EP1706413A1 - Tricyclic benzazepine derivatives as squalene synthase inhibitors used for the treatment of cardiovascular diseases - Google Patents

Abstract

The invention relates to novel tricyclic benzazepine derivatives of formula (I), methods for the production thereof, the use thereof for treating and/or preventing diseases, and the use thereof for producing medicaments used for the treatment and/or prophylaxis of diseases, preferably cardiovascular diseases, particularly dyslipidemia, arteriosclerosis, restenosis, and ischemia.

Description

 TRICYCLIC BENZAZEPINE DERIVATIVES AS SQUALENE SYNTHASE INHIBITORS FOR TREATING CARDIOVASCULAR DISEASES '

The present application relates to new tricyclic benzazepine derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, preferably for the treatment and / or prevention cardiovascular diseases, especially dyslipidemia, arteriosclerosis, restenosis and ischemia.

A large number of epidemiological studies have shown a causal link between dyslipidemia and cardiovascular diseases. Isolated plasma cholesterol is one of the largest risk factors for cardiovascular diseases such as arteriosclerosis. This applies to both isolated hypercholesterolemia and hypercholesterolemia combined with e.g. increased plasma triglycerides or low plasma HDL cholesterol. Substances that lower cholesterol or combined cholesterol and triglycerides should therefore be suitable for the treatment and prevention of cardiovascular diseases.

Squalene synthase inhibitors have already been shown to lower plasma cholesterol and triglycerides in animal models. Squalene synthase (EC 2.5.1.21) catalyzes the conversion of farnesyl pyrophosphate to squalene by reductive condensation. This is a crucial step in cholesterol biosynthesis. While farnesyl pyrophosphate and precursors are also important for other cellular metabolic pathways and reactions, squalene only serves as a precursor for cholesterol. Inhibiting squalene synthase thus leads directly to a reduction in cholesterol biosynthesis and thus to a decrease in plasma cholesterol levels. In addition, squalene synthase inhibitors have also been shown to reduce plasma triglyceride levels. Inhibitors of squalene synthase could thus be used for the treatment and / or prevention of cardiovascular diseases, such as, for example, dyslipidemia, arteriosherosis, ischemia / reperfusion, restenosis and arterial inflammation [cf. e.g. Eur. Heart J. 19 (Suppl. A), A2-A11 (1998); Prog. Med. Chem. 33: 331-378 (1996); Europ. J. Pharm. 431, 345-352 (2001)].

The object of the present invention was to provide new compounds which can be used as squalene synthase inhibitors for the treatment and / or prevention, in particular of cardiovascular diseases.

Benzoxazepines with CNS activity are claimed in US 4,374,842 and US 4,476,133. No. 3,812,259 describes benzodiazepine derivatives as animal feed additives. The use of certain azepine derivatives to control the blood plasma levels of lipoproteins is claimed in EP 875 247. Triazolooxazepines for the treatment of inflammatory conditions and allergies are in JP 05 345 785. EP 638 560 claims the use of azepine derivatives for the treatment of osteoporosis.

The present invention relates to compounds of the general formula (T)

in which for (C ₆ -Cιo) aryl or 5- to 10-membered heteroaryl, each up to three times, the same or different, selected by substituents from the group halogen, cyano, nitro, trifluoromethyl, hydroxy, fluoromethoxy, trifluoromethoxy, (CC ₆ ) alkyl, (-C-C ₆ ) - alkoxy, amino, mono- and di- (-C-C ₆ ) alkylamino may be substituted, or for a group of the formula

stands,

X represents O, S or NR ⁵ , wherein

Εf is hydrogen or (CC ₆ ) -AlkyI,

Y represents N or CR ⁶ , wherein

R is hydrogen, hydroxy or (-CC ₆ ) alkyl,

n represents the number 1, 2 or 3, R ¹ and R ^{2 are the} same or different and independently of one another represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-CC ₆ ) -alkyl or (CC ₆ ) -alkoxy,

R ³ for (CC ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, which can be substituted by (C ₃ -C ₈ ) cycloalkyl, or for (C ₃ -C ₈ ) cycloalkyl, where (-C-Cs) alkyl, (C ₂ -C ₈ ) alkenyl, (CC ₈ ) alkyl and (C ₃ -C ₈ ) cycloalkyl each by hydroxy, (CC ₆ ) Alkoxy, (C ₂ -C ₆ ) alkenoxy, (CC ₆ ) acyloxy, amino, mono- or di- (C ₁ -C ₆ ) alkylamino or by a 4- to 8-membered saturated, via a N atom-bonded heterocycle, which may contain a further heteroatom from the O or S series, may be substituted,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , wherein

R ⁷ denotes hydrogen or (dC ₆ ) alkyl,

R ⁸ and R ^{9 are the} same or different and are independently hydrogen, (-C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, selected by substituents from the group carboxyl, (-C ₆ ) alkoxycarbonyl , Aminocarbonyl, mono- and di- (CC ₆ ) alkyl-a inocarbonyl may be substituted, mean or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycle which contain a further ring heteroatom from the series NR ¹⁰ , O, S, SO or S0 ₂ and selected by substituents from the group hydroxyl, oxo, amino, (C ₁ -C ₆ ) -alkyl, carboxyl, (C _r C ₆ ) -alkoxycarbonyl, aminocarbonyl, mono- and di- (C ₁ -C ₆ ) -alkylaminocarbonyl may be substituted, wherein in turn, can be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C ₁ -C ₆ ) -alkoxycarbonyl, aminocarbonyl, mono- and di- (C 1 -C ₆ ) alkylaminocarbonyl and

R ^{10 is} hydrogen, (CC ₄ ) alkyl, (CC ₄ ) acyl or (C _r C ₄ ) alkoxycarbonyl, wherein (CC) alkyl can in turn be substituted by carboxyl or (-C ₄ ) alkoxycarbonyl,

and their salts, solvates and solvates of the salts.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas mentioned below and their salts, solvates and solvates of the salts and those of the formula (ϊ) encompassed by the formula (I) , compounds mentioned below as exemplary embodiments and their salts, solvates and solvates of the salts, provided that the compounds mentioned by formula (1) below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore encompasses the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not themselves suitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzene acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylaminoethanol, procain, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the invention, solvates are those forms of the compounds according to the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water. Hydrates are preferred as solvates in the context of the present invention.

The present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" encompasses compounds which can themselves be biologically active or inactive, but are converted to compounds according to the invention during their residence time in the body (for example metabolically or hydrolytically).

In the context of the present invention, unless otherwise specified, the substituents have the following meaning:

(Cr-CgVAlkyl, (C CfiVAlkyl and (-CbhAlkyl are within the scope of the invention for a straight-chain or branched alkyl radical with 1 to 8, 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkyl radical with 1 to 6 or 1 to 4 carbon atoms, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is particularly preferred, and examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

In the context of the invention, (C ₂ -Cg) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 8 carbon atoms. A straight-chain or branched alkenyl radical having 2 to 6, particularly preferably 2 to 4, carbon atoms is preferred. The following may be mentioned by way of example and preferably: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.

In the context of the invention, (C7-Ca) -alkynyl stands for a straight-chain or branched alkynyl radical having 2 to 8 carbon atoms. A straight-chain or branched alkynyl radical having 2 to 6, particularly preferably 2 to 4, carbon atoms is preferred. Examples and preferably mentioned are: ethynyl, n-prop-2-yn-l-yl and n-but-2-yn-yl

In the context of the invention, (C Cg) cycloalkyl and (C Cfi) cycloalkyl stand for a monocyclic cycloalkyl group with 3 to 8 or 3 to 6 carbon atoms. A cycloalkyl radical having 3 to 6 carbon atoms is preferred. The following may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohepryl. (Cfi-CinVAryl in the context of the invention represents an aromatic radical having preferably 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (C ₁ -Cb) alkoxy and (Ci-CjValkoxy) represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.

In the context of the invention, (C ₂ -Cfi) alkenoxy represents a straight-chain or branched alkene oxy radical having 2 to 6 carbon atoms. A straight-chain or branched alkenoxy radical having 2 to 4 carbon atoms is preferred. Examples and preferably mentioned are: allyloxy, isopropenyloxy, 2-methylprop-2-en-1-yloxy, n-but-2-en-1-yloxy and n-but-3-en-1-yloxy.

In the context of the invention, (-CgValkoxycarbonyl and (C4) -alkoxycarbonyl) stand for a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group. A straight-chain or branched alkoxycarbonyl radical with 1 is preferred up to 4 carbon atoms in the alkoxy group, and examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, mono-fG-CrtV alkylamino and mono- (C) -alkylamino stand for an amino group with a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. A straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

In the context of the invention, di- (C Cg) -alkylamino and di- (C C) -alkylamino represent an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms. Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. The following may be mentioned as examples and preferably: NN-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N -methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

In the context of the invention, mono- or DHd-CgValkylaminocarbonyl or mono- or di- ^ - CaValkylaminocarbonyl stand for an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents each has 1 to 6 or 1 to 4 carbon atoms. The following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, NN-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl and N-tert-buryl-N-methylaminocarbonyl.

In the context of the invention, (C _{1 =} C ₄ ) _I acyl [(CC ₄ ) alkanoyl] stands for a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1-position and via which 1 position is linked. The following may be mentioned by way of example and preferably: formyl, acetyl, propionyl, n-butyryl and isobutyryl.

In the context of the invention, (Cj-CW) -acyloxy stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double bonded oxygen atom in the 1 position and is linked via a further oxygen atom in the 1 position. An acyloxy radical having 1 to 4 carbon atoms is preferred. Examples and preferably mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.

In the context of the invention, 5- to 10-membered heteroaryl stands for a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) with up to three identical or different heteroatoms from the series Ν, O and / or S, which is via a ring carbon atom or optionally linked via a ring nitrogen atom of the heteroaromatic. Examples include: furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isolylolol, indolylolol, indolylolol, indolylolol, indolylolol, indolylolol, indolylolol, indolylolol, indolylolylol Νaphthyridinyl, quinazolinyl, quinoxalinyl. 5- to 6-membered heteroaryl radicals having up to two heteroatoms from the series Ν, O and / or S, such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, are preferred.

A 4- to 8-. 5- to 7- or 5- to 6-membered heterocycle in the context of the invention represents a saturated or partially unsaturated heterocycle having 4 to 8, 5 to 7 or 5 to 6 ring atoms, which contains a ring nitrogen atom, is linked via this and can contain a further heteroatom from the series Ν, O, S, SO or SO ₂ . A 5- to 7-membered saturated, Ν-linked heterocycle, which can contain a further heteroatom from the series Ν, O or S, is preferred. Examples include: pyrrolidinyl, pyrrolinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, 1,4-diazepinyl. Piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl and thiazolidinyl are particularly preferred.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred. If radicals in the compounds according to the invention are substituted, the radicals can, unless otherwise specified, be substituted one or more times. In the context of the present invention, the meaning of all radicals which occur more than once is independent of one another. A substitution with one, two or three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.

Preference is given to compounds of the formula (I) in which phenyl, naphthyl or pyridyl, each up to two times, identical or different, selected by substituents from the group fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, fluoromethoxy, trifluoromethoxy, (CC ₄ ) alkyl, (-C ^ alkoxy, amino, mono- and di- (-C-C) alkylamino may be substituted, or

represents a group of the formula or

X stands for O,

Y represents N or CR ⁶ , wherein

R is hydrogen, hydroxy or (C _r C ₄ ) -alkyl,

n represents the number 1, 2 or 3,

R ¹ and R ^{2 are the} same or different and are independently hydrogen, fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-G -alkyl or (-C-C ₄ ) -alkoxy),

R ^{3 represents} (-C-C ₆ ) alkyl, which can be substituted by (C ₃ -C ₆ ) cycloalkyl, or represents (C ₃ -C ₆ ) - cycloalkyl, where

(C ₁ -C ₆ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl can each be substituted by hydroxy, (-C-C ₄ ) alkoxy or amino,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , wherein R ⁷ denotes hydrogen or (CC ₆ ) alkyl,

R ⁸ and R ^{9 are the} same or different and are independently hydrogen, (-C _ö ) - alkyl or (C ₃ -C ₆ ) cycloalkyl, which are selected by substituents from the group carboxyl, (-C-C ₆ ) alkoxycarbonyl, Aminocarbonyl, mono- and di- (CC ₆ ) -alkylaminocarbonyl may be substituted, mean or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle which contain a further ring hetero atom from the series NR ¹⁰ , O, S or SO ₂ and are selected from the group by substituents Hydroxy, oxo, amino, (-C-C ₆ ) -alkyl, carboxyl, (-C-C ₆ ) -alkoxycarbonyl, aminocarbonyl, mono- and di- (-C-C6) -alkylaminocarbonyl may be substituted, form, in which

(C ₁ -C ₆ ) alkyl in turn can be substituted by substituents selected from the group consisting of hydroxy, amino, carboxyl, (C ₁ -C ₆ ) alkoxycarbonyl, aminocarbonyl, mono- and di- (C 1 -C ₆ ) alkylaminocarbonyl and

R ^{10 is} hydrogen, (CC ₄ ) alkyl, (CC ₄ ) acyl or (CC ₄ ) alkoxycarbonyl, wherein

(CC) alkyl can in turn be substituted by carboxyl or (-C ₄ ) alkoxycarbonyl,

and their salts, solvates and solvates of the salts.

Compounds of the formula (I) in which

A represents phenyl which is mono- or disubstituted, identical or different, by fluorine, chlorine, bromine, methyl, methoxy, ethoxy, fluoromethoxy or dimethylamino,

X stands for O,

Y stands for N,

n stands for the number 1, R ¹ and R ² independently of one another represent hydrogen or chlorine,

R ^{3 represents} (C _r C ₆ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, which may be substituted by hydroxy, (CC ₄ ) -alkoxy or amino,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , wherein

R ⁷ denotes hydrogen or (Cj -C ₄ ) alkyl,

R ⁸ and R ^{9 are} identical or different and independently of one another are hydrogen or (C 1 -C ₄ ) -alkyl, which can be substituted by carboxyl or (-C-C ₄ ) -alkoxycarbonyl, or

R ^s and R ⁹ together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle, which contain a further ring heteroatom from the series NR ¹⁰ , O, S or S0 ₂ and selected by substituents from the Hydroxy, oxo, amino, (C 1 -C ₄ ) -alkyl, carboxyl, (C 1 -C) -alkoxycarbonyl, amino-carbonyl, mono- and di- (C _r C) -alkylaminocarbonyl may be substituted, form, in which

(-C-C ₄ ) alkyl in turn by substituents selected from the group hydroxy, amino, carboxyl, (CC) alkoxycarbonyl, aminocarbonyl, mono- and di- (CC) alkylaminocarbonyl and can be substituted

R ¹⁰ denotes hydrogen, (CC ₄ ) -alkyl or (-C-C ₄ ) -acyl,

and their salts, solvates and solvates of the salts.

Compounds of the general formula (IA) are of particular importance

in which

A, X, Y, n, R ¹ , R ² , R ³ and R ⁴ each have the meanings given above,

and their salts, solvates and solvates of the salts.

Compounds of the general formula (I-B) are of particular importance

in which

A, Y, R ¹ , R ² , R ³ and R ⁴ each have the meanings given above,

and their salts, solvates and solvates of the salts.

The radical definitions given in the respective combinations or preferred combinations of radicals are replaced independently of the radical combinations of the radicals given by radical definitions of other combinations.

Combinations of two or more of the preferred ranges mentioned above are very particularly preferred.

The invention furthermore relates to a process for the preparation of the compounds according to the invention, characterized in that compounds of the formula (H)

in which R, R, A, X and n each have the meanings given above and

T stands for (Ci-G -alkyl,

first in an inert solvent with a suitable sulfurizing agent, such as, for example, diphosphorus pentasulfide, in compounds of the formula (TΩ)

in which. R, R, A, T, X and n each have the meanings given above,

transferred [cf. e.g. Ma et al., Tetrahedron Lett. 41 (12), 1947-1950 (2000)], then in an inert solvent with a compound of formula (IV)

in which Y and R ³ each have the meanings given above,

with cyclization to compounds of formula (V)

in which R, R, R, A, T, X, Y and n each have the meanings given above,

implements [cf. e.g. Weber et al., Justus Liebigs Ann. Chem., 1250-1256 (1978)], these under acidic conditions to carboxylic acids of the formula (VT)

in which R ¹ , R ² , R ³ , A, X, Y and n each have the meanings given above,

hydrolyzed and then converted into the compounds of formula (I) by methods known from the literature for the esterification or amidation of carboxylic acids

and optionally reacting the compounds of the formula (I) with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

Inert solvents for process step (H) - »(HT) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions. It is also possible to use mixtures of the solvents mentioned. Glycol dimethyl ether (1,2-dimethoxyethane) is preferred.

Diphosphorus pentasulfide, which is used in an amount of 1 to 1.5 mol, based on 1 mol of the compound of the formula (II), is preferably used as the sulfurizing agent. The reaction is preferably carried out in the presence of 1 to 2 equivalents of sodium hydrogen carbonate, based on the compound of the formula (II).

The reaction generally takes place in a temperature range from + 20 ° C to + 150 ° C, preferably from + 50 ° C to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (ET) + (IV) - »(V) are, for example, ethers such as

Diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or dipolar aprotic solvents such as dimethylformamide, dimethyl sulfoxide or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Dioxane is preferred.

The compound of formula (IV) is used in an amount of 1.5 to 10 mol, preferably 2 to 5 mol, based on 1 mol of the compound of formula (ID). The reaction generally takes place in a temperature range from + 20 ° C. to + 150 ° C., preferably from + 80 ° C. to + 120 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Inert solvents for process step (V) - »(VI) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert.- Butanol, or dipolar aprotic solvents such as acetone, dimethylformamide, dimethyl sulfoxide or acetonitrile, or water. It is also possible to use mixtures of the solvents mentioned. Ethanol / water is preferred.

Suitable acids are aqueous solutions of the usual inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid. Hydrochloric acid is preferred. The reaction generally takes place in a temperature range from + 20 ° C to + 150 ° C, preferably from + 50 ° C to + 100 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Process step (VI) -> (I) is carried out according to methods known from the literature for esterification or amidation (amide formation) of carboxylic acids.

Inert solvents for amidation in process step (NT) -> (ϊ) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, and , 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, Ν, Ν'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), acetonitrile or acetone. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, dimethylformamide or mixtures of these two solvents are preferred.

Suitable condensing agents for amide formation in process step (VI) - »(I) are, for example, carbodiimides such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclo - hexylcarbodiimide (DCC), N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), or phosgene derivatives such as N, N'-carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert.-butyl-5- methyl isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propane-phosphonic anhydride, isobutylchloroformate, bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride, benzotriazol-l-yloxy- tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), O- (benzotriazol-l-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -l, l, 3,3-tetramethyl uronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-l-yl) -N , N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), optionally in combination with other auxiliaries such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, and as bases alkali metal carbonates, for example sodium or potassium carbonate or bicarbonate, or organic bases such as trialkylamine e, for example triethylamine, N-methylmorpholine, N-methylpiperidine or N, N-diisopropylethylamine. PyBOP is preferably used in combination with N-diisopropylethylamine.

Amide formation in process step (VI) - »(I) is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 40 ° C. The reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

The compounds of the formula (II) can be prepared analogously to processes known from the literature, for example by the fact that compounds of the formula (NU)

in which R ¹ and R ² each have the meanings given above,

first with acetic anhydride in benzoxazin-4-one derivatives of the formula (NEW)

in which R ¹ and R ² each have the meanings given above, transferred [cf. eg Jiang et al, J. Med. Chem. 33 (6), 1721-1728 (1990)], this then in an inert solvent with an organometallic compound of the formula (IX)

A-M (IX),

in which A has the meaning given above and

M represents lithium or the Grignard residue -MgCl, -MgBr or -Mgl,

and subsequent acidic hydrolysis to give compounds of the formula (X)

in which A, R ¹ and R ² each have the meanings given above,

implements [cf. e.g. Miki et al., Bioorg. Med. Chem. 10, 401-414 (2002)], then by methods customary in the literature in compounds of the formula (XI)

in which A, R ¹ and R ² each have the meanings given above and

PG stands for a suitable amino protective group, such as preferably allyl,

transferred, this then in an inert solvent in the presence of a base with a compound of formula (XII)

in which T has the meaning given above,

to compounds of the formula (XIII)

in which A, T, PG, R ¹ and R ² each have the meanings given above,

implements [cf. eg Miki et al., J. Med. Chem. 45 (20), 4571-4580 (2002)], then in an inert solvent using a borohydride, such as sodium borohydride, selectively to compounds of the formula (XTV ^" )

in which A, T, PG, R ¹ and R ² each have the meanings given above,

reduced [cf. e.g. Miki et al., Bioorg. Med. Chem. 10, 401-414 (2002)], then in an inert solvent in the presence of a base to give compounds of the formula (XV)

in which R, R, A, T and PG each have the meanings given above,

cyclized [cf. eg Miki et al., J. Med. Chem. 45 (20), 4571-4580 (2002)] and finally the amino protective group is split off again according to methods customary in the literature. The Cyclization (XTV) - lo -

- »(XV) can occur entirely or partially even in situ during the described borohydride reduction of the compound of formula (XIU).

The compounds of the formulas (IN), (VE), (IX), (XU) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.

Compounds of the general formula (I) in which X represents S or Ν-R ⁵ can, starting from compounds of the formula (XI), (XIU) or (XIV), by appropriate transformations of the carbonyl or hydroxyl group known from the literature and further reaction be prepared analogously to the reaction sequence described above.

Compounds of the general formula (I) in which n represents the number 2 or 3 can, starting from compounds of the formula (H), (HI), (V) or (VI), in which n each represents the number 1 stands, by methods known from the literature for the homologation of carbonyl compounds (for example Arndt-Eistert, Wittig, Horner reaction) and further reaction analogously to the reaction sequence described above. Compounds of the general formula (I) in which n represents the number 3 can also, starting from a compound of the formula (XI), via a reaction analogous to process step (XI) + (XU) - »(XIU) with a compound of Formula (XVI)

in which T has the meaning given above,

subsequent reduction of the keto group [analogous to (XIU) -> (XTV)], cyclization via 1,5 addition to the dienoate system, hydrogenation of the remaining double bond and further reaction analogous to the reaction sequence described above.

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes: Scheme 1

Scheme 2

[Abbreviations: Ac ₂ O = acetic anhydride; aq. = watery; dppp = 1,3-bis (diphenylphosphino) propane; Et = ethyl; HOAc = acetic acid; Me = methyl; 'Pr = isopropyl; n-Bu = n-butyl; PyBOP = benzotriazole-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate].

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals. In particular, the compounds according to the invention are highly effective inhibitors of squalene synthase and inhibit cholesterol biosynthesis. The compounds according to the invention bring about a lowering of the cholesterol level and of the triglyceride level in the blood. They can therefore be used to treat and prevent cardiovascular diseases, in particular hypolipoproteinemia, dyslipidaemia, hyperlipidaemia or arteriosclerosis. The Compounds according to the invention can also be used for the treatment and prevention of obesity and obesity. The compounds according to the invention are furthermore suitable for the treatment and prevention of strokes (stroke) and Alzheimer's disease.

The present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

The present invention furthermore relates to the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

The present invention furthermore relates to a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds according to the invention.

The present invention furthermore relates to medicaments containing at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and / or prophylaxis of the aforementioned diseases. Examples of suitable combination active ingredients which may be mentioned are: cholesterol-lowering statins, cholesterol absorption inhibitors, HDL-increasing or triglyceride-lowering and / or apolipoprotein B-lowering substances, antioxidants or anti-inflammatory compounds. Combinations with these active substances are preferably suitable for the treatment of dyslipidemias, combined hyperlipidemias, hypercholesterolemias or hypertriglyceridemias.

The combinations mentioned can also be used for primary or secondary prevention of coronary heart diseases (e.g. myocardial infarction) and for peripheral arterial diseases.

Statins in the context of the invention are, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin. Cholesterol absorption inhibitors are e.g. Cholestyramine or ezetimibe; HDL-increasing or triglyceride-lowering or apolipoprotein B-lowering substances are e.g. Fibrates, niacin, PPAR agonists, BAT, MTP and CETP inhibitors. Anti-inflammatory compounds are e.g. Aspirin.

The present invention furthermore relates to the combination of the compounds according to the invention with a glucosidase and / or amylase inhibitor for the treatment of familial hyperlipidemia, obesity (obesity) and diabetes mellitus. Glucosidase and / or amylase inhibitors in the context of the invention are, for example, acarbose, adiposins, Voglibose, Miglitol, Emiglitate, MDL-25637, Camiglibose (MDL-73945), Tendamistate, AI-3688, Trestatin, Pradimicin-Q and Salbostatin. The combination of acarbose, miglitol, emiglitate or voglibose with one of the compounds according to the invention is preferred.

The compounds according to the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration, according to the state of the art, suitable administration forms which deliver the compounds according to the invention quickly and / or modified and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as e.g. Tablets (non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be done by bypassing an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other application routes, e.g. Inhaled drug forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets to be applied lingually, sublingually or buccally, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes ), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, scattering powder, implants or stents.

Oral or parenteral administration is preferred, in particular oral administration. The compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as for example ascorbic acid), dyes (for example inorganic pigments such as for example iron oxides) and taste and / or smell corrections.

The present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and to their use for the purposes mentioned above.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg of body weight in the case of parenteral administration in order to achieve effective results. In the case of oral administration, the dosage is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg and very particularly preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the upper limit mentioned must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several single doses over the day.

The following exemplary embodiments explain the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume. A. Examples

Abbreviations;

CI chemical ionization (for MS) DCI direct chemical ionization (for MS)

DMSO dimethyl sulfoxide d. Th. Of theory (with yield)

EI electron impact ionization (for MS)

ESI electrospray ionization (for MS)

GC / MS gas chromatography-coupled mass spectroscopy h hour (s)

HPLC high pressure, high performance liquid chromatography

LC / MS liquid chromatography-coupled mass spectroscopy min. Minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

PyBOP benzotriazol-l-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate

RT room temperature Rt retention time (with HPLC)

LC / MS. GC / MS and HPLC methods:

Method 1:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml HCKV1 water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nra.

Method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μm; Eluent A: 5 ml HCIO ₄ / I water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm. Method 3:

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% Ä; Flow: 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 µm.

Method 4:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A -> • 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.

Method 5:

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20mm x 4mm; Eluent A: 1 1 water + 0.5 ml 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 6:

Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35MS, 30 mx 250 μm x 0.25 μm; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 ° C (hold for 0.30 min), 50 ° C / min → 120 ° C, 16 ° C / min → 250 ° C, 30 ° C / min → 300 ° C (hold 1.7 min).

Method 7:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 125 mm x 4 mm, 5 μm; Eluent A: 4 bottles of PIC B7 / 1 water, eluent B: acetonitrile; PIC B7: heptanesulfonic acid from Millipore / Waters Corp .; Gradient: 0.0 min 2% B → 1 min 2% B → 9 min 90% B → 13 min 90% B; Flow: 2 ml / min; Oven: 30 ° C; UV detection: 210 nm. Output Connections and Inter ediate;

Example 1A

6-chloro-2-methyl-4H-3, 1-benzoxazin-4-one

A mixture of 9.42 g of 2-amino-5-chlorobenzoic acid (54.9 mmol) and 31.1 ml of acetic anhydride (33.6 g, 329 mmol) is heated under reflux for 2 h. After cooling, the precipitate formed is suction filtered and washed twice with 50 ml of diethyl ether. 9.01 g (83% of theory) of the product are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 3.32 (s, 3H), 7.60 (d, 1H), 7.94 (dd, 1H), 8.06 (d, 1H).

MS (EI): m / z = 195 [M] ⁺

HPLC (method 1): R _t = 3.97 min.

Example 2A

(2-Amino-5-chlorophenyl) (2,3-dimethoxyphenyl) methanone

9.07 ml of veratrol (9.28 g, 47.4 mmol) are dissolved in 40 ml of tetrahydrofuran under argon. At 0 ° C, 22.0 ml of ra-butyllithium (3.53 g, 55.0 mmol; 1.6 M solution in hexane) are slowly added. After 30 min. this suspension is added at 0 ° C. to 9.28 g of the compound from Example 1A in 40 ml of tetrahydrofuran. After 30 min. the solvent is removed under reduced pressure. The residue is taken up in 48 ml of ethanol and 20 ml of water, 32 ml of concentrated hydrochloric acid are added and the mixture is heated under reflux for 3 h. 100 ml of water are added given, and then extracted three times with 75 ml of diethyl ether. The combined organic phases are washed with 1N sodium hydroxide solution and with saturated sodium chloride solution (100 ml each), dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by chromatography on a silica gel column (mobile phase: cyclohexane / ethyl acetate 4: 1). 6.53 g (47% of theory) of the product are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 3.62 (s, 3H), 3.87 (s, 3H), 6.81 (d, 1H), 6.88 (d, 1H), 6.96 (s, 1H), 7.15-7.22 (m, 2H), 7.30 (d, 1H), 7.52 (s, 2H).

MS (CI): m / z = 292 [M + H] ⁺

HPLC (method 1): R _t = 4.79 min.

Example 3A

[2- (allylamino) -5-chlorophenyl] (2,3-dimethoxyphenyl) methanone

33.2 mg of tetra-n-butylammonium bromide (0.10 mmol) and 1.65 g of sodium hydroxide (41.1 mmol) are added under argon to 3.00 g of the compound from Example 2A (10.3 mmol) in 60 ml of tetrahydrofuran. After 5 min. Stirring at room temperature, 2.67 ml AUyl bromide (3.73 g, 30.9 mmol) are added and the mixture is heated under reflux for two days. Then 150 ml of ethyl acetate are added and it is extracted with 150 ml of water. The organic phase is separated off, dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified by chromatography on a silica gel column (mobile phase: cyclohexane / methylene chloride 1: 1). 3.25 g (90% of theory) of the product are obtained. 'H NMR (300 MHz, DMSO-d ₆ ): δ = 3.63 (s, 3H), 3.88 (s, 3H), 3.96-4.02 (m, 2H), 5.20 (dd, IH), 5.25 (dd, IH), 5.91-6.05 (ddt, IH), 6.83 (dd, IH), 6.86 (d, IH), 7.06 (d, IH), 7.14-7.24 (m, 2H),

7.43 (dd, IH), 8.95 (t, IH).

MS (CI): m / z = 332 [M + H] ⁺

HPLC (method 1): R _t = 5.36 min.

Example 4A

(2 ^ -4- {allyl [4-cWor-2- (2,3-dimethoxybenzoyl) phenyl] amino} -4-oxobut-2-enoate

2.92 g of the compound from Example 3A (8.80 mmol) are dissolved in 50 ml of ethyl acetate. 1.11 g of sodium bicarbonate (13.2 mmol) and 1.57 g of 3-chlorocarbonyl acrylate (9.68 mmol) are added [representation analogous to J. Amer. Chem. Soc. 70, 3356-3357 (1948)]. The mixture is stirred at room temperature for 1 h. Then it is diluted with 50 ml of ethyl acetate and extracted twice with 75 ml of water. The organic phase is dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue is purified chromatographically on a silica gel column (mobile phase: cyclohexane / ethyl acetate 5: 1). 3.58 g (89% of theory) of the product are obtained.

MS (CI): m / z = 480 [M + H] ⁺

HPLC (method 1): R _t = 5.10 min. Example 5A

(2 £ -4- (Allyl {4-chloro-2 - [(2,3-dimethoxyphenyl) (hydroxy) methyl] phenyl} amino) -4-oxobut-2-enoic acid ethyl ester (racemic)

160 mg of sodium borohydride (4.24 mmol) are added to 3.53 g of the compound from Example 4A (7.72 mmol) in 70 ml of ethanol. After 4 hours of stirring at room temperature, 150 ml of ethyl acetate are added to the mixture. Then it is extracted with 100 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and freed from the solvent under reduced pressure. 3.45 g of the crude product (56% purity, 54% of theory) are obtained, which is used in the next stage without further purification.

LC / MS (Method 3): m / z = 460.2 [M + H] ⁺ .

Example 6A

[l-Allyl-7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] ethyl acetate (racemic diastereomer pair)

1.04 g of potassium carbonate (7.51 mmol) are added to 3.46 g of the compound from Example 5A (7.51 mmol) in 70 ml of ethanol. After stirring at room temperature overnight, 100 ml of ethyl acetate are added. It is extracted with 100 ml of water and with 100 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and freed from the solvent. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 2.40 g (69% of theory) of the product are obtained.

MS (ESI): mz = 460.2 [M + H] ⁺

HPLC (method 1): R _t = 5.25 and 5.36 min.

Example 7A

[7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] ethyl acetate (racemic diastereomer pair)

0.2 g of palladium dichloride (1 mmol) is added to 2.38 g of the compound from Example 6A (5.18 mmol) in 20 ml of acetic acid. The mixture is refluxed overnight. The mixture is suctioned off over kieselguhr and 100 ml of ethyl acetate are added to the filtrate. It is extracted three times with 50 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and freed from the solvent. The residue is purified by chromatography on a silica gel column (mobile phase: cyclohexane / ethyl acetate 3: 1). 1.34 g (56% of theory) of the product are obtained.

MS (CI): m / z = 419.9 [M + H] ⁺

HPLC (method 1): R _t = 4.80 and 4.88 min. Example 8A

[7-chloro-5- (2,3-dimethoxyphenyl) -2-thioxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] ethyl acetate (racemic diastereomer pair)

120 mg of sodium hydrogen carbonate (1.43 mmol) and 232 mg of diphosphorus pentasulfide (1.05 mmol) are added to 400 mg of the compound from Example 7A (0.95 mmol) in 12 ml of 1,2-dimethoxyethane. The mixture is refluxed overnight. The batch is suctioned off over kieselguhr and the filtrate is concentrated. The residue is purified by chromatography on a silica gel column (mobile phase: cyclohexane / ethyl acetate 4: 1). 380 mg (92% of theory) of the product are obtained.

MS (ESI): m / z = 436.2 [M + H] ⁺

HPLC (method 1): R _t = 5.14 and 5.19 min.

Example 9A

Propanoylhydrazid

10.0 g of hydrazine hydrate (200 mmol) are heated to boiling. 19.8 ml of ethyl propionate (17.0 g, 166 mmol) are slowly added. The mixture is heated under reflux for 8 h. Fractional distillation (120 ° C / 13 mbar) gives 7.66 g (44% of theory) of the product.

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.99 (t, 3H), 2.01 (q, 2H), 4.10 (br. S, 2H), 8.89 (br. S, 1 H).

GC / MS (Method 6): R _t = 3.52 min., M / z = 89 [M + H] ⁺ . Example 10A

4-Piperidylessigsäureethylester

2.0 g of ethyl 4-pyridylacetate in 20 ml of ethanol are mixed with 400 mg of palladium black (20% by weight), adjusted to pH 2 with 1 N hydrochloric acid and hydrogenated at 3 bar for 2 days at room temperature. Solids are suctioned off over diatomaceous earth and the solvent of the filtrate is removed under reduced pressure. The residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The aqueous phase is adjusted to pH 13 with 1 N sodium hydroxide solution and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. 1.21 g (58% of theory) of the product are obtained.

GC / MS (Method 6): R _t = 5.93 min., M / z = 172 [M + H] ⁺ .

Example 11A

[l - {[(tert-butoxycarbonyl) amino] methyl} -8-chloro-6- (2,3-dimethoxyphenyl) - _J ff, 67J- [l, 2,4] - triazolo [4,3-α ] [4, l] benzoxazepine-4-yl] acetic acid ethyl ester

A solution of 590 mg (1.35 mmol) of the compound from Example 8A and 380 mg (2.03 mmol) of N-tert-butoxycarbonylglycine hydrazide [CAS no. 6926-09-6] in 10 ml of dioxane is heated to 140 ° C. overnight in an autoclave. The solvent is then rotated on the steamer removed and the residue purified by preparative HPLC. 149 mg (19% of theory) of the title compound are obtained.

Diastereomer mixture 11A-1:

LC / MS (Method 3): R _t = 2.45 min (59%), m / z = 573 [M + H] ⁺ ; 2.52 min (33%), m / z = 573 [M + Hf.

The diastereomers are separated chromatographically (Reprosol ODS-A, 5 μm, 250 mm x 20 mm; eluent: water / acetonitrile (40:60); flow: 25 ml / min; oven: 40 ° C; UV detection: 210 nm). 63 mg of diastereomer 11A-2 and 41 mg of diastereomer 11 A-3 are obtained.

Diastereomer 11A-2. racemic:

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 1.27 (s, 9H), 2.83 (broad, IH), 3.06 (broad, IH), 3.37 (s, 3H), 3.74 (s, 3H), 4.08 (q, 2H), 4.28-4.33 (m, IH), 4.44 (wide, IH), 5.23 (wide, IH), 6.13 (wide, IH), 6.58 (wide, IH) , 6.93-6.99 (m, 2H), 7.12 (broad, IH), 7.33 (broad, IH), 7.62 (dd, IH), 7.75 (d, IH).

Diastereomer 11A-3. racemic:

Η NMR (300 MHz, DMSO-d ₆ ): δ - 1.18 (t, 3H), 1.19 (s, 9H), 3.08 (dd, IH), 3.28 (dd, IH), 3.37 (s, 3H), 3.81 (s, 3H), 4.09 (q, 2H), 4.41 (dd, IH), 4.78 (t, IH), 4.89 (dd, IH), 5.56 (s, IH), 6.61 (d, IH), 7.11 -7.13 (m, 2H), 7.22 (d, IH), 7.36-7.40 (m, IH), 7.67 (dd, IH), 7.89 (d, IH).

Example 12A

4 - [(tert-butoxycarbonyl) amino] butanoic acid ethyl ester

1.0 g (6.0 mmol) of ethyl 4-aminobutyrate hydrochloride is dissolved in 0.9 ml (664 mg, 6.6 mmol) of triethylamine and 10 ml of dichloromethane. The solution is cooled to 0 ° C. and 1.37 g (6.3 mmol) of di-tert-butyl dicarbonate are added in portions. Allow to warm to room temperature and stir for 18 hours. 10 ml IN hydrochloric acid are added, the organic phase is separated off, washed with water and dried over sodium sulfate. After removing the solvent in vacuo, the crude product is purified by preparative HPLC (eluent: Acetonitrile / water, gradient 20:80 → 80:20). 450 mg (33% of theory) of the title compound are obtained.

MS (ESI): m / z = 232 [M + H] ⁺ .

Example 13A

tert-butyl (4-hydrazinyl-4-oxobutyl) carbamate

430 mg (1.86 mmol) of the compound from Example 12A are mixed with 103 mg (2.05 mmol) of hydrazine hydrate and 2 ml of ethanol and stirred under reflux for 24 hours. Another 94 mg (1.86 mmol) of hydrazine hydrate are added and the mixture is stirred under reflux for a further 16 hours. After removing the solvent, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 147 mg (34% of theory) of the title compound are obtained.

HPLC (method 1): R _t = 3.12 min.

MS (ESI): m / z = 218 [M + H] ⁺ .

Example 14A

[l- {3 - [(tert-Butoxycarbonyl) amino] propyl} -8-chloro-6- (2,3-dimethoxyphenyl) - ^ H, 67i - [l, 2,4] - triazolo [4,3 -a] [4, 1] benzoxazepin-4-yl] ethyl acetate (racemic diastereomer)

200 ml (0.46 mmol) of the compound from Example 8A and 109 mg (0.50 mmol) of the compound from Example 13A are mixed with 4 ml of dioxane and stirred under reflux for 7 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 40 mg (15% of theory) of the title compound are obtained.

HPLC (method 2): R _t = 4.96 min.

MS (ESI): mz = 601 [M + H] ⁺ .

Example 15A

3- (allyloxy) propansäuremethylester

1.0 g (7.68 mmol) of 3- (allyloxy) propionic acid is dissolved in 20 ml of acetone, and 1.59 g (11.5 mmol) of potassium carbonate and 2.4 ml (5.4 g, 38.4 mmol) of iodomethane are added. The mixture is heated under reflux for 5 hours, then the reaction solution is concentrated in vacuo and the residue is taken up in 20 ml of an aqueous 10% potassium carbonate solution. 20 ml of diethyl ether are added, the organic phase is separated off and washed with water and a saturated aqueous sodium chloride solution. The organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo. 877 mg (79% of theory) of the title compound are obtained.

GC / MS (method 6): R _t = 3:54 min, m / z = 113 [M-OCH _3] ^+..

Example 16A

3- (allyloxy) propanoic acid

860 mg (6.0 mmol) of the compound from Example 15A are dissolved in 10 ml of methanol. 896 mg (17.9 mmol) of hydrazine hydrate are added and the mixture is stirred at room temperature overnight. The solution is concentrated and hydrazine residues are removed in vacuo. 835 mg (90% of theory) of the title compound are isolated.

HPLC (method 7): R _t = 9.68 min.

MS (DCT): mz = 145 [M + H] ⁺ .

Example 17A

(2-Amino-5-chlorophenyl) (2-methoxyphenyl) methanone

3.00 g (15.3 mmol) of the compound from Example 1A are dissolved in 10 ml of tetrahydrofuran and cooled to 0 ° C. At this temperature, 18.4 ml of a 1 N solution of 2-methoxyphenylmagnesium bromide in tetrahydrofuran are added dropwise. The mixture is stirred at room temperature for 1 hour, then 10 ml of 1N hydrochloric acid are added, the mixture is extracted with 25 ml of ethyl acetate and the organic phase is concentrated. The residue is taken up in 20 ml of ethanol and 10 ml of semi-concentrated hydrochloric acid and heated under reflux for 4 hours. A pH of 9 is adjusted with 1 N aqueous sodium hydroxide solution and extracted with 25 ml of ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 9: 1). 1.22 g (30% of theory) of the title compound are obtained.

LC / MS (Method 3): R _t = 2.34 min., M / z = 262 [M + H] ⁺ .

Example 18A

[2- (allylamino) -5-chlohenyl] (2-methoxyphenyl) methanone

1.53 g (5.85 mmol) of the compound from Example 17A are dissolved in 35 ml of tetrahydrofuran and 935 mg (23.38 mmol) of sodium hydroxide and 19 mg (0.06 mmol) of tetra-n-butylammonium bromide are added. 1.52 ml (2.12 g, 17.54 mmol) of AUyl bromide are added and the reaction mixture is stirred at 60 ° C. for 16 hours. After removing the solvent in vacuo, the residue is mixed with ethyl acetate, washed with water, dried over sodium sulfate and purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). 1.02 g (56% of theory) of the title compound are obtained.

HPLC (method 1): R _t = 5.32 min.

MS (ESI): mz = 302 [M + H] ⁺ .

Example 19A

(2E) -4- {allyl [4-chloro-2- (2-methoxybenzoyl) phenyl] amino} -4-oxobut-2-enoate

1.0 g (3.3 mmol) of the compound from Example 18A is placed in 10 ml of ethyl acetate, and 418 mg (5.0 mmol) of sodium hydrogen carbonate are added. A solution of 646 mg (4.0 mmol) of (2 lbs) -4-chloro-4-oxobut-2-enoic acid ethyl ester in 10 ml of ethyl acetate is added while cooling with ice. The mixture is stirred overnight at room temperature and then the reaction solution is diluted with 20 ml of ethyl acetate. The organic phase becomes saturated with water and - DO -

aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and the residue purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1). 1.15 g (81% of theory) of the title compound are obtained.

HPLC (method 1): R _t = 5.06 min.

MS (ESI): mz = 428 [M + H] ⁺ .

Example 20A

[1-Allyl-7-chloro-5- (2-methoxyphenyl) -2-oxo-1, 2,3, 5-tetrahydro-4, 1-benzoxazepin-3 -yl] ethyl acetate (racemic mixture of diastereomers)

1.10 g (2.6 mmol) of the compound from Example 19A are dissolved in 20 ml of ethanol. 53 mg (1.4 mmol) of sodium borohydride are added and the reaction mixture is stirred at room temperature for 1 day. 10 ml of 1N hydrochloric acid are added and the mixture is extracted with ethyl acetate. The organic extracts are washed with water and a saturated aqueous sodium chloride solution. After the solvent has been removed in vacuo, the residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1). 736 mg (67% of theory) of the title compound are obtained.

HPLC (method 2): R _t = 5.24 min. (Diastereomer 1) and 5.35 min. (Diastereomer 2)

MS (ESI): m / z = 430 [M + H] ⁺ .

Example 21A

[7-chloro-5- (2-methoxyphenyl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] ethyl acetate (racemic mixture of diastereomers)

670 mg (1.6 mmol) of the compound from Example 20A are placed in 6 ml of acetic acid. 55 mg (0.3 mmol) of palladium (H) chloride are added and the reaction mixture is stirred under reflux for 36 hours. The reaction mixture is filtered through kieselguhr, washed with ethyl acetate and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After the solvent has been removed in vacuo, the residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 150 mg (25% of theory) of the title compound are obtained.

HPLC (method 2): R _t = 4.79 min. (Diastereomer 1) and 4.86 min. (Diastereomer 2)

MS (ESI): m / z = 390 [M + H] ⁺ .

Example 22A

[7-chloro-5- (2-methoxyphenyl) -2-thioxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] ethyl acetate (racemic mixture of diastereomers)

80 mg (0.4 mmol) of diphosphorus pentasulfide and 40 mg (0.5 mmol) of sodium hydrogen carbonate are added to 120 mg (0.3 mmol) of the compound from Example 21A. 4 ml of 1,2-dimethoxyethane are added and the reaction mixture is heated to reflux for 1 hour. It is then filtered through kieselguhr, the filtrate is concentrated in vacuo and the residue is treated with ethyl acetate. The organic phase is washed with a saturated aqueous Sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After removing the solvent in vacuo, the residue is purified by column chromatography on silica gel (eluent: cyclohexane, ethyl acetate 7: 3). 105 mg (82% of theory) of the title compound are obtained.

LC / MS (Method 4): R _t = 2.82 min. (Diastereomer 1) and 2.87 min. (Diastereomer 2), m / z = 406 [M + H] ⁺ .

Example 23A

N-allyl-4-chloroaniline

4.0 g (31.4 mmol) of 4-chloroaniline are dissolved in 80 ml of tetrahydrofuran and 5.0 g (125.4 mmol) of sodium hydroxide and 101 mg (0.3 mmol) of tetra-n-butylammonium bromide are added. 4.1 ml (5.7 g, 47.0 mmol) of AUyl bromide are added and the reaction mixture is stirred at 60 ° C. for 16 hours. After removing the solvent in vacuo, the residue is mixed with ethyl acetate, washed with water, dried over sodium sulfate and purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 9: 1). 2.0 g (39% of theory) of the title compound are obtained.

HPLC (method 1): R _t = 3.62 min.

MS (ESI): m / z = 168 [M + H] ⁺ .

Example 24A

[2- (allylamino) -5-chlorophenyl] (2,3-dihydro-1,4-benzodioxin-5-yl) methanol

900 mg (5.5 mmol) of boron trichloride are placed in 6 ml of toluene. A solution of 920 mg (5.5 mmol) of the compound from Example 23A in 2 ml of toluene is added. The mixture is stirred at 90 ° C. for 4 hours. A solution of 901 mg (5.5 mmol) of 2,3-dihydrol, 4-benzodioxin-5-carbaldehyde and 0.92 ml (666 mg, 6.6 mmol) of triethylamine in 3 ml of toluene is then added with ice bath cooling. The mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 16 hours. Then water is added and the solution is made basic by adding sodium hydrogen carbonate. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 9: 1). 450 mg (24% of theory) of the title compound are obtained.

HPLC (method 2): R _t = 4.50 min.

MS (DCI): mz = 332 [M + H] ⁺ .

Example 25A

(2E) -A- (Allyl {4-chloro-2- [2,3-dihydro-1,4-benzodioxin-5-yl (hydroxy) methyl] phenyl} amino) -4-oxo-but-2-enoic acid ethyl ester

400 mg (1.2 mmol) of the compound from Example 24A are placed in 6 ml of ethyl acetate, and 180 mg (1.3 mmol) of potassium carbonate are added. A solution of 646 mg (4.0 mmol) of (2 lbs) -4-chloro-4-oxobut-2-enoic acid ethyl ester in 6 ml of ethyl acetate is added while cooling with ice. The mixture is stirred overnight at room temperature and then the reaction solution is diluted with 20 ml of ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product is implemented directly in the next stage without further purification. Example 26A

[l-Allyl-7-chloro-5- (2,3-dihydro-l, 4-benzodioxin-5-yl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepine-3 -yl] ethyl acetate (racemic mixture of diastereomers)

220 mg (0.48 mmol) of the compound from Example 25A are dissolved in 4 ml of ethanol. 70 mg (0.48 mmol) of potassium carbonate are added and the reaction mixture is stirred at room temperature for 16 hours. Water is added and the solid is filtered off. 165 mg (75% of theory) of the title compound are obtained.

HPLC (method 2): R _t = 4.70 min. (Diastereomer 1) and 4.85 min. (Diastereomer 2)

MS (ESI): m / z = 458 [M + H] ⁺ .

Example 27A

[7-chloro-5- (2,3-dihydro-l, 4-benzodioxin-5-yl) -2-oxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] - ethyl acetate (racemic mixture of diastereomers)

150 mg (0.33 mmol) of the compound from Example 26A are dissolved in 3 ml of toluene. 7 mg (0.01 mmol) of 1,3-bis (diphenylphosphino) propane nickel (II) chloride and 0.18 ml (26 mg, 0.36 mmol) of a 2 M solution of trimethylaluminum in toluene are added over a period of 5 minutes. After 90 minutes, 210 minutes and 240 minutes, a further 0.03 ml (5 mg, 0.07 mmol) of the 2 M trimethylaluminum solution in toluene are added. The reaction solution is then stirred into 6 ml of a 1: 1 mixture of ethyl acetate and a half-concentrated potassium sodium tartrate solution. The organic phase is separated off, dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 7: 3). 70 mg (50% of theory) of the title compound are obtained.

HPLC (method 1): R _t = 4.81 min.

MS (ESI): mz = 418 [M + H] η ⁺ +

Example 28A

[7-chloro-5- (2,3-dihydro-l, 4-benzodioxin-5-yl) -2-thioxo-l, 2,3,5-tetrahydro-4, l-benzoxazepin-3-yl] - ethyl acetate (racemic mixture of diastereomers)

38 mg (0.17 mmol) of diphosphorus pentasulfide and 20 mg (0.23 mmol) of sodium hydrogen carbonate are added to 65 mg (0.16 mmol) of the compound from Example 27A. 2 ml of 1,2-dimethoxyethane are added and the reaction mixture is heated to reflux for 3 hours. It is then filtered through kieselguhr, the filtrate is concentrated in vacuo and the residue is treated with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. After removing the solvent in vacuo, the residue is purified by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate 4: 1). 57 mg (84% of theory) of the title compound are obtained. LC / MS (Method 3): R _t = 2.60 min., M / z = 434 [M + H] ⁺ .

Example 29A

(3-hydrazino-2,2-dimethyl-3-oxopropyl) carbamic acid tert-butyl ester

2.20 g (8.97 mmol) of 3 - [(tert-butoxycarbonyl) amino] -2,2-dimethylpropanoic acid ethyl ester in 2.18 ml (44.8 mmol) of hydrazine hydrate are stirred under reflux for 2 days. The mixture is purified directly by means of preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 95: 5). 1.09 g (53% of theory) of the title compound are obtained.

Η NMR (400 MHz, CDC1 ₃ ): δ = 1.19 (s, 6H), 1.44 (s, 9H), 3.24 (d, 2H), 3.88 (br, 2H), 5.11 (br, IH), 7.44 ( br, IH).

LC / MS (Method 5): R _t = 1.26 min, m / z = 232 [M + H] ⁺ .

Example 30A

[1 - {2 - [(tert-butoxycarbonyl) amino] - 1,1 -dimethylethyl} -8-chloro-6- (2,3-dimethoxyphenyl) -4H, 6H- [1,2,4] triazolo [ 4,3-α] [4, l] benzoxazepin-4-yl] acetate ethyl ester

500 mg (1.15 mmol) of the compound from Example 8A are stirred with 424 mg (1.84 mmol) of the compound from Example 29A in 5 ml of dioxane under reflux for 3 days. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 95: 5). 139 mg (19.7% of theory) of racemic diastereomer 30A-1 and 134 mg (19.0% of theory) of the racemic diastereomer 30A-2.

Diastereomer 30A-1. racemic:

HPLC (method 2): R _t = 5.04 min.

Diastereomer 30A-2. racemic:

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (s, 3H and t, 3H), 1.31 (s, 12H), 3.08 (dd, IH), 3.18-3.26 (m, 2H), 3.38 (s, 3H), 3.57 (dd, IH), 3.81 (s, 3H), 4.08 (q, 2H), 4.56 (t, IH), 5.36 (s, IH), 6.57 (d, IH), 7.03- 7.14 (m, 3H), 7.21 (t, IH), 7.77 (dd, IH), 8.12 (d, IH).

HPLC (method 2): R _t = 5.22 min.

MS (ESI): mz = 615.5 [M + H] ⁺ .

EXAMPLES

example 1

[8-chloro-6- (2,3-dimethoxyphenyl) -l-methyl-4H, 6H- [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine-4-yl] - acetate

158 mg of acetohydrazide (2.06 mmol) are added to 500 mg of the compound from Example 8A (1.15 mmol) in 23 ml of dioxane. The mixture is heated under reflux for 4 days. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 261 mg (49% of theory) of the title compound are obtained. MS (ESI): m / z = 458.3 [M + H] ⁺

HPLC (method 1): R _t = 4.53 and 4.63 min.

By preparative HPLC on a chiral phase [Agilent 1100 with DAD detection; Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; Eluent: isohexane / ethanol 1: 1; Flow: 15 ml / min .; Oven: 30 ° C; UV detection: 220 nm] the diastereomers and enantiomers are separated:

Stereoisomer 1-1:

R _t = 6.87 min. [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; Eluent: isohexane / ethanol 1: 1; Flow: 1 ml / min .; Oven: 30 ° C; UV detection: 220 nm]

Stereoisomer 1-2:

R _t = 7.41 min.

Stereoisomer 1-3:

R _t = 10.11 min.

Stereoisomer 1-4:

R _t = 10.76 min.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 3.08 and 3.27 (AB signal, additionally split as d, 2H), 3.35 (s, 3H), 3.73 (s, 3H ), 4.09 (q, 2H), 4.80 (dd, IH), 5.45 (s, IH), 6.68 (s, IH), 7.13 (dd, IH), 7.75 (dd, IH), 7.88 (d, IH) ,

Example 2

[8-Chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] ethyl acetate (racemic pair of diastereomers)

The title compound is prepared analogously to Example 1 (the corresponding starting acylhydrazide is prepared analogously to Example 9A).

HPLC (method 2): R _t = 4.60 and 4.73 min.

MS (ESI): m / z = 486.3 [M + H] ⁺ .

By preparative HPLC on a chiral phase [Agilent 1100 with DAD detection; Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; Eluent: isohexane / isopropanol 1: 1 or isohexane / ethanol 1: 1; Flow: 15 ml / min .; Oven: 25 ° C; UV detection: 220 nm] the diastereomers and enantiomers are separated:

Stereoisomer 2-1:

R = 4.38 min. [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; Eluent: isohexane / isopropanol 1: 1; Flow: 1 ml / min .; Oven: 25 ° C; UV detection: 220 nm]

Stereoisomer 2-2:

R _t = 5.48 min.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 (d, 3H), 1.17 (t, 3H), 1.52 (d, 3H), 3.08 and 3.25 (AB signal, additionally split as d, 2H ), 3.32 (s, 3H), 3.51 (septet, IH), 3.80 (s, 3H), 4.08 (q, 2H), 4.76 (dd, IH), 5.35 (s, IH), 6.62 (s, IH) , 7.12-7.17 (m, 2H), 7.22 (dd, IH), 7.73 (dd, IH), 7.95 (d, IH).

Stereoisomer 2-3:

R _t = 5.55 min. Stereoisomer 2-4:

R _t = 7.1 l min.

Example 3

[8-Chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] acetic acid (racemic diastereomer)

1.27 g (2.61 mmol) of the compound from Example 2 (racemic diastereomer pair) in 15 ml of ethanol are mixed with 1 ml of concentrated hydrochloric acid and stirred at 80 ° C. for 2 days. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 814 mg (68% of theory) of the product are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 and 1.51 (2 d, 6H), 3.00 and 3.23 (AB signal, additionally split as d, 2H), 3.34 (s, 3H), 3.50 ( septett, IH), 3.82 (s, 3H), 4.72 (dd, IH), 5.34 (s, IH), 6.63 (d, IH), 7.12-7.18 (m, 2H), 7.23 (dd, IH), 7.74 (dd, IH), 7.96 (d, IH), 12.5 (br. s, IH).

LC MS (method 3): R _t = 2.08 min, m / z = 458 [M + H] ⁺ .

Stereoisomer 3-3:

Starting from stereoisomer 2-3 from Example 2, the corresponding diastereomerically and enantiomerically pure compound is obtained in an analogous manner in a yield of 74% of theory. Th. Received.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.55 (d, 3H), 3.01 and 3.23 (AB signal, additionally split as d, 2H), 3.32 (s, 3H ), 3.51 (septet, IH), 3.82 (s, 3H), 4.72 (dd, IH), 5.36 (s, IH), 6.63 (d, IH), 7.12-7.19 (m, 2H), 7.25 (dd, IH), 7.75 (dd, IH), 7.96 (d, IH), 12.48 (br. s, IH ).

LC / MS (Method 3): R _t = 2.07 min, m / z = 458 [M + H] ⁺

[oc] = + 6.2 ° (solvent: dichloromethane, wavelength: 589 nm, temperature: 19.9 ° C, concentration 0.5150 g / 100 ml, layer thickness 100.0 mm).

Example 4

8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4- (2-oxo-2-piperidin-l-ylethyl) -4H, 67J- [l, 2,4] - triazolo [4, 3-a] [4, l] benzoxazepine (racemic diastereomer)

58.9 mg of PyBOP (0.113 mmol) and 14.6 mg of NN-diisopropylethylamine (0.113 mmol) are added to 47.1 mg (0.103 mmol) of the compound from Example 3 in 2 ml of tetrahydrofuran and 100 μl of dimethylformamide. After stirring at room temperature for 1 h, 11.1 μl of piperidine (9.63 mg, 0.113 mmol) are added. After 1 h the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 49.3 mg (91% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 and 1.51 (2 d, 6H), 1.36-1.44 (m, 2H), 1.48-1.62 (m, 4H), 3.05 (dd, IH), 3.33 (s, 3H), 3.34-3.45 (m, IH), 3.81 (s, 3H), 4.80 (dd, IH), 5.31 (s, IH), 6.63 (d, IH), 7.13 (dd, IH) , 7.17-7.26 (m, 2H), 7.74 (dd, IH), 7.96 (d IH).

HPLC (method 2): R _t = 4.78 min.

MS (ESI): m / z = 525.3 [M + H] ⁺ . By preparative HPLC on a chiral phase [Agilent 1100 with DAD detection; Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 20 mm; Eluent: methanol; Flow: 18 ml / min .; Oven: 24 ° C; UV detection: 260 nm] the enantiomers are separated:

Enantiomer4-l:

R _t = 4.26 min. [Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 4.6 mm; Eluent: methanol; Flow: 1 ml / min .; Oven: 24 ° C; UV detection: 260 nm]

Enantiomer 4-2:

R _t = 11.41 min.

LC / MS (Method 3): R _t = 2.47 min, m / z = 525 [M + Hf

[α] = -28.3 ° (solvent: dichloromethane, wavelength: 589 nm, temperature: 19.9 ° C, concentration 0.500 g / 100 ml, layer thickness 100.0 mm).

X-ray structure analysis of enantiomer 4-2 revealed an S configuration at C-6 and an R configuration at C-4 for this stereoisomer.

Example 5

[8-chloro-6- (2,3-dimethoxyphenyl) -l-ethyl-4H, 6H [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine-4-yl] - ethyl acetate (racemic pair of diastereomers)

The title compound is represented analogously to Example 1.

MS (ESI): m / z = 472.2 [M + H] ⁺

HPLC (method 2): R _t = 4.71 and 4.87 min. Example 6

[1-5ec-Butyl-8-chloro-6- (2,3-dimethoxyphenyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl-acetic acid, ethyl ester (racemic pair of diastereomers)

The title compound is prepared analogously to Example 1 (the corresponding starting acylhydrazide is prepared analogously to Example 9A).

LC / MS (Method 4): R _t = 2.78 and 2.81 min, m / z = 500.2 [M + H] ⁺ .

Example 7

[8-Chloro-l-cyclohexyl-6- (2,3-dimethoxyphenyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazeρin-4-yl] ethyl acetate (racemic diastereomer)

The title compound is prepared analogously to Example 1 (the corresponding starting acylhydrazide is prepared analogously to Example 9A). HPLC (method 2): R _t = 5.28 min. MS (ESI): mz = 526.3 [M + H] ⁺ .

Example 8

[8-Chloro-l-cyclopropyl-6- (2,3-dimethoxyphenyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] ethyl acetate (racemic diastereomer)

The title compound is represented analogously to Example 1 (the corresponding starting acylhydrazide is prepared analogously to Example 9A).

HPLC (method 2): R _t = 4.77 min. MS (ESI): m / z = 484.2 [M + H] ⁺ .

The following compound is prepared analogously to the examples described above from the corresponding starting compounds:

Example 9

[8-Chloro-6- (2,3-dimethoxyphenyl) -1- (l-ethylpropyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine -4-yl] acetate

Example 10

[8-Chloro-6- (2,3-dimethoxyphenyl) -1-isobutyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl-acetic acid, ethyl ester

62.5 mg of 3-methylbutanoylhydrazide (0.57 mmol) are added to 50 mg of the compound from Example 8A (0.11 mmol) in 23 ml of dioxane. The mixture is refluxed for 6 days. A further 30 mg of 3-methylbutanoylhydrazide (0.26 mmol) are added and the mixture is refluxed overnight. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% Formic acid, gradient 10:90 - »95: 5). 11 mg (18% of theory) of the racemic diastereomer 10-1 and 22 mg (39% of theory) of the racemic diastereomer 10-2 are obtained.

Diastereomer 10-1. racemic:

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.82 (d, 3H), 0.86 (d, 3H), 1.19 (t, 3H), 1.83 (septet, IH), 2.90 and 3.02 (AB signal , additionally split to doublet, 2H), 3.09 and 3.29 (AB signal, additionally split to doublet, 2H), 3.35 (s, 3H), 3.82 (s, 3H), 4.11 (q, 2H), 4.80 (dd, IH), 5.49 (s, IH), 6.63 (d, 1H), 7.12-7.17 (m, 2H), 7.20-7.27 (m, IH), 7.75 (dd, IH), 7.90 (d, IH).

LC / MS (Method 5): R _t = 2.84 min, m / z - 500.1 [M + H] ⁺ .

Diastereomer 10-2. racemic:

LC / MS (Method 5): R _t = 2.71 min, m / z = 500.1 [M + H] ⁺ .

The following compounds are prepared analogously to the examples described above from the corresponding starting compounds:

Example 11

[8-Chloro-6- (2-fluorophenyl) -1-methyl-4H, 67J- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] ethyl acetate

Example 12

[8-chloro-l-ethyl-6- (2-fluorophenyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazeρin-4-yl] ethyl acetate

Example 13

[8-Chloro-6- (2-fluorophenyl) -l-isopropyl-47J, 67J- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] ethyl acetate

Example 14

[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1, 2.4] triazolo [4.3-a] [4, l] benzoxazepin-4-yl] acetic acid tert. butyl

Example 15

2- [8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl ] -N-ethyl acetamide

Example 16

2- [8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl ] -N-ethyl-N-methylacetamide

Example 17

4 - ({[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine-4 -yl] acetyl} amino) butansäuremethylester

Example 18

4 - ({[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine-4 -yl] acetyl} amino) butanoic acid

Example 19

N - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine 4- yl] acetyl} -beta-alanine methyl ester

Example 20

N- {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4, 1] benzoxazepine 4- yl] acetyl} -beta-alanine

Example 21

8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4- (2-oxo-2-pyrrolidin-l-ylethyl) -4H, 6H- [l, 2,4] - triazolo [4, 3 -a] [4, 1] benzoxazepine

62.5 mg of PyBOP (0.120 mmol) and 21 μl of NN-diisopropylethylamine (15.5 mg, 0.120 mmol) are added to 50 mg of the compound from Example 3 (0.109 mmol) in 2 ml of tetrahydrofuran and 50 μl of dimethylformamide at 0 ° C. The mixture is stirred at RT for 1 h and then 10 μl pyrrolidine (8.5 mg, 0.12 mmol) are added. The mixture is stirred at RT for 1 h and then the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 22 mg (40% of theory) of the title compound are obtained.

Η-ΝMR (300 MHz, DMSO-d ₆ ): δ = 1.00 (d, 3H), 1.52 (d, 3H), 1.72-1.96 (m, 4H), 3.00 (dd, IH), 3.22-3.31 (m , 3H), 3.35 (s, 3H), 3.46-3.64 (m, 3H), 3.82 (s, 3H), 4.80 (dd, IH), 5.36 (s, IH), 6.63 (d, IH), 7.11- 7.28 (m, 3H), 7.74 (dd, IH), 7.96 (d, IH). LC / MS (Method 5): R _t = 2.54 min, m / z = 511.1 [M + H] ⁺ .

Example 22

(l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4H, 6H- [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine-4 -yl] acetyl} piperidin-4-yl) acetic acid ethyl ester

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 59 mg (0.45 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 47 mg (0.23 mmol) of ethyl 4-piperidinyl acetate hydrochloride are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 50 mg (47% of theory) of a white solid are obtained.

'H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.17 and 1.18 (2t, 3H), 1.00-1.30 (m, 2H), 1.51 (d, 3H), 1.60- 1.73 (m, 2H), 1.87-1.99 (m, IH), 2.22 (dd, 2H), 2.57 (m, partially covered by DMSO signal), 2.98-3.14 (m, 2H), 3.49 (m, IH) , 3.80 (s, 3H), 3.69-4.09 (m, 3H), 4.29 (m, IH), 4.78 (dd, IH), 5.30 and 5.31 (2s, IH), 6.62 (d, IH), 7.12-7.26 (m, 3H), 7.72 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.84 min.

MS (ESI): m / z = 611.4 and 613.4 [M + H] ⁺ .

Example 23

(l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4H, 6H- [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine-4 -yl] acetyl} piperidin-4-yl) acetic acid

A solution of 44 mg (0.07 mmol) of the compound from Example 22 in 1.5 ml of dioxane is mixed with a few drops of concentrated hydrochloric acid and stirred at 60 ° C. overnight. The mixture is then evaporated to dryness on a rotary evaporator and the residue is purified by preparative HPLC. 18 mg (44% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 1.61-1.99 (m, 3H), 2.04 (dd, 2H), 3.01-3.53 (m , partially covered by H ₂ 0 signal), 3.80 (s, IH), 3.98 (m, IH), 4.30 (m, IH), 4.79 (dd, IH), 5.30 (s, IH), 6.61 (d, IH), 7.12-7.26 (m, 3H), 7.73 (dd, IH), 7.97 (d, IH).

HPLC (method 1): R _t = 4.32 min.

MS (ESI): m / z = 583.4 and 585.4 [M + H.

Example 24

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,1 jbenzoxazepin-4-yl ] acetyl} piperidin-4-ol

A solution of 270 mg (0.59 mmol) of the compound from Example 3 (stereoisomer 3-3) in 15 ml of anhydrous tetrahydrofuran is successively mixed with 399 mg (0.77 mmol) of PyBOP and 99 mg (0.77 mmol) of NN-diisopropylethylamine at room temperature. After 30 minutes, 78 mg (0.77 mmol) of 4-hydroxypiperidine are added and the mixture is stirred at room temperature overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 178 mg (56% of theory) of a white solid are obtained.

'H NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 1.62-1.81 (m, 2H), 2.97-3.09 (m, 2H), 3.28 ( s, 3H), 3.50 (m, IH), 3.66-3.72 (m, IH), 3.76-3.88 (m, IH), 3.80 (s, 3H), 4.78 (dd, IH), 5.30 (s, IH) , 6.62 (d, IH), 7.11-7.26 (m, 3H), 7.73 (dd, IH), 7.89 (d, IH).

HPLC (method 2): R _t = 4.13 min.

MS (ESI): m / z = 541.4 and 543.4 [M + H] ⁺ .

The following compound is prepared analogously to the examples described above from the corresponding starting compounds:

Example 25

8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4- [2- (4-methylpiperazin-l-yl) -2-oxoethyl] -4H, 6H- [1,2,4] triazolo [4,3-a] [4, l] benzoxazepine

Example 26

8-chloro-6- (2,3-dimethoxyphenyl) -l-isoρroρyl-4- [2- (morpholin-4-yl) -2-oxoethyl] -4H, 6H- [l, 2,4] - triazolo [ 4,3-a] [4, 1 jbenzoxazepine

A solution of 200 mg (0.44 mmol) of the compound from Example 3 (stereoisomer 3-3) in 10 ml of water-free tetrahydrofiiran is successively mixed with 295 mg (0.57 mmol) PyBOP and 73 mg (0.57 mmol) NN-diisopropylethylamine at room temperature. After 30 minutes, 50 mg (0.57 mmol) of morpholine are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 143 mg (62% of theory) of a white solid are obtained.

'H NMR (400 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 3.09 (dd, IH), 3.37 (m, partially covered by H ₂ 0 signal) , 3.42-3.62 (m, 8H), 4.80 (dd, IH), 5.31 (s, IH), 6.62 (d, IH), 7.13- 7.26 (m, 3H), 7.73 (dd, IH), 7.97 (d , IH).

HPLC (method 2): R _t = 4.45 min.

MS (ESI): m / z = 527.3 and 529.3 [M + H] ⁺ .

Example 27

8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4- [2- (4-methylpiperidin-l-yl) -2-oxoethyl] -4 / J, 6H- [1, 2.4 ] triazolo [4,3-a] [4, 1] benzoxazepine

62.5 mg of PyBOP (0.120 mmol) and 21 μl of NN-diisopropylethylamine (16 mg, 0.12 mmol) are added to 50 mg of the compound from Example 3 (0.109 mmol) in 2 ml of tetrahydrofuran and 50 μl of dimethylformamide at 0 ° C. The mixture is stirred at RT for 1 h and then 8.2 μl of 4-methylpiperidine (12 mg, 0.12 mmol) are added. The mixture is stirred at RT for 1 h and then the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 -> 95: 5). 20 mg (28% of theory) of racemic diastereomer 27-1 and 28 mg (48% of theory) of racemic diastereomer 27-2 are obtained.

Diastereomer 27-1. racemic:

HPLC (method 2): R _t = 5.03 min.

MS (ESI): m / z = 539.5 [M + H] ⁺ .

Diastereomer 27-2. racemic:

HPLC (method 1): R _t = 4.80 min.

MS (ESI): m / z = 539.5 [M + H] ⁺ .

Example 28

[8-chloro-6- (2,3-dimethoxyphenyl) -l-ethyl-4H, 6H [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine-4-yl] - acetic acid

25 mg of the compound from Example 5 (0.053 mmol) in 3 ml of dioxane are mixed with 200 μl of concentrated hydrochloric acid and stirred at 80 ° C. overnight. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 9 mg (34% of theory) of the title compound are obtained.

^! H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 2.93-3.06 (m, 2H), 3.07-3.28 (m, 3H), 3.34 (s, 3H, under H ₂ 0 Signal), 3.82 (s, 3H), 4.75 (dd, IH), 5.38 (s, IH), 6.64 (d, IH), 7.13-7.18 (m, 2H), 7.19-7.26 (m, IH), 7.74 (dd, IH), 7.92 (d, IH).

LC / MS (Method 5): R _t = 2.19 min, m / z = 444.1 [M + H] ⁺ .

The following compounds are prepared analogously to the examples described above from the corresponding starting compounds:

Example 29

[8-chloro-l-isopropyl-6- (2-methoxyphenyl) -4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepin-4-yl] acetic acid

Example 30

{6- [2,3-bis (dimethylaιmno) phenyl] -8-chloro-l-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,] -benzoxazepine 4-yl} acetic acid

Example 31

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1 -isopropyl- ^ H, 6H- [1, 2.4] triazolo [4,3-] [4, 1] benzoxazepine 4- yl] acetyl} -D-prolin-tert. butyl

A solution of 70 mg (0.15 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 103 mg (0.2 mmol) of PyBOP and 26 mg (0.2 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 34 mg (0.2 mmol) of D-proline tert. -butyl ester was added and the mixture was stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 63 mg (68% of theory) of a solid are obtained. 'H NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 (d, 3H), 1.33 (s, 6H), 1.39 (s, 3H), 1.74-1.92 (m, 3H), 2.04-2.28 ( m, 2H), 3.12 (dd, IH), 3.22 (dd, IH), 3.34 (s, 3H, partially covered by H ₂ 0- signal), 3.50 (pseudo-quint, IH), 3.58-3.69 (m, IH), 3.81 (s, 3H), 4.18 (dd, IH), 4.78 (dd, IH), 5.32 (s, IH), 6.62 (d, IH), 7.13 (d, 2H), 7.17-7.26 (m , IH), 7.73 (dd, IH), 7.92 (d, IH).

HPLC (method 2): R _t = 4.98 min.

MS (ESI): m / z = 611.4 and 613.4 [M + H] ⁺ .

Example 32

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-H, 67J- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepm- 4- yl] acetyl} -D-prolin

A solution of 59 mg (0.1 mmol) of the compound from Example 31 in 1 ml of dichloromethane is mixed with 0.5 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. The mixture is then evaporated to dryness and extracted with ethyl acetate against water. The crude product obtained in this way is purified by means of preparative HPLC. 33 mg (62% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.52 (d, 3H), 1.77-2.32 (m, 4H), 3.13 (dd, IH), 3.24 (dd, IH ), 3.43-3.67 (m, 3H), 4.23 (dd, IH), 4.79 (m, IH), 5.32 (s, IH), 6.62 (dd, IH), 7.13- 7.27 (m, 3H), 7.73 ( dd, IH), 7.93 (d, IH), 12.78 (IH).

HPLC (method 1): R _t = 4.34 min. + MS (ESI): m / z = 555.4 and 557.4 [M + H] Example 33

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H, 67ϊ- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepm- 4 -yl] acetyl} piperidin-3-carboxylate

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of NN-diisopropylethylamine at room temperature. After 30 minutes, 36 mg (0.23 mmol) of ethyl piperidine-3-carboxylate (as a racemate) are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 80 mg (77% of theory) of a white solid are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.17 and 1.18 (2t, 3H), 1.31-1.42 (m, IH), 1.51 (d, 3H), 1.53-1.78 (m, 2H), 1.85-1.99 (m, IH), 2.27-2.37 and 2.53-2.59 (2m, IH), 2.72 and 2.83 (2dd, IH), 3.01-3.22 (m, 2H), 3.32 (s, 3H), 3.80 (s, 3H), 3.79-3.91 (m, IH), 4.07 (q, 2H), 4.27 and 4.37 (2m, IH), 4.79 (m, IH), 5.31 (s, IH), 6.62 (s, IH), 7.12-7.24 (m, 3H), 7.73 (d, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.81 min.

MS (ESI): m / z = 597.4 and 599.4 [M + H] ⁺ .

Example 34

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4, 1] benzoxazepine 4- yl] acetyl} piperidine-3-carboxylic acid

A solution of 62 mg (0.1 mmol) of the compound from Example 33 in 2.5 ml of dioxane is mixed with 1 ml of concentrated hydrochloric acid and heated to 60 ° C. for 4 hours. The reaction mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 44 mg (74% of theory) of a white solid are obtained.

'H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.14-1.38 (m, IH), 1.51 (d, 3H), 1.53-1.72 (m, 2H), 1.87- 2.00 (m, IH), 2.18-2.30 and 2.59-2.77 (2m, IH), 3.00-3.13 (m, IH), 3.38-3.54 (m, 4H), 3.81 (s, 3H), 3.75-3.97 (m , IH), 4.33 and 4.41 (2m, IH), 4.78 (m, IH), 5.31 (s, IH), 6.62 (d, IH), 7.11-7.27 (m, 3H), 7.73 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.40 min.

MS (ESI): m / z = 569.3 and 571.3 [M + H] ⁺ .

Example 35

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-47J, 6Η- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepm- 4- yl] acetyl} piperidine-2-carboxylic acid ethyl ester

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 36 mg (0.23 mmol) of ethyl piperidine-2-carboxylate (as a racemate) are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 83 mg (80% of theory) of a white solid are obtained.

HPLC (method 2): R _t = 4.96 min.

MS (ESI): m / z = 597.4 and 599.4 [M + H]

Example 36

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H, 6H- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine-4 -yl] acetyl} piperidine-2-carboxylic acid

A solution of 62 mg (0.1 mmol) of the compound from Example 35 in 2.5 ml of dioxane is mixed with 1 ml of concentrated hydrochloric acid and heated to 60 ° C. for 10 hours. The reaction mixture is then evaporated to dryness and the residue is purified by preparative HPLC. The two diastereomeric products are obtained separately from each other as white solids.

Diastereomer 36-1:

ll mg (19% of theory)

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 2H), 1.22-1.32 (m, 2H), 1.52 (d, 3H), 1.47-1.58 (m, IH), 1.62-1.71 (m, 2H), 2.10 (m, 2H), 2.98-3.20 (m, 2H), 3.47-3.55 (m, 2H), 3.81 (s, 3H), 3.97 (m, IH), 4.75-4.87 (m, IH), 4.98 (m, IH), 5.29 (s, IH), 6.61 (s, IH), 7.11-7.29 (m, 3H), 7.73 (dd, IH), 7.97 (d, IH), 12.70 (br. s, IH).

HPLC (method 2): R _t = 4.48 min.

MS (ESI): m / z = 569.3 and 571.3 [M + H] ⁺ .

Diastereomer 36-2:

ll mg (19% of theory)

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 2H), 1.20-1.38 (m, 2H), 1.51 (d, 3H), 1.55-1.70 (, 3H), 2.07-2.28 ( m, 2H), 3.80 (s, 3H), 4.08 (m, IH), 4.78 (m, IH), 5.01 (m, IH), 5.31 (s, IH), 6.62 (d, IH), 7.12-7.23 (m, 3H), 7.73 (dd, IH), 7.94 (d, IH).

HPLC (method 2): R _t = 4.61 min.

MS (ESI): m / z = 569.3 and 571.3 [M + H] ⁺ .

Example 37

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4H, (5H- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine-4 yl] acetyl} pyrrolidine-2-one

A solution of 100 mg (0.22 mmol) of the compound from Example 3 (stereoisomer 3-3) in 2 ml of 1,2-dichloroethane is successively mixed with 80 μl of thionyl chloride (1.09 mmol) and 2 drops of N, N-dimethylformamide. It is stirred for 5 hours at room temperature. The mixture is then evaporated to dryness, the residue is taken up in a little toluene and concentrated again. The residue is dissolved in 2 ml of anhydrous tetrahydrofuran, 76 μl (0.44 mmol) of N, N-diisopropylethylamine and 18 μl of 2-pyrrolidone are added and the mixture is stirred overnight at room temperature. After this time, the mixture is evaporated to dryness and the residue is purified by preparative HPLC. 35 mg (30% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.52 (d, 3H), 1.95 (quint, 2H), 2.58 (dt, 2H), 3.46-3.56 (m, 2H ), 3.60-3.67 (m, 2H), 3.82 (s, 3H), 3.87 (dd, IH), 4.86 (dd, IH), 5.32 (s, IH), 6.63 (d, IH), 7.12-2.72 ( m, 3H), 7.74 (dd, IH), 7.98 (d, IH).

HPLC (method 2): R _t = 4.63 min.

MS (ESI): m / z = 525.3 and 527.3 [M + H] ⁺ .

Example 38

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4H, 67ϊ- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine 4- yl] acetyl} piperidin-4-carbonsäuremethylester

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of NN-diisopropylethylamine at room temperature. After 30 minutes, 33 mg (0.23 mmol) of piperidine-4-carboxylic acid methyl ester are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 64 mg (63% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.30-1.43 (m, IH), 1.51 (d, 3H), 1.48-1.67 (m, IH), 1.77-1.91 (m, 2H), 2.57-2.80 (m, 2H), 3.01-3.22 (m, 2H), 3.32-3.53 (m, 2H), 3.61 and 3.63 (2s, 3H), 3.81 (s, 3H), 3.97 (m, IH), 4.18 (m, IH), 4.79 (t, IH), 5.30 (s, IH), 6.62 (d, IH), 7.12-7.26 (m, 3H), 7.72 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.60 min. MS (ESI): m / z = 583.3 and 585.3 [M + H] ⁺ .

Example 39

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl-4H, 677- [1,2,4] triazolo [4,3-α] [4, lbenzoxazepin-4-yl] acetyl} piperidine-4-carboxylic acid

A solution of 56 mg (0.1 mmol) of the compound from Example 38 in 1.5 ml of dioxane is mixed with 0.5 ml of concentrated hydrochloric acid and heated to 60 ° C. overnight. The reaction mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 20 mg (36% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.29-1.39 (m, IH), 1.51 (d, 3H), 1.48-1.62 (m, IH), 1.76-1.89 (m, 2H), 2.66-2.80 (m, 2H), 2.97-3.37 (m, 3H), 3.38-3.54 (m, 2H), 3.81 (s, 3H), 3.94 (m, IH), 4.17 (m , IH), 4.71 and 4.79 (2t, IH), 5.30 and 5.33 (2s, IH), 6.62 (d, IH), 7.12-7.27 (m, 3H), 7.73 (dd, IH), 7.98 (d, IH ), 12.32 (br. S, IH).

HPLC (method 2): R _t = 4.31 min.

MS (ESI): m / z = 569.3 and 571.3 [M + H] ⁺ .

Example 40

1 - {[8-Chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 677- [1,2,4] triazolo [4,3-a] [4,1 jbenzoxazepin-4-yl ] acetyl) -L-prolin

Analogously to the manner described in Examples 31 and 32, starting from the compound from Example 3 (stereoisomer 3-3) and L-proline tert. -butyl ester obtained the title compound.

'H NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 1.83-2.00 (m, 3H), 2.09-2.19 (m, IH), 3.04 ( dd, IH), 3.48-3.53 (m, 3H), 3.63-3.71 (m, 2H), 3.80 (s, 3H), 4.18 (dd, IH), 4.76 (t, IH), 5.31 (s, IH) , 6.61 (dd, IH), 7.12 (dd, IH), 7.21 (dd, IH), 7.31 (dd, IH), 7.72 (dd, IH), 7.96 (d, IH), 12.48 (br. S, IH ).

HPLC (method 1): R _t = 4.19 min.

MS (ESI): m / z = 555.4 and 557.4 [M + H] ⁺ .

Example 41

8-chloro-6- (2,3-dimethoxyphenyl) -l-isoρroρyl-4- [2-oxo-2- (1,3-thiazolidin-3-yl) ethyl] -4H, 677- [1,2 4] triazolo [4,3-α] [4, 1] benzoxazepine

A solution of 150 mg (0.33 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively treated with 222 mg (0.43 mmol) of PyBOP and 74 μl (0.43 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 34 μl (0.43 mmol) of thiazolidine are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 134 mg (77% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 2.99 (t, IH), 3.07-3.17 (m, 2H), 3.31 (s, 3H ), 3.64-3.79 (m, 3H), 3.81 (s, 3H), 3.82-3.91 (m, IH), 4.42 (m, IH), 4.71 (dd, IH), 4.79 (t, IH), 5.32 ( s, IH), 6.62 (d, IH), 7.12-2.27 (m, 3H), 7.73 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R, = 4.57 min.

MS (ESI): m / z = 529.4 and 531.4 [M + H] ⁺ .

Example 42

((2R) -l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H, 67f- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepin-4-yl] acetyl} pyrrolidin-2-yl) methanol

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 23 mg (0.23 mmol) of (R) -2- (hydroxymethyl) pyrrolidine are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 74 mg (76% of theory) of a white solid are obtained. 'H NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.52 (d, 3H), 1.73-1.94 (m, 4H), 2.99-3.12 (m, IH), 3.18- 3.37 (m, 2H), 3.41-3.60 (m, AH), 3.81 (s, 3H), 3.92 and 4.22 (2m, IH), 4.69, 4.79 and 4.92 (3m, 2H), 5.31 and 5.32 (2s, IH ), 6.62 (dd, IH), 7.12-7.27 (m, 3H), 7.73 (dd, IH), 7.98 (d, IH).

HPLC (method 2): R _t = 4.35 min.

MS (ESI): m / z = 541.4 and 543.3 [M + H] ⁺ .

Example 43

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 67J- [1, 2,4] triazolo [4,3-a] [4, 1] benzoxazepine 4- yl] acetyl} pyrrolidine-3-carboxylic acid tert. butyl

A solution of 100 mg (0.22 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 148 mg (0.28 mmol) of PyBOP and 37 mg (0.28 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 97 mg (0.28 mmol) 3-pyrrolidinecarboxylic acid tert. -butyl ester (as a racemate) was added and the mixture was stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 91 mg (68% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.41 (s, 9H), 1.52 (d, 3H), 1.39-2.19 (m, 2H), 2.97-3.19 (m , 3H), 3.48-3.71 (m, 3H), 3.82 (s, 3H), 4.78 (t, IH), 5.31 (s, IH), 6.62 (dd, IH), 7.12- 7.27 (m, 3H), 7.74 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.95 min.

MS (ESI): m / z = 611.5 and 613.5 [M + Hf Example 44

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 677- [1, 2.4] triazolo [4.3 -α] [4, 1] benzoxazepine 4- yl] acetyl} pyrrolidine-3-carboxylic acid

A solution of 69 mg (0.11 mmol) of the compound from Example 43 in 1.5 ml of dichloromethane is mixed with 0.7 ml of trifluoroacetic acid and stirred for one hour at room temperature. The mixture is then evaporated to dryness and the residue obtained is purified by preparative HPLC. 42 mg (67% of theory) of a white solid are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (s, 9H), 1.52 (d, 3H), 1.92-2.21 (m, 2H), 2.97-3.20 (m , 3H), 3.42-3.71 (m, 4H), 3.81 (s, 3H), 4.77 (m, IH), 5.31 (s, IH), 6.62 (dd, IH), 7.12- 7.26 (m, 3H), 7.73 (dd, IH), 7.95 (d, IH), 12.52 (br. S, IH).

HPLC (method 2): R _t = 4.21 min.

MS (ESI): m / z = 555 and 557 [M + H] ⁺ .

Example 45

1 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H - [\, 2,4] triazolo [4,3-a] [4, 1] benzoxazepine 4- yl] acetyl} pyrrolidin-3 -ol

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 20 mg (0.23 mmol) of 3-hydroxypyrrolidine (as a racemate) are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 76 mg (82% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 1.70-2.01 (m, 2H), 2.90-3.08 (m, IH), 3.42-3.74 (m, 4H), 3.81 (s, 3H), 4.24 and 4.32 (2m, IH), 4.78 (t, IH), 5.31 (s, IH), 6.62 (d, IH), 7.12-7.27 (m, 3H ), 7.73 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.15 min.

MS (ESI): m / z = 527.3 and 529.3 [M + H] ⁺ .

Example 46

8-chloro-6- (2,3-dimethoxyphenyl) -4- [2- (l, l-dioxo-l, 3-thiazolidin-3-yl) -2-oxoethyl] -l-isopropyl- ^ H, 6H - [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine

A solution of 80 mg (0.15 mmol) of the compound from Example 41 in 3 ml of a mixture of glacial acetic acid and water (5: 1) is mixed with a solution of 36 mg (0.23 mmol) of potassium permanganate in a little water at room temperature. After stirring for one hour, 30 ml of water are added and the mixture is extracted twice with 50 ml of ethyl acetate each time. The combined organic extracts are washed successively with sodium bisulfite solution, water and saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture is filtered, the solvent is stripped off in vacuo and the residue is purified by preparative HPLC. 77 mg (91% of theory) of a white solid are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 (d, 3H), 1.51 (d, 3H), 3.39-3.57 (m, 4H), 3.72-3.86 (m, IH), 3.81 (s , 3H), 4.18 (m, IH), 4.48 (dd, IH), 4.80 (m, IH), 4.87 (dd, IH), 5.33 (d, IH), 6.63 (d, IH), 7.12-7.25 ( m, 3H), 7.73 (dd, IH), 7.97 (d, IH).

HPLC (method 2): R _t = 4.43 min.

MS (ESI): m / z = 561.4 and 563.4 [M + H] ⁺ .

Example 47

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (l-methoxy-l-methylethyl) - ^ H, 6H- [1,2,4] triazolo [4,3-] [4,4 ] - benzoxazepin-4-yl] ethyl acetate

A solution of 5.6 g (12.85 mmol) of the compound from Example 8A and 2.55 g (19.27 mmol) of 2-methoxy-2-methylpropanoyl hydrazide [CAS no. 54871-29-3] in 60 ml of dioxane is heated to reflux. After 15 hours a further 1.95 g of the hydrazide are added and heating under reflux is continued for another day. The solvent is then removed on a rotary evaporator and the residue is purified by flash chromatography on silica gel (mobile phase gradient cyclohexane / ethyl acetate 10: 1 → 2: 1). 4.38 g (66% of theory) of the title compound are obtained. In addition, 0.9 g (16% of theory) of the thioamide used are recovered.

Diastereomer mixture 47-1:

HPLC (method 2): R _t = 4.88 min. (56%) and 5.05 min. (44%)

MS (ESI): m / z = 516.5 and 518.5 [M + H] ⁺ .

The diastereomers are separated chromatographically (Kromasil 100 C18, 5 μm, 250 mm x 20 mm; eluent: 0.2% trifluoroacetic acid in water / acetonitrile (35:65); flow rate: 25 ml / min; oven: 40 ° C; UV -Detection: 210 nm). 2.22 g of the diastereomer 47-2 and 1.69 g of the diastereomer 47-3 are obtained.

Diastereomer 47-2. racemic:

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.38 (s, 3H), 1.17 (t, 3H), 1.43 (s, 3H), 3.00 (s, 3H), 3.27 (s, 3H), 3.18-3.42 (m, 2H, partially covered by H ₂ O signal), 3.64 (s, 3H), 4.09 (q, 2H), 4.77 (dd, IH), 6.13 (d, IH), 6.25 (s, IH), 6.72 (dd, IH), 6.84 (d, IH), 7.62-7.72 (m, 2H), 8.02 (d, IH).

HPLC (method 2): R _t = 4.88 min.

MS (ESI): m / z = 516 and 518 [M + H] ⁺ . Diastereomer 47-3. racemic:

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 1.33 (s, 3H), 1.78 (s, 3H), 3.12 (dd, IH), 3.15 (s, 3H), 3.28 (dd, IH), 3.30 (s, 3H), 3.81 (s, 3H), 4.10 (2q, 2H), 4.69 (dd, IH), 5.37 (s, IH), 6.58 (d, IH), 7.09 -7.26 (m, 3H), 7.73 (dd, IH), 7.88 (d, IH).

HPLC (method 2): R _t = 5.05 min.

MS (ESI): m / z = 516 and 518 [M + H]

Example 48

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (l-methoxy-l-methyl) - ^ H, 6H- [1,2,4] triazolo [4,3-ö] [4 , l] - benzoxazepin-4-yl] acetic acid

1.6 g (3.10 mmol) of the compound from Example 47-3 are dissolved in 50 ml of dioxane, mixed with 11 ml of concentrated hydrochloric acid and stirred at 60 ° C. overnight. The mixture is then evaporated to dryness and dried in a high vacuum. 1.4 g (93% of theory) of a white solid are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.34 (s, 3H), 1.78 (s, 3H), 3.03 (dd, IH), 3.16 (s, 3H), 3.22 (dd, IH), 3.33 (s, 3H), 3.81 (s, 3H), 4.65 (dd, IH), 5.37 (s, IH), 6.59 (d, IH), 7.13 (d, 2H), 7.22 (dd, IH), 7.74 (dd, IH), 7.88 (d, IH).

HPLC (method 1): R _t = 4.43 min.

MS (ESI): m / z = 488.1 and 490.1 [M + H] ⁺ . Example 49

8-chloro-6- (2,3-dimethoxyphenyl) -4- [2- (l, l-dioxothiomopholin-4-yl) -2-oxoethyl] -l-isopropyl-4H, <5H- [l, 2, 4] triazolo [4,3-α] [4, l] benzoxazepine

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 31 mg (0.23 mmol) of thiomopholin SS dioxide are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 100 mg (99% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.52 (d, 3H), 2.97-3.11 (m, 2H), 3.19 (dd, 2H), 3.46-3.57 (m , 2H), 3.80 (s, 3H), 3.78-3.89 (m, 2H), 3.99 (m, 2H), 4.79 (dd, IH), 5.32 (s, IH), 6.63 (d, IH), 7.12- 7.27 (m, 3H), 7.74 (dd, IH), 7.99 (d, IH).

HPLC (method 2): R _t = 4.41 min.

MS (ESI): mz = 575.3 and 577.3 [M + H] ⁺ .

Example 50

4- [2- (4-Acetylpiperazin-l-yl) -2-oxoethyl] -8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H, 6 ^' H ^' - [1, 2 , 4] triazolo [4,3-a] [4, 1 jbenzoxazepine

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of NN-diisopropylethylamine at room temperature. After 30 minutes, 29 mg (0.23 mmol) of N-acetylpiperazine are added and the mixture is stirred for eight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 63 mg (63% of theory) of a white solid are obtained.

'H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 2.01 (s, 3H), 3.12 (dd, IH), 3.37- 3.64 (m, 10H), 3.81 (s, 3H), 4.81 (dd, IH), 5.31 (s, IH), 6.62 (d, IH), 7.12-7.27 (m, 3H), 7.74 (dd, IH), 7.98 (d , IH).

HPLC (method 2): R _t = 4.19 min.

MS (ESI): m / z = 568.3 and 570.3 [M + H] ⁺

Example 51

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H _J 67ϊ- [l, 2,4] triazolo [4,3-] [4, l] benzoxazepm- 4- yl] acetyl} -L-prolinamide

A solution of 80 mg (0.17 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 118 mg (0.23 mmol) of PyBOP and 29 mg (0.23 mmol) of N, N-diisopropylethylamine at room temperature , After 30 minutes, 26 mg (0.23 mmol) of L-prolinamide are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 82 mg (84% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 1.72-2.12 (m, 4H), 3.04 (dd, IH), 3.42-3.54 (m , 2H), 3.61-3.69 (m, IH), 3.80 (s, 3H), 4.12 (dd, IH), 4.72 (dd, IH), 5.30 (s, IH), 6.62 (d, IH), 6.90 ( br. s, IH), 7.10-7.28 (m, 4H), 7.72 (dd, IH), 7.95 (d, IH).

HPLC (method 2): R _t = 4.11 min.

MS (ESI): m / z = 554.3 and 556.3 [M + H] ⁺ .

Example 52

[l- (Aminomethyl) -8-chloro-6- (2,3-dimethoxyphenyl) - ^ H, 67ϊ- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine 4-yl] acetic acid hydrochloride

A solution of 65 mg (0.11 mmol) of the compound from Example 11A-3 in 5 ml of dioxane is mixed with 0.2 ml of concentrated hydrochloric acid and heated to 60 ° C. overnight. The reaction mixture is then evaporated to dryness on a rotary evaporator and the residue is purified by preparative HPLC. 36 mg (65% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 3.01 (dd, IH), 3.23 (dd, IH), 3.37 (s, 3H), 3.82 (s, 3H), 4.23 (m, 2H), 4.78 (t, IH), 5.47 (s, IH), 6.67 (d, IH), 7.12-7.24 (m, 3H), 7.75 (dd, IH), 8.04 (d, IH), 8.70 (broad, 4H) ,

HPLC (method 2): R _t = 3.77 min.

MS (ESI): m / z = 445.2 and 447.2 [M + H] ⁺ .

Example 53

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (2-methoxy l) - ^ H, ό7J- [l, 2,4] triazolo [4,3-a] [4, l] benzox - azepin-4-yl] ethyl acetate (racemic diastereomer)

500 ml (1.15 mmol) of the compound from Example 8A and 271 mg (2.29 mmol) of 3-methoxypropane hydrazide are mixed with 5 ml of dioxane and stirred under reflux for 48 h. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 -> 80:20). 154 mg (26% of theory) of the title compound are obtained.

'H NMR (300 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 3.04-3.25 (m, 4H), 3.17 (s, 3H), 3.38 (s, 3H), 3.65 (t, 2H), 3.82 (s, 3H), 4.09 (q, 2H), 4.80 (dd, IH), 5.42 (s, IH), 6.64 (d, IH), 7.06-7.25 (m, 3H), 7.74 (dd , IH), 7.91 (d, IH).

HPLC (method 2): R _t = 4.71 min. MS (ESI): m / z = 502 [M + H] ⁺ .

Example 54

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (2-methoxyethyl) - ^ H; 6 ^' H- [1,2,4] triazolo [4,3-a] [4,4 ] benzox-azepin-4-yl] acetic acid (racemic diastereomer)

130 mg (0.26 mmol) of the compound from Example 53 are dissolved in 5.2 ml of dioxane and five drops of concentrated hydrochloric acid are added. The mixture is stirred for 24 hours at room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 -> 80:20). 50 mg (41% of theory) of the title compound are obtained.

'H NMR (400 MHz, DMSO-d ₆ ): δ = 3.00 (dd, IH), 3.17 (s, 3H), 3.19-3.34 (m, 3H), 3.38 (s, 3H), 3.61-3.65 ( m, 2H), 3.82 (s, 3H), 4.75 (dd, IH), 5.43 (s, IH), 6.64 (d, IH), 7.14-7.25 (m, 3H), 7.74 (dd, IH), 7.92 (d, IH).

HPLC (method 2): R _t = 4.26 min.

MS (ESI): m / z = 474 [M + H] ⁺ .

Example 55

8-Chloro-6- (2,3-dime oxyphenyl) -l- (2-memoxye l) -4- (2-oxo-2-piperidin-l-ylethyl) - ^ H, 67ϊ ^' - [1, 2 , 4] triazolo [4,3-a] [4, 1] benzoxazepine (racemic diastereomer)

31 mg of PyBOP (0.06 mmol) and 8 mg of NN-diisopropylethylamine (0.06 mmol) are added to 26 mg (0.06 mmol) of the compound from Example 54 in 1 ml of NN-dimethylformamide. After stirring at room temperature for 1 h, 5 mg of piperidine (0.06 mmol) are added. After stirring for 16 h at room temperature, the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 - 80:20). 28 mg (88% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.40-1.57 (m, 8H), 3.02-3.09 (m, IH), 3.17 (s, 3H), 3.25-3.34 (m, 3H), 3.36 (s, 3H), 3.43-3.54 (m, 2H), 3.64 (t, 2H), 3.81 (s, 3H), 4.83 (dd, IH), 5.43 (s, IH), 6.65 (d, IH), 7.12-7.25 (m, 3H), 7.73 (dd, IH), 7.92 (d, IH).

HPLC (method 2): R _t = 4.65 min.

MS (ESI): m / z = 541 [M + H] ⁺ .

Example 56

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (l-hyα ^ oxy-l-methylethyl) - ^ H, 6 ^'H- [l, 2,4] triazolo [4,3-a ] [4, l] - benzoxazepin-4-yl] ethyl acetate

1.2 g (2.06 mmol) of the compound from Example 8A and 365 mg (3.10 mmol) of 2-hydroxy-2-methylpropanoic acid hydrazide are mixed with 18 ml of dioxane and heated to 140 ° C. overnight in an autoclave. After the solvent has been removed in vacuo, the residue is purified by preparative HPLC. 587 mg of a diastereomeric mixture are obtained.

Diastereomer mixture 56-1:

HPLC (method 1): R _t = 4.42 min. (55%) and 4.57 min. (35%)

MS (ESI): m / z = 502.3 and 504.3 [M + H] ⁺ .

The diastereomers are separated chromatographically (Kromasil 100 C 18, 5 μm, 250 mm x 20 mm; eluent: 0.2% trifluoroacetic acid in water / acetonitrile (60:40); flow rate: 25 ml / min; oven: 22 ° C; UV detection: 210 nm). 118 mg of diastereomer 56-2 and 141 mg of diastereomer 56-3 are obtained.

Diastereomer 56-2, racemic:

LC / MS (method 3): 2.12 min, m / z = 502.1 [M + H] ⁺ .

Diastereomer 56-3. racemic:

LC / MS (method 3): 2.24 min, m / z = 502.1 [M + H] ⁺ .

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 1.25 (s, 3H), 1.81 (s, 3H), 3.05 (dd, IH), 3.21-3.27 (m, IH ), 3.31 (s, 3H), 3.81 (s, 3H), 4.08 (q, 2H), 4.66 (dd, IH), 5.35 (s, IH), 6.58 (d, IH), 7.12-7.26 (m, 3H), 7.75 (dd, IH), 8.27 (d, IH).

HPLC (method 2): R _t = 4.68 min.

MS (ESI): m / z = 502 [M + H] ⁺ .

Example 57

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (l-hydroxy-l-methylethyl) - ^ H, 6 7- [l, 2,4] triazolo [4,3-a] [4 , l] - benzoxazepin-4-yl] acetic acid

32 mg (0.06 mmol) of the compound from Example 56-3 are dissolved in 6 ml of dioxane and four drops of concentrated hydrochloric acid are added. The mixture is stirred for 24 hours at room temperature, the solvent is removed in vacuo and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 7 mg (23% of theory) of the title compound are obtained.

Racemat 57-1:

Η NMR (400 MHz, CDC1 ₃ ): δ = 1.41 (s, 3H), 1.96 (s, 3H), 3.15-3.23 (m, 2H), 3.42 (s, 3H), 3.86 (s, 3H), 4.69-4.78 (m, IH), 5.50 (s, IH), 6.77 (d, IH), 6.96 (d, IH), 7.16-7.26 (m, 2H), 7.75 (dd, IH), 8.27 (d, IH).

HPLC (method 2): R _t = 4.09 min.

MS (ESI): m / z = 474 [M + H] ⁺ .

By preparative HPLC on a chiral phase [Agilent 1100 with DAD detection; Column: KBD 6175, 250 mm x 20 mm, 10 μm, based on the selector poly (N-methacryloyl-L-leucine-d-menthyl amide); Eluent: iso-hexane / ethyl acetate 2: 3; Flow: 25 ml / min .; Oven: 24 ° C; UV detection: 254 nm] the enantiomers are separated. Enantiomer 57-2 is the enantiomer with the shorter retention time.

Enantiomer 57-2:

Starting from 312 mg (84% purity) of the racemic diastereomer 57-1, 40 mg of the enantiomer 57-2 are isolated.

HPLC (method 2): R _t = 4.09 min.

MS (ESI): m / z = 474 [M + H] ⁴ Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.27 (s, 3H), 1.81 (s, 3H), 3.03 (dd, IH), 3.19-3.27 (m, IH), 3.25 (s, 3H) ), 3.81 (s, 3H), 4.62 (dd, IH), 5.34 (s, IH), 6.77 (d, IH), 7.13-7.26 (m, 3H), 7.74 (dd, IH), 8.27 (d, IH).

Example 58

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (memoxymethyl) - ^ H, H- [1,2,4] triazolo [4,3-a] [4,4] benzoxazepine 4-yl] ethyl acetate (racemic diastereomer)

500 ml (1.15 mmol) of the compound from Example 8A and 239 mg (2.29 mmol) of 2-methoxyacetic acid hydrazide are mixed with 5 ml of dioxane and stirred under reflux for 48 h. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 115 mg (19% of theory, 91% purity) of the title compound are obtained.

HPLC (method 2): R _t = 4.77 min.

MS (ESI): m / z = 488 [M + H] ⁺ .

Example 59

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (methoxymethyl) - ^ 7J; 6 ^' H- [1,2,4] triazolo [4,3-a] [4,4] benzox- azepin-4-yl] acetic acid (racemic diastereomer)

100 mg (0.20 mmol) of the compound from Example 58 are dissolved in 4 ml of dioxane and four drops of concentrated hydrochloric acid are added. The mixture is stirred for 3 days at 80 ° C., the solvent is removed in vacuo and the residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 75 mg (79% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 3.04 (dd, IH), 3.21-3.28 (m, IH), 3.24 (s, 3H), 3.34 (s, 3H), 3.82 (s, 3H ), 4.63 (d, IH), 4.81 (dd, IH), 5.02 (d, IH), 5.46 (s, IH), 6.64 (d, IH), 7.12-7.25 (m, 3H), 7.74 (dd, IH), 7.94 (d, IH).

HPLC (method 2): R _t = 4.25 min.

MS (ESI): mz = 460 [M + H] ⁺ .

Example 60

8-chloro-6- (2,3-dimethoxyphenyl) - 1 - (methoxymethyl) -4- (2-oxo-2-piperidin-1-ethyl) - ¥ H, 6H- [1,2,4] triazolo [ 4,3-a] [4, l] benzoxazepine (racemώcAeΛ'Z) tßΛ'tereo / who)

65 mg PyBOP (0.12 mmol) and 16 mg NN-diisopropylethylamine (0.12 mmol) are added to 52 mg (0.11 mmol) of the compound from Example 59 in 2 ml of NN-dimethylformamide. After 1 h Stirring at room temperature, 11 mg piperidine (0.12 mmol) are added. After stirring for 16 h at room temperature, the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 - »80:20). 42 mg (70% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.40-1.57 (m, 8H), 3.04 (dd, IH), 3.21-3.28 (m, IH), 3.24 (s, 3H), 3.34 (s , 3H), 3.36-3.58 (m, 2H), 3.82 (s, 3H), 4.63 (d, IH), 4.81 (dd, IH), 5.02 (d, IH), 5.46 (s, IH), 6.64 ( d, IH), 7.12-7.25 (m, 3H), 7.74 (dd, IH), 7.94 (d, IH).

HPLC (method 2): R _t = 4.66 min.

MS (ESI): mz = 527 [M + H] ⁺ .

Example 61

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (2-hydroxy-l, l-dimethylethyl) - ^ Hf5H- [l, 2,4] triazolo [4,3-a] - [4 , l] benzoxazepin-4-yl] ethyl acetate (racemic diastereomer)

500 ml (1.15 mmol) of the compound from Example 8A and 303 mg (2.29 mmol) of 3-hydroxy-2,2-dimethylpropanoic acid hydrazide are mixed with 8 ml of dioxane and stirred under reflux for 3 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 55 mg (9% of theory) of the title compound are obtained.

Diastereomer 61-1. racemic:

HPLC (method 2): R _t = 4.46 min.

MS (ESI): m / z = 516 [M + H] ⁺ . Diastereomer 61-2. racemic:

HPLC (method 2): R _t = 4.61 min.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.19 (t, 3H), 1.23 (s, 3H), 1.39 (s, 3H), 3.04 (dd, IH), 3.24 (dd, IH), 3.39 (s, 3H), 3.64 (dd, 2H), 3.82 (s, 3H), 4.09 (q, 2H), 4.57 (dd, IH), 5.37 (s, IH), 6.57 (d, IH), 7.08 -7.24 (m, 3H), 7.74 (dd, IH), 8.02 (d, IH).

HPLC (method 2): R _t = 4.72 min.

MS (ESI): m / z = 516 [M + H] ⁺ .

Example 62

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (2-hydroxy-l, l-dimethylethyl) - ^ H, 67f- [l, 2,4] triazolo [4,3-a] - [4, l] benzoxazepin-4-yl] acetic acid (racemic diastereomer)

42 mg (0.08 mmol) of the compound from Example 61-2 are dissolved in 2 ml of dioxane and 240 μl of 1 N hydrochloric acid are added. The mixture is stirred at 80 ° C. for 18 hours, the solvent is removed in vacuo and the residue is washed with 20 ml of diethyl ether. 36 mg (91% of theory) of the title compound are obtained.

Diastereomer 62-1. racemic:

^! H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.23 (s, 3H), 1.40 (s, 3H), 3.00 (dd, IH), 3.20 (dd, IH), 3.39 (s, 3H), 3.64 (dd, 2H), 3.82 (s, 3H), 4.54 (dd, IH), 5.38 (s, IH), 6.57 (d, IH), 7.11-7.25 (m, 3H), 7.73 (dd, IH) , 8.02 (d, IH).

HPLC (method 2): R _t = 4.26 min. MS (ESI): mz = 488 [M + H] ⁺ .

The racemic diastereomer 62-1 is chromatographically separated into its enantiomers [column: KBD 5326B, 250 mm x 30 mm, based on the selector poly (N-methacryloyl-L-leucine dicyclopropylmethylamide); Eluent: isohexane / ethyl acetate 20:80; Flow: 25 ml / min .; Oven: 22 ° C; UV detection: 254 nm].

Enantiomer 62-2:

HPLC (column: KBD 5326B, 250 mm x 4.6 mm; eluent: isohexane / ethyl acetate 20:80; flow: 1 ml / min; oven: 22 ° C; UV detection: 254 nm): R _t = 6.92 min.

Η-ΝMR (400 MHz, DMSO-d ₆ ): δ = 1.23 (s, 3H), 1.38 (s, 3H), 2.99 (dd, IH), 3.20 (dd, IH), 3.39 (s, 3H), 3.58-3.70 (m, 2H), 3.81 (s, 3H), 4.53 (dd, IH), 5.15 (t, IH), 5.34 (s, IH), 6.57 (d, IH), 7.11-7.23 (m, 3H), 7.72 (dd, IH), 8.02 (d, IH), 12.47 (broad, IH).

HPLC (method 2): R _t = 4.14 min.

MS (ESI): m / z = 488.3 and 490.3 [M + H] ⁺ .

Enantiomer 62-3:

HPLC (column: KBD 5326B, 250 mm x 4.6 mm; eluent: isohexane / ethyl acetate 20:80; flow: 1 ml / min; oven: 22 ° C; UV detection: 254 nm): R _t = 11.13 min.

Example 63

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (hydroxymethyl) - ^ H, f5H- [1,2,4] triazolo [4,3-a] [4,4] benzoxazepine 4-yl] acetate

770 mg (1.77 mmol) of the compound from Example 8A and 318 mg (3.53 mmol) of 2-hydroxyacetic acid hydrazide are mixed with 7.7 ml of dioxane and stirred under reflux for 4 days. Then another 7.7 ml of dioxane and 318 mg (3.53 mmol) of 2-hydroxyacetic acid hydrazide are added. The mixture is again stirred under reflux for 2 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 - »80:20), the resulting diastereomers being separated from one another. 103 mg (12% of theory) of diastereomer 63-1 are obtained.

Diastereomer 63-1. racemic:

^! H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 3.04 (dd, IH), 3.25-3.28 (m, IH), 3.32 (s, 3H), 3.81 (s, 3H) ), 4.09 (q, 2H), 4.60 (dd, IH), 4.86 (dd, IH), 4.96 (dd, IH), 5.48 (s, IH), 5.87 (t, OH), 6.64 (d, IH) , 7.11-7.26 (m, 3H), 7.76 (dd, IH), 8.04 (d, IH).

HPLC (method 1): R _t = 4.50 min.

MS (ESI): m / z = 474 [M + H] ⁺ .

Example 64

[8-chloro-6- (2,3-dimethoxyphenyl) -l - (^ ydroxymethyl) - Hi <5H- [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepine 4-yl] acetic acid (racemic diastereomer)

80 mg (0.17 mmol) of the compound from Example 63-1 are dissolved in 2.5 ml of dioxane and 150 μl of concentrated hydrochloric acid are added. The mixture is stirred at 80 ° C. for 18 hours, then 50 μl of concentrated hydrochloric acid are again added and the mixture is stirred at 80 ° C. for a further 2 days. The solvent is then removed in vacuo and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 43 mg (46% of theory, 81% purity) of the title compound are obtained. HPLC (method 2): R _t = 3.97 min.

MS (ESI): m / z = 446 [M + H] ⁺ .

Example 65

[8-chloro-6- (2,3-dimethoxyphenyl) -4- (2-oxo-2-piperidm-l-yl-ethyl) - ^ H67ϊ- [l, 2,4] triazolo [4,3-a] - [4, l] benzoxazepin-l-yl] methanol (racemic diastereomer)

51 mg of PyBOP (0.10 mmol) and 11 mg of NN-diisopropylethylamine (0.10 mmol) are added to 40 mg (0.09 mmol) of the compound from Example 64 in 1.8 ml of N, N-dimethylformamide. After stirring for 1 h at room temperature, 8 mg of piperidine (0.10 mmol) are added. After stirring for 16 h at room temperature, the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 - »80:20). 4 mg (8% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.39-1.57 (m, 8H), 3.03-3.09 (m, IH), 3.25-3.28 (m, IH), 3.32 (s, 3H), 3.36 -3.48 (m, 2H), 3.81 (s, 3H), 4.60 (dd, IH), 4.85 (dd, IH), 4.95 (dd, IH), 5.43 (s, IH), 5.85 (s, IH), 6.65 (d, IH), 7.12-7.25 (m, 3H), 7.76 (dd, IH), 8.04 (d, IH).

HPLC (method 2): R _t = 4.45 min.

MS (ESI): m / z = 513 [M + H] ⁺ .

Example 66

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (piperidin-l-ylmethyl) - ^ 7J, r5H- [l, 2,4] triazolo [4,3-a] [4, l] benz-oxazepin-4-yl] ethyl acetate

5 ml of dioxane are added to 620 mg (1.42 mmol) of the compound from Example 8A and 447 mg (2.85 mmol) of 2-piperidin-l-yl-acetic acid hydrazide and the mixture is stirred under reflux for 22 hours. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 - »80:20), the resulting diastereomers being separated from one another. 52 mg (6% of theory) of diastereomer 66-1 are obtained.

Diastereomer 66-1. racemic:

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 1.27-1.42 (m, 6H), 2.31-2.37 (m, 4H), 3.05 (dd, IH), 3.25-3.30 (m, IH), 3.32 (s, 3H), 3.67 (dd, IH), 3.81 (s, 3H), 4.02 (dd, IH), 4.07-4.13 (m, 2H), 4.83 (dd, IH), 5.46 (s, IH), 6.60 (d, IH), 7.11-7.25 (m, 3H), 7.72 (dd, IH), 8.10 (d, IH).

HPLC (method 2): R, = 4.56 min.

MS (ESI): m / z = 541 [M + H] ⁺ .

Example 67

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (mo holin-4-ylmethyl) -4H, ό ^' H- [1,2,4] triazolo [4,3-a] [4, l] - benzoxazepin-4-yl] ethyl acetate (racemic diastereomer)

620 ml (1.42 mmol) of the compound from Example 8A and 453 mg (2.85 mmol) of 2-Moφholin-4-yl-acetic acid hydrazide are mixed with 5 ml of dioxane and stirred under reflux for 22 hours. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 84 mg (11% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 2.32-2.43 (m, 4H), 3.09 (dd, IH), 3.18-3.30 (m, 3H), 3.32 (see , 3H), 3.39-3.42 (m, 2H), 3.70-3.77 (m, IH), 3.82 (s, 3H), 4.05-4.15 (m, 3H), 4.84 (dd, IH), 5.46 (s, IH ), 6.60 (d, IH), 7.12-7.25 (m, 3H), 7.72 (dd, IH), 8.10 (d, IH).

HPLC (method 2): R _t = 4.43 min.

MS (ESI): m / z = 543 [M + H] ⁺ .

Example 68

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (moφholin-4-ylmethyl) -4fH, 6H [l, 2,4] triazolo [4,3-a] [4, l] - benzoxazepin-4-yl] acetic acid (racemic diastereomer)

56 mg (0.10 mmol) of the compound from Example 67 are dissolved in 2.5 ml of dioxane and 150 μl of concentrated hydrochloric acid are added. The mixture is stirred at 80 ° C. for 22 hours. The solvent is then removed in vacuo, the residue is washed with diethyl ether and purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 30 mg (56% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 2.35-2.48 (m, AB), 3.09 (dd, IH), 3.18-3.30 (m, 3H), 3.32 (s, 3H), 3.39-3.42 (m, 2H), 3.75 (d, IH), 3.82 (s, 3H), 4.08 (d, IH), 4.85 (dd, IH), 5.44 (s, IH), 6.60 (d, IH), 7.12- 7.25 (m, 3H), 7.72 (dd, IH), 8.10 (d, IH).

HPLC (method 2): R _t = 4.01 min.

MS (ESI): m / z = 515 [M + H] ⁴

Example 69

[l- (3-aminopropyl) -8-chloro-6- (2,3-dimethoxyphenyl) -4H; 6 ^' H- [1,2,4] triazolo [4,3-a] [4,4] benzox - azepin-4-yl] acetic acid (racemic diastereomer)

200 mg (0.33 mmol) of the compound from Example 14A are dissolved in 6 ml of dioxane, and 100 μl of concentrated hydrochloric acid are added. The mixture is stirred at 80 ° C. for 22 hours. Another 100 μl of concentrated hydrochloric acid are added and the mixture is stirred at 80 ° C. for a further 22 hours. The solvent is then removed in vacuo and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 83 mg (53% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.84-1.91 (m, 2H), 2.78-2.87 (m, 4H), 3.13 (dd, IH), 3.36 (s, 3H), 3.36-3.42 (m, IH), 3.81 (s, 3H), 4.76 (dd, IH), 5.35 (s, IH), 6.63 (d, IH), 7.12-7.25 (m, 3H), 7.73 (dd, IH), 7.98 (d, IH).

HPLC (method 1): R _t = 3.94 min.

MS (ESI): m / z = 473 [M + H] ⁺ .

Example 70

[l- [2- (allyloxy) ethyl] -8-chloro-6- (2,3-dimethoxyphenyl) - ^ H, ό ^'H- [l, 2,4] triazolo [4,3-a] [4 , l] benzox-azepin-4-yl] ethyl acetate (racemic diastereomer)

600 ml (1.38 mmol) of the compound from Example 8A and 397 mg (2.75 mmol) of the compound from Example 16A are mixed with 20 ml of dioxane and stirred under reflux for 3 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 120 mg (15% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.18 (t, 3H), 3.07 (dd, IH), 3.20-3.28 (m, 3H), 3.36 (s, 3H), 3.72 (t, 2H ), 3.81 (s, 3H), 3.89-3.91 (m, 2H), 4.09 (q, 2H), 4.79 (dd, IH), 5.09 (dd, IH), 5.16 (dd, IH), 5.43 (s, IH), 5.78 (ddt, IH), 6.64 (d, IH), 7.11-7.24 (m, 3H), 7.74 (dd, IH), 7.94 (d, IH).

HPLC (method 2): R _t = 4.94 min.

MS (ESI): m / z = 528 [M + H] ⁴ .

Example 71

[8-Chloro-6- (2,3-dimethoxyphenyl) -1- (2-hydroxyethyl) -4H; öH ^' - [1,2,4] triazolo [4,3-a] [4,4] benzox- azepin-4-yl] acetic acid (racemic diastereomer)

105 mg (0.20 mmol) of the compound from Example 70 are dissolved in 5 ml of dioxane, and 597 μl of 1 N hydrochloric acid are added. The mixture is stirred at 80 ° C. for 2 days. After removing the solvent, the residue is dissolved in 4 ml of acetic acid and 69 mg (0.06 mmol) of tetrakis (triphenylphosphm) palladium (O) and 21 mg (0.30 mmol) of pyrrolidine are added. The mixture is stirred for 22 hours at room temperature and then the solvent is removed in vacuo. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 -> 80:20). 16 mg (17% of theory) of the title compound are obtained. Η NMR (400 MHz, CDC1 ₃ ): δ = 3.01-3.05 (m, IH), 3.20-3.27 (m, 3H), 3.45 (s, 3H), 3.86 (s, 3H), 4.08-4.16 (m , 2H), 4.90 (dd, IH), 5.57 (s, IH), 6.82-6.84 (m, IH), 6.97 (d, IH), 7.16-7.26 (m, 3H), 7.46-7.50 (m, IH ).

HPLC (method 2): R _t = 4.02 min.

MS (ESI): m / z = 460 [M + H] ⁺ .

Example 72

[8-chloro-l-isopropyl-6- (2-me oxyphenyl) - ^ H, 67i - [l, 2,4] triazolo [4,3-a] [4, l] benzoxazepin-4-yl] - ethyl acetate (racemic diastereomer)

100 ml (0.25 mmol) of the compound from Example 22A and 50 mg (0.49 mmol) of 2-methylpropanic acid hydrazide are mixed with 1.5 ml of dioxane and stirred under reflux for 2 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 15 mg (12% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.97 (d, 3H), 1.18 (t, 3H), 1.50 (d, 3H), 3.09 (dd, IH), 3.23-3.29 (m, IH ), 3.29 (s, 3H), 3.45-3.50 (m, IH), 4.10 (q, 2H), 4.78 (dd, IH), 5.31 (s, IH), 6.60 (d, IH), 7.02 (d, IH), 7.11 (dd, IH), 7.41 (dd, IH), 7.52 (d, IH), 7.74 (dd, IH), 7.94 (d, IH).

HPLC (method 1): R _t = 4.98 min.

MS (ESI): m / z = 456 [M + H] ⁴ Example 73

[8-Cωor-6- (2,3-dihydro-l, 4-benzodioxin-5-yl) -l-isopropyl- ^ H, ^ ό7 - [l, 2,4] triazolo [4,3-a] [4, l] benz-oxazepin-4-yl] ethyl acetate (racemic diastereomer)

47 mg (0.11 mmol) of the compound from Example 28A and 22 mg (0.22 mmol) of 2-methylpropanic acid hydrazide are mixed with 0.7 ml of dioxane and stirred under reflux for 2 days. After removing the solvent in vacuo, the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 20:80 → 80:20). 16 mg (31% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.96 (d, 3H), 1.18 (t, 3H), 1.50 (d, 3H), 3.07 (dd, IH), 3.25 (dd, IH), 3.46 (tt, IH), 3.92-3.98 (m, 2H), 4.03-4.15 (m, 4H), 4.76 (dd, IH), 5.28 (s, IH), 6.71 (d, IH), 6.91-7.00 ( m, 2H), 7.07 (d, IH), 7.74 (dd, IH), 7.93 (d, IH).

HPLC (method 2): R _t = 4.89 min.

MS (ESI): m / z = 484 [M + H] ⁴ .

Example 74

4- {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H 6H- [1, 2,4] triazolo [4,3-a] [4, 1] benzoxazepine 4- yl] acetyl} piperazin-2-one (racemic diastereomer)

150 mg of PyBOP (0.29 mmol) and 37 mg of NN-diisopropylethylamine (0.29 mmol) are added to 120 mg (0.26 mmol) of the compound from Example 3 in 2.4 ml of NN-dimethylformamide. After stirring at room temperature for 1 h, 29 mg of piperazinone (0.29 mmol) are added. After stirring at room temperature for 5 hours, the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water, gradient 20:80 -> • 80:20). 11 mg (8% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.98 (d, 3H), 1.51 (d, 3H), 3.08-3.20 (m, 2H), 3.37-3.50 (m, 4H), 3.50-3.72 (m, 3H), 3.82 (s, 3H), 4.74-4.82 (m, IH), 5.23 (s, IH), 6.63 (d, IH), 7.13-7.23 (m, 3H), 7.74 (d, IH ), 7.96 (d, IH).

HPLC (method 2): R _t = 4.14 min.

MS (ESI): m / z = 484 [M + H].

Example 75

(4- {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl- / J, 6H- [1,2,4] triazolo [4,3 a] [4, 1 jbenzoxazepine-4- yl] acetyl} piperazin-l -yl) ethyl acetate

118 mg PyBOP (0.23 mmol) and 29.3 mg NN-diisopropylethylamine (0.23 mmol) are added to 80.0 mg (0.18 mmol) of the compound from Example 3 (stereoisomer 3-3) in 5 ml of tetrahydrofuran. After stirring for 0.5 h at room temperature, 39.1 mg of l- (ethoxycarbonylmethyl) piperazine (0.23 mmol) are added. After stirring at RT for 18 h, the solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 95: 5). 80 mg (75% of theory) of the title compound are obtained.

'H NMR (400 MHz, CD ₃ CN): δ = 1.06 (d, 3H), 1.22 (t, 3H), 1.55 (d, 3H), 2.46-2.63 (m, 4H), 3.12 (dd, IH ), 3.21 (s, 2H), 3.36 (dd, IH), 3.39 (s, 3H), 3.44 (m, IH), 3.48-3.62 (m, 4H), 3.83 (s, 3H), 4.11 (q, 2H), 4.87 (t, IH), 5.43 (s, IH), 6.71 (d, IH), 7.08 (t, IH), 7.21 (d, 2H), 7.59 (dd, IH), 7.65 (d, IH ).

LC / MS (Method 4): R _t = 2.08 min, mz = 612 [M + H] ⁺ .

Example 76

4 - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl- ^ H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine-4 -yl] acetyl} piperazin-l-yl) acetic acid

30 mg (0.05 mmol) of the compound from Example 75 are dissolved in 1 ml of dioxane, 0.1 ml of concentrated hydrochloric acid is added and the mixture is stirred at 60 ° C. for 30 h. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 5:95 - »95: 5). 9 mg (33% of theory) of the title compound are obtained.

Η NMR (400 MHz, DMSO-d ₆ ): δ = 0.99 (d, 3H), 1.52 (d, 3H), 3.17 (dd, IH), 3.33 (s, 3H), 3.42-3.53 (m, 6H ), 3.66-3.75 (m, 4H), 3.81 (s, 3H), 4.17 (s, 2H), 4.80 (t, IH), 5.33 (s, IH), 6.64 (d, IH), 7.12-7.28 ( m, 3H), 7.75 (dd, IH), 7.97 (d, IH).

LC / MS (Method 5): R _t = 1.92 min, m / z = 584 [M + H] ⁴ .

Example 77

4 - ({[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine-4 -yl] acetyl} amino) butyric acid

125 mg PyBOP (0.240 mmol) and 42 μl NN-diisopropylethylamine (31 mg, 0.240 mmol) are added to 100 mg of the compound from Example 3 (0.218 mmol) in 3 ml tetrahydrofuran and 100 μl NN-dimethylformamide at 0 ° C. The mixture is stirred at RT for 1 h and then 22 μl of ethyl 4-aminobutylate (32 mg, 0.240 mmol) are added. The mixture is stirred at RT for 1 h and then the solvent is removed under reduced pressure. The residue is purified by means of preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 → 95: 5). 24 mg (17% of theory) of the title compound are obtained.

Η-ΝMR (300 MHz, DMSO-d ₆ ): δ = 1.00 (d, 3H), 1.17 (t, 3H), 1.52 (d, 3H), 1.67 (tt, 2H), 2.30 (t, 2H), 2.89-3.09 (m, 3H), 3.16 (m, IH), 3.34 (s, 3H), 3.49 (m, IH), 3.81 (s, 3H), 4.06 (q, 2H), 4.76 (dd, IH) , 5.82 (s, IH), 6.61 (d, IH), 7.09-7.23 (m, 3H), 7.72 (dd, IH), 7.92 (d, IH), 8.09 (t, IH).

HPLC (method 2): R _t = 4.61 min.

MS (ESI): m / z = 571.3 [M + H] ⁺ .

Example 78

N - {[8-chloro-6- (2,3-dimethoxyphenyl) -1-isopropyl-4H, 6H- [1,2,4] triazolo [4,3-a] [4,4,1] benzoxazepine 4- yl] acetyl} -ß-alanine ethyl ester (racemic diastereomer)

125 mg of PyBOP (0.240 mmol) and 42 μl of NN-diisopropylethylamine (31 mg, 0.240 mmol) are added to 100 mg of the compound from Example 3 (0.218 mmol) in 3 ml of tetrahydrofuran and 100 μl of NN-dimethylformamide at 0 ° C. The mixture is stirred at RT for 1 h and then 28 mg of ethyl 3-aminopropionate (0.240 mmol) are added. The mixture is stirred at RT for 1 h and then the solvent is removed under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile / water with 0.1% formic acid, gradient 10:90 - »• 95: 5). 16 mg (12% of theory) of the title compound are obtained. Η NMR (400 MHz, DMSO-d ₆ ): δ = 1.00 (d, 3H), 1.19 (t, 3H), 1.52 (d, 3H), 2.42-2.57 (m, superimposed by the DMSO signal, 2H) , 2.92 and 2.98 (AB signal, in addition to the d split, 2H), 3.27 and 3.50 (2 m, AB signal, 2H), 3.30 (s, 3H), 3.83 (s, 3H), 4.06 (q, 2H ), 4.57 (dd, IH), 5.32 (s, IH), 6.62 (d, IH), 7.09-7.17 (m, 2H), 7.18-7.26 (m, IH), 7.75 (dd, IH), 7.95 ( d, IH), 8.24 (t, IH).

LC / MS (Method 3): R _t = 2.25 min, m / z = 557 [M + H] ⁴ .

Example 79

2- {8-chloro-6- (2,3-dimethoxyphenyl) -4- [2- (l, l-dioxothiomoφholin-4-yl) -2-oxoethyl] - ^ H, 6 ^'H- [1, 2 , 4] triazolo [4,3-a] [4, ljbenzoxazepin- 1 -yl} -2-methylρropan- 1 -ol

A solution of 70 mg (0.14 mmol) of the compound from Example 62 (stereoisomer 62-2) in 5 ml of anhydrous tetrahydrofuran is successively mixed with 142 mg (0.27 mmol) of PyBOP and 35 mg (0.27 mmol) of NN-diisopropylethylamine at room temperature. After 30 minutes, 37 mg (0.27 mmol) of Thiomoφholin-S, S-dioxide are added and the mixture is stirred overnight. The mixture is then evaporated to dryness and the residue is purified by preparative HPLC. 38 mg (44% of theory) of a white solid are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.22 (s, 3H), 1.38 (s, 3H), 3.03 (m, IH), 3.18 (dd, IH), 3.38 (s, 3H), 3.48 (s, 3H), 3.63 (m, 2H), 3.81 (s, 3H), 3.98 (m, 2H), 4.60 (dd, IH), 5.21 (t, IH), 5.33 (s, IH), 6.59 (d, IH), 7.12-7.27 (m, 3H), 7.73 (dd, IH), 8.03 (d, IH).

HPLC (method 2): R _t = 4.20 min.

MS (ESI): m / z = 605 and 607 [M + H] ⁴ .

The following compounds are prepared analogously to the examples described above from the corresponding starting compounds: Example 80

[L - [(iS) -l-aminoethyl] -8-chloro-6- (2,3-dimethoxyphenyl) - ^ H, öH- [l, 2,4] triazolo [4,3-Ω] [4, l] benzoxazepin-4-yl] acetic acid hydrochloride

Example 81

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l- (2-hydroxy-l, l-dimethylethyl) - ^ H, 6H- [l, 2,4] triazolo [4,3- α] [4, l] benzoxazepine-4-yl] acetyl} pyrrolidin-3-ol

Example 82

2- {8-chloro-6- (2,3-dimethoxyphenyl) -4- [2- (l, l-dioxothiomopholin-4-yl) -2-oxoethyl] - ^ H, <5H- [1, 2, 4] triazolo [4,3-α] [4, 1 jbenzoxazepine-1-yl} -2-methylpropane-1-amine

Example 83

l - {[l- (2-Amino-l, l-dimethylethyl) -8-chloro-6- (2,3-dimethoxyphenyl) - H, 6 ^' H- [1,2,4] triazolo [4,3 -α] - [4, l] benzoxazepin-4-yl] acetyl} pyrrolidin-3-ol

Example 84

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l- (l-methoxy-l-methylethyl) -4H, 677- [l, 2,4] triazolo [4,3-α] - [4, l] benzoxazepine-4-yl] acetyl} pyrrolidin-3-ol

Example 85

[8-Chloro-6- (2,3-dimethoxyphenyl) -l- (2-methoxy-l, l-dimethylethyl) - ^ H, 6 ^" H- [l, 2,4] triazolo [4,3-α ] - [4, l] benzoxazepin-4-yl] ethyl acetate

Example 86

[8-chloro-6- (2,3-dimethoxyphenyl) -l- (2-methoxy-l, l-dimethylethyl) - ^ H, (5H- [l, 2,4] triazolo [4,3-α] - [4, l] benzoxazepin-4-yl] acetic acid

Example 87

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l- (2-methoxy-l, l-dimethylethyl) - ^ H, (5H- [l, 2,4] triazolo [4,3- - α] [4, l] benzoxazepin-4-yl] acetyl} pyrrolidin-3-ol

Example 88

l - {[8-chloro-6- (2,3-dimethoxyphenyl) -l-isopropyl- ^ H, 67ϊ- [l, 2,4] triazolo [4,3-α] [4, l] benzoxazepine-4 -yl] acetyl} pyrrolidine-3,4-diol

Example 89

[l- (2-amino-l, l-dimethylemyl) -8-chloro-6- (2,3-dimethoxyphenyl) -4 H, 6 ^'H- [l, 2,4] triazolo [4,3] - [4, l] benzoxazepine-4-yl] acetate

55.0 mg (0.09 mmol) of the compound from Example 30A-2 are dissolved in 2 ml of dioxane, 0.1 ml of concentrated hydrochloric acid is added and the mixture is stirred at 80 ° C. for 20 h. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 95: 5). 11 mg (24% of theory) of the title compound are obtained.

Η-NMR (300 MHz, DMSO-d ₆ ): δ = 1.18 (s, 3H and t, 3H), 1.61 (s, 3H), 3.12 (d, IH), 3.13 and 3.27 (AB signal, additionally as d split, 2H), 3.36 (s, 3H), 3.58 (d, IH), 3.82 (s, 3H), 4.11 (q, 2H), 4.61 (t, IH), 5.58 (s, IH), 6.58 ( d, IH), 7.09-7.25 (m, 3H), 7.76 (dd, IH), 7.88 (dd, IH), 8.02 (br. s, 3H).

LC / MS (Method 4): R _t = 1.95 min, m / z = 515 [M + H]. Example 90

[l- (2-amino-l, l-dimethylethyl) -8-chloro-6- (2,3-dimethoxyphenyl) - ^ H, 6 ^'H- [l, 2,4] triazolo [4,3-ö ] - [4, 1] benzoxazepin-4-yl] acetic acid

135 mg (0.22 mmol) of the compound from Example 30A-2 are dissolved in 5 ml of dioxane, 0.5 ml of concentrated hydrochloric acid is added and the mixture is stirred at 80 ° C. for 40 h. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 → 95: 5). 32 mg (28% of theory) of the title compound are obtained.

Η NMR (300 MHz, DMSO-d ₆ ): δ = 1.19 (s, 3H), 1.59 (s, 3H), 3.01 and 3.22 (AB signal, additionally borrowed as d, 2H), 3.15 (d , IH), 3.41 (s, 3H), 3.53 (d, IH), 3.82 (s, 3H), 4.56 (t, IH), 5.55 (s, IH), 6.58 (d, IH), 7.09-7.25 ( m, 3H), 7.75 (dd, IH), 7.88 (dd, IH), 8.02 (br. s, 3H).

LC / MS (Method 3): R _t = 1.47 min, m / z = 486 [M + H] ⁴

B. Evaluation of pharmacological effectiveness

The pharmacological activity of the compounds according to the invention can be shown in the following assays:

1. Squalene synthase inhibition assay

a) Obtaining microsomes:

Microsomes from rat liver are prepared as a source of squalene synthase for the activity assay. The rat livers are in double volume homogenization buffer [100 mM Tris / HCl, 0.2 M sucrose, 30 mM nicotinamide, 14 mM sodium fluoride, 5 mM dithiothreitol, 5 mM MgCl ₂ , protease inhibitor cocktail (Sigma, Taufkirchen), pH 7.5] crushed and homogenized (dounce homogenizer). The supernatant from a 10,000 g centrifugation is then centrifuged at 100,500 g. The pelleted microsomes are taken up in homogenization buffer, diluted to 10 mg / ml protein and stored at -80 ° C.

b) Squalene synthase activity assay:

The conversion of trans, trans- [l- ³ H] -farnesyl pyrophosphate to [ ³ H] -squales by the microsomal squalene synthase takes place under the following reaction conditions: rat liver microsomes (protein content 65 μg ml), 1 mM NADPH, 6 mM glutathione, 10% PBS, 10 mM sodium fluoride, 5 mM MgCl ₂ , pH 7.5. The compound to be tested is dissolved in DMSO and added to the assay in a defined concentration. The reaction is started by adding farnesyl pyrophosphate (final concentration 5 μM) and 20 kBq / ml trans, trans- [l- ³ H] -farnesyl pyrophosphate and for 10 min. incubated at 37 ° C. Then 100 μl of the reaction solution are mixed with 200 μl chloroform, 200 μl methanol and 60 μl 5N sodium hydroxide solution and adjusted to 2 mM squalene. After intensive mixing and subsequent phase separation, an aliquot of the organic phase is transferred to scintillation liquid (Packard Ultima Gold LSC Cocktail) and the organically extractable radioactive compounds are quantified (LS 6500, Beckman). The reduction in the radioactive signal is directly proportional to the inhibition of squalene synthase by the compound used.

The exemplary embodiments show IC ₅₀ values of <10 μM in this test.

2. Inhibition of squalene and cholesterol synthesis in the liver of mice

Male NMRI mice are kept in metabolic cages on a normal rodent diet (NAFAG 3883). The light / dark cycle is 12 hours, from 6 a.m. to 6 p.m. and from 6 p.m. to 6 a.m. Clock. The animals are used in the experiments with a body weight between 25 g and 40 g in groups of 8-10 animals. Food and drinking water are available to the animals ad libitum.

Depending on their solubility, the substances are administered orally in aqueous tragacanth suspension (0.5%) or in Solutol HS15 / saline solution (20:80) with the gavage in a volume of 10 ml / kg body weight or in Solutol HS15 / saline Solution (20:80) or DMSO / saline solution (20:80) injected subcutaneously. The corresponding control groups receive only the corresponding formulation agent without active ingredient. One or two hours after substance administration, the animals are injected with radiolabelled ¹⁴ C-mevalonolactone intraperitoneally. One or two hours after the injection of ¹⁴ C-mevalonolactone, or 2-4 hours after the substance application, the animals are sacrificed, the abdominal cavity is opened and liver tissue is removed. Immediately after removal, the tissue is dried on the surface, weighed and homogenized in isopropanol. The further processing and extraction of the synthesized squalene and its secondary products is carried out according to a method by I. Duncan et al. (J. Chromatogr. 1979, 162), modified from H. Bischoff et al. (Ether osclerosis 1997, 135).

The extracted lipid fraction is taken up in 1 ml of isopropanol, transferred into scintillation tubes, made up with 15 ml of Ultima Gold ^® scintillation liquid (Packard) and counted in a liquid scintillation counter (Beckmann Coulter LS 6500).

After calculating the specific ¹⁴ C activity of the lipid fraction (dpm / g liver tissue), the synthesis rate of the radioactively labeled ¹⁴ C squalene and the ¹⁴ C follow-on metabolites of the animals treated with active substance are compared with the synthesis rate of the radioactively labeled ¹⁴ C squalene and the ¹⁴ C-subsequent metabolites of the control animals treated only with formulation agent. A reduction in the synthesis rate by> 30% compared to the synthesis rate of the control animals (= 100%) is considered to be pharmacologically effective if the statistical assessment with Student's test shows a p-value <0.05.

Table 1. Inhibition of sterol biosynthesis in the mouse

3. Inhibition of squalene and cholesterol synthesis in the liver of rats

Male Wistar rats are kept on a normal rodent diet (NAFAG 3883) in Makrolon ^® -type Di-cages. The light / dark cycle is 12 hours, from 6 a.m. to 6 p.m. and from 6 p.m. to 6 a.m. The animals are used in the experiments with a body weight between 150 g and 200 g in groups of 6-8 animals. The feed is removed from the animals 18-22 hours before the start of the experiment, drinking water is available ad libitum until the end of the experiment.

Depending on their solubility, the substances are administered orally in a volume of 10 ml / kg body weight in aqueous tragacanth suspension (0.5%) or in Solutol HS15 / sodium chloride solution (20:80) or in Solutol HS15 / sodium chloride solution. Solution (20:80) or DMSO / saline solution (20:80) injected subcutaneously. The corresponding control groups receive only the corresponding formulation agent without active ingredient. One or two hours after substance administration, the animals are injected with radiolabelled ¹⁴ C-mevalonolactone intraperitoneally. One or two hours after the injection of ¹⁴ C-mevalonolactone, or 2-4 hours after the substance application, the animals are sacrificed, the abdominal cavity is opened and liver tissue is removed. Immediately after removal, the tissue is dried on the surface, weighed and homogenized in isopropanol. The further processing and extraction of the synthesized squalene and its secondary products is carried out according to a method by I. Duncan et al. (/. Chromatogr. 1979, 162), modified from H. Bischoff et al. (Atherosclerosis 1997, 135).

The extracted lipid fraction is taken up in 1 ml of isopropanol, transferred into scintillation tubes, made up with 15 ml of Ultima Gold ^® scintillation liquid (Packard) and counted in a liquid scintillation counter (Beckmann Coulter LS 6500).

After calculating the specific ¹⁴ C activity of the lipid fraction (dpm / g liver tissue), the synthesis rate of the radioactively labeled ¹⁴ C squalene and the ¹⁴ C follow-on metabolites of the animals treated with active substance are compared with the synthesis rate of the radioactively labeled ¹ C squalene and the ¹⁴ C follow-up metabolite of the control animals treated with formulation agent only. A reduction in the synthesis rate by> 30% compared to the synthesis rate of the control animals (= 100%) is considered pharmacologically effective if the statistical assessment with Student's t-test shows a p-value <0.05.

C. Embodiments of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. After drying, the granules are mixed with the magnesium stearate for 5 minutes. This mixture is veφresst with a conventional tablet press (format of the tablet see above). A pressing force of 15 kN is used as a guideline for the compression.

Oral suspension;

Composition:

1000 of the compound of the invention, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. The water is added with stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete. Orally applicable solution:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound of the invention corresponds to 20 g of oral solution.

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

iv solution:

The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically compatible solvent (e.g. isotonic saline, 5% glucose solution and / or 30% PEG 400 solution). The solution is filtered sterile and filled into sterile and pyrogen-free injection containers.

Claims

claims

Compound of formula (I)

in which for (C ₆ -C ₁₀ ) aryl or 5- to 10-membered heteroaryl, each up to triple, identical or different, by substituents selected from the group halogen, cyano, nitro, trifluoromethyl, hydroxy, fluoromethoxy, trifluoromethoxy , (C ₁ -C ₆ ) -alkyl, (-CC ₆ ) alkoxy, amino, mono- and di- (-C ₆ ) -alkylamino can be substituted, or for a group of the formula

stands,

X represents O, S or NR ⁵ , wherein

R ⁵ denotes hydrogen or (C _r C ₆ ) alkyl,

Y represents N or CR ⁶ , wherein R ^{6 is} hydrogen, hydroxy or (-CC ₆ ) alkyl,

n represents the number 1, 2 or 3,

R ¹ and R ^{2 are} identical or different and independently of one another represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, (-CC ₆ ) -alkyl or (C Cβ) -alkoxy,

R ^{3 is} for (CC ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, which can be substituted by (C ₃ -C ₈ ) cycloalkyl, or for ( C ₃ -C ₈ ) cycloalkyl, where

(CC ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl and (C ₃ -C ₈ ) cycloalkyl each through hydroxy, (CC ₆ ) alkoxy, (C ₂ -C ₆ ) -alkenoxy, (CC ₆ ) -acyloxy, amino, mono- or di- (-C-C ₆ ) alkylammo or by a 4- to 8-membered saturated heterocycle bonded via an N atom, the one can contain further heteroatoms from the series O or S, can be substituted,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , in which R ^{7 is} hydrogen or (-CO-alkyl,

R ⁸ and R ^{9 are the} same or different and are independently hydrogen, (-C ₆ ) alkyl or (C ₃ -C ₈ ) cycloalkyl, selected by substituents from the group carboxyl, (-C ₆ ) alkoxycarbonyl , Aminocarbonyl, mono- and di- (CrC ₆ ) -alkylaminocarbonyl may be substituted, mean or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycle which contain a further ring hetero atom from the series NR ¹⁰ , O, S, SO or S0 ₂ and by substituents - selected from the group hydroxy, oxo, amino, (CC ₆ ) -alkyl, carboxyl, (-C-C ₆ ) -alkoxycarbonyl, aminocarbonyl, mono- and di- (-C-C ₆ ) -alkyl-amino-carbonyl may be substituted, form what (Cj-C ₆ ) -Alkyl in turn by substituents selected from the group hydroxy, amino, carboxyl, (-C-C ₆ ) -alkoxycarbonyl, aminocarbonyl, mono- and di- (C _r C ₆ ) -alkylaminocarbonyl and R ¹⁰ denotes hydrogen, (dC ₄ ) -alkyl, (CC ₄ ) -acyl or (CC ₄ ) -alkoxycarbonyl, in which

(-C-C) alkyl can in turn be substituted by carboxyl or (-C-C) alkoxy carbonyl,

and their salts, solvates and solvates of the salts.

A compound of formula (I) according to claim 1, in which

A for phenyl, naphthyl or pyridyl, each of which is up to two, identical or different, by substituents selected from the group fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, fluoromethoxy, trifluoromethoxy, (C 1 -C ₄ ) -alkyl, ( Ci- C) alkoxy, amino, mono- and di- (-C-C) alkylamino may be substituted, or

for a group of the formula ° the stands,

X stands for O,

Y is N or CR ⁶ , in which R ^{6 is} hydrogen, hydroxy or (C _r C ₄ ) -alkyl,

n represents the number 1, 2 or 3,

R ¹ and R ^{2 are the} same or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CC ₄ ) -alkyl or (-C-C ₄ ) -alkoxy, R ^{3 represents} (CC _ö ) alkyl, which can be substituted by (C ₃ -C ₆ ) cycloalkyl, or represents (C ₃ -C ₆ ) cycloalkyl, where

(CC ₆ ) alkyl and (C ₃ -C ₆ ) cycloalkyl can each be substituted by hydroxy, (CC ₄ ) alkoxy or amino,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , wherein

R ⁷ denotes hydrogen or (CC ₆ ) alkyl,

R ⁸ and R ^{9 are the} same or different and independently of one another hydrogen, (CC ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, selected by substituents from the group carboxyl, (-C-C ₆ ) alkoxycarbonyl, aminocarbonyl , Mono- and di- (-C ₆ ) alkylaminocarbonyl may be substituted, mean or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle which contain a further ring hetero atom from the series NR ¹⁰ , O, S or S0 ₂ and selected by substituents from the Group hydroxy, oxo, amino, (-C ₆ -C) alkyl, carboxyl, (-C ₆ -C) alkoxycarbonyl, aminocarbonyl, mono- and di- (-C ₆ ) alkylamino-carbonyl may be substituted, in which (-CC ₆ ) alkyl in turn can be substituted by substituents selected from the group hydroxy, amino, carboxyl, (-C-C6) alkoxycarbonyl, aminocarbonyl, mono- and di- (C ₁ -C6) alkylaminocarbonyl and

R ^{10 is} hydrogen, (CC ₄ ) alkyl, (CC ₄ ) acyl or (C _r C ₄ ) alkoxycarbonyl, in which

(-C-C ₄ ) alkyl in turn can be substituted by carboxyl or (-G -alkoxy- carbonyl,

and their salts, solvates and solvates of the salts. A compound of formula (I) according to claim 1 or 2, in which

A represents phenyl which is mono- or disubstituted, identical or different, by fluorine, chlorine, bromine, methyl, methoxy, ethoxy, fluoromethoxy or dimethylamino,

X stands for O,

Y stands for N,

n stands for the number 1,

R ¹ and R ² independently of one another represent hydrogen or chlorine,

R ^{3 represents} (CC ₆ ) alkyl or (C ₃ -C ₆ ) cycloalkyl, which can be substituted by hydroxy, (CC ₄ ) alkoxy or amino,

and

R ^{4 represents} a group of the formula -OR ⁷ or -NR ⁸ R ⁹ , wherein

R ^{7 represents} hydrogen or (-C ₄ ) alkyl,

R ⁸ and R ^{9 are the} same or different and are independently hydrogen or (-CC) alkyl, which may be substituted by carboxyl or (-C-C ₄ ) alkoxycarbonyl, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycle which contain a further ring heteroatom from the series NR ¹⁰ , O, S or S0 ₂ and selected from the group by substituents Hydroxy, oxo, amino, (-CC) -alkyl, carboxyl, (CC) -alkoxycarbonyl, aminocarbonyl, mono- and di- (-C-C ₄ ) -alkylamino-carbonyl group can be substituted, form in which

(C 1 -C ₄ ) alkyl in turn can be substituted by substituents selected from the group hydroxy, amino, carboxyl, (C 1 -C ₄ ) alkoxycarbonyl, aminocarbonyl, mono- and di- (C 1 -C) alkylaminocarbonyl and R ^{10 is} hydrogen, (-CC ₄ ) -alkyl or (C _r C ₄ ) -acyl, and their salts, solvates and solvates of the salts.

4. Compound of Formula (I-A)

in which

A, X, Y, n, R ¹ , R ² , R ³ and R ⁴ each have the meanings given in claims 1 to 3, and their salts, solvates and solvates of the salts.

5. Compound of Formula (I-B)

in which

A, Y, R ¹ , R ² , R ³ and R ⁴ each have the meanings given in claims 1 to 3, and their salts, solvates and solvates of the salts.

6. A process for the preparation of a compound of the formula (I), (IA) or (IB) as defined in claims 1 to 5, characterized in that compounds of the formula (π)

in which R ¹ , R ² , A, X and n each have the meanings given in claims 1 to 5 and

T represents (CC ₄ ) alkyl,

first in an inert solvent with a suitable sulfurizing agent, such as diphosphopentasulfide, in compounds of the formula (TU)

in which R, R, A, T, X and n each have the meanings given above,

transferred, then in an inert solvent with a compound of formula (IV)

in which Y and R ³ each have the meanings given in Claims 1 to 5,

with cyclization to compounds of formula (V)

in which R, R, R, A, T, X, Y and n each have the meanings given above,

converts them under acidic conditions to carboxylic acids of the formula (VT)

in which R, R, R, A, X, Y and n each have the meanings given above,

hydrolyzed and then converted into the compounds of formula (I) by methods known from the literature for the esterification or amidation of carboxylic acids

and optionally separating the compounds of the formula (ϊ) into the stereochemically uniform isomers and / or reacting them with the corresponding (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

A compound as defined in any one of claims 1 to 5 for the treatment and / or prophylaxis of diseases.

Use of a compound as defined in any one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prevention of dyslipidemia, arteriosclerosis, restenosis and ischemia.

Medicament containing a compound, as defined in one of claims 1 to 5, in combination with a further active ingredient selected from the group consisting of cholesterol-lowering statins, cholesterol-absorption inhibitors, HDL-increasing, triglyceride-lowering and / or apolipoprotein B-lowering Substances, antioxidants and anti-inflammatory compounds.

10. Medicament containing a compound as defined in one of claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically suitable excipient.

11. Medicament according to claim 9 or 10 for the treatment and / or prevention of dyslipidemia, arteriosclerosis, restenosis and ischemia.

12. A method of treating and / or preventing dyslipidemia, arteriosclerosis, restenosis and ischemia in humans and animals by administering an effective amount of at least one compound as defined in any one of claims 1 to 5, or a medicament as in any one of claims 9 defined to 11.