Derivatives of benzodiazepine, medicinal agent comprising thereof and method for their preparing

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

 

The present invention relates to compounds of General formula I

in which

X denotes a single bond or etendering group,

moreover, when X denotes a single bond,

R1denotes a hydrogen atom; halogen; nitro-group; lower alkyl, respectively (ness.)alkyl; halo-(ness.)alkyl; alkoxycarbonyl; (ness.)cycloalkyl, optionally substituted by an oxygen atom; a benzoyl, optionally substituted (ness.)the alkyl, halo-(ness.)the alkyl or a halogen atom; phenyl, optionally substituted by halogen atom, hydroxyl, (ness.)the alkyl, halo-(ness.)the alkyl, (ness.)cycloalkyl, (ness.)alkoxy, halo-(ness.)alkoxy or cyano; styrenic; phenylethyl; naphthyl; diphenyl; benzofuranyl or 5 - or 6-membered heterocyclic ring, optionally substituted by exography, benzyloxy, Besora, methanesulfonyl, benzosulfimide or acetyl;

in the case where X denotes etendering group,

R1denotes a hydrogen atom, (ness.)alkyl, optionally substituted by hydroxyl; halo-(ness.)alkyl; (ness.)cycloalkyl, optionally substituted by hydroxyl, (ness.)the alkyl, halo-(ness.)the alkyl, (ness.)alkoxy, halo-(ness.)alkoxy or halogen atom; (ness.)cycloalkenyl, optionally substituted (ness.)the alkyl, halo-(ness.)the alkyl, (ness.)alkoxy, halo-(ISS.)alkoxy, a halogen atom or oxopropoxy; (ness.)alkenyl; phenyl, optionally substituted by a halogen atom, (ness.)the alkyl, halo-(ness.)the alkyl, (ness.)cycloalkyl, (ness.)alkoxy or halo; 5 - or 6-membered heterocyclic ring, optionally substituted (ness.)the alkyl, a halogen atom, exography, benzyloxy, benzoyl, methanesulfonyl, benzosulfimide, acetyl, pivaloyl, t-butoxycarbonyl or tert-BUTYLCARBAMATE; or benzofuranyl;

R3denotes phenyl; pyridine; thiophenyl or thiazolyl, which is optionally substituted by halogen atom, cyano-, nitro-group, azido, hydroxyl, carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilylethynyl, (ness.)the alkyl, (ness.)the quinil, (ness.)alkoxy, halo-(ness.)the alkyl, 4-(ness.)alkylpiperazine-1-carbonyl, (ness.)alkylaminocarbonyl, which is optionally substituted by amino, (ness.)alkylamino, acylamino, exography, hydroxyl; (ness.)alkoxy, (ness.)alkylthio or carboxyla, which is optionally esterified or amitirova; or 5-membered aromatic heterocycle, optionally substituted amino, (ness.)alkylamino, acylamino, exography, hydroxyl, (ness.)alkoxy, (ness.)alkylthio, carboxyla, which is optionally esterified (ness.)the alkyl or amitirova (ness.)alkylaminocarbonyl, which in the final account replaced by hydroxyl, or (ness.)the alkyl, which is optionally substituted by halogen atom, hydroxyl, amino, (ness.)alkylamino, acylamino-or amedieval group that is optionally substituted (ness.)by alkyl, -C(NRR’)=NR’ (where each of R, R’ and R’ represent a hydrogen atom or (ness.)alkyl), hydroxyl. (ness.)alkoxy, (ness.)alkylthio, acyloxy, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, (ness.)alkoxy-(ness.)alkylsulfanyl, (ness.)alkylsulfanyl, cycloalkylcarbonyl, cycloalkylcarbonyl, hydroxyimino or (ness.)alkoxyimino, which does not necessarily etherification or liderovna, (ness.)alkenyl, oxo, cyano, carbamoylated or sulfamoyl, which is optionally substituted (ness.)the alkyl,

provided that, if X denotes a single bond, a R3denotes a pyridinyl, R1does not denote a hydrogen atom or methyl;

and their pharmaceutically acceptable acid additive salts.

It was found that the compounds of formula I are metabotropic antagonists of glutamate receptor. The compounds of formula I possess significant therapeutic effect.

In the Central nervous system (CNS), the transmission of the stimulus is due to the interaction of the neurotransmitter that is sent by a neuron, with neuroreceptors.

L-glutamic acid is the most commonly meetings is decomposing in the Central nervous system neurotransmitter, plays a key role in a large number of physiological processes. Receptors glutamate-dependent stimulus divided into two main groups. The first main group forms a ligand-controlled ion channels. Metabotropic glutamate receptors (mGluR) form the second group and, therefore, belong to the family of G-beloxepin receptors.

To the present time famous eight different members of these mGluR and some of them even are divided into subtypes. Based on the structural parameters of various influences on the synthesis of secondary metabolites and different affinity to low molecular weight chemical compounds these eight receptors can be divided into three groups: mGluR1and mGluR5belonging to group I mGluR2and mGluR3belonging to the group II mGluR4, mGluR6, mGluR7and mGluR8belonging to the group III.

Ligands metabotropic glutamate receptors belonging to the group II, can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, impairment of cognitive abilities and impaired memory.

Other therapeutic indications associated with impaired brain function caused by bypass operations or transplants and, poor circulation in the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, depression of cardiac activity and hypoglycaemia. Moreover, indications are chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (als), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism and parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as, for example, mythicise spasms, convulsions, migraine, urinary incontinence, nicotine addiction, ophiomyia, anxiety, vomiting, dyskinesia and depression.

Objects of the present invention are the compounds of formula I, their pharmaceutically acceptable salts, as such and as pharmaceutically active substances, their getting medicines on the basis of one or more compounds in accordance with the invention and their preparation and use of compounds in accordance with the invention for the treatment or prevention of diseases of the aforementioned type and, therefore, to prepare the drugs.

Preferred are those compounds of formula 1 in which R3represents phenyl substituted in the meta-position by cyano; halogen atom or imides is poured, which is optionally substituted (ness.)by alkyl; or 1,3-thiazolyl, which is optionally substituted hydroxy-(ness.)by alkyl, carboxy, or-CO-NH-(CH2)2OH; 1,3-oxazolyl; 1,2,3-triazole; 1,2,4-triazolyl, which is optionally substituted (ness.)by alkyl; tetrazolyl or isoxazolyl, which is optionally substituted (ness.)the alkyl. Examples of such compounds are:

3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

4-(3-chlorophenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

8-(4-perforating)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-perforating)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-forfinal)-4-[3-(4-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-fluoro-2-were)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-fluoro-2-hydroxyphenyl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-perforating)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-forfinal)-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,4-differenl)-4-(-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,3-differenl)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-forfinal)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid;

(2-hydroxyethyl)amide 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}-4-methylthiazole-5-carboxylic acid and

4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-yl)phenyl]-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

Preferred are also the compounds of formula I in which R3denotes thiophenyl, preferably thiophene-2-yl, optionally substituted by a halogen atom or cyano; or pyridinyl, preferably pyridine-4-yl, optionally substituted, preferably in the 2-position, halogen atom or cyano.

Examples of such compounds are:

8-(4-perforating)-4-(2-imidazol-1-espiridion-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

2-[7-(4-forfinal)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile;

4-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile and

4-[7-(2,4-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile.

The present description also includes all tautomeric forms of the compounds according to the invention.

Used in this opionionated "(ness.)alkyl" is used to denote saturated remotemachine or branched hydrocarbon residue, containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.

Used in the present description the term "(ness.)quinil" is used to denote unsaturated remotemachine or branched hydrocarbon residue containing from 2 to 7 carbon atoms, preferably from 2 to 4 carbon atoms, such as ethinyl, n-PROPYNYL, etc.

The term "(ness.)cycloalkyl" in the present description refers to a cyclic saturated hydrocarbon residue with 3 to 5 carbon atoms, preferably 3 carbon atoms, such as cyclopropyl.

The term "(ness.)alkoxy" means (ness.)the alkyl residue in the sense in which it is presented above, linked through an oxygen atom.

The term "halogen" includes fluorine atoms, chlorine, bromine and iodine.

The phrase "5 - or 6-membered heterocyclic ring" includes thiophene, furan, thiazole, pyridine, partially hydrated pyridine, such as 2-pyridone, partially hydrogenated pyridine, for example, tetrahydropyridine, five-membered aromatic heterocycle comprising up to 4 heteroatoms selected from O, S, N, including imidazol-1-yl, imidazol-2-yl, imidazol-4-yl; pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl; 1,3-thiazol-2-yl, 1,3-the thiazol-4-yl, 1,3-thiazol-5-yl; 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5 is, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl; 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-2-yl; 1,2,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl; 1,2,4-thiadiazole-2-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,3-thiadiazole-4-yl, 1,2,3-thiadiazole-5-yl; tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl;

The proposed compounds of General formula I and their pharmaceutically acceptable salts can be obtained in accordance with the following methods.

Scheme And

Compounds of General formula I, in which R1, R3and X have the meanings indicated above, can be obtained in accordance with the scheme And, for example, by removal of protecting group BOC in connection with the General formula II and concomitant cyclization freed from the protective groups of the compound. The stage of removal of the protective group/cyclization may be carried out by treatment of compounds of General formula II with the acid Bronsted, such, for example, triperoxonane acid (TFA), in an inert solvent, such, for example, dichloromethane (DHM). In a preferred embodiment, the reaction is carried out at a temperature between 0 and 50° C. In the reaction mixture, it may be appropriate also using anisole or 1,3-dimethoxybenzene as acceptor carbocation. In another Varian is e instead of VOS can be used any other suitable misamisaiwai group, such as, for example, FMOC (fluorenylmethoxycarbonyl) or benzyloxycarbonyl.

Schema

Compounds of General formula II in which R1, R3and X have the same meanings as above, can be obtained in accordance with the scheme, for example by reaction of compounds of General formula III with dioxanone (General formula (IV) in an inert solvent, such, for example, toluene or xylene, at elevated temperatures, preferably in the range of 80 and 160° C.

Alternatively compounds of General formula II can be obtained, for example, by reaction of compounds of General formula III with β -ketefian (General formula IVa), in which R3has the same meanings as above, using the same conditions as those described for the reaction with dioxanone.

Scheme

In accordance with the scheme With compounds of General formula III in which R1has the same meanings as those indicated above for the compounds in which X denotes a single bond, can be obtained in a different way from iodine compounds IX depending on the nature of R1. As shown in the diagram, the key steps are the reaction of a combination-type reactions in Suzuki and Stille in the presence or absence of carbon monoxide. The exact conditions for the respective compounds which can be found in the experimental part.

Scheme D

MD (General method) And method: diphosgene, tO, 77°; then tert-VION

Ω A, method b: Vos2Oh, Cs2CO3, 2-butanone, 52°

OM AND method: (i) Vos2Oh, DMAP (N,N-dimethylaminopropylamine), THF;

ii) TFA, DHM, 0°

In accordance with scheme D key intermediate iodide IX can be obtained from the technically available 2-nitroaniline implementation of a standard sequence iodination protection.

Scheme E

In accordance with scheme E, compounds of General formula IIIa, in which

R1has the same meanings as those indicated above for the compound in which X denotes etendering group, can be obtained in a different way from iodine compounds IX depending on the nature of R1. As shown in scheme E, the transformation of, for example, can be

a) direct connection R1-alcantarilha substituent by reaction of a combination type Sonogashira reaction, followed by reduction of the nitro group or

b) two sequential reactions combination reactions Sonogashira, where first by the reaction of a combination of trimethylsilylacetamide with iodide IX obtaining after removal of the protective group with sodium hydroxide in methanol intermediate XII, which can then be subjected to the transformation carried out the eat the second reaction combination type Sonogashira reaction with the appropriate reagent R 1-I, R1-Sh or R1-S2CF3and restoration of the nitro group to obtain the target compounds.

The exact conditions for the respective compounds can be found in the experimental part.

Scheme F

In accordance with scheme F dioxanone and β -ketoesters as the building blocks of the General formulae IV and IVa can be obtained by methods which some experts in the art known from the corresponding derivatives of R3-COR carboxylic acids, i.e. of the free acid, the methyl or ethyl esters and anhydrides of the acids. The exact conditions for the respective compounds can be found in the experimental part.

Another way synthetic obtain the compounds of General formula IC, in which R and X have the same meanings as above, a R3means phenolcarboxylic General formula C(O)NR4R5in which R4and R5represent a hydrogen atom or (ness.)alkyl, or R4and R5together form morpholinyl residue or N-methylpiperazin presented in figure G.

Scheme G

The exact conditions for obtaining the corresponding compounds can be found in the experimental part.

However, another way of obtaining compounds of General formula I consists in carrying out the reaction of 4-aryl--iodine-1,3-dihydrobenzo[b][1,4]diazepin-2-ones (General formula Id, the scheme for synthesis of N) with alkynes of General formula R1With≡ -, in which R1has the same meanings as above, the reaction of a combination of Sonogashira.

Scheme N

The exact conditions for obtaining the corresponding compounds can be found in the experimental part.

Pharmaceutically acceptable salts can be easily obtained in accordance with known methods and taking into account the nature of the turn in the Sol connection. To obtain pharmaceutically acceptable salts of basic compounds of formula I are acceptable mineral and organic acids, such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and citric acid, formic acid, fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, p-toluensulfonate etc.

The compounds of formula I and their pharmaceutically acceptable salts are metabotropic antagonists of glutamate receptor and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, a disorder of cognitive and memory impairment. Other therapeutic indications associated with impaired brain function, you is designed by bypass operations or transplants, poor circulation in the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, depression of cardiac activity and hypoglycaemia. Moreover, indications are chronic and acute pain, Huntington's chorea, BASS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism and parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as, for example, mythicise spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychosis, ophiomyia, anxiety, vomiting, dyskinesia and depression.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicines, for example in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

When the pharmaceutical preparation of the compounds of formula I and their pharmaceutically acceptable salts can be combined with pharmaceutically inert inorganic or organic the ski media. As such carriers in the manufacture of tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch and its derivatives, talc, stearic acid and its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, solid fats, semi-solid and liquid polyols and the like, But in the case of soft gelatin capsules, depending on the nature of the active substance is usually no media required. Preparation of solutions and syrups acceptable carriers are, for example, water, polyols, sucrose, invert sugar, glucose, etc. For the preparation of aqueous solutions for injection of water-soluble salts of compounds of formula I can be applied adjuvants such as alcohols, polyols, glycerine, vegetable oils and the like, but typically, they are optional. Acceptable for the manufacture of suppositories carriers are, for example, natural or hardened oils, waxes, solid fats, semisolid and liquid polyols and the like

Moreover, the pharmaceutical preparations can include preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffers, masking additive is an antioxidant. However, they may also include other therapeutically valuable substances.

As mentioned above, drugs, containing one or more compounds of the formula I or their pharmaceutically acceptable salts and a therapeutically inert fillers, are also the object of the present invention, as the method of preparation of such medicines, which includes making one or more compounds of the formula I or their pharmaceutically acceptable salts and, if necessary, one or more other therapeutically valuable substances in the form of measured Galanova drug together with one or more therapeutically inert carriers.

The dose can be varied within wide intervals, and in each case it obviously has to fit individual needs. Typically, the effective dose for oral or parenteral administration is in the range from 0.01 to 20 mg/kg/day, and for all the above indications, the preferred dose is from 0.1 to 10 mg/kg/day. Therefore, the daily dose for an adult weighing 70 kg is in the range from 0.7 to 1400 mg, preferably in the range from 7 to 700 mg.

The object of the present invention is also the use of compounds of the formula I and their pharmaceutically acceptable salts for the sentence is the service of medicines, mainly for the treatment or prevention of acute and/or chronic neurological disorders of the above type.

Compounds of the present invention are antagonists of mGlu receptor group II, as determined using the test described Cartmell and others (Br. J.Pharmacol. 1998, 123(3), 497-504).

The compounds exhibit activity, determined as described below, and equal to 50 μm or less, more typically 3 μm or less and ideally 0.5 micron and less. In the table, below, presents some specific values of the pKipreferred compounds.

ConnectionKimGlu(MKM)
3-(7-iodine-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile0,017
4-(3-chlorophenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,040
4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,006
3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile0,055
8-(4-perforating)-4-(3-imidazol-1-ylphenyl)1,3-dihydrobenzo[b][1,4]diazepin-2-he0,004
8-(4-perforating)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,049
8-(4-perforating)--(2-imidazol-1-espiridion-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he 0,004
8-(4-forfinal)-4-[3-(4-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,016
8-(4-fluoro-2-were)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,050
8-(4-fluoro-2-hydroxyphenyl)-4-(3-imidazol-1-0,170
ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he 
2-[7-(4-forfinal)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile0,250
8-(4-perforating)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-hebeing 0.036
4-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile0,039
4-[7-(2,4-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile0,026
8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,008
8-(4-forfinal)-4-[3-(3-methylisoxazol-5-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,289
8-(2,4-differenl)-4-(3-[1,2,3]triazole-1-yl)-phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,010
8-(2-forfinal)-4-(2-imidazol-1-iltiazem-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,298
8-(2,3-differenl)-4-(3-[1,2,3]is resol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he 0,013
8-(2-forfinal)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he0,016
2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-karbonovye acid0,016
(2-hydroxyethyl)amide 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}-4-methylthiazole-5-carboxylic acid0,049
4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-yl)phenyl]-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-heto 0.108

Binding of [3H]-LY354740 on the cell membranes of Cho, transfection mGlu2

Transfection and cell culture

cDNA encoding mGlu2 protein receptor in rats, the plasmid pBluesceipt II received from Prof. S.Nakanishi (Kyoto, Japan) and was subcloned into the eukaryotic expressing vector pcDNA-I-amp firms Invitrogen (NV Leek, the Netherlands). This vector design (pcDlmCR2) and psvNeo a plasmid encoding the gene of resistance to neomycin, was built in Cho cells, modified calcium phosphate method described by Chen and Okayama (1988). Cells were incubated in medium Dulbecco Modified Eagle containing a lower concentration of L-glutamine (final concentration: 2 mm) and 10%cialisbuynow fetal calf serum from the company Gibro BRL (Basel, Switzerland). Selection was performed in the presence of G-418 (end-the end of the acidity 1000 ál/ml). The clones identified by the method of reverse transcription of 5 μg of total RNA with the subsequent stage of the NDP, using specific primers receptor mGluz 5’-atcactgcttgggtttctggcactg-3’ and 5’-agcatcactgtgggtggcataggagc-3’ in 60 mm Tris HCl (pH 10), 15 mm (NH4)2SO4, 2 mm MgCl2in the presence of 25 u/ml of Tag polymerase. The PCR reaction was performed in mode 30 cycles of annealing at 60° C for 1 min, elongation at 72° C for 30 s, and denaturation at 95° C for 1 min

Preparation of membranes

Cells, cultured as described above were collected and washed three times with cold saline solution with phosphate buffer and frozen at -80° C. the Precipitate resuspendable in cold 20 mm HEPES-NaOH buffer, containing 10 mm EDTA (pH 7.4), and homogenized with Poltrona (firm Kinematica AG, Littau, Switzerland) for 10 s at 10000 rpm After centrifugation for 30 min at 4° C, the precipitate was washed once with the same buffer, once with cold 20 mm HEPES-NaOH buffer including 0.1 mm EDTA (pH 7.4). The protein content was determined using the method of the Pier (firm Socochim, Lausanne, Switzerland), using as a standard bovine serum albumin.

Binding of [3H]-LY354740

After thawing, the membranes resuspendable in cold 50 mm Tris-Hcl buffer containing 2 mm MgCl2and 2 mm l3(at pH 7) buffer (buffer for binding). The end is th concentration of the membranes in the experiment was 25 µg protein/ml Experiments on the inhibition was performed with membranes, incubated with 10 nm [3H]-LY354740 for 1 h at room temperature in the presence of test compounds at various concentrations. After incubation the membrane was filtered on glass fiber filters Whatmann GF/C and washed 5 times with cold buffer for binding. Nonspecific binding was determined in the presence of 10 μm DCG IV (TOCRIS No. 0975). After migration filters in plastic tubes containing 10 ml of Ultima-gold scintillare fluid (Packard, Zurich, Switzerland), the radioactivity was determined by the method of liquid scintillation in the counter Tri-Carb 2500 TR (Packard, Zurich, Switzerland).

Data analysis

Curves of inhibition were processed using the four parameter logistic equation, obtaining values IR50and the coefficients of the hill.

EXAMPLES

General method a (scheme synthesis D)

Obtain tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid from 4-iodine-2-nitroaniline.

Method and

4.1 ml of diphosgene from 34.1 mmol) in 40 ml of EtOAc at 0° C was added a solution of 4-iodine-2-nitroaniline (to 45.5 mmol) in 200-500 ml of EtOAc and the mixture is boiled under reflux for 18 hours Under vacuum solvent was removed, resulting in the remaining brown solid, which was ground into powder with 200 ml of hot hexane. This solid materialmaterial and the filtrate was concentrated under reduced pressure, resulting in a yellow solid remained pure 4-iodine-2-nitrophenylhydrazine. This material was boiled under reflux in a mixture of excess tert-VION in CH2CL2within 2.5 hours after removal of the solvent left an orange solid, which was purified by column chromatography on silica gel using hexane/tO, receiving a yellow solid tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid.

Method b

In a mixture of 4-iodine-2-nitroaniline (142 mmol) and of 55.5 g of cesium carbonate (170 mmol) in 740 ml of 2-butanone was added dropwise a solution of 37.8 g VOS2(173 mmol) in 170 ml of 2-butanone and the resulting mixture was stirred at 52° C for 26 h Under vacuum solvent was removed, the residue was treated with a mixture of 240 ml of N2Oh and 240 ml Meon and were extracted with hexane (3 servings 500 ml). The combined hexane layer was washed with brine (200 ml) and all water layers are re-extracted with hexane (300 ml). All combined hexane layers were dried over MgSO4that was filtered under vacuum solvent was removed to obtain an orange solid, which was purified by column chromatography on silica gel using hexane/EtOAc, receiving a yellow solid tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid.

Method in

the solution of 4-iodine-2-nitroaniline (550 mmol) and 1.22 g DMAP (N,N-dimethylaminopropylamine) (10 mmol) in 1000 ml of THF at 23° C for 70 min was added dropwise a solution of 246 g VOS2(1128 mmol) in 500 ml THF and stirring was continued at 23° C for 75 minutes the Entire mixture is evaporated to dryness and dried under high vacuum, resulting remained 253,59 g of dark brown solid. This material was dissolved in 1100 ml DHM, cooled to 0° and was added dropwise 84 ml of TFA (1100 mmol). The mixture was stirred at 0° C for 2 h, poured into ice saturated solution Panso3, were extracted DHM, washed with brine and dried over MgSO4. After removal of the solvent under vacuum remained dark brown solid (199,71 g), which was placed on silica gel and purified by column chromatography on silica gel using hexane/EtOAc, receiving a yellow solid tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid.

Example A1

tert-Butyl ester (4-iodine-2-nitrophenyl)carbamino acid.

Isocyanate was prepared from 12.0 g of 4-iodine-2-nitroaniline (45,5 mmol; obtained from 2-nitroaniline in accordance with the work of Wilson, Gerald J.; Hunt, Frederick C. Aust.J.Chem. 1983, 36, 2317-25; CAS-No. [20691-72-9]) by reaction with a 4.1 ml diphosgene from 34.1 mmol) in 250 ml of EtOAc followed by treatment of 12 ml of tert-VION in 60 ml of CH2CL2in accordance with the General method A (method a). Received in the form 8,23 g yellow solid (yield: 82%).

MS EI) 390 (M +); tPL: 92-94° C.

Example A2

tert-Butyl ester (4-isopropyl-2-nitrophenyl)carbamino acid.

Prepared from 4-isopropyl-2-nitroaniline (CAS-No. [63649-64-9]) by reaction with VOS2Oh and a catalytically effective amount of DMAP in THF followed by treatment TFA in CH2Cl2in accordance with the General method A (method b). Was obtained as a yellow oil (14.1 g).

MS (EI) 280 (M+).

Example A3

tert-Butyl ester (4-cyclopropyl-2-nitrophenyl)carbamino acid.

Prepared from 4-cyclopropyl-2-nitrophenylamino obtained by the nitration of N-(4-cyclopropylmethyl)ndimethylacetamide 65%NGO3in AU2Oh and by subsequent saponification 6N. NaOH boiling under reflux in dioxane (CAS-No. [63649-64-9]), by reaction with VOS2Oh and a catalytically effective amount of DMAP in THF followed by treatment TFA in CH2Cl2in accordance with the General method A (method b). Received in the form of 2.33 g of an orange liquid.

MS (EI) 278 (M+).

General method (synthesis scheme C)

Obtain tert-butyl ester (4-aryl-2-nitrophenyl)carbamino acid direct reaction mix for Suzuki tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid arylboronic acids.

A mixture of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (3.0 mmol), arylboronic acid (4.5 mmol) and dl2(h3 )2(2 mol.%) boiled under reflux in 25 ml of 1,4-dioxane and 7.5 ml of a 2 M solution of PA3CO3[or, alternatively, with 7.5 ml of 1 M solution of NaHCO3, LiCl (6.0 mmol) and (PH3R)4PD (3 mol.%) in 30 ml of DME (dimethyl ether); it is also possible with Et3N (9.0 mmol), Pd(OAc)2(3 mol.%), h3(6 mol.%) in 10 ml of DMF at 100°] until then, until thin layer chromatography indicated the complete conversion of the iodide. The mixture was transferred into a separate funnel, was added 25 ml of N2Oh and the product was extracted with diethyl ether or tO (3 portions of 30 ml). The combined organic layers were washed with brine (50 ml) and dried over Na2SO4. After removal of the solvent left a brown residue, which was purified by column chromatography on silica gel using cyclohexane/diethyl ether or cyclohexane/tO, getting mentioned in the title compound.

Example B1

tert-Butyl ether (4’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-methoxyphenylacetic acid according to General method C. was Obtained as yellow solid (637 mg).

MS (ISN) 343 [(M-N)-]; tPL: 107-109° C.

Example B2

tert-Butyl ether (2-nitro-4-thiophene-3-ylphenyl)carbamino sour is you.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 3-tiefenbronn acid according to General method C. was Obtained as yellow solid (326 mg).

MS (ISN) 319 [(M-N)-].

Example B3

tert-Butyl ester (4-furan-2-yl-2-nitrophenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and furan-2-Bronevoy acid according to General method C. was Obtained as an orange solid (282 mg).

MS (EI) 304 (M+); tPL: 169-172° C.

Example B4

tert-Butyl ether (4’-ethyl-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-ethylbenzophenone acid according to General method C. was Obtained as an orange solid (689 mg).

MS (EI) 343 [(M+H)+]; tPL: 94-99° C.

Example B5

tert-Butyl methyl ether (3-nitrobiphenyl-4-yl)carbamino acid.

Prepared from 994 mg of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (2,73 mmol) and 576 mg of phenylboronic acid (3.00 mmol) according to General method C. was Obtained as a bright yellow solid (800 mg).

MS(EI)314(M+);tPL: 119-121° C.

Example B6

tert-Butyl ester (4-furan-3-yl-2-nitrophenyl)CT is amino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and furan-3-Bronevoy acid according to General method C. was Obtained as an orange solid (855 mg).

MS (ISP) 322(M+NH4)+] 327 [(M+Na)+]; tPL: 105-110° C.

Example B7

tert-Butyl ester(4-naphthalene-1-yl-2-nitrophenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 1-NativeWindow acid according to General method C. was Obtained as a yellow foam (1.0 g).

MS (ISN) 363 [(M-N)-]; tPL: 60-66° C.

Example B8

tert-Butyl ether (3’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 3-methoxyphenylacetic acid according to General method C. was Obtained as an orange solid (818 mg).

MS (ISP) 345 [(M+N)+], 362 [M+NH4)+] 367 [(M+Na)+]; tPL:104-107° C.

Example B9

tert-Butyl methyl ether (3-nitro-4’-trifloromethyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-(triptoreline)benthivorous acid according to General method C. was Obtained as an orange solid (569 mg).

MS (ISN) 397 [(M-N) ]; tPL: 145-147° C.

Example 10

tert-Butyl ether (2’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 2-ferbinteanu acid according to General method C. was Obtained as yellow solid (1.48 g).

MS (ISN) 331 [(M-N)-]; tPL: 131-133° C.

Example B11

tert-Butyl ether (3’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 3-ferbinteanu acid according to General method C. was Obtained as yellow solids (a 3.87 g).

MS (ISN) 331 [(M-N)-]; tPL: 93-96° C.

Example 12

tert-Butyl ether (4’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-ferbinteanu acid according to General method C. was Obtained as yellow solid (1.08 g).

MS (ISN) 331 [(M-N)-]; tPL: 155-167° C.

Example B13

tert-Butyl ether (4’-fluoro-2’-methyl-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-fluoro-2-methylbenzeneboronic acid [CAS-No. 139911-29-8; obtained from 2-bromo-5-Tortolla of reaction what s with n-BuLi at -78° With subsequent processing(OMe)3and subsequent hydrolysis] in accordance with the General method C. was Obtained as yellow solid (1,71 g),

MS (EI) 346 (M+),

Example 14

tert-Butyl ether (4’-fluoro-2’-methoxyethoxy-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 4-fluoro-2-methoxyethoxyethoxy acid [obtained from 1-bromo-4-fluoro-2-(methoxyethoxy)benzene (CAS-No. 162269-78-5) by reaction with n-BuLi at -78° With subsequent processing(OMe)3and subsequent hydrolysis] in accordance with the General method C. was Obtained as yellow solid (0.96 g).

MS (EI) 392 (M+).

Example 15

tert-Butyl ether (2’,4’-debtor-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 2.4-differentviews acid according to General method C. was Obtained as yellow solid (3,26 g).

MS (ISN) 349 [(M-N)-].

Example 16

tert-Butyl ether (2’-fluoro-6’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 2-fluoro-6-methoxybenzeneboronic acid according to General method C. was Obtained as yellow solid (0,95 is).

MS (ISN) 361 [(M-N)-]; tPL: 65-68° C.

Example 17

tert-Butyl ether (2’,5’-debtor-3-nitrative Neil-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and 2.5-differentviews acid according to General method C. was Obtained as yellow solid (2.85 g).

MS (ISN) 349 [(M-N)-]; tPL: 104° C.

Example 18

tert-Butyl ester (4-benzofuran-2-yl-2-nitrophenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) and benzo[b]furan-2-Bronevoy acid according to General method C. was Obtained as an orange solid (711 mg).

MS (EI) 354 (M+); tPL: 175-177° C.

Example 19

tert-Butyl ether (2’,3’-debtor-3-nitrobiphenyl-4-yl)carbamino acid.

Prepared from of 3.64 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (10 mmol) and 2.35 g of 2,3-differentviews acid (14.9 mmol) according to General method C. was Obtained as yellow solid (3,22 g).

MS (ISN) 349 [(M-N)-]; tPL: 93° C.

General method (synthesis scheme C)

Obtain tert-butyl ester (4-aryl-2-nitrophenyl)carbamino acid reaction mix for Suzuki tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid is bis(pinacolato)diboron and subsequent reaction with aryl halides.

A mixture of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (2.0 mmol), bis(pinacolato)Debora (2.2 mmol), COAs (6.0 mmol) and PdCl2(PPh3)2(3 mol.%) in 25 ml of 1,4-dioxane was stirred at 100° until then, until TLC indicated the complete conversion of the iodide [cf. Tetr.Lett. 1997, 38, 3841-3844]. After adding helgaleena (4.0 mmol), dl2(h3)2(3 mol.%) and 7.5 ml of a 2 M solution of Na2CO3the mixture was stirred at 100° until then, until TLC indicated the complete conversion of the intermediate broowaha ether. The mixture was transferred into a separate funnel, was added 30 ml of N2Oh and the product was extracted with diethyl ether or EtOAC (3 portions of 50 ml). The combined organic layers were washed with brine (100 ml) and dried over Na2SO4. After removal of the solvent left a brown residue, which was purified by column chromatography on silica gel using cyclohexane/diethyl ether or cyclohexane/tO, getting mentioned in the title compound.

Example C1

tert-Butyl ether (2’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 2-iodoanisole in accordance with the General method C. Received is in the form of a yellow solid (735 mg). MS (EI) 344 (M+).

Example C2

tert-Butyl ether (4’-chloro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 1-chloro-4-iodobenzoyl in accordance with the General method C. was Obtained as yellow solid (779 mg).

MS (ISN) 347 [(M-N)-]; tPL: 150-155° C (decomposition).

Example C3

tert-Butyl ether (2-nitro-4-thiophene-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 2-idioten in accordance with the General method C. was Obtained as yellow solid (91 mg).

MS (ISN)319(M-H)-].

Example C4

tert-Butyl ether (4’-methyl-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 4-iodotoluene in accordance with the General method C. was Obtained as an orange solid (542 mg).

MS (ISP) 346(M+NH4)+] 367 [(M+Na)+]; tPL: 105-108° C.

Example C5

tert-Butyl ether (2-nitro-4-pyridine-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 2-bromopyridine in accordance with the General m is Todd C. Received in the form of a yellow solid (407 mg).

MS (ISP) 316 [(M+N)+].

Example C6

tert-Butyl ether (3’-methyl-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 3-iodotoluene in accordance with the General method C. was Obtained as yellow solid (524 mg).

MS (ISP) 346 (M+) and 674 [(2M+NH4)+]; tPL: 83-85° C.

Example C7

tert-Butyl ether (3’,4’-dichloro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 3,4-dichlorobenzoyl in accordance with the General method C. was Obtained as yellow solid (540 mg).

MS (EI) 382 (M+).

Example C8

tert-Butyl ether (2’-chloro-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 1-chloro-2-iodobenzoyl in accordance with the General method C. was Obtained as a yellow oil (886 mg).

MS (ISN) 347 [(M-N)-].

Example C9

tert-Butyl ether (2’-methyl-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 2-iodotoluene in compliance and with the General method C. Was obtained as a yellow oil (755 mg).

MS (ISN) 327 [(M-N)+-].

Example C10

tert-Butyl ether (2-nitro-4-pyridin-3-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 3-bromopyridine in accordance with the General method C. was Obtained as yellow solid (587 mg).

MS (ISP) 316 [(M+N)+]; tPL: 107-109° C.

Example C11

tert-Butyl ether (2-nitro-4-pyridin-4-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 4-bromopyridine in accordance with the General method C. was Obtained as yellow solid (379 mg).

MS (ISP) 316 [(M+N)+].

Example 12

tert-Butyl ether (3’-nitro-[1,1’;4’,1’]terphenyl-4’-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 4-bromodiphenyl in accordance with the General method C. was Obtained as yellow solid (1.29 g).

MS (EI) 390 (M+).

Example 13

tert-Butyl ether (4’-cyano-3-nitrobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1), bis(pinacolato)Debora and 4-bromobenzonitrile in accordance with the General IU the Odom C. Received in the form of a yellow solid (1.38 in).

MS (ISN) 338 [(M-N)-].

General method D (synthesis scheme C)

Obtain tert-butyl ester (4-aroyl-2-nitrophenyl)carbamino acid carbonyliron by the reaction of a combination of Suzuki tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid arylboronic acids

A mixture of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (1.0 mmol), arylboronic acid (1.1 mmol), K2CO3(3.0 mmol) and PdCl2(PPh3)2(3 mol.%) in 6 ml of anisole was stirred at 80° in the atmosphere FROM until until TLC indicated the complete conversion of the iodide [cf. Tetr.Lett. 1993, 34, 7595-7598]. The mixture was transferred into a separate funnel, was added 30 ml of N2Oh and the product was extracted with EtOAc (2 servings on 100 ml). The combined organic layers were washed with brine (50 ml) and dried over Na2SO4. After removal of the solvent left a yellow residue, which was purified by column chromatography on silica gel using hexane/tO, getting mentioned in the title compound.

Example D1

tert-Butyl ester (4-benzoyl-2-nitrophenyl)carbamino acid.

Prepared from 364 mg of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (1.0 mmol) and 134 mg of phenylboronic acid (1.1 mmol) with regard to the availa able scientific C with the General method D. Received in the form of a yellow solid (242 mg).

MS (EI) 342 (M+).

Example D2

tert-Butyl ether (2-nitro-4-tributylstannyl)carbamino acid.

A solution of 3.64 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (10 mmol), 7.5 ml of hexamethyldisilazane (15 mmol) and 116 mg (Ph3P)4Pd (0.1 mmol) in 20 ml of toluene kept at 60° C for 5 days [cf. Bull.Chem.Soc.Jpn. 1983, 56, 3855-3856]. The reaction mixture was diluted with 150 ml of toluene, washed with an aqueous solution of KF (2 portions of 50 ml), brine and dried over MgSO4. After removal of the solvent under vacuum, in the form of a brown oil remained substance, which was purified by column chromatography on silica gel using hexane/diethyl ether in the ratio of 49:1, receiving in the form of a yellow liquid 3.8 g of tert-butyl methyl ether (2-nitro-4-tributylstannyl)carbamino acid (yield 72%).

MS (EI) 467, 469, 471 [(M-butyl)+].

General method E (synthesis scheme C)

Obtain tert-butyl ester (4-aryl-2-nitrophenyl)carbamino acid or tert-butyl esters (4-{alkenyl-, cycloalkenyl or geteroseksualen}-2-nitrophenyl)carbamino acid reaction mix according to Steele tert-butyl ether (2-nitro-4-tributylstannyl)carbamino acid with aryl halides or vinylsilane or the reaction mix along With the illu tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid with trialkylsilanes.

A mixture of 525 mg of tert-butyl methyl ether (2-nitro-4-tributylstannyl)carbamino acid (example D2) (1.0 mmol), helgaleena or vinestreet (0,95-6.0 mmol), 126 mg of anhydrous Lid (3.0 mmol) and PD(h3)4(5 mol.%) in 3 ml of DME was stirred at 100° in an argon atmosphere until then, until TLC indicated full consumption of stannane. The reaction mixture was cooled to 23° C, stirred with saturated aqueous KF (5 ml) for 45 min, filtered through brownmillerite, washed with diethyl ether and the filtrate was dried over MgSO4. After removal of the solvent under vacuum, in the form of a brown oil remained substance, which was purified by column chromatography on silica gel using hexane/EtOAc, getting mentioned in the title compound.

Example E1

tert-Butyl ester 4-(4-tert-butoxycarbonylamino but-3-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid.

Prepared from 3,18 g of tert-butyl methyl ether (2-nitro-4-tributylstannyl)carbamino acid (example D2) (the 6.06 mmol) and 1.99 g of tert-butyl methyl ether 4-tripterocalyx-3,6-dihydro-2H-pyridine-1-carboxylic acid (6.0 mmol) [obtained from BOC-4-piperidone treatment GAVE (diisopropylamide lithium in THF at -78° followed by reaction with N-phenylbis(triftoratsetofenona) according to Wustrow the other in Synthesis 1991, 1993] in accordance with the General method that is Received 1,304 g as an orange solid (yield: 52%).

MS (ISP) 420 [(M+N)+], 442 [(M+Na)+] 458 [(M+K)+]; tPL: 85-87° C.

Example E2

tert-Butyl ether (2-nitro-4-thiazol-2-ylphenyl)carbamino acid.

Was prepared from 1.0 g of tert-butyl methyl ether (2-nitro-4-tributylstannyl)carbamino acid (example D2) (1.9 mmol) and 0.56 ml of 2-bromothiazole (6,27 mmol) according to General method that is Received in the form of a yellow solid (160 mg).

MS (EI) 321 (M+).

Example E3

tert-Butyl ester [4-(6-benzyloxypyridine-3-yl)-2-nitrophenyl]carbamino acid.

Prepared from 728 mg of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (2.0 mmol) and 766 mg of 2-(phenylmethoxy)-5-(tributylstannyl)pyridine (2.2 mmol) [CAS-No. [188881-22-3], WO 9709311] in accordance with the General method that is Received in the form of a yellow solid (876 mg).

MS (ISP) 422(M+H)+];tPL: 119-122° C.

General method F (scheme of synthesis of (E)

Obtain tert-butyl ester (4-quinil-2-nitrophenyl)carbamino acid reaction mix by Sonogashira tert-butyl ester (4-iodine-2-nitrophenyl)carbamino acid with acetylene compounds, and the reaction mix by Sonogashira tert-butyl ester (4-ethinyl-2-nitrophenyl)carbamino acid with aryl halides and reaction combin who were Sonogashira 8-iodine-4-aryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones with acetylene compounds.

A mixture of halide (3,0-4,5 mmol), acetylene compounds (3,0-4,5 mmol), Et3N (13.5 mmol), dl2(h3)2(5 mol.%) and h3(to 2.5 mol.%) in 12 ml of THF [very insoluble material-DMF (12 ml), which could be added] was stirred for 20 min at 23° while bubbling argon. Added Cul (1,2 mol.%) and stirring continued at 60° in an argon atmosphere until then, until TLC indicated the complete conversion of smaller component [cf. J.Org.Chem. 1998, 63, 8551]. The mixture was transferred into a separate funnel, was added 50 ml of 5%citric acid and the product was extracted with EtOAc (2 servings on 100 ml). The combined organic layers were washed with saturated solution of NaHCO3(50 ml) and brine (50 ml) followed by drying over MgSO4. After removal of the solvent left a yellow residue, which was purified by column chromatography on silica gel using hexane/tO and/or rubbed into powder with hexane or water EtOH, getting mentioned in the title compound.

Example F1

tert-Butyl ether (2-nitro-4-trimethylsilylethynyl)carbamino acid.

Prepared from of 3.64 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (10 mmol) and 4.2 ml of trimethylsilylacetamide (30 mmol) according to General method F. Palusalu the form of a green oil (3.6 g).

MS (EI) 334 (M+).

Example F2

tert-Butyl ester (4-ethinyl-2-nitrophenyl)carbamino acid.

In a solution of 3.54 g of tert-butyl methyl ether (2-nitro-4-trimethylsilylethynyl)carbamino acid (example F1) (10.6 mmol) in 10 ml of Meon and 20 ml of THF at 0° With added 13 ml of 1N. NaOH and stirring was continued at 23° C for 30 minutes was Poured into cold 5%citric acid, was extracted with 300 ml EtOAc, washed with saturated solution of Panso3and brine, dried over MgSO4. The result of removal under vacuum of the solvent in the form of a dark brown oil remained substance, which was purified by column chromatography on silica gel using hexane/tO in the ratio of 19:1. Received in the form of a yellow solid (2.4 g).

MS (EI) 262 (M+); tPL: 102° C.

Example F3

tert-Butyl ether (2-nitro-4-phenylethylene)carbamino acid.

Prepared from 5,64 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (15 mmol) and 2,47 ml phenylacetylene (to 22.5 mmol) according to General method f was Obtained as yellow solid (4,96 g).

MS (EI) 338 (M+); mp 146-148° C.

Example F4

tert-Butyl ether (2-nitro-4-p-collateralfor)carbamino acid.

Prepared from 728 mg of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (2.0 mmol) and 349 mg 4-tolylacetic is on (3.0 mmol) according to General method F. Received in the form of a yellow solid (632 mg).

MS (EI) 352 (M+); tPL: 164-165° C.

Example F5

tert-Butyl ester [4-(2-chloronicotinyl)-2-nitrophenyl]carbamino acid.

Prepared from 1,82 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (5.0 mmol) and of 1.02 g of 2-chlorophenylacetyl (7.5 mmol) according to General method f was Obtained as a yellow solid (1.8 g).

MS (ISN) 371 [(M-N)-] 373 [(M+2-N)-]; tPL: 152-155° C.

Example F6

tert-Butyl ester [4-(4-chloronicotinyl)-2-nitrophenyl]carbamino acid.

Prepared from 728 mg of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (2.0 mmol) and 416 mg of 4-chlorophenylacetyl (3.0 mmol) according to General method f was Obtained as yellow solid (658 mg).

MS (EI) 372 (M+) and 374 [(M+2)+]; tPL: 213-218° C.

Example F7

tert-Butyl ether (2-nitro-4-thiazol-2-retinylidene)carbamino acid.

Prepared from 262 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) (1.00 mmol) and 0.14 ml of 2-bromothiazole (1.50 mmol) according to General method f was Obtained as yellow solid (215 mg).

MS (ISN) 344 [(M-N)-]; tPL: 137° C.

Example F8

tert-Butyl ether (2-nitro-4-pyridine-2-retinylidene)carbamino acid.

Prepared and is 262 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) (1.0 mmol) and 0.15 ml of 2-bromopyridine (1.6 mmol) according to General method F. Received in the form of a yellow solid (293 mg).

MS (ISP) 340 [(M+N)+]; tPL: 142-144° C.

Example F9

tert-Butyl ester [4-(4-perforating)-2-nitrophenyl]carbamino acid.

Prepared from 525 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) (2.0 mmol) and 0.35 ml of 1-fluoro-4-iodobenzoyl (3 mmol) according to General method f was Obtained as yellow solid (793 mg).

MS (ISN) 355 [(M-N)-]; tPL: 157-158° C.

Example F10

tert-Butyl ester [4-(2-perforating)-2-nitrophenyl]carbamino acid.

Prepared from 525 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) (2.0 mmol) and 0.35 ml of 2-fluoro-1-iodobenzoyl (3 mmol) according to General method f was Obtained as yellow solid (759 mg).

MS (ISN) 355 [(M-N)-]; tPL: 140-142° C.

Example F11

tert-Butyl ester [4-(2,4-differentiating)-2-nitrophenyl]carbamino acid.

Prepared from 525 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) (2.0 mmol) and 0.36 ml of 2,4-debtor-1-iodobenzoyl (3 mmol) according to General method f was Obtained as yellow solid (807 mg).

MS (ISN) 373 [(M-N)-]; tPL: 134-136° C.

Example F12

tert-Butyl ether [2-nitro-4-(4-cryptomaterial)phenyl]carbamino acid.

Preparing the C 701 mg of tert-butyl methyl ether (4-ethinyl-2-nitrophenyl)carbamino acid (example F2) or 2.67 mmol) and 1.0 g of 1-iodine-4-(triptoreline)benzene (3,47 mmol) according to General method F. Received in the form of a yellow solid (1.10 g).

MS (ISN) 421 [(M-N)-]; tPL: 129-131° C.

General method G (synthesis scheme (E)

Obtain tert-butyl ester (2-AMINOPHENYL)carbamino acid recovery tert-butyl ester (2-nitrophenyl)carbamino acid, and obtaining 4-aryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones recovery and concomitant cyclization of 3-aryl-N-(2-nitrophenyl)-3-oxopropionate. Method a: catalytic hydrogenation of the Mixture of nitro compounds (1.0 mmol) in Meon or EtOH and THF (ratio of from 1:1 to 1:9, about 20 ml) and 20 mg of 10%palladium on coal or 20 mg of Raney Ni was intensively stirred at 23° in a hydrogen atmosphere until then, until thin layer chromatography indicated on the completeness of the transformation. The catalyst was filtered, thoroughly washed Meon or EtOH and THF (1:1 ratio), under vacuum solvent was removed, getting mentioned in the title compound, which was, in General, sufficiently pure for further transformations.

Method b: recovery using SnCl2·2H2O the Mixture of nitro compounds (1.0 mmol) and Snl2·2H2About (5.0 mmol) in 30 ml of EtOH was stirred at 70-80° in an argon atmosphere until then, until thin layer chromatography indicated on the completeness of the transformation [cf. Tetr.Lett. 1984, 25, 839]. Dopaminereleasing solution of NaHCO 3the pH of the reaction mixture was brought to 8 and was extracted with EtOAc (2 servings on 100 ml). The combined organic layer was washed with brine and dried over Na2SO4. After removal of the solvent left a yellow solid, which (if necessary) could be purified by column chromatography on silica gel.

Method: recovery using Zn and NH4CL In the mixture of nitro compounds (1.0 mmol) and EtOH/THF/saturated solution of NH4Cl (in the ratio 1:1:1, 30 ml) was added zinc dust (3.0 mmol) and the mixture was stirred at 70° in an argon atmosphere until then, until thin layer chromatography indicated on the completeness of the transformation. Water treatment as described in method B.

Method g: recovery using Fe and the SPLA In the mixture of nitro compounds (1.0 mmol) in THF/N2About (in the ratio of 4:1, 10-50 ml) was added Fe powder (6.0 mmol), and then the SPLA (10-12 drops) and the mixture was stirred at 70° in an argon atmosphere until then, until thin layer chromatography indicated on the completeness of the transformation. Water treatment, as described in method B.

Example G1

tert-Butyl ether (2-amino-4-itfeel)carbamino acid.

Prepared from of 2.18 g of tert-butyl methyl ether (4-iodine-2-nitrophenyl)carbamino acid (example A1) (6.0 mmol) recovery using 6,77 SnCl 2·2H2O (30 mmol) according to General method G (method b). Was obtained as a brown-yellow solid (2.0 g).

MS (EI) 334 (M+); tPL: 127-130° C.

Example G2

tert-Butyl ether (2-amino-4-phenylethylene)carbamino acid.

Prepared from 403 mg of tert-butyl methyl ether (2-nitro-4-phenylethylene)carbamino acid (example F3) (1,19 mmol) recovery with the use of 1.34 g of SnCl2·H2O (5,96 mmol) according to General method G (method b). Was obtained as an orange solid (237 mg).

MS (ISP) 309 [(M+N)+]; tPL: 177-178° C.

Example G3

tert-Butyl ether (2-amino-4-p-collateralfor)carbamino acid.

Prepared from 640 mg of tert-butyl methyl ether (2-nitro-4-p-collateralfor)carbamino acid (example F4) (1.82 mmol) recovery using 2.0 g SnCl2·H2O (9.1 mmol) according to General method G (method b). Received in the form of a beige solid (569 mg).

MS (ISP) 323 [(M+N)+]; tPL: 175° C.

Example G4

tert-Butyl ether [2-amino-4-(2-chloronicotinyl)phenyl]carbamino acid.

Prepared from of 1.61 g of tert-butyl methyl ether (4-(2-chloronicotinyl)-2-nitrophenyl)carbamino acid (example F5) (4.3 mmol) recovery using 5.3g SnCl2·H2O (23.5 mmol) in soo is according to General method G (method b). Was obtained as a pale brown solid (1.1 g).

MS (EI) 342 (M+and 344 [(M+2)+]; tPL: 120-122° C.

Example G5

tert-Butyl methyl ether (3-amino-4’-methoxybiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid (example B1) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (77 mg).

MS (ISP) 315 [(M+N)+] 337 [(M+Na)+].

Example G6

tert-Butyl ether (2-amino-4-thiophene-3-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (2-nitro-4-thiophene-3-ylphenyl)carbamino acid (example B2) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (278 mg).

MS (ISP) 291 [(M+N)+].

Example G7

tert-Butyl ether (2-amino-4-furan-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-furan-2-yl-2-nitrophenyl)carbamino acid (example B3) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Was obtained as a gray powder (212 mg).

MS (EI) 274 (M+).

Example G8

tert-Butyl methyl ether (3-amino-4’-acidifier-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-ethyl-3-nitrobiphenyl-4-yl)carbamino is islote (example B4) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (311 mg).

MS (ISP) 313 [(M+N)+] 335 [(M+Na)+].

Example G9

tert-Butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid.

Was prepared from 100 mg of tert-butyl methyl ether (3-nitrobiphenyl-4-yl)carbamino acid (example B5) (0.32 mmol) by catalytic hydrogenation using Pd/C in accordance with the General method G (method a). Received in the form of a white solid (85 mg).

MS (ISP) 285 [(M+N)+]; tPL: 137° C.

Example G10

tert-Butyl methyl ether (3-amino-2’-methoxybiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid (example C1) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (169 mg).

MS (ISP) 315 [(M+N)+].

Example G11

tert-Butyl ether (2-amino-4-furan-3-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-furan-3-yl-2-nitrophenyl)carbamino acid (example B6) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a light brown solid. (744 mg).

MS (ISP) 275 [(M+N)+] 297 [(M+Na)+]; tPL: 158-161° C (decomposition).

Example G12

tert-Butyl methyl ether (3-amino-4’-chlorodiphenyl-4-yl)carbamino acid.

Cook and from tert-butyl ether (4’-chloro-3-nitrobiphenyl-4-yl)carbamino acid (example C2) restoring Zn/NH 4Cl in accordance with the General method G (method b). Was obtained as a green solid (162 mg).

MS (EI) 318 (M+).

Example G13

tert-Butyl ether [2-amino-4-(4-chlorpheniramine)phenyl]carbamino acid.

Prepared from 606 mg of tert-butyl methyl ether(4-(4-chloronicotinyl)-2-nitrophenyl)carbamino acid (example F6) (1,63 mmol) recovery using 1,83 g Snl2·2H2O (8.1 mmol) according to General method G (method b). Received in the form of a beige solid (406 mg).

MS (ISP) 343 [(M+N)+] 345 [(M+2+N)+]; tPL: 170-173° C.

Example G14

tert-Butyl ether (2-amino-4-naphthalene-1-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-naphthalene-1-yl-2-nitrophenyl)carbamino acid (example B7) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (226 mg).

MS (EI) 334 (M+).

Example G15

tert-Butyl ether (2-amino-4-thiazole-2-retinylidene)carbamino acid.

Prepared from 205 mg of tert-butyl methyl ether (2-nitro-4-thiazol-2-retinylidene)carbamino acid (example F7) (0.59 mmol) recovery using 668 mg SnCl2·2H2O (2,95 mmol) according to General method G (method b). Received in the form of a yellow solid (108 mg).

MS (ISP) 316 [(M+N)+ ]; tPL: 182° C.

Example G16

tert-Butyl methyl ether (3-amino-4’-methylbiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-methyl-3-nitrobiphenyl-4-yl)carbamino acid (example C4) by catalytic hydrogenation using Pd/C in accordance with the General method G (method a). Received in the form of a white solid (125 mg).

MS (ISP) 299 [(M+N)+], 321 [(M+Na)+] 337 [(M+K)+].

Example G17

tert-Butyl ether (2-amino-4-pyridine-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (2-nitro-4-pyridine-2-ylphenyl)carbamino acid (example C5) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Was obtained as a pale brown solid (339 mg).

MS (ISP) 286 [(M+N)+] 308 [(M+Na)+].

Example G18

tert-Butyl ether (2-amino-4-thiophene-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (2-nitro-4-thiophene-2-ylphenyl)carbamino acid (example C3) by catalytic hydrogenation using Pd/C in accordance with the General method G (method a). Received in the form of a beige powder (151 mg).

MS (ISP) 291 [(M+N)+].

Example G19

tert-Butyl ether (2-amino-4-pyridine-2-retinylidene)carbamino acid.

Prepared from 262 mg of tert-butyl methyl ether (2-nitro-4-pyridine-2-retinylidene)carbamino acid is (example F8) (0,772 mmol) recovery using 871 mg SnCl 2·H2O (3,86 mmol) according to General method G (method b). Was obtained as a pale brown solid (130 mg).

MS (EI) 309 (M+); tPL: 178° C.

Example G20

tert-Butyl methyl ether (3-amino-3’-methylbiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (3’-methyl-3-nitrobiphenyl-4-yl)carbamino acid (example C6) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white powder (212 mg).

MS (EI) 298 (M+).

Example G21

tert-Butyl methyl ether (3-amino-3’,4’-dichlorobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (3’,4’-dichloro-3-nitrobiphenyl-4-yl)carbamino acid (example C7) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (485 mg).

MS (ISP) 353 (M+); tPL: 168-171° C.

Example G22

tert-Butyl methyl ether (3-amino-2’-chlorodiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’-chloro-3-nitrobiphenyl-4-yl)carbamino acid (example C8) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (180 mg).

MS (ISP) 319(M+H)+], 341 [(M+Na)+] 357 [(M+K)+].

Example G23

tert-Butyl methyl ether (3-amino-2’-Matilde enyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’-methyl-3-nitrobiphenyl-4-yl)carbamino acid (example C9) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white powder (281 mg).

MS (ISP) 299 [(M+N)+], 321 [(M+Na)+] 337 [(M+K)+].

Example G24

tert-Butyl ether (2-amino-4-benzoylphenyl)carbamino acid.

Prepared from 280 mg of tert-butyl methyl ether (4-benzoyl-2-nitrophenyl)carbamino acid (example D1) (0.82 mmol) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Was obtained as a yellow foam (269 mg).

MS(ISP)313(M+H)+].

Example G25

tert-Butyl methyl ether (3-amino-3’-methoxybiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (3’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid (example B8) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (165 mg).

MS(ISP)315 [(M+H)+].

Example G26

tert-Butyl ether (2-amino-4-pyridine-3-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (2-nitro-4-pyridin-3-ylphenyl)carbamino acid (example 10) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Was obtained as a gray powder (200 mg).

MS(ISP)286 [(M+N)+].

Example G27

tert-Bout levy ether (3-amino-4’-trifloromethyl-4-yl)carbamino acid.

Was prepared from tert-butyl methyl ether (3-nitro-4’-trifloromethyl-4-yl)carbamino acid (example B9) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a white solid (371 mg).

MS (ISP) 369 [(M+N)+] 391 [(M+Na)+].

Example G28

tert-Butyl ether (2-amino-4-pyridine-4-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (2-nitro-4-pyridin-4-ylphenyl)carbamino acid (example 11) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of a light grey powder (305 mg).

MS (ISP) 286 [(M+N)+].

Example G29

tert-Butyl ester 4-(3-amino-4-tert-butoxycarbonylamino)-3,6-dihydro-2H-pyridine-1-carboxylic acid.

Prepared from 256 mg tert-butyl ester 4-(4-tert-butoxycarbonylamino-3-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (example E1) (0.61 mmol) recovery using Zn/NH4Cl in accordance with the General method G (method b). Was obtained as an orange foam (75 mg).

MS (EI) 389 (M+).

Example G30

tert-Butyl ether [2-amino-4-(6-benzyloxypyridine-3-yl)phenyl]carbamino acid

Prepared from 768 mg tert-butyl ester [4-(6-benzyloxypyridine-3-yl)-2-nitrophenyl]carbamino acid (example E3) (1.82 mmol) restoring Zn/NH4Cl in accordance with the relevant method G (method b). Was obtained as a pale brown solid (678 mg).

MS (ISP) 392 [(M+N)+]; tPL: 176-177° C.

Example G31

tert-Butyl ether [2-amino-4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl]carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether [2-amino-4-(6-benzyloxypyridine-3-yl)phenyl]carbamino acid (example G30) (0,409 mmol) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of not-quite-white solid (136 mg).

MS (ISP) 302(M+H)+]; tPL: 120-124° C (decomposition).

Example G32

tert-Butyl ether (3’-amino-[1,1’;4’,1’]terphenyl-4’-yl)carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether (3’-nitro-[1,1’;4’,1’]terphenyl-4’-yl)carbamino acid (example 12) (0,409 mmol) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of a beige solid (175 mg).

MS (ISP) 361(M+H)+]; tPL: 206-207° C.

Example G33

tert-Butyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid.

Was prepared from 10.0 g of tert-butyl ester [4-(4-perforating)-2-nitrophenyl]carbamino acid (example F9) (28.1 mmol) recovery using 31,7 g Snl2·H2About (to 140.5 mmol) according to General method G (method b). Was obtained as a yellow solid substances is a (7,08 g).

MS (ISP) 327 [(M+N)+]; tPL: 180° C.

Example G34

tert-Butyl ether [2-amino-4-(2-perforating)phenyl]carbamino acid.

Prepared from 713 mg tert-butyl ester [4-(2-perforating)-2-nitrophenyl]carbamino acid (example F10) (2 mmol) recovery with the use of 2.26 g of SnCl2·H2O (10 mmol) according to General method G (method b). Was obtained as an orange solid (757 mg).

MS (ISP) 327 [(M+N)+]; tPL: 137-139° C.

Example G35

tert-Butyl ether [2-amino-4-(2,4-differentiating)phenyl]carbamino acid.

Prepared from 750 mg of tert-butyl ester [4-(2,4-differentiating)-2-nitrophenyl]carbamino acid (example F11) (2 mmol) recovery with the use of 2.26 g of SnCl2·2H2O (10 mmol) according to General method G (method b). Was obtained as a brown solid (688 mg).

MS (ISP) 345 [(M+N)+]; tPL: 113-116° C.

Example G36

tert-Butyl ether [2-amino-4-(4-cryptomaterial)phenyl]carbamino acid.

Prepared from 1,09 g tert-butyl ester [2-nitro-4-(4-cryptomaterial)phenyl]carbamino acid (example F12) (2.58 mmol) restoration using only 2.91 g of SnCl2·2H2O (12.9 mmol) according to General method G (method b). Received in the form of a light brown solid is th substances (690 mg).

MS (ISP) 393 [(M+N)+]; tPL: 167-169° C.

Example G37

tert-Butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid (example 10) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of a yellow solid (1.31 g).

MS (ISP) 303 [(M+N)+]; tPL: 100-103° C.

Example G38

tert-Butyl methyl ether (3-amino-3’-forgivenes-4-yl)carbamino acid.

Was prepared from tert-butyl ether (3’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid (example B11) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Was obtained as a brown solid (3,40 g).

MS (ISP) 303 [(M+N)+]; tPL: 125-128° C.

Example G39

tert-Butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-fluoro-3-nitrobiphenyl-4-yl)carbamino acid (example 12) by catalytic hydrogenation with Raney Nickel in accordance with the General method G (method a). Was obtained as a pale yellow solid (3,40 g).

MS (ISP) 303 [(M+N)+].

Example G40

tert-Butyl methyl ether (3-amino-4’-cyanobiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-cyano-3-nitrobiphenyl-4-yl)carbamino acid (note the p 13) recovery using Snl 2·2H2In accordance with the General method G (method b). Received in the form of a yellow solid (360 mg).

MS (ISP) 310 [(M+N)+]; tPL: 195° C (decomposition).

Example G41

tert-Butyl methyl ether (3-amino-3’-forgivenes-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-fluoro-2’-methyl-3-nitrobiphenyl-4-yl)carbamino acid (example 13) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Was obtained as a pale yellow solid (1.51 g).

MS (ISP) 317 [(M+N)+]; tPL: 143° C.

Example G42

tert-Butyl methyl ether (3-amino-4’-fluoro-2’-methoxyethoxymethyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (4’-fluoro-2’-methoxyethoxy-3-nitrobiphenyl-4-yl)carbamino acid (example 14) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of light purple foam (577 mg).

MS (ISP) 363 [(M+N)+].

Example G43

tert-Butyl methyl ether (3-amino-2’,4’-giftgiver-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’,4’-debtor-3-nitrobiphenyl-4-yl)carbamino acid (example 15) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Was obtained as a pale yellow solid (1.77 g).

MS (ISP) 321 [(M+N)+]; tPL: 120° C (with decomposition is eating).

Example G44

tert-Butyl methyl ether (3-amino-2’-fluoro-6’-methoxybiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’-fluoro-6’-methoxy-3-nitrobiphenyl-4-yl)carbamino acid (example 16) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of light purple foam (577 mg).

MS (ISP) 333 [(M+N)+]; tPL: 165-167° C.

Example G45

tert-Butyl methyl ether(3-amino-2’,5’-giftgiver-4-yl)carbamino acid.

Was prepared from tert-butyl ether (2’,5’-debtor-3-nitrobiphenyl-4-yl)carbamino acid (example 17) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Received in the form of a light yellow resin (2,18 g).

MS(ISN)319 [(M-N)-].

Example G46

tert-Butyl ether (2-amino-4-benzofuran-2-ylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-benzofuran-2-yl-2-nitrophenyl)carbamino acid (example 18) restoring SnCl2·2H2O in accordance with the General method G (method b). Was obtained as an orange solid (579 mg).

MS (ISN) 323 [(M-N)+]; tPL: 165° C.

Example of a G47

tert-Butyl ether (2-amino-4-isopropylphenyl)carbamino acid.

Was prepared from tert-butyl ether (4-isopropyl-2-nitrophenyl)carbamino acid (example A2) the catalytic hydrogenization is with Pd/C in accordance with the General method G (method a). Received in the form of a white solid (12,59 g).

MS (ISP) 251 [(M+N)+]; tPL: 100-101° C.

Example G48

tert-Butyl ether (2-amino-4-cyclopropylmethyl)carbamino acid.

Was prepared from tert-butyl ether (4-cyclopropyl-2-nitrophenyl)carbamino acid (example A3) recovery using SnCl2·2H2O in accordance with the General method G (method b). Was obtained as a dark solid (1,96 g).

MS(ISP)249(M+H)+].

Example G49

tert-Butyl methyl ether (3-amino-2’,3’-giftgiver-4-yl)carbamino acid.

Prepared from 3,14 g of tert-butyl methyl ether (2’,3’-debtor-3-nitrobiphenyl-4-yl)carbamino acid (example 19) (8,96 mmol) by catalytic hydrogenation with Pd/C in accordance with the General method G (method a). Was obtained as a green solid (2.91 in g).

MS (ISP) 321 [(M+N)+]; tPL: 78° C.

General method H (synthesis scheme (F)

Method a) Obtaining ethyl - or tert-butyl-3-aryl-3-oxopropionate

Ethyl - or tert-butyl-3-aryl-3-oxopropionate received from arylchloranhydrides acids and the potassium salt of ethyl - or tert-butylmalonate [CAS-No. 6148-64-7 and 75486-33-8] Et3N and MgCl2in CH3CN at a temperature of from 0° to 23° in accordance with the above Synthesis in 1993, 290. When this reaction was used free arylcarbamoyl acid before reaction with malonate salt is activated it handles etelcharge.com and Et 3N in THF/CH3JV at 0° C.

Method b) Obtain tert-butyl 3-aryl-3-oxopropionate

Alternatively tert-butyl-3-aryl-3-oxopropionate was prepared from methyl or utiliziation processing tert-butyl acetate lithium [obtained by treating tert-butyl acetate by diisopropylamide lithium in THF at -78° C] in the presence of tert-butoxide lithium in accordance with the above in Synthesis 1985, 45. If after processing, the product contained residual source material, it therefore can be eliminated by selective saponification LiOH in TTF/Meon/H2At 23° C.

Method C) Obtaining 3-aryl-3-oxopropionate acids

3-aryl-3-oxopropionate acid was prepared from arylchloranhydrides acids and bis(trimethylsilyl)malonate with Et3N and LiBr in CH3CN at 0° in accordance with the stated Synth.Commun. 1985, 15, 1039 (method B1) or with n-BuLi in diethyl ether at a temperature of from -60 to 0° in accordance with the above in Synthesis 1979, 787 (method B2).

Example H1

Ethyl ester of 3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionic acid.

Prepared from 3-[1,2,4]triazole-4-eventing acid [obtained by the reaction of 3-aminobenzoic acid with hydrazinehydrate and triethylorthoformate in acetic acid at 120°] by activating etelcharge.com/Et3N and reaction with ethylmalonate potassium salt with Et3N and MgCl2in CH3CN in line the AI with the General method H (method a). Received in the form of a white solid (5,74 g).

MS (EI) 259 (M+).

Example H2

Ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid.

Prepared from 3-[1,2,3]triazole-1-eventing acid [obtained by boiling under reflux methyl-3-azidobenzoyl [CAS-No. 93066-93-4] trimethylsilylacetamide with subsequent saponification aqueous NaOH boiling under reflux in EtOH] by activating etelcharge.com/Et3N and reaction with ethylmalonate potassium salt, Et3N and MgCl2in CH3JV in accordance with the General method H (method a). Was obtained as a pale yellow solid (2,22 g).

MS (EI) 259 (M+); tPL: 72-74° C.

Example H3

tert-Butyl ether 3-(3-cyanophenyl)-3-oxopropanoic acid.

Prepared from methyl-3-cyanobenzoate [CAS-No. 13531-48-1] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of an oily light brown semi-solid substance.

MS (EI) 245 (M+).

Example H4

tert-Butyl ether 3-(3-imidazol-1-ylphenyl)-3-oxopropanoic acid.

Prepared from methyl-3-(1H-imidazol-1-yl)benzoate [was obtained from 3-(1H-imidazol-1-yl)benzoic acid (J.Med.Chem. 1987, 30, 1342; CAS-No. [108035-47-8] by boiling under reflux in concentrated H2SO4/MeOH] treatment of tert-butyl acetate lithium in accordance with the General method is m H (method b). Received in the form of an orange-brown oil

MS (ISP) 287 [(M+N)+].

Example H5

tert-Butyl ether 3-(2-imidazol-1-espiridion-4-yl)-3-oxopropanoic acid.

Was prepared from the hydrochloride of 2-imidazol-1-isonicotinohydrazide [obtained by the reaction of tert-butyl-2-horizontallayout with imidazole and NaH in DMF at 80° C, treatment with formic acid at 50° and by reaction with thionyl chloride in toluene at 100°] and tert-butylmalonate potassium salt with Et3N and MgCl2in CH3JV in accordance with the General method H (method a). Was obtained as a brown solid (10.8 g).

MS (EI) 287 (M+); tPL: 80° C (decomposition).

Example N6

tert-Butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid.

Prepared from methyl-3-[1,2,4]triazole-1-eventout [CAS-No. 167626-27-9] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as an orange liquid (2,41 g).

MS (EI) 287 (M+).

Example H7

tert-Butyl ester 3-[3-(4-Mei-1-yl)phenyl]-3-oxopropanoic acid.

Prepared from methyl 3-(4-Mei-1-yl)benzoate [corresponding acid was obtained from 3-isothiocyanatobenzene acid and dimethylacetal 2-aminopropionitrile as described in J.Med.Chem. 1987, 30, 1342, followed by boiling under reflux in concentrated H2 SO4/MeOH] treatment of tert-butyl acetate lithium in accordance with the General method (method b). Was obtained as a yellow-brown oil (10,69 g).

MS (EI) 300 (M+).

Example H8

tert-Butyl ester 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(2-Mei-1-yl)benzoate [obtained by the reaction of ethyl-3-aminobenzoate hydrochloride of ethylacetamide in EtOH at 0° With direct treatment diethylacetal of aminoacetaldehyde in EtOH at 23° followed by the addition of concentrated H2SO4and boiling under reflux] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as a brown oil (9,66 g)

MS(ISN)299(M-H)+].

Example H9

tert-Butyl ester 3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(2,4-dimethylimidazole-1-yl)benzoate [obtained by the reaction of ethyl-3-aminobenzoate hydrochloride of ethylacetamide in EtOH at 0° direct treatment dimethylacetal 2-aminopropionitrile in EtOH at 23° followed by the addition of concentrated H2SO4and boiling under reflux] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as a yellow-brown oil (6,00 g).

MS (ISN) 313(M-H)+].

Example N10

tert-Bout levy ester 3-(2-cyano-4-yl)-3-oxopropanoic acid.

Was prepared from the ethyl ester of 2-lanoitanretni acid [CAS-No. 58481-14-4] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as a pale brown solid (7,70 d).

MS (ISN)245(M-H)+].

Example H11

tert-Butyl ester 3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionic acid.

Prepared from methyl-3-[1,2,4]triazole-4-eventout [obtained by the reaction of 3-aminobenzoic acid with hydrazinehydrate and triethylorthoformate in acetic acid at 120° With subsequent esterification of concentrated H2SO4while boiling under reflux in the Meon] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of a light yellow resin (870 mg).

MS (ISN) 286 [(M-H)+].

Example H12

tert-Butyl ester 3-[3-(2-ethoxymethyleneamino-1-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(2-ethoxymethyleneamino-1-yl)benzoate [obtained by esterification of 3-(2-ethoxymethyleneamino-1-yl)benzoic acid [CAS-No. 108035-46-7] concentrated H2SO4in EtOH, followed by processing chloromethylation ether and NaH in THF/DMF)] by treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as an orange oil (1,82 g).

MS (EI) 362 (M+).

Example H13

tert-Butyl EPE is 3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(2-methylsulfonylamino-1-yl)benzoate [obtained by esterification of 3-(2-ethoxymethyleneamino-1-yl)benzoic acid [CAS-No. 108035-46-7] concentrated H2SO4in EtOH, followed by processing methyliodide and NaH in THF/DMF)] by treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of a light brown oil (to 4.41 g).

MS (ISP) 333 [(M+N)+].

Example H14

tert-Butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(3-methylisoxazol-5-yl)benzoate [obtained by the reaction of ethyl-3-ethynylbenzoate [CAS-No. 178742-95-5] with NCS, acetaldoxime, Et3N and a catalytically effective amount of pyridine in l3at 50° as described in Tetrahedron 1984, 40, 2985-2988] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of a yellow solid (2,54 g).

MS (ISP) 302 [(M+N)+]; tPL: 50-56° C.

Example H15

Ethyl ester of 3-oxo-3-(3-tetrazol-1-ylphenyl)propionic acid.

Prepared from 3-tetrazol-1-eventing acid [CAS-No. 204196-80-5] by activating etelcharge.com/Et3H and reaction with ethylmalonate potassium salt, Et3N and MgCl2in CH3JV in accordance with the General method H (method a). Was obtained as a pale yellow solid (211 mg).

MS (EI 260 (M +).

Example H16

Ethyl ester of 3-(3-chlorothiophene-2-yl)-3-oxopropanoic acid.

Prepared from 3-chloro-2-thiophenecarbonitrile [CAS-No. 86427-02-3] reaction with ethylmalonate potassium salt, Et3N and MgCl2in CH3JV in accordance with the General method H (method a). Was obtained as a brown oil (6,84 g).

MS (EI) 232 (M+and 234 [(M+2)+].

Example H17

tert-Butyl ether 3-(5-cyanothiophene-2-yl)-3-oxopropanoic acid.

Prepared from ethyl-5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of a yellow solid (6,66 g).

MS (EI)251 (M+); tPL: 78° C.

Example H18

Ethyl ester of 3-(5-cyano-2-forfinal)-3-oxopropanoic acid.

Prepared from 5-cyano-2-tormentilla [were obtained from the corresponding acid [CAS-No. 146328-87-2] processing SOCl2and a catalytically effective amount of DMF in toluene at 80°] reaction with ethylmalonate potassium salt, Et3N and MgCl2in CH3CN in accordance with the General method H (method a). Was obtained as a pale yellow solid (3,85 g).

MS (EI) 235 (M+); tPL: 55-60° C.

Example H19

tert-Butyl ether 3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropanoic acid.

Prepared from ethyl-2-imidazol-1-iltiazem-4-carboxylate [CAS-No. 256420-32-3] processing tre is-lithium butyl acetate according to General method N. (method b). Was obtained as an orange oil (12.0 g).

Example H20

tert-Butyl ester 3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropanoic acid.

Prepared from ethyl-2-(4-Mei-1-yl)thiazole-4-carboxylate [obtained from ethyl-2-amino-4-thiazolecarboxamide (CAS-No. [256420-32-3]) by implementing the following sequence of synthesis: 1) NaH, 2-isothiocyanato-1,1-dimethoxypropane, DMF, 23°; 2) water (H2SO4, boiling under reflux; 3) EtOH, concentrated H2SO4on 23° S; 4) 30%N2About2, SPLA, 23°] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Was obtained as a brown oil (8,73 g).

MS (EI) 307 (M+).

Example n

tert-Butyl ester 3-[3-(1-methyl - 1H-imidazol-2-yl)phenyl]-3-oxopropanoic acid.

Prepared from ethyl-3-(1-methyl-1H-imidazol-2-yl)benzoate [CAS-No. 168422-44-4] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received in the form of a light yellow liquid (1.26 g).

MS (ISP) 301,3 [(M+N)+].

General method J (synthesis scheme (F)

Getting 6-aryl-2,2-dimethyl[1,3]dioxin-4-ones

Method (a)

6-aryl-2,2-dimethyl[1,3]dioxin-4-ones were prepared from 3-aryl-3-oxopropanoic acid and a catalytically effective amount of concentrated H2SO4or triperoxonane acid (TFA) in isopropenylacetate at 23° With regard to the availa able scientific C out Chem.Pharm.Bull. 1983, 31, 1896. The final products were purified by column chromatography on silica gel using hexane/EtOAc.

Method b)

6-aryl-2,2-dimethyl[1,3]dioxin-4-ones were prepared from tert-butyl 3-aryl-3-oxopropionate processing triperoxonane anhydride (TFCA) in a mixture of TFA and acetone at 23° as described in Tetrahedron Lett. 1998, 39, 2253. The final products, if necessary, purified by column chromatography on silica gel using hexane/EtOAc.

Example J1

2,2-dimethyl-6-thiophene-2-yl[1,3]dioxin-4-one.

3-oxo-3-thiophene-2-ylpropionic acid was obtained from 5,3 ml thiophene-2-carbonylchloride (50 mmol) and 25.6 ml of bis(trimethylsilyl)malonate (100 mmol) with 62.5 ml of n-BuLi (1.6 M in hexane) in diethyl ether at temperatures from -60° 0° in accordance with the General method H (method B2). Raw material (7,88 g) was converted to the specified in the title compound by stirring isopropenylacetate and TPA in accordance with the General method J (method a). Received in the form of a yellow solid (4.09 g).

MS (EI) 210 (M+); tPL: 42° C (decomposition).

Example J2

6-(3-chlorothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-one.

3-(3-chlorothiophene-2-yl)-3-oxopropionate acid was obtained from of 7.82 g of 3-chlorothiophene-2-carbonylchloride (43.2 mmol) and 11.6 ml of bis(trimethylsilyl)malonate (to 45.4 mmol) with 12,65 ml Et3N (90,7 mmol) and of 3.53 g of LiBr (and 47.5 mmol) in CH3CN at 0° in line With the AI with the General method H (method B1). Raw material (5,69 g) was converted to the specified in the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as an orange solid (2.3 g).

MS (EI) 244 (M+) and 246 [(M+2)+]; tPL: 88-89° C (decomposition).

Example J3

6-(3-cyanothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-one.

3-(3-cyanothiophene-2-yl)-3-oxopropionate acid was prepared from 24,33 g 3-cyanothiophene-2-carbonylchloride (140,6 mmol) and 38.0 ml of bis(trimethylsilyl)malonate (a 147.7 mmol) with 41 ml Et3N (295,4 mmol) and 13.5 g of LiBr (154,7 mmol) in CH3JV at 0° in accordance with the General method H (method B1). Raw material (24.8 g) was converted to the specified in the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as an orange solid (5.6 g).

MS (EI) 235 (M+); tPL: 116-120° C (decomposition).

Example J4

3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile.

3-(3-cyanophenyl)-3-oxopropionate acid was prepared from 828 mg 3-cyanobenzaldehyde (5 mmol) and of 2.56 ml of bis(trimethylsilyl)malonate (10 mmol) of 6.25 ml of n-BuLi (1.6 M in hexane) in diethyl ether at temperatures from -60° 0° in accordance with the General method H (method B2). Raw material (1.04 g) was converted to the specified in the-Lavie connection by stirring isopropenylacetate and TPA in accordance with the General method J (method a). Was obtained as a pale yellow solid (0.8 g).

MS (EI) 229 (M+); tPL: 138° C (decomposition).

Example J5

2,2-dimethyl-6-(3-triptoreline)-[1,3]dioxin-4-one.

3-oxo-3-(3-triptoreline)propionic acid was prepared from 10 ml of 3-triftormetilfullerenov (67,6 mmol) and 18.2 ml of bis(trimethylsilyl)malonate (71 mmol) with 20 ml Et3N (142 mmol) and 6,46 g of LiBr (of $ 74.4 mmol) in CH3CN at 0° in accordance with the General method H (method B1). Raw material (7.0 g obtained from the 15.4 g) was converted to the specified in the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as a pale yellow solid (5.3g).

MS (EI) 272 (M+); tPL: 77-78° C (decomposition).

Example J6

6-(3-chlorophenyl)-2,2-dimethyl[1,3]dioxin-4-one.

3-(3-chlorophenyl)-3-oxopropionate acid was prepared from 11 ml 3-chlorobenzylchloride (85,7 mmol) and 23.0 ml of bis(trimethylsilyl)malonate (90,0 mmol) with 25 ml Et3N (180 mmol) and 8,19 g of LiBr (94,3 mmol) in CH3CN at 0° in accordance with the General method H (method B1). Raw material (17.1 g) was converted to the specified in the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as a yellow-brown solid (8.0 g).

MS (EI) 28 (M +and 240 [(M+2)+]; tPL: 87-88° C (decomposition).

Example J7

6-(3-itfeel)-2,2-dimethyl[1,3]dioxin-4-one. 3-(3-itfeel)-3-oxopropionate acid was prepared from 21,0 g 3-identified (78,8 mmol) and 21.0 ml of bis(trimethylsilyl)malonate (82,8 mmol) with 23 ml Et3N (165,5 mmol) and rate of 7.54 g of LiBr (to 86.7 mmol) in CH3CN at 0° in accordance with the General method H (method B1). Raw material (of 21.9 g) was converted to the specified in the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Received in the form of a yellow solid (9.6 g).

MS (EI) 330 (M+); tPL: 79-80° C (decomposition).

Example J8

2,2-dimethyl-6-(3-trifloromethyl)-[1,3]dioxin-4-one.

3-oxo-3-(3-trifloromethyl)propionic acid was prepared from 3-cryptomaterial and bis(trimethylsilyl)malonate with Et3N and LiBr in CH3JV at 0° in accordance with the General method H (method B1). The crude material was made in accordance to the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as an orange solid (2,27 g).

MS (EI) 288 (M+); tPL: 49-54° C (decomposition).

Example J9

2,2-dimethyl-6-pyridin-4-yl[1,3]dioxin-4-one.

Prepared from 3-oxo-3-pyridin-4-rprop is about acid [obtained from 4-acetylpyridine, methylcarbonate magnesium and CO2in DMF at 120° as described in Journal of Antibiotics 1978, 31, 1245] treatment with acetone, TPA, TFCA in accordance with the General method J (method b). Received in the form of a white solid (1.3 g).

MS (EI) 205 (M+).

Example J10

6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-one.

3-(3-imidazol-1-ylphenyl)-3-oxopropionate acid was prepared from the hydrochloride of 3-(1H-imidazol-1-yl)benzoyl chloride [obtained by treating 3-(1H-imidazol-1-yl)benzoic acid (J.Med.Chem. 1987, 30, 1342; CAS-No. [108035-47-8]) SOCl2] and bis(trimethylsilyl)malonate with Et3N and LiBr in CH3CN at 0° in accordance with the General method H (method B1). The crude material was made in accordance to the title compound by stirring isopropenylacetate and concentrated H2SO4in accordance with the General method J (method a). Was obtained as an orange semi-solid substances (617 g).

MS (EI) 270 (M+).

Example J11

2,2-dimethyl-6-(3-methoxyphenyl)-[1,3]dioxin-4-one.

3-(3-methoxyphenyl)-3-oxopropionate acid was prepared from 10.3 g of 3-methoxybenzylamine (60,4 mmol) and 16.2 ml of bis(trimethylsilyl)malonate (and 63.4 mmol) from 17.7 ml Et3N (127 mmol) and 5,77 g of LiBr (66,4 mmol) in CH3CN at 0° in accordance with the General method H (method B1). Raw material (6,38 g) was converted to the specified in the title compound by stirring isopropenylacetate and the end of tirovannoj H 2SO4in accordance with the General method J (method a). Was obtained as a yellow oil (640 mg).

MS (ISP) 235 [(M+N)+] 252 [(M+NH4)+].

Example J12

2,2-dimethyl-6-(3-nitrophenyl)-[1,3]dioxin-4-one. tert-Butyl ether 3-(3-nitrophenyl)-3-oxopropanoic acid was prepared from 2,71 g 3-nitrobenzotrifluoride (14.6 mmol) and 6.0 g of tert-butylmalonate potassium salt (30.0 mmol) with 4.5 ml Et3N (32,2 mmol) and 3,48 g MgCl2(36,52 mmol) in CH3CN in accordance with the General method H (method a). Raw material (3.88 g) was converted to the specified in the title compound by stirring in TFA/acetone with TFCA in accordance with the General method J (method b). Received in the form of a yellow solid (2.76 g).

MS (EI) 249 (M+); tPL: 110-117° C.

Example J13

2,2-dimethyl-6-(3-[1,2,4]triazole-1-ylphenyl)-[1,3]dioxin-4-one.

tert-Butyl ester 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid was prepared from the methyl ester of 3-[1,2,4]triazole-1-eventing acid [CAS-No. 167626-27-9] treatment of tert-butyl acetate lithium in accordance with the General method H (method b). Received from the product of example N6 by stirring in TFA/acetone with TFCA in accordance with the General method J (method b). Received in the form of a yellow solid (539 mg).

MS (EI) 271 (M+).

Example J14

6-(2-imidazol-1-espiridion-4-yl)-2,2-dimethyl[1,3]dioxin-4-one.

Was prepared from tert-butyl ether 3-(2-imidazol-1-Lai who ridin-4-yl)-3-oxopropanoic acid (example N5) by stirring in TFA/acetone with TFCA in accordance with the General method J (method b). Was obtained as a brown solid (10.8 g).

MS (EI) 271 (M+); tPL: 151° C (decomposition).

Example J15

2,2-dimethyl-6-[3-(2-Mei-1-yl)phenyl]-[1,3]dioxin-4-one.

Was prepared from tert-butyl ether 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid (example N8) by stirring in TFA/acetone with TFCA in accordance with the General method J (method b). Received in the form of a beige solid (2,13 g).

MS (EI) 284 (M+); tPL: 122° C.

Example J16

4-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)pyridine-2-carbonitrile.

Was prepared from tert-butyl ether 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) by stirring in TFA/acetone with TFCA in accordance with the General method J (method b). Was obtained as a brown solid (3,30 g).

MS (EI) 230 (M+); tPL: 132° C (decomposition).

General method (scheme synthesis In)

Obtain tert-butyl ester of {2-[3-aryl-3-oxopropionate]-4-arylvinyl}carbamino acid by the reaction of tert-butyl esters (2-amino-4-arylvinyl)carbamino acid with ethyl - or tert-butyl-3-aryl-3-oxopropionate or 6-aryl-2,2-dimethyl[1,3]dioxin-4-areas, as well as 3-aryl-N-(2-nitro-4-arylvinyl)-3-oxopropionate by the reaction of 2-nitro-4-allfamilies with 6-aryl-2,2-dimethyl[1,3]dioxin-4-areas.

A mixture of tert-butyl methyl ether (2-amino-4-arylvinyl)carbamino acid sludge is 2-nitro-4-allterrain (1.0 mmol) and ethyl - or tert-butyl-3-aryl-3-oxopropionate, or 6-aryl-2,2-dimethyl[1,3]dioxin-4-it (from 0.8 to 1.5 mmol) was boiled under reflux in 4-8 ml of toluene until then, until TLC indicated the complete consumption of the smaller component. The solution was allowed to cool to 23° S, then the overall product crystallized (in cases where crystallization is not manifested, it was initiated by the addition of hexane or the entire reaction mixture was subjected to direct chromatography). The solid was filtered off, washed with diethyl ether or mixtures of diethyl ether/hexane and dried under vacuum, obtaining tert-butyl ester of {2-[3-aryl-3-oxopropionate]-4-arylvinyl}carbamino acid or 3-aryl-N-(2-nitro-4-arylvinyl)-3-oxopropionate, which was used directly in the subsequent stage or (if necessary) was purified by recrystallization or by column chromatography on silica gel.

Example K1

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-itfeel}carbamino acid.

Prepared from 900 mg of tert-butyl methyl ether (2-amino-4-itfeel)carbamino acid (example G1) (2.7 mmol) and 880 mg of ethyl ester of 3-(3-cyanophenyl)-3-oxopropanoic acid (4.1 mmol) according to General method K. Obtained as a yellow solid (1.2 g).

MS (ISP) 506 [(M+N)+] 528 [(M+Na)+]; tPL: 182-183° C.

Example K2

Tr is t-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene} carbamino acid.

Prepared from 214 mg of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (0.7 mmol) and 250 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]voxip-4-yl)benzonitrile (example J4) (1.1 mmol) according to General method C. was Obtained as a pale yellow solid (260 mg).

MS (ISP) 480 [(M+N)+], 497 [(M+NH4)+] 502 [(M+Na)+]; tPL: 168-170° C (decomposition).

Example K3

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-methoxybiphenyl-4-yl} carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-methoxybiphenyl-4-yl)carbamino acid (example G5) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light brown solid (207 mg).

MS (ISP) 486 [(M+N)+], 508 [(M+Na)+] 524 [(M+K)+]

Example K4

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-thiophene-3-ylphenyl} carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-thiophene-3-ylphenyl)carbamino acid (example G6) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to General method C. was Obtained as brown solid (104 mg) and used in the next stage in its raw form (example 7).

Example K5

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-furan-ylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-furan-2-ylphenyl)carbamino acid (example G7) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to General method C. was Obtained in the form of a beige powder (271 mg).

MS (ISP) 446 [(M+N)+], 468 [(M+Na)+] 484 [(M+K)+].

Example K6

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from 250 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (0.88 mmol) and 243 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (1.06 mmol) according to General method C. was Obtained as a white solid (324 mg).

MS (ISP) 456 [(M+N)+]; tPL: 168° C (decomposition).

Example C7

tert-Butyl ether {2-[3-(3-itfeel)-3-oxopropionate]-4-phenylethylene}carbamino acid.

Was prepared from 1.0 g of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (3,24 mmol) and 1.78 g of 6-(3-itfeel)-2,2-dimethyl[1,3]dioxin-4-it (example J7) (3,57 mmol) according to General method C. was Obtained as a pale yellow solid (1.9 g).

MS (ISP) 581 [(M+N)+] 603 [(M+Na)+]; tPL: 193-195° C (decomposition)

Example K8

tert-Butyl ether {3-[3-(3-azidophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Prepared 569 mg of tert-BU is silt ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (2 mmol) and 700 mg of ethyl ester of 3-(3-azidophenyl)-3-oxopropanoic acid [3 mmol; was obtained from 3-azidobenzoyl (Bioorg.Chem. 1986, 134) using the method described in Synthesis, 1993, 290, method A; MS (EI) 233 (M+)] in accordance with the General method K. was Isolated as an orange solid (367 mg).

MS (ISP) 472 [(M+N)+] 494 [(M+Na)+]

Example CA

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,3’-giftgiver-4-yl}carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether (3-amino-2’,3’-giftgiver-4-yl)carbamino acid (example G49) (0.5 mmol) and 115 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.5 mmol) according to General method C. was Obtained as a white solid (53 mg).

MS (ISP) 492 [(M+N)+]; tPL: 118° C.

Example K9

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-furan-3-ylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-furan-3-ylphenyl)carbamino acid (example G11) and ethyl ester of 3-(3-cyanophenyl)-3-oxopropanoic acid (Pol.J. Chem. 1978, 25) according to General method C. was Obtained as an orange solid (460 mg).

MS (ISP) 446 [(M+N)+], 463 [M+NH4)+] 468 [(M+Na)+]

Example K10

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-naphthalene-1-ylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-naphthalene-1-ylphenyl)carbamino acid (example G14) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Received in the form of not-quite-white solid (92 mg) and was used in crude form in the next stage (example 20).

Example C

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-thiazole-2-retinylidene}carbamino acid.

Prepared from 89 mg of tert-butyl methyl ether (2-amino-4-thiazole-2-retinylidene)carbamino acid (example G11) (0.28 mmol) and 74 mg of ethyl ester of 3-(3-cyanophenyl)-3-oxopropanoic acid {Pol.J.Chem. 1978, 25) (0.34 mmol) according to General method C. was Obtained as a pale yellow solid (129 mg).

MS (ISP) 487 [(M+N)+]; tPL: 131° C.

Example 12

tert-Butyl ether {2-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-4-pyridine-2-ylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-pyridine-2-ylphenyl)carbamino acid (example G17) and 6-(3-chlorothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J2) in accordance with the General method K. was Obtained as a brown amorphous solid (145 mg).

MS (ISP) 472 [(M+N)+] 494 [(M+Na)+].

Example K13

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-pyridine-2-ylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-pyridine-2-ylphenyl)carbamino acid (example G17) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light brown solid (90 mg).

MS (ISP) 457 [(M+N)+] 479 [(M+Na)+].

Example K14

tert-Butyl ether [3-(3-oxo-3-thiophene-3-ylpropionic)diphenyl-4-yl]carbamino acid.

Prepared from 144 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (0.51 mmol) and 151 mg of ethyl ester of 3-oxo-3-thiophene-3-ylpropionic acid (FR 7191887) (0,76 mmol) according to General method K. Obtained as a yellow foam (181 mg).

MS (ISN) 435 [(M+N)+].

Example K15

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-3’-methylbiphenyl-4-yl} carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-3’-methylbiphenyl-4-yl)carbamino acid (example G20) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to General method C. was Obtained in the form of a viscous orange oil (290 mg).

MS (ISP) 470 [(M+N)+], 492 [(M+Na)+] 508 [(M+K)+].

Example 16

tert-Butyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-2’-methylbiphenyl-4-yl} carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-methylbiphenyl-4-yl)carbamino acid (example G23) and 6-(3-chlorothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J2) in accordance with the General method K. was Obtained as a viscous brown oil (154 mg).

MS (ISP) 485 [(M+N)+], 507 [(M+Na)+] 523 [(M+K)+].

Example R17

tert-Butyl ester {4-benzoyl--[3-(3-chlorophenyl)-3-oxopropionate] phenyl} carbamino acid.

Prepared from 205 mg of tert-butyl methyl ether (2-amino-4-benzoylphenyl)carbamino acid (example G24) (0.66 mmol) and 174 mg of 6-(3-chlorophenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J6) (0.73 mmol) according to General method C. was Obtained as a brown foam (232 mg).

MS (ISP) 493 [(M+N)+].

Example 18

tert-Butyl ester {4-benzoyl-2-[3-(3-cyanophenyl)-3-oxopropionate] phenyl} carbamino acid.

Prepared from 375 mg tert-butyl ether (2-amino-4-benzoylphenyl)carbamino acid (example G24) (1.20 mmol) and 313 mg of ethyl ester of 3-(3-cyanophenyl)-3-oxopropanoic acid {Pol.J.Chem. 1978, 25) (1.44 mmol) according to General method C. was Obtained as a pale yellow solid (170 mg).

MS (ISP) 484 [(M+N)+], 501 [(M+NH4)+] 506 [(M+Na)+]; tPL: 168° C (decomposition).

Example 19

tert-Butyl ester [4-benzoyl-2-(3-oxo-3-thiophene-2-ylpropionic)phenyl]carbamino acid.

Prepared from 259 mg of tert-butyl methyl ether (2-amino-4-benzoylphenyl)carbamino acid (example G24) (0.5 mmol) and 135 mg of 2,2-dimethyl-6-thiophene-2-yl[1,3]dioxin-4-it (example L) (0.55 mmol) according to General method C. was Obtained as a pale yellow solid (60 mg).

MS (ISP) 465 [(M+N)+].

Example C

tert-Butyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from 100 mg of tert-BU is silt ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (0.35 mmol) and 95 mg of 6-(3-chlorothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J2) (0,39 mmol) according to General method K. Received in the form of a white solid (127 mg).

MS (ISP) 471 [(M+N)+]; tPL: 165° C.

Example C

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-3’-methoxybiphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-3’-methoxybiphenyl-4-yl)carbamino acid (example G25) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to General method C. was Obtained in the form of a beige solid (238 mg).

MS (ISP) 486 [(M+N)+], 508 [(M+Na)+] 524 [(M+K)+].

Example C

tert-Butyl ester of [5-(6-oxo-1,6-dihydropyridines-3-yl)-2-(3-oxo-3-thiophene-2-ylpropionic)phenyl]carbamino acid.

Was prepared from 200 mg of tert-butyl methyl ether [2-amino-4-(6-oxo-1,6-dihydropyridines-3-yl)phenyl]carbamino acid (example G31) (0,664 mmol) and 140 mg of 2,2-dimethyl-6-thiophene-2-yl[1,3]dioxin-4-it (example J1) (0,665 mmol) according to General method C. was Obtained in the form of a beige solid (235 mg).

MS (ISP) 454 [(M+N)+]

Example C

tert-Butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-oxo-3-(3-triptoreline)propionamido]phenyl}carbamino acid.

Prepared from 203 mg of tert-butyl methyl ether [2-amino-4-(6-benzyloxypyridine-3-yl)phenyl]carbamino acid (example G30) (0.52 mmol) and 150 mg of 2,2-dimethyl-6-(3-triptoreline)-[1,3]dioxin-4-it (example J5) (0.55 mmol) according to General the method K. Received in the form of not-quite-white solid (213 mg).

MS (ISP) 606 [(M+N)+]; tPL: 190° C (decomposition).

Example K24

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-trifloromethyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-trifloromethyl-4-yl)carbamino acid (example G27) and ethyl ester of 3-(3-cyanophenyl)-3-oxopropanoic acid (Pol.J.Chem,1978, 25) according to General method C. was Obtained as a brown semi-solid substances (94 mg).

MS (ISP) 540 [(M+N)+], 557 [M+NH4)+] 562 [(M+Na)+].

Example C

tert-Butyl ether 4-{4-tert-butoxycarbonylamino-3-[3-(3-cyanophenyl)-3-oxopropionate]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid.

Prepared from 544 mg tert-butyl ester 4-(3-amino-4-tert-butoxycarbonylamino)-3,6-dihydro-2H-pyridine-1-carboxylic acid (example G29) (1.4 mmol) and 336 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (1.5 mmol) according to General method C. was Obtained as an orange solid (722 mg).

MS (ISP) 561(M+H)+]; tPL: 75-79° C (decomposition).

Example C

tert-Butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]phenyl}carbamino acid.

Prepared from 216 mg of tert-butyl methyl ether [2-amino-4-(6-benzyloxy the DIN-3-yl)phenyl]carbamino acid (example G30) (0.55 mmol) and 142 mg of 6-(3-chlorothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J2) (0,58 mmol) according to General method K. Received in the form of a beige solid (172 mg).

MS (ISP) 578 [(M+N)+]; tPL: 158-159° C (decomposition).

Example C

tert-Butyl ether {2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid.

Prepared from 154 mg of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (0.5 mmol) and 135 mg 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0.5 mmol) according to General method C. was Obtained as an orange oil (179 mg).

MS (ISN) 519(M-H)-].

Example C

tert-Butyl ester {4-benzofuran-2-yl-2-[3-(3-cyanophenyl)-3-oxopropionate] phenyl} carbamino acid.

Prepared from 324 mg of tert-butyl methyl ether (2-amino-4-benzofuran-2-ylphenyl)carbamino acid (example G46) (1.0 mmol) and 252 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (1.1 mmol) according to General method K. Obtained as a yellow solid (299 mg).

MS (ISP) 496 [(M+N)+]; tPL: 115° C.

Example K29

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-[1,1’;4’,1’]terphenyl-4-yl} carbamino acid.

Prepared from 159 mg of tert-butyl methyl ether (3’-amino[1,1’;4’,1’]terphenyl-4’-yl)carbamino acid (example G32) (0.44 mmol) and 111 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.49 mmol) according to General met the house of K. Received in the form of not-quite-white solid (156 mg).

MS (ISN) 530 [(M-N)+]; tPL: 214-216° C.

Example C

tert-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(4-cryptomaterial)phenyl]carbamino acid.

Prepared from 196 mg of tert-butyl methyl ether [2-amino-4-(4-cryptomaterial)phenyl]carbamino acid (example G36) (0.5 mmol) and 126 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.55 mmol) according to General method C. was Obtained in the form of not-quite-white solid (175 mg).

MS (ISP) 564(M+H)+]; tPL: 152-154° C.

Example C

tert-Butyl ether {2-[3-(3-nitrophenyl)-3-oxopropionate]-4-phenylethylene} carbamino acid.

Was prepared from 1.1 g of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (4.0 mmol) and 1.23 g of 2,2-dimethyl-6-(3-nitrophenyl)-[1,3]dioxin-4-it (example J12) (4.4 mmol) according to General method C. was Obtained as a pale yellow solid (989 mg).

MS (ISN) 498 [(M-N)+]; tPL: 177-179° C.

Example C

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-forgivenes-4-yl} carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-4’-forgivenes-4-yl)carbamino acid (example G39) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according the General method K. Received in the form of a yellow solid (257 mg).

MS (ISP) 474 [(M+N)+]; tPL: 177-179° C.

Example C

tert-Butyl ester {4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate] phenyl} carbamino acid.

Was prepared from tert-butyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. Obtained as an orange oil (207 mg).

MS (ISN) 537 [(M-N)+].

Example C

tert-Butyl ether {3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-diphenyl-4-yl}carbamino acid.

Prepared from 142 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (0.5 mmol) and 170 mg of 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0,63 mmol) according to General method K. Obtained as a light yellow foam (248 mg).

MS (ISN) 495 [(M-N)+].

Example K35

tert-Butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropanal-amino]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. Obtained as a light yellow solid (489 mg).

MS (ISN) 513 [(M-N)+].

Example C tert-Bout levy ether (3-amino-4’-methoxybiphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-methoxybiphenyl-4-yl)carbamino acid (example G5) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. Obtained as a yellow liquid (195 mg).

Example kastrofylakas k37

tert-Butyl ester {4-(4-perforating)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl} carbamino acid. Was prepared from tert-butyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) and 2,2-dimethyl-6-(3-[1,2,4]triazole-1-ylphenyl)-[1,3]dioxin-4-it (example J13) in accordance with the General method K. Obtained as a yellow solid (230 mg). tPL: 131-139° C.

Example C

tert-Butyl ester {4-(2-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid.

Prepared from 245 mg of tert-butyl methyl ether [2-amino-4-(2-perforating)phenyl]carbamino acid (example G34) (0.75 mmol) and 300 mg of 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (1.1 mmol) according to General method K. Obtained as a yellow-brown foam (211 mg).

MS (ISN) 537 [(M-N)+].

Example C

tert-Butyl ester {4’-fluoro-3-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)-propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and 2,2-dimethyl-6-(3-[1,2,4]Tr is the azole-1-ylphenyl)-[1,3]dioxin-4-it (example J13) in accordance with the General method K. Was obtained as an orange foam (233 mg).

Example 40

tert-Butyl ester {4’-cyano-3-[3-(3-cyanophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-cyanobiphenyl-4-yl)carbamino acid (example G40) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light red solid (185 mg).

Example C

tert-Butyl ester {4’-cyano-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-cyanobiphenyl-4-yl)carbamino acid (example G40) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. Obtained as a yellow solid (228 mg).

Example C

tert-Butyl ester {4’-fluoro-3-[3-(3-nitrophenyl)-3-oxopropionate]-diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and 2,2-dimethyl-6-(3-nitrophenyl)-[1,3]dioxin-4-it (example J12) in accordance with the General method K. Obtained as a light yellow solid (1.01 g).

Example C

tert-Butyl ester {4-(4-perforating)-2-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]phenyl}carbamino acid.

Was prepared from tert-butyl ether is [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) and 6-(2-imidazol-1-espiridion-4-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J14) in accordance with the General method K. Was obtained as a brown solid (284 mg).

MS (ISP) 540 [(M+N)+]; tPL: 169° C.

Example K44

tert-Butyl ester {4’-fluoro-3-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and 6-(2-imidazol-1-espiridion-4-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J14) in accordance with the General method K. was Obtained as a brown solid (361 mg). MS (ISP) 516 [(M+N)+]; tPL: 124° C (decomposition).

Example C

tert-Butyl ether {2’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. was Obtained as a brown solid (352 mg).

MS (ISP) 515(M+H)+]; tPL: 50-58° C.

Example K46

tert-Butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid.

Prepared from 196 mg of tert-butyl methyl ether [2-amino-4-(6-benzyloxypyridine-3-yl)phenyl]carbamino acid (example G30) (0.5 mmol) and 229 mg of 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0.85 mmol) according to General the m method K. Received in the form of a yellow solid (209 mg).

MS (ISN) 602 [(M-N)+]; tPL: 79-83° C.

Example C

tert-Butyl ether (4’-fluoro-3-{3-[3-(4-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Prepared from 362 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (1.2 mmol) and 300 mg of tert-butyl ester 3-[3-(4-Mei-1-yl)phenyl]-3-oxopropanoic acid (example H7) (1.0 mmol) according to General method C. was Obtained as a pale yellow solid (392 mg).

MS (ISP) 529 [(M+N)+]; tPL: 124° C.

Example C

tert-Butyl ether {2’-fluoro-3-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and 6-(2-imidazol-1-espiridion-4-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J14) in accordance with the General method K. Obtained as an orange solid (103 mg).

MS (ISP) 516 [(M+N)+].

Example C

tert-Butyl ester (4-(4-perforating)-2-{3-[3-(4-Mei-1-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid

Prepared from 392 mg of tert-butyl methyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) (1.2 mmol) and 300 mg of tert-butyl ester 3-[3-(4-Mei-1-yl)phenyl]-3-oxop pianoboy acid (example H7) (1.0 mmol) according to General method K. Received in the form of a yellow solid (407 mg).

MS (ISP) 553 [(M+N)+]; tPL: 166° C.

Example K50

tert-Butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2’-methylbiphenyl-4-yl}carbamino acid.

Prepared from 158 mg of tert-butyl methyl ether (3-amino-3’-forgivenes-4-yl)carbamino acid (example G41) (0.5 mmol) and 186 mg of 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0.69 mmol) according to General method C. was Obtained as an orange oil (168 mg).

MS (ISP) 529 [(M+N)+].

Example C

tert-Butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2’-methoxyethoxymethyl-4-yl}carbamino acid.

Prepared from 181 mg of tert-butyl methyl ether (3-amino-4’-fluoro-2’-methoxy-methoxybiphenyl-4-yl)carbamino acid (example G42) (0.5 mmol) and 135 mg 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (221 mg).

MS(ISN) 573 [(M-N)+].

Example C

tert-Butyl ether (2’-fluoro-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Prepared from 362 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.2 mmol) and 300 mg of tert-butyl ester 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid (example is 8) (1.0 mmol) according to General method K. Was obtained as a yellow amorphous substance (312 mg).

MS (ISP) 529 [(M+N)+].

Example C

tert-Butyl ether (4’-fluoro-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Prepared from 362 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (1.2 mmol) and 300 mg of tert-butyl ester 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid (example H8) (1.0 mmol) according to General method K. Obtained as a yellow amorphous substance (302 mg).

MS (ISP) 529 [(M+N)+].

Example C

tert-Butyl ether {3-[3-(3-cyanothiophene-2-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid.

Made from 302 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (1.0 mmol) and 250 mg 6-(3-cyanothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J3) (1.06 mmol) according to General method C. was Obtained as a pale yellow solid (251 mg).

MS (ISP) 480 [(M+N)+]; tPL: 156-157° C.

Example GOST types K55

tert-Butyl ether {3-[3-(3-cyanothiophene-2-yl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid.

Made from 302 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.0 mmol) and 280 mg of 6-(3-cyanothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example J3) (1,19 mmol) according to General m is Todd K. Was obtained as a pale yellow solid (446 mg).

MS (ISP) 480 [(M+N)+]; tPL: 63-66° C.

Example C

tert-Butyl ester {4’-fluoro-3-[3-oxo-3-(3-tetrazol-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and ethyl ester of 3-oxo-3-(3-tetrazol-1-ylphenyl)propionic acid (example H15) in accordance with the General method K. Obtained as a light yellow solid (159 mg).

MS (ISN) 515 [(M-N)+].

Example C

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light yellow foam (239 mg).

MS (ISP) 474 [(M+N)+].

Example C

tert-Butyl ether {2’-fluoro-3-[3-oxo-3-(3-tetrazol-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and ethyl ester of 3-oxo-3-(3-tetrazol-1-ylphenyl)propionic acid (example n) in accordance with the General method K. Obtained as a light red solid (129 mg).

MS (ISP) 517 [(M+N)+].

Example C

tert-Butyl methyl ether (3-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-4’-forgivenes-4-yl)carbamino acid.

Prepared from 227 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (0.75 mmol) and 157 mg of tert-butyl ester 3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropanoic acid (example H9) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (127 mg).

MS (ISP) 543(M+H)+].

Example K60

tert-Butyl ether (2-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-4-phenylethylene)carbamino acid.

Prepared from 231 mg of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (0.75 mmol) and 157 mg of tert-butyl ester 3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropanoic acid (example H9) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (140 mg). MS (ISP) 549 [(M+N)+].

Example C

tert-Butyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid.

Prepared from 360 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (1.2 mmol) and 350 mg of ethyl ester of 3-(3-chlorothiophene-2-yl)-3-oxopropanoic acid (example W16) (1.5 mmol) according to General method C. was Obtained in the form of Belozerova TV is Gogo substances (353 mg).

MS (ISP) 489 [(M+N)+] 491 [(M+2+N)+]; tPL: 168-169° C.

Example C

tert-Butyl ether {2’-fluoro-3-[3-(3-nitrophenyl)-3-oxopropionate]diphenyl-4-yl} carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and 2,2-dimethyl-6-(3-nitrophenyl)-[1,3]dioxin-4-it (example J12) in accordance with the General method K. Obtained as a yellow solid (113 mg).

MS (ISN) 492 [(M-N)+]; tPL: 167° C.

Example C

tert-Butyl ether {3-[3-(2-cyano-4-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and tert-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method K. was Obtained as a red solid (118 mg).

Example C

tert-Butyl ether {3-[3-(2-cyano-4-yl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) and tert-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method K. was Obtained as a white solid (151 mg). tPL: 190° C (decomposition).

Example K65

tert-Butyl ether {3-3-(3-cyanophenyl)-3-oxopropionate]-3’-forgivenes-4-yl}carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-3’-forgivenes-4-yl)carbamino acid (example G38) (0.5 mmol) and 175 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0,76 mmol) according to General method C. was Obtained as an orange solid (141 mg).

MS (ISP) 474 [(M+N)+]; tPL: 148-150° C.

Example C

tert-Butyl ether ({3’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-3’-forgivenes-4-yl)carbamino acid (example G38) (0.5 mmol) and 135 mg 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) (0.5 mmol) according to General method C. was Obtained as an orange solid (150 mg).

MS (ISP) 515 [(M+N)+]; tPL: 70-83° C.

Example C

tert-Butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-phenylethylene}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) and tert-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method K. was Obtained as a white solid (174 mg). tPL: 189° C (decomposition).

Example C

tert-Butyl ether {2’-fluoro-3-[3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]diphenyl-4-yl} carbamino acid is.

Made from 302 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.0 mmol) and 345 mg of tert-butyl ester 3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionic acid (example H11) (1.2 mmol) according to General method K. Obtained as a yellow amorphous substance (207 mg).

MS(ISP)516 [(M+N)+].

Example C

tert-Butyl ether {3-[3-(5-cyanothiophene-2-yl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid.

Made from 302 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.0 mmol) and 276 mg of tert-butyl methyl ether 3-(5-cyanothiophene-2-yl)-3-oxopropanoic acid (example H17) (1.1 mmol) according to General method K. Obtained as a yellow solid (451 mg).

MS (ISP) 480 [(M+N)+]; tPL: 201° C.

Example K70

tert-Butyl methyl ether (3-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-2’-forgivenes-4-yl)carbamino acid.

Prepared from 333 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.1 mmol) and 314 mg tert-butyl ester 3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropanoic acid (example H9) (1.0 mmol) according to General method C. was Obtained as a pale yellow solid (374 mg).

MS (ISP) 543 [(M+N)+]; tPL: 145° C.

Example C

tert-Butyl ether (2’-ft is R-3-{3-[3-(2-ethoxymethyleneamino-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Made from 303 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.0 mmol) and 512 mg of tert-butyl ester 3-[3-(2-ethoxymethyleneamino-1-yl)phenyl]-3-oxopropanoic acid (example N 12) (1,41 mmol) according to General method C. was Obtained as a pale yellow solid (552 mg).

MS (ISN) 589 [(M-N)-]; tPL: 83-86° C.

Example C

tert-Butyl ether {3-[3-(5-cyano-2-forfinal)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid.

Made from 302 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (1.0 mmol) and 362 mg of ethyl ester of 3-(5-cyano-2-forfinal)-3-oxopropanoic acid (example H18) (1.5 mmol) according to General method K. Obtained as a yellow-brown solid (352 mg).

MS (ISP) 492 [(M+N)+]; tPL: 170° C.

Example C

tert-Butyl ether {3-[3-(2-cyano-4-yl)-3-oxopropionate]-2’,4’-giftgiver-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’,4’-giftgiver-4-yl)carbamino acid (example G43) and tert-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method K. Obtained as a light brown solid (207 mg).

MS (ISN) 491 [(M-N)-]; tPL: 160-161° C.

Example C

t is et-Butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-isopropylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-isopropylphenyl)carbamino acid (example G47) and tert-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method K. Obtained as a light brown solid (183 mg).

MS (ISN) 421 [(M-N)-]; tPL: 163-165° C.

Example K75

tert-Butyl ether (2’-fluoro-3-{3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (0.5 mmol) and 154 mg of tert-butyl ester 3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropanoic acid (example H20) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (157 mg).

MS (ISN) 534 [(M-N)+].

Example C

tert-Butyl ether (4’-fluoro-3-{3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (0.5 mmol) and 154 mg of tert-butyl ester 3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropanoic acid (example H20) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (225 mg).

MS (ISN) 534 [(M-N)+].

Example C

tert-Butyl ether {2’-fluoro-3-[3-oxo-3(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Prepared from 152 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (0.5 mmol) and 200 mg of ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (0.77 mmol) according to General method K. Obtained as a yellow oil (191 mg).

MS(ISP)516 [(M+N)+].

Example K78

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-cyclopropylmethyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-cyclopropylmethyl)carbamino acid (example G48) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light brown solid (92 mg).

MS (EI)419 (M+).

Example C

tert-Butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-cyclopropylmethyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-cyclopropylmethyl)carbamino acid (example G48) and 4-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)pyridine-2-carbonitrile (example J16) in accordance with the General method K. Obtained as a light brown solid (148 mg).

MS (ISP)421 [(M+N)+].

Example C

tert-Butyl ester {4-cyclopropyl-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-cyclopropylmethyl)carbamino KIS is the notes (example G48) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J10) in accordance with the General method K. Was obtained as a pale yellow solid (79 mg).

MS(ISP)461 [(M+H)+].

Example C

tert-Butyl ester {4’-fluoro-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Prepared from 152 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (0.5 mmol) and 200 mg of ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (0.77 mmol) according to General method K. Obtained as a yellow oil (107 mg).

MS(ISP)516(M+H)+].

Example C

tert-Butyl ester {4-(4-perforating)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid.

Prepared from 163 mg of tert-butyl methyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) (0.5 mmol) and 181 mg of ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (0.7 mmol) according to General method K. Obtained as a yellow oil (107 mg).

MS (ISP) 540 [(M+N)+].

Example C

tert-Butyl ester {4’-fluoro-3-[3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (0.5 mmol) and 235 mg of tert-butyl ester 3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropanoic acid (example HI 9) (0.8 mmol) according to bsim method K. Was obtained as an orange oil (162 mg).

MS (ISP) 522(M+H)+].

Example C

tert-Butyl ether (4’-fluoro-3-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) (0.5 mmol) and 190 mg of tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example H14) (0,63 mmol) according to General method C. was Obtained in the form of not-quite-white solid (86 mg).

MS (ISP) 530 [(M+N)+]; tPL: 100-101° C.

Example C

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,4’-giftgiver-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’,4’-giftgiver-4-yl)carbamino acid (example G43) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to General method C. was Obtained as an orange oil (95 mg).

MS (ISP) 492 [(M+N)+].

Example C

tert-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-isopropylphenyl}carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-isopropylphenyl)carbamino acid (example G47) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. Obtained as a light red solid (100 mg).

MS (IS) 422(M+H) +]; tPL: 179-180° C.

Example C

tert-Butyl ether (4’-fluoro-3-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) and tert-butyl ester 3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropanoic acid (example H13) in accordance with the General method K. Obtained as a light yellow oil (181 mg).

MS (ISP) 561 [(M+N)+].

Example C

tert-Butyl ester (4-isopropyl-2-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid.

Was prepared from tert-butyl ether (2-amino-4-isopropylphenyl)carbamino acid (example G47) and 2,2-dimethyl-6-[3-(2-Mei-1-yl)phenyl]-[1,3]-dioxin-4-it (example J15) in accordance with the General method K. Obtained as a yellow oil (186 mg).

MS (ISP) 477 [(M+N)+].

Example C

tert-Butyl ether (2’,4’-debtor-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’,4’-giftgiver-4-yl)carbamino acid (example G43) and 2,2-dimethyl-6-[3-(2-Mei-1-yl)phenyl]-[1,3]dioxin-4-it (example J15) in accordance with the General method K. Obtained as a yellow oil (145 mg).

MS (ISP) 547 [(M+N)+].

Example C

tert-Butyl ether {2’,4 is-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from tert-butyl methyl ether (3-amino-2’,4’-giftgiver-4-yl)carbamino acid (example G43) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) in accordance with the General method K. Obtained as a light yellow oil (164 mg).

MS (ISP) 534(M+H)+].

Example C

tert-Butyl ether {2’-fluoro-3-[3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (0.5 mmol) and 235 mg of tert-butyl ester 3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropanoic acid (example H19) (0.8 mmol) according to General method C. was Obtained as a white solid (98 mg).

MS (ISP) 522 [(M+N)+]; tPL: 115-130° C.

Example K92

tert-Butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,5’-giftgiver-4-yl}carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether (3-amino-2’,5’-giftgiver-4-yl)carbamino acid (example G45) (0.5 mmol) and 115 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.5 mmol) according to General method C. was Obtained in the form of a white amorphous substance (110 mg).

MS (ISN)490(M-H)+].

Example C

tert-Butyl ether {2’,5’-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether (3-amino-2’,5’-giftgiver-4-yl)carbamino acid (example G45) (0.5 mmol) and 130 mg of ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (0.5 mmol) according to General method C. was Obtained as amorphous not quite white matter (129 mg).

MS (ISN) 532 [(M-H)+].

Example C

tert-Butyl ether (2’-fluoro-3-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid.

Was prepared from 151 mg of tert-butyl methyl ether (3-amino-2’-forgivenes-4-yl)carbamino acid (example G37) (0.5 mmol) and 190 mg of tert-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example H14) (0,63 mmol) according to General method C. was Obtained as a white solid (213 mg).

MS (ISN) 528 [(M-N)+]; tPL: 158-160° C.

Example C

tert-Butyl ether {2’,3’-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid.

Was prepared from 160 mg of tert-butyl methyl ether (3-amino-2’,3’-giftgiver-4-yl)carbamino acid (example G49) (0.5 mmol) and 130 mg of ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (0.5 mmol) according to General method K. Obtained as a yellow amorphous substance (166 mg).

MS (ISP) 534 [(M+N)+].

Example C

tert-Butyl ether [2-[3-(3-CANopen is)-3-oxopropionate]-4-(2,4-differentiating)phenyl]carbamino acid.

Prepared from 172 mg of tert-butyl methyl ether [2-amino-4-(2,4-differentiating)phenyl]carbamino acid (example G35) (0.5 mmol) and 126 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.55 mmol) according to General method C. was Obtained as an orange oil (198 mg).

MS (ISP) 516 [(M+N)+].

Example C

tert-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(2-perforating)phenyl]carbamino acid.

Prepared from 163 mg of tert-butyl methyl ether [2-amino-4-(2-perforating)phenyl]carbamino acid (example G34) (0.5 mmol) and 126 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.55 mmol) according to General method C. was Obtained as brown solid (143 mg).

MS (ISN) 496 [(M-N)+]; tPL: 216-217° C.

Example C

tert-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(4-perforating)phenyl]carbamino acid.

Prepared from 245 mg of tert-butyl methyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) (0.75 mmol) and 190 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0,825 mmol) according to General method K. Obtained as a yellow oil (318 mg).

MS (ISN) 496 [(M-N)+].

General method M (synthesis scheme C)

Obtain 4,8-diaryl-1,3-dihydrobenzo[[b]][1,4]diazepin-2-ones, 4-aryl-8-aroyl-1,3-dihydrobenzo[[b]][1,4]diazepin-2-ones and 4-the RIL-8-allatini-1,3-dihydrobenzo[[b]][1,4]diazepin-2-ones

A suspension of tert-butyl methyl ether {2-[3-aryl-3-oxopropionate]-4-arylvinyl}carbamino acid or tert-butyl methyl ether {2-[3-aryl-3-oxopropionate]-4-arelatively} carbamino acid (1.0 mmol) in 5 ml of CH2Cl2[if necessary, you can add from 5 to 25 mmol of anisole or 1,3-dimethoxybenzene] when 0° were treated With 0.5 to 5.0 ml of TFA and stirring was continued at 23° until then, until TLC indicated full consumption of the starting material. Under vacuum, the solvent was removed, the residue was treated with a small amount of diethyl ether, after which it crystallized. This solid was stirred with a saturated solution Panso3was filtered off , washed with N2O and diethyl ether or mixtures of diethyl ether/hexane and dried, obtaining mentioned in the title compound, which if necessary can be removed by crystallization from THF/CH2CL2/diethyl ether/hexane.

Example 1

3-(7-iodine-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from of 1.15 g of tert-butyl methyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-itfeel} carbamino acid (example K1) (2.3 mmol) by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (880 mg).

MS (EI) 387 (M+ ); tPL: 198-200° C (decomposition).

Example 2

3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 230 mg of tert-butyl methyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example K2) (0.48 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (135 mg).

MS (EI) 361 (M+); tPL: 245° C (decomposition).

Example 3

3-(4-oxo-7-p-trilateral-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 161 mg of tert-butyl methyl ether (2-amino-4-p-collateralfor)carbamino acid (example G3) (0.5 mmol) and 183 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.6 mmol) according to General method C. was Obtained as a pale yellow solid (228 mg). This connection was removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (86 mg).

MS (EI) 375 (M+); tPL: 236-239° C (decomposition).

Example 4

3-[7-(2-chloronicotinyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 172 mg of tert-butyl methyl ether [2-amino-4-(2-chloronicotinyl)phenyl]carbamino acid (example G4) (0.5 mmol) and 230 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]is iaxin-4-yl)benzonitrile (example J4) (0.75 mmol, 75%purity) in accordance with the General method K. Obtained as a yellow solid (321 mg). This connection was removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (148 mg).

MS (EI) 395 (M+) and 397 [(M+2)+]: tPL: 239-240° C (decomposition).

Example 5

4-(3-chlorophenyl)-8-phenylethynyl-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) and 6-(3-chlorophenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J6) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as an orange solid (155 mg).

MS (EI): 370 (M+).

Example 6

3-[7-(4-methoxyphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-methoxybiphenyl-4-yl}carbamino acid (example K3) treatment TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow powder (122 mg).

MS (ISP) 368 [(M+N)+]; tPL: 236-237° C (decomposition).

Example 7

3-(4-oxo-7-thiophene-3-yl-4,5-dihydro-3H-benzo[[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-thiophene-3-ylphenyl}carbamino acid (example K4) processing TFA in CH2CL2in accordance with the General method M was Obtained as a beige solid (54 mg).

MS (EI) 343 (M+); tPL: 238-243° C (decomposition).

Example 8

3-(7-furan-2-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-furan-2-ylphenyl}carbamino acid (example K5) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a brown powder (73 mg).

MS (EI) 327 (M+); tPL: 205-210° C (decomposition).

Example 9

3-[7-(4-ethylphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-4’-acidifier-4-yl)carbamino acid (example G8) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a beige solid (67 mg).

MS (EI) 365 (M+); tPL: 225-229° C (decomposition).

Example 10

3-(4-oxo-7-phenyl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile

Goto the or of 268 mg of tert-butyl methyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example K6) (0.59 mmol) by treatment TFA in CH 2Cl2in accordance with the General method M was Obtained as a white solid (188 mg).

MS (EI) 337 (M+); tPL: 238-240° C (decomposition).

Example 11

4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Prepared from 871 mg of tert-butyl methyl ether {2-[3-(3-itfeel)-3-oxopropionate]-4-phenylethylene}carbamino acid (example C7) (1.5 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (542 mg).

MS (EI) 462 (M+); tPL: 227-229° C (decomposition).

Example 12

8-phenylethynyl-4-pyridin-4-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) and 2,2-dimethyl-6-pyridin-4-yl[1,3]dioxin-4-it (example J9) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as brown solid (50 mg).

MS (EI) 337 (M+); tPL: 198-200° C (decomposition).

Example 13

3-[7-(2-methoxyphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-2’-methoxybiphenyl-4-yl)carbamino acid (example G10) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzo is nitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a pale green powder (30 mg).

MS (EI) 367 (M+).

Example 14

3-(7-furan-3-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-furan-3-ylphenyl}carbamino acid (example K9) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow powder (73 mg).

MS (EI) 327 (M+); tPL: 228-233° C (decomposition).

Example 15

3-[7-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-4’-chlorodiphenyl-4-yl)carbamino acid (example G12) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow powder (79 mg).

MS (EI) 371 (M+); tPL: 244-250° C (decomposition).

Example 16

3-[7-(4-chlorpheniramine)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 187 mg of tert-butyl methyl ether [2-amino-4-(4-chlorpheniramine)phenyl]carbonin the howling acid (example G13) (0.5 mmol) and 184 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.6 mmol) according to General method K. The resulting compound (234 mg) was removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow powder (93 mg).

MS (EI) 395 (M+) and 397 [(M+2)+]; tPL: 237-240° C (decomposition).

Example 17

8-phenyl-4-thiophene-2-yl-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Was prepared from 69 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (0,243 mmol) and 54 mg of 2,2-dimethyl-6-thiophene-2-yl[1,3]dioxin-4-it (example J1) (0,257 mmol) according to General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a brown solid (46 mg).

MS (ISP)319(M+H)+].

Example 18

8-phenylethynyl-4-(3-triptoreline)-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) and 2,2-dimethyl-6-(3-trifloromethyl)-[1,3]dioxin-4-it (example J8) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (157 mg).

MS (EI) 404 (M+).

Example 19

4-(3-harfe who yl)-8-phenyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 284 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (1.0 mmol) and 358 mg of 6-(3-chlorophenyl)-2,2-dimethyl[1,3]dioxin-4-it (example J6) (1.2 mmol) according to General method K. The resulting compound (339 mg) was removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (188 mg).

MS (EI) 346 (M+and 348 [(M+2)+]; tPL: 208° C (decomposition).

Example 20

3-(7-naphthalene-1-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-naphthalene-1-ylphenyl}carbamino acid (example K10) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow powder (41 mg).

MS (ISP) 388 [(M+N)+]; tPL: 240-245° C (decomposition).

Example 21

3-(4-oxo-7-thiazol-2-ylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 119 mg of tert-butyl methyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-thiazole-2-retinylidene}carbamino acid (example C) (0.24 mmol) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (36 mg).

MS (EI) 368 (M+); tPL: 230° C (decomposition).

Example 22

3-(oxo-7-p-tolyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-4’-methylbiphenyl-4-yl)carbamino acid (example G16) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a white solid (76 mg).

MS (ISP) 352 [(M+N)+]; tPL: 242-245° C (decomposition).

Example 23

4-(3-chlorothiophene-2-yl)-8-pyridin-2-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-4-pyridine-2-ylphenyl}carbamino acid (example K12) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale brown powder (51 mg).

MS (EI) 353 (M+); tPL: 220-225° C (decomposition).

Example 24

3-(4-oxo-7-thiophene-2-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether (2-amino-4-thiophene-2-ylphenyl)carbamino acid (example G18) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow Tverdov the substance (108 mg).

MS (EI) 343 (M+); tPL: >250° C (decomposition).

Example 25

8-iodine-4-thiophene-2-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-amino-4-itfeel)carbamino acid (example G1) and 2,2-dimethyl-6-thiophene-2-yl[1,3]dioxin-4-it (example J1) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (30 mg).

MS (EI) 368 (M+); tPL: >260° C.

Example 26

3-(4-oxo-7-pyridin-2-ylethynyl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile

Prepared from 124 mg of tert-butyl methyl ether (2-amino-4-pyridine-2-retinylidene)carbamino acid (example G19) (0.4 mmol) and 147 mg of 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) (0.48 mmol) according to General method K. The resulting compound (199 mg) was removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (124 mg).

MS (EI) 362 (M+); tPL: 229-231° C (decomposition).

Example 27

4-(3-methoxyphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) and 2,2-d is methyl-6-(3-methoxyphenyl)-[1,3]dioxin-4-it (example J11) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (131 mg).

MS (EI) 366 (M+).

Example 28

3-(4-oxo-7-pyridin-2-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-pyridine-2-ylphenyl}carbamino acid (example K13) processing TFA in CH2CL2in accordance with the General method M was Obtained as a brown powder (29 mg).

MS (EI) 338 (M+); tPL: 243-244° C (decomposition).

Example 29

8-phenyl-4-thiophene-3-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from 110 mg of tert-butyl methyl ether [3-(3-oxo-3-thiophene-3-ylpropionic)diphenyl-4-yl]carbamino acid (example K14) (0.25 mmol) by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (53 mg).

MS (EI) 318 (M+); tPL: 233° C (decomposition).

Example 30

3-(4-oxo-7-m-tolyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-3’-methylbiphenyl-4-yl}carbamino acid (example 15) processing TFA in CH2CL2in accordance with the General method M was Obtained as light yellow is th powder (145 mg).

MS (ISP) 352 [(M+N)+]; tPL: 248-251° C (decomposition).

Example 31

3-[7-(3,4-dichlorophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-3’,4’-dichlorobiphenyl-4-yl)carbamino acid (example G21) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (150 mg).

MS (EI) 405 (M+); tPL: 252-255° C (decomposition).

Example 32

8-phenyl-4-(3-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 284 mg of tert-butyl methyl ether (3-aminobiphenyl-4-yl)carbamino acid (example G9) (1.0 mmol) and 408 mg of 2,2-dimethyl-6-(3-triptoreline)-[1,3]dioxin-4-it (example J5) (1.2 mmol) according to General method K. The resulting compound (392 mg) was removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (238 mg).

MS (EI) 380 (M+); tPL: 210° C (decomposition).

Example 33

3-[7-(2-chlorophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-2’-hardy enyl-4-yl)carbamino acid (example G22) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a white powder (43 mg).

MS (ISP) 372 [(M+N)+]; tPL: 240-244° C (decomposition).

Example 34

4-(3-chlorothiophene-2-yl)-8-o-tolyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-2’-methylbiphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow powder (60 mg).

MS (ISP) 366 (M+) and 368 [(M+2)+]; tPL: 247-248° C (decomposition).

Example 35

8-benzoyl-4-(3-chlorophenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 193 mg tert-butyl ester {4-benzoyl-2-[3-(3-chlorophenyl)-3-oxopropionate]phenyl}carbamino acid (example K-17) (0,39 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (93 mg).

MS (EI) 374 (M+) and 376 [(M+2)+]; tPL: 199-202° C (decomposition).

Example 36

3-(7-benzoyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 263 mg tert-butyl ester {4-benzoyl-2-[3-(3-cyanophenyl)-3-oxopropanenitrile} carbamino acid (example K-18) (0.54 mmol) by treatment TFA in CH 2CL2in accordance with the General method M was Obtained as an orange solid (77 mg).

MS (EI) 365 (M+); tPL: 207° C (decomposition).

Example 37

8-benzoyl-4-thiophene-2-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from 54 mg tert-butyl ester [4-benzoyl-2-(3-oxo-3-thiophene-2-ylpropionic)phenyl]carbamino acid (example 19) (0.12 mmol) by treatment with TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (8 mg).

MS (EI) 346 (M+).

Example 38

4-(3-chlorothiophene-2-yl)-8-phenyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from 100 mg of tert-butyl methyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) (0.21 mmol) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (93 mg).

MS (EI) 352 (M+) and 354 [(M+2)+]; tPL: 228° C (decomposition).

Example 39

3-[7-(3-methoxyphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-3’-methoxybiphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow powder (118 mg).

MS (ISP) 368 [(M+N)+]; tPL: 240-243° C (razlozheny is m).

Example 40

3-(4-oxo-7-pyridin-3-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether (2-amino-4-perigee-3-ylphenyl)carbamino acid (example G26) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained in the form of a beige powder (161 mg).

MS (EI) 338 (M+); tPL: 210-214° C (decomposition).

Example 41

8-(6-oxo-1,6-dihydropyridines-3-yl)-4-thiophene-2-yl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 127 mg tert-butyl ester [5-(6-oxo-1,6-dihydropyridines-3-yl)-2-(3-oxo-3-thiophene-2-ylpropionic)phenyl]carbamino acid (example C) (0.28 mmol) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (57 mg).

MS (ISP) 336 [(M+N)+]; tPL: >250° C.

Example 42

8-(6-benzyloxypyridine-3-yl)-4-(3-triptoreline)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 198 mg tert-butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-oxo-3-(3-triptoreline)propionamido] phenyl} carbamino acid (example C) (0.33 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid ve is esta (49 mg). MS (ISP) 488 [(M+N)+]; tPL: 195° C (decomposition).

Example 43

3-[4-oxo-7-(4-trifloromethyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-trifloromethyl-4-yl}carbamino acid (example K24) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow powder (23 mg).

MS (EI) 421 (M+); tPL: 237-24 HS (decomposition).

Example 44

3-(4-oxo-7-pyridin-4-yl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether (2-amino-4-pyridine-4-ylphenyl)carbamino acid (example G28) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl3in accordance with the General method M was Obtained as a red-brown solid (25 mg).

MS (EI) 338 (M+); tPL: >200° C (decomposition).

Example 45

3-[7-(1-benzazolyl-1,2,3,6-tetrahydropyridine-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 56 mg of 3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile [obtained from 690 mg of tert-butyl ester 4-{4-tert-butoxycarbonylamino-3-[3-(3-what anafanil)-3-oxopropionate]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (example C) (1,23 mmol) by treatment of TPA in CH 2CL2in accordance with the General method M was Isolated as a brown solid (309 mg)] (0,164 mmol) and benzosulfimide (0,164 mmol) in 2 ml THF at 23° C. was Obtained as a brown solid (40 mg).

MS (ISP) 483 [(M+N)+]; tPL: 92-95° C (decomposition).

Example 46

3-[7-(1-methanesulfonyl-1,2,3,6-tetrahydropyridine-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 60 mg of 3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile [obtained from 690 mg of tert-butyl ester 4-{4-tert-butoxycarbonylamino-3-[3-(3-cyanophenyl)-3-oxopropionate]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (example C) (1,23 mmol) processing TFA in CH2Cl2in accordance with the General method M was Isolated as a brown solid (309 mg)] (0,175 mmol), of 0.014 ml methanesulfonanilide (0,175 mmol) and 0.025 ml of E t3N (0,175 mmol) in 3 ml THF at 23° C. was Obtained as an orange solid (35 mg).

MS (ISP) 421 [(M+N)+]; tPL: 211-213° C (decomposition).

Example 47

3-[7-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 54 mg of 3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile [obtained from 690 mg of tert-butyl ester 4-{4-tert-butoxycarbonylamino-3-[3(3-cyanophenyl)-3-oxopropionate]phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid (example C) (1,23 mmol) processing TFA in CH 2CL2in accordance with the General method M was Isolated as a brown solid (309 mg)] (0,158 mmol) and 0.017 ml AU2On (0,173 mmol) in 3 ml THF at 23° C. was Obtained as an orange solid (65 mg).

MS (EI) 384 (M+); tPL: 220-222° C (decomposition).

Example 48

8-(6-benzyloxypyridine-3-yl)-4-(3-chlorothiophene-2-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 172 mg tert-butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]phenyl}carbamino acid (example C) (0.3 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (38 mg).

MS (ISP) 460 [(M+N)+]; tPL: 213-215° C (decomposition).

Example 49

3-[7-(4-methoxyphenylacetyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 290 mg of 3-(7-iodine-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 1) (0.75 mmol) and 350 mg of 4-methoxyphenylacetylene (1.57 mmol) according to General method f was Obtained as a pale yellow solid (172 mg).

MS (EI) 391 (M+); tPL: 234-235° C (decomposition).

Example 50

3-(4-oxo-7-thiophene-2-ylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 185 mg of 3-(7-iodine-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 50) (0.48 mmol) and 78 mg of 2-idenitify (,72 mmol) [obtained from 2-thiophenecarboxaldehyde as described in J.Org.Chem. 1982, 47, 2201-2204] in accordance with the General method F. was Obtained as a pale yellow solid (146 mg).

MS (EI) 367 (M+); tPL: 235-238° C (decomposition).

Example 51

3-[7-(2,3-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 35 mg of tert-butyl methyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,3’-giftgiver-4-yl}carbamino acid (example K8) (0.07 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a gray solid (23 mg).

MS (ISP) 374 [(M+N)+]; tPL: 240° C.

Example 52

4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 170 mg of tert-butyl methyl ether {2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example C) (0.33 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a brown solid (64 mg).

MS (EI) 402 (M+); tPL: 193-196° C.

Example 53

3-(7-benzofuran-2-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 255 mg tert-butyl ester {4-benzofuran-2-yl-2-[3-(3-cyanophenyl)-3-oxopropionate]phenyl}carbamino acid (example C) (0.51 mmol) by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (260 is g).

MS (EI) 377 (M+); tPL: >250° C.

Example 54

3-(7-diphenyl-4-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Prepared from 135 mg tert-butyl ester {3-[3-(3-cyanophenyl)-3-oxopropionate]-[1,1’;4’,1’]terphenyl-4-yl}carbamino acid (example K29) (0.25 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (100 mg). MS (EI) 413 (M+); tPL: 251-253° C.

Example 55

3-[4-oxo-7-(4-cryptomaterial)-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl]benzonitrile

Prepared from 170 mg of tert-butyl methyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(4-cryptomaterial)phenyl]carbamino acid (example C) (0.3 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a beige solid (112 mg).

MS (EI) 445 (M+); tPL: 239-241° C.

Example 56

4-(3-nitrophenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 970 mg of tert-butyl methyl ether {2-[3-(3-nitrophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example C) (1.94 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (631 mg).

MS (EI) 381 (M+); tPL: 228-229° C.

Example 57

3-[7-(4-forfinal)-4-oxo-4,5-digitron-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as an orange solid (141 mg).

MS (EI) 355 (M+).

Example 58

8-(4-perforating)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a beige solid (89 mg).

MS (EI) 420 (M+); tPL: 216-218° C.

Example 59

4-(3-imidazol-1-ylphenyl)-8-phenyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (125 mg).

MS (EI) 378 (M+); tPL: 201-205° C.

Example 60

8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-Dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example K35) processing TFA in CH2Cl2rela is availa able scientific C with the General method M Was obtained as an orange solid (261 mg).

MS (EI) 396 (M+).

Example 61

4-(3-imidazol-1-ylphenyl)-8-(4-methoxyphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl methyl ether (3-amino-4’-methoxybiphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (100 mg).

MS (EI) 408 (M+); tPL: 207-208° C.

Example 62

8-(4-perforating)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo [b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(4-perforating)-2-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example kastrofylakas k37) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (156 mg).

MS (EI) 421 (M+); tPL: 217-218° C.

Example 63

8-(2-perforating)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(2-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (99 mg).

MS (EI) 420 (M+); tPL: 201-203° C.

Example 64

8-(4-forfinal)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b]1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (115 mg).

MS (EI) 397 (M+); tPL: 241-245° C.

Example 65

3-[7-(4-cyanophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ester {4’-cyano-3-[3-(3-cyanophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example 40) the processing of TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (102 mg).

MS (EI) 362 (M+); tPL: 240° C (decomposition).

Example 66

4-[2-(3-imidazol-1-ylphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-yl]benzonitrile

Was prepared from tert-butyl ester {4’-cyano-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (128 mg).

MS (EI) 403 (M+); tPL: 209-213° C (decomposition).

Example 67

8-(4-forfinal)-4-(3-nitrophenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(3-nitrophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino the Oh of the acid (example C) processing TFA in CH 2CL2in accordance with the General method M was Obtained as a pale yellow solid (719 mg).

MS (ISP) 376 [(M+N)+]; tPL: 220-226° C (decomposition).

Example 68

8-(4-perforating)-4-(2-imidazol-1-Ilinden-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(4-perforating)-2-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]phenyl }carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as light brown solid (189 mg).

MS (ISP) 422 [(M+N)+]; tPL: 206° C (decomposition).

Example 69

8-(4-forfinal)-4-(2-imidazol-1-espiridion-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as light brown solid (209 mg).

MS (ISP) 398 [(M+N)+]; tPL: 213° C (decomposition).

Example 70

4-(3-AMINOPHENYL)-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 8-(4-forfinal)-4-(3-nitrophenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 67) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Received in the form of light relegating substances (16 mg).

MS (ISP) 346 [(M+N)+]; tPL: 210-217° C (decomposition).

Example 71

8-(2-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (176 mg).

MS (ISP) 397 [(M+N)+]; tPL: 179-182° C.

Example 72

N-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}ndimethylacetamide

Prepared from 4-(3-AMINOPHENYL)-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 70) processing AU2About in the SPLA at 80° C. was Obtained as a pale yellow solid (9 mg).

MS (EI) 387 (M+).

Example 73

N-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}methanesulfonamide

Prepared from 4-(3-AMINOPHENYL)-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 70) treatment methanesulfonanilide and Et3N in THF at 23° C. was Obtained as a pale yellow solid (24 mg).

MS (ISP) 424 [(M+N)+]; tPL: 232-235° C.

Example 74

8-(6-benzyloxypyridine-3-yl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(6-benzyloxypyridine-3-yl)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropyl is ylamino]phenyl}carbamino acid (example K46) processing TFA in CH 2CL2in accordance with the General method M was Obtained as a pale yellow solid (75 mg).

MS (ISP) 486(M+H)+]; tPL: 225-231° C.

Example 75

4-(3-imidazol-1-ylphenyl)-8-(6-oxo-1,6-dihydropyridines-3-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 8-(6-benzyloxypyridine-3-yl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 74) by catalytic hydrogenation with Raney Ni in accordance with the General method G (method a). Was obtained as a pale yellow solid (17 mg).

MS (ISP) 396 [(M+N)+].

Example 76

8-(4-forfinal)-4-[3-(4-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4’-fluoro-3-{3-[3-(4-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (196 mg).

MS (EI) 410 (M+); tPL: 215° C.

Example 77

8-(2-forfinal)-4-(2-imidazol-1-espiridion-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-(2-imidazol-1-espiridion-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as light brown solid (32 mg).

MS (EI) 397 (M+ ).

Example 78

8-(4-perforating)-4-[3-(4-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4-(4-perforating)-2-{3-[3-(4-Mei-1-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (122 mg).

MS (EI) 434 (M+); tPL: 210° C.

Example 79

8-(4-fluoro-2-were)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2’-methylbiphenyl-4-yl}carbamino acid (example K50) processing TFA in CH2CL2in accordance with the General method M was Obtained as a beige solid (82 mg).

MS (EI) 410 (M+); tPL: 170-172° C.

Example 80

8-(4-fluoro-2-hydroxyphenyl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2’-methoxyethoxymethyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (13 mg).

MS (ISP) 413 [(M+N)+]; tPL: 220° C.

Example 81

8-(2-forfinal)-4-[3-(2-Mei-1-yl)phenyl]-1,3-Digi is robinso[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2’-fluoro-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (174 mg).

MS (ISP) 411 [(M+N)+]; tPL: 187° C.

Example 82

8-(4-forfinal)-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4’-fluoro-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (178 mg).

MS (ISP) 411 [(M+N)+]; tPL: 227° C.

Example 83

2-[7-(4-forfinal)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanothiophene-2-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as an orange solid (209 mg).

MS (EI) 361 (M+); tPL: 239-240° C.

Example 84

2-[7-(2-forfinal)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanothiophene-2-yl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino the acid (example GOST types K55) processing TFA in CH 2CL2in accordance with the General method M was Obtained as a yellow solid (258 mg).

MS (EI) 361 (M+); tPL: 238-240° C.

Example 85

8-(4-forfinal)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-oxo-3-(3-tetrazol-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (54 mg).

MS (EI) 398 (M+).

Example 86

3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (128 mg).

MS (EI) 355 (M+).

Example 87

8-(4-perforating)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether [2-amino-4-(4-perforating)phenyl]carbamino acid (example G33) and ethyl ester of 3-oxo-3-(3-tetrazol-1-ylphenyl)propionic acid (example H15) in accordance with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the laws the AI with the General method M Received in the form of a beige powder (5.5 mg).

MS (EI) 422 (M+).

Example 88

8-(2-forfinal)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-oxo-3-(3-tetrazol-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (31 mg).

MS (EI) 398 (M+); tPL: 179-180° C.

Example 89

4-[3-(2,4-dimethylimidazole-1-yl)phenyl]-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl methyl ether (3-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-4’-forgivenes-4-yl)carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (54 mg).

MS (EI) 424 (M+); tPL: 188° C.

Example 90

4-[3-(2,4-dimethylimidazole-1-yl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-4-phenylethylene)carbamino acid (example K60) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (57 mg).

MS (EI) 430 (M+); tPL: 134° C (decomposition).

Example 91

4-(3-chlorothiophene-2-yl)8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {3-[3-(3-chlorothiophene-2-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (232 mg).

MS (EI) 370 (M+); tPL: 255-256° C.

Example 92

3-[7-(2-fluoro-6-methoxyphenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl methyl ether (3-amino-2’-fluoro-6’-methoxybiphenyl-4-yl)carbamino acid (example G44) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example J4) according to the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a white solid (47 mg).

MS (EI) 385 (M+).

Example 93

8-(2-forfinal)-4-(3-nitrophenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-(3-nitrophenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (62 mg).

MS (EI) 375 (M+).

Example 94

4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was prepared from tert-butyl ether {3-[3-(2-tzia is pyridin-4-yl)-3-oxopropionate]-4’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH 2Cl2in accordance with the General method M was Obtained as an orange solid (23 mg).

MS (EI) 356 (M+).

Example 95

4-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was prepared from tert-butyl ether {3-[3-(2-cyano-4-yl)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a green solid (40 mg).

MS (EI) 356 (M+).

Example 96

3-[7-(3-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-3’-forgivenes-4-yl}carbamino acid (example K65) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (57 mg).

MS (EI) 355 (M+); tPL: 232-235° C.

Example 97

8-(3-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-Dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {3’-fluoro-3-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (69 mg).

MS (EI) 396 (M+); tPL: 200-201° C.

Example 98

4-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo is[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile

Was prepared from tert-butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as yellow solid (10 mg).

MS (EI) 362 (M+).

Example 99

8-(2-forfinal)-4-(3-[1,2,4]triazole-4-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]diphenyl-4-yl} carbamino acid (example C) processing TFA in CH2CL2; in accordance with the General method M was Obtained as a pale yellow solid (79 mg).

MS (EI) 397 (M+); tPL: 198° C.

Example 100

5-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiophene-2-carbonitrile

Was prepared from tert-butyl ether {3-[3-(5-cyanothiophene-2-yl)-3-oxopropionate]-2’-forgivenes-4-yl} carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (263 mg).

MS (EI) 361 (M+); tPL: >250° C.

Example 101

4-[3-(2,4-dimethylimidazole-1-yl)phenyl]-8-(2-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl methyl ether (3-{3-[3-(2,4-dimethylimidazole-1-yl)phenyl]-3-oxopropionate}-2’-forgivenes-4-yl)carbamino acid (example K70) quenching the rigid TFA in CH 2Cl2in accordance with the General method M was Obtained as a yellow solid (92 mg).

MS (EI) 424 (M+); tPL: 92° C.

Example 102

8-(2-forfinal)-4-[3-(2-ethoxymethyleneamino-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2’-fluoro-3-{3-[3-(2-methoxymethyl-sulfanilimide-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (100 mg).

MS (EI) 472 (M+); tPL: 189-190° C.

Example 103

4-fluoro-3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(5-cyano-2-forfinal)-3-oxopropionate]-2’-forgivenes-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (92 mg).

MS (EI) 373 (M+); tPL: 239° C.

Example 104

4-[7-(2,4-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was prepared from tert-butyl ether {3-[3-(2-cyano-4-yl)-3-oxopropionate]-2’,4’-giftgiver-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow t Agogo substances (24 mg).

MS (ISP) 375 [(M+N)+]; tPL: 250-253° C.

Example 105

4-(7-isopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile

Was prepared from tert-butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-isopropylphenyl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (33 mg).

MS (ISP) 305(M+H)+]; tPL: 173-178° C.

Example 106

8-(2-forfinal)-4-[2-(4-Mei-1-yl)thiazol-4-yl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2’-fluoro-3-{3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example K75) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (75 mg).

MS (ISP) 418 [(M+N)+]; tPL: 229° C.

Example 107

8-(4-forfinal)-4-[2-(4-Mei-1-yl)thiazol-4-yl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4’-fluoro-3-{3-[2-(4-Mei-1-yl)thiazol-4-yl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a yellow solid (101 mg).

MS (ISP) 418 [(M+N)+]; tPL: 229° C.

Example 108

3-(4-oxo-7-phenethyl-4,5-dihydro-3H-benzo is[[b]][1,4]diazepin-2-yl)benzonitrile

Prepared from 3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile (example 2) by catalytic hydrogenation using Pd/C in accordance with the General method G (method a). Was obtained as a pale yellow solid (156 mg).

MS (EI) 365 (M+); tPL: 212-214° C.

Example 109

3-(4-oxo-7-styryl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile

Prepared from 3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile (example 2) by catalytic hydrogenation with Lindlar catalyst in the presence of 10 equiv. cyclohexene in accordance with the General method G (method a). Was obtained as a pale yellow solid (159 mg).

MS (EI) 363 (M+); tPL: 185-188° C.

Example 110

8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method m was Obtained as a pale yellow solid (100 mg).

MS (EI) 397 (M+); tPL: 209-212° C.

Example 111

3-(7-cyclopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-cyclopropylmethyl}carbamino acid (note the R K78) processing TFA in CH 2Cl2in accordance with the General method m was Obtained as a pale yellow solid (44 mg).

MS (ISP) 302 [(M+N)+]; tPL: 204-209° C.

Example 112

4-(7-cyclopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile

Was prepared from tert-butyl ether {2-[3-(2-cyano-4-yl)-3-oxopropionate]-4-cyclopropylmethyl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method m was Obtained as light brown solid (88 mg).

MS (ISP) 303 [(M+N)+]; tPL: 227-230° C.

Example 113

8-cyclopropyl-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-cyclopropyl-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid (example C) processing TFA in CH3CL3in accordance with the General method m was Obtained as light brown solid (41 mg).

MS (ISP) 303 [(M+H)+]; tPL: 198-200° C.

Example 114

8-(4-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (29 mg).

MS (EI) 397 (M+); tPL: 218-220° C.

Example 115

8-(4-perforating)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4-(4-perforating)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (53 mg).

MS (EI) 421 (M+); tPL: 246-248° C.

Example 116

8-(4-forfinal)-4-(2-imidazol-1-iltiazem-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ester {4’-fluoro-3-[3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as light brown solid (64 mg).

MS (ISP) 404 [(M+N)+]; tPL: 214° C.

Example 117

8-(4-forfinal)-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4’-fluoro-3-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (33 mg).

MS (EI) 411 (M+); tPL: >250° C.

Example 118

3-[7-(2,4-differenl)-4-ox is -4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,4’-giftgiver-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (37 mg).

MS (ISP) 374 [(M+N)+].

Example 119

3-(7-isopropyl-4-oxo-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl)benzonitrile

Was prepared from tert-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-isopropylphenyl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained in the form of not-quite-white solid (25 mg).

MS (ISP) 304 [(M+N)+].

Example 120

8-(4-forfinal)-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4’-fluoro-3-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (104 mg).

MS (ISP) 443 [(M+N)+].

Example 121

8-isopropyl-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (4-isopropyl-2-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}phenyl)carbamino acid (example C) processing TFA in CH CL2in accordance with the General method M was Obtained as light brown solid (94 mg).

MS (ISP) 359 [(M+N)+].

Example 122

8-(2,4-differenl)-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2’,4’-debtor-3-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as light brown solid (71 mg).

MS (ISP) 429 [(M+N)+].

Example 123

8-(2,4-differenl)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’,4’-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as light brown solid (78 mg).

MS (ISP) 416 [(M+N)+].

Example 124

8-(2-forfinal)-4-(2-imidazol-1-iltiazem-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’-fluoro-3-[3-(2-imidazol-1-iltiazem-4-yl)-3-oxopropionate]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (46 mg).

MS (ISP) 404 [(M+N)+]; tPL: 194-197° C.

Example 125

3-[7-(2,5-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether {3-[3-(3-cyanophenyl)-3-oxopropionate]-2’,5’-giftgiver-4-yl}carbamino acid (example K92) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (49 mg).

MS (EI) 373 (M+); tPL: 247° C.

Example 126

8-(2,5-differenl)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether {2’,5’-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (67 mg).

MS (EI)415 (M+tPL: 231° C.

Example 127

8-(2-forfinal)-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from tert-butyl ether (2’-fluoro-3-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}diphenyl-4-yl)carbamino acid (example C) processing TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (100 mg). MS (EI) 411 (M+); tPL: 222-224° C.

Example 128

7-methyl-4-[3-(1-methyl-1H-imidazol-2-yl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Goth is wheelie out of 620 mg of tert-butyl methyl ether (2-amino-4-phenylethylene)carbamino acid (example G2) (2.0 mmol) and 1.26 g of tert-butyl ester 3-[3-(1-methyl-1H-imidazol-2-yl)phenyl]-3-oxopropanoic acid (example n) (4.2 mmol) according with the General method K. The resulting compounds were removed protective group, and he was subjected to cyclization by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (81 mg).

MS (ISP) 417,2 [(M+N)+]; tPL: 202-205 are° C.

Example 129

8-(2,3-differenl)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 118 mg of tert-butyl methyl ether {2’,3’-debtor-3-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]diphenyl-4-yl}carbamino acid (example C) (0.22 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a yellow solid (74 mg). tPL:230° C.

Example 130

3-[7-(2,4-differentiating)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(2,4-differentiating)phenyl]carbamino acid (example C) processing TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (87 mg).

MS (EI) 397 (M+); tPL: 240-24B° C.

Example 131

3-[7-(2-perforating)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from tert-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(2-perforating)phenyl]carbamino acid (example C) treatment of TPA is CH 2CL2in accordance with the General method M was Obtained as a yellow solid (82 mg).

MS (EI) 379 (M+); tPL: 213-214° C.

Example 132

8-phenylethynyl-4-(3-trimethylsilylethynyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 231 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (0.5 mmol) and 0.4 ml of trimethylsilylacetamide (1.0 mmol) according to General method f was Obtained as light brown solid (102 mg).

MS (EI) 432 (M+); tPL: 169-171° C (decomposition).

Example 133

4-(3-ethynylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was prepared from 63 mg 8-phenylethynyl-4-(3-trimethylsilylethynyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 132) (0,146 mmol) 1H processing. NaOH (3 drops) in 3 ml Meon and 0.5 ml of THF at 23° C for 2 h was Obtained as a brown solid (31 mg).

MS (ISP) 361 [(M+N)+]; tPL: >250° C (decomposition).

Example 134

3-[7-(3-hydroxy-3-methylbut-1-inyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 194 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (0.5 mmol) and 105 mg of 2-methyl-3-butyn-2-ol (1.25 mmol) according to General method f was Obtained as yellow solid (147 mg).

MS (EI) 343 (M+); tPL: 243° C.

Example 135

3-[7-(1-hydroxy shall illogicalities)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 308 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (0.80 mmol) and 248 mg of 1-ethinyl-1-cyclohexanol (2.00 mmol) according to General method f was Obtained as a beige solid (262 mg).

MS (ISP) 384 [(M+N)+]; tPL: 196° C.

Example 136

3-(7-cyclohex-1-unilateral-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was prepared from 50 mg of 3-[7-(1-hydroxycyclohexyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 135) (0.13 mmol) by treatment TFA in CH2CL2in accordance with the General method M was Obtained as a pale yellow solid (22 mg).

MS (EI) 365 (M+); tPL: 228° C.

Example 137

3-[7-(3-methylbut-3-EN-1-inyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl] benzonitrile

Was prepared from 50 mg of 3-[7-(3-hydroxy-3-methylbut-1-inyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 134) (0.15 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained in the form of solid sand color (33 mg).

MS (ISP) 326 [(M+N)+]; tPL: 231° C.

Example 138

3-[7-(3,6-dihydro-2H-Piran-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 50 mg of 3-[7-(4-hydroxyethylamino-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile [obtained from 387 mg of 4-(3-itfeel)-8-FeNi is ethinyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (1.0 mmol) and 315 mg of 4-ethynyltestosterone-4-ol [CAS-No. 57385-16-7] (2.5 mmol) according to General method f was Isolated as a yellow solid (296 mg)] (0.13 mmol) by treatment TFA in CH2Cl2in accordance with the General method M was Obtained as a pale yellow solid (16 mg).

MS (EI) 367 (M+); tPL: 238° C.

Example 139

tert-Butyl ester 4-[2-(3-cyanophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-ylethynyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid

Prepared from of 1.16 g of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (3.0 mmol) and 0,93 g tert-butyl ester 4-ethinyl-3,6-dihydro-2H-pyridine-1-carboxylic acid [CAS-No. 177984-28-0] (4.5 mmol) according to General method f was Obtained as a yellow solid (620 mg).

MS (ISP) 467 [(M+N)+]; tPL: 239° C.

Example 140

3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 573 mg tert-butyl ester 4-[2-(3-cyanophenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-ylethynyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid (example 139) (1.13 mmol) processing TFA in CH2CL2in accordance with the General method M was Obtained in the form of not-quite-white solid (434 mg).

MS (ISP) 367 [(M+N)+]; tPL: 184° C.

Example 141

3-[7-(1-acetyl-1,2,3,6-tetrahydropyridine-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]Bentonit the l

Was prepared from 55 mg of 3-[4-oxo-7-(1,2,3,g-tetrahydropyridine-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 140) (0.15 mmol) by treatment of 0.017 ml AU2On (0,165 mmol) in 3 ml THF at 23° C for 1 h was Obtained in the form of solid sand color (59 mg).

MS (ISP) 409 [(M+N)+]; tPL: 203° C.

Example 142

3-[7-(1-methanesulfonyl-1,2,3,6-tetrahydropyridine-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 55 mg of 3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 140) (0.15 mmol) by treatment of a 0.012 ml methanesulfonamide (0.15 mmol) and 0,021 ml Et3N (0.15 mmol) in 3 ml THF at 23° C for 23 hours was Obtained as a yellow solid (38 mg).

MS (EI) 444 (M+); tPL: 235° C.

Example 143

3-{7-[1-(2,2-dimethylpropionic)-1,2,3,6-tetrahydropyridine-4-ylethynyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl}benzonitrile

Was prepared from 55 mg of 3-[4-oxo-7-(1,2,3,6-tetrahydropyridine-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 140) (0.15 mmol) by treatment with 0.02 ml of pivaloate (0,165 mmol) and 0,021 ml Et3N (0.15 mmol) in 3 ml THF at 23° C for 19 hours Received in the form of solid sand color (26 mg).

MS (ISP) 451(M+H)+]; tPL: 219° C.

Example 144

3-[4-oxo-7-(3-oxocyclohexa-1-unilateral)-4,5-dihydro-3 is-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was prepared from 500 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (1,29 mmol) and 310 mg of 3-ethynylcyclohexanol-2-Aenon [CAS-No. 124267-26-1] (2.58 mmol) according to General method f was Obtained as yellow solid (346 mg).

MS (EI) 379 (M+); tPL: 110° C.

Example 145

3-[7-(4-perforating)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Prepared from 307 mg of tert-butyl methyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-4-(4-perforating)phenyl]carbamino acid (example C) (0,62 mmol) processing TFA in CH2Cl2in accordance with the General method M was Obtained in the form of a solid color eggshell (146 mg).

MS (EI) 379 (M+); tPL: 245-246° C.

The following examples relate to catalyzed by palladium carbonyliron 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it is in the presence of secondary amines, which leads to immediate receipt of the corresponding amides, as shown in the diagram synthesis H.

General method N

Getting 4-[3-(amino-4-carbonyl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones catalyzed by Pd carbonyliron by aminating 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it

A solution of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (1.0 mmol), secondary amine (5.0 mmol who), h3(6 mol.%) or dppp (3 mol.%), Pd(OAC)2(3 mol.%) and Et3N (2.0 mmol) in 4 ml of DMF was stirred at 23° in the atmosphere FROM until until TLC indicated full consumption of iodide. After dilution tO, washing with saturated solution of NaHCO3and brine the organic phase was dried over Na2SO4. After removal of the solvent remained substance in the form of a brown oil, which was purified by column chromatography on silica gel using hexane/tO, getting mentioned in the title compound.

Example 146

4-[3-(morpholine-4-carbonyl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 471 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (1,02 mmol) and 0.44 ml of the research (5,09 mmol) according to General method N. was Obtained as a pale yellow solid (324 mg).

MS (ISP) 450 [(M+N)+]; tPL: 142-145° C (decomposition).

Example 147

4-[3-(4-methylpiperazin-1-carbonyl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Prepared from 231 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (0.5 mmol) and 0.28 ml of N-methylpiperazine (2.5 mmol) according to General method N. was Obtained as a pale yellow solid (65 mg).

MS (ISP) 463 [(M+N)+]; tPL: 168-172° C (decomposition).

p> Example 148

3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzamid

Prepared from 231 mg of 4-(3-itfeel)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 11) (0.5 mmol) and 0.52 ml hexamethyldisilazane (2.5 mmol) according to General method N. was Obtained as a yellow solid (104 mg).

MS (EI) 379 (M+); tPL: >250° C (decomposition).

Example 149

3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide

Getting 4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide (in accordance with the work of Pen-Yuan Lin and others, published in the Synthesis 1992, 1219).

To a solution of 1.45 g hexamethyldisilane (8.0 mmol) in 8 ml of 1,3-dimethyl-2-imidazolidinone at 23° With added 0.31 g of sodium methoxide (6.8 mmol). The mixture was stirred for 5 min and then the resulting blue solution was added to a solution of 1.42 g of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 57) (4 mmol) in 12 ml of 1,3-dimethyl-2-imidazolidinone. The mixture was stirred for 3 h at 23° and then was poured into 100 ml of water. Stirring was continued for 0.5 h, the precipitate was isolated by filtration and triturated to powder with 50 ml of ethyl acetate, getting mentioned in the title compound as a pale yellow solid (1.38 in).

MS (ISN) 387,9 [(M-N)+]; tPL: 267-270° C (decomposition).

Example 150

3-[7-(2-ftoh the Nile)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide

of 0.53 g of 3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 86) was subjected processed analogously to example 149 obtaining after grinding to a powder of the crude product with ethyl acetate specified in the title compound as a pale yellow solid (0,46 g).

MS (ISN) 387,9 [(M-N)+]; tPL: 232-234° C (decomposition).

Example 151

Amide 4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carboxylic acid

0.36 g of product (example 94) was subjected processed analogously to example 149 obtaining after grinding to a powder of the crude product with acetone specified in the title compound as a pale yellow solid (0.33 g).

MS (ISN) 388,9 [(M-N)+]; tPL: 280-283° C (decomposition).

Example 152

8-(4-forfinal)-4-[3-(4-methylthiazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

To a suspension of 97 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide (example 149) (0.25 mmol) in 5 ml of ethanol was added 0.1 ml of chloroacetone (1.25 mmol) and the mixture is boiled under reflux. After 1 h and after 5 h of aging at elevated temperature was added an additional chlorate (2 times in 0.1 ml, 1.25 mmol). After 20 h the mixture was cooled to 0° C, stirred for 0.5 h and specified in the title compound was isolated by filtration as a pale yellow firmly what about the substance (61 mg).

MS (ISP) 428,4 [(M+N)+]; tPL: 259-261° C (decomposition).

Example 153

Ethyl ester of 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid

A mixture of 39 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide (example 149) (0.1 mmol) and 29 mg of ethylbromoacetate (0.15 mmol) in 0.5 ml of ethanol was boiled under reflux for 7 hours, the Solution was cooled to 0° C, stirred for 0.5 h and specified in the title compound was isolated by filtration as a pale yellow solid (29 mg).

MS (ISN) 484,2 [(M-N)+]; tPL: 236-238° C (decomposition).

Example 154

Ethyl ester of 2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid

0.24 g of 3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide (example 150) were subjected to processing as in example 153. The reaction mixture is evaporated under vacuum and the residue was ground into powder with ethyl acetate, getting mentioned in the title compound as a pale yellow solid (0.29 grams).

MS (ISP) 503,4 [(M+NH4)+]; tPL: 172-175° C.

Example 155

Ethyl ester of 2-{4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-yl}thiazole-4-carboxylic acid

160 mg of amide 4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridin-carboxylic acid (example 151) were subjected to processing as in example 153. The cooled reaction solution was diluted with ethyl acetate, washed with a solution Panso3and brine, dried over Na2SO4and evaporated under vacuum. The crude product was chromatographically on silica gel using ethyl acetate/hexane (2:1) as eluent, and the purified product was ground into powder with dichloromethane/diethyl ether, obtaining mentioned in the title compound as a pale yellow solid (40 mg).

MS (ISN) 485,1 [(M-N)+]; tPL: 238-240° C (decomposition).

Example 156

8-(4-forfinal)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

To a solution of 110 mg of ethyl ester of 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid (example 153) (0.23 mmol) in 7 ml THF was added to 0.66 ml of a 3.5 M solution of digeridoo(2 methoxyethoxy)of sodium aluminate in toluene (2.3 mmol). The reaction mixture was stirred at 23° C for 15 min, and then poured into ice and 10%aqueous acetic acid. The mixture was extracted with ethyl acetate and the organic layer is successively washed with N2Oh, a saturated solution PA2CO3and brine, dried over Na2SO4and evaporated under vacuum. The residue was ground into powder with ethyl acetate to obtain specified in the title compound as a pale yellow solid which CSOs substances (48 mg).

MS (ISN) 442,1 [(M-N)+]; tPL: 235-239° C (decomposition).

Example 157

8-(2-forfinal)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

97 mg of ethyl ester of 2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid (example 154) were subjected to treatment similar to example 156 obtaining specified in the title compound as a pale yellow solid (30 mg).

MS (ISN) 442,1 [(M-N)-]; tPL: 238-244° C (decomposition).

Example 158

8-(4-forfinal)-4-[2-(4-hydroxymethylimidazole-2-yl)pyridine-4-yl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

84 mg of ethyl ester of 2-{4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-yl}thiazole-4-carboxylic acid (example 155) were subjected to processing as in example 156. The crude product was chromatographically on silica gel using ethyl acetate/hexane (2:1 ratio) and ethyl acetate as eluent, and the purified product was led from ethyl acetate/hexane, getting mentioned in the title compound as a pale yellow solid (16 mg).

MS (ISP) 445,2 [(M+N)+]; tPL: 225-229° C.

Example 159

2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid

To a solution of 49 mg of ethyl ester of 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-and the]phenyl}thiazol-4-carboxylic acid (example 153) (0.1 mmol) in a mixture of 1 ml of the Meon and 1.5 ml of DMSO was added 1 ml of 2n. KOH (2 mmol). The mixture was stirred at 23° C for 0.5 h and then was divided between ethyl acetate and N2O. the Addition of 3h. HCl of pH of the aqueous phase was brought to 3 and then stirred in an ice bath for 0.5 hours the Precipitate was collected by filtration, triturated to powder with EtOH/Et2O (ratio 1/1) and dried, obtaining mentioned in the title compound as a pale yellow solid (25 mg).

MS (ISN) 456,4 [(M-N)-]; tPL: 286-290° C (decomposition).

Example 160

2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid

97 mg of ethyl ester of 2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid (example 154) were subjected to treatment similar to example 159 obtaining specified in the title compound as a pale yellow solid (60 mg).

MS (ISN) 456,2 [(M-N)-]; tPL: 261-263° C (decomposition).

Example 161

(2-hydroxyethyl)amid-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid

A solution of 49 mg of ethyl ester of 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid (example 153) (0.1 mmol) in 2-aminoethanol kept at 40° C for 40 minutes the Cooled solution was separated between ethyl acetate and N2Oh, the organic layer was dried on the Na 2SO4and evaporated under vacuum. The residue was ground into powder with ethyl acetate, getting mentioned in the title compound as a pale yellow solid (21 mg).

MS (ISP) 518,3 [(M+NH4)+]; tPL: 238-245° C (decomposition).

Example 162

(2-hydroxyethyl)amide 2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}-4-methylthiazole-5-carboxylic acid

A mixture of 78 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiobenzamide (example 149) (0.2 mmol) and 164 mg of ethyl-4-chloro-3-oxobutanoate (1.0 mmol) in 4 ml of ethanol was boiled under reflux for 24 hours the Solution was cooled to 0° and was stirred for 0.5 hours, the Crystals were isolated by filtration and subsequently suspended in 4 ml of 2-aminoethanol. The mixture was stirred at 70° C for 4 h, cooled to 23° and was divided between ethyl acetate and N2O. the Organic layer was dried over Na2SO4and evaporated under vacuum, and the residue was ground into powder with ethyl acetate, getting mentioned in the title compound as a pale yellow solid (37 mg).

MS (ISP) 515,3 [(M+N)+]; tPL: 248-251° C (decomposition).

Example 163

3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid

In the suspension 355 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 57) (1 m is ol) in 2 ml EtOH was added 5 ml of 2n. CON. The mixture was boiled under reflux for 3 h, then was cooled to 23° and was divided between ethyl acetate and N2O.

The addition of 3h. HCl of pH of the aqueous phase was brought to 3, the formed precipitate. The mixture was stirred in an ice bath for 0.5 hours, the Crystalline solid was collected by filtration, triturated to powder with ethyl acetate and dried, obtaining mentioned in the title compound as a pale yellow solid (218 mg).

MS (ISN) 373,3 [(M-N)+]; tPL: 290-296° C (decomposition).

Example 164

4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carboxylic acid

356 mg of 4-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile (example 94) was subjected to processing as in example 163. The reaction mixture was separated between ethyl acetate and N2Oh and by the addition of 3h. HCl of pH of the aqueous phase was brought to 3; formed precipitate. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4and evaporated under vacuum. The residue was ground into powder with EtOH to obtain specified in the title compound as a yellow solid (190 mg).

MS (ISN) 374,2 [(M-N)+]; tPL: 211-213° C (decomposition).

Example 165

8-(4-forfinal)-4-[3-(5-methyl[1,3,4]oxadiazol-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

SMEs mg hydrazide 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid (starting material 8A-2) (0.15 mmol) and 74 mg of the hydrochloride of ethylacetamide (0.6 mmol) in 0.6 ml of pyridine was kept at 100° C for 2 h the Mixture was cooled to 23° C, diluted with 30 ml of N2About and was stirred for 20 minutes the Precipitate was collected by filtration and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was led out of N2O/hexane, getting mentioned in the title compound as a pale yellow solid (28 mg).

MS (ISP) 430,3 [(M+NH4)+]; tPL: 254-256° C (decomposition).

Source material 8A-1

Allyl ester 3-[7-(3-formationl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid

In the solution 749 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid (example 163) (2 mmol) and 230 mg of 1,1,3,3,-tetramethylguanidine (2 mmol) in 24 ml of DMSO was added 242 mg allylbromide (2 mmol) and the mixture was stirred at 23° for 2.5 hours was Added 100 ml of N2Oh, and the stirring was continued for 20 minutes the Precipitate was collected by filtration and triturated to powder with ethyl acetate/Et2About (in the ratio 1:1) to obtain specified in the title compound as a pale yellow solid (705 mg).

MS (ISP) 415,2 [(M+N)+]; tPL: 226-228° C.

Source material 8A-2

The hydrazide 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid

In the suspension 207 mg alllow the th ether 3-[7-(3-formationl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[[b]][1,4]diazepin-2-yl]benzoic acid (starting material 8A-1) (0.5 mmol) in 3.5 ml Meon was added 0.25 ml of hydrazine hydrate is added (5 mmol). The mixture was stirred at 60° C for 15 h, then was cooled to 23° and diluted With 35 ml of N2O. the Precipitate was collected by filtration and dried, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:1 ratio) as eluent. The purified product was led out of N2O/hexane to obtain specified in the title compound as a pale yellow solid (64 mg).

MS (ISN) 387,0 [(M-N)+]; tPL: 256-258° C (decomposition).

Example 166

4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-yl)phenyl]-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 234 mg of hydrazide 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid (starting material 8A-2) (0.6 mmol) and 185 mg of the hydrochloride of ethylacetamide (1.5 mmol) in 12 ml of EtOH was heated under reflux for 0.5 hours the Mixture was cooled and was divided between ethyl acetate and N2O. the Organic layer was dried over Na2SO4and evaporated under vacuum, obtaining the amorphous residue (261 mg). A sample of this compound (92 mg) was dissolved in 3 ml of 33%solution of methylamine in EtOH. After stirring for 0.5 h at 23° the reaction mixture is evaporated under vacuum and the residue was kept at 100° With 5 ml of 1,4-dioxane for 2 hours the Solvent is evaporated under vacuum and the crude product was chromatographically on silica the Le using ethyl acetate and ethyl acetate/methanol (ratio 4:1) as eluent. The purified product was ground into powder with ethyl acetate, getting mentioned in the title compound as a pale yellow solid (26 mg).

MS (ISP) 426,4 (M+N)+]; tPL: 238-240° C (decomposition).

Example 167

3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxybenzamide

Stir in suspension 355 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile (example 57) (1 mmol) in 60 ml EtOH for 6 h at 23° With 6 portions were added 3,48 ml of a 50%aqueous solution of hydroxylamine (60 mmol). The mixture was cooled in an ice bath, diluted with 100 ml of N2About and was stirred for 1 h the Precipitate was collected by filtration, washed with water and Et2O and was ground into powder with ethyl acetate to obtain specified in the title compound as a pale yellow solid (336 mg).

MS (ISP) 389,2 [(M+N)+]; tPL: 257-259° C (decomposition).

Example 168

8-(4-forfinal)-4-{3-[5-(3-hydroxypropyl)-[1,2,4]oxadiazol-3-yl]phenyl}-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Stir in suspension 78 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxybenzamide (example 167) (0.2 mmol) in 3 ml EtOH at 23° With added sodium hydride (55%dispersion in oil, 32 mg, 0.8 mmol) and the mixture was stirred at 23° C for 5 minutes was Added 103 mg butyrolactone (1,2 mmol) and the mixture remove ivali at 70° C for 3 hours, the Reaction mixture was cooled to 23° and was divided between ethyl acetate and N2O. the Organic layer was dried over Na2SO4, evaporated under vacuum and the residue was led from dichloromethane, getting mentioned in the title compound as a pale yellow solid (60 mg).

MS (ISP) 457,3 [(M+N)+]; tPL: 220-222° C.

Example 169

8-(4-forfinal)-4-[3-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

To a solution of 262 mg of 3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzoic acid (example 163) (0.7 mmol) and 130 mg of 1-hydroxybenzotriazole (0.84 mmol) in CH3SP/DMF (7 ml/10 ml), cooled to 0° introduced 161 mg DEK [N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide] (0.84 mmol) and the mixture was stirred at 0° C for 1 h was Added 62 mg of N-hydroxyazetidine (0.84 mmol) and stirring was continued for 4 h at 23° C. the Reaction mixture was separated between ethyl acetate and N2Oh, the organic layer was dried over Na2SO4and evaporated under vacuum. The residue was boiled under reflux in 30 ml of toluene for 20 hours the Mixture was cooled, evaporated under vacuum and the residue was chromatographically on silica gel using ethyl acetate/hexane (2:1) as eluent. The purified product was ground into powder with ethyl acetate, the floor of the tea mentioned in the title compound as a pale yellow solid (49 mg).

MS (ISN) 411,2 [(M-N)+]; tPL: 266-268° C.

Example 170

8-(4-forfinal)-4-(2-hydroxyphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

A mixture of 121 mg of 4’-forgivenes-3,4-diamine [prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) processing TFA] (0.6 mmol) and 97 mg of 4-hydroxycoumarin (0.6 mmol) in 8 ml of xylene kept at 130° C for 6 hours after approximately 1 hour and began to form a yellow precipitate. The mixture was cooled to 23° C, were diluted with 8 ml of ethyl acetate and 8 ml of hexane and stirring was continued for 15 minutes the Precipitate was collected by filtration and triturated to powder with ethyl acetate/hexane (1:1 ratio), getting mentioned in the title compound in the form of a mixture with the isomeric 7-(4-forfinal)-4-(2-hydroxyphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-one as a yellow solid (117 mg).

MS (ISP) 347,3 [(M+N)+].

Example 171

4-(3-chloro-2,4-dihydroxyphenyl)-8-(4-forfinal)-1,3-dihydrobenzo[[b]][1,4]diazepin-2-he

Exposing 121 mg of 4’-forgivenes-3,4-diamine [prepared from tert-butyl methyl ether (3-amino-4’-forgivenes-4-yl)carbamino acid (example G39) for interaction with TPA] (0.6 mmol) and 128 mg of 8-chloro-4,8-dihydroxycoumarin (0.6 mmol) processed analogously to example 170, specified in the title compound was obtained in the form of a mixture of isomeric 4-(3-chloro-2,4-dihydroxyphenyl)-7-(4-Fortini is)-1,3-dihydrobenzo[b][1,4]diazepin-2-one as a pale yellow solid (103 mg).

MS (ISN) 395,1 [(M-N)+].

Example I

Ordinary method to prepare tablets of the following composition (mg/tablet:

The active component 100

Poroshkoobra lactose 95

White corn starch 35

Polyvinylpyrrolidone 8

Na-carboximetilkrahmal 10

Magnesium stearate 2

Weight tablets 250

Example II

Ordinary method to prepare tablets of the following composition (mg/tablet:

The active component 200

Poroshkoobra lactose 100

White corn starch 64

Polyvinylpyrrolidone 12

Na-carboximetilkrahmal 20

Magnesium stearate 4

Weight tablets 400

Prepare capsules with the contents of the following composition (mg/tablet:

The active component 50

Crystalline lactose 60

Microcrystalline cellulose 34

Talc 5

Magnesium stearate 1

Weight capsules 150

The active component, characterized by an acceptable particle size, crystalline lactose and microcrystalline cellulose homogeneous mix among themselves, sift, and then mixed with talc and magnesium stearate. Ready mix fill hard gelatin capsules of suitable size.

1. Derivative of benzodiazepine General formula I

in which X denotes a single bond or etendering group, and when X represents Odin is a relative link,

R1denotes a halogen atom; (ness.)alkyl; (ness.)alkylsulphonyl, (ness.)cycloalkyl, benzoyl, phenyl, optionally substituted by halogen atom, hydroxyl, (ness.)the alkyl, (ness.)alkoxy, halo-(ness.)alkoxy or cyano; styryl; phenylethyl; naphthyl; diphenyl; benzofuranyl or 5 - or 6-membered heterocyclic ring, representing thiophenyl, furanyl, pyridinyl, dihydropyridines, tetrahydropyridine and optionally substituted by exography, benzyloxy, methanesulfonyl, benzosulfimide or acetyl; when X denotes etendering group,

R1denotes a hydrogen atom; (ness.)alkyl, optionally substituted by hydroxyl; (ness.)cycloalkyl substituted by hydroxyl; (ness.)cycloalkenyl, optionally substituted oxopropoxy; (ness.)alkenyl; phenyl, optionally substituted by a halogen atom, (ness.)the alkyl, (ness.)alkoxy or halo(ness.)alkoxy; a 5 - or 6-membered heterocyclic ring, representing thiophenyl, thiazolyl, pyridinyl, dihydropyridines, tetrahydropyridine or dihydropyran and optionally substituted by methanesulfonyl, acetyl, tert-butoxycarbonyl or tert-BUTYLCARBAMATE;

R3denotes phenyl; pyridine; thiophenyl or thiazolyl, which is optional substituted with halogen atom, amino, cyano-, nitro-group, a hydroxyl, CT is hydroxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl, trimethylsilylethynyl, (ness.)the quinil, (ness.)alkoxy, halo-(ness.)the alkyl, N-hydroxymethylpropane, (ness.)alkylsulfonamides, 4-(ness.)alkylpiperazine-1-carbonyl, (ness.)alkylcarboxylic; (ness.)alkoxy or carboxyla, which is optionally esterified; or 5-membered aromatic heterocycle representing imidazolyl, isoxazolyl, oxadiazolyl, thiazolyl, tetrazolyl and triazolyl, optionally substituted carboxyla, which is optionally esterified (ness.)the alkyl or amitirova (ness.)alkylaminocarbonyl, which ultimately replaces the hydroxy, (ness.)the alkyl, which is optionally substituted by hydroxy, (ness.)alkoxy(ness.)alkylsulfanyl, (ness.)alkylsulfanyl and amidon carbothiolate provided that, if X denotes a single bond, a R3denotes a pyridinyl, R1does not denote a hydrogen atom or methyl,

and their pharmaceutically acceptable acid additive salt.

2. Compounds according to claim 1, in which R represents phenyl substituted in metaprogram a cyano; a halogen atom or imidazolyl, which is optionally substituted (ness.)by alkyl; or 1,3-thiazolium, which is optionally substituted by hydroxy(ness.)by alkyl, carboxy, or-CO-NH-(CH2)2OH; 1,2,3-triazolyl; 1,2,4-Tria what ollom, which is optionally substituted (ness.)by alkyl; tetrazolyl or isoxazolyl, which is optionally substituted (ness.)the alkyl.

3. Compounds according to claim 2, which represent

3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

4-(3-chlorophenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

8-(4-perforating)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-perforating)-4-(3-[1,2,4]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-forfinal)-4-[3-(4-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-fluoro-2-were)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-fluoro-2-hydroxyphenyl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-perforating)-4-(3-tetrazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-forfinal)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-forfinal)-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,4-differenl)-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,3-differenl)-4-(3-[1,2,3]triazole-1-Ilf the Nile)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-forfinal)-4-[3-(4-hydroxymethylimidazole-2-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

2-{3-[7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}thiazol-4-carboxylic acid;

(2-hydroxyethyl)amide-2-{3-[7-(4-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]phenyl}-4-methylthiazole-5-carboxylic acid and

4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-yl)phenyl]-8-(4-forfinal)-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

4. The compounds of formula I according to claim 1, in which R3denotes thiophenyl, optionally substituted by a halogen atom or cyano; or pyridinyl, optionally substituted by imidazolyl or cyano.

5. Compounds according to claim 4, which represent

8-(4-perforating)-4-(2-imidazol-1-espiridion-4-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

2-[7-(4-forfinal)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile;

4-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)pyridine-2-carbonitrile and

4-[7-(2,4-differenl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile.

6. Drug for treatment or prevention of acute and/or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, a disorder of cognition and memory disorders, including one or more connected the th according to any one of claims 1 to 5, and pharmaceutically acceptable excipients.

7. Method of producing compounds of the formula I according to claim 1, which includes the interaction of the compounds of formula III

where R1and X have the meanings indicated in claim 1, and Y denotes aminosidine group that represents tert-butoxycarbonyl,

with the compound of the formula IV or IVa

in which R represents ethyl or butyl and R3matter specified in claim 1,

obtaining the compounds of formula II

where R1, R3, X and Y have the above values,

which is further subjected to release with removal aminosidine group and cyclization to obtain the compounds of formula I according to claim 1.

8. The compound according to any one of claims 1 to 5 obtained by the method according to claim 7.

9. Compounds according to any one of claims 1 to 5 for the treatment of acute and/or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, impairment of cognitive abilities and impaired memory.

10. Compounds according to any one of claims 1 to 5 and/or one or more of their pharmaceutically acceptable acid additive salts intended for the preparation of drugs for treatment or prevention of acute and/or chronic neurological disorders, including psychosis, Shi is ofreneo, Alzheimer's disease, a disorder of cognitive abilities and impaired memory.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of aminomethylpyrrolidine of the formula (I) , their salts or hydrates wherein R1 represents aryl with from 6 to 10 carbon atoms or heteroaryl wherein heteroaryl is a five-membered ring or a six-membered ring and comprises from 1 to 2 heteroatoms taken among nitrogen, oxygen and sulfur atom; aryl and heteroaryl can comprise one or more substitutes taken among the group consisting of halogen atom or (C1-C6)-alkoxyl; each radical among R2, R3, R4, R5, R6, R7 and R8 represents hydrogen atom (H) independently; Q represents incomplete structure representing by the following formula: wherein R9 means (C3-C6)-cyclic alkyl that can be substituted with halogen atom; R10 means hydrogen atom (H); R11 means hydrogen atom (H), NH2; X1 means halogen atom; A1 represents incomplete structure representing by the formula (II): wherein X2 means hydrogen atom (H), halogen atom, halogenmethoxyl group, (C1-C6)-alkyl or (C1-C6)-alkoxyl group; X2 and above indicated R9 can be combined to form the ring structure and inclusion part of the main skeleton and such formed ring comprises oxygen, nitrogen or sulfur atom as a component atom of the ring and the ring can comprise (C1-C6)-alkyl as a substitute; Y means hydrogen atom (H). Compounds of the formula (I) elicit an antibacterial effect and can be used for preparing a therapeutic agent.

EFFECT: valuable medicinal properties of compounds.

2 tbl, 61 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl

FIELD: organic chemistry, agriculture.

SUBSTANCE: substituted benzoylisoxazols of general formula I are described, wherein R1 is cycloalkyl; R2 is hydrogen, alkoxycarbonyl; R3 is halogen, substituted alkyl, alkoxyl; R4 is halogen, alkoxil; Z is substituted 5-membered saturated or unsaturated heterocycle having 1-3 nitrogen atoms and additionally including one oxogroup (C=O). Also disclosed is herbicidal agents, containing compounds of formula I.

EFFECT: effective suppression of weeds in such cultures as maize and wheat.

16 cl, 6 tbl, 4 ex

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