-7.38 (m, 5H), 7.64 (s, br, 1H).

Example 36A

()-8-Bromo-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine

(98) ##STR00055##

(99) The preparation was carried out analogously to Example 35A from 336 mg (966 mol) of 8-bromo-1-(4-chlorophenyl)-4-methyl-5H-2,3-benzodiazepine (Example 31A) and 304 mg (4.83 mmol) of sodium cyanoborohydride in 33 ml of methanol and 0.5 ml of 2M hydrochloric acid. The crude product (282 mg) was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 141 mg (42% of theory) of the product as an orange foam.

(100) LCMS (Method 1): R.sub.t=1.39 min; m/z=349; 351; 353 (BrCl isotope pattern, M+H).sup.+

(101) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.26 (d, 3H), 2.65 (dd, 1H), 2.92 (dd, 1H), 4.02-4.13 (m, 1H), 5.46 (s, br, 1H), 7.12 (d, 1H), 7.22 (d, 1H), 7.34 (d, 2H), 7.42-7.48 (m, 3H).

Example 37A

()-8-Methoxy-4-methyl-1-(pyridin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine

(102) ##STR00056##

(103) The preparation was carried out analogously to Example 35A from 400 mg (1.51 mmol) of crude 8-methoxy-4-methyl-1-(pyridin-3-yl)-5H-2,3-benzodiazepine (Example 32A) and 473 mg (7.54 mmol) of sodium cyanoborohydride in 20 ml of methanol and 0.6 ml of 2M hydrochloric acid. This gave 155 mg (about 38% of theory) of the crude product as a brown resin. It was directly reacted further.

(104) LCMS (Method 2): R.sub.t=0.77 min; m/z=268 (M+H).sup.+

(105) The following compounds were prepared analogously to Example 35A from the appropriate 5H-2,3-benzodiazepines:

(106) TABLE-US-00007 No Structure Name Analytical data 38A ()-7-chloro-1-(4- chlorophenyl)-4- methyl-8- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.11 (d, 3H), 2.78 (dd, 1H), 3.02 (dd, 1H), 3.73-3.83 (m, 1H), 6.99 (d, 1H), 7.31-7.38 (m, 4H), 7.58 (s, 1H), 7.84 (d, 1H). LCMS (Method 2): R.sub.t = 1.26 min; m/z = 389/391 (M + H, Cl isotope pattern).sup.+ 39A ()-1-(4-chlorophenyl)- 4,5-dihydro-8- methoxy-4-methyl-3H- 2,3-benzodiazepine .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.24 (d, 3H), 2.60 (dd, 1H), 2.90 (dd, 1H), 3.70 (s, 3H), 4.07 (qdd, 1H), 6.61 (d, 1H), 6.89 (dd, 1H), 7.16 (d, 1H), 7.32 (d, 2H), 7.51 (d, 2H). LCMS (Method 3): R.sub.t = 1.09 min; m/z = 301; 303 (Cl isotope pattern, M + H).sup.+

Example 40A

1-(3,4-Dimethoxyphenyl)propan-2-ol

(107) ##STR00059##

(108) At 0 C., 147 mg (3.86 mmol) of lithium aluminium hydride were initially charged in 30 ml of THF, and 1.00 g (5.15 mmol) of 1-(3,4-dimethoxyphenyl)propan-2-one, dissolved in 10 ml of THF, were added dropwise. The mixture was stirred at 0 C. for another 2 h, and 0.1 ml of water, 0.1 ml of 2M aqueous sodium hydroxide solution and a further 0.3 ml of water were then added carefully in succession. After a further 30 min of stirring at RT, the mixture was filtered off through silica gel/sodium sulphate, the silica gel washed with ethyl acetate and the filtrate was concentrated on a rotary evaporator. This gave 950 mg of product (82% of theory) which was directly reacted further.

(109) LCMS (Method 2): R.sub.t=0.82 min; m/z=197 (M+H).sup.+; 179 (MH.sub.2O+H).sup.+

(110) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.98 (d, 3H), 2.43 (dd, 1H), 2.59 (dd, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 3.70-3.79 (m, 1H), 4.43 (d, 1H), 6.65 (dd, 1H), 6.75 (d, 1H), 6.79 (d, 1H).

Example 41A

1-(4-Bromophenyl)-3,4-dihydro-6,7-dimethoxy-3-methyl-1H-2-benzopyran

(111) ##STR00060##

(112) At RT, 950 mg (4.84 mmol) of 1-(3,4-dimethoxyphenyl)propan-2-ol (Example 40A) and 950 mg (5.14 mmol) of 4-bromobenzaldehyde (CAS [1122-91-4]) were initially charged in 4 ml of dioxane, and 7.70 ml of zinc chloride solution (0.7 M in THF, CAS [7646-85-7]) and 2.45 ml of hydrochloric acid (4 M in dioxane, CAS [7647-01-0]) were added. The mixture was then heated under reflux for 3 h and stirred at RT for a further 14 h. The mixture was added to water and extracted to ethyl acetate, and the combined organic phases were washed with sat. sodium bicarbonate solution and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator. This gave 3.0 g of crude product as a light-brown oil which was directly reacted further without purification.

(113) LCMS (Method 2): R.sub.t=1.44 min; m/z=363; 365 (Br isotope pattern, M+H).sup.+

(114) Alternative preparation procedure for Example 41A

(115) At RT, 349.2 g (1.779 mol) of ()-1-(3,4-dimethoxyphenyl)propan-2-ol (Example 40A) and 329.2 g (1.779 mol) of 4-bromobenzaldehyde (CAS [1122-91-4]) were initially charged in 3 l of toluene, and 140 ml of hydrochloric acid (36% aqueous solution) were added and the mixture was stirred at RT for 2 days. The mixture was then poured onto 21 of water and extracted with 22 l of ethyl acetate, and the combined organic phases were washed 1 with saturated aqueous sodium hydrogencarbonate solution and 1 with 21 of water, and dried using sodium sulphate. The solvent was reduced on a rotary evaporator. The product precipitated as a colourless solid. Shortly before dryness, 1 l of hexane was added and the mixture was cooled in an ice bath. The solid was isolated by suction filtration, washed with hexane and then dried under reduced pressure at 50 C. This gave 598.9 g (93% of theory) of the product (isomer mixture), which was directly reacted further without purification.

(116) The following compound was prepared analogously to Example 41A from Example 40A and 3-bromobenzaldehyde:

(117) TABLE-US-00008 No Structure Name Analytical data 42A 1-(3-bromophenyl)- 3,4-dihydro-6,7- dimethoxy-3-methyl- 1H-2-benzopyran LCMS (Method 3): R.sub.t = 1.40 min; m/z = 363; 365 (M + H, Br isotope pattern).sup.+

Example 43A

1-[2-(4-Bromobenzoyl)-4,5-dimethoxyphenyl]propan-2-one

(118) ##STR00062##

(119) At 0 C., 3.00 g (8.26 mmol) of 1-(4-bromophenyl)-3,4-dihydro-6,7-dimethoxy-3-methyl-1H-2-benzopyran (Example 41A) together with 3 g of silica gel were initially charged in 30 ml of acetone. A solution of 3.01 g (30.1 mmol) of chromium(VI) oxide (CAS [1333-82-0]) in 10 ml of conc. sulphuric acid and 20 ml of water was then slowly added dropwise, and the mixture was stirred at RT for 1 h. The mixture, which was now red-brown, was added to water and extracted with ethyl acetate. The organic phases were washed with sat. sodium chloride solution until neutral and dried with sodium sulphate, and the solvents were removed on a rotary evaporator. The residue (3 g) was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 1.03 g (33% of theory, 2 steps) of the product as a yellow solid.

(120) LCMS (Method 2): R.sub.t=1.26 min; m/z=377; 379 (Br isotope pattern, M+H).sup.+

Alternative Preparation Procedure for Example 43A

(121) Preparation of Jones Reagent:

(122) 267 g of chromium(VI) oxide (CrO.sub.3) were introduced cautiously into 230 ml of sulphuric acid (95-97%). Cooling took place with water/ice and water so that the internal temperature was 35-40 C. To start with an orange crystallisate was obtained, which slowly dissolved with the addition of water. Following addition of 500 ml of water, everything was in solution apart from a slight sediment. Stirring was carried out at RT for 30 minutes, after which the material was transferred to a bottle and made up to 1000 ml with water. This gave an approximately 2.6 M solution.

(123) 496.5 g (1.367 mol) of ()-1-(4-bromophenyl)-3,4-dihydro-6,7-dimethoxy-3-methyl-1H-2-benzopyran (Example 13A) were initially charged in 5 l of acetone, cooled to 0 C. and admixed with 50 g of silica gel. Then 1.9 l of chromosulphuric acid (Jones reagent) were added dropwise over the course of 4 hours, followed by stirring at RT for 1 hour. After reaction had taken place, 41 of water were added slowly to the reaction mixture. Extraction was carried out with 34 l of ethyl acetate. The combined organic phases were washed with 4 l of saturated aqueous sodium hydrogencarbonate solution and with 34 l of saturated aqueous sodium chloride solution, and dried using sodium sulphate. The solvent was reduced on a rotary evaporator. The product precipitated as a colourless solid. Shortly before dryness, 500 ml of hexane were added and the mixture was cooled in an ice bath. The solid was isolated by suction filtration, washed with hexane and then dried under reduced pressure at 50 C. This gave 334.1 g (65% of theory) of the product, which was directly reacted further without purification.

(124) The following compound was prepared analogously to Example 43A from Example 42A:

(125) TABLE-US-00009 No Structure Name Analytical data 44A 1-[2-(3- bromobenzoyl)-4,5- dimethoxyphenyl]- propan-2-one LCMS (Method 3): R.sub.t = 1.21 min; m/z = 377; 379 (M + H, Br isotope pattern).sup.+

Example 45A

1-(4-Bromophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine

(126) ##STR00064##

(127) 730 mg (1.94 mmol) of 1-[2-(4-bromobenzoyl)-4,5-dimethoxyphenyl]propan-2-one (Example 43A) were stirred with 513 mg (10.3 mmol) of hydrazine hydrate in 7 ml of ethanol at a bath temperature of 100 C. for 1 h. After cooling, the mixture was saturated with hydrogen chloride gas (introduced for about 5 min) The reaction solution was added to water, made alkaline with 1M aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic phases were dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue (1 g yellow solid) was purified by flash chromatography (SiO.sub.2, dichloromethane/methanol 0-3%). This gave 390 mg (50% of theory) of the product as a yellow solid.

(128) LCMS (Method 2): R.sub.t=1.20 min; m/z=373; 375 (Br isotope pattern, M+H).sup.+

(129) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =2.02 (s, 3H), 2.71 (d, 1H), 3.42 (d, 1H), 3.59 (s, 3H), 3.83 (s, 3H), 6.70 (s, 1H), 7.06 (s, 1H), 7.50 (d, 2H), 7.61 (d, 2H).

Alternative Preparation Procedure for Example 45a

(130) At 0 C., 471 g (1.249 mol) of 1-[2-(4-bromobenzoyl)-4,5-dimethoxyphenyl]propan-2-one (Example 43A) were initially charged in 4.5 l of ethanol and admixed dropwise with 402 ml of hydrazine hydrate (6.62 mol). The mixture was allowed to come to RT and was stirred at this temperature for 2 days. It was decantered to remove the solid, and the clear supernatant was concentrated on a rotary evaporator. The concentrate was combined with the solid. Following addition of 8 l of ice-water, stirring took place for 2 days. The resulting precipitate was isolated by filtration with suction, washed with water and then dried under reduced pressure at 50 C. This gave 409.8 g (88% of theory) of the product, which was directly reacted further without purification.

(131) The following compound was prepared analogously to Example 45A from Example 44A:

(132) TABLE-US-00010 No Structure Name Analytical data 46A 1-(3-bromophenyl)- 7,8-dimethoxy-4- methyl-5H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.15 (s, 3H), 2.98 (d, 1H), 3.27 (d, 1H), 3.75 (s, 3H), 3.97 (s, 3H), 6.73 (s, 1H), 6.75 (s, 1H), 7.27 (dd, 1H), 7.55 (dbr, 1H), 7.61 (dbr, 1H), 7.86 (m, 1H). LCMS (Method 3): R.sub.t = 1.15 min; m/z = 373; 375 (M + H, Br isotope pattern).sup.+

Example 47A

()-1-(4-Bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine

(133) ##STR00066##

(134) At RT, 1.99 g (5.33 mmol) of 1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine (prepared according to the procedure in Example 45A) were initially charged in 200 ml of methanol, 3.0 ml of 2M hydrochloric acid were added and 1.68 g (26.6 mmol) of sodium cyanoborohydride were introduced. The mixture was stirred at RT for 1 h and then made alkaline with 2M aqueous sodium hydroxide solution (pH about 8). Most of the methanol was removed on a rotary evaporator, and the residue was partitioned between water and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 1.56 g (78% of theory) of the product as a yellow crystallizing resin.

(135) LCMS (Method 2): R.sub.t=0.96 min; m/z=375; 377 (Br isotope pattern, M+H).sup.+

(136) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.09 (d, 3H), 2.58 (dd, 1H), 2.83 (dd, 1H), 3.27 (s, 3H), 3.51 (s, 3H), 3.77-3.82 (m, 1H), 6.47 (s, 1H), 6.85 (s, 1H), 7.01 (d, 1H), 7.33 (d, 2H), 7.47 (d, 2H).

(137) The following compound was prepared analogously to Example 47A from Example 46A:

(138) TABLE-US-00011 No Structure Name Analytical data 48A ()-1-(3-bromophenyl)- 7,8-dimethoxy-4- methyl-4,5-dihydro- 3H-2,3-benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.28 (d, 3H), 2.62 (dd, 1H), 2.89 (dd, 1H), 3.71 (s, 3H), 3.94 (s, 3H), 4.11 (m, 1H), 6.59 (s, 1H), 6.76 (s, 1H), 7.22 (dd, 1H), 7.45 (dbr, 1H), 7.48 (dbr, 1H), 7.75 (m, 1H). LCMS (Method 3): R.sub.t = 0.99 min; m/z = 375; 377 (M + H, Br isotope pattern).sup.+

Example 49A

()-1-(4-Bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(139) ##STR00068##

(140) At RT, 1.56 g (4.16 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine (Example 47A) were dissolved in 50 ml of THF, 1.68 g (8.31 mmol) of 4-nitrophenyl chloroformate (CAS [7693-46-1]) were added dropwise and the mixture was stirred at RT for 1 h. During this time, the clear yellow solution slowly became turbid. 20.8 ml (41.6 mmol) of a 2M solution of methylamine in THF were added dropwise, and the mixture was stirred at 60 C. for 5 h. The mixture was allowed to warm slowly to RT and concentrated on a rotary evaporator, the mixture was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator.

(141) Since the reaction was incomplete (UPLC/MS control), the reaction with the resulting crude product/intermediate/starting material mixture was repeated in an analogous manner to achieve complete conversion. The crude product then obtained was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 1.90 g (100% of theory) of the desired product as a yellow foam.

(142) LCMS (Method 2): R.sub.t=1.33 min; m/z=432; 434 (Br isotope pattern, M+H).sup.+

(143) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.92 (d, 3H), 2.64 (d, 3H), 2.67 (dd, 1H), 2.91 (dd, 1H), 3.53 (s, 3H), 3.80 (s, 3H), 5.03-5.11 (m, 1H), 6.47 (s, 1H), 6.60 (q, 1H), 6.98 (s, 1H), 7.56 (s, 4H).

Enantiomer Separation of Example 49A

()-1-(4-Bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(144) ##STR00069##

(145) 19.9 g of the compound prepared according to the procedure in Example 49A were separated into the enantiomers by chiral preparative HPLC under the following conditions:

(146) System: SFC Prep 400; column: Chiralpak AZ-H 5 m 25050 mm; mobile phase: CO.sub.2/isopropanol 75:25 (v/v); flow rate: 300 ml/min; temperature: 38 C.; pressure 80 bar; solution: 5 g/100 ml of methanol/acetonitrile 50:50 (v/v); detection: UV 220 nm.

Example 49.1A: (4R)-1-(4-Bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(147) 9.29 g, light-yellow solid, HPLC (Method T): R.sub.t=3.29 min, purity>99%

(148) Optical rotation: [].sub.D.sup.20=89.3 (c=1.00; methanol)

Example 49.2A: (4S)-1-(4-Bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(149) 9.9 g, light-yellow solid, HPLC (Method T): R.sub.t=4.55 min, purity 96%

(150) Optical rotation: [].sub.D.sup.20=+81.3 (c=1.00; methanol)

Alternative Preparation Procedure for Example 49a

(151) At RT, 260 g (415.70 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine used in crude form (cf. Example 47A) were dissolved in 2000 ml of THF, 167.6 g (831.4 mmol) of 4-nitrophenyl chloroformate (CAS [7693-46-1]) were added, and subsequently 64.47 g (498.8 mmol) of diisopropylethylamine were added dropwise. Counter-cooling with an ice bath was carried out, owing to the development of heat. The batch was stirred at RT for 6 hours. Then 2078 ml (4157 mmol) of a 2-molar solution of methylamine in THF were added dropwise with ice-bath cooling, after which the batch was stirred at RT for 16 hours. The yellow suspension was admixed with 2-molar sodium hydroxide solution and thereafter extracted with three times 700 ml of ethyl acetate. The combined organic phases were washed with four times 200 ml of 2-molar sodium hydroxide solution, dried using sodium sulphate, and the solvent was removed on a rotary evaporator. The crude product obtained was purified by chromatography. This gave 147.5 g (51% of theory over 2 stages) of the desired product.

(152) The following compounds were prepared analogously to Example 49A from the appropriate 4,5-dihydro-3H-2,3-benzodiazepines:

(153) TABLE-US-00012 No Structure Name Analytical data 50A 0 ()-1-(4-chlorophenyl)- 8-methoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 2.86 (dd, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 3.69 (s, 3H), 5.43 (m, 1H), 6.59 (d, 1H), 6.88 (dd, 1H), 7.13 (d, 1H), 7.36 (d, 2H), 7.42 (d, 2H). LCMS (Method 3): R.sub.t = 1.35 min; m/z = 358; 360 (Cl isotope pattern, M + H).sup.+ 51A ()-1-(3-bromophenyl)- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.95 (d, 3H), 2.86 (dd, 1H), 2.90 (d, 3H), 3.12 (dd, 1H), 3.66 (s, 3H), 3.93 (s, 3H), 5.48 (m, 1H), 6.50 (m, 1H), 6.54 (s, 1H), 6.71 (s, 1H), 7.26 (dd, 1H), 7.39 (dbr, 1H), 7.52 (dbr, 1H), 7.64 (m, 1H). LCMS (Method 3): R.sub.t = 1.27 min; m/z = 432; 434 (M + H, Br isotope pattern).sup.+

Example 52A

()-8-Bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(154) ##STR00072##

(155) At RT, 100 mg (286 mol) of 8-bromo-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine (Example 36A) were dissolved in 5 ml of THF, 58 mg (286 mol) of 4-nitrophenyl chloroformate (CAS [7693-46-1]) were added and the mixture was stirred at RT for 2 h. 1.43 ml (2.86 mmol) of a 2M solution of methylamine in THF were added dropwise to the clear orange solution, and the mixture was stirred at 60 C. for 16 h. The mixture was allowed to warm to RT and partitioned between water and ethyl acetate, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed water and sat. sodium chloride solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 92 mg (79% of theory) of the desired product as an orange foam.

(156) LCMS (Method 1): R.sub.t=1.49 min; m/z=406; 408; 410 (BrCl isotope pattern, M+H).sup.+

(157) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.91 (d, 3H), 2.89 (d, 3H), 2.90 (dd, 1H), 3.09 (dd, 1H), 5.43-5.53 (m, 1H), 6.43-6.51 (m, 1H), 7.11 (d, 1H), 7.21 (d, 1H), 7.39 (s, 4H), 7.45 (dd, 1H).

Enantiomer Separation

(158) By chiral preparative HPLC, 320 mg of ()-8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide were separated into the enantiomers under the following conditions:

(159) System: Agilent: Prep 1200, 2 Prep Pump G1361A, DLA G2258A, MWD G1365D, Prep FC G1364B; column: Chiralpak IC 5 m 25020 mm; mobile phase: hexane/ethanol 95:05 (v/v); flow rate: 30 ml/min; temperature: RT; solution: 320 mg/3.4 ml of MeOH; injection: 2200 ml, 5400 ml; detection: UV 254 nm.

Example 52.1A

(160) 116 mg, colourless solid, HPLC (Method C): R.sub.t=2.6 min, purity>99%

(161) Optical rotation: [].sub.D.sup.20=111.20.08 (c=1.00; methanol)

Example 52.2A

(162) 123 mg, colourless solid, HPLC (Method C): R.sub.t=3.1 min, purity 99.5%

(163) Optical rotation: [].sub.D.sup.20=111.20.08 (c=1.00; methanol)

Example 53A

()-1-(4-Aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(164) ##STR00073##

(165) The preparation of the title compound is described in WO97/28135 A1 (Schering AG) as Example 5.

(166) UPLC/MS (Method 3): R.sub.t=0.92 min; m/z=339 (M+H).sup.+

(167) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.07 (d, 3H), 2.37 (dd, 1H), 2.60 (d, 3H), 2.81 (dd 1H), 3.69 (s, 3H), 4.74 (m, 1H), 5.70 (sbr, 2H), 6.19 (qbr, 1H), 6.53 (d, 1H), 6.57 (d, 2H), 6.98 (dd, 1H), 7.28 (d, 1H), 7.45 (d, 2H).

Enantiomer Separation (Preparative Method III)

Example 53.1A

(4R)-1-(4-Aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(168) 1.64 g, yellow solid, HPLC (Method C): R.sub.t=5.05 min, purity 99%, [].sub.D.sup.20=637.80.12 (c=1.040; MeOH)

Example 53.2A: (4S)-1-(4-Aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(169) 1.71 g, yellow solid, HPLC (Method C): R.sub.t=6.75 min, purity 95%, [].sub.D.sup.20=+604.90.10 (c=1.030; MeOH)

Example 54A

(4S)-1-(4-Bromophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(170) ##STR00074##

(171) 1000 mg (2.96 mmol) of (4S)-1-(4-aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 53.2A) were dissolved in 20 ml of acetonitrile, 528 mg (2.36 mmol) of copper(II) bromide and 351 l (2.96 mmol) of tert-butyl nitrite were added and the mixture was stirred at room temperature for 2 hours. The mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography. This gave 505 mg (42% of theory) of the title compound.

(172) UPLC/MS (Method 3): R.sub.t=1.37 min; m/z=402; 404 (Br isotope pattern, M+H).sup.+

(173) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.91 (d, 3H), 2.85 (dd, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 3.69 (s, 3H), 5.44 (m, 1H), 6.48 (m, 1H), 6.59 (d, 1H), 6.87 (dd, 1H), 7.13 (d, 1H), 7.35 (d, 2H), 7.52 (d, 2H).

Example 55A

()-1-(4-Chlorophenyl)-8-hydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(174) ##STR00075##

(175) With ice-bath cooling, 38 ml (38.1 mmol) of boron tribromide were slowly added dropwise to a solution of 2.27 g (6.34 mmol) of ()-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 50A) in 100 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours. The reaction was poured onto ice-water and extracted with dichloromethane. The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. This gave 2.16 g (99% of theory) of the title compound.

(176) UPLC/MS (Method 3): R.sub.t=1.12 min; m/z=344; 346 (Cl isotope pattern, M+H).sup.+

(177) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.90 (d, 3H), 2.63 (dd, 1H), 2.65 (d, 3H), 2.89 (dd, 1H), 5.02 (m, 1H), 6.63 (m, 1H), 6.37 (d, 1H), 6.79 (dd, 1H), 7.16 (d, 1H), 7.47 (d, 2H), 7.61 (d, 2H), 9.53 (sbr, 1H).

Example 56A

1-(3-Bromo-4-fluorophenyl)-6,7-dimethoxy-3-methyl-3,4-dihydro-1H-2-benzopyran

(178) ##STR00076##

(179) The preparation was carried out analogously to Example 41A starting with commercially available 3-bromo-4-fluorobenzaldehyde (CAS [77771-02-9]).

(180) LCMS (Method 3): R.sub.t=1.44 min; m/z=381; 383 (Br isotope pattern, M+H).sup.+

Example 57A

1-[2-(3-Bromo-4-fluorobenzoyl)-4,5-dimethoxyphenyl]propan-2-one

(181) ##STR00077##

(182) The preparation was carried out analogously to Example 43A.

(183) LCMS (Method 3): R.sub.t=1.25 min; m/z=395; 397 (Br isotope pattern, M+H).sup.+

Example 58A

1-(3-Bromo-4-fluorophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine

(184) ##STR00078##

(185) The preparation was carried out analogously to Example 45A.

(186) LCMS (Method 3): R.sub.t=1.21 min; m/z=381; 383 (Br isotope pattern, M+H).sup.+

(187) .sup.1H-NMR (400 MHz, CDCl.sub.3): =2.16 (s, 3H), 2.99 (d, 1H), 3.29 (d, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 6.74 (s, 2H), 7.16 (dd, 1H), 7.62 (ddd, 1H), 7.94 (dd, 1H).

Example 59A

()-1-(3-Bromo-4-fluorophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine

(188) ##STR00079##

(189) The preparation was carried out analogously to Example 47A.

(190) LCMS (Method 3): R.sub.t=1.03 min; m/z=393; 395 (Br isotope pattern, M+H).sup.+

(191) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.29 (d, 3H), 2.61 (dd, 1H), 2.89 (dd, 1H), 3.72 (s, 3H), 3.95 (s, 3H), 4.12 (m, 1H), 6.57 (s, 1H), 6.77 (s, 1H), 7.10 (dd, 1H), 7.45 (ddd, 1H), 7.81 (dd, 1H).

Example 60A

()-1-(3-Bromo-4-fluorophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(192) ##STR00080##

(193) The preparation was carried out analogously to Example 49A.

(194) LCMS (Method 3): R.sub.t=1.31 min; m/z=450; 452 (Br isotope pattern, M+H).sup.+

(195) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.95 (d, 3H), 2.86 (dd, 1H), 2.90 (d, 3H), 3.10 (dd, 1H), 3.67 (s, 3H), 3.93 (s, 3H), 5.48 (m, 1H), 6.44 (m, 1H), 6.52 (s, 1H), 6.71 (s, 1H), 7.14 (dd, 1H), 7.39 (ddd, 1H), 7.69 (dd, 1H).

(196) The following compound was prepared analogously to Example 8A from 4-nitrobenzaldehyde:

(197) TABLE-US-00013 No Structure Name Analytical data 61A 2-methyl-3-(4- nitrophenyl)acrylic acid .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 2.01 (s, 3H), 7.62 (s, 1H), 7.70 (d, 2H), 8.23 (d, 2H), 12.8 (s, br, 1H). LCMS (Method 2): R.sub.t = 0.99 min; m/z [ES.sup.] = 206 (M H).sup.

Example 62A

()-3-(4-Aminophenyl)-2-methylpropanoic acid

(198) ##STR00082##

(199) 41 g (0.2 mol) of 2-methyl-3-(4-nitrophenyl)acrylic acid were reduced analogously to Example 10A. This gave 21 g (90%) of the desired compound as a yellow crystallizing oil.

(200) LCMS (Method 2): R.sub.t=0.48 min; m/z=180 (M+H).sup.+

(201) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.95 (d, 3H), 2.36 (dd, 1H), 2.42-2.45 (m, 1H), 2.70 (dd, 1H), 6.43 (d, 2H), 6.78 (d, 2H).

Example 63A

()-6-Amino-2-methylindan-1-one

(202) ##STR00083##

(203) 310 g of polyphosphoric acid were added to 38 g (11.1 mmol) of ()-3-(4-aminophenyl)-2-methylpropanoic acid (Example 62A), and the mixture was stirred at 150 C. for 7 h using a pressurized air stirrer. After cooling, the mixture was carefully, a little at a time, diluted with water and then, with ice cooling, made alkaline using 32% strength aqueous sodium hydroxide solution (pH=10). The mixture was extracted with dichloromethane and the combined organic phases dried with sodium sulphate. The solvents were removed on a rotary evaporator and the crude product (26 g) was directly reacted further.

(204) LCMS (Method 2): R.sub.t=0.69 min; m/z=162; 203 (M+H; M+ACN+H).sup.+

(205) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.11 (d, 3H), 2.53-2.60 (m, 1H), 2.68 (dd, 1H), 3.15 (dd, 1H), 5.25 (s, br, 2H), 6.71 (d, 1H), 6.88 (dd, 1H), 7.16 (d, 1H).

Example 64A

()-tert-Butyl(2-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)carbamate

(206) ##STR00084##

(207) 15.0 g (93.0 mmol) of ()-6-amino-2-methylindan-1-one were dissolved in 450 ml of dichloromethane, the solution was stirred in an ice bath for 10 min, 21.3 g (97.7 mmol) of di-tert-butyl dicarbonate were then added and the mixture was stirred at RT for a further 16 h. The mixture was added to water and extracted with dichloromethane, the combined organic phases were washed with sat. sodium chloride solution and the solvents were removed on a rotary evaporator. The crude product was purified chromatographically (SiO.sub.2, hexane/ethyl acetate 0-30%). This gave 13.3 g (50% of theory) as a yellow foam.

(208) LCMS (Method 2): R.sub.t=1.21 min; m/z=262; 303 (M+H).sup.+; (M+ACN+H).sup.+

(209) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.14 (d, 3H), 1.45 (s, 9H), 2.58 (dd, 1H), 2.61-2.70 (m, 1H), 3.25 (dd, 1H), 7.40 (d, 1H), 7.63 (dd, 1H), 7.77 (d, 1H), 9.51 (s, 1H).

(210) The following indanones were prepared analogously to Example 15A from the appropriate carboxylic acids:

(211) TABLE-US-00014 No Structure Name Analytical data 65A ()-6-tert-butyl-2- methylindan-1-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.31 (d, 3H), 1.34 (s, 9H), 2.65-2.77 (m, 2H), 3.31-3.40 (m, 1H), 7.39 (d, 1H), 7.66 (dd, 1H), 7.78 (d, 1H). LCMS (Method 2): R.sub.t = 1.35 min; m/z = 244 (M + CH.sub.3CN).sup.+. 66A ()-6-chloro-5- methoxy-2- methylindan-1-one .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.29 (d, 3H), 2.61-2.78 (m, 2H), 3.28-3.40 (m, 1H), 3.98 (s, 3H), 6.92 (s, 1H), 7.75 (s, 1H). LCMS (Method 2): R.sub.t = 1.10 min; m/z = 211 (M + H).sup.+.

(212) The following compounds were prepared analogously to Example 17A from the appropriate indanones by reaction with 4-chlorophenylmagnesium bromide and subsequent elimination of water using 4-toluenesulphonic acid:

(213) TABLE-US-00015 No Structure Name Analytical data 67A 5-tert-butyl-3-(4- chlorophenyl)-2- methyl-1H-indene .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.31 (s, 9H), 2.11 (s, 3H), 3.41 (s, 2H), 7.18-7.25 (m, 2H), 7.31-7.41 (m, 3H), 7.46 (d, 2H). LCMS (Method 3): R.sub.t = 1.0 min; m/z = 499 (M + H).sup.+. 68A 5-chloro-3-(4- chlorophenyl)-6- methoxy-2-methyl-1H- indene .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.10 (s, 3H), 3.42 (s, 2H), 3.93 (s, 3H), 7.09 (s, 1H), 7.14 (s, 1H), 7.31 (d, 2H), 7.44 (d, 2H). LCMS (Method 2): R.sub.t = 1.68 min; m/z = 305 (M + H).sup.+. 69A 3-(4-chlorophenyl)-2,5- dimethyl-1H-indene .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.11 (s, 3H), 2.35 (s, 3H), 3.42 (s, 2H), 6.96-7.02 (m, 2H), 7.31 (d, 1H), 7.33 (d, 2H), 7.45 (d, 2H). LCMS (Method 2): R.sub.t = 1.70 min; m/z = 255 (M + H).sup.+. 70A 0 tert-butyl [3-(4- chlorophenyl)-2- methyl-1H-inden-5- yl]carbamate LCMS (Method 2): R.sub.t = 1.64 min; m/z = 256 (M + H).sup.+

(214) The following compounds were prepared analogously to Example 25A from the appropriate 1H-indenes:

(215) TABLE-US-00016 No Structure Name Analytical data 71A 1-[4-tert-butyl-2-(4- chlorobenzoyl)phenyl]- propan-2-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.28 (s, 9H), 2.18 (s, 3H), 3.96 (s, 2H), 7.19 (d, 1H), 7.38 (d, 1H), 7.45 (d, 2H), 7.50 (dd, 1H), 7.77 (d, 2H). LCMS (Method 2): R.sub.t = 1.54 min; m/z = 329 (M + H).sup.+. 72A 1-[4-chloro-2-(4- chlorobenzoyl)-5- methoxyphenyl]- propan-2-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.24 (s, 3H), 3.98 (s, 3H), 4.01 (s, 2H), 6.80 (s, 1H), 7.43 (s, 1H), 7.45 (d, 2H), 7.70 (d, 2H). LCMS (Method 2): R.sub.t = 1.39 min; m/z = 337; 339 (Cl isotope pattern, M + H).sup.+. 73A 1-[2-(4-chlorobenzoyl)- 4-methylphenyl]- propan-2-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.17 (s, 3H), 2.34 (s, 3H), 3.93 (s, 2H), 7.15 (d, 1H), 7.17 (s, br, 1H), 7.29 (dd, 1H), 7.44 (d, 2H), 7.76 (d, 2H). LCMS (Method 2): R.sub.t = 1.37 min; m/z = 287 (M + H).sup.+. 74A tert-butyl [3-(4- chlorobenzoyl)-4-(2- oxopropyl)phenyl]- carbamate .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.39 (s, 9H), 2.01 (s, 3H), 3.83 (s, 2H), 7.20 (d, 1H), 7.44 (d, 1H), 7.51- 7.57 (m, 1H), 7.59 (d, 2H), 7.69 (d, 2H), 9.42 (s, 1H). LCMS (Method 2): R.sub.t = 1.39 min; m/z = 388 (M + H).sup.+

Example 75A

8-tert-Butyl-1-(4-chlorophenyl)-4-methyl-5H-2,3-benzodiazepine

(216) ##STR00095##

(217) 7.0 g (21.29 mmol) of 1-[4-tert-butyl-2-(4-chlorobenzoyl)phenyl]propan-2-one (Example 71A) and 7.46 g (149 mmol) of hydrazine hydrate in 80.6 ml of ethanol were stirred at RT for 72 h. The reaction solution was added to water, made alkaline with 1M aqueous sodium hydroxide solution and extracted with dichloromethane. The combined organic phases were dried with sodium sulphate and the solvent was removed on a rotary evaporator. This gave 6.5 g (94% of theory) of the crude product which was reacted in the next reaction step without further purification. A portion of the residue was purified by preparative HPLC.

(218) LCMS (Method 2): R.sub.t=1.54 min; m/z=325 (M+H).sup.+.

(219) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.26 (s, 9H), 2.15 (s, 3H), 3.04 (d, 1H), 3.33 (d, 1H), 7.21 (d, 1H), 7.31 (d, 1H), 7.38 (d, 2H), 7.55 (dd, 1H), 7.64 (d, 2H).

Example 76A

tert-Butyl[1-(4-chlorophenyl)-4-methyl-5H-2,3-benzodiazepin-8-yl]carbamate

(220) ##STR00096##

(221) Together, 5.10 g (13.1 mmol) of tert-butyl[3-(4-chlorobenzoyl)-4-(2-oxopropyl)phenyl]carbamate (Example 74A) and 3.49 g (69.7 mmol) of hydrazine hydrate were heated in 100 ml of ethanol at 100 C. for 1.5 h. The mixture was then cooled, added to water and extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution, dried with sodium sulphate and concentrated. This gave 5 g of crude product which was directly used further, without further purification.

(222) LCMS (Method 1): R.sub.t=1.37 min; m/z=384 (M+H).sup.+

(223) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.48 (s, 9H), 2.13 (s, 3H), 3.03 (d, 1H), 3.30 (d, 1H), 6.48 (s, br, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.37 (d, 2H), 7.62 (d, 2H), 7.73 (d, 1H).

(224) The following compounds were prepared analogously to Example 75A from the appropriate diketo compounds:

(225) TABLE-US-00017 No Structure Name Analytical data 77A 8-chloro-1-(4- chlorophenyl)-7- methoxy-4-methyl-5H- 2,3-benzodiazepine .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.25 (s, 3H), 3.12 (d, 1H), 3.41 (d, 1H), 4.01 (s, 3H), 6.82 (s, 1H), 7.32 (s, 1H), 7.42 (d, 2H), 7.62 (d, 2H). LCMS (Method 2): R.sub.t = 1.37 min; m/z = 333; 335 (Cl isotope pattern, M + H).sup.+. 78A 1-(4-chlorophenyl)-4,8- dimethyl-5H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.13 (s, 3H), 2.33 (s, 3H), 3.03 (d, 1H), 3.31 (d, 1H), 7.10 (s, br, 1H), 7.17 (d, 1H), 7.34 (dd, 1H), 7.38 (d, 2H), 7.62 (d, 2H). LCMS (Method 2): R.sub.t = 1.36 min; m/z = 283 (M + H).sup.+.

(226) The following compounds were prepared analogously to Example 47A:

(227) TABLE-US-00018 No Structure Name Analytical data 79A ()-8-tert-butyl-1-(4- chlorophenyl)-4- methyl-4,5-dihydro- 3H-2,3-benzodiazepine LCMS (Method 2): R.sub.t = 1.42 min; m/z = 327 (M + H).sup.+. 80A 00 ()-8-chloro-1-(4- chlorophenyl)-7- methoxy-4-methyl-4,5- dihydro-3H-2,3- benzodiazepine LCMS (Method 2): R.sub.t = 1.25 min; m/z = 335; 337 (Cl isotope pattern, M + H).sup.+. 81A 01 ()-1-(4-chlorophenyl)- 4,8-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.27 (d, 3H), 2.28 (s, 3H), 2.59 (dd, 1H), 2.92 (dd, 1H), 4.06-4.20 (m, 1H), 6.89 (s, 1H), 7.16 (s, br, 2H), 7.34 (d, 2H), 7.51 (d, 2H). LCMS (Method 2): R.sub.t = 1.17 min; m/z = 285 (M + H).sup.+. 82A 02 ()-tert-butyl-[1-(4- chlorophenyl)-4- methyl-4,5-dihydro- 3H-2,3-benzodiazepin- 8-yl]carbamate .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 1.60 (d, 3H), 1.37 (s, 9H), 2.58 (dd, 1H), 2.82 (dd, 1H), 3.75-3.81 (m, 1H), 7.07 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.33-7.38 (m, 4H), 9.16 (s, br, 1H). LCMS (Method 2): R.sub.t = 1.23 min; m/z = 386 (M + H).sup.+

(228) The following compounds were prepared analogously to Example 49A from the appropriate 4,5-dihydro-3H-2,3-benzodiazepines:

(229) TABLE-US-00019 No Structure Name Analytical data 83A 03 ()-8-tert-butyl-1-(4- chlorophenyl)-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.95 (d, 3H), 1.21 (s, 9H), 2.86 (dd, 1H), 2.89 (d, 3H), 3.09 (dd, 1H), 5.36-5.49 (m, 1H), 6.43 (q, 1H), 7.08 (d, 1H), 7.15 (d, 1H), 7.32-7.40 (m, 3H), 7.41- 7.47 (m, 2H). LCMS (Method 2): R.sub.t = 1.61 min; m/z = 384 (M + H).sup.+. 83.1A 04 (4S)-8-tert-butyl-1-(4- chlorophenyl)-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.61 min; m/z = 384 (M + H).sup.+ HPLC (Method M): R.sub.t = 2.48 min [].sub.D.sup.20 = 133.8 (c = 1.00; chloroform) 83.2A 05 (4R)-8-tert-butyl-1-(4- chlorophenyl)-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.61 min; m/z = 384 (M + H).sup.+ HPLC (Method M): R.sub.t = 2.84 min [].sub.D.sup.20 = 167.7 (c = 1.00; chloroform) 84A 06 ()-8-chloro-1-(4- chlorophenyl)-7- methoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.88 (s, br, 3H), 2.88-2.94 (m, 1H), 3.14 (dd, 1H), 3.96 (s, 3H), 5.45-5.54 (m, 1H), 6.46 (s, br, 1H), 6.77 (s, 1H), 7.08 (s, 1H), 7.38 (s, br, 4H). LCMS (Method 2): R.sub.t = 1.46 min; m/z = 392; 394 (Cl isotope pattern, M + H).sup.+. 84.1A 07 (4S)-8-chloro-1-(4- chlorophenyl)-7- methoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.46 min; m/z = 392; 394 (Cl isotope pattern, M + H).sup.+. HPLC (Method O): R.sub.t = 3.67 min [].sub.D.sup.20 = 70.5 (c = 1.00; methanol) 84.2A 08 (4R)-8-chloro-1-(4- chlorophenyl)-7- methoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.46 min; m/z = 392; 394 (Cl isotope pattern, M + H).sup.+. HPLC (Method O): R.sub.t = 2.47 min 85A 09 ()-1-(4-chlorophenyl)- N,4,8-trimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.93 (d, 3H), 2.25 (s, 3H), 2.86 (dd, 1H), 2.88 (s, br, 3H), 3.09 (dd, 1H), 5.36- 5.48 (m, 1H), 6.44 (s, br, 1H), 6.86 (s, br, 1H), 7.08-7.18 (m, 2H), 7.36 (d, 2H), 7.42 (d, 2H). LCMS (Method 2): R.sub.t = 1.47 min; m/z = 342 (M + H).sup.+. 85.1A 0 (4S)-1-(4- chlorophenyl)-N,4,8- trimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XV analyt. HPLC (Method H): R.sub.t = 1.82 min LCMS (Method 2): R.sub.t = 1.46 min; m/z = 342 (M + H).sup.+. [].sub.D.sup.20 = 213.9 (c = 1.00; methanol) 85.2A (4R)-1-(4- chlorophenyl)-N,4,8- trimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XV analyt. HPLC (Method H): R.sub.t = 1.32 min LCMS (Method 2): R.sub.t = 1.46 min; m/z = 342 (M + H).sup.+. [].sub.D.sup.20 = 181.9 (c = 1.00; methanol) 86A ()-tert-butyl [1-(4- chlorophenyl)-4- methyl-3- (methylcarbamoyl)- 4,5-dihydro-3H-2,3- benzodiazepin-8- yl]carbamate .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 0.89 (d, 3H), 1.37 (s, 9H), 2.60-2.66 (m, 1H), 2.63 (d, 3H), 2.90 (dd, 1H), 4.97-5.05 (m, 1H), 6.61 (q, 1H), 7.14 (d, 1H), 7.21 (d, 1H), 7.43-7.47 (m, 1H), 7.45 (d, 2H), 7.62 (d, 2H), 9.30 (s, br, 1H). LCMS (Method 2): R.sub.t = 1.45 min; m/z = 443 (M + H).sup.+

Example 87A

()-8-Amino-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(230) ##STR00113##

(231) 4.50 g (10.2 mmol) of ()-tert-butyl 1-(4-chlorophenyl)-4-methyl-3-(methylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepin-8-yl]carbamate (Example 86A) were initially charged in 100 ml of dichloromethane, 15 ml (20.3 mmol) of trifluoroacetic acid were added at 0 C. and the mixture was then stirred at RT for a further 4 h. The mixture was added carefully to 20% strength potassium carbonate solution and extracted with dichloromethane. The combined organic phases were dried with sodium sulphate and the solvents were removed on a rotary evaporator. This gave 3.40 g (97% of theory) of the desired product as a brownish solid.

(232) LCMS (Method 2): R.sub.t=1.12 min; m/z=343 (M+H).sup.+

(233) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.88 (d, 3H), 2.52 (dd, 1H), 2.63 (d, 3H), 2.80 (dd, 1H), 4.89-5.05 (m, 1H), 5.01 (s, br, 2H), 6.19 (d, 1H), 6.52-6.59 (m, 2H), 6.96 (d, 1H), 7.44 (d, 1H), 7.61 (d, 2H).

Example 88A

()-1-[8-tert-Butyl-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl]ethanone

(234) ##STR00114##

(235) 300 mg (0.918 mmol) of ()-8-tert-butyl-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine (Example 79A) were suspended in 3.5 ml of dichloromethane, and 281 mg (2.75 mmol) of acetic anhydride were added at RT. A clear, light-yellow solution was formed. The solution was stirred for 16 h, the pH was then adjusted to 6 by addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted twice with dichloromethane. The combined organic phases were dried with sodium sulphate and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC. This gave 210 mg (62% of theory) of the product as a solid.

(236) LCMS (Method 2): R.sub.t=1.61 min; m/z=369 (M+H)+.

(237) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.18 (d, 3H), 1.24 (s, 9H), 2.17 (s, 3H), 2.72 (dd, 1H), 2.93 (dd, 1H), 5.24-5.37 (m, 1H), 7.06 (d, 1H), 7.21 (d, 1H), 7.36-7.45 (m, 3H), 7.59 (d, 2H).

Example 89A

()-8-Acetamido-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(238) ##STR00115##

(239) 840 mg (2.45 mmol) of ()-8-amino-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 87A) were dissolved in dichloromethane and, at 0 C., 0.41 ml (2.94 mmol) of triethylamine and 0.21 ml (2.94 mmol) of acetyl chloride were added and the mixture was stirred for 1 h. The mixture was then added to water and extracted with dichloromethane, the combined organic phases dried with sodium sulphate and the solvents were removed on a rotary evaporator. This gave 940 mg (99%) of the desired product as a brownish solid foam.

(240) LCMS (Method 2): R.sub.t=1.15 min; m/z=385 (M+H).sup.+

(241) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.87 (d, 3H), 1.93 (s, 3H), 2.64 (d, 3H), 2.69 (dd, 1H), 2.93 (dd, 1H), 5.02-5.10 (m, 1H), 6.66 (q, 1H), 7.22 (d, 1H), 7.25 (d, 1H), 7.45 (d, 2H), 7.60 (d, 2H), 7.60-7.63 (m, 1H), 9.88 (s, 1H).

Example 90A

()-1-(4-Bromophenyl)-7-hydroxy-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(242) ##STR00116##

(243) 2.5 g (18.5 mmol) of aluminium trichloride were initially charged in 40 ml of dichloromethane, and a solution of 2.0 g (4.6 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) in 20 ml of dichloromethane was added dropwise at RT. The suspension, which was yellow first and then orange, was stoned at RT for a further 2 h. The mixture was then added to water and extracted with dichloromethane, and the combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the crude product was purified chromatographically (SiO.sub.2, hexane/ethyl acetate 0-70%). This gave 1.14 g (59% of theory) of the desired 7-hydroxy compound as a yellow solid. Also obtained was 0.63 g (32% of theory) of the regioisomeric ()-1-(4-bromophenyl)-8-hydroxy-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide.

(244) LCMS (Method 2): R.sub.t=1.23 min; m/z=418/420 (M+H).sup.+, Br isotope pattern

(245) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.90 (d, 3H), 2.56 (dd, 1H), 2.63 (d, 3H), 2.82 (dd, 1H), 3.54 (s, 3H), 4.96-5.07 (m, 1H), 6.44 (s, 1H), 6.58 (q, 1H), 6.74 (s, 1H), 7.56 (s, 4H), 9.59 (s, 1H).

Example 91A

()-1-(4-Bromophenyl)-7,8-dihydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(246) ##STR00117##

(247) 1.5 g (3.47 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) were initially charged in 15 ml of dichloromethane, 6.94 ml of a 1M solution of boron tribromide in dichloromethane were slowly added dropwise at 0 C. and the mixture was stirred at RT for 16 h. A further 3.5 ml of boron tribromide solution were added, and the mixture was stirred for a further 20 h. 25 ml of 4M hydrochloric acid were added to the orange-brown solution, and the mixture was stirred for 10 min and then extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the crude product was purified chromatographically. This gave 1.17 g (83% of theory) of the desired product.

(248) LCMS (Method 2): R.sub.t=1.12 min; m/z=404/406 (M+H).sup.+, Br isotope pattern

(249) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.87 (d, 3H), 2.58 (dd, 1H), 2.63 (d, 3H), 2.81 (dd, 1H), 5.01-5.09 (m, 1H), 6.34 (s, 1H), 6.58 (q, 1H), 6.66 (s, 1H), 7.49 (d, 2H), 7.56 (d, 2H).

Example 92A

()-1-(4-Bromophenyl)-7,8-bis(difluoromethoxy)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(250) ##STR00118##

(251) 115 mg (2.28 mmol) of sodium hydroxide were suspended in 7.5 ml of DMF, 200 mg (495 mol) of ()-1-(4-bromophenyl)-7,8-dihydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide were added at RT and the mixture was stirred for 15 min. The mixture was cooled to 0 C., and 0.63 ml (4.95 mmol) of chlorodifluoroacetate were added slowly. The mixture was allowed to warm to RT and then stirred at 70 C. for a further 5 h. After cooling, the mixture was added to water. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate. The crude product was purified chromatographically (SiO.sub.2, hexane/ethyl acetate 0-50-75%). This gave 113 mg (17% of theory) of the product.

(252) LCMS (Method 2): R.sub.t=1.44 min; m/z=504/506 (M+H).sup.+, Br isotope pattern

Example 93A

()-1-(4-Bromophenyl)-7,8-diethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(253) ##STR00119##

(254) 133 mg (329 mol) of ()-1-(4-bromophenyl)-7,8-dihydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 91A) were initially charged in 5 ml of DMF, 236 mg (724 mol) of caesium carbonate and 54 l (724 mol) of bromoethane were added at RT and the mixture was stirred at RT for 16 h. The mixture was added to water and extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator. This gave 152 mg (100% of theory) of the desired product.

(255) LCMS (Method 2): R.sub.t=1.47 min; m/z=460/462 (M+H).sup.+, Br isotope pattern

(256) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.90 (d, 3H), 1.18 (t, 3H), 1.32 (t, 3H), 2.64 (d, 3H), 2.66 (dd, 1H), 2.90 (dd, 1H), 3.72-3.80 (m, 2H), 4.08 (q, 2H), 5.03-5.11 (m, 1H), 6.45 (s, 1H), 6.62 (q, 1H), 6.96 (s, 1H), 7.52-7.58 (m, 4H).

Example 94A

(4S)-1-(4-{[(2-Chloroethoxy)acetyl]amino}phenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(257) ##STR00120##

(258) Under argon, 60 mg (0.177 mmol) of (4S)-1-(4-aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2.3-benzodiazepine-3-carboxamide (Example 53.2A) were initially charged in 3 ml of toluene, and 33 mg (0.213 mmol) of (2-chloroethoxy)acetyl chloride were added. The mixture was heated at 100 C. for 5 h. After cooling, water was added, followed by a little saturated aqueous sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried and freed from the solvent on a rotary evaporator. The crude product (112 mg) was used without further purification for the next reaction step.

(259) UPLC/MS (Method 1): R.sub.t=1.2 min; m/z=459 (M+H).sup.+

Example 95A

()-7-Bromo-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(260) ##STR00121##

(261) At room temperature, 638 mg (1.69 mmol) of ()-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 50A) were dissolved in 50 ml of dichloromethane, and 2.17 g (6.78 mmol) of pyridinium tribromide (CAS [39416-48-3]) were added. The orange solution was heated at reflux for 16.5 hours. A further 1.08 g (3.49 mmol) of pyridinium tribromide were added, and the mixture was heated at reflux for 2 days. The reaction mixture was added to saturated aqueous sodium thiosulphate solution and extracted three times with dichloromethane. The combined organic phases were washed with saturated aqueous sodium thiosulphate solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 642 mg (82% of theory) of the desired product as a yellow foam.

(262) LCMS (Method 3): R.sub.t=1.44 min; m/z=436; 438; 440 (BrCl isotope pattern; M+H).sup.+

(263) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.93 (d, 3H), 2.83 (dd, 1H), 2.89 (d, 3H), 3.07 (dd, 1H), 3.67 (s, 3H), 5.46 (m, 1H), 6.49 (m, 1H), 6.57 (s, 1H), 7.38 (d, 2H), 7.40 (s, 1H), 7.41 (d, 2H).

Example 96A

()-1-(4-Chlorophenyl)-7-cyan-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(264) ##STR00122##

(265) 640 mg (1.39 mmol) of ()-7-bromo-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 95A) were dissolved in 12 ml of toluene, and 173 mg (1.39 mmol) of 1-butyl-1H-imidazole, 118 mg (0.28 mmol) of potassium hexacyanoferrate(II), ground in a mortar and dried, and 26.5 mg (0.14 mmol) of copper(I) iodide were added. The reaction mixture was irradiated in a microwave reactor at 160 C. for 6 hours. For work-up, the reaction mixture was filtered through Celite, the filter cake washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 430 mg (79% of theory) of the desired product as a grey foam.

(266) LCMS (Method 3): R.sub.t=1.30 min; m/z=383; 385 (Cl isotope pattern; M+H).sup.+

(267) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.89 (d, 3H), 2.90 (d, 3H), 2.91 (dd, 1H), 3.09 (dd, 1H), 3.71 (s, 3H), 5.50 (m, 1H), 6.52 (qbr, 1H), 6.66 (s, 1H), 7.38 (d, 2H), 7.39 (s, 1H), 7.41 (d, 2H).

Example 97A

()-1-(4-Bromophenyl)-7-(difluoromethoxy)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(268) ##STR00123##

(269) 1.58 g (39.5 mmol) of sodium hydroxide were suspended in 42 ml of DMF. At RT, 1.14 g (2.73 mmol) of ()-1-(4-bromophenyl)-7-hydroxy-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 90A) were added, and the mixture was stirred at RT for 15 min and then at 0 C. for 10 min. At 0 C., 4.32 g (27.3 mmol) of ethyl chloro-(difluoro)acetate (CAS [383-62-0]) were added, and the mixture was stirred at 70 C. for 5 h. After cooling, the mixture was added to water and extracted with ethyl acetate, and the combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the crude product was purified chromatographically (SiO.sub.2, hexane/ethyl acetate 0-60%). This gave 370 mg (29% of theory) of the desired product as a pale-yellow foam.

(270) LCMS (Method 2): R.sub.t=1.42 min; m/z=468/470 (M+H).sup.+, Br isotope pattern

(271) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.91 (d, 3H), 2.64 (d, 3H), 2.65 (dd, 1H), 2.92 (dd, 1H), 3.61 (s, 3H), 4.99-5.08 (m, 1H), 6.65 (q, 1H), 6.67 (s, 1H), 7.13 (t, J=75 Hz, 1H), 7.20 (s, 1H), 7.59 (s, 4H).

(272) The following compounds were prepared analogously to Example 8A from the appropriate commercially available aldehydes:

(273) TABLE-US-00020 No. Structure Name Analytical data 98A (2E)-3-[4-chloro-3- (trifluoromethoxy) phenyl]-2- methacrylic acid .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.13 (s, 3H), 7.30 (d, 1H), 7.38 (s, br, 1H), 7.52 (d, 1H), 7.73 (s, br, 1H). LCMS (Method 2): R.sub.t = 1.31 min; m/z [ES.sup.] = 279/281 (M H, Cl isotopes).sup. 99A (2E)-3-[4-methoxy- 3- (trifluoromethoxy) phenyl]-2- methacrylic acid .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.15 (d, 3H), 3.93 (s, 3H), 7.03 (d, 1H), 7.33-7.40 (m, 2H), 7.72 (s, br, 1H). LCMS (Method 1): R.sub.t = 1.16 min; m/z [ES.sup.] = 277 (M + H).sup.+

(274) The following compounds were prepared analogously to Example 10A from Example 98A and Example 99A respectively:

(275) TABLE-US-00021 No. Structure Name Analytical data 100A 3-[4-chloro-3- (trifluoromethoxy) phenyl]-2- methylpropanoic acid .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.21 (d, 3H), 2.67-2.81 (m, 2H), 2.98-3.08 (m, 1H), 7.08 (dd, 1H), 7.16 (t, 1H), 7.38 (d, 1H). LCMS (Method 2): R.sub.t = 1.27 min; m/z [ES.sup.] = 281/283 (M H, Cl isotopes).sup. 101A 3-[4-methoxy-3- (trifluoromethoxy) phenyl]-2- methylpropanoic acid .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.19 (d, 3H), 2.60-2.79 (m, 2H), 2.99 (dd, 1H), 3.85 (s, 3H), 6.91 (d, 1H), 7.03- 7.10 (m, 2H). LCMS (Method 2): R.sub.t = 1.16 min; m/z [ES.sup.] = 278 (M H).sup.

(276) The following indanones were prepared analogously to Example 15A from the corresponding carboxylic acid (Example 100A and Example 101A):

(277) TABLE-US-00022 No. Structure Name Analytical data 102A 6-chloro-2-methyl-5- (trifluoromethoxy) indan-1-one .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.32 (d, 3H), 2.68-2.84 (m, 2H), 3.40 (dd, 1H), 7.40 (s, br, 1H), 7.85 (s, 1H). LCMS (Method 2): R.sub.t = 1.36 min; m/z = 266 (M + H).sup.+ 103A 6-methoxy-2-methyl-5- (trifluoromethoxy) indan-1-one .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.31 (d, 3H), 2.63-2.81 (m, 2H), 3.35 (dd, 1H), 3.91 (s, 3H), 7.30 (s, br, 2H). LCMS (Method 2): R.sub.t = 1.27 min; m/z = 261 (M + H).sup.+

(278) The following compounds were prepared analogously to Example 17A from the corresponding indanones, which are possibly available commercially, by reaction with 4-chlorophenylmagnesium bromide and subsequent elimination of water using 4-toluenesulphonic acid:

(279) TABLE-US-00023 No. Structure Name Analytical data 104A 0 6-bromo-3-(4- chlorophenyl)-2- methyl-1H-indene .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.11 (s, 3H), 3.44 (s, 2H), 7.02 (d, 1H), 7.30 (d, 2H), 7.35 (dd, 1H), 7.44 (d, 2H), 7.56 (d, 1H). LCMS (Method 2): R.sub.t = 1.75 min; m/z = 319; 321 (Br isotope pattern, M + H).sup.+ 105A 5-chloro-3-(4- chlorophenyl)-2- methyl-1H-inden-6-yl trifluoromethyl ether .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.13 (s, 3H), 3.46 (s, 2H), 7.20 (s, 1H), 7.29 (d, 2H), 7.38 (s, br, 1H), 7.46 (d, 2H). LCMS (Method 2): R.sub.t = 1.75 min; m/z = 357; 359 (Cl isotope pattern, M + H).sup.+ 106A 3-(4-chlorophenyl)-5- methoxy-2-methyl-6- (trifluoromethoxy)-1H- indene .sup.1H-NMR (400 MHz, CDCl.sub.3): = 2.11 (s, 3H), 3.41 (s, 2H), 3.81 (s, 3H), 6.76 (s, 1H), 7.30 (s, 1H), 7.31 (d, 2H), 7.47 (d, 2H). LCMS (Method 1): R.sub.t = 1.72 min; m/z = 355 (M + H).sup.+

Example 107A

(3,4-Dimethoxyphenyl)acetaldehyde

(280) ##STR00133##

(281) 18 g (96.81 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were initially charged in 395 ml of dichloromethane and 50.8 g (116.17 mmol) of Dess-Martin reagent were added in portions. The temperature was held at 20 C. The reaction mixture was stirred at RT for 3 h. The suspension was admixed with 200 ml of saturated aqueous sodium hydrogencarbonate solution and 200 ml of saturated aqueous sodium dithionite solution. It was stirred for 30 minutes and then the organic phase was separated off. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed once with sodium hydrogencarbonate solution and once with water. After drying using sodium sulphate and removal of the solvent, 16.6 g of product were obtained (95% of theory), which was directly reacted further.

(282) LCMS (Method 1): R.sub.t=0.74 min; m/z=181 (M+H).sup.+

(283) .sup.1H-NMR (300 MHz, CDCl.sub.3): =3.66 (d, 2H), 3.91 (s, 6H), 6.73 (d, 1H), 6.81 (t, 1H), 6.90 (d, 1H), 9.75 (t, 1H).

Example 108A

()-1-(3,4-Dimethoxyphenyl)butan-2-ol

(284) ##STR00134##

(285) Under argon, 22.19 g (166.48 mmol) of ethylmagnesium bromide were initially charged and cooled to 40 C. 25 g (138.7 mmol) of (3,4-dimethoxyphenyl)acetaldehyde (Example 107A) were dissolved in 60 ml of THF and added slowly dropwise over the course of 30 minutes to the Grignard solution. An internal bath temperature of not more than 35 C. was maintained. Following the addition, the reaction mixture was stirred at RT for 2 h. It was worked up by adding 300 ml of cooled, saturated aqueous ammonium chloride solution, and the organic phase was separated off. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were washed once with water and once with saturated aqueous sodium chloride solution. Drying using sodium sulphate and removal of the solvent gave 21.53 g of product (64% of theory), which was further reacted directly.

(286) LCMS (Method 1): R.sub.t=0.92 min; m/z=211 (M+H).sup.+; 193 (MH.sub.2O+H).sup.+

(287) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.03 (t, 3H), 1.52-1.66 (m, 2H), 2.59 (dd, 1H), 2.82 (dd, 1H), 3.69-3.80 (m, 1H), 3.84-3.96 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 6.77 (s, 1H), 6.78 (d, 1H), 6.85 (d, 1H).

Example 109A

()-1-(3,4-Dimethoxyphenyl)-3-methylbutan-2-ol

(288) ##STR00135##

(289) Under argon, 6.16 g (59.93 mmol) of 2-propylmagnesium chloride were initially charged, and cooled to 40 C. 9 g (49.9 mmol) of (3,4-dimethoxyphenyl)acetaldehyde (Example 107A) were dissolved in 30 ml of THF and added slowly dropwise over the course of 30 minutes to the Grignard solution. Following the addition, the reaction mixture was stirred at RT for 2 h. It was worked up by adding 150 ml of cooled, saturated aqueous ammonium chloride solution, and the organic phase was separated off. The aqueous phase was extracted 3 with ethyl acetate and the combined organic phases were washed once with water and once with saturated aqueous sodium chloride solution. Drying using sodium sulphate and removal of the solvent gave 9.76 g or product (58% of theory), which was further reacted directly.

(290) LCMS (Method 1): R.sub.t=1.03 min; m/z=225 (M+H).sup.+; 207 (MH.sub.2O+H).sup.+

(291) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.03 (d, 6H), 1.51 (s, br, 1H), 1.72-1.84 (m, 1H), 2.56 (dd, 1H), 2.84 (dd, 1H), 3.58 (m, 1H), 3.89 (s, 3H), 3.91 (s, 3H), 6.74-6.88 (m, 3H).

(292) The following compounds were prepared analogously to Example 41A from Example 108A and Example 109A, respectively, and 4-bromobenzaldehyde:

(293) TABLE-US-00024 No. Structure Name Analytical data 110A 1-(4-bromophenyl)-3- ethyl-6,7-dimethoxy- 3,4-dihydro-1H- isochromene LCMS (Method 1): R.sub.t = 1.53 min; m/z = 377; 379 (Br isotope pattern, M + H).sup.+ 111A 1-(4-bromophenyl)-3- isopropyl-6,7- dimethoxy-3,4- dihydro-1H- isochromene LCMS (Method 5): R.sub.t = 1.58 min; m/z = 391; 393 (Br isotope pattern, M + H).sup.+

(294) The following diketones were prepared analogously to Example 43A:

(295) TABLE-US-00025 No. Structure Name Analytical data 112A 1-[2-(4- bromobenzoyl)-4,5- dimethoxyphenyl]butan- 2-one .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.06 (t, 3H), 2.54 (q, 2H), 3.80 (s, 3H), 3.92 (s, 2H), 3.97 (s, 3H), 6.78 (s, 1H), 6.92 (s, 1H), 7.63 (d, 2H), 7.68 (d, 2H). LCMS (Method 1): R.sub.t = 1.33 min; m/z = 391; 393 (M + H, Br isotope pattern).sup.+ 113A 1-[2-(4- bromobenzoyl)-4,5- dimethoxyphenyl]-3- methylbutan-2-one .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.12 (d, 6H), 2.69-2.80 (m, 1H), 3.80 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 6.77 (s, 1H), 6.91 (s, 1H), 7.62 (d, 2H), 7.68 (d, 2H). LCMS (Method 1): R.sub.t = 1.59 min; m/z = 407, 409 (M + H, Br isotope pattern).sup.+ 114A 0 1-[5-bromo-2-(4- chlorbenzoyl)phenyl] acetone .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.19 (s, 3H), 4.00 (s, 2H), 7.24 (d, 1H), 7.40-7.51 (m, 4H), 7.73 (d, 2H). LCMS (Method 2): R.sub.t = 1.40 min; m/z = 351, 353 (M + H, Br isotope pattern).sup.+ 115A 1-[4-chloro-2-(4- chlorobenzoyl)-5- (trifluoromethoxy) phenyl]acetone .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.20 (s, 3H), 4.04 (s, 2H), 7.21 (s, br, 1H), 7.45-7.52 (m, 3H), 7.77 (d, 2H). LCMS (Method 2): R.sub.t = 1.40 min; m/z = 391, 393 (M + H, Cl isotope pattern).sup.+ 116A 1-[2-(4-chlorobenzoyl)- 4-methoxy-5- (trifluoromethoxy) phenyl]acetone .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.19 (s, 3H), 3.83 (s, 3H), 3.95 (s, 2H), 6.99 (s, 1H), 7.15 (s, 1H), 7.49 (d, 2H), 7.81 (d, 2H). LCMS (Method 1): R.sub.t = 1.44 min; m/z = 387 (M + H).sup.+

(296) The following benzodiazepines were prepared analogously to Example 45A, but at RT and without introduction of hydrogen chloride gas:

(297) TABLE-US-00026 No. Structure Name Analytical data 117A 1-(4-bromophenyl)-4- ethyl-7,8-dimethoxy- 5H-2,3-benzodiazepine .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.20 (t, 3H), 2.40-2.58 (m, 2H), 2.99 (d, 1H), 3.32 (d, 1H), 3.77 (s, 3H), 3.99 (s, 3H), 6.74 (s, 1H), 6.77 (s, 1H), 7.56 (d, 2H), 7.62 (d, 2H). LCMS (Method 2): R.sub.t = 1.19 min; m/z = 387, 389 (Br isotope pattern, M + H).sup.+ 118A 1-(4-bromophenyl)-4- isopropyl-7,8- dimethoxy-5H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.19 (d, 3H), 1.24 (d, 3H), 2.71 (m, 1H), 2.93 (d, 1H), 3.43 (d, 1H), 3.78 (s, 3H), 3.98 (s, 3H), 6.75 (s, 1H), 6.77 (s, 1H), 7.56 (d, 2H), 7.61 (d, 2H). LCMS (Method 5): R.sub.t = 1.28 min; m/z = 401, 403 (Br isotope pattern, M + H).sup.+ 119A 7-bromo-1-(4- chlorophenyl)-4- methyl-5H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.27 (s, 3H), 3.13 (d, 1H), 3.40 (d, 1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.51 (s, 1H), 7.55 (d, 1H), 7.61 (d, 2H). LCMS (Method 2): R.sub.t = 1.41 min; m/z = 347, 349 (Br isotope pattern, M + H).sup.+ 120A 8-chloro-1-(4- chlorophenyl)-4- methyl-7- (trifluoromethoxy)-5H- 2,3-benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 2.20 (s, 3H), 3.11 (d, 1H), 3.41 (d, 1H), 7.30 (s, 1H), 7.45 (d, 2H), 7.47 (s, 1H), 7.62 (d, 2H). LCMS (Method 1): R.sub.t = 1.55 min; m/z = 387, 389 (Cl isotope pattern, M + H).sup.+ 121A 1-(4-chlorophenyl)-8- methoxy-4-methyl-7- (trifluoromethoxy)-5H- 2,3-benzodiazepine LCMS (Method 1): R.sub.t = 1.44 min; m/z = 383 (M + H).sup.+

(298) The following amines were prepared analogously to Example 47A from the corresponding 5H-2,3-benzodiazepines:

(299) TABLE-US-00027 No. Structure Name Analytical data 122A ()-1-(4-bromophenyl)- 4-ethyl-7,8-dimethoxy- 4,5-dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.04 (t, 3H), 1.56-1.71 (m, 2H), 2.66 (dd, 1H), 2.91 (dd, 1H), 3.73 (s, 3H), 3.87 (quin, 1H), 3.97 (s, 3H), 5.48 (s, br, 1H), 6.60 (s, 1H), 6.78 (s, 1H), 7.46 (d, 2H), 7.52 (d, 2H). LCMS (Method 2): R.sub.t = 0.96 min; m/z = 389, 391 (Br isotope pattern, M + H).sup.+ 123A ()-1-(4-bromophenyl)- 4-isopropyl-7,8- dimethoxy-4,5- dihydro-3H-2,3- benzodiazepine LCMS (Method 5): R.sub.t = 1.17 min; m/z = 403, 405 (Br isotope pattern, M + H).sup.+ 124A 0 ()-7-bromo-1-(4- chlorophenyl)-4- methyl-4,5-dihydro- 3H-2,3-benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.29 (d, 3H), 2.65 (dd, 1H), 2.93 (dd, 1H), 4.04-4.17 (m, 1H), 6.97 (d, 1H), 7.30- 7.51 (m, 6H). LCMS (Method 2): R.sub.t = 1.43 min; m/z = 349, 351 (Br isotope pattern, M + H).sup.+ 125A ()-8-chloro-1-(4- chlorophenyl)-4- methyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.34 (d, 3H), 2.72 (dd, 1H), 2.99 (dd, 1H), 4.07-4.21 (m, 1H), 7.24 (s, 1H), 7.29 (s, 1H), 7.39 (d, 2H), 7.49 (d, 2H). LCMS (Method 2): R.sub.t = 1.63 min; m/z = 389, 391 (Cl isotope pattern, M + H).sup.+ 126A ()-1-(4-chlorophenyl)- 8-methoxy-4-methyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine LCMS (Method 3): R.sub.t = 1.63 min; m/z = 385 (M + H).sup.+

(300) The following compounds were prepared analously to Example 49A from the corresponding 4,5-dihydro-3H-2,3-benzodiazepines:

(301) TABLE-US-00028 No. Structure Name Analytical data 127A ()-1-(4-bromophenyl)- 4-ethyl-7,8-dimethoxy- N-methyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.86 (t, 3H), 1.04-1.17 (m, 1H), 1.32-1.44 (m, 1H), 2.91 (d, 3H), 3.01 (dd, 1H), 3.08 (dd, 1H), 3.68 (s, 3H), 3.95 (s, 3H), 5.27-5.36 (m, 1H), 6.58 (s, 1H), 6.68 (q, 1H), 6.73 (s, 1H), 7.37 (d, 2H), 7.54 (d, 2H). LCMS (Method 2): R.sub.t = 1.53 min; m/z = 446; 448 (Br isotope pattern, M + H).sup.+ 128A ()-1-(4-bromophenyl)- 4-isopropyl-7,8- dimethoxy-N-methyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.84 (d, 3H), 0.86 (d, 3H), 0.97 (t, 1H), 2.90 (d, 3H), 3.01 (dd, 1H), 3.15 (dd, 1H), 3.67 (s, 3H), 3.95 (s, 3H), 5.16- 5.32 (m, 1H), 6.61 (s, 1H), 6.66 (q, 1H), 6.75 (s, 1H), 7.36 (d, 2H), 7.55 (d, 2H). LCMS (Method 5): R.sub.t = 1.40 min; m/z = 460; 462 (Br isotope pattern, M + H).sup.+ 129A ()-7-bromo-1-(4- chlorophenyl)-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.93 (d, 3H), 2.84-2.94 (m, 4H), 3.11 (d, 1H), 5.44-5.56 (m, 1H), 6.44-6.55 (m, 1H), 6.95 (d, 1H), 7.33 (dd, 1H), 7.36-7.42 (m, 5H). LCMS (Method 1): R.sub.t = 1.51 min; m/z = 406; 408 (Br isotope pattern, M + H).sup.+ 130A ()-8-chloro-1-(4- chlorophenyl)-N,4- dimethyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.95 (d, 3H), 2.92 (d, 3H), 2.96 (dd, 1H), 3.16 (dd, 1H), 5.51-5.60 (m, 1H), 6.50 (q, 1H), 7.22 (dd, 1H), 7.23 (s, 1H), 7.40 (d, 2H), 7.43 (d, 2H). LCMS (Method 1): R.sub.t = 1.61 min; m/z = 446; 448 (Cl isotope pattern, M + H).sup.+ 131A (4S)-8-chloro-1-(4- chlorophenyl)-N,4- dimethyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method VIIIa Analyt. HPLC (Method Da): R.sub.t = 2.37 min [].sub.D.sup.20 = +73.0 (c = 1.00; MeOH) LCMS (Method 2): R.sub.t = 1.64 min; m/z = 446; 448 (Cl isotope pattern, M + H).sup.+ 132A ()-1-(4-chlorophenyl)- 8-methoxy-N,4- dimethyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.96 (d, 3H), 2.88 (dd, 1H), 2.92 (d, 3H), 3.12 (dd, 1H), 3.69 (s, 3H), 5.44-5.54 (m, 1H), 6.46-6.54 (m, 1H), 6.71 (s, 1H), 7.12 (s, 1H), 7.41 (d, 2H), 7.46 (d, 2H). LCMS (Method 1): R.sub.t = 1.50 min; m/z = 442 (M + H).sup.+

Example 133A

()-1-[1-(4-Bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl]ethanone

(302) ##STR00159##

(303) 274 mg (0.73 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine (Example 47A) were admixed with 7 ml (73 mmol) of acetic anhydride and stirred at a jacket temperature of 140 C. for 1 hour. After this mixture had cooled, 25 ml of saturated sodium hydrogencarbonate solution were added. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried using sodium sulphate, and the solvent was removed on a rotary evaporator. The residue was purified by chromatography. This gave 195 mg (64% of theory) of the product as a brown oil.

(304) LCMS (Method 1): R.sub.t=1.29 min; m/z=417/419 (M+H).sup.+, Br isotope pattern.

(305) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.19 (d, 3H), 2.22 (s, 3H), 2.76 (dd, 1H), 2.95 (dd, 1H), 3.74 (s, 3H), 3.97 (s, 3H), 5.33-5.42 (m, 1H), 6.57 (s, 1H), 6.80 (s, 1H), 7.53 (d, 2H), 7.59 (d, 2H).

Example 134A

()-4-[7,8-Dimethoxy-4-methyl-3-[(methylamino)carbonyl]-4,5-dihydro-3H-2,3-benzodiazepin-1-yl]benzoic acid

(306) ##STR00160##

(307) 5.03 g (11.64 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) were suspended in 65 ml of dimethyl sulphoxide and admixed with 1.33 g (2.33 mmol) of 1,1-bis(diphenylphosphino)ferrocene (CAS [12150-46-8]), 130 mg (0.58 mmol) of palladium(II) acetate and 4.5 g (46.5 mmol) of potassium acetate. The mixture was exposed for half an hour at room temperature to a carbon monoxide pressure of 19 bar, with stirring. It was then let down, evacuated, and at 100 C. again stirred under a carbon monoxide pressure of 20 bar for 20 hours. It was worked up by filtration, washing with ethyl acetate, washing of the organic phase three times with saturated aqueous sodium chloride solution, drying using sodium sulphate, and removal of the solvent on a rotary evaporator. The residue was purified by chromatography. This gave 466 mg (10% of theory) of the product as a dark solid.

(308) LCMS (Method 3): R.sub.t=0.96 min; m/z=398 (M+H).sup.+.

(309) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.96 (d, 3H), 2.89 (dd, 1H), 2.91 (d, 3H), 3.17 (dd, 1H), 3.64 (s, 3H), 3.94 (s, 3H), 5.52 (m, 1H), 6.53 (s, 1H), 6.58 (m, 1H), 6.72 (s, 1H), 7.58 (d, 2H), 8.13 (d, 2H).

Example 135A

7,8-Dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-5H-2,3-benzodiazepine

(310) ##STR00161##

(311) The compound was prepared analogously to Example 7 from 1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine (Example 45A).

(312) LCMS (Method 3): R.sub.t=0.71 min; m/z=393 (M+H)

(313) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =2.02 (s, 3H), 2.22 (s, 3H), 2.45 (m, 4H), 2.73 (d, 1H), 3.23 (m, 4H), 3.38 (d, 1H), 3.62 (s, 3H), 3.86 (s, 3H), 6.74 (s, 1H), 6.96 (d, 2H), 7.05 (s, 1H), 7.45 (d, 2H).

Example 136A

()-7,8-Dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine

(314) ##STR00162##

(315) The compound was prepared analogously to Example 7 from 7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-5H-2,3-benzodiazepine (Example 135A).

(316) LCMS (Method 3): R.sub.t=0.57 min; m/z=395 (M+H)

(317) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.09 (s, 3H), 2.21 (s, 3H), 2.41 (m, 1H), 2.43 (m, 4H), 2.74 (dd, 1H), 3.17 (m, 4H), 3.58 (s, 3H), 3.81 (s, 3H), 3.88 (m, 1H), 6.18 (m, 1H), 6.53 (s, 1H), 6.89 (d, 2H), 6.90 (s, 1H), 7.34 (d, 2H).

Example 137A

()-1-(4-Bromophenyl)-N-ethyl-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(318) ##STR00163##

(319) A solution of 150 mg (0.4 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine (Example 47A) in 6 ml of dichloromethane was admixed at RT with 56.8 mg (0.8 mmol) of ethyl isocyanate and stirred at this temperature for 16 h. The batch was freed from the solvent on a rotary evaporator and the residue was purified by means of preparative HPLC. This gave 120 mg (67% of theory) of the title compound as a solid.

(320) LCMS (Method 5): R.sub.t=1.35 min; m/z=446; 448 (Br isotope pattern, M+H).sup.+

(321) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.96 (d, 3H), 1.18 (t, 3H), 2.84 (dd, 1H), 3.12 (dd, 1H), 3.29-3.39 (m, 2H), 3.66 (s, 3H), 3.93 (s, 3H), 5.40-5.50 (m, 1H), 6.53 (t, 1H), 6.55 (s, 1H), 6.71 (s, 1H), 7.36 (d, 2H), 7.53 (d, 2H).

(322) The compounds 49.1A; 49.2A; 50A; 51A; 52A; 52.1A; 52.2A; 54A; 55A; 60A; 83A; 83.1A; 83.2A; 84A; 84.1A; 84.2A; 85A; 85.1A; 85.2A; 87A to 93A and 95A to 97A; 127A to 133A and 137A, mentioned in the examples above, are thus useful selected intermediates of the general formula (Ia), which are used with preference in the preparation of the compounds according to the invention.

(323) The invention therefore also provides the intermediates of the general formula Ia according to the invention: (4R)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(3-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4R)-8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-1-(4-bromophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-chlorophenyl)-8-hydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(3-bromo-4-fluorophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-8-tert-butyl-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-8-tert-butyl-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4R)-8-tert-butyl-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-8-chloro-1-(4-chlorophenyl)-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-8-chloro-1-(4-chlorophenyl)-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4R)-8-chloro-1-(4-chlorophenyl)-7-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-chlorophenyl)-N,4,8-trimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-1-(4-chlorophenyl)-N,4,8-trimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4R)-1-(4-chlorophenyl)-N,4,8-trimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-8-amino-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-[8-tert-butyl-1-(4-chlorophenyl)-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl]ethanone ()-8-acetamido-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7-hydroxy-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7,8-dihydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7,8-bis(difluoromethoxy)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7,8-diethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-7-bromo-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-chlorophenyl)-7-cyano-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-7-(difluoromethoxy)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-4-ethyl-7,8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-bromophenyl)-4-isopropyl-7,8-dimethoxy-N-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-7-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-8-chloro-1(4-chlorophenyl)-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (4S)-8-chloro-1(4-chlorophenyl)-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-(4-chlorophenyl)-8-methoxy-N,4-dimethyl-7-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide ()-1-[1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl]ethanone ()-1-(4-bromophenyl)-N-ethyl-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

Preparation of the Compounds of the General Formula I According to the Invention

Example 1

()-1-(4-Chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(324) ##STR00164##

(325) 145 mg (3.64 mmol) of sodium hydroxide were dissolved in 8.7 ml of water, and a solution of 860 mg (2.42 mmol) of ()-1-(4-chlorophenyl)-4-methyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine (Example 35A) in 35 ml of ethyl acetate was added at 0 C. After 20 min of stirring at 0 C., 877 mg (7.27 mmol, 0.80 ml) of isopropenyl chloroformate (CAS [57933-83-2]) were added, and the mixture was stirred vigorously at 0 C. for 2.5 h. The phases were then separated, and the organic phase was dried with sodium sulphate and evaporated to dryness. The residue was dissolved in 35 ml of THF, and 2 mg (0.02 mmol) of 1-methylpyrrolidine and 6.1 ml (12.1 mmol) of a 2M solution of methylamine in THF were added. In a sealed pressure tube, the reaction mixture was stirred at 70 C. for a total of 10 h. After 5 h, the reaction was interrupted, the mixture was cooled and a further 6.1 ml of methylamine solution were added and the mixture was heated at 70 C. for another 5 h. At RT, the mixture was then partitioned between water and ethyl acetate, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 540 mg (54% of theory) of the desired product as a yellow oil which, after concentration from dichloromethane, was obtained as a solid foam. Also isolated were 428 mg (36% of theory) of the intermediate isopropenyl 1-(4-chlorophenyl)-4-methyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxylate. (LCMS byproduct (Method 2): R.sub.t=1.60 min; m/z=439 (M+H).sup.+).

(326) Analysis of the title compound: LCMS (Method 2): R.sub.t=1.53 min; m/z=412; 414 (Cl isotope pattern, M+H).sup.+

(327) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.91 (d, 3H), 2.90 (d, 3H), 2.96 (dd, 1H), 3.14 (dd, 1H), 5.46-5.55 (m, 1H), 6.47-6.52 (m, 1H), 6.94 (s, br, 1H), 7.17-7.29 (m, 2H), 7.39 (s, 4H).

Enantiomer Separation

(328) By chiral preparative HPLC, 488 mg of ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 1) were separated into the enantiomers under the following conditions:

(329) System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501; column: Chiralpak IC 5 m 25030 mm; mobile phase: hexane/2-propanol 80:20 (v/v); flow rate: 50 ml/min; temperature: RT; solution: 488 mg/8 ml of DCM/EtOH; injection: 160.5 ml; detection: UV 254 nm.

Example 1.1: (4S)-1-(4-Chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(330) 224 mg, HPLC (Method A): R.sub.t=3.31 min, purity>99.9%

(331) Optical rotation: [].sub.D.sup.20=265.90.21 (c=1.00; chloroform)

Example 1.2: (4R)-1-(4-Chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(332) 231 mg, HPLC (Method A): R.sub.t=4.18 min, purity 99.5%

(333) Optical rotation: [].sub.D.sup.20=+254.70.16 (c=1.00; chloroform)

Example 2

()-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(334) ##STR00165##

(335) 1.13 g (2.61 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) were dissolved in 18 ml of 1,4-dioxane, and 932 mg (6.61 mmol) of 3,5-dimethylisoxazole-4-boronic acid (CAS [16114-47-9]), 2.90 ml of 1.5 M aqueous potassium carbonate solution and 363 mg (0.44 mmol) of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (complex with CH.sub.2Cl.sub.2, CAS [95464-05-4]) were added. The mixture was divided into 3 portions, and each portion was irradiated in a microwave reactor at 130 C. for in each case 15 min. The divided reactions were combined again and concentrated to dryness on a rotary evaporator. The residue was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 900 mg (73% of theory) of the desired product as a brown foam.

(336) LCMS (Method 2): R.sub.t=1.22 min; m/z=449 (M+H).sup.+

(337) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.97 (d, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.65 (d, 3H), 2.61-2.67 (m, 1H), 2.91 (dd, 1H), 3.56 (s, 3H), 3.81 (s, 3H), 4.99-5.08 (m, 1H), 6.54 (s, 1H), 6.56 (q, 1H), 7.01 (s, 1H), 7.41 (d, 2H), 7.74 (d, 2H).

Enantiomer Separation

(338) By preparative chiral HPLC, 900 mg of ()-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 2) were separated into the enantiomers under the following conditions:

(339) System: Agilent: Prep 1200, 2 Prep Pump G1361A, DLA G2258A, MWD G1365D, Prep FC G1364B; column: Chiralpak ID 5 m 25020 mm; mobile phase: hexane/isopropanol 70:30 (v/v); flow rate: 40 ml/min; temperature: RT; solution: 900 mg/6 ml of MeOH/MeCl; injection: 120.1 ml, 130.2 ml; detection: UV 280 nm.

Example 2.1: (4R)-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(340) 324 mg, colourless solid, HPLC (Method B): R.sub.t=7.6 min, purity>99%

(341) Optical rotation: [].sub.D.sup.20=150.90.08 (c=1.06; methanol)

Example 2.2: (4S)-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(342) 321 mg, colourless solid, HPLC (Method B): R.sub.t=9.0 min, purity 98.6%

(343) Optical rotation: [].sub.D.sup.20=+148.00.08 (c=1.03; methanol)

(344) The absolute stereochemistry of Example 2.2 was determined by X-ray structural analysis of the complex from Example 2.2 and of the bromodomain 1 of BRD4.

Example 3

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(1H-pyrazol-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(345) ##STR00166##

(346) Analogously to Example 2, the reaction was carried out using 100 mg (231 mol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A), 2 ml of 1,4-dioxane, 65 mg (585 mol) of 1H-pyrazole-5-boronic acid (CAS [376584-63-3]), 0.25 ml of 1.5 M aqueous potassium carbonate solution and 32 mg (0.44 mmol) of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (complex with CH.sub.2Cl.sub.2, CAS [95464-05-4]). This gave 55 mg (56% of theory) of the product.

(347) LCMS (Method 2): R.sub.t=1.04 min; m/z=420 (M+H).sup.+

(348) 1H-NMR (300 MHz, DMSO-d.sub.6): =0.97 (d, 3H), 2.61-2.67 (m, 1H), 2.65 (d, 3H), 2.91 (dd, H), 3.54 (s, 3H), 3.81 (s, 3H), 4.99-5.08 (m, 1H), 6.50-6.53 (m, 2H), 7.76-7.78 (m, 1H), 7.00 (s, 1H), 7.66 (d, 2H), 7.73-7.75 (m, 1H), 7.84 (s, 2H), 12.92 (br, 1H).

(349) The following exemplary compounds were prepared analogously to Example 2 from Example 49A and the appropriate commercially available boronic acid derivatives:

(350) TABLE-US-00029 No Structure Name Analytical data 4 ()-1-[4-(2- chloropyridin-3- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d6): = 0.96 (d, 3H), 2.65 (d, 3H), 2.66-2.71 (m, 1H), 2.93 (dd, H), 3.55 (s, 3H), 3.81 (s, 3H), 5.00-5.11 (m, 1H), 6.54 (s, 1H), 6.60 (q, 1H), 7.01 (s, 1H), 7.52 (d, 2H), 7.51-7.55 (m, 1H), 7.76 (d, 2H), 7.92 (dd, 1H), 8.43 (dd, 1H). LCMS (Method 2): R.sub.t = 1.24 min; m/z = 465 (M + H).sup.+ 4.1 (R)-1-[4-(2- chloropyridin-3- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XXII analyt. HPLC (Method B): R.sub.t = 7.75 min 4.2 (S)-1-[4-(2-chloropyridin- 3-yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XXII analyt. HPLC (Method B): R.sub.t = 8.89 min 5 0 ()-5-(4-{7,8-dimethoxy- 4-methyl-3- [(methylamino)carbonyl]- 4,5-dihydro-3H-2,3- benzodiazepin-1- yl}phenyl)thiophene-2- carboxylic acid LCMS (Method 2): R.sub.t = 1.15 min; m/z = 480 (M + H).sup.+ 6 ()-4-{7,8-dimethoxy-4- methyl-3- [(methylamino)carbonyl]- 4,5-dihydro-3H-2,3- benzodiazepin-1- yl}biphenyl-2-carboxylic acid LCMS (Method 2): R.sub.t = 1.19 min; m/z = 474 (M + H).sup.+

Example 7

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(351) ##STR00172##

(352) 100 mg (231 mol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) were dissolved in 2 ml of toluene, and 24 mg (278 mol) of morpholine, 56 mg (578 mol) of sodium tert-butoxide, 2 mg (2 mol) of tris(dibenzylideneacetone)dipalladium(0) (CAS [51364-51-3]) and 5.5 mg (12 mol) of 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl (CAS [564483-18-7]) were added. The mixture was irradiated in a microwave reactor at 130 C. for 15 min. The catalyst was filtered off, the filtrate was evaporated to dryness on a rotary evaporator and the residue was purified by preparative HPLC. This gave 7 mg (9% of theory) of the desired product as a colourless solid.

(353) LCMS (Method 2): R.sub.t=1.09 min; m/z=439 (M+H).sup.+

(354) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.02 (d, 3H), 2.39-2.44 (m, 1H), 2.60 (d, 3H), 2.81 (dd, H), 3.14-3.22 (m, 4H), 3.58 (s, 3H), 3.68-3.74 (m, 4H), 3.80 (s, 3H), 4.82-4.94 (m, 1H), 6.27 (q, 1H), 6.51 (s, 1H), 6.93 (d, 2H), 6.99 (s, 1H), 7.57 (s, 2H).

Example 8

()-1-(4-Chlorophenyl)-N,4-dimethyl-8-(pyridin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(355) ##STR00173##

(356) 100 mg (246 mol) of 8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 52A) were dissolved in 1.3 ml of toluene and 0.2 ml of water, and 30 mg (246 mol) of pyridine-4-boronic acid (CAS [1692-15-5]), 51 mg (369 mol) of potassium carbonate and 18 mg (25 mol) of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (CAS [95464-05-4]) were added. The mixture was stirred at 70 C. for 16 h. Sat. sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator. The brown residue (88 mg) was purified by preparative HPLC. This gave 6.8 mg (7% of theory) of the desired product as a slightly yellowish solid.

(357) UPLC/MS (Method 3): R.sub.t=1.03 min; m/z=405 (M+H).sup.+

(358) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.97 (d, 3H), 2.91 (d, 3H), 2.99 (dd, 1H), 3.19 (dd, 1H), 5.47-5.57 (m, 1H), 6.48 (q, 1H), 7.33-7.49 (m, 8H), 7.61 (dd, 1H), 8.62 (d, 2H).

(359) The following exemplary compounds were prepared analogously to Example 8 from Example 52A and the appropriate commercially available boronic acid derivatives:

(360) TABLE-US-00030 No Structure Name Analytical data 9 ()-1-(4-chlorophenyl)-8- cyclopropyl-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide LCMS (Method 3): R.sub.t = 1.54 min; m/z = 368 (M + H).sup.+ .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.53- 0.58 (m, 2H), 0.86-0.94 (m, 2H), 0.93 (d, 3H), 1.73-1.82 (m, 1H), 2.85 (dd, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 5.47-5.48 (m, 1H), 6.40-6.46 (m, br, 1H), 6.78 (d, 1H), 7.00 (dd, 1H), 7.11 (d, 1H), 7.35-7.44 (m, 4H). 10 ()-1-(4-chlorophenyl)- N,4-dimethyl-8-{4- [(methylamino)sulphonyl] phenyl}-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide LCMS (Method 3): R.sub.t = 1.32 min; m/z = 497 (M + H).sup.+ .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.69 (d, 3H), 2.91 (d, 3H), 2.99 (dd, 1H), 3.19 (dd, 1H), 3.09 (dd, 1H), 4.26 (q, 1H), 5.47- 5.56 (m, 1H), 6.48 (q, 1H), 7.30- 7.48 (m, 6H), 7.55-7.61 (m, 3H), 7.88 (d, 2H).

Example 11

()-1-(4-Chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(361) ##STR00176##

(362) 200 mg (492 mol) of 8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 52A) were dissolved in 4 ml of toluene, and 52 mg (590 mol) of morpholine, 118 mg (1.23 mmol) of sodium tert-butoxide, 4.5 mg (5 mol) of tris(dibenzylideneacetone)dipalladium(0) (CAS [51364-51-3]) and 15 mg (25 mol) of (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (CAS [98327-87-8]) were added. Sat. sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by flash chromatography. This gave 44 mg (22% of theory) of the desired product as an orange foam.

(363) LCMS (Method 2): R.sub.t=1.33 min; m/z=413 (M+H).sup.+

(364) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.93 (d, 3H), 2.82 (dd, 1H), 2.88 (d, 3H), 2.81 (dd, H), 2.97-3.00 (m, 4H), 3.07 (dd, 1H), 3.78-3.81 (m, 4H), 5.35-5.45 (m, 1H), 6.44 (q, br, 1H), 6.58 (d, 1H), 6.89 (dd, 1H), 7.12 (d, 1H), 7.36 (d, 2H), 7.44 (d, 2H).

Enantiomer Separation

(365) By chiral preparative HPLC, 14 mg of ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 11) were separated into the enantiomers under the following conditions:

(366) System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501; column: Chiralpak IC 5 m 25020 mm; mobile phase: ethanol/methanol 50:50 (v/v); flow rate: 15 ml/min; temperature: RT; solution: 14 mg/1.2 ml of EtOH/MeOH; injection: 11.2 ml; detection: UV 254 nm.

Example 11.1: (4S)-1-(4-Chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(367) 6 mg, colourless solid, HPLC (Method E): R.sub.t=2.88 min, purity 99.9%

Example 11.2: (4R)-1-(4-Chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(368) 6 mg, colourless solid, HPLC (Method E): R.sub.t=3.22 min, purity 97.1%

Example 12

()-1-(4-Chlorophenyl)-N,4-dimethyl-8-(4-methylpiperazin-1-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(369) ##STR00177##

(370) 100 mg (246 mol) of 8-bromo-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 52A) were dissolved in 2 ml of 1,4-dioxane, and 30 mg (295 mol) of 1-methylpiperazine (CAS [109-01-3]), 33 mg (34 mol) of sodium tert-butoxide, 11 mg (12 mol) of tris(dibenzylideneacetone)dipalladium(0) (CAS [51364-51-3]) and 6 mg (12 mol) of Xphos (=2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl, CAS [564483-18-7]) were added. The mixture was irratiated in a microwave reactor (150 W) at 130 C. for 15 min Sat. sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by preparative HPLC. This gave 7 mg (7% of theory) of the desired product as a slightly yellow solid.

(371) LCMS (Method 3): R.sub.t=0.91 min; m/z=426 (M+H).sup.+

(372) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.94 (d, 3H), 2.32 (s, 3H), 2.50-2.53 (m, 4H), 2.81 (dd, 1H), 2.88 (d, 3H), 3.00-3.09 (m, 5H), 5.33-5.45 (m, 1H), 6.38-6.46 (m, 1H), 6.60 (d, 1H), 6.90 (dd, 1H), 7.11 (d, 1H), 7.36 (d, 2H), 7.45 (d, 2H).

(373) The following exemplary compound was prepared analogously to Example 12 from Example 52A and the appropriate commercially available amine:

(374) TABLE-US-00031 No Structure Name Analytical data 13 ()-1-(4-chlorophenyl)- N,4-dimethyl-8- (piperidin-1-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.35 min; m/z = 411 (M + H).sup.+ .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.94 (d, 3H), 1.55-1.69 (m, 5H), 2.79 (dd, 1H), 2.88 (d, 3H), 2.96-3.00 (m, 4H), 3.05 (dd, 1H), 5.33-5.43 (m, 1H), 6.38-6.45 (m, 1H), 6.60 (d, 1H), 6.92 (dd, 1H), 7.09 (d, 1H), 7.36 (d, 2H), 7.45 (d, 2H).

Example 14

()-8-Methoxy-N,4-dimethyl-1-(pyridin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(375) ##STR00179##

(376) The compound was prepared analogously to Example 49A from 155 mg (0.48 mmol) of crude 8-methoxy-4-methyl-1-(pyridin-3-yl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 37A), 230 mg (1.16 mmol) of 4-nitrophenyl chloroformate and 3.0 ml of 2M methylamine solution in 8 ml of THF. This gave 26 mg (about 13% of theory) of product as an orange foam.

(377) UPLC/MS (Method 3): R.sub.t=0.97 min; m/z=325 (M+H).sup.+

(378) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.90 (d, 3H), 2.90 (d, 3H), 2.91 (dd, 1H), 3.14 (dd, 1H), 3.69 (s, 3H), 5.47-5.53 (m, 1H), 6.51-6.60 (m, 1H), 6.60 (d, 1H), 6.89 (dd, 1H), 7.15 (d, 1H), 7.29-7.33 (m, 1H), 7.71-7.75 (m, 1H), 8.62 (dd, 2H), 8.77 (d, 1H).

(379) The following exemplary compound was prepared analogously to Example 49A from the appropriate 4,5-dihydro-3H-2,3-benzodiazepine:

(380) TABLE-US-00032 No Structure Name Analytical data 15 0 ()-7-chloro-1-(4- chlorophenyl)-N,4- dimethyl-8- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 0.86 (d, 3H), 2.65 (d, 3H), 2.87 (dd, 1H), 3.04 (dd, 1H), 5.11-5.21 (m, 1H), 6.81 (q, 1H), 7.06 (s, 1H), 7.45 (d, 2H), 7.60 (d, 2H), 7.75 (s, 1H). LCMS (Method 1): R.sub.t = 1.57 min; m/z = 446; 448 (Cl isotope pattern, M + H).sup.+

Enantiomer Separation

Preparative HPLC According to Method IV

Example 15.1: 7-Chloro-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, enantiomer 1

(381) HPLC (Method F): R.sub.t=2.86 min, purity>99%

Enantiomer 2: 7-Chloro-1-(4-chlorophenyl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide, enantiomer 2

(382) HPLC (Method F): R.sub.t=3.70 min, purity>99%

Example 16

(4S)-1-[4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(383) ##STR00181##

(384) Under argon, 100 mg (0.30 mmol) of (4S)-1-(4-aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 53.2A) were dissolved in 5 ml of concentrated hydrochloric acid, and the solution was cooled to 0 C. Over a period of 25 min, a solution of 24.5 mg sodium nitrite in 1 ml of water was metered in, and the mixture was stirred at this temperature for 30 min. A solution of 140 mg of tin(II) chloride in 1 ml of concentrated hydrochloric acid was then slowly added dropwise over a period of 30 min. The ice bath was removed and the mixture was stirred at RT for 45 min. 60.7 l (0.59 mmol) of 2,4-pentanedione were then added, and the mixture was stirred for 30 min Finally, 2 ml of acetonitrile were added, and the mixture was stirred at RT for 1 h. The reaction was poured into ice-water, the pH was adjusted to 10 using aqueous sodium hydroxide solution and the mixture was extracted three times with ethyl acetate. The solvent was removed on a rotary evaporator and the residue was purified by flash chromatography. This gave 79 mg (63% of theory) of the desired product.

(385) UPLC/MS (Method 2): R.sub.t=1.32 min; m/z=418 (M+H).sup.+

(386) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.95 (d, 3H), 2.32 (s, 3H), 2.37 (s, 3H), 2.86 (dd, 1H), 2.90 (d, 3H), 3.11 (dd 1H), 3.69 (s, 3H), 5.39-5.48 (m, 1H), 6.03 (s, 1H), 6.46-6.54 (m, 1H), 6.66 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.48 (d, 2H), 7.57 (d, 2H).

Example 17

(4S)-8-Methoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(387) ##STR00182##

(388) Under argon, 100 mg (0.30 mmol) of (4S)-1-(4-aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 53.2A) were dissolved in 4 ml of N,N-dimethylacetamide, and 103 mg (0.44 mmol) of 1-bromo-2-(2-bromoethoxyl)ethane and 0.1 ml (0.59 mmol) of diisopropylethylamine were added. The mixture was stirred at 120 C. for three days. The reaction was added to water and extracted three times with ethyl acetate. The solvent was removed on a rotary evaporator and the residue was purified by flash chromatography. This gave 95 mg (79% of theory) of the desired product.

(389) UPLC/MS (Method 2): R.sub.t=1.18 min; m/z=409 (M+H).sup.+

(390) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.07 (d, 3H), 2.72 (dd, 1H), 2.86 (d, 3H), 2.95 (dd, 1H), 3.25 (m 4H), 3.71 (s, 3H), 3.89 (m, 4H), 5.19-5.30 (m, 1H), 6.12 (m, 1H), 6.67 (d, 1H), 6.89 (dd, 1H), 6.92 (d, 2H), 7.15 (d, 1H), 7.51 (d, 2H).

Example 18

(4S)-1-[4-(4-Isoxazolyl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(391) ##STR00183##

(392) The reaction was carried out analogously to Example 3 using 100 mg (249 mol) of (4S)-1-(4-bromophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 54A), 3.6 ml of 1,4-dioxane, 56 mg (497 mol) of isoxazole-4-boronic acid (CAS [1008139-25-0]), 0.25 ml of 2 M aqueous potassium carbonate solution and 4 l mg (50 mol) of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (complex with CH.sub.2Cl.sub.2, CAS [95464-05-4]). This gave 6 mg (6% of theory) of the title compound.

(393) UPLC/MS (Method 3): R.sub.t=1.17 min; m/z=391 (M+H).sup.+

(394) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.94 (d, 3H), 2.87 (dd, 1H), 2.89 (d, 3H), 3.11 (dd, 1H), 3.69 (s, 3H), 5.43 (m, 1H), 6.51 (m, 1H), 6.65 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.51 (d, 2H), 7.55 (d, 2H), 8.60 (s, 1H), 8.73 (s, 1H).

(395) The following exemplary compounds were prepared analogously to Example 3 using the appropriate, commercially available boronic acids, from the compound obtained in Example 54A:

(396) TABLE-US-00033 No Structure Name Analytical data 19 (4S)-8-methoxy-N,4- dimethyl-1-[4-(1- methyl-1H-pyrazol-5- yl)phenyl]-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.95 (d, 3H), 2.87 (dd, 1H), 2.90 (d, 3H), 3.11 (dd, 1H), 3.71 (s, 3H), 3.95 (s, 3H), 5.44 (m, 1H), 6.36 (d, 1H), 6.52 (m, 1H), 6.68 (d, 1H), 6.90 (dd, 1H), 7.15 (d, 1H), 7.45 (d, 2H), 7.54 (d, 1H), 7.58 (d, 2H). UPLC/MS (Method 3): R.sub.t = 1.16 min; m/z = 404 (M + H).sup.+ 20 (4S)-1-[4-(3,5- dimethyl-4- isoxazolyl)phenyl]-8- methoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.86 (dd, 1H), 2.90 (d, 3H), 3.11 (dd, 1H), 3.72 (s, 3H), 5.42 (m, 1H), 6.48 (m, 1H), 6.70 (d, 1H), 6.90 (dd, 1H), 7.16 (d, 1H), 7.28 (d, 2H), 7.57 (d, 2H). UPLC/MS (Method 3): R.sub.t = 1.25 min; m/z = 419 (M + H).sup.+ 21 (4S)-8-methoxy-N,4- dimethyl-1-[4-(1- methyl-1H-pyrazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.82 (dd, 1H), 2.89 (d, 3H), 3.06 (dd, 1H), 3.69 (s, 3H), 3.97 (s, 3H), 5.38 (m, 1H), 6.42 (m, 1H), 6.68 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.48 (d, 2H), 7.51 (d, 2H), 7.66 (s, 1H), 7.80 (s, 1H). UPLC/MS (Method 3): R.sub.t = 1.08 min; m/z = 404 (M + H).sup.+ 22 (4S)-8-methoxy-N,4- dimethyl-1-[4-(1,3,5- trimethyl-1H-pyrazol- 4-yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.29 (s, 6H), 2.82 (dd, 1H), 2.90 (d, 3H), 3.07 (dd, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 5.38 (m, 1H), 6.41 (m, 1H), 6.73 (d, 1H), 6.90 (dd, 1H), 7.16 (d, 1H), 7.27 (d, 2H), 7.56 (d, 2H). UPLC/MS (Method 3): R.sub.t = 1.16 min; m/z = 432 (M + H).sup.+ 23 (4S)-8-methoxy-N,4- dimethyl-1-[4-(1H- pyrazol-5-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.85 (dd, 1H), 2.90 (d, 3H), 3.09 (dd, 1H), 3.68 (s, 3H), 5.41 (m, 1H), 6.49 (m, 1H), 6.68 (d, 1H), 6.68 (sbr, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.57 (d, 2H), 7.81 (d, 2H), 7.66 (sbr, 1H). UPLC/MS (Method 3): R.sub.t = 1.04 min; m/z = 390 (M + H).sup.+

(397) The following exemplary compound was prepared analogously to Example 16 starting with the aniline derivative 53.2A by reaction with the appropriate, commercially available diketones. The use of asymmetrical diketones results in each case in the formation of regioisomers which can be separated by preparative HPLC.

(398) TABLE-US-00034 No Structure Name Analytical data 24 (4S)-8-methoxy-N,4- dimethyl-1-[4-(1- methyl-1H-pyrazol-5- yl)phenyl]-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.46 min; m/z = 458 (M + H).sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.79- 0.84 (m, 2H), 0.95 (d, 3H), 0.97- 1.01 (m, 2H), 1.24 (t, 3H), 2.02-2.07 (m, 1H), 2.69 (q, 2H), 2.83-2.93 (m, 4H), 3.11 (dd, 1H), 3.69 (s, 3H), 5.39- 5.47 (m, 1H), 5.92 (s, 1H), 6.50 (m, 1H), 6.66 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.46 (d, 2H), 7.58 (d, 2H). 25 0 (4S)-1-[4-(5- cyclopropyl-3-ethyl- 1H-pyrazol-1- yl)phenyl]-8-methoxy- N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.47 min; m/z = 458 (M + H).sup.+. .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.79- 0.84 (m, 2H), 0.95 (d, 3H), 1.0-1.06 (m, 2H), 1.28 (t, 3H), 1.8-1.9 (m, 1H), 2.71 (q, 2H), 2.84-2.95 (m, 4H), 3.07-3.14 (m, 1H), 3.69 (s, 3H), 5.37-5.47 (m, 1H), 5.84 (s, 1H), 6.45- 6.54 (m, 1H), 6.66 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.59 (d, 2H), 7.67 (d, 2H). 26 (4S)-8-methoxy-1-{4- [3-(methoxymethyl)-5- methyl-1H-pyrazol-1- yl]phenyl}-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.25 min; m/z = 448 (M + H).sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.94 (d, 3H), 2.40 (s, 3H), 2.84-2.93 (m, 4H), 3.12 (dd, 1H), 3.45 (s, 3H), 3.69 (s, 3H), 4.52 (s, 2H), 5.44 (m, 1H), 6.28 (s, 1H), 6.51 (m, 1H), 6.66 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.48 (d, 2H), 7.59 (d, 2H). 27 (4S)-8-methoxy-1-{4- [5-(methoxymethyl)-3- methyl-1H-pyrazol-1- yl]phenyl}-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.28 min; m/z = 448 (M + H).sup.+. .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.95 (d, 3H), 2.36 (s, 3H), 2.82-2.93 (m, 4H), 3.10 (dd, 1H), 3.41 (s, 3H), 3.68 (s, 3H), 4.42 (dd, 2H), 5.37-5.48 (m, 1H), 6.29 (s, 1H), 6.49 (m, 1H), 6.67 (d, 1H), 6.89 (dd, 1H), 7.14 (d, 1H), 7.58 (d, 2H), 7.64 (d, 2H). 28 (4S)-1-{4-[5- cyclopropyl-3-(pyridin- 2-yl)-1H-pyrazol-1- yl]phenyl}-8-methoxy- N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.24 min; m/z = 507 (M + H).sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.88- 0.92 (m, 2H), 0.96 (d, 3H), 1.08- 1.13 (m, 2H), 1.90-1.96 (m, 1H), 2.85-2.94 (m, 4H), 3.13 (dd, 1H), 3.71 (s, 3H), 5.45 (m, 1H), 6.38 (s, 1H), 6.53 (m, 1H), 6.70 (d, 1H), 6.91 (dd, 1H), 7.16 (d, 1H), 7.47 (br. s., 1H), 7.64 (d, 2H), 7.74 (d, 2H), 8.32 (d, 1H), 8.59 (br s, 1H), 9.10 (br s, 1H). 29 (4S)-1-{4-[3- cyclopropyl-5-(pyridin- 2-yl)-1H-pyrazol-1- yl]phenyl}-8-methoxy- N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide UPLC/MS (Method 2): R.sub.t = 1.32 min; m/z = 507 (M + H).sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.85- 0.89 (m, 2H), 0.93 (d, 3H), 1.00- 1.06 (m, 2H), 2.07 (tt, 2H), 2.82- 2.91 (m, 4H), 3.08 (dd, 1H), 3.68 (s, 3H), 5.38-5.45 (m, 1H), 6.30 (s, 1H), 6.45 (m, 1H), 6.59 (d, 1H), 6.87 (dd, 1H), 7.12 (d, 1H), 7.28 (d, 2H), 7.32- 7.44 (m, 1H), 7.49 (d, 2H), 7.66 (d, 1H), 8.59 (br s, 1H).

Example 30

(4S)-8-Methoxy-N,4-dimethyl-1-[4-(1H-tetrazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(399) ##STR00195##

(400) Under argon, 100 mg (0.30 mmol) of (4S)-1-(4-aminophenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 53.2A) were stirred with 157 ml (0.95 mmol) of triethyl orthoformate, 271 ml (4.73 mmol) of acetic acid and 24 mg (0.37 mmol) of sodium azide at 80 C. for 3 hours. The reaction was poured into saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The solvent was removed on a rotary evaporator and the residue was purified by flash chromatography. This gave 74 mg (63% of theory) of the desired product.

(401) UPLC/MS (Method 3): R.sub.t=1.04 min; m/z=392 (M+H).sup.+

(402) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.91 (d, 3H), 2.92 (dd, 1H), 2.90 (d, 3H), 3.15 (dd, 1H), 3.70 (s, 3H), 5.50 (m, 1H), 6.55 (m, 1H), 6.61 (d, 1H), 6.90 (dd, 1H), 7.16 (d, 1H), 7.69 (d, 2H), 7.74 (d, 2H), 9.05 (s, 1H).

Example 31

()-1-[3-(3,5-Dimethylisoxazol-4-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(403) ##STR00196##

(404) The reaction was carried out analogously to Example 2 using 170 mg (393 mol) of ()-1-(3-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 51A), 4 ml of 1,4-dioxane, 111 mg (768 mol) of 3,5-dimethylisoxazole-4-boronic acid (CAS [16114-47-9]), 0.39 ml of 2 M aqueous potassium carbonate solution and 64 mg (79 mol) of dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) (complex with CH.sub.2Cl.sub.2, CAS [95464-05-4]). This gave 97 mg (54% of theory) of the title compound.

(405) UPLC/MS (Method 3): R.sub.t=1.16 min; m/z=449 (M+H).sup.+

(406) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.98 (d, 3H), 2.27 (s, 3H), 2.41 (s, 3H), 2.86 (dd, 1H), 2.89 (d, 3H), 3.13 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.46 (m, 1H), 6.52 (m, 1H), 6.61 (s, 1H), 6.73 (s, 1H), 7.29 (m, 1H), 7.33 (sbr, 1H), 7.47 (m, 1H), 7.51 (m, 1H).

Example 32

()-1-(4-Chlorophenyl)-N,4-dimethyl-8-[2-(morpholin-4-yl)ethoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(407) ##STR00197##

(408) 272 mg of caesium carbonate were added to a solution of 57.4 mg (167 mol) of ()-1-(4-chlorophenyl)-N,4-dimethyl-8-hydroxy-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 55A) in 5 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. 77.7 mg (417 mol) of 4-(2-chloroethyl)morpholine were then added. The mixture was stirred at 60 C. for 16 hours. For work-up, the reaction mixture was concentrated, water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated. Flash chromatography afforded 26 mg (33% of theory) of the title compound.

(409) UPLC/MS (Method 3): R.sub.t=0.88 min; m/z=457; 459 (M+H, Cl isotope pattern).sup.+

(410) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.92 (d, 3H), 2.53 (m, 4H), 2.73 (m, 2H), 2.85 (dd, 1H), 2.88 (d, 3H), 3.08 (dd, 1H), 3.72 (m, 4H), 3.97 (m, 2H), 5.42 (m, 1H), 6.60 (d, 1H), 6.88 (dd, 1H), 7.12 (d, 1H), 7.36 (d, 2H), 7.41 (d, 2H).

(411) The following exemplary compound was prepared analogously to Example 32 using the appropriate, commercially available heterocyclylchloroalkane:

(412) TABLE-US-00035 No Structure Name Analytical data 33 ()-1-(4-chlorophenyl)- N,4-dimethyl-8-[2- (pyrrolidin-1- yl)ethoxy]-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 1.81 (m, 4H), 2.63 (m, 4H), 2.85 (dd, 1H), 2.87 (m, 2H), 2.88 (d, 3H), 3.08 (dd, 1H), 4.00 (m, 2H), 5.42 (m, 1H), 6.45 (m, 1H), 6.61 (d, 1H), 6.90 (dd, 1H), 7.11 (d, 1H), 7.36 (d, 2H), 7.41 (d, 2H). UPLC/MS (Method 3): R.sub.t = 0.88 min; m/z = 457; 459 (M + H, Cl isotope pattern).sup.+

Example 34

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(2-oxooxazolidin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(413) ##STR00199##

(414) Under argon, 100 mg (0.231 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A), 22 mg (0.254 mmol) of oxazolidin-2-one, 98 mg (0.46 mmol) of potassium phosphate and 88 mg (0.46 mmol) of copper(I) iodide were initially charged in 4 ml of degassed dioxane. Under argon, 82 mg (0.93 mmol) of N,N-dimethylethylenediamine were then added, and the mixture was degassed again and heated at 130 C. for 3 hours. After cooling, ethyl acetate and saturated aqueous ammonium chloride solution were added to the mixture. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases dried with sodium sulphate. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC. This gave 50 mg (49% of theory) of the desired product as a solid.

(415) LCMS (Method 2): R.sub.t=1.0 min; m/z=439 (M+H).sup.+

(416) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.03 (d, 3H), 2.82 (dd, 1H), 2.88 (s, br, 3H), 3.08 (dd, 1H), 3.67 (s, 3H), 3.94 (s, 3H), 4.09-4.16 (m, 2H), 4.53 (t, 2H), 5.37-5.47 (m, 1H), 6.41 (m, 1H), 6.59 (s, 1H), 6.74 (s, 1H), 7.55 (d, 2H), 7.60 (d, 2H).

Example 34.1

(4S)-7,8-Dimethoxy-N,4-dimethyl-1-[4-(2-oxooxazolidin-3-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(417) Analogously to the preparation of Example 34, 100 mg (0.231 mmol) of (4S)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49.2A) gave, by reaction with 22 mg (0.254 mmol) of oxazolidin-2-one, after purification by preparative HPLC, 84 mg (82% of theory) of the desired product as a solid.

(418) LCMS (Method 2): R.sub.t=1.0 min; m/z=439 (M+H).sup.+

(419) [].sub.D.sup.20=237.1 (c=1.00; methanol)

(420) The following exemplary compounds were prepared analogously to Example 34 from Example 49A or Example 49.2A and the appropriate commercially available lactams or cyclic carbamates:

(421) TABLE-US-00036 No Structure Name Analytical data 35 00 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2- oxopiperidin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 1.92-2.02 (m, 2H), 2.54-2.65 (m, 2H), 2.80 (dd, 1H), 2.88 (s, br, 3H), 3.06 (d, 1H), 3.67 (s, 3H), 3.68- 3.75 (m, 2H), 3.93 (s, 3H), 5.41 (q, 1H), 6.44 (m, 1H), 6.63 (s, 3H), 6.72 (s, 1H), 7.30 (d, 2H), 7.53 (d, 2H). LCMS (Method 2): R.sub.t = 1.04 min; m/z = 451 (M + H).sup.+ 36 01 ()-1-[4-(4-benzyl-2- oxopiperazin-1- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.78-2.87 (m, 3H), 2.89 (d, 3H), 3.08 (dd, 1H), 3.37 (s, 2H), 3.65 (s, 2H), 3.67 (s, 3H), 3.69-3.77 (m, 2H), 3.93 (s, 3H), 5.38-5.47 (m, 1H), 6.45 (m, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.30-7.39 (m, 7H) 7.53 (d, 2H). LCMS (Method 2): R.sub.t = 1.06 min; m/z = 542 (M + H).sup.+ 37 02 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 2-oxo-1,4-diazepan-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.06-2.20 (m, 2H), 2.70 (s, 3H), 2.82 (dd, 1H), 2.88 (d, 3H), 3.08 (dd, 1H), 3.18 (m, 2H), 3.68 (s, 3H), 3.82 (s, br, 2H), 3.90-4.01 (m, 2H), 3.93 (s, 3H), 5.43 (m, 1H), 6.46 (q, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.28 (d, 2H) 7.53 (d, 2H). LCMS (Method 2): R.sub.t = 0.70 min; m/z = 480 (M + H).sup.+ 38 03 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2-oxo- 1,3-oxazinan-3- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.20-2.30 (m, 2H), 2.82 (dd, 1H), 2.88 (d, 3H), 3.08 (dd, 1H), 3.67 (s, 3H), 3.78 (t, 2H), 3.93 (s, 3H), 4.45 (t, 2H), 5.37-5.48 (m, 1H), 6.45 (m, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.38 (d, 2H), 7.54 (d, 2H). LCMS (Method 2): R.sub.t = 0.96 min; m/z = 453 (M + H).sup.+ 39 04 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2- oxopyrrolidin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.03 (d, 3H), 2.16-2.25 (m, 2H), 2.65 (t, 2H), 2.80 (dd, 1H), 2.88 (d, 3H), 3.07 (dd, 1H), 3.66 (s, 3H), 3.88-3.93 (m, 2H), 3.93 (s, 3H), 5.35-5.45 (m, 1H), 6.40 (s, br, 1H), 6.60 (s, 1H), 6.73 (s, 1H), 7.53 (d, 2H), 7.68 (d, 2H). LCMS (Method 2): R.sub.t = 1.04 min; m/z = 437 (M + H).sup.+ 40 05 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(3- oxomorpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.82 (dd, 1H), 2.89 (d, 3H), 3.08 (dd, 1H), 3.68 (s, 3H), 3.80-3.86 (m, 2H), 3.94 (s, 3H), 4.07 (t, 2H), 4.37 (s, 2H), 5.39-5.49 (m, 1H), 6.46 (s, br, 1H), 6.62 (s, 1H), 6.73 (s, 1H), 7.40 (d, 2H), 7.57 (d, 2H). LCMS (Method 2): R.sub.t = 0.95 min; m/z = 453 (M + H).sup.+ 40.1 06 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(3- oxomorpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.83 (dd, 1H), 2.89 (s, br, 3H), 3.09 (dd, 1H), 3.67 (s, 3H), 3.80- 3.86 (m, 2H), 3.94 (s, 3H), 4.06 (t, 2H), 4.37 (s, 2H), 5.39-5.49 (m, 1H), 6.47 (s, br, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.40 (d, 2H), 7.56 (d, 2H). LCMS (Method 2): R.sub.t = 0.95 min; m/z = 453 (M + H).sup.+. [].sub.D.sup.20 = 135.4 (c = 1.00; methanol) 41 07 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2-methyl- 5-oxomorpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide (stereoisomer mixture) .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.01 (d, 3H), 1.36 (d, 3H), 2.82 (dd, 1H), 2.89 (s, br, 3H), 3.09 (d, 1H), 3.54- 3.62 (s, 1H), 3.68 (s, 3H), 3.69-3.77 (m, 1H), 3.94 (s, 3H), 4.05-4.16 (m, 1H), 4.35 (d, 1H), 4.43 (d, 1H), 5.44 (m, 1H), 6.45 (s, br, 1H), 6.62 (s, 1H), 6.73 (s, 1H), 7.39 (d, 2H), 7.56 (d, 2H). LCMS (Method 2): R.sub.t = 1.03 min; m/z = 467 (M + H).sup.+ 42 08 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2-methyl- 3-oxomorpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide (stereoisomer mixture) .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.01 (d, 3H), 1.57 (dd, 3H), 2.82 (dd, 1H), 2.88 (s, br, 3H), 3.09 (d, 1H), 3.61- 3.66 (m, 1H), 3.67/3.68 (s, 3H), 3.94 (s, 3H), 3.98-4.08 (m, 2H), 4.11-4.18 (m, 1H), 4.38-4.46 (m, 1H), 5.39-5.49 (m, 1H), 6.45 (s, br, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 7.38 (d, 2H), 7.56 (d, 2H). LCMS (Method 2): R.sub.t = 1.02 min; m/z = 467 (M + H).sup.+ 43 09 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 2-oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.84 (dd, 1H), 2.89 (s, 3H), 2.99 (s, 3H), 3.11 (dd, 1H), 3.37 (br. s., 1H), 3.64 (br. s., 1H), 3.67 (s, 3H), 3.77 (br. s., 2H), 3.94 (s, 3H), 4.27 (br. s., 1H), 4.83 (br. s., 1H), 5.46 (td, 1H), 6.49 (br. s., 1H), 6.59 (s, 1H), 6.72 (s, 1H), 7.38 (d, 2H), 7.56 (d, 2H). LCMS (Method 2): R.sub.t = 0.70 min; m/z = 466 (M + H).sup.+. 43.1 0 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 2-oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XIV analyt. HPLC (Method S): R.sub.t = 8.73 min LCMS (Method 2): R.sub.t = 0.70 min; m/z = 466 (M + H).sup.+. [].sub.D.sup.20 = 107.0 (c = 1.00; methanol) 43.2 (4R)-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 2-oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XIV analyt. HPLC (Method S): R.sub.t = 5.90 min LCMS (Method 2): R.sub.t = 0.70 min; m/z = 466 (M + H).sup.+. [].sub.D.sup.20 = 119.4 (c = 1.00; methanol)

Example 44

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(2-oxopiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(422) ##STR00212##

(423) Under argon, 87 mg (0.161 mmol) of ()-1-[4-(4-benzyl-2-oxopiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 36) were initially charged in 1 ml of ethanol, and 17 mg of palladium on carbon (10%) were added. The mixture was hydrogenated with hydrogen in a fitted balloon for 16 h. As the conversion was still incomplete, another spatula tip of catalyst was added and the mixture was hydrogenated with hydrogen for a further 16 h. The crude mixture was freed from the catalyst using a PTFE filter, the catalyst washed with ethyl acetate and the solvent was then removed on a rotary evaporator. The residue was purified by preparative HPLC. This gave 20 mg (20% of theory) of the desired product as a solid.

(424) LCMS (Method 2): R.sub.t=0.67 min; m/z=452 (M+H).sup.+

(425) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.98 (d, 3H), 2.78-2.87 (m, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 3.49 (m, 2H), 3.67 (s, 3H), 3.74-3.79 (m, 1H), 3.86-3.91 (m, 1H), 3.93 (s, 3H), 3.95-4.01 (m, 2H), 4.22 (s, br 1H), 5.39-5.49 (m, 1H), 6.44-6.51 (m, 1H), 6.60 (s, 1H), 6.72 (s, 1H), 7.35 (d, 2H), 7.55 (d, 2H).

(426) The following exemplary compounds were prepared analogously to Example 2 from Example 49A or Example 49.2A and the appropriate commercially available boronic acid derivatives:

(427) TABLE-US-00037 No. Structure Name Analytical data 45 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(1-methyl- 1H-1,2,3-triazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.84 (dd, 1H), 2.90 (d, 3H), 3.12 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 4.18 (s, 3H), 5.40-5.50 (m, 1H), 6.46-6.53 (m, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 7.57 (d, 2H), 7.80 (s, 1H), 7.86 (d, 2H). LCMS (Method 2): R.sub.t = 1.01 min; m/z = 435 (M + H).sup.+ 45.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(1-methyl- 1H-1,2,3-triazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide LCMS (Method 2): R.sub.t = 1.00 min; m/z = 435 (M + H).sup.+ [].sub.D.sup.20 = 71.3 (c = 1.00; chloroform) 46 ()-1-[4-(2,4- dimethylthiazol-5- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.51 (s, 3H), 2.71 (s, 3H), 2.84 (dd, 1H), 2.90 (d, 3H), 3.12 (dd, 1H), 3.68 (s, 3H), 3.94 (s, 3H), 5.44 (m, 1H), 6.48 (q, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 7.44 (d, 2H), 7.55 (d, 2H). LCMS (Method 2): R.sub.t = 1.24 min; m/z = 465 (M + H).sup.+ 46.1 (4S)-1-[4-(2,4- dimethylthiazol-5- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide enantiomer 1 of Ex. 46 separation HPLC Method VIII HPLC (Method L): R.sub.t = 5.9 min 46.2 (4R)-1-[4-(2,4- dimethylthiazol-5- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide enantiomer 2 of Ex. 46 separation HPLC Method VIII HPLC (Method L): R.sub.t = 8.9 min [].sub.D.sup.20 = 127.2 (c = 1.00; methanol) 47 ()-1-[4-(1,2-dimethyl- 1H-imidazol-5- yl)phenyl]-7,8- dimethoxy-N-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.46 (s, 3H), 2.83 (dd, 1H), 2.89 (d, 3H), 3.10 (dd, 1H), 3.58 (s, 3H), 3.68 (s, 3H), 3.94 (s, 3H), 5.43 (m, 1H), 6.47 (q, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 7.03 (s, 1H), 7.39 (d, 2H), 7.57 (d, 2H). LCMS (Method 2): R.sub.t = 0.75 min; m/z = 448 (M + H).sup.+ 48 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[2- (trifluoromethyl)pyridin- 3-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.87 (dd, 1H), 2.92 (d, 3H), 3.17 (dd, 1H), 3.67 (s, 3H), 3.94 (s, 3H), 5.50 (m, 1H), 6.56 (q, 1H), 6.59 (s, 1H), 6.73 (s, 1H), 7.37 (d, 2H), 7.54-7.61 (m, 3H), 7.79 (dd, 1H), 8.76 (dd, 1H). LCMS (Method 2): R.sub.t = 1.28 min; m/z = 499 (M + H).sup.+ 49 0 ()-1-[4-(6- hydroxypyridin-3- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.84 (dd, 1H), 2.91 (d, 3H), 3.12 (dd, 1H), 3.68 (s, 3H), 3.95 (s, 3H), 5.45 (m, 1H), 6.48 (q, 1H), 6.62 (s, 1H), 6.69-6.80 (s, br 1H), 6.74 (s, 1H), 7.46 (s, br, 2H), 7.58 (d, 2H), 7.73 (s, br, 1H), 7.86 (s, br, 1H). LCMS (Method 2): R.sub.t = 0.94 min; m/z = 447 (M + H).sup.+ 49.1 (4S)-1-[4-(6- hydroxypyridin-3- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 0.97 min; m/z = 447 (M + H).sup.+ [].sub.D.sup.20 = 102.3 (c = 1.00; CHCl.sub.3) 50 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[6- (trifluoromethyl)pyridin- 3-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.86 (dd, 1H), 2.91 (d, 3H), 3.15 (dd, 1H), 3.68 (s, 3H), 3.95 (s, 3H), 5.49 (m, 1H), 6.54 (m, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 7.65 (s, br, 4H), 7.79 (d, 1H), 8.10 (dd, 1H), 9.0 (s, br, 1H). LCMS (Method 2): R.sub.t = 1.35 min; m/z = 499 (M + H).sup.+ 50.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-{4-[6- (trifluoromethyl)pyridin- 3-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method IIIa analyt. HPLC (Method K1): R.sub.t = 3.24 min [].sub.D.sup.20 = 109.2 (c = 1.00; MeOH) LCMS (Method 1): R.sub.t = 1.36 min; m/z = 499 (M + H).sup.+ 50.2 (4R)-7,8-dimethoxy-N,4- dimethyl-1-{4-[6- (trifluoromethyl)pyridin- 3-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method IIIa analyt. HPLC (Method K1): R.sub.t = 2.54 min [].sub.D.sup.20 = 113.2 (c = 1.00; MeOH) LCMS (Method 1): R.sub.t = 1.36 min; m/z = 499 (M + H).sup.+ 51 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(1,3,5- trimethyl-1H-pyrazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.05 (d, 3H), 2.29 (s, 6H), 2.82 (dd, 1H), 2.90 (d, 3H), 3.08 (dd, 1H), 3.69 (s, 3H), 3.81 (s, 3H), 3.95 (s, 3H), 5.41 (m, 1H), 6.42 (qbr, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.28 (d, 2H), 7.56 (d, 2H). LCMS (Method 3): R.sub.t = 1.11 min; m/z = 462 (M + H).sup.+ 51.1 (4R)-7,8-dimethoxy-N,4- dimethyl-1-[4-(1,3,5- trimethyl-1H-pyrazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XVI analyt. HPLC (Method U): R.sub.t = 7.78 min [].sub.D.sup.20 = 199.0 (c = 1.00; MeOH) 51.2 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(1,3,5- trimethyl-1H-pyrazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XVI analyt. HPLC (Method U): R.sub.t = 10.16 min [].sub.D.sup.20 = +183.3 (c = 1.00; MeOH) 52 ()-1-[4-(isoxazol-4- yl)phenyl]-7,8- dimethoxy-N-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.85 (dd, 1H), 2.90 (d, 3H), 3.12 (dd, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.46 (m, 1H), 6.50 (m, 1H), 6.60 (s, 1H), 6.73 (s, 1H), 7.51 (d, 2H), 7.56 (d, 2H), 8.61 (s, 1H), 8.74 (s, 1H). LCMS (Method 3): R.sub.t = 1.12 min; m/z = 421 (M + H).sup.+

(428) The following exemplary compounds were prepared analogously to Example 2 from Example 51A and the appropriate commercially available boronic acid derivatives:

(429) TABLE-US-00038 No Structure Name Analytical data 53 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(1,3,5- trimethyl-1H-pyrazol-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.01 (d, 3H), 2.24 (s, 3H), 2.25 (s, 3H), 2.83 (dd, 1H), 2.88 (d, 3H), 3.11 (dd, 1H), 3.67 (s, 3H), 3.78 (s, 3H), 3.93 (s, 3H), 5.44 (m, 1H), 6.51 (qbr, 1H), 6.65 (s, 1H), 6.72 (s, 1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.44 (m, 2H). LCMS (Method 3): R.sub.t = 1.12 min; m/z = 462 (M + H).sup.+ 54 0 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(1-methyl- 1H-pyrazol-4-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.86 (dd, 1H), 2.88 (d, 3H), 3.13 (dd, 1H), 3.63 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 5.48 (m, 1H), 6.51 (m, 1H), 6.61 (s, 1H), 6.73 (s, 1H), 7.36 (m, 1H), 7.39 (dd, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.61 (s, 1H), 7.76 (s, 1H). LCMS (Method 3): R.sub.t = 1.04 min; m/z = 434 (M + H).sup.+ 55 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(1-methyl- 1H-pyrazol-5-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.87 (dd, 1H), 2.89 (d, 3H), 3.14 (dd, 1H), 3.65 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 5.48 (m, 1H), 6.33 (d, 1H), 6.50 (qbr, 1H), 6.59 (s, 1H), 6.73 (s, 1H), 7.42-7.58 (m, 4H), 7.54 (d, 1H). LCMS (Method 3): R.sub.t = 1.07 min; m/z = 434 (M + H).sup.+

(430) The following exemplary compounds were prepared analogously to Example 2 from Example 60A and the appropriate commercially available boronic acid derivatives:

(431) TABLE-US-00039 No Structure Name Analytical data 56 ()-1-[4-fluoro-3-(1,3,5- trimethyl-1H-pyrazol-4- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.18 (s, 6H), 2.83 (dd, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 3.68 (s, 3H), 3.78 (s, 3H), 3.93 (s, 3H), 5.43 (m, 1H), 6.44 (qbr, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.17 (dd, 1H), 7.28 (dd, 1H), 7.46 (ddd, 1H). LCMS (Method 3): R.sub.t = 1.15 min; m/z = 480 (M + H).sup.+ 57 ()-1-[4-fluoro-3-(1- methyl-1H-pyrazol-4- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.85 (m, 1H), 2.89 (d, 3H), 3.12 (dd, 1H), 3.64 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 5.47 (m, 1H), 6.46 (m, 1H), 6.59 (s, 1H), 6.73 (s, 1H), 7.14 (dd, 1H), 7.31 (m, 1H), 7.64 (dd, 1H), 7.79 (s, 1H), 7.83 (s, 1H). LCMS (Method 3): R.sub.t = 1.14 min; m/z = 452 (M + H).sup.+ 58 ()-1-[3-(3,5- dimethylisoxazol-4-yl)-4- fluoroophenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.23 (s, 3H), 2.36 (s, 3H), 2.86 (dd, 1H), 2.89 (d, 3H), 3.11 (dd, 1H), 3.68 (s, 3H), 3.94 (s, 3H), 5.46 (m, 1H), 6.45 (qbr, 1H), 6.58 (s, 1H), 6.72 (s, 1H), 7.21 (dd, 1H), 7.30 (dd, 1H), 7.53 (ddd, 1H). LCMS (Method 3): R.sub.t = 1.25 min; m/z = 467 (M + H).sup.+

(432) The following exemplary compounds were prepared analogously to Example 2 from Example 49A and the appropriate commercially available boronic acid derivatives:

(433) TABLE-US-00040 LCMS data (Method 4) No Structure Name R.sub.t [min] [M + H].sup.+ 59 ()-7,8-dimethoxy-N,4- dimethyl-1-(3-nitrobiphenyl- 4-yl)-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.34 475 60 ()-1-(biphenyl-4-yl)-7,8- dimethoxy-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.39 430 61 ()-1-(2,4-dichlorobiphenyl- 4-yl)-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.57 498 62 ()-1-(4-fluorobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.39 448 63 ()-1-(4-chlorobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.49 464 64 0 ()-7,8-dimethoxy-N,4- dimethyl-1-(4- methylbiphenyl-4-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.47 444 65 ()-7,8-dimethoxy-1-(4- methoxybiphenyl-4-yl)-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.35 460 66 ()-7,8-dimethoxy-1-[4-(6- methoxypyridin-3-yl)phenyl]- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.27 461 67 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (methylsulphinyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.05 492 68 ()-7,8-dimethoxy-N,4- dimethyl-1-{2- [(methylsulphonyl)amino]- biphenyl-4-yl}-4,5-dihydro- 3H-2,3-benzodiazepine-3- carboxamide 1.16 523 69 ()-7,8-dimethoxy-N,4- dimethyl-1-[2- (methylsulphonyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.16 508 70 ()-7,8-dimethoxy-N,4- dimethyl-1-{4- [(methylsulphonyl)amino] biphenyl-4-yl}-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.10 523 71 ()-7,8-dimethoxy-N,4- dimethyl-1-{3- [(methylsulphonyl)amino] biphenyl-4-yl}-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.13 523 72 ()-7,8-dimethoxy-N,4- dimethyl-1-(2- methylbiphenyl-4-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.45 444 73 ()-7,8-dimcthoxy-N,4- dimethyl-1-[3- (methylsulphonyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.14 508 74 0 ()-7,8-dimethoxy-1-[4-(2- methoxypyrimidin-5- yl)phenyl]-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.12 462 75 ()-1-(3-cyano-4- fluorobiphenyl-4-yl)-7,8- dimethoxy-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.31 473 76 ()-7,8-dimethoxy-1-[4-(2- methoxypyridin-3-yl)phenyl]- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.27 461 77 ()-1-(3-carbamoylbiphenyl- 4-yl)-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.03 473 78 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(pyrrolidin-1- ylcarbonyl)biphenyl-4-yl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.19 527 79 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(morpholin-4- ylcarbonyl)biphenyl-4-yl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.10 543 80 ()-7,8-dimethoxy-1-[4-(5- methoxypyridin-3-yl)phenyl]- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.06 461 81 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(5- methylpyridin-3-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 0.94 445 82 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4- methylpyridin-3-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 0.85 445 83 ()-1-[4- (cyclopropylcarbamoyl) biphenyl-4-yl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.13 513 84 0 ()-1-[4-(3-fluoropyridin-4- yl)phenyl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.15 449 85 ()-7,8-dimethoxy-N,4- dimethyl-1-[3- (trifluoromethyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.48 498 86 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (trifluoromethyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.49 498 87 ()-7,8-dimethoxy-1-(3- methoxybiphenyl-4-yl)-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.36 460 88 ()-1-[4-(5-chlorothien-2- yl)biphenyl-4-yl]-7,8- dimethoxy-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.52 470 89 ()-1-(3-fluorobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.40 448 90 ()-7,8-dimethoxy-1-(2- methoxybiphenyl-4-yl)-N,4- 40dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.37 460 91 ()-7,8-dimethoxy-N,4- dimethyl-1-[2- (trifluoromethyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.45 498 92 ()-1-(2-chlorobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.44 464 93 ()-1-(2-fluorobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.38 448 94 0 ()-1-[4- (hydroxymethyl)biphenyl-4- yl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.10 460 95 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (trifluoromethoxy)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.51 514 96 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(pyrrolidin-1- ylcarbonyl)biphenyl-4-yl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.20 527 97 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(piperidin-1- ylcarbonyl)biphenyl-4-yl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.29 541 98 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(morpholin-4- ylcarbonyl)biphenyl-4-yl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.12 543 99 ()-1-[3- (cyclopropylcarbamoyl)- biphenyl-4-yl]-7,8-dimethoxy- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.15 513 100 ()-1-(2,4-difluorobiphenyl- 4-yl)-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.41 466 101 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(1-methyl-1H- pyrazol-5-yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.09 434 102 ()-7,8-dimethoxy-N,4- dimethyl-1-(4-nitrobiphenyl- 4-yl)-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.34 475 103 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(pyridin-3- yl)phenyl]-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 0.93 431 104 0 ()-7,8-dimethoxy-1-[4-(4- methoxypyridin-3-yl)phenyl]- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 0.77 461 105 ()-1-(3-cyanobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.28 455 106 ()-1-(4-cyanobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.27 455 107 ()-7,8-dimethoxy-N,4- dimethyl-1-[2- (trifluoromethoxy)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.48 514 108 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (methylsulphonyl)biphenyl-4- yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.12 508 109 ()-1-(2-cyanobiphenyl-4-yl)- 7,8-dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.27 455 110 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(morpholin-4- yl)biphenyl-4-yl]-4,5-dihydro- 3H-2,3-benzodiazepine-3- carboxamide 1.29 515 111 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(pyrimidin-5- yl)phenyl]-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.01 432 112 ()-1-[2- (hydroxymethyl)biphenyl-4- yl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.17 460 113 ()-1-(3-{[2- (dimethylamino)ethyl]carb- amoyl}biphenyl-4-yl)-7,8- dimethoxy-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 0.84 544 114 0 ()-7,8-dimethoxy-N,4- dimethyl-1-(3- sulphamoylbiphenyl-4-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.06 509 115 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (methylsulphamoyl)biphenyl- 4-yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.13 523 116 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(1-methyl-1H- pyrrol-2-yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.28 433 117 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(6- methylpyridin-3-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 0.87 445 118 ()-1-[4- (cyclopropylsulphamoyl)- biphenyl-4-yl]-7,8-dimethoxy- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.20 549 119 ()-1-(3-fluoro-5- hydroxybiphenyl-4-yl)-7,8- dimethoxy-N,4-dimethyl-4,5- diliydro-3H-2,3- benzodiazepine-3-carboxamide 1.20 464 120 ()-1-(3-fluoro-5- methylbiphenyl-4-yl)-7,8- dimethoxy-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.48 462 121 ()-7,8-dimethoxy-N,4- dimethyl-1-[3- (methylsulphamoyl)biphenyl- 4-yl]-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.15 523 122 ()-1-[4-(5-fluoropyridin-3- yl)phenyl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.18 449 123 ()-1-[4-(4-fluoropyridin-3- yl)phenyl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.11 449 124 00 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(2- methylpyridin-3-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 0.84 445 125 01 ()-7,8-dimethoxy-1-[4-(2- methoxypyridin-4-yl)phenyl]- N,4-dimethyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide 1.26 461 126 02 ()-1-[4-(5-cyanopyridin-3- yl)phenyl]-7,8-dimethoxy-N,4- dimethyl-4,5-dihydro-3H-2,3- benzodiazepine-3-carboxamide 1.14 456

Alternative Process for Preparing Example 7

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(434) ##STR00303##

(435) Under argon, 100 mg (231 mol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A) were initially charged in 5 ml of degassed toluene. 22 l (22 mg, 254 mol) of morpholine, 31 mg (324 mol) of sodium tert-butoxide and 9 mg (12 mol) of chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)]palladium(II) (CAS [1310584-14-5]) were added. The mixture was degassed again, saturated with argon and then stirred at 110 C. for 6 hours. After cooling, the mixture was partitioned between 15 ml of sat. sodium bicarbonate solution and 15 ml of ethyl acetate, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue (156 mg yellow oil) was purified by flash chromatography (SiO.sub.2, hexane/ethyl acetate). This gave 87 mg (86% of theory) of the desired product as a yellow solid.

(436) LCMS (Method 2): R.sub.t=1.08 min; m/z=439 (M+H).sup.+

(437) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.10 (d, 3H), 2.73 (dd, 1H), 2.86 (d, 3H), 2.95 (dd, 1H), 3.25-3.28 (m, 4H), 3.70 (s, 3H), 3.88-3.91 (m, 4H), 3.93 (s, 3H), 5.25-5.35 (m, 1H), 6.14 (q, 1H), 6.63 (s, 1H), 6.75 (s, 1H), 6.93 (d, 2H), 7.51 (d, 2H).

Enantiomer Separation

(438) By chiral preparative HPLC using Method V, 78 mg of ()-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 7) were separated into the enantiomers:

Example 7.1: (4R)-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(439) 20 mg yellowish solid, HPLC (Method G): R.sub.t=6.08 min, purity 100%

Example 7.2: (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(440) 20 mg yellowish solid, HPLC (Method G): R.sub.t=7.42 min, purity 99.3%

Example 127.1

(4S)-7,8-Dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(441) ##STR00304##

(442) Under argon, 1.30 g (3.01 mmol) of (4S)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49.2A) were initially charged in 65 ml of degassed toluene. 0.37 ml (331 mg, 3.31 mmol) of 1-methylpiperazine, 405 mg (4.21 mmol) of sodium tert-butoxide and 118 mg (0.15 mmol) of chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)]palladium(II) (CAS [1310584-14-5]) were added. The mixture was degassed again, saturated with argon and then stirred at 80 C. for 12 hours. After cooling, the mixture was added to sat. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue (1.5 g orange foam) was purified by flash chromatography (SiO.sub.2, dichloromethane/methanol 0-3-10%). This gave 850 mg (63% of theory) of the desired product as a yellow solid.

(443) LCMS (Method 2): R.sub.t=0.69 min; m/z=452 (M+H).sup.+

(444) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.02 (d, 3H), 2.19 (s, 3H), 2.38-2.44 (m, 4H), 2.46-2.51 (m, 1H), 2.60 (d, 3H), 2.80 (dd, 1H), 3.18-3.24 (m, 4H), 3.57 (s, 3H), 3.80 (s, 3H), 4.82-4.90 (m, 1H), 6.25 (q, 1H), 6.51 (s, 1H), 6.91 (d, 2H), 6.99 (s, 1H), 7.55 (d, 2H).

(445) Specific optical rotation: [].sub.D.sup.20=374.4+/0.17 (c=1.00; methanol)

(446) The following exemplary compounds were prepared analogously to Example 127.1 from Example 49A or Example 49.2A and the appropriate commercially available amines, where appropriate with subsequent enantiomer separation by chiral preparative HPLC:

(447) TABLE-US-00041 No Structure Name Analytical data 128 05 ()-1-[4-(azetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.17 (d, 3H), 2.39-2.46 (m, 2H), 2.70 (dd, 1H), 2.85 (d, 3H), 2.89 (dd, 1H), 3.71 (s, 3H), 3.93 (s, 3H), 3.95-3.99 (m, 4H), 5.19-5.27 (m, 1H), 5.96 (q, 1H), 6.42 (d, 2H), 6.64 (s, 1H), 6.76 (s, 1H), 7.49 (d, 2H). LCMS (Method 2): R.sub.t = 1.18 min; m/z = 409 (M + H).sup.+ 128.1 06 (4R)-1-[4-(azetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method VII analyt. HPLC (Method J): R.sub.t = 2.93 min [].sub.D.sup.20 = 415 (c = 1.00; methanol) 128.2 07 (4S)-1-[4-(azetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method VII analyt. HPLC (Method J): R.sub.t = 3.68 min [].sub.D.sup.20 = 442 (c = 1.00; methanol) 129 08 ()-1-[4-(3- fluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.12 (d, 3H), 2.72 (dd, 1H), 2.86 (d, 3H), 2.93 (dd, 1H), 3.70 (s, 3H), 3.93 (s, 3H), 3.98-4.10 (m, 2H), 4.20-4.31 (m, 2H), 5.21-5.31 (m, 1H), 5.32- 5.39 and 5.52-5.58 (m, 1H), 6.05 (q, 1H), 6.47 (d, 2H), 6.62 (s, 1H), 6.75 (s, 1H), 7.48 (d, 2H). LCMS (Method 2): R.sub.t = 1.15 min; m/z = 427 (M + H).sup.+ 129.1 09 (4R)-1-[4-(3- fluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method VII analyt. HPLC (Method J): R.sub.t = 2.93 min [].sub.D.sup.20 = 340 (c = 1.00; methanol) 129.2 0 (4S)-1-[4-(3- fluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method VII analyt. HPLC (Method J): R.sub.t = 3.68 min [].sub.D.sup.20 = 401 (c = 1.00; methanol) 130 ()-1-[4-(4- hydroxypiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.02 (d, 3H), 1.35-1.47 (m, 2H), 1.72-1.83 (m, 2H), 2.36-2.50 (m, 1H), 2.59 (d, 3H), 2.79 (dd, 1H), 2.88- 3.00 (m, 2H), 3.57 (s, 3H), 3.57- 3.67 (m, 3H), 3.80 (s, 3H), 4.65 (d, 1H), 4.78-4.90 (m, 1H), 6.22 (q, 1H), 6.52 (s, 1H), 6.90 (d, 2H), 6.99 (s, 1H), 7.54 (d, 2H). LCMS (Method 2): R.sub.t = 0.93 min; m/z = 453 (M + H).sup.+ 130.1 (4S)-1-[4-(4- hydroxypiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide [].sub.D.sup.20 = 336 (c = 1.00; methanol) LCMS (Method 2): R.sub.t = 0.93 min; m/z = 453 (M + H).sup.+ 131 ()-7,8-dimethoxy-N,4- dimethyl-1-[4- (piperazin-1-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.02 (d, 3H), 2.38-2.49 (m, 1H), 2.59 (d, 3H), 2.80 (dd, 1H), 2.84- 2.87 (m, 4H), 3.16-3.19 (m, 4H), 3.56 (s, 3H), 3.80 (s, 3H), 4.80-4.91 (m, 1H), 6.26 (q, 1H), 6.50 (s, 1H), 6.91 (d, 2H), 6.99 (s, 1H), 7.56 (d, 2H). LCMS (Method 2): R.sub.t = 0.69 min; m/z = 438 (M + H).sup.+ 131.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4- (piperazin-1-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide [].sub.D.sup.20 = +323.7 (c = 1.00; methanol) LCMS (Method 1): R.sub.t = 0.70 min; m/z = 438 (M + H).sup.+ 127 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.10 (d, 3H), 2.39 (s, 3H), 2.58-2.66 (m, 4H), 2.72 (dd, 1H), 2.86 (d, 3H), 2.94 (dd, 1H), 3.29-3.37 (m, 4H), 3.70 (s, 3H), 3.93 (s, 3H), 5.24-5.34 (m, 1H), 6.10 (q, 1H), 6.64 (s, 1H), 6.74 (s, 1H), 6.92 (d, 2H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 0.73 min; m/z = 452 (M + H).sup.+ 132 ()-1-[4-(4- acetylpiperazin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.01 (d, 3H), 2.01 (s, 3H), 2.39-2.50 (m, 1H), 2.59 (d, 3H), 2.81 (dd, 1H), 3.16-3.31 (m, 4H), 3.51-3.59 (m, 4H), 3.56 (s, 3H), 3.80 (s, 3H), 4.80- 4.92 (m, 1H), 6.28 (q, 1H), 6.50 (s, 1H), 6.94 (d, 2H), 6.99 (s, 1H), 7.58 (d, 2H). LCMS (Method 2): R.sub.t = 0.97 min; m/z = 480 (M + H).sup.+ 132.1 (4R)-1-[4-(4- acetylpiperazin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XI analyt. HPLC (Method L): R.sub.t = 7.27 min 132.2 (4S)-1-[4-(4- acetylpiperazin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide prep. HPLC: Method XI analyt. HPLC (Method L): R.sub.t = 8.98 min 133 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (trifluoroacetyl)piperazin- 1-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.01 (d, 3H), 2.40-2.49 (m, 1H), 2.60 (d, 3H), 2.81 (dd, 1H), 3.31- 3.40 (m, 4H), 3.56 (s, 3H), 3.65- 3.75 (m, 4H), 3.80 (s, 3H), 4.82- 4.94 (m, 1H), 6.29 (q, 1H), 6.50 (s, 1H), 6.95 (d, 2H), 6.99 (s, 1H), 7.59 (d, 2H). LCMS (Method 2): R.sub.t = 1.22 min; m/z = 534 (M + H).sup.+ 134 0 ()-1-{4-[4-(2-hydroxy- 2-methylpropanoyl)- piperazin-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.08 (d, 3H), 1.54 (s, 6H), 2.74 (dd, 1H), 2.87 (d, 3H), 2.97 (dd, 1H), 3.27- 3.34 (m, 4H), 3.69 (s, 3H), 3.65- 3.92 (m, 4H), 3.93 (s, 3H), 4.07 (s, 1H), 6.25-6.37 (m, 1H), 6.17 (q, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 6.92 (d, 2H), 7.50 (d, 2H). LCMS (Method 1): R.sub.t = 1.02 min; m/z = 524 (M + H).sup.+ 134.1 (4S)-1-{4-[4-(2-hydroxy- 2-methylpropanoyl)piper- azin-1-yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide [].sub.D.sup.20 = +291.8 (c = 1.00; methanol) LCMS (Method 1): R.sub.t = 1.01 min; m/z = 524 (M + H).sup.+ 135 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (methylsulphonyl)piper- azin-1-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.01 (d, 3H), 2.38-2.49 (m, 1H), 2.60 (d, 3H), 2.81 (dd, 1H), 2.89 (s, 3H), 3.17-3.26 (m, 4H), 3.30-3.38 (m, 4H), 3.56 (s, 3H), 3.80 (s, 3H), 4.82-4.94 (m, 1H), 6.29 (q, 1H), 6.51 (s, 1H), 6.97 (d, 2H), 6.99 (s, 1H), 7.58 (d, 2H). LCMS (Method 2): R.sub.t = 1.04 min; m/z = 516 (M + H).sup.+ 135.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (methylsulphonyl)piper- azin-1-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide [].sub.D.sup.20 = +314.3 (c = 1.00; methanol) LCMS (Method 1): R.sub.t = 1.08 min; m/z = 516 (M + H).sup.+ 136 (4S)-1-[4-(1,1- dioxidothiomorpholin-4- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.01 (d, 3H), 2.40-2.50 (m, 1H), 2.60 (d, 3H), 2.81 (dd, 1H), 3.06- 3.15 (m, 4H), 3.57 (s, 3H), 3.80 (s, 3H), 3.82-3.98 (m, 4H), 4.82-4.94 (m, 1H), 6.29 (q, 1H), 6.52 (s, 1H), 7.00 (s, 1H), 7.01 (d, 2H), 7.59 (d, 2H). LCMS (Method 2): R.sub.t = 0.96 min; m/z = 487 (M + H).sup.+ [].sub.D.sup.20 = +309.1 (c = 1.00; methanol) 137 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(3- oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.02 (d, 3H), 2.38-2.51 (m, 1H), 2.60 (d, 3H), 2.81 (dd, 1H), 3.26- 3.33 (m, 2H), 3.44-3.50 (m, 2H), 3.56 (s, 3H), 3.76-3.79 (m, 2H), 3.80 (s, 3H), 4.80-4.93 (m, 1H), 6.27 (q, 1H), 6.50 (s, 1H), 6.89 (d, 2H), 6.99 (s, 1H), 7.58 (d, 2H), 8.08 (s, 1H). LCMS (Method 2): R.sub.t = 0.88 min; m/z = 452 (M + H).sup.+ 138 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 3-oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.09 (d, 3H), 2.73 (dd, 1H), 2.87 (d, 3H), 2.96 (dd, 1H), 3.06 (s, 3H), 3.49- 3.54 (m, 2H), 3.55-3.61 (m, 2H), 3.69 (s, 3H), 3.93 (s, 3H), 3.96 (s, 2H), 5.26-5.35 (m, 1H), 6.15 (q, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 6.86 (d, 2H), 7.51 (d, 2H). LCMS (Method 2): R.sub.t = 0.96 min; m/z = 466 (M + H).sup.+ 138.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 3-oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide [].sub.D.sup.20 = +327.3 (c = 1.00; methanol) LCMS (Method 1): R.sub.t = 0.95 min; m/z = 466 (M + H).sup.+ 139 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(piperidin- 1-yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.13 (d, 3H), 1.56-1.76 (m, 6H), 2.71 (dd, 1H), 2.86 (d, 3H), 2.91 (dd, 1H), 3.24-3.32 (m, 4H), 3.70 (s, 3H), 3.93 (s, 3H), 5.20-5.30 (m, 1H), 6.03 (q, 1H), 6.65 (s, 1H), 6.75 (s, 1H), 6.91 (d, 2H), 7.49 (d, 2H). LCMS (Method 2): R.sub.t = 1.24 min; m/z = 437 (M + H).sup.+

(448) The following exemplary compounds were prepared analogously to Example 7 (alternative method) from Example 51A and the appropriate commercially available amines.

(449) TABLE-US-00042 No Structure Name Analytical data 140 ()-7,8-dimethoxy-N,4- dimethyl-1-[3- (morpholin-4-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.83 (dd, 1H), 2.87 (d, 3H), 3.10 (dd, 1H), 3.16 (m, 4H), 3.65 (s, 3H), 3.86 (m, 4H), 3.93 (s, 3H), 5.45 (m, 1H), 6.47 (qbr, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 6.96 (dbr, 1H), 7.00 (sbr, 1H), 7.03 (dbr, 1H), 7.31 (dd, 1H). LCMS (Method 3): R.sub.t = 1.11 min; m/z = 439 (M + H).sup.+ 141 0 ()-1-[3-(3,3- difluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.84 (dd, 1H), 2.87 (d, 3H), 3.11 (dd, 1H), 3.66 (s, 3H), 3.93 (s, 3H), 4.23 (m, 4H), 5.46 (m, 1H), 6.48 (m, 1H), 6.55 (dbr, 1H), 6.59 (m, 2H), 6.71 (s, 1H), 6.96 (dbr, 1H), 7.28 (dd, 1H). LCMS (Method 3): R.sub.t = 1.22 min; m/z = 445 (M + H).sup.+ 142 ()-1-[3-(azetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.40 (m, 2H), 2.82 (dd, 1H), 2.87 (d, 3H), 3.09 (dd, 1H), 3.67 (s, 3H), 3.91 (m, 4H), 3.93 (s, 3H), 5.43 (m, 1H), 6.48 (m, 1H), 6.57 (m, 2H), 6.62 (s, 1H), 6.71 (s, 1H), 6.89 (m, 1H), 7.24 (dd, 1H). LCMS (Method 3): R.sub.t = 1.22 min; m/z = 409 (M + H).sup.+ 143 ()-7,8-dimethoxy-N,4- dimethyl-1-[3-(4- methylpiperazin-1- yl)phenyl]-4,5-dihydro 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.36 (s, 3H), 2.59 (m, 4H), 2.83 (dd, 1H), 2.86 (d, 3H), 3.09 (dd, 1H), 3.22 (m, 4H), 3.64 (s, 3H), 3.93 (s, 3H), 5.43 (m, 1H), 6.47 (qbr, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 6.99 (m, 2H), 7.01 (sbr, 1H), 7.28 (dd, 1H). LCMS (Method 3): R.sub.t = 0.76 min; m/z = 452 (M + H).sup.+

(450) The following exemplary compounds were prepared analogously to Example 7 (alternative method) from Example 60A and the appropriate commercially available amines.

(451) TABLE-US-00043 No Structure Name Analytical data 144 ()-1-[4-fluoro-3- (morpholin-4-yl)phenyl]- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.85 (dd, 1H), 2.88 (d, 3H), 3.08 (m, 1H), 3.09 (m, 4H), 3.66 (s, 3H), 3.88 (m, 4H), 3.94 (s, 3H), 5.45 (m, 1H), 6.43 (qbr, 1H), 6.56 (s, 1H), 6.72 (s, 1H), 7.02-7.18 (m, 3H). LCMS (Method 3): R.sub.t = 0.96 min; m/z = 457 (M + H).sup.+ 145 ()-1-[3-(3,3- difluoroazetidin-1-yl)-4- fluorophenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.83 (dd, 1H), 2.88 (d, 3H), 3.09 (dd, 1H), 3.68 (s, 3H), 3.94 (s, 3H), 4.32 (m, 4H), 5.45 (m, 1H), 6.41 (m, 1H), 6.56 (d, 1H), 6.63 (dd, 1H), 6.72 (s, 1H), 6.91 (ddd, 1H), 7.02 (dd, 1H). LCMS (Method 3): R.sub.t = 1.31 min; m/z = 463 (M + H).sup.+ 146 ()-1-[4-fluoro-3-(4- hydroxypiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.00 (d, 3H), 1.76 (m, 2H), 2.03 (m, 2H), 2.82 (dd, 1H), 2.85 (m, 2H), 2.88 (d, 3H), 3.07 (m, 1H), 3.34 (m, 2H), 3.66 (s, 3H), 3.85 (m, 1H), 3.94 (s, 3H), 5.42 (m, 1H), 6.40 (m, 1H), 6.56 (s, 1H), 6.72 (s, 1H), 7.00-7.14 (m, 3H). LCMS (Method 3): R.sub.t = 1.03 min; m/z = 471 (M + H).sup.+

Example 147

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(5-methyl-3-phenyl-1H-pyrazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(452) ##STR00336##

(453) Under argon, 100 mg (0.231 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A), 44 mg (0.28 mmol) of 5-methyl-3-phenyl-1H-pyrazole, 67 mg (0.49 mmol) of potassium carbonate and 4.4 mg (0.023 mmol) of copper(I) iodide were initially charged in 2 ml of degassed toluene. Under argon, 13.2 mg (0.093 mmol) of ()-(trans)-N,N-dimethylcyclohexane-1,2-diamine were then added, and the mixture was degassed again and heated at 140 C. for 16 hours. After cooling, the mixture was filtered off and the filter cake washed with ethyl acetate and dried under reduced pressure. The residue was purified by preparative HPLC. This gave 17 mg (14% of theory) of the desired product as a solid.

(454) LCMS (Method 2): R.sub.t=1.44 min; m/z=510 (M+H).sup.+

(455) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.01 (d, 3H), 2.45 (s, 3H), 2.87 (dd, 1H), 2.92 (d, 3H), 3.14 (dd, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 5.43-5.52 (m, 1H), 6.48-6.56 (m, 1H), 6.58 (s, 1H), 6.65 (s, 1H), 6.74 (s, 1H), 7.34 (t, 1H), 7.39-7.47 (m, 2H), 7.58 (d, 2H), 7.63 (d, 2H), 7.89 (d, 2H).

(456) The following exemplary compounds were prepared analogously to Example 147 starting with the bromo derivative 49A by reaction with the appropriate, commercially available pyrazoles. Using the enantiomerically pure bromide 49.2A, it was possible to obtain the corresponding enantiomerically pure products directly.

(457) TABLE-US-00044 No Structure Name Analytical data 147.1 (4S)-7,8-dimethoxy- N,4-dimethyl-1-[4-(5- methyl-3-phenyl-1H- pyrazol-1-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.44 min; m/z = 510 (M + H).sup.+. [].sub.D.sup.20 = 68.8 (c = 1.00; methanol) 148 ()-1-[4-(5- cyclopropyl-3- phenyl-1H-pyrazol-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.89 (d, 2H), 1.01 (d, 3H), 1.07 (d, 2H), 1.84-1.98 (m, 1H), 2.86 (dd, 1H), 2.92 (d, 3H), 3.14 (d, 1H), 3.70 (s, 3H), 3.95 (s, 3H), 5.40-5.53 (m, 1H), 6.35 (s, 1H), 6.52 (s, br, 1H), 6.65 (s, 1H), 6.74 (s, 1H), 7.34 (d, 1H), 7.42 (t, 2H), 7.64 (d, 2H), 7.77 (d, 2H), 7.88 (d, 2H). LCMS (Method 2): R.sub.t = 1.52 min; m/z = 536 (M + H).sup.+. 148.1 (4S)-1-[4-(5- cyclopropyl-3- phenyl-1H-pyrazol-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.52 min; m/z = 536 (M + H).sup.+. [].sub.D.sup.20 = 103.9 (c = 1.00; methanol) 149 0 ()-7,8-dimethoxy- N,4-dimethyl-1-{4- [3-phenyl-5- (trifluoromethyl)-1H- pyrazol-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.79-2.88 (m, 1H), 2.90 (s, br., 3H), 3.12 (d, 1H), 3.65 (s, 3H), 3.93 (s, 3H), 5.41-5.53 (m, 1H), 6.42- 6.52 (m, 1H), 6.53 (s, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 7.26-7.31 (m, 2H), 7.31-7.41 (m, 5H), 7.49 (d, 2H). LCMS (Method 2): R.sub.t = 1.52 min; m/z = 564 (M + H).sup.+. 150 ()-1-{4-[3-(4- fluorophenyl)-1H- pyrazol-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.02 (d, 3H), 2.86 (dd, 1H), 2.91 (s, 3H), 3.13 (d, 1H), 3.67 (s, 3H), 3.95 (s, 3H), 5.46 (m, 1H), 6.49 (m, 1H), 6.63 (s, 1H), 6.72-6.81 (m, 2H), 7.09-7.19 (m, 2H), 7.62 (d, 2H), 7.81 (d, 2H), 7.87-7.95 (m, 2H), 7.99-8.04 (m, 1H). LCMS (Method 2): R.sub.t = 1.46 min; m/z = 514 (M + H).sup.+. 150.1 (4S)-1-{4-[3-(4- fluorophenyl)-1H- pyrazol-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method V analyt. HPLC (Method F): R.sub.t = 12.1 min LCMS (Method 2): R.sub.t = 1.46 min; m/z = 514 (M + H).sup.+. [].sub.D.sup.20 = 142.0 (c = 1.00; methanol) 150.2 (4R)-1-{4-[3-(4- fluorophenyl)-1H- pyrazol-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method V analyt. HPLC (Method F): R.sub.t = 7.6 min LCMS (Method 2): R.sub.t = 1.46 min; m/z = 514 (M + H).sup.+. [].sub.D20 = 137.3 (c = 1.00; methanol) 151 ()-7,8-dimethoxy- N,4-dimethyl-1-{4- [5-methyl-3- (trifluoromethyl)-1H- pyrazol-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.41 (s, 3H), 2.84-2.95 (m, 4H), 3.15 (dd, 1H), 3.67 (s, 3H), 3.94 (s, 3H), 5.46-5.53 (m, 1H), 6.50 (s, 1H), 6.51-6.55 (m, 1H), 6.60 (s, 1H), 6.73 (s, 1H), 7.49 (d, 2H), 7.60-7.65 (m, 2H). LCMS (Method 2): R.sub.t = 1.38 min; m/z = 502 (M + H).sup.+.

Example 152

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(458) ##STR00345##

(459) Under argon, 100 mg (0.231 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A), 19 mg (0.28 mmol) of 1H-1,2,4-triazole, 98 mg (0.46 mmol) of potassium phosphate, 2.2 mg (0.012 mmol) of copper(I) iodide and 3.3 mg (0.023 mmol) of ()-(trans)-N,N-dimethylcyclohexane-1,2-diamine were initially charged in 2 ml of DMF, the solution was degassed and the mixture was heated at 110 C. for 16 hours. As the conversion was poor, a further 2 mg of copper(I) iodide were added, and the mixture was degassed again and heated at 140 C. for a further 10 h. After cooling, sat. aqueous ammonium chloride solution was added, the mixture was extracted three times with ethyl acetate and the combined organic phases were dried under reduced pressure. The residue was purified by preparative HPLC. This gave 15 mg (2% of theory) of the desired product as a solid.

(460) LCMS (Method 2): R.sub.t=1.01 min; m/z=421 (M+H).sup.+

(461) .sup.1H-NMR (500 MHz, DMSO-d.sub.6): =0.98 (d, 3H), 2.70 (d, 3H), 2.73 (dd, 1H), 2.97 (dd, 1H), 3.57 (s, 3H), 3.85 (s, 3H), 5.09-5.17 (m, 1H), 6.55 (s, 1H), 6.67 (q, 1H), 7.03 (s, 1H), 7.80-7.85 (m, 2H), 7.89-7.94 (m, 2H), 8.26 (s, 1H), 9.39 (s, 1H).

(462) The following exemplary compounds were prepared analogously to Example 152 from the bromo derivative 49A by reaction with the appropriate, commercially available triazoles.

(463) TABLE-US-00045 No Structure Name Analytical data 153 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(5- methyl-1H-1,2,4- triazol-1-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.51 (s, 3H), 2.87-2.95 (dd, 1H), 2.90 (d, 3H), 3.14 (dd, 1H), 3.65 (s, 3H), 3.94 (s, 3H), 5.43-5.53 (m, 1H), 6.51 (q, 1H), 6.58 (s, 1H), 6.73 (s, 1H), 7.61 (d, 2H), 7.68 (d, 2H), 8.51 (s, br, 1H). LCMS (Method 2): R.sub.t = 1.04 min; m/z = 435 (M + H)+. 154 ()-1-[4-(3,5-dimethyl- 1H-1,2,4-triazol-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.50 (s, 3H), 2.64 (s, br, 3H), 2.88 (dd, 1H), 2.91 (d, 3H), 3.15 (d, 1H), 3.66 (s, 3H), 3.94 (s, 3H), 5.43-5.55 (m, 1H), 6.53 (q, 1H), 6.57 (s, 1H), 6.73 (s, 1H), 7.48 (d, 2H), 7.61-7.70 (m, 2H). LCMS (Method 2): R.sub.t = 1.01 min; m/z = 449 (M + H).sup.+.

Example 155

()-8-tert-Butyl-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(464) ##STR00348##

(465) 150 mg (0.391 mmol) of ()-8-tert-butyl-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 83A) were dissolved in 7.3 ml of a 1:0.1 mixture of THF and water and degassed with argon. 113.5 mg (1.95 mmol) of potassium fluoride, 57.3 mg (0.41 mmol) of (3,5-dimethylisoxazol-4-yl)boronic acid and 15.4 mg (0.02 mmol) of chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)]palladium(II) (CAS [1310584-14-5]) were then added, and the reaction mixture was once more degassed carefully with argon. The mixture was heated at 80 C. for 5 h. After cooling, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried and evaporated to dryness on a rotary evaporator. The residue was purified by preparative HPLC. This gave 43 mg (25% of theory) of the desired product as a solid.

(466) LCMS (Method 2): R.sub.t=1.50 min; m/z=445 (M+H)+

(467) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.99 (d, 3H), 1.22 (s, 9H), 2.33 (s, 3H), 2.46 (s, 3H), 2.87 (dd, 1H), 2.90 (d, 3H), 3.10 (dd, 1H), 5.36-5.49 (m, 1H), 6.45 (q, 1H), 7.14 (d, 1H), 7.18 (d, 1H), 7.30 (d, 2H), 7.37 (dd, 1H), 7.59 (d, 2H).

Example 156

()-7-Chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(468) ##STR00349##

(469) The preparation was carried out analogously to the process for the preparation of Example 155 using Example 15 as starting material. This gave a mixture of the desired compound with the regioisomeric ()-1-(4-chlorophenyl)-7-(3,5-dimethylisoxazol-4-yl)-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide. The regioisomers were separated by preparative HPLC (method: system: Waters AutoPurification System: Pump 254, Sample Manager 2767, CFO, DAD 2996, SQD 3100, Prep FC; column: XBrigde C18 5 m 10030 mm; mobile phase: A=H.sub.2O+0.1% HCOOH (99%), B=acetonitrile; gradient: 0-8 min 60-80% B flow rate: 50 ml/min; temperature: RT; detection: DAD scan range 210-400 nm). 100 mg of Example 15 gave, in addition to 14.7 mg of the regioisomer (LCMS (Method 2): R.sub.t=1.54 min; m/z=507 (M+H).sup.+; .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.97 (d, 3H), 2.20 (s, 3H), 2.34 (s, 3H), 2.92 (d, 3H), 2.98 (dd, 1H), 3.18 (dd, 1H), 5.53-5.59 (m, 1H), 6.52 (q, 1H), 7.10 (s, 1H), 7.13 (s, 1H), 7.40-7.46 (m, 4H).), 5 mg of the desired compound.

(470) LCMS (Method 2): R.sub.t=1.51 min; m/z=507 (M+H).sup.+

(471) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.90 (d, 3H), 2.26 (s, 3H), 2.40 (s, 3H), 2.85 (d, 3H), 2.88 (dd, 1H), 3.08 (dd, 1H), 5.44-5.52 (m, 1H), 6.48 (q, 1H), 7.05 (d, 1H), 7.24 (s, 1H), 7.28 (d, 2H), 7.45 (d, 2H)

Enantiomer Separation

(472) 35 mg of ()-7-chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 165) were separated into the enantiomers by chiral preparative HPLC using Method XVIII:

Example 156.1: (4S)-7-Chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(473) 15 mg yellowish solid, HPLC (Method W): R.sub.t=1.91 min, purity 98%

Example 156.2: (4R)-7-Chloro-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(trifluoromethoxy)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(474) 10 mg yellowish solid, HPLC (Method W): R.sub.t=2.86 min, purity 96%

(475) The following compounds were prepared from the appropriate chlorophenyl precursors using the process for the preparation of Example 155:

(476) TABLE-US-00046 No Structure Name Analytical data 157 0 ()-8-chloro-1-[4- (3,5-dimethyl- isoxazol-4-yl)- phenyl]-7-methoxy- N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.84-2.97 (m, 4H), 3.14 (dd, 1H), 3.97 (s, 3H), 5.43-5.55 (m, 1H), 6.43- 6.55 (m, 1H), 6.80 (s, 1H), 7.17 (s, 1H), 7.30 (d, 2H), 7.53 (d, 2H). LCMS (Method 2): R.sub.t = 1.35 min; m/z = 453 (M + H).sup.+. 157.1 (4S)-8-chloro-1-[4- (3,5- dimethylisoxazol-4- yl)phenyl]-7- methoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.35 min; m/z = 453 (M + H).sup.+ HPLC (Method N): R.sub.t = 2.82 min [].sub.D.sup.20 = 131.8 (c = 1.00; chloroform) 157.2 (4R)-8-chloro-1-[4- (3,5- dimethylisoxazol-4- yl)phenyl]-7- methoxy-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide LCMS (Method 2): R.sub.t = 1.35 min; m/z = 453 (M + H).sup.+ HPLC (Method N): R.sub.t = 4.27 min 158 ()-1-[4-(3,5- dimethylisoxazol-4- yl)phenyl]-N,4,8- trimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (600 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.28 (s, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.87 (dd, 1H), 2.90 (d, 3H), 3.10 (dd, 1H), 5.39-5.44 (m, 1H), 6.45 (q, 1H), 6.96 (s, 1H), 7.12- 7.17 (m, 2H), 7.30 (d, 2H), 7.57 (d, 2H). LCMS (Method 2): R.sub.t = 1.35 min; m/z = 403 (M + H).sup.+.

Example 160

()-7,8-Bis(difluoromethoxy)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(477) ##STR00354##

(478) 286 mg (7.17 mmol) of ()-1-(4-bromophenyl)-7,8-bis(difluoromethoxy)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 92A) were reacted analogously to Example 155, and the crude product was purified by preparative HPLC. This gave 22 mg (19% of theory) of the desired product.

(479) LCMS (Method 2): R.sub.t=1.35 min; m/z=521 (M+H).sup.+

(480) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.96 (d, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.65 (d, 3H), 2.74 (dd, 1H), 3.02 (dd, 1H), 5.02-5.12 (m, 1H), 6.67 (q, 1H), 6.97 (s, 1H), 7.08 (t, J=74 Hz, 1H), 7.27 (t, J=74 Hz, 1H), 7.41 (s, 1H), 7.43 (d, 2H), 7.74 (d, 2H).

Example 161

()-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-7,8-diethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(481) ##STR00355##

(482) The preparation was carried out analogously to Example 160 using Example 93A as starting material.

(483) LCMS (Method 1): R.sub.t=1.35 min; m/z=477 (M+H).sup.+

(484) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.95 (d, 3H), 1.20 (t, 3H), 1.32 (t, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.59-2.69 (m, 1H), 2.64 (d, 3H), 2.90 (dd, 1H), 3.79 (q, 2H), 4.08 (q, 2H), 4.97-5.09 (m, 1H), 6.51 (s, 1H), 6.59 (q, 1H), 6.99 (s, 1H), 7.41 (d, 2H), 7.72 (d, 2H).

(485) The following exemplary compounds were prepared from Example 97A and the appropriate commercially available boronic acid using the process for the preparation of Example 155:

(486) TABLE-US-00047 No Structure Name Analytical data 162 ()-7- (difluoromethoxy)-1- [4-(3,5-dimethyl- isoxazol-4-yl)phenyl]- 8-methoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 0.96 (d, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.58-2.65 (m, 1H), 2.65 (d, 3H), 2.93 (dd, 1H), 3.64 (s, 3H), 4.94- 5.05 (m, 1H), 6.60 (q, 1H), 6.73 (s, 1H), 7.14 (t, J = 75 Hz, 1H), 7.23 (s, 1H), 7.42 (d, 2H), 7.76 (d, 2H). LCMS (Method 2): R.sub.t = 1.32 min; m/z = 485 (M + H).sup.+ 162.1 (4S)-7- (difluoromethoxy)-1- [4-(3,5-dimethyl- isoxazol-4-yl)phenyl]- 8-methoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XII analyt. HPLC (Method Q): R.sub.t = 8.39 min 162.2 (4R)-7- (difluoromethoxy)-1- [4-(3,5-dimethyl- isoxazol-4-yl)phenyl]- 8-methoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XII analyt. HPLC (Method Q): R.sub.t = 10.53 min

(487) The following exemplary compounds were prepared analogously to Example 127.1 from Example 97A and the appropriate commercially available amines:

(488) TABLE-US-00048 No Structure Name Analytical data 163 ()-7- (difluoromethoxy)- 8-methoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 1.02 (d, 3H), 2.20 (s, 3H), 2.37-2.44 (m, 5H), 2.60 (d, 3H), 2.84 (dd, 1H), 3.19-3.25 (m, 4H), 3.65 (s, 3H), 4.77-4.86 (m, 1H), 6.30 (q, 1H), 6.70 (s, 1H), 6.93 (d, 2H), 7.13 (t, 1H), 7.21 (s, 1H), 7.58 (d, 2H). LCMS (Method 2): R.sub.t = 0.80 min; m/z = 488 (M + H).sup.+ 163.1 0 (4R)-7- (difluoromethoxy)- 8-methoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XII analyt. HPLC (Method Q): R.sub.t = 5.01 min 163.2 (4S)-7- (difluoromethoxy)- 8-methoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XII analyt. HPLC (Method Q): R.sub.t = 7.00 min

(489) The following exemplary compounds were prepared analogously to Example 32 using the appropriate commercially available heterocyclylchloroalkanes or heteroarylchloroalkanes:

(490) TABLE-US-00049 No Structure Name Analytical data 164 ()-1-(4- chlorophenyl)-N,4- dimethyl-8-[3-(4- methylpiperazin-1- yl)propoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 1.89 (m, 2H), 2.28 (s, 3H), 2.46 (m, 10H), 2.84 (dd, 1H), 2.88 (d, 3H), 3.08 (dd, 1H), 3.87 (m, 2H), 5.42 (m, 1H), 6.45 (qbr, 1H), 6.58 (d, 1H), 6.87 (dd, 1H), 7.11 (d, 1H), 7.36 (d, 2H), 7.42 (d, 2H). LC/MS (Method 3): R.sub.t = 0.89 min; m/z = 484; 486 (M + H, Cl isotope pattern).sup.+ 164.1 (4R)-1-(4- chlorophenyl)-N,4- dimethyl-8-[3-(4- methylpiperazin-1- yl)propoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide (Comparative Example) prep. HPLC: Method XVII analyt. HPLC (Method K): R.sub.t = 1.88 min [].sub.D.sup.20 = 124.2 (c = 1.00; MeOH) 164.2 (4S)-1-(4- chlorophenyl)-N,4- dimethyl-8-[3-(4- methylpiperazin-1- yl)propoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide prep. HPLC: Method XVII analyt. HPLC (Method K): R.sub.t = 2.41 min [].sub.D.sup.20 = +114.2 (c = 1.00; MeOH) 165 ()-1-(4- chlorophenyl)-N,4- dimethyl-8-[3- (morpholin-4- yl)propoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 1.93 (m, 2H), 2.49 (m, 4H), 2.51 (m, 2H), 2.84 (dd, 1H), 2.89 (d, 3H), 3.08 (dd, 1H), 3.73 (m, 4H), 3.88 (m, 2H), 5.42 (m, 1H), 6.45 (qbr, 1H), 6.58 (d, 1H), 6.87 (dd, 1H), 7.11 (d, 1H), 7.36 (d, 2H), 7.42 (d, 2H). LC/MS (Method 3): R.sub.t = 0.89 min; m/z = 471; 473 (M + H, Cl isotope pattern).sup.+ 166 ()-1-(4- chlorophenyl)-N,4- dimethyl-8-[2-(4- methylpiperazin-1- yl)ethoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 2.42 (s, 3H), 2.69 (m, 8H), 2.78 (tbr, 2H), 2.85 (m, 1H), 2.88 (d, 3H), 3.08 (dd, 1H), 3.95 (tbr, 2H), 5.42 (m, 1H), 6.45 (qbr, 1H), 6.58 (d, 1H), 6.87 (dd, 1H), 7.12 (d, 1H), 7.36 (d, 2H), 7.41 (d, 2H). LC/MS (Method 3): R.sub.t = 0.94 min; m/z = 470; 472 (M + H, Cl isotope pattern).sup.+ 167 ()-1-(4- chlorophenyl)-N,4- dimethyl-8-[(6- methylpiperazin-2- yl)methoxy]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (d, 3H), 2.53 (s, 3H), 2.85 (dd, 1H), 2.88 (d, 3H), 3.07 (dd, 1H), 4.99 (d, 1H), 5.04 (d, 1H), 5.43 (m, 1H), 6.47 (qbr, 1H), 6.64 (d, 1H), 6.98 (dd, 1H), 7.08 (d, 1H), 7.13 (d, 1H), 7.23 (d, 1H), 7.29 (d, 2H), 7.33 (d, 2H), 7.58 (dd, 1H). LC/MS (Method 3): R.sub.t = 1.31 min; m/z = 449; 451 (M + H, Cl isotope pattern).sup.+

Example 168

()-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-8-hydroxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(491) ##STR00368##

(492) The title compound was prepared analogously to Example 55A from the racemate of the compound described in Example 20.

(493) LCMS (Method 3): R.sub.t=1.06 min; m/z=405 (M+H).sup.+

(494) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.95 (d, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.57 (dd, 1H), 2.65 (d, 3H), 2.88 (dd, 1H), 4.95 (m, 1H), 6.44 (d, 1H), 6.58 (qbr, 1H), 6.81 (dd, 1H), 7.18 (d, 1H), 7.43 (d, 2H), 7.73 (d, 2H), 9.63 (sbr, 1H).

Example 169

()-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-[3-(morpholin-4-yl)propoxy]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(495) ##STR00369##

(496) The preparation was carried out analogously to Example 32.

(497) LCMS (Method 3): R.sub.t=0.88 min; m/z=532 (M+H).sup.+

(498) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.98 (d, 3H), 1.96 (m, 2H), 2.33 (s, 3H), 2.47 (s, 3H), 2.51 (m, 4H), 2.54 (m, 2H), 2.84 (dd, 1H), 2.90 (d, 3H), 3.08 (dd, 1H), 3.73 (m, 4H), 3.93 (m, 2H), 5.40 (m, 1H), 6.44 (qbr, 1H), 6.69 (d, 1H), 6.90 (dd, 1H), 7.14 (d, 1H), 7.29 (d, 2H), 7.58 (d, 2H).

Example 170

()-7-Cyano-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(499) ##STR00370##

(500) The preparation was carried out analogously to Example 155.

(501) LCMS (Method 3): R.sub.t=1.19 min; m/z=444 (M+H).sup.+

(502) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.94 (d, 3H), 2.33 (s, 3H), 2.47 (s, 3H), 2.90 (dd, 1H), 2.92 (d, 3H), 3.11 (dd, 1H), 3.73 (s, 3H), 5.50 (m, 1H), 6.54 (qbr, 1H), 6.74 (s, 1H), 7.33 (d, 2H), 7.42 (s, 1H), 7.54 (d, 2H).

Example 171

()-8-Acetamido-N,4-dimethyl-1-[4-(morpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(503) ##STR00371##

(504) Under argon, 200 mg (520 mol) of ()-8-acetamido-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 89A) were initially charged in 8 ml of degassed toluene. 47 l (47 mg, 540 mol) of morpholine, 70 mg (728 mol) of sodium tert-butoxide and 20 mg (26 mol) of chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl) [2-(2-amino-1,1-biphenyl)]palladium(II) [CAS 1310584-14-5] were added. The mixture was degassed again, saturated with argon and then stirred at 110 C. for 5 hours. A further 25 mg of morpholine, 35 mg of sodium tert-butoxide and 10 mg of catalyst were added, and the mixture was stirred at 110 C. for a further 7 h. After cooling, the mixture was partitioned between sat. sodium bicarbonate solution and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by preparative HPLC. This gave 9.8 mg (4.2% of theory) of the desired product.

(505) LCMS (Method 2): R.sub.t=0.98 min; m/z=436 (M+H).sup.+

(506) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.00 (d, 3H), 1.94 (s, 3H), 2.34-2.40 (m, 1H), 2.59 (d, 3H), 2.82 (dd, 1H), 3.14-3.22 (m, 4H), 3.66-3.77 (m, 4H), 4.76-4.89 (m, 1H), 6.31 (q, 1H), 6.94 (d, 2H), 7.25 (d, 1H), 7.31 (d, 1H), 7.52-7.60 (m, 3H), 9.90 (s, 1H).

Example 172

()-8-Acetamido-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(507) ##STR00372##

(508) The compound was prepared analogously to Example 127.1.

(509) LCMS (Method 2): R.sub.t=0.65 min; m/z=449 (M+H).sup.+

(510) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.01 (d, 3H), 1.94 (s, 3H), 2.19 (s, 3H), 2.34-2.53 (m, 5H), 2.59 (d, 3H), 2.82 (dd, 1H), 3.20-3.24 (m, 4H), 4.75-4.86 (m, 1H), 6.28 (q, 1H), 6.92 (d, 2H), 7.25 (d, 1H), 7.31 (d, 1H), 7.54 (d, 2H), 7.52-7.57 (m, 1H), 9.90 (s, 1H).

Example 173

()-8-Acetamido-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(511) ##STR00373##

(512) 200 mg (520 mol) of ()-8-acetamido-1-(4-chlorophenyl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide were dissolved in 8 ml of degassed THF/water 10:1, and 76 mg (540 mol) of 3,5-dimethylisoxazole-4-boronic acid, 150 mg (260 mol) of potassium fluoride and 20 mg (26 mol) of chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) were added. The reaction mixture was degassed again and stirred under an atmosphere of argon at 80 C. for 7 hours. The mixture was then partitioned between sat. sodium bicarbonate solution and ethyl acetate, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and sat. sodium chloride solution and dried with sodium sulphate. The solvents were removed on a rotary evaporator and the residue was purified by preparative HPLC. This gave 24.4 mg (11% of theory) of the desired product.

(513) LCMS (Method 2): R.sub.t=1.09 min; m/z=446 (M+H).sup.+

(514) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.94 (d, 3H), 1.93 (s, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.59-2.68 (m, 1H), 2.64 (d, 3H), 2.92 (dd, 1H), 4.93-5.05 (m, 1H), 6.58 (q, 1H), 7.28 (d, 1H), 7.29 (s, 1H), 7.43 (d, 1H), 7.64 (dd, 1H), 7.74 (d, 2H), 9.92 (s, 1H).

Example 174

()-1-(4-Chlorophenyl)-8-(3,5-dimethyl-1H-pyrazol-1-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(515) ##STR00374##

(516) The compound was prepared analogously to Example 16 in a yield of 87%.

(517) LCMS (Method 1): R.sub.t=1.38 min; m/z=422 (M+H).sup.+

(518) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.91 (d, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 2.65 (d, 3H), 2.83 (dd, 1H), 3.05 (dd, 1H), 5.10-5.18 (m, 1H), 5.98 (s, 1H), 6.71 (q, 1H), 7.02 (d, 1H), 7.45 (d, 2H), 7.43-7.53 (m, 2H), 7.64 (d, 2H).

Example 175

()-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-8-(3,5-dimethyl-1H-pyrazol-1-yl)-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(519) ##STR00375##

(520) The compound was prepared analogously to Example 155 in a yield of 24%.

(521) LCMS (Method 1): R.sub.t=1.31 min; m/z=483 (M+H).sup.+

(522) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.95 (d, 3H), 2.07 (s, 3H), 2.19 (s, 3H), 2.23 (s, 3H), 2.41 (s, 3H), 2.65 (d, 3H), 2.80 (dd, 1H), 3.05 (dd, 1H), 5.05-5.15 (m, 1H), 5.99 (s, 1H), 6.69 (q, 1H), 7.08 (d, 1H), 7.43 (d, 2H), 7.44-7.55 (m, 2H), 7.75 (d, 2H).

Example 176

()-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(523) ##STR00376##

(524) The compound was prepared analogously to Example 155 from ()-1-(4-chlorophenyl)-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 11).

(525) LCMS (Method 2): R.sub.t=1.24 min; m/z=474 (M+H).sup.+

(526) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =0.96 (d, 3H), 2.24 (s, 3H), 2.42 (s, 3H), 2.56 (dd, 1H), 2.64 (d, 3H), 2.87 (dd, 1H), 2.92-2.98 (m, 4H), 3.61-3.67 (m, 4H), 4.89-4.97 (m, 1H), 6.52-6.56 (m, 2H), 7.02 (dd, 1H), 7.23 (d, 1H), 7.42 (d, 2H), 7.76 (d, 2H).

Enantiomer Separation

(527) 90 mg of ()-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 185) were separated into the enantiomers by chiral preparative HPLC using Method XIII:

Example 176.1: (4R)-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(528) 27 mg of a solid, HPLC (Method R): R.sub.t=2.58 min, purity 98.2%/100% ee

Example 176.2: (4S)-1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]-N,4-dimethyl-8-(morpholin-4-yl)-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(529) 23 mg of a solid, HPLC (Method R): R.sub.t=3.06 min, purity 96.3%/92.7% ee

Example 177

(4S)-8-Methoxy-N,4-dimethyl-1-[4-(3-oxomorpholin-4-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(530) ##STR00377##

(531) 112 mg (0.244 mmol) of (4S)-1-(4-{[(2-chloroethoxy)acetyl]amino}phenyl)-8-methoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 94A) were dissolved in 1.1 ml of acetonitrile, and 71 mg (0.512 mmol) of potassium carbonate were added. After addition of a catalytic amount of sodium iodide, the mixture was heated at reflux for 5 h. The reaction was filtered, the filter cake washed with acetonitrile and the solvent was removed on a rotary evaporator. The residue was purified by preparative HPLC. This gave 16 mg (15% of theory) of the desired product as a solid.

(532) UPLC/MS (Method 1): R.sub.t=1.0 min; m/z=423 (M+H).sup.+

(533) The following exemplary compounds were prepared analogously to Example 127.1 from Example 49A or Example 49.2A and the appropriate commercially available amines:

(534) TABLE-US-00050 No. Structure Name Analytical data 178 ()-1-{4-[4-(2- hydroxyethyl)piperazin- 1-yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.11 (d, 3H), 2.61-2.64 (m, 2H), 2.69-2.71 (m, 4H), 2.73 (dd, 1H), 2.87 (d, 3H), 2.94 (dd, 1H), 3.30- 3.32 (m, 4H), 3.65-3.69 (m, 2H), 3.70 (s, 3H), 3.93 (s, 3H), 5.24- 5.33 (m, 1H), 6.12 (q, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 6.91 (d, 2H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 0.72 min; m/z = 482 (M + H).sup.+ 179 ()-7,8-dimethoxy-1- [4-(4- methoxypiperidin-1- yl)phenyl]-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.12 (d, 3H), 1.68-1.75 (m, 2H), 1.99-2.05 (m, 2H), 2.72 (dd, 1H), 2.86 (d, 3H), 2.92 (dd, 1H), 3.04- 3.09 (m, 2H), 3.39 (s, 3H), 3.60- 3.64 (m, 2H), 3.70 (s, 3H), 3.93 (s, 3H), 5.24-5.30 (m, 1H), 6.07 (q, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 6.91 (d, 2H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 1.13 min; m/z = 467 (M + H).sup.+ 179.1 0 (4R)-7,8-dimethoxy-1- [4-(4-methoxypiperidin- 1-yl)phenyl]-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 7.77 min 179.2 (4S)-7,8-dimethoxy- 1-[4-(4- methoxypiperidin-1- yl)phenyl]-N,4- dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 12.0 min 180 ()-1-{4-[4- (dimethylamino) piperidin-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.05 (d, 3H), 1.52-1.62 (m, 3H), 1.85-1.91 (m, 2H), 2.25 (s, 6H), 2.65 (dd, 1H), 2.72-2.78 (m, 2H), 2.79 (d, 3H), 2.85 (dd, 1H), 3.63 (s, 3H), 3.76-3.82 (m, 2H), 3.86 (s, 3H), 5.17-5.23 (m, 1H), 6.00 (q, 1H), 6.58 (s, 1H), 6.68 (s, 1H), 6.84 (d, 2H), 7.41 (d, 2H). LCMS (Method 1): R.sub.t = 0.76 min; m/z = 480 (M + H).sup.+ 180.1 (4R)-1-{4-[4- (dimethylamino) piperidin-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 9.20 min 180.2 (4S)-1-{4-[4- (dimethylamino) piperidin-1-yl]phenyl}- 7,8-dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 14.3 min 181 ()-1-[4-(3,3- difluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.10 (d, 3H), 2.74 (dd, 1H), 2.87 (d, 3H), 2.96 (dd, 1H), 3.70 (s, 3H), 3.94 (s, 3H), 4.29 (t, 4H), 5.27-5.34 (m, 1H), 6.14 (q, 1H), 6.50 (d, 2H), 6.61 (s, 1H), 6.75 (s, 1H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 1.21 min; m/z = 445 (M + H).sup.+ 182 ()-1-[4-(4- acetamidopiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.11 (d, 3H), 1.50-1.58 (m, 2H), 1.99 (s, 3H), 2.04 -2.10 (m, 2H), 2.72 (dd, 1H), 2.86 (d, 3H), 2.92- 2.98 (m, 3H), 3.70 (s, 3H), 3.73- 3.80 (m, 2H), 3.93 (s, 3H), 3.95- 4.03 (m, 1H), 5.25-5.32 (m, 1H), 5.34 (d, 1H), 6.10 (q, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 6.91 (d, 2H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 0.94 min; m/z = 494 (M + H).sup.+ 183 ()-1-{4-[4-(2- hydroxyethyl)piperidin- 1-yl]phenyl}-7,8- dimcthoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (500 MHz, CDCl.sub.3): = 1.13 (d, 3H), 1.35-1.43 (m, 2H), 1.56-1.60 (m, 2H), 1.63-1.71 (m, 1H), 1.81-1.87 (m, 2H), 2.71 (dd, 1H), 2.78-2.84 (m, 2H), 2.86 (d, 3H), 2.91 (dd, 1H), 3.70 (s, 3H), 3.74-3.77 (m, 2H), 3.78-3.83 (m, 2H), 3.93 (s, 3H), 5.23-5.29 (m, 1H), 6.05 (q, 1H), 6.65 (s, 1H), 6.75 (s, 1H), 6.92 (d, 2H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 0.96 min; m/z = 481 (M + H).sup.+ 184 ()-1-[4-(3- hydroxyazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.16 (d, 3H), 2.21 (d, 1H), 2.73 (dd, 1H), 2.88 (d, 3H), 2.92 (dd, 1H), 3.73 (s, 3H), 3.80 (dd, 2H), 3.96 (s, 3H), 4.27 (t, 2H), 4.80- 4.87 (m, 1H), 5.22-5.31 (m, 1H), 6.02 (q, 1H), 6.47 (d, 2H), 6.65 (s, 1H), 6.76 (s, 1H), 7.50 (d, 2H). LCMS (Method 1): R.sub.t = 0.91 min; m/z = 425 (M + H).sup.+ 185 ()-1-[4-(3-hydroxy-3- methylazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.16 (d, 3H), 1.66 (s, 3H), 2.10 (s, br, 1H), 2.73 (dd, 1H), 2.88 (d, 3H), 2.92 (dd, 1H), 3.73 (s, 3H), 3.86 (d, 2H), 3.95 (d, 2H), 3.96 (s, 3H), 5.22-5.30 (m, 1H), 6.02 (q, 1H), 6.48 (d, 2H), 6.65 (s, 1H), 6.76 (s, 1H), 7.50 (d, 2H). LCMS (Method 1): R.sub.t = 0.97 min; m/z = 439 (M + H).sup.+ 185.1 0 (4R)-1-[4-(3-hydroxy- 3-methylazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XXI Analyt. HPLC (Method Y): R.sub.t = 2.35 min 185.2 (4S)-1-[4-(3-hydroxy- 3-methylazetidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XXI Analyt. HPLC (Method Y): R.sub.t = 3.13 min 186 ()-1-[4-(4- Isopropylpiperazin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.12-1.14 (m, 9H), 2.71-2.79 (m, 6H), 2.89 (d, 3H), 2.96 (dd, 1H), 3.32-3.35 (m, 4H), 3.72 (s, 3H), 3.96 (s, 3H), 5.26-5.34 (m, 1H), 6.11 (q, 1H), 6.67 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.52 (d, 2H). LCMS (Method 1): R.sub.t = 0.76 min; m/z = 480 (M + H).sup.+ 187 ()-7,8-dimethoxy-1-[4- (3-methoxyazetidin-1- yl)phenyl]-N,4-dimethyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.16 (d, 3H), 2.73 (dd, 1H), 2.88 (d, 3H), 2.93 (dd, 1H), 3.38 (s, 3H), 3.73 (s, 3H), 3.80-3.84 (m, 2H), 3.96 (s, 3H), 4.17-4.22 (m, 2H), 4.37-4.43, 5.22-5.32 (m, 1H), 6.02 (q, 1H), 6.47 (d, 2H), 6.65 (s, 1H), 6.78 (s, 1H), 7.50 (d, 2H). LCMS (Method 1): R.sub.t = 1.11 min; m/z = 439 (M + H).sup.+ 188 ()-1-[4-(4-hydroxy-4- methylpiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.15 (d, 3H), 1.34 (s, 3H), 1.71-1.84 (m, 4H), 2.74 (dd, 1H), 2.89 (d, 3H), 2. 95 (dd, 1H), 3.29-3.35 (m, 2H), 3.49-3.54 (m, 2H), 3.73 (s, 3H), 3.96 (s, 3H), 5.24-5.33 (m, 1H), 6.08 (q, 1H), 6.68 (s, 1H), 6.78 (s, 1H), 6.95 (d, 2H), 7.51 (d, 2H). LCMS (Method 1): R.sub.t = 0.96 min; m/z = 467 (M + H).sup.+ 188.1 (4R)-1-[4-(4-hydroxy-4- methylpiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 5.45 min 188.2 (4S)-1-[4-(4-hydroxy-4- methylpiperidin-1- yl)phenyl]-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XX Analyt. HPLC (Method L): R.sub.t = 8.05 min 189 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (methylcarbamoyl) piperidin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.14 (d, 3H), 1.82-2.06 (m, 4H), 2.24-2.38 (m, 1H), 2.72 (dd, 1H), 2.81-3.02 (m, 9H), 3.73 (s, 3H), 3.89 (d, 2H), 3.96 (s, 3H), 5.29 (m, 1H), 5.55 (m, 1H), 6.10 (m, 1H), 6.67 (s, 1H), 6.77 (s, 1H), 6.93 (d, 2H), 7.51 (d, 2H). LCMS (Method 1): R.sub.t = 0.93 min; m/z = 494 (M + H).sup.+ 189.1 (4S)-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (methylcarbamoyl) piperidin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XIX Analyt. HPLC (Method V): R.sub.t = 7.35 min [].sub.D.sup.20 = 292.7 (c = 1.00; MeOH) 189.2 (4R)-7,8-dimethoxy-N,4- dimethyl-1-{4-[4- (methylcarbamoyl) piperidin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XIX Analyt. HPLC (Method V): R.sub.t = 6.23 min [].sub.D.sup.20 = 311.5 (c = 1.00; MeOH) 190 00 ()-1-{4-[(3S)-3- hydroxypyrrolidin-1- yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide LCMS (Method 2): R.sub.t = 0.80 min; m/z = 439 (M + H).sup.+ 190.1 01 (4S)-1-{4-[(3S)-3- hydroxypyrrolidin-1- yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.20 (d, 3H), 1.74 (s, br, 1H), 2.07- 2.30 (m, 2H), 2.71 (dd, 1H), 2.88 (d, 3H), 2.90 (dd, 1H), 3.37 (d, 1H), 3.47 (dt, 1H), 3.57-3.65 (m, 2H), 3.74 (s, 3H), 3.96 (s, 3H), 4.68 (m, 1H), 5.17-5.30 (m, 1H), 5.94 (q, 1H), 6.59 (d, 2H), 6.68 (s, 1H), 6.79 (s, 1H), 7.54 (d, 2H). LCMS (Method 1): R.sub.t = 0.92 min; m/z = 439 (M + H).sup.+ 191 02 ()-tert-butyl (1-{4- [7,8-dimethoxy-4- methyl-3- (methylcarbamoyl)- 4,5-dihydro-3H-2,3- benzodiazepin-1- yl]phenyl}-4- methylpiperidin-4- yl)carbamate .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.14 (d, 3H), 1.43 (s, 3H), 1.47 (s, 9H), 1.77 (dt, 2H), 2.16 (d, br, 2H), 2.74 (dd, 1H), 2.88 (d, 3H), 2.95 (dd, 1H), 3.16 (dt, 2H), 3.43-3.54 (m, 2H), 3.73 (s, 3H), 3.96 (s, 3H), 4.41 (s, br, 1H), 5.23-5.37 (m, 1H), 6.10 (q, 1H), 6.67 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.51 (d, 2H). LCMS (Method 2): R.sub.t = 1.29 min; m/z = 566 (M + H).sup.+ 192 03 ()-1-{4-[(2S,5R)-2,5- dimethylpiperazin-1- yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.05 (d, 3H), 1.10 (dd, 3H), 1.15 (d, 3H), 2.65 (dd, 1H), 2.73-2.84 (m, 2H), 2.90 (d, 3H), 3.02 (dt, 1H), 3.10-3.29 (m, 4H), 3.71 (s, 3H), 3.96 (s, 3H), 5.30-5.42 (m, 1H), 6.21-6.31 (m, 1H), 6.65 (s, 1H), 6.76 (s, 1H), 7.09 (d, 2H), 7.51 (d, 2H). LCMS (Method 2): R.sub.t = 0.64 min; m/z = 466 (M + H).sup.+ 193 04 ()-1-{4-[4-(2,2- difluoroethyl)piperazin- 1-yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (600 MHz, DMSO-d.sub.6): = 1.05 (d, 3H), 2.44-2.49 (m, 1H), 2.63 (d, 3H), 2.66-2.69 (m, 4H), 2.76-2.87 (m, 3H), 3.23-3.28 (m, 4H), 3.60 (s, 3H), 3.84 (s, 3H), 4.90 (dquin, 1H), 6.07-6.33 (m, 2H), 6.55 (s, 1H), 6.95 (d, 2H), 7.02 (s, 1H), 7.59 (d, 2H). LCMS (Method 2): R.sub.t = 0.90 min; m/z = 502 (M + H).sup.+ 194 05 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(3- oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.59-2.69 (m, 5H), 2.92 (dd, 1H), 3.03 (t, 2H), 3.41 (s, 2H), 3.59 (s, 3H), 3.63-3.68 (m, 2H), 3.84 (s, 3H), 4.97-5.10 (m, 1H), 6.50-6.56 (m, 2H), 7.03 (s, 1H), 7.40 (d, 2H), 7.70 (d, 2H). LCMS (Method 1): R.sub.t = 0.69 min; m/z = 452 (M + H).sup.+ 195 06 (4S)-1-{4-[(2R,6S)-2,6- dimethylmorpholin-4- yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.13 (d, 3H), 1.31 (d, 6H), 2.52 (dd, 2H), 2.75 (dd, 1H), 2.89 (d, 3H), 2.98 (dd, 1H), 3.58 (d, 2H), 3.72 (s, 3H), 3.78-3.90 (m, 2H), 3.96 (s, 3H), 5.25-5.39 (m, 1H), 6.15 (q, 1H), 6.66 (s, 1H), 6.77 (s, 1H), 6.92 (d, 2H), 7.52 (d, 2H). LCMS (Method 1): R.sub.t = 1.23 min; m/z = 467 (M + H).sup.+ 196 07 ()-7,8-dimethoxy-N,4- dimethyl-1-[4-(4- oxopiperidin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.13 (d, 3H), 2.62 (t, 4H), 2.76 (dd, 1H), 2.89 (d, 3H), 2.98 (dd, 1H), 3.73 (s, 3H), 3.71-3.79 (m, 4H), 3.97 (s, 3H), 5.27-5.39 (m, 1H), 6.12-6.20 (m, 1H), 6.68 (s, 1H), 6.78 (s, 1H), 6.99 (d, 2H), 7.56 (d, 2H). LCMS (Method 5): R.sub.t = 0.92 min; m/z = 451 (M + H).sup.+ 197 08 ()-7,8-dimethoxy-N,4- dimethyl-1-{4-[4-(2,2,2- trifluoroethyl)piperazin- 1-yl]phenyl}-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.12 (d, 3H), 2.75 (dd, 1H), 2.85- 2.92 (m, 4H), 2.88 (d, 3H), 2.97 (dd, 1H), 3.08 (q, 2H), 3.31-3.39 (m, 4H), 3.72 (s, 3H), 3.96 (s, 3H), 5.27-5.37 (m, 1H), 6.12-6.19 (m, 1H), 6.66 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.52 (d, 2H). LCMS (Method 5): R.sub.t = 1.22 min; m/z = 520 (M + H).sup.+ 198 09 (4S)-1-{4-[(3R,5S)-3,5- dimethylpiperazin-1- yl]phenyl}-7,8- dimethoxy-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.14 (d, 3H), 1.19 (d, 6H), 2.40 (t, 2H), 2.74 (dd, 1H), 2.88 (d, 3H), 2.96 (dd, 1H), 3.01-3.13 (m, 2H), 3.66 (dd, 2H), 3.73 (s, 3H), 3.96 (s, 3H), 5.24-5.37 (m, 1H), 6.11 (q, 1H), 6.67 (s, 1H), 6.77 (s, 1H), 6.93 (d, 2H), 7.51 (d, 2H). LCMS (Method 1): R.sub.t = 0.77 min; m/z = 466 (M + H).sup.+

Example 199

()-7,8-Dihydroxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(535) ##STR00410##

(536) The compound was prepared analogously to Example 91A from Example 127.

(537) LCMS (Method 1): R.sub.t=1.01 min; m/z=424 (M+H).sup.+

(538) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =0.97 (d, 3H), 2.50 (m, 1H), 2.60 (d, 3H), 3.11 (s, 3H), 3.22-3.53 (m, 5H), 3.77-3.94 (m, 4H), 4.80-4.90 (m, 1H), 6.26-6.32 (m, 1H), 6.36 (s, 1H), 6.69 (s, 1H), 6.99 (d, 2H), 7.57 (d, 2H), 8.91 (s, br, 1H), 9.36 (s, br, 1H).

Example 200

()-7,8-Diethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(539) ##STR00411##

(540) The compound was prepared analogously to Example 93A from Example 199.

(541) LCMS (Method 1): R.sub.t=1.48 min; m/z=480 (M+H).sup.+

(542) .sup.1H-NMR (600 MHz, DMSO-d.sub.6): =1.03 (d, 3H), 1.22 (t, 3H), 1.35 (t, 3H), 2.51 (m, 1H), 2.64 (d, 3H), 2.84 (dd, 1H), 3.14 (s, 3H), 3.30-3.37 (m, 2H), 3.51 (d, 2H), 3.77-3.88 (m, 4H), 3.92 (d, 2H), 4.11 (q, 2H), 4.90-4.96 (m, 1H), 6.37 (q, 1H), 6.50 (s, 1H), 7.00 (s, 1H), 7.02 (d, 2H), 7.62 (d, 2H).

(543) The following exemplary compounds were prepared analogously to Example 127.1 from Example 127A and the appropriate commercially available amines:

(544) TABLE-US-00051 No. Structure Name Analytical data 201 ()-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(4-methylpiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.21-1.37 (m, 1H), 1.50-1.61 (m, 1H), 2.40 (s, 3H), 2.56-2.69 (m, 4H), 2.84 (dd, 1H), 2.88 (d, 3H), 2.99 (dd, 1H), 3.29- 3.39 (m, 4H), 3.71 (s, 3H), 3.96 (s, 3H), 5.12-5.24 (m, 1H), 6.22-6.32 (m, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 6.94 (d, 2H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 0.65 min; m/z = 466 (M + H).sup.+ 201.1 (4S)-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(4-methylpiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XIIa Analyt. HPLC (Method Q): R.sub.t = 10.90 min [].sub.D.sup.20 = 100.8 (c = 1.00; CHCl.sub.3) LCMS (Method 5): R.sub.t = 0.64 min; m/z = 466 (M + H).sup.+ 202 ()-4-ethyl-7,8- dimethoxy-N-methyl- 1-[4-(piperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.23-1.38 (m, 1H), 1.52-1.61 (m, 1H), 2.85 (dd, 1H), 2.88 (d, 3H), 2.99 (dd, 1H), 3.04- 3.11 (m, 4H), 3.23-3.31 (m, 4H), 3.71 (s, 3H), 3.96 (s, 3H), 5.13- 5.22 (m, 1H), 6.26 (q, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.93 (d, 2H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 0.65 min; m/z = 452 (M + H).sup.+ 202.1 (4S)-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(piperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XXa Analyt. HPLC (Method L1): R.sub.t = 4.10 min [].sub.D.sup.20 = 86.2 (c = 1.00; CHCl.sub.3) LCMS (Method 5): R.sub.t = 0.63 min; m/z = 452 (M + H).sup.+ 202.2 (4R)-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(piperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XXa Analyt. HPLC (Method L1): R.sub.t = 5.50 min [].sub.D.sup.20 = 103.4 (c = 1.00; CHCl.sub.3) LCMS (Method 5): R.sub.t = 0.63 min; m/z = 452 (M + H).sup.+ 203 ()-4-ethyl-7,8- dimethoxy-N-methyl-1- {4-[4-(methylsulphonyl) piperazin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.89 (t, 3H), 1.18-1.33 (m, 1H), 1.46-1.59 (m, 1H), 2.87 (s, 3H), 2.81-2.88 (m, 1H), 2.89 (d, 3H), 3.01 (dd, 1H), 3.35-3.47 (m, 8H), 3.70 (s, 3H), 3.96 (s, 3H), 5.15- 5.25 (m, 1H), 6.30-6.38 (m, 1H), 6.66 (s, 1H), 6.76 (s, 1H), 6.95 (d, 2H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 1.01 min; m/z = 530 (M + H).sup.+ 203.1 (4S)-4-ethyl-7,8- dimethoxy-N-methyl-1- {4-[4-(methylsulphonyl) piperazin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method IVa Analyt. HPLC (Method Fa): R.sub.t = 6.22 min [].sub.D.sup.20 = 252.5 (c = 1.00; MeOH) LCMS (Method 5): R.sub.t = 1.0 min; m/z = 530 (M + H).sup.+ 203.2 (4R)-4-ethyl-7,8- dimethoxy-N-methyl-1- {4-[4-(methylsulphonyl) piperazin-1-yl]phenyl}- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method IVa Analyt. HPLC (Method Fa): R.sub.t = 4.37 min [].sub.D.sup.20 = 257.4 (c = 1.00; MeOH) LCMS (Method 5): R.sub.t = 1.0 min; m/z = 530 (M + H).sup.+ 204 0 ()-4-ethyl-1-[4-(3- fluoroazetidin-1- yl)phenyl]-7,8- dimethoxy-N-methyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.92 (t, 3H), 1.26-1.46 (m, 1H), 1.53-1.71 (m, 1H), 2.83 (m, 1H), 2.87 (d, 3H), 2.98 (dd, 1H), 3.72 (s, 3H), 3.96 (s, 3H), 4.0-4.15 (m, 2H), 4.23-4.37 (m, 2H), 5.10-5.23 (m, 1H), 5.49 (d, 1H), 6.20 (q, 1H), 6.49 (d, 2H), 6.67 (s, 1H), 6.78 (s, 1H), 7.52 (s, br, 2H). LCMS (Method 5): R.sub.t = 1.13 min; m/z = 441 (M + H).sup.+ 205 ()-1-[4-(4- acetylpiperazin-1- yl)phenyl]-4-ethyl-7,8- dimethoxy-N-methyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.19-1.36 (m, 1H), 1.47-1.62 (m, 1H), 2.18 (s, 3H), 2.83-2.93 (m, 1H), 2.88 (d, 3H), 3.01 (dd, 1H), 3.26-3.38 (m, 4H), 3.66-3.73 (m, 2H), 3.70 (s, 3H), 3.80-3.88 (m, 2H), 3.96 (s, 3H), 5.14-5.26 (m, 1H), 6.29-6.38 (m, 1H), 6.66 (s, 1H), 7.77 (s, 1H), 6.96 (d, 2H), 7.51 (d, 2H). LCMS (Method 5): R.sub.t = 0.92 min; m/z = 494 (M + H).sup.+ 206 ()-1-[4-(1,1- dioxidothiomorpholin- 4-yl)phenyl]-4-ethyl- 7,8-dimethoxy-N- methyl-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.17-1.34 (m, 1H), 1.45-1.59 (m, 1H), 2.85-2.95 (m, 1H), 2.89 (d, 3H), 3.02 (dd, 1H), 3.12-3.20 (m, 4H), 3.72 (s, 3H), 3.97 (s, 3H), 3.96-4.03 (m, 4H), 5.17-5.28 (m, 1H), 6.34-6.43 (m, 1H), 6.66 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.53 (d, 2H). LCMS (Method 5): R.sub.t = 0.92 min; m/z = 501 (M + H).sup.+ 207 ()-4-ethyl-1-[4-(4- hydroxypiperidin-1- yl)phenyl]-7,8- dimethoxy-N-methyl- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.25-1.38 (m, 1H), 1.51-1.64 (m, 2H), 1.67-1.78 (m, 2H), 2.01-2.10 (m, 2H), 2.84 (dd, 1H), 2.88 (d, 3H), 2.98 (dd, 1H), 3.07 (dt, 2H), 3.66-3.71 (m, 2H), 3.71 (s, 3H), 3.89-3.95 (m, 1H), 3.96 (s, 3H), 5.12-5.21 (m, 1H), 6.20-6.26 (m, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.48 (d, 2H). LCMS (Method 5): R.sub.t = 0.87 min; m/z = 467 (M + H).sup.+ 208 ()-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(morpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.20-1.36 (m, 1H), 1.50-1.65 (m, 1H), 2.86 (dd, 1H), 2.88 (d, 3H), 3.00 (dd, 1H), 3.24- 3.31 (m, 4H), 3.71 (s, 3H), 3.87- 3.94 (m, 4H), 3.96 (s, 3H), 5.13- 5.24 (m, 1H), 6.30 (q, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 6.93 (d, 2H), 7.50 (d, 2H). LCMS (Method 5): R.sub.t = 1.06 min; m/z = 453 (M + H).sup.+ 209 (4S)-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(morpholin-4- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide Prep. HPLC: Method XIIa Analyt. HPLC (Method V): R.sub.t = 12.46 min [].sub.D.sup.20 = 75.1 (c = 1.00; CHCl.sub.3) LCMS (Method 5): R.sub.t = 1.06 min; m/z = 453 (M + H).sup.+

(545) The following exemplary compounds were prepared analogously to Example 127.1 from Example 130A and the appropriate commercially available amines. In many cases, under the reaction conditions, mixtures of mono- and di-aminated products, and also mono-dehalogenated coupling products, were obtained, and were separated by chromatography.

(546) TABLE-US-00052 No. Structure Name Analytical data 210 ()-8-chloro-1-[4-(1,1- dioxidothiomorpholin-4- yl)phenyl]-N,4-dimethyl- 7-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.02 (d, 3H), 2.79-2.92 (m, 4H), 3.06 (dd, 1H), 3.11-3.18 (m, 4H), 3.92-4.01 (m, 4H), 5.35-5.48 (m, 1H), 6.27 (br. s., 1H), 6.95 (d, 2H), 7.21 (d, 1H), 7.26 (s, 1H), 7.46 (d, 2H). LCMS (Method 1): R.sub.t = 1.28 min; m/z = 545 (M + H).sup.+ 211 ()-8-chloro-N,4- dimethyl-1-[4- (piperazin-1-yl)phenyl]- 7-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.07 (d, 3H), 2.79 (dd, 1H), 2.86 (d, 3H), 3.00 (dd, 1H), 3.05-3.11 (m, 4H), 3.26-3.35 (m, 4H), 5.27- 5.37 (m, 1H), 6.12 (q, 1H), 6.92 (d, 2H), 7.21 (s, br, 1H), 7.28 (s, 1H), 7.44 (d, 2H). LCMS (Method 1): R.sub.t = 0.93 min; m/z = 496 (M + H).sup.+ 212 ()-8-chloro-1-[4-(4- hydroxypiperidin-1- yl)phenyl]-N,4-dimethyl- 7-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.11 (d, 3H), 1.72-1.86 (m, 2H), 1.99-2.11 (m, 2H), 2.78 (dd, 1H), 2.88 (d, 3H), 3.00 (dd, 1H), 3.04- 3.16 (m, 2H), 3.66-3.78 (m, 2H), 3.88-4.01 (m, 1H), 5.25-5.38 (m, 1H), 6.05-6.15 (m, 1H), 6.95 (d, 2H), 7.23 (s, 1H), 7.29 (s, 1H), 7.46 (d, 2H). LCMS (Method 1): R.sub.t = 1.26 min; m/z = 511 (M + H).sup.+ 213 ()-8-chloro-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.04 (d, 3H), 2.61 (br. s., 3H), 2.73-2.93 (m, 7H), 3.03 (dd, 2H), 3.51 (d, 4H), 5.37 (br. s., 1H), 6.20 (br. s., 1H), 6.93 (d, 2H), 7.20 (s, 1H), 7.25 (s, 1H), 7.43 (d, 2H). LCMS (Method 1): R.sub.t = 0.95 min; m/z = 510 (M + H).sup.+ 214 0 ()-8-chloro-N,4- dimethyl-1-{4-[4- (methylsulphonyl) piperazin-1-yl]phenyl}- 7-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.06 (d, 3H), 2.85 (dd, 1H), 2.87 (s, 3H), 2.90 (d, 3H), 3.06 (d, 1H), 3.39-3.51 (br. s., 8H), 5.34-5.46 (m, 1H), 6.25 (q, 1H), 6.97 (d, 2H), 7.23 (s, 1H), 7.28 (s, 1H), 7.47 (d, 2H). LCMS (Method 1): R.sub.t = 1.35 min; m/z = 574 (M + H).sup.+ 215 ()-8-(1,1- dioxidothiomorpholin- 4-yl)-1-[4-(1,1- dioxidothiomorpholin- 4-yl)phenyl]-N,4- dimethyl-7- (trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.08 (d, 3H), 2.80 (dd, 1H), 2.90 (s, 3H), 3.01 (dd, 1H), 3.15-3.20 (m, 8H), 3.42-3.48 (m, 4H), 3.98- 4.03 (m, 4H), 5.31-5.41 (m, 1H), 6.12-6.26 (m, 1H), 6.86 (s, 1H), 6.97 (d, 2H), 7.16 (d, 1H), 7.51 (d, 2H). LCMS (Method 1): R.sub.t = 1.11 min; m/z = 644 (M + H).sup.+ 216 ()-1-(4-chlorophenyl)- 8-(1,1- dioxidothiomorpholin- 4-yl)-N,4-dimethyl-7- (trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 0.95 (d, 3H), 2.68 (d, 3H), 2.75 (dd, 1H), 2.91 (s, 3H), 2.92-3.05 (m, 5H), 3.16-3.23 (m, 4H), 5.02-5.13 (m, 1H), 6.70 (q, 1H), 6.76 (s, 1H), 7.39 (d, 1H), 7.49 (d, 2H), 7.69 (d, 2H). LCMS (Method 5): R.sub.t = 1.33 min; m/z = 574 (M + H).sup.+ 217 ()-1-[4-(4- acetylpiperazin-1- yl)phenyl]-N,4- dimethyl-7- (trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.09 (d, 3H), 2.18 (s, 3H), 2.84 (dd, 1H), 2.89 (d, 3H), 3.06 (dd, 1H), 3.26-3.36 (m, 4H), 3.68 (t, 2H), 3.82 (t, 2H), 5.33-5.42 (m, 1H), 6.19 (q, 1H), 6.94 (d, 2H), 7.08 (d, 1H), 7.13 (s, br, 1H), 7.20 (d, 1H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 1.21 min; m/z = 504 (M + H).sup.+ 218 ()-1-{4-[4-(2- hydroxyethyl)piperazin- 1-yl]phenyl}-N,4- dimethyl-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.07 (d, 3H), 2.83 (d, 1H), 2.90 (d, 3H), 2.93 (d, 1H), 2.94-3.01 (m, 2H), 3.04-3.17 (m, 5H), 3.52- 3.61 (m, 4H), 3.89-3.96 (m, 2H), 5.32-5.44 (m, 1H), 6.18-6.25 (m, 1H), 6.95 (d, 2H), 7.08 (d, 1H), 7.13 (s, br, 1H), 7.19 (d, 1H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 1.03 min; m/z = 506 (M + H).sup.+ 219 ()-8-methoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-7- (trifluoromethoxy)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.11 (d, 3H), 2.40 (s, 3H), 2.58- 2.65 (m, 4H), 2.73 (dd, 1H), 2.89 (d, 3H), 2.96 (dd, 1H), 3.32-3.39 (m, 4H), 3.73 (s, 3H), 5.24-5.34 (m, 1H), 6.12 (q, 1H), 6.79 (s, 1H), 6.95 (d, 2H), 7.14 (s, br, 1H), 7.51 (d, 2H). LCMS (Method 5): R.sub.t = 0.80 min; m/z = 506 (M + H).sup.+

(547) The following exemplary compounds were prepared analogously to Example 2 from Example 127A or Example 128A and the appropriate commercially available boronic acid derivatives:

(548) TABLE-US-00053 No. Structure Name Analytical data 220 ()-4-ethyl-7,8- dimethoxy-N-methyl-1- [4-(1,3,5-trimethyl-1H- pyrazol-4-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.90 (t, 3H), 1.13-1.26 (m, 1H), 1.42-1.56 (m, 1H), 2.32 (s, 6H), 2.92 (d, 3H), 2.98 (dd, 1H), 3.08 (dd, 1H), 3.70 (s, 3H), 3.83 (s, 3H), 3.97 (s, 3H), 5.24-5.32 (m, 1H), 6.57 (q, 1H), 6.71 (s, 1H), 6.76 (s, 1H), 7.30 (d, 2H), 7.56 (d, 2H). LCMS (Method 5): R.sub.t = 1.10 min; m/z = 476 (M + H).sup.+ 221 ()-4-ethyl-1-(4- fluorobiphenyl-4-yl)- 7,8-dimethoxy-N- methyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.89 (t, 3H), 1.11-1.23 (m, 1H), 1.39-1.51 (m, 1H), 2.92 (d, 3H), 3.01 (dd, 1H), 3.10 (dd, 1H), 3.69 (s, 3H), 3.97 (s, 3H), 5.27-5.35 (m, 1H), 6.63 (q, 1H), 6.69 (s, 1H), 6.76 (s, 1H), 7.18 (dd, 2H), 7.55-7.66 (m, 6H). LCMS (Method 5): R.sub.t = 1.42 min; m/z = 462 (M + H).sup.+ 222 ()-4-ethyl-7,8- dimethoxy-N-methyl- 1-[4-(1-methyl- 1H-1,2,3- triazol-4-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.88 (t, 3H), 1.08-1.22 (m, 1H), 1.37-1.49 (m, 1H), 2.92 (d, 3H), 3.01 (dd, 1H), 3.10 (dd, 1H), 3.67 (s, 3H), 3.96 (s, 3H), 4.20 (s, 3H), 5.27-5.37 (m, 1H), 6.63 (q, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.57 (d, 2H), 7.82 (s, 1H), 7.88 (d, 2H). LCMS (Method 5): R.sub.t = 0.97 min; m/z = 449 (M + H).sup.+ 223 ()-1-[4-(3,5-dimethyl- 1,2-oxazol-4- yl)phenyl]-4-ethyl- 7,8-dimethoxy-N- methyl-4,5-dihydro- 3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.89 (t, 3H), 1.07-1.23 (m, 1H), 1.36-1.52 (m, 1H), 2.35 (s, 3H), 2.49 (s, 3H), 2.92 (d, 3H), 3.01 (dd, 1H), 3.10 (dd, 1H), 3.70 (s, 3H), 3.97 (s, 3H), 5.26-5.37 (m, 1H), 6.62 (q, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.32 (d, 2H), 7.59 (d, 2H). LCMS (Method 5): R.sub.t = 1.21 min; m/z = 463 (M + H).sup.+ 224 0 ()-4-isopropyl-7,8- dimethoxy-N-methyl- 1-[4-(1,3,5- trimethyl-1H- pyrazol-4-yl)phenyl]- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.87 (d, 3H), 0.89 (d, 3H), 1.32- 1.46 (m, 1H), 2.32 (s, 6H), 2.90 (d, 3H), 3.0 (dd, 1H), 3.13 (dd, 1H), 3.69 (s, 3H), 3.83 (s, 3H), 3.96 (s, 3H), 5.14-5.24 (m, 1H), 6.64 (q, 1H), 6.73 (s, 1H), 6.77 (s, 1H), 7.30 (d, 2H), 7.55 (d, 2H). LCMS (Method 5): R.sub.t = 1.17 min; m/z = 490 (M + H).sup.+

(549) The following exemplary compounds were prepared analogously to Example 34 from Example 127A and the appropriate commercially available lactams or cyclic carbamates:

(550) TABLE-US-00054 No. Structure Name Analytical data 225 ()-4-ethyl-7,8- dimethoxy-N- methyl-1-[4-(2- oxopyrrolidin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.88 (t, 3H), 1.10-1.22 (m, 1H), 1.38-1.50 (m, 1H), 2.22 (pent, 2H), 2.67 (dd, 2H), 2.91 (d, 3H), 2.97 (dd, 1H), 3.07 (dd, 1H), 3.68 (s, 3H), 3.93 (dd, 2H), 3.95 (s, 3H), 5.23-5.31 (m, 1H), 6.56 (q, 1H), 6.64 (s, 1H), 6.75 (s, 1H), 7.52 (d, 2H), 7.68 (d, 2H). LCMS (Method 1): R.sub.t = 1.11 min; m/z = 452 (M + H).sup.+ 226 ()-4-ethyl-7,8- dimethoxy-N- methyl-1-[4-(3- oxomorpholin-4- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.87 (t, 3H), 1.07-1.19 (m, 1H), 1.34-1.47 (m, 1H), 2.91 (d, 3H), 2.99 (dd, 1H), 3.07 (dd, 1H), 3.69 (s, 3H), 3.81-3.90 (m, 2H), 3.96 (s, 3H), 4.09 (t, 2H), 4.39 (s, 2H), 5.26-5.34 (m, 1H), 6.61 (q, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.41 (d, 2H), 7.55 (d, 2H). LCMS (Method 5): R.sub.t = 0.91 min; m/z = 467 (M + H).sup.+ 227 ()-4-ethyl-7,8- dimethoxy-N- methyl-1-[4-(2- oxopiperidin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.88 (t, 3H), 1.08-1.21 (m, 1H), 1.36-1.48 (m, 1H), 1.94-2.06 (m, 4H), 2.62 (t, 2H), 2.90 (d, 3H), 2.98 (dd, 1H), 3.06 (dd, 1H), 3.69 (s, 3H), 3.73 (t, 2H), 3.95 (s, 3H), 5.24-5.33 (m, 1H), 6.59 (q, 1H), 6.68 (s, 1H), 6.74 (s, 1H), 7.32 (d, 2H), 7.53 (d, 2H). LCMS (Method 5): R.sub.t = 1.01 min; m/z = 465 (M + H).sup.+ 228 ()-4-ethyl-7,8- dimethoxy-N- methyl-1-[4- (2-oxo-1,3- oxazolidin-3- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.88 (t, 3H), 1.07-1.24 (m, 1H), 1.35-1.51 (m, 1H), 2.91 (d, 3H), 2.98 (dd, 1H), 3.08 (dd, 1H), 3.68 (s, 3H), 3.96 (s, 3H), 4.15 (dd, 2H), 4.56 (t, 2H), 5.23-5.34 (m, 1H), 6.56 (q, 1H), 6.63 (s, 1H), 6.75 (s, 1H), 7.53 (d, 2H), 7.61 (d, 2H). LCMS (Method 5): R.sub.t = 0.97 min; m/z = 453 (M + H).sup.+

(551) The following exemplary compounds were prepared analogously to Example 34 from Example 49.2A and the appropriate commercially available lactams or cyclic carbamates:

(552) TABLE-US-00055 No. Structure Name Analytical data 229 (4S)-7,8-dimethoxy-N,4- dimethyl-1-[4-(4-methyl- 2-oxo-1,4-diazepan-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.08 (m, 2H), 2.64 (s, 3H), 2.81 (dd, 1H), 2.88 (d, 3H), 3.03-3.16 (m, 3H), 3.68 (s, 3H), 3.75 (s, br, 2H), 3.87-3.92 (m, 2H), 3.93 (s, 3H), 5.36- 5.49 (m, 1H), 6.45 (q, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 7.27 (d, 2H), 7.52 (d, 2H). LCMS (Method 1): R.sub.t = 0.72 min; m/z = 480 (M + H).sup.+

(553) The following exemplary compounds were prepared analogously to Example 34 from Example 129A and the appropriate commercially available lactams or cyclic carbamates.

(554) TABLE-US-00056 No. Structure Name Analytical data 230 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(2-oxo- 1,3-oxazolidin-3-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.97 (d, 3H), 2.92 (d, 3H), 2.99 (dd, 1H), 3.20 (d, 1H), 4.07-4.20 (m, 2H), 4.54 (t, 2H), 5.48-5.59 (m, 1H), 6.47-6.57 (m, 1H), 7.12 (d, 1H), 7.34-7.46 (m, 5H), 7.53 (d, 1H). LCMS (Method 1): R.sub.t = 1.23 min; m/z = 413 (M + H).sup.+ 230.1 (4S)-1-(4-chlorophenyl)- N,4-dimethyl-7-(2-oxo- 1,3-oxazolidin-3-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XXIa Analyt. HPLC (Method Y1): R.sub.t = 3.93 min [].sub.D.sup.20 = 108.1 (c = 1.00; MeOH) LCMS (Method 1): R.sub.t = 1.36 min; m/z = 499 (M + H).sup.+ 231 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(2- oxopiperidin-1-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 1.93-2.05 (m, 4H), 2.61 (t, 2H), 2.88-2.95 (m, 1H), 2.91 (d, 3H), 3.15 (dd, 1H), 3.65-3.76 (m, 2H), 5.43-5.53 (m, 1H), 6.42-6.50 (m, 1H), 7.09-7.17 (m, 2H), 7.21 (d, 1H), 7.39 (d, 2H), 7.46 (d, 2H). LCMS (Method 1): R.sub.t = 1.22 min; m/z = 425 (M + H).sup.+ 232 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(3- oxomorpholin-4-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.91 (d, 3H), 2.94 (dd, 1H), 3.17 (dd, 1H), 3.77-3.89 (m, 2H), 4.08 (t, 2H), 4.38 (s, 2H), 5.46-5.56 (m, 1H), 6.42-6.50 (m, 1H), 7.15 (d, 1H), 7.24 (dd, 1H), 7.31 (d, 1H), 7.39 (d, 2H), 7.45 (d, 2H). LCMS (Method 1): R.sub.t = 1.15 min; m/z = 427 (M + H).sup.+

(555) The following exemplary compounds were prepared analogously to Example 127.1 from Example 129A and the appropriate commercially available amines. In many cases, under the reaction conditions, mixtures of mono- and di-aminated products were obtained, and were separated by chromatography.

(556) TABLE-US-00057 No. Structure Name Analytical data 233 0 ()-1-(4-chlorophenyl)- N,4-dimethyl-7- (morpholin-4-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.88 (dd, 1H), 2.90 (d, 3H), 3.16 (dd, 1H), 3.24-3.33 (m, 4H), 3.86-3.95 (m, 4H), 5.44-5.57 (m, 1H), 6.49 (q, 1H), 6.67-6.79 (m, 2H), 6.99 (d, 1H), 7.37 (d, 2H), 7.43 (d, 2H). LCMS (Method 1): R.sub.t = 1.34 min; m/z = 413 (M + H).sup.+ 234 ()-1-(4-chlorophenyl)- N,4-dimethyl-7- (pyrrolidin-1-yl)-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.04 (d, 3H), 2.00-2.11 (m, 4H), 2.88 (dd, 1H), 2.89 (d, 3H), 3.15 (dd, 1H), 3.36 (m, 4H), 5.44-5.55 (m, 1H), 6.35 (dd, 1H), 6.40 (d, 1H), 6.48 (q, 1H), 6.91 (d, 1H), 7.36 (d, 2H), 7.44 (d, 2H). LCMS (Method 1): R.sub.t = 1.56 min; m/z = 397 (M + H).sup.+ 235 ()-1-(4-chlorophenyl)- 7-(1,1- dioxidothiomorpholin-4- yl)-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.80-3.00 (m, 1H), 2.89 (d, 3H), 3.13 (s, br, 5H), 3.97 (s, br, 4H), 5.43-5.60 (m, 1H), 6.42-6.54 (m, 1H), 6.64-6.79 (m, 2H), 7.02 (d, 1H), 7.33- 7.50 (m, 4H). LCMS (Method 1): R.sub.t = 1.21 min; m/z = 461 (M + H).sup.+ 236 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(4- methylpiperazin-1-yl)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.43 (s, 3H), 2.66 (t, 4H), 2.87 (dd, 1H), 2.90 (d, 3H), 3.15 (dd, 1H), 3.37 (t, 4H), 5.44-5.54 (m, 1H), 6.48 (q, 1H), 6.69 (dd, 1H), 6.73 (d, 1H), 6.96 (d, 1H), 7.37 (d, 2H), 7.43 (d, 2H). LCMS (Method 1): R.sub.t = 0.91 min; m/z = 426 (M + H).sup.+ 237 ()-N,4-dimethyl-7-(4- methylpiperazin-1-yl)-1- [4-(4-methylpiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.12 (d, 3H), 2.42 (s, 3H), 2.43 (s, 3H), 2.63-2.71 (m, 8H), 2.77 (dd, 1H), 2.87 (d, 3H), 2.98 (dd, 1H), 3.36 (t, 8H), 5.27-5.37 (m, 1H), 6.13 (q, 1H), 6.71 (dd, 1H), 6.76 (d, 1H), 6.92 (d, 2H), 7.03 (d, 1H), 7.49 (d, 2H). LCMS (Method 1): R.sub.t = 0.55 min; m/z = 490 (M + H).sup.+ 238 ()-N,4-dimethyl-7-(4- methyl-3-oxopiperazin- 1-yl)-1-[4-(4-methyl-3- oxopiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 1.17 (d, 3H), 2.79 (dd, 1H), 2.86 (d, 3H), 2.98 (dd, 1H), 3.08 (s, 6H), 3.50-3.57 (m, 4H), 3.59-3.67 (m, 4H), 4.00 (s, br, 4H), 5.29-5.39 (m, 1H), 6.15 (q, 1H), 6.67 (dd, 1H), 6.72 (d, 1H), 6.89 (d, 2H), 7.07 (d, 1H), 7.59 (d, 2H). LCMS (Method 1): R.sub.t = 0.87 min; m/z = 518 (M + H).sup.+

(557) The following exemplary compounds were prepared analogously to Example 2 from Example 129A and the appropriate commercially available boronic acid derivatives:

(558) TABLE-US-00058 No. Structure Name Analytical data 239 ()-1-(4-chlorophenyl)- 7-(4-fluorophenyl)-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.00 (d, 3H), 2.93 (s, br, 3H), 3.02 (d, 1H), 3.24 (d, 1H), 5.49-5.65 (m, 1H), 6.46- 6.62 (m, 1H), 7.13-7.23 (m, 3H), 7.36-7.51 (m, 6H), 7.59 (d, 1H), 7.62 (d, 1H). LCMS (Method 1): R.sub.t = 1.60 min; m/z = 422 (M + H).sup.+ 240 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(pyridin- 4-yl)-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, MeOD): = 1.06 (d, 3H), 2.82 (s, br, 3H), 3.03 (dd, 1H), 3.22 (dd, 1H), 5.27-5.38 (m, 1H), 7.29 (d, 1H), 7.46 (d, 2H), 7.60- 7.68 (m, 3H), 7.81 (d, 1H), 7.91 (s, 1H), 8.17 (s, br, 2H), 8.78 (s, br, 2H). LCMS (Method 1): R.sub.t = 1.07 min; m/z = 405 (M + H).sup.+ 241 ()-1-(4-chlorophenyl)- 7-(6-hydroxypyridin-3- yl)-N,4-dimethyl-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, MeOD): = 1.06 (d, 3H), 2.81 (s, br, 3H), 2.93 (dd, 1H), 3.13 (d, 1H), 5.21-5.33 (m, 1H), 6.63-6.74 (m, 1H), 7.13 (d, 1H), 7.40- 7.49 (m, 3H), 7.53-7.67 (m, 4H), 7.84 (s, br, 1H), 8.05 (s, br, 1H). LCMS (Method 1): R.sub.t = 1.15 min; m/z = 421 (M + H).sup.+ 242 ()-1-(4-chlorophenyl)- 7-(3,5-dimethyl-1,2- oxazol-4-yl)-N,4- dimethyl-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.33 (s, 3H), 2.47 (s, 3H), 2.94 (s, br, 3H), 3.01 (d, 1H), 3.22 (d, 1H), 5.49-5.63 (m, 1H), 6.46-6.58 (m, 1H), 7.09-7.22 (m, 3H), 7.41 (d, 2H), 7.48 (d, 2H). LCMS (Method 1): R.sub.t = 1.42 min; m/z = 423 (M + H).sup.+ 243 0 ()-1-(4-chlorophenyl)- N,4-dimethyl-7-(1- methyl-1H-1,2,3-triazol- 4-yl)-4,5-dihydro-3H- 2,3-benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 0.98 (d, 3H), 2.92 (d, 3H), 3.03 (dd, 1H), 3.22 (dd, 1H), 4.20 (s, 3H), 5.48-5.63 (m, 1H), 6.50-6.60 (m, 1H), 7.17 (d, 1H), 7.40 (d, 2H), 7.45 (d, 2H), 7.64 (d, 1H), 7.77 (s, 1H), 7.82 (s, 1H). LCMS (Method 1): R.sub.t = 1.22 min; m/z = 409 (M + H).sup.+

Example 130.2

(4R)-1-[4-(4-Hydroxypiperidin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(559) ##STR00461##

(560) Under argon, 1.0 g (2.3 mmol) of (4R)-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49.1A) were charged in 25 ml of THF. 63.5 mg (0.069 mmol) of tris(dibenzylideneacetone)dipalladium (CAS [51364-51-3]) and 91 mg (0.231 mmol) of 2-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (CAS [213697-53-1]) were added and the mixture was briefly degassed with argon. Then 311 mg (3.24 mmol) of sodium tert-butoxide and thereafter 936 mg (9.25 mmol) of piperidin-4-ol were added, degassing was carried out again, and the mixture was stirred at 70 C. oil bath temperature for 1 h. After cooling, the batch was admixed with diatomaceous earth, the solvent was removed on a rotary evaporator and the residue was purified by flash chromatography (amino phase). This gave 590 mg (55% of theory) of the desired product as a solid.

(561) LCMS (Method 5): R.sub.t=0.80 min; m/z=453 (M+H).sup.+

(562) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.05 (d, 3H), 1.36-1.51 (m, 2H), 1.74-1.87 (m, 2H), 2.42 (d, 1H), 2.61 (d, 3H), 2.82 (dd, 1H), 2.96 (t, 2H), 3.59 (s, 3H), 3.61-3.72 (m, 3H), 3.82 (s, 3H), 4.70 (d, 1H), 4.80-4.94 (m, 1H), 6.25 (q, 1H), 6.54 (s, 1H), 6.93 (d, 2H), 7.02 (s, 1H), 7.57 (d, 2H).

(563) Specific optical rotation: []D.sup.20=385.5+/0.18 (c=1.00; methanol)

(564) The following exemplary compounds were prepared analogously to Example 130.2 from Example 49.1A and methylpiperazine:

(565) TABLE-US-00059 No. Structure Name Analytical data 127.2 (4R)-7,8-dimethoxy-N,4- dimethyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5-dihydro- 3H-2,3-benzodiazepine- 3-carboxamide [].sub.D.sup.20 = 361.8 (c = 1.00; MeOH) LCMS (Method 5): R.sub.t = 0.56 min; m/z = 452 (M + H).sup.+

Example 244

()-1-[4-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(566) ##STR00463##

(567) 100 mg (0.231 mmol) of ()-1-(4-bromophenyl)-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 49A), 33.6 mg (0.278 mmol) of 1,2-thiazolidine 1,1-dioxide (CAS [5908-62-3]), 64 mg (0.46 mmol) of potassium carbonate and 13 mg (0.023 mmol) of allylchloropalladium dimer (CAS [12012-95-2]) are charged in 3 ml of 2-methyltetrahydrofuran and the suspension is degassed with argon for 10 min. Then 39 mg (0.093 mmol) of di-tert-butyl(2,4,6-triisopropylbiphenyl-2-yl)phosphane (CAS [564483-19-8]) are added, degassing with argon is carried out again, and the mixture is heated at 80 C. for 16 h. The crude mixture is filtered, and then the solvent is removed and the residue obtained is purified by preparative HPLC. This gave 32 mg (29% of theory) of the desired product as a solid.

(568) LCMS (Method 5): R.sub.t=0.90 min; m/z=473 (M+H).sup.+

(569) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.04 (d, 3H), 2.61 (pent, 2H), 2.83 (dd, 1H), 2.91 (d, 3H), 3.09 (dd, 1H), 3.46 (t, 2H), 3.70 (s, 3H), 3.87 (t, 2H), 3.96 (s, 3H), 5.37-5.50 (m, 1H), 6.42 (q, 1H), 6.62 (s, 1H), 6.75 (s, 1H), 7.30 (d, 2H), 7.55 (d, 2H).

Example 245

()-1-{7,8-Dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone

(570) ##STR00464##

(571) Making analogous use of the process for preparing Example 127.1, the desired compound was obtained from ()-1-[1-(4-bromophenyl)-7,8-dimethoxy-4-methyl-4,5-dihydro-3H-2,3-benzodiazepin-3-yl]ethanone (Example 133A).

(572) LCMS (Method 1): R.sub.t=0.70 min; m/z=437 (M+H).sup.+

(573) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.33 (d, 3H), 2.07 (s, 3H), 2.39 (s, 3H), 2.59-2.62 (m, 4H), 2.65-2.82 (m, 2H), 3.35-3.38 (m, 4H), 3.77 (s, 3H), 3.96 (s, 3H), 5.23-5.36 (m, 1H), 6.65 (s, 1H), 6.82 (s, 1H), 6.96 (d, 2H), 7.64 (d, 2H).

Enantiomer Separation

Preparative HPLC by Method VIa

Example 245.1: 1-{(4S)-7,8-Dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone (enantiomer 1)

(574) HPLC (Method Ea): R.sub.t=5.38 min, purity>99%

(575) Specific optical rotation: [].sub.D.sup.20=225.3+/0.33 (c=1.00; methanol)

Enantiomer 2: 1-{(4R)-7,8-Dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepin-3-yl}ethanone

(576) HPLC (Method Ea): R.sub.t=4.13 min, purity>99%

(577) Specific optical rotation: [].sub.D.sup.20=201.4+/0.27 (c=1.00; methanol)

(578) The following exemplary compound was prepared analogously to Example 2 from Example 133A and the appropriate commercially available boronic acid derivative:

(579) TABLE-US-00060 246 ()-1-{1-[4-(3,5- dimethyl-1,2-oxazol-4- yl)phenyl]-7,8- dimethoxy-4-methyl-4,5- dihydro-3H-2,3- benzodiazepin-3- yl}ethanone .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.24 (d, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 2.49 (s, 3H), 2.78 (dd, 1H), 2.94 (dd, 1H), 3.77 (s, 3H), 3.98 (s, 2H), 5.32- 5.44 (m, 1H), 6.66 (s, 1H), 6.83 (s, 1H), 7.36 (d, 2H), 7.77 (d, 2H). LCMS (Method 1): R.sub.t = 1.19 min; m/z = 434 (M + H).sup.+

Example 247

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(580) ##STR00466##

(581) Added at 0 C. to a solution of 163 mg (410 mol) of ()-4-[7,8-dimethoxy-4-methyl-3-[(methylamino)carbonyl]-4,5-dihydro-3H-2,3-benzodiazepin-1-yl]benzoic acid (Example 134A) in 10 ml of N,N-dimethylformamide were 69.9 mg (431 mol) of N,N-carbonyldiimidazole. After 4.5 hours 46 mg (616 mol) of acetic hydrazide were added, and the mixture was stirred at 80 C. overnight. It was worked up by addition of water and extraction three times with ethyl acetate. The organic phase washed with saturated aqueous sodium chloride solution and with water, dried using sodium sulphate, and the solvent was removed on a rotary evaporator. The crude product was then dissolved in 10 ml of dichloromethane and admixed at 0 C. with 23 mg (331 mol) of 1H-imidazole, 76 mg (291 mol) of triphenylphosphine and 97 mg (291 mol) of carbon tetrabromide. This mixture was stirred at room temperature overnight. It was worked up by adding water and carrying out extraction three times with ethyl acetate. The organic phase washed with saturated aqueous sodium chloride solution and dried using sodium sulphate, and the solvent was removed on a rotary evaporator. Chromatography gave 10 mg of the title compound as a yellow film.

(582) LCMS (Method 3): R.sub.t=1.01 min; m/z=436 (M+H).sup.+

(583) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.96 (d, 3H), 2.64 (s, 3H), 2.88 (dd, 1H), 2.91 (d, 3H), 3.16 (dd, 1H), 3.64 (s, 3H), 3.94 (s, 3H), 5.50 (m, 1H), 6.55 (s, 1H), 6.58 (sbr, 1H), 6.72 (s, 1H), 7.62 (d, 2H), 8.05 (d, 2H).

Example 248

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(584) ##STR00467##

(585) A solution of 175 mg (440 mol) of ()-4-[7,8-dimethoxy-4-methyl-3-[(methylamino)carbonyl]-4,5-dihydro-3H-2,3-benzodiazepin-1-yl]benzoic acid (Example 134A), 49 mg (661 mol) of N-hydroxyethanimideamide (CAS [22059-22-9]), 184 ml (1.32 mmol) of triethylamine and 643 l (1.10 mmol) of 1-propanephosphonic cyclo-anhydride (CAS [68957-94-8]) in 20 ml of ethyl acetate was heated at 80 C. for 48 hours. It was worked up by addition of saturated aqueous sodium hydrogen carbonate solution and extraction three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and dried using sodium sulphate, and the solvent was removed on a rotary evaporator. Chromatography gave 26 mg (13% of theory) of the title compound as a yellow foam.

(586) LCMS (Method 3): R.sub.t=1.21 min; m/z=436 (M+H).sup.+

(587) .sup.1H-NMR (400 MHz, CDCl.sub.3): =0.96 (d, 3H), 2.50 (s, 3H), 2.89 (dd, 1H), 2.91 (d, 3H), 3.17 (dd, 1H), 3.64 (s, 3H), 3.94 (s, 3H), 5.52 (m, 1H), 6.55 (s, 1H), 6.57 (q, 1H), 6.72 (s, 1H), 7.63 (d, 2H), 8.14 (d, 2H).

(588) Using the process for preparing Example 155, Example 249 was prepared from Example 1. This was followed by separation into the enantiomers by preparative chiral HPLC.

(589) TABLE-US-00061 No. Structure Name Analytical data 249 ()-N,4-dimethyl-8- (trifluoromethoxy)-1- [4-(1,3,5-trimethyl- 1H-pyrazol-4- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (400 MHz, CDCl.sub.3): = 0.99 (d, 3H), 2.30 (s, 6H), 2.91 (d, 3H), 2.92 (dd, 1H), 3.13 (dd, 1H), 3.80 (s, 3H), 5.46 (m, 1H), 6.47 (q, 1H), 7.06 (d, 1H), 7.21 (dd, 1H), 7.29 (d, 1H), 7.29 (d, 2H), 7.51 (d, 2H). LCMS (Method 3): R.sub.t = 1.34 min; m/z = 486 (M + H).sup.+. 249.1 (4S)-N,4-dimethyl-8- (trifluoromethoxy)-1- [4-(1,3,5-trimethyl- 1H-pyrazol-4- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XVIa Analyt. HPLC (Method Ca): R.sub.t = 4.77 min [].sub.D.sup.20 = 198.1 (c = 1.00; MeOH) 249.2 0 (4R)-N,4-dimethyl-8- (trifluoromethoxy)-1- [4-(1,3,5-trimethyl- 1H-pyrazol-4- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XVIa Analyt. HPLC (Method Ca): R.sub.t = 7.21 min [].sub.D.sup.20 = 189.7 (c = 1.00; MeOH)

(590) Using the process for preparing Example 171, optionally with subsequent enantiomer separation by chiral preparative HPLC, the following compounds were prepared from Example 1:

(591) TABLE-US-00062 No. Structure Name Analytical data 250 ()-N,4-dimethyl-1- [4-(4-methyl-1- piperazinyl)phenyl]- 8-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.07 (d, 3H), 2.37 (s, 3H), 2.58 (m, 4H), 2.79 (dd, 1H), 2.87 (d, 3H), 3.00 (dd, 1H), 3.32 (m, 4H), 5.30 (m, 1H), 6.12 (q, 1H), 6.91 (d, 2H), 7.02 (d, 1H), 7.19 (dd, 1H), 7.26 (d, 1H), 7.45 (d, 2H). LCMS (Method 3): R.sub.t = 0.88 min; m/z = 476 (M + H).sup.+. 250.1 (4R)-N,4-dimethyl-1- [4-(4-methyl-1- piperazinyl)phenyl]- 8-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XXb Analyt. HPLC (Method Ra): R.sub.t = 1.88 min [].sub.D.sup.20 = 442.8 (c = 1.00; MeOH) 250.2 (4S)-N,4-dimethyl-1- [4-(4-methyl-1- piperazinyl)phenyl]- 8-(trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide Prep. HPLC: Method XXb Analyt. HPLC (Method Ra): R.sub.t = 2.32 min [].sub.D.sup.20 = 428.6 (c = 1.00; MeOH) 251 ()-1-[4-(4-hydroxy- 1-piperidinyl) phenyl]-N,4- dimethyl-8- (trifluoromethoxy)- 4,5-dihydro-3H-2,3- benzodiazepine-3- carboxamide .sup.1H-NMR (300 MHz, CDCl.sub.3): = 1.08 (d, 3H), 1.69 (m, 2H), 2.02 (m, 2H), 2.78 (dd, 1H), 2.86 (d, 3H), 2.99 (dd, 1H), 3.06 (m, 2H), 3.69 (m, 2H), 3.92 (m, 1H), 5.28 (m, 1H), 6.08 (q, 1H), 6.92 (d, 2H), 7.02 (d, 1H), 7.19 (dd, 1H), 7.27 (d, 1H), 7.45 (d, 2H). LCMS (Method 3): R.sub.t = 0.88 min; m/z = 476 (M + H).sup.+.

Example 252

()-1-[2,4-Dibromo-5-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(592) ##STR00475##

(593) The compound was prepared analogously to Example 95A from ()-7,8-dimethoxy-N,4-dimethyl-1-[3-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 143).

(594) LCMS (Method 3): R.sub.t=0.94 min; m/z=608, 610, 612 (Br.sub.2 isotope pattern, M+H)

(595) .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.96 (d, 3H), 2.85 (d, 3H), 2.96 (s, 3H), 2.97 (dd, 1H), 3.22 (dd, 1H), 3.45 (mbr, 8H), 3.61 (s, 3H), 3.92 (s, 3H), 5.63 (m, 1H), 6.25 (s, 1H), 6.52 (q, 1H), 6.71 (s, 1H), 7.08 (s, 1H), 7.85 (s, 1H).

Example 253

(4S)-1-[3-Bromo-4-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(596) ##STR00476##

(597) The compound was prepared analogously to Example 95A from (4S)-7,8-dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 127.1).

(598) LCMS (Method 3): R.sub.t=0.78 min; m/z=529, 532 (Br isotope pattern, M+H)

(599) .sup.1H-NMR (300 MHz, CDCl.sub.3): =1.02 (d, 3H), 2.42 (s, 3H), 2.60-2.76 (m, 4H), 2.82 (dd, 1H), 2.91 (d, 3H), 3.07 (dd, 1H), 3.12-3.26 (m, 4H), 3.71 (s, 3H), 3.96 (s, 3H), 5.36-5.49 (m, 1H), 6.38 (q, 1H), 6.62 (s, 1H), 6.75 (s, 1H), 7.08 (d, 1H), 7.43 (dd, 1H), 7.76 (d, 1H).

Example 254

(4S)-1-[3-Cyano-4-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(600) ##STR00477##

(601) The compound was prepared analogously to Example 96A from (4S)-1-[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]-7,8-dimethoxy-N,4-dimethyl-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example 253).

(602) LCMS (Method 3): R.sub.t=0.72 min; m/z=477 (M+H).sup.+.

(603) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.01 (d, 3H), 2.41 (s, 3H), 2.68 (t, 4H), 2.83 (dd, 1H), 2.92 (d, 3H), 3.09 (dd, 1H), 3.32-3.42 (m, 4H), 3.72 (s, 3H), 3.96 (s, 3H), 5.40-5.50 (m, 1H), 6.37 (q, 1H), 6.56 (s, 1H), 6.75 (s, 1H), 7.02 (d, 1H), 7.61 (dd, 1H), 7.76 (d, 1H).

(604) Specific optical rotation: [].sub.D.sup.20=154.6+/0.28 (c=1.00; methanol)

(605) Using the process for preparing Example 88A, the following compounds were prepared from Example 136A

(606) TABLE-US-00063 No. Structure Name Analytical data 255 ()-7,8-dimethoxy-4- methyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-3-(1- oxopropyl)-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 0.89 (t, 3H), 1.15 (d, 3H), 2.13 (m, 1H), 2.22 (s, 3H), 2.34 (m, 1H), 2.44 (m, 4H), 2.49 (m, 1H), 2.84 (dd, 1H), 3.27 (m, 4H), 3.62 (s, 3H), 3.84 (s, 3H), 5.00 (m, 1H), 6.60 (s, 1H), 6.99 (d, 2H), 7.05 (s, 1H), 7.51 (d, 2H). LCMS (Method 3): R.sub.t = 0.75 min; m/z = 451 (M + H).sup.+. 256 ()-3-(cyclopropyl- carbonyl)-7,8- dimethoxy-4-methyl- 1-[4-(4-methyl- piperazin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (400 MHz, DMSO-d.sub.6): = 0.57 (m, 1H), 0.65 (m, 1H), 0.74 (m, 2H), 1.15 (d, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 2.50 (m, 1H), 2.84 (dd, 1H), 3.27 (m, 4H), 3.63 (s, 3H), 3.84 (s, 3H), 5.01 (m, 1H), 6.62 (s, 1H), 6.99 (d, 2H), 7.05 (s, 1H), 7.54 (d, 2H). LCMS (Method 3): R.sub.t = 0.74 min; m/z = 463 (M + H).sup.+.

(607) Using the process for preparing Example 49A, the following compound from Example 136A was prepared with cyclopropylamine:

(608) TABLE-US-00064 No. Structure Name Analytical data 257 0 ()-N-cyclopropyl- 7,8-dimethoxy-4- methyl-1-[4-(4- methylpiperazin-1- yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 0.45 (m, 2H), 0.56 (m, 2H), 1.05 (d, 3H), 2.22 (s, 3H), 2.39 (m, 1H), 2.44 (m, 4H), 2.47 (m, 1H), 2.85 (dd, 1H), 3.24 (m, 4H), 3.69 (s, 3H), 3.83 (s, 3H), 4.90 (m, 1H), 6.29 (d, 1H), 6.56 (s, 1H), 6.95 (d, 2H), 7.02 (s, 1H), 7.51 (d, 2H). LCMS (Method 3): R.sub.t = 1.12 min; m/z = 478 (M + H).sup.+.

Example 258

()-7,8-Dimethoxy-N,4-dimethyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carbothioamide

(609) ##STR00481##

(610) A solution of 100 mg (215 mol) of ()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine (Example 136A), 79 mg (1077 mol) of methyl isothiocyanate and 37.5 l (215 mol) of triethylamine in 2.5 ml of tetrahydrofuran was heated at reflux overnight. It was worked up by addition of saturated aqueous ammonium carbonate solution and extraction three times with ethyl acetate. The organic phase washed with saturated aqueous ammonium carbonate solution and with water and dried using sodium sulphate, and the solvent was removed on a rotary evaporator. Chromatography gave 77 mg (69% of theory) of the title compound as a yellow foam.

(611) LCMS (Method 3): R.sub.t=0.85 min; m/z=468 (M+H).sup.+

(612) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =1.24 (d, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 2.47 (m, 1H), 2.86 (m, 1H), 2.89 (d, 3H), 3.29 (m, 4H), 3.63 (s, 3H), 3.84 (s, 3H), 5.73 (m, 1H), 6.58 (s, 1H), 6.97 (d, 2H), 7.09 (s, 1H), 7.18 (q, 1H), 7.68 (d, 2H).

Example 259

Methyl()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxylate

(613) ##STR00482##

(614) A solution of 100 mg (215 mol) of ()-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine (Example 136A) and 50 l (646 mol) of methyl chloroformate in 4 ml of dichloromethane was heated at 40 C. for an hour. It was worked up by addition of saturated aqueous sodium hydrogen carbonate solution and extraction three times with dichloromethane. The organic phase washed with saturated aqueous sodium hydrogen carbonate solution and with water and dried using sodium sulphate, and the solvent was removed on a rotary evaporator. Chromatography gave 53 mg (52% of theory) of the title compound as a yellow foam.

(615) LCMS (Method 3): R.sub.t=0.78 min; m/z=453 (M+H).sup.+

(616) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =1.21 (d, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 2.39 (m, 1H), 2.82 (dd, 1H), 3.55 (s, 3H), 3.26 (m, 4H), 3.63 (s, 3H), 3.84 (s, 3H), 4.69 (m, 1H), 6.58 (s, 1H), 6.98 (d, 2H), 7.06 (s, 1H), 7.50 (d, 2H).

(617) The following compound was prepared analogously to Example 259 from Example 136A with ethyl chloroformate:

(618) TABLE-US-00065 No. Structure Name Analytical data 260 Ethyl ()-7,8- dimethoxy-4-methyl-1- [4-(4-methylpiperazin- 1-yl)phenyl]-4,5- dihydro-3H-2,3- benzodiazepine-3- carboxylate .sup.1H-NMR (300 MHz, DMSO-d.sub.6): = 1.15 (t, 3H), 1.21 (d, 3H), 2.22 (s, 3H), 2.44 (m, 4H), 2.40 (m, 1H), 2.82 (dd, 1H), 3.26 (m, 4H), 3.63 (s, 3H), 3.84 (s, 3H), 3.99 (q, 2H), 4.69 (m, 1H), 6.58 (s, 1H), 6.98 (d, 2H), 7.06 (s, 1H), 7.50 (d, 2H). LCMS (Method 3): R.sub.t = 0.85 min; m/z = 467 (M + H).sup.+.

Example 261

()-N-Ethyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(619) ##STR00484##

(620) Using the process for preparing Example 127.1, Example 261 was prepared from the intermediate 137A.

(621) LCMS (Method 5): R.sub.t=0.62 min; m/z=466 (M+H).sup.+

(622) .sup.1H-NMR (400 MHz, CDCl.sub.3): =1.13 (d, 3H), 1.20 (t, 3H), 2.39 (s, 3H), 2.58-2.64 (m, 4H), 2.74 (dd, 1H), 2.97 (dd, 1H), 3.27-3.40 (m, 6H), 3.73 (s, 3H), 3.96 (s, 3H), 5.25-5.35 (m, 1H), 6.20 (t, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 6.94 (d, 2H), 7.51 (d, 2H).

Enantiomer Separation

(623) 56 mg of ()-N-ethyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide (Example X) was separated into the enantiomers by means of chiral preparative HPLC using Method Va. The following working example was obtained:

Example 261.1: (4S)N-Ethyl-7,8-dimethoxy-4-methyl-1-[4-(4-methylpiperazin-1-yl)phenyl]-4,5-dihydro-3H-2,3-benzodiazepine-3-carboxamide

(624) 22 mg of solid, analyt. HPLC (Method Ua): R.sub.t=7.53 min, purity 99%

(625) [].sub.D.sup.20=384.1 (c=1.00; MeOH)

(626) Biological Activity of the Compounds According to the Invention

(627) 1. Assays

(628) 1.1 Protein-Protein Interaction Assay

(629) Binding Assay BRD4/Acetylated Peptide H4 (PRO)

(630) To assess the BRD4 binding of the substances described in the present application, their ability to inhibit the interaction between BRD4 (BD1) and acetylated histone H4 in a dose-dependent manner was quantified (Filippakopoulos et al., Cell, 2012, 149: 214-231).

(631) For this purpose, use was made of a time-resolved fluorescence resonance energy transfer (TR-FRET) assay which measured binding between N-terminally His.sub.6-tagged BRD4 (BD1) (amino acids 67-152, with relatively long constructs also being possible, preferably amino acids 44-168) and a synthetic acetylated histone H4 (AcH4) peptide having the sequence GRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHGSGSK-biotin. The recombinant BRD4 protein-produced according to Filippakopoulos et al., Cell, 2012, 149: 214-231was expressed in E. coli and purified by (Ni-NTA) affinity and (Sephadex G-75) size exclusion chromatography. The AcH4 peptide is commercially available, for example from Biosyntan (Berlin, Germany). In a typical assay, 11 different concentrations of each substance (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 M, 0.51 M, 1.7 M, 5.9 M and 20 M) were measured in duplicate on the same microtitre plate. To this end, 100-fold concentrated solutions in DMSO were prepared by serial dilution (1:3.4) of a 2 mM stock solution in a clear 384-well microtitre platte (Greiner Bio-One, Frickenhausen, Germany) 50 nl of these were transferred into a black test plate (Greiner Bio-One, Frickenhausen, Germany). The test was started by addition of 2 l of a 2.5-fold concentrated BRD4 solution (final concentration usually 10 nM in the 5 ml of the reaction volume) in aqueous assay buffer [50 mM HEPES pH 7.5. 50 mM sodium chloride (NaCl), 0.25 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the test plate. This was followed by a 10-minute incubation step at 22 C. to pre-equilibrate putative complexes between BRD4 and the substances. This was followed by the addition of 3 l of a 1.67-fold concentrated solution (in the assay buffer) consisting of AcH4 peptide (83.5 nM) and TR-FRET detection reagents [16.7 nM anti-6His-XL665 and 3.34 nM streptavidin cryptate (both from Cisbio Bioassays, Codolet, France), and 668 mM potassium fluoride (KF)].

(632) The mixture was then incubated in the dark for one hour at 22 C. and then for at least 3 hours and at most overnight at 4 C. Formation of BRD4/AcH4 complexes was determined by measuring the resonance energy transfer from the streptavidin-Eu cryptate to the anti-6His-XL665 antibody in the reaction. To this end, the fluorescence emission was measured at 620 nm and 665 nm after excitation at 330-350 nm in a TR-FRET measuring device, for example a Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emission at 665 nm and at 622 nm was used as an indicator for the amount of BRD4/AcH4 complexes formed.

(633) The data obtained (ratios) were normalized, with 0% inhibition corresponding to the mean of the measured values of a set of controls (usually 32 data points) comprising all reagents. Here, 50 nl of DMSO (100%) were used instead of test substances. An inhibition of 100% corresponded to the mean of the measured values of a set of controls (usually 32 data points) comprising all reagents except for BRD4. The IC.sub.50 was determined by regression analysis based on a 4-parameter equation (minimum, maximum, IC.sub.50, Hill; Y=Max+(MinMax)/(1+(X/IC 50).sup.Hill)).

(634) 1.2 Cell Assays

(635) Cell Proliferation Assays

(636) In accordance with the invention, the capability of the substances to inhibit cell proliferation was determined Cell viability was determined using the alamarBlue reagent (Invitrogen) in a Victor X3 Multilabel Reader (Perkin Elmer). The excitation wavelength was 530 nm and the emission wavelenth 590 nM.

(637) The MOLM-13 cells (DSMZ, ACC 554) were sown at a concentration of 4000 cells/well in 100 l growth medium (RPMI1640, 10% FCS) on 96-well microtitre plates.

(638) The MV4-11 cells (ATCC, CRL 9591) were sown at a concentration of 5000 cells/well in 100 l growth medium (RPMI1640, 10% FCS) on 96-well microtitre plates.

(639) The B16F10 cells (ATCC, CRL-6475) were sown at a concentration of 300-500 cells/well in 100 l growth medium (DMEM with phenol red, 10% FCS) on 96-well microtitre plates.

(640) The LOX-IMVI cells (NCI-60) were sown at a concentration of 1000 cells/well in 100 l growth medium (RPMI1640, 10% FCS) on 96-well microtitre plates.

(641) The MOLP-8 cells (DSMZ, ACC 569) were sown at a concentration of 4000 cells/well in 100 l growth medium (RPMI1640, 20% FCS) on 96-well microtitre plates.

(642) The KMS-12-PE cells (DSMZ, ACC 606) were sown at a concentration of 4000 cells/well in 100 l growth medium (RPMI1640, 20% FCS) on 96-well microtitre plates.

(643) The LAPC-4 cells (ATCC, PTA-1441TM) were sown at a concentration of 4000 cells/well in 100 l growth medium (RPMI1640, 2 mM L-glutamine, 10% cFCS) on 96-well microtitre plates. A day later, the LAPC-4 cells were treated with 1 nM methyltrienolone and various substance dilutions.

(644) The MDA-MB-231 cells (DSMZ, ACC 732) were sown at a concentration of 4000 cells/well in 100 l growth medium (DMEM/Ham's F12 medium, 10% FCS) on 96-well microtitre plates. The Caov-3 cells (ATCC, HTB-75) were sown at a concentration of 2000 cells/well in 100 l growth medium (MEM Earle's medium, 10% FCS) on 96-well microtitre plates.

(645) After an overnight incubation at 37 C., the fluorescence values (CI values) were determined. The plates were then treated with various substance dilutions (1E-5 M, 3E-6 M, 1E-6M, 3E-7 M, 1E-7 M, 3E-8 M, 1E-8 M) and incubated at 37 C. for 72 (MV4-11-, LOX-IMVI cells), 96 (MOLM-13-, B16F10-, MDA-MB-431-, Caov-3 cells), 120 (MOLP-8-, KMS-12-PE cells) or 168 (LAPC-4 cells) hours. The fluorescence values (CO values) were then determined. For the data analysis, the CI values were subtracted from the CO values and the results were compared between cells treated with different dilutions of the substance or with buffer solution only. These were used to calculate the IC 50 values (substance concentration required for 50% inhibition of cell proliferation).

(646) The substances were tested in the cell lines of Table 1 which represent, in an exemplary manner, the given indications:

(647) TABLE-US-00066 TABLE 1 Cell line Source Indication MOLM-13 DSMZ acute myeloid leukaemia MV4-11 ATCC acute myeloid leukaemia B16F10 ATCC melanoma (BRAF wild-type) LOX IMVI NCI-60 melanoma (BRAF mutated) MOLP-8 DSMZ multiple myeloma KMS-12-PE DSMZ multiple myeloma LAPC-4 ATCC prostate cancer MDA-MB-231 DSMZ breast carcinoma Caov-3 ATCC ovarian carcinoma
2. Results:
2.1 Binding Assay

(648) Table 2 shows the results from the BRD4 (BD1) binding assay.

(649) TABLE-US-00067 TABLE 2 IC.sub.50 (BRD4) Example (mol/l) 1 0.19 1.1 0.06 1.2 2.50 2 0.08 2.1 0.25 2.2 0.06 3 0.05 4 0.08 4.1 0.78 4.2 0.06 5 0.03 6 0.91 7 0.03 7.1 3.19 7.2 0.03 8 0.09 9 0.12 10 0.16 11 0.31 11.1 0.08 11.2 2.51 12 0.54 13 0.21 14 0.59 15 0.87 15.1 0.45 16 0.05 17 0.04 18 0.16 19 0.04 20 0.07 21 0.13 22 0.03 23 0.09 24 0.25 25 0.16 26 0.04 27 0.03 28 0.01 29 0.13 30 0.23 31 0.18 32 0.38 33 0.77 34 0.05 34.1 0.04 35 0.22 36 0.26 37 0.12 38 0.12 39 0.08 40 0.28 40.1 0.12 41 0.26 42 0.20 43 0.30 43.1 0.17 43.2 4.52 44 0.05 45 0.04 45.1 0.07 46 0.03 46.1 0.96 46.2 1.16 47 0.11 48 0.11 49 0.04 49.1 0.02 50 0.15 50.1 0.11 50.2 18.90 51 0.03 51.1 1.86 51.2 0.03 52 0.05 53 0.04 54 0.05 55 0.12 56 0.18 57 0.09 58 0.25 59 0.07 60 0.08 61 0.57 62 0.06 63 0.17 64 0.11 65 0.10 66 0.07 67 0.04 68 0.07 69 0.13 70 0.04 71 0.04 72 0.21 73 0.03 74 0.08 75 0.13 76 0.05 77 0.04 78 0.04 79 0.05 80 0.05 81 0.05 82 0.08 83 0.03 84 0.06 85 0.29 86 0.39 87 0.11 88 0.29 89 0.14 90 0.07 91 0.34 92 0.18 93 0.12 94 0.04 95 0.63 96 0.04 97 0.05 98 0.03 99 0.03 100 0.11 101 0.06 102 0.09 103 0.04 104 0.03 105 0.08 106 0.09 107 0.26 108 0.06 109 0.05 110 0.06 111 0.08 112 0.08 113 0.04 114 0.04 115 0.05 116 0.07 117 0.05 118 0.07 119 0.09 120 0.19 121 0.04 122 0.06 123 0.05 124 0.09 125 0.07 126 0.09 127 0.08 127.1 0.05 127.2 8.80 128 0.03 128.1 3.98 128.2 0.02 129 0.05 129.1 6.62 129.2 0.02 130 0.03 130.1 0.02 130.2 9.87 131 0.05 131.1 0.07 132 0.03 132.1 4.08 132.2 0.02 133 0.05 134 0.05 134.1 0.03 135 0.05 135.1 0.04 136 0.02 137 0.06 138 0.03 138.1 0.04 139 0.04 140 0.06 141 0.07 142 0.10 143 0.17 144 0.19 145 0.11 146 0.47 147 0.03 147.1 0.03 148 0.04 148.1 0.03 149 1.62 150 0.08 150.1 0.11 150.2 12.300 151 0.02 152 0.07 153 0.11 154 0.17 155 0.04 156 0.23 156.1 0.33 156.2 2.24 157 0.21 157.1 0.13 157.2 0.47 158 0.06 160 0.26 161 0.11 162 0.13 162.1 0.10 162.2 0.56 163 0.06 163.1 8.94 163.2 0.03 164 0.06 164.1 >20.0 (Comparative Example) 164.2 0.06 165 0.13 166 0.27 167 0.31 168 0.11 169 0.03 170 0.07 171 0.12 172 0.13 173 0.18 174 0.25 175 0.19 176 0.04 176.1 0.73 176.2 0.04 177 0.07 178 0.07 179 0.07 179.1 3.77 179.2 0.04 180 0.07 180.1 0.39 180.2 0.06 181 0.07 182 0.05 183 0.04 184 0.06 185 0.07 185.1 1.49 185.2 0.03 186 0.13 187 0.08 188 0.05 188.1 0.27 188.2 0.03 189 0.06 189.1 0.04 189.2 17.40 190 0.09 190.1 0.03 191 0.07 192 0.09 193 0.09 194 0.48 195 0.69 196 0.09 197 0.08 198 5.30 199 1.02 200 0.50 201 1.37 201.1 0.71 202 1.23 202.1 0.64 202.2 6.54 203 0.84 203.1 0.26 203.2 11.20 204 1.22 205 1.08 206 0.93 207 1.22 208 1.10 209 0.37 210 0.25 211 0.30 212 0.31 213 0.36 214 1.23 215 0.38 216 0.52 217 1.73 218 0.88 219 0.37 220 0.49 221 1.98 222 0.96 223 0.32 224 7.69 225 1.72 226 8.76 227 6.28 228 1.69 229 0.07 230 0.24 230.1 0.33 231 3.37 232 2.84 233 3.45 234 3.83 235 5.02 236 2.20 237 1.07 238 0.13 239 11.40 240 4.50 241 2.56 242 2.69 243 0.32 244 0.03 245 0.62 245.1 0.39 246 0.33 247 0.19 248 0.19 249 0.03 249.1 0.02 249.2 2.34 250 0.04 250.1 9.89 250.2 0.02 251 0.03 252 5.29 253 0.04 254 0.11 255 0.24 256 0.61 257 2.00 258 0.19 259 0.52 260 6.49 261 1.49 261.1 1.22
2.2 Cell Assays

(650) Tables 3A and 3B show results from various cell proliferation assays. The indications corresponding to the respective cell lines can be found in Table 1.

(651) TABLE-US-00068 TABLE 3A LOX MOLM-13 MV4-11 B16F10 IMVI MOLP-8 KMS-12-PE IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example (mol/l) (mol/l) (mol/l) (mol/l) (mol/l) (mol/l) 1 1.26 0.69 1.1 0.39 0.39 0.51 1.2 >10 >10 2 0.17 0.11 0.18 0.43 0.12 0.09 2.1 1.51 1.05 2.2 0.13 0.10 0.11 0.33 0.12 0.11 3 0.24 0.26 0.11 0.95 0.28 0.23 4 0.19 0.12 0.11 0.45 0.17 0.11 4.1 4.2 5 0.82 0.69 7 0.20 0.17 0.14 0.57 0.12 0.09 7.1 >10 7.2 0.10 0.06 0.19 0.05 0.05 8 0.38 0.19 9 0.65 0.54 10 0.31 0.27 11 1.91 1.12 11.1 0.57 11.2 7.74 12 1.61 1.32 13 1.44 0.92 14 3.07 2.63 15 3.45 15.1 3.05 16 0.22 0.27 0.64 0.29 0.25 17 0.17 0.13 0.30 0.11 0.11 18 0.25 0.30 0.76 0.34 0.35 19 0.17 0.27 0.65 0.27 0.27 20 0.19 0.14 0.33 0.12 0.11 21 0.56 22 0.08 0.88 0.10 0.24 0.09 0.11 23 0.27 24 1.17 25 0.74 26 0.43 27 0.63 28 0.04 0.03 0.04 0.02 0.03 29 0.36 30 0.79 31 0.27 32 1.18 33 3.31 34 0.35 34.1 0.24 0.12 0.44 0.08 0.08 35 1.47 36 1.16 37 1.13 38 0.73 39 0.70 40 1.47 40.1 0.96 0.76 0.79 0.33 0.59 0.08 41 1.35 42 1.29 43 0.84 43.1 0.81 43.2 9.85 44 0.21 45 0.23 0.14 0.35 0.13 0.13 45.1 0.22 46 0.19 0.11 0.37 0.16 0.12 46.1 5.14 46.2 >10 9.47 47 0.53 48 0.19 0.22 0.65 0.25 0.26 49 0.42 49.1 0.23 50 0.56 50.1 0.37 51 0.21 0.12 0.35 0.12 0.09 51.1 >10 51.2 0.11 0.05 0.17 0.05 0.04 52 0.24 0.14 0.45 0.15 0.13 53 0.35 54 0.44 55 0.90 56 0.90 57 0.79 58 0.99 59 0.62 60 0.48 61 2.11 62 0.65 63 0.77 64 0.88 65 0.63 66 0.63 67 0.47 68 1.17 69 1.21 70 0.30 71 0.25 0.05 0.15 0.09 0.08 72 0.66 73 0.30 74 0.55 75 0.66 76 0.75 77 0.49 78 0.37 79 0.46 80 0.56 81 0.30 82 0.55 83 0.45 84 0.34 85 1.08 86 1.43 87 0.56 88 0.67 89 0.38 90 0.46 91 0.55 92 0.85 93 0.46 94 0.38 95 2.76 96 0.25 0.07 0.22 0.09 0.07 97 0.45 98 0.27 99 0.27 100 0.53 101 0.65 102 0.96 103 0.35 104 0.26 105 0.67 106 2.55 107 0.63 108 1.56 109 1.16 110 0.36 111 0.81 112 0.63 113 1.42 114 0.30 115 0.46 116 0.49 117 0.38 118 0.50 119 0.41 120 0.80 121 0.27 122 0.66 123 0.63 124 1.07 125 1.16 126 0.74 127 0.18 0.12 0.25 0.09 0.09 127.1 0.11 0.07 0.10 0.29 0.06 0.09 127.2 >10 128 0.23 0.39 0.10 0.10 128.1 >10 128.2 0.15 0.07 0.19 0.05 0.05 129 0.22 0.18 0.58 0.15 0.12 129.1 >10 129.2 0.15 0.08 130 0.17 130.1 0.07 0.05 0.10 0.19 0.05 0.07 131 0.11 0.04 0.07 0.03 0.03 131.1 0.11 0.06 132 0.20 0.13 0.42 0.12 0.11 132.1 7.56 132.2 0.23 133 0.18 0.08 0.17 0.07 0.08 134 0.36 134.1 0.08 135 0.20 0.12 0.36 0.13 0.12 135.1 0.15 0.08 136 0.20 137 0.49 138 0.28 138.1 0.18 139 0.21 0.13 0.38 0.13 0.11 140 0.47 141 0.55 142 0.68 143 0.84 144 0.96 145 0.83 146 1.15 147 0.07 0.05 0.18 0.08 0.06 147.1 0.06 0.02 0.51 0.02 0.03 148 0.08 0.07 0.25 0.09 0.08 148.1 0.08 0.05 0.09 0.05 0.05 149 3.00 150 0.48 150.1 0.23 0.13 0.34 0.23 0.18 150.2 9.87 151 1.31 152 0.43 153 0.48 154 2.08 155 0.38 156 0.79 156.1 0.56 156.2 >10 157 0.09 0.19 0.58 0.12 0.24 157.1 0.12 157.2 2.19 158 0.43 160 0.40 161 0.28 162 0.38 162.1 0.21 162.2 1.68 163 0.21 163.1 7.08 163.2 0.26 164 0.58 164.2 0.42 165 0.88 166 0.67 167 3.24 2.95 168 0.39 0.22 169 0.24 0.41 0.12 0.12 170 0.52 171 1.91 172 1.91 173 1.21 174 2.34 2.03 175 0.44 176 0.52 176.1 2.19 176.2 0.25 177 0.49 178 0.18 179 0.29 179.2 0.08 180 0.37 180.1 2.70 180.2 0.05 181 0.30 0.17 182 0.40 184 0.30 0.13 185 0.28 0.16 185.2 0.10 186 0.33 0.24 187 0.33 0.17 188 0.20 0.10 188.1 1.13 188.2 0.07 189 0.44 0.21 189.1 0.21 0.10 0.08 190 0.08 191 0.17 192 0.27 193 0.11 200 0.18 201.1 1.99 202.1 0.58 203 3.31 203.1 1.27 209 0.19 210 0.17 212 0.82 213 0.86 215 2.27 216 1.03 218 0.30 219 0.57 220 2.40 222 2.12 229 0.14 230 0.23 243 0.34 245 0.86 246 2.06 247 0.57 248 0.14 249.1 0.06 250 0.14 0.10 250.2 0.05 0.04 251 0.10 253 0.06 254 0.17

(652) TABLE-US-00069 TABLE 3B LAPC-4 MDA-MB-231 Caov-3 Example IC.sub.50 (mol/l) IC.sub.50 (mol/l) IC.sub.50 (mol/l) 1 0.60 0.90 1.1 0.60 0.53 1.2 5.17 >10.00 2 0.24 0.31 0.31 2.1 0.71 1.39 2.2 0.09 0.20 0.25 3 0.11 0.21 0.55 4 0.09 0.17 0.32 5 0.27 1.35 7 0.09 0.25 0.40 8 0.18 0.28 9 0.43 0.73 10 0.12 0.26 11 0.45 2.58 11.1 0.31 1.11 11.2 10.00 12 0.87 1.85 13 0.90 1.30 14 1.65 3.64 15 6.23 16 0.11 0.47 0.37 17 0.10 0.21 0.22 18 0.28 0.48 19 0.11 0.41 20 0.12 0.22 0.24 21 22 0.06 0.15 0.11 23 0.19 26 0.13 27 0.18 28 0.02 0.04 34.1 0.31 40.1 0.29 1.28 45 0.24 46 0.28 48 0.47 51 0.28 51.2 0.13 52 0.35 71 0.15 96 0.17 127 0.24 127.1 0.04 0.13 0.17 128 0.32 128.2 0.16 129 0.42 130.1 0.05 0.14 0.003 131 0.05 132 0.32 133 0.18 135 0.30 139 0.31 147 0.18 147.1 0.08 148 0.30 148.1 0.13 150.1 0.34 157 0.42 169 0.37