Derivatives of benzodiazepine and medicinal agent comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

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

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

 

The present invention relates to compounds of General formula I

where

X is single bond or etendering group, in which when X is single bond,

R1means halogen or phenyl, which is optionally substituted by halogen, C1-C7by alkyl;

in the case when X is etendering group,

R1means phenyl, optionally substituted by halogen,

R2means halogen, hydroxy, lower alkyl, NISS. alkoxy,

hydroxymethyl, hydroxyethoxy, lower alkoxy(ethoxy)n(n=1-4), cyanoethoxy, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, 4-oxopiperidin-1-yl, 4-sessioncookiepath-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxyphenyl-1-yl, 4-(ness.)alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di(ness.)alkylaminocarbonyl, N,N-bis(nits.)alkylamino(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl, (ness.)alkylcarboxylic(ness.)alkyl, lower alkoxycarbonylmethyl, carboxymethylchitin, 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, carboxy(ness.)alkoxy, cyano(ness.)alkyl, 2-oxo[1,3]dioxolane-4-yl(ness.)alkoxy, (2-hydroxy(ness.)alkyl)-(ness.)alkylamino, hydroxycarbamoyl(ness.)alkoxy, 2,2-dimethylether [1,3]dioxolo[4,5-C] pyrrol-5-yl, lower alkoxycarbonyl(ness.)alkoxy, (3R)-g is proximinality-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxoacridine-3-yl, lower alkylcarboxylic, carbamoylphenoxy, carbamoylmethyl, carboxy(ness.)alkyl;

R3means phenyl, thiophenyl or pyridinyl, which is substituted by halogen, cyano or carbamoyl, imidazolyl, 1,2,3-triazolium, 1,2,4-triazolium or isoxazolyl where groups 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl optionally substituted C1-C7the alkyl or C1-C7alkylsulfanyl

and their pharmaceutically acceptable salts.

It was unexpectedly found that compounds of General formula I are antagonists of metabotropic glutamate receptors. The compounds of formula I differ valuable therapeutic properties.

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

L-Glutamic acid, the most common neurotransmitter in the Central nervous system, plays an important role in many physiological processes. Glutamate-dependent receptors incentives are divided into two main groups. The first main group forms a controlled ligand ion channels. Metabotropic glutamate receptors (mGluR) form the second group and, moreover, belong to the family of receptors coupled with G-protein.

Currently known in the häme various members of these mGluR, and some of them even have subtypes. On the basis of 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 subgroups: group I belong mGluR1 and mGluR5, to belong to group II mGluR2 and mGluR3, and to belong to group III mGluR4, mGluR6, mGluR7 and mGluRS.

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

In this regard, other indications for treatment are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Other indications for treatment are chronic and acute pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as States, which lead to glutamate-deficiency functions, such as muscle spasms, convulsions, migration is ü, urinary incontinence, nicotine addiction, drug addiction, anxiety, vomiting, dyskinesia and depression.

The purpose of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, as such and as pharmaceutically active substances, their production, products based on the connection according to the invention, and receive them, as well as the use of compounds according to the invention for the control or prevention of diseases of the aforementioned type and respectively to obtain the corresponding products.

Preferred compounds of formula I in the scope of the present invention are those in which R3means phenyl substituted in the meta-position cyano, halogen; or imidazolyl, which is optionally substituted (ness.)the alkyl or methylsulfanyl; 1,2,3-triazolium, 1,2,4-triazolium or isoxazolyl, which is optionally substituted (ness.)the alkyl.

Examples of such compounds are the following.

3-(8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

3-[8-(4-Methylpiperazin-1-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo [b][1,4]diazepin-2-yl] benzonitrile;

3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

Methyl ester [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulphonyl]acetic acid is;

2-[4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-2-yl]diazepin-7-yl]ndimethylacetamide;

3-(8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4] diazepin-2-yl] benzonitrile;

3-(8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

4-(3-Itfinal)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

4-(3-Imidazol-1-ylphenyl)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

[RS]-3-[4-Oxo-8-(2-oxo[1,3]dioxolane-4-ylethoxy)-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

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

[4-(3-Imidazol-1-ylphenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetonitrile;

8-(4-Perforating)-7-hydroxymethyl-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

7-(2-Hydroxyethoxy)-4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-Forfinal)-7-[4-(2-hydroxyethoxy)piperidine-1-yl]-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-Forfinal)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-methoxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Fortini is)-7-hydroxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo [b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,5-Differenl)-7-methoxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo [b][1,4]diazepin-2-he;

3-[7-(2,5-Differenl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

8-(4-Perforating)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

8-(4-Perforating)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it.

Preferred are also the compounds of formula I, where R3means thiophenyl, preferably thiophene-2-yl, which is optionally substituted by cyano or halogen; or R3means pyridinyl, preferably pyridine-4-yl, which is optionally substituted in position 2 cyano or halogen, or R3means thiazolyl, which is optionally substituted in position 2 by imidazolyl or 4-methylimidazolium.

Especially preferred are the following compounds.

5-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiophene-2-carbonitrile;

2-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-1H-benzo[b] [1,4]diazepin-2-yl]thiophene-3-carbonitrile;

4-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonite is;

4-[7-(4-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile;

4-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile;

All tautomeric forms of the compounds according to the invention are also included in it.

The term "(ness.)alkyl"used in the present description, means linear or branched hydrocarbon residue with 1 to 7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n - propyl, isopropyl and the like.

The term "(ness.)cycloalkyl"used in the present description, means a cyclic saturated hydrocarbon residues 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 of the above definitions, linked through an oxygen atom.

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

The term "5 - or 6-membered aryl or heteroaryl" includes phenyl, thiophenyl, pyridine, partially hydrated pyridine.

The expression "five-membered aromatic heterocycle" include furan, thiazole, imidazole, pyrazole, 1,3-thiazole, 1,3-oxazole, 1,2-oxazole, 1,2-thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,2,3-oxadiazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole and tetrazole.

Compounds of General formula I and their pharmaceutically PR is acceptable salts can be obtained in accordance with the following methods.

In accordance with the scheme And compounds of General formula I, in which X, R1, R2and R3have the meanings described above, can be obtained from compounds of General formula II using the sequence of reactions acylation-removal protection-cyclization.

For example, the interaction of compounds of General formula II with dioxanone IV, in which R3has the above significance, in an inert solvent, such as toluene or xylene, at elevated temperature, preferably between 80°and 160°leads to compounds of General formula III.

Alternative compounds of General formula III can be obtained, for example, by reaction of compounds of General formula II with β-ketefian (General formula IVa), in which R3above, using the same conditions described for the reaction with dioxanone.

Subsequently, cleavage of the BOC(tert-butyloxycarbonyl)-protective group in compounds of General formula III and concomitant cyclization of the released compound gives the desired compounds of General formula I. alternatively, instead of the BOC group can be used any appropriate aminosidine group, such as Fmoc (fluorenylmethoxycarbonyl) or benzyloxycarbonyl (Z).

Stage release-cyclization can be carried out obrabotka the compounds of General formula III, for example, acid Bronsted, such as triperoxonane acid (TFA), in an inert solvent, such as dichloromethane (DHM). Preferably the reaction is carried out at temperatures of 0-50°C. the Advantage may be the use of anisole or 1,3-dimethoxybenzene as a trap carbocation in the reaction mixture.

OS - Ls method

In accordance with scheme B, compounds of General formula II in which R1has the values described previously for compounds where X is a single bond, and R2has the above meanings, can be obtained in different ways, depending on the nature of R1in iodine-containing compounds of General formula V in which R2described above. As shown in scheme B, the key steps are condensation type reactions Suzuki and Stille in the presence or in the absence of carbon monoxide.

The exact conditions for the corresponding compounds of General formula II can be found in the experimental part.

Compounds of General formula V in which R2such as described above can be obtained in various ways, depending on their unique remainder R2.

Schema

OS B, method a: diphosgene, ethyl acetate; then tert.-butanol

OS B, method b: Vos2O Cs2CO3 , 2-butanone, 52°

OS B, method: (i) Vos2Oh, DMAP (dimethylaminopyridine), THF; (ii) DHM, 0°C.

As shown in scheme V, compounds of General formula Va, in which R2means (ness.)alkyl, halogen or alkoxycarbonyl, can be obtained from known compounds of General formula XI by ladirovannye and subsequent protection of the synthesized intermediate compounds of General formula XII.

Phase iodination can be carried out, for example, with the use of chloride of iodine in acetic acid in the presence of sodium acetate. The reaction can be carried out, for example, at temperatures of 20-80°C.

Protection of the amino group can be achieved, for example, the interaction of the compounds of General formula XII with di-tert.-BUTYLCARBAMATE in the presence of such grounds, as cesium carbonate. The reaction can be carried out in polar solvents, such as acetone or butanone, and the like, at temperatures of 20-60°C.

As shown in scheme D, compounds of General formula V and V, in which R2attached via a sulfur atom or nitrogen (e.g., R2means morpholine-4-yl, thiomorpholine-4-yl, dialkylamino, carboxymethylchitin etc.), respectively, can be obtained from the intermediate derivative XIII by reaction of nucleophilic substitution with the corresponding amines or mercaptans in the presence of a suitable base.

DIPEA - diisopropylethylamine

The reaction is preferably carried out in a polar aprotic solvent such as dimethylformamide, N-organic or dimethylsulfoxide and the like. The base can be selected from sterically obstructed amines, such as base Hunya, alkoxides, such as sodium methylate and tert.-butyl, or hydrides, such as sodium hydride. The reaction can be conducted at temperatures 20-110°C, depending on the individual compounds to be synthesized.

Compounds of General formula VG, in which R2attached via an oxygen atom (for example, R2means (ness.)alkoxy, halogen(ness.)alkoxy, (ness.)cycloalkane, (ness.)alkoxy(ness.)alkoxy and so on), can be obtained, as shown for example in scheme D, the reaction of the nucleophilic aromatic substitution with the appropriate alcohol in the presence of a suitable base and followed by protection of the amino group.

OS B, method a: diphosgene, ethyl acetate, 77°With, then tert.-butanol

OS B, method b: (i) Re2Oh, DMAP, THF, ii) TFA, DHM, 0°C

DABCO - diazabicyclo[2.2.2]octane

The base can be selected from a class of bases Bronsted, such as potassium hydroxide and the like. The reaction is carried out preferably in the floor of the Pnom aprotic solvent, such as dimethylformamide, N-organic or dimethylsulfoxide and the like, at temperatures from 20 to 100°C.

Protection of the amino group can be carried out, for example, the interaction of the compounds of General formula XV with di-tert.-butoxycarbonyl in the presence of a base such as cesium carbonate. The reaction can be carried out in polar solvents, such as acetone or butanone, and the like, at temperatures of 20-60°C.

Another way to implement this stage of protection is to first convert the amino group of compounds of General formula XV isocyanate by reaction with phosgene or an equivalent amount of phosgene in the presence of a suitable base, which is then treated with tert-butyl alcohol, getting the desired compounds of General formula VG.

Another suitable way to implement this stage of protection is to first convert the amino group of compounds of General formula XV into the corresponding di-BOC-derivative by reaction with an excess of di-tert.-butoxycarbonyl in the presence of 4-dimethylaminopyridine (DMAP), which is then treated with 2 EQ. TFA in dichloromethane (DHM)to give the desired compounds of General formula VG.

This reverse order of steps, namely, the implementation of the first nucleophilic aromatic substitution at a key intermediate compound XIV and then protect the amino group, as is shown in the diagram of the synthesis of D, can also be applied to compounds of General formula V and VC (scheme synthesis G).

Another method of obtaining compounds of General formula VG is the use of O-allyl derivative of the nineteenth and the sequence of reactions dezalkilirovania-alkylation as shown in scheme D. Dezalkilirovania carried out preferably by isomerization catalyzed by the transition metal, for example, in the presence of salts of rhodium(I), such, for example, the catalyst of Wilkinson [(PPh3)3RhCl], or salts of palladium(II), such as [(PPh3)2PdCl2), followed by hydrolysis of the resulting simple vinyl ether aqueous acid. An example of this method can be found in J. Org. Chem. 1973, 38, 3224. Alkylation of phenol XX in the desired compound of General formula VG can be done using the electrophilic reagent of General formula R-X, in which R has the value (ness.)of alkyl, (ness.)alkenyl, alkyl acetate or benzyl, and X is a leaving group, for example, anion iodide, bromide, methanesulfonate or tamilselvan, in an appropriate solvent in the presence of a base. Preferably the reaction is carried out in a polar aprotic solvent, for example, chlorinated solvents such as dichloromethane, chloroform or dichloroethane, or in Amidah, for example, dimethylformamide, dimethylacetamide and N-organic, is whether sulfoxidov, for example, dimethyl sulfoxide. The base can be selected from sterically obstructed amines, such as base Hunya, alkoxides, such as sodium methylate and tert.-butyl, hydrides such as sodium hydride, hydroxides such as potassium hydroxide, carbonates such as potassium carbonate or acid carbonates, such as potassium bicarbonate. The reaction can be performed in the temperature-20-80°C, depending on the individual connections that need to be synthesized. For the synthesis of O-tert.-butylphosphonic General formula VG phenol XX can be treated with di-tert.-butylacetate DMF in toluene or benzene at 80°as described in Synthesis, 1983, 135.

In accordance with the scheme of synthesis E.

OS - Ls method

TGP - O-tetrahydropyranyl

compounds of General formula V and Ve, in which R2attached via a carbon atom (R2means, for example, (ness.)allyloxycarbonyl, cyanomethyl etc), can be obtained from compound XIII or XIV, for example, by reaction with ether or poluation malonic acid in the presence of base, followed by removal of one of alkylcarboxylic groups by decarboxylation. The exact reaction conditions vary depending on the nature of individual compounds described in the examples.

Key intermediate derivatives XIII and XIV can be p is obtained, as already described in scheme C.

For compounds containing one Deputy General formula V-V synthesis starting from the known methyl ester 3-amino-4-nitrobenzoic acid. Standard iodination as described in scheme synthesis, leads to the iodide XXI, which, in turn, can be protected with a BOC-group. The recovery of the methyl ester may, for example, be carried out by treatment with lithium borohydride, sodium borohydride or hydride diisobutylaluminum in an aprotic solvent, for example THF, ether or toluene. The presence of alcohol, such as methanol, ethanol or isopropanol, may be useful. Preferably, the recovery is carried out at temperatures between -20°s and 0°C. conversion of functional groups, such as the transformation of the formed derivative of benzyl alcohol V in chloride (V)come standard methods known in the art. The exact reaction conditions vary depending on the nature of individual compounds described in the examples.

In accordance with the scheme W compounds of General formula II in which R1has the values described previously for compounds where X means etendering group, can be obtained in various ways from improsoned V, depending on the nature of the Deputy is th R 1and R2. As shown in scheme G, the transformation can be carried out, for example,

(a) direct attach alcantarillado Deputy R1to the compound of General formula V by condensation-type reactions Sonogashira and subsequent reduction of the nitro group or

(b) a two-step condensations on the type of reaction Sonogashira, in which the first trimethylsilylacetamide condensed with the compound of General formula V with education after removal protection with sodium hydroxide in methanol intermediate derived XVIII, which can then be converted using the second condensation-type reactions Sonogashira with an appropriate reagent R1-I, R1-Br or R1-OSO2CF3and nitrogroup reduction in the desired compound of General formula II.

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

LDA - diisopropylamide lithium

TN - triperoxonane anhydride

In accordance with scheme 3 dioxanonane and β-ketoamine building blocks of the General formula IV and Va can be obtained by methods known in the art, from the corresponding derivatives of carboxylic acids R3-COR, ie, free acids, methyl or ethyl esters and acid chlorides. The exact conditions for the relevant soy is ineni can be found in the experimental part.

Another synthetic method for obtaining compounds of General formula I, in which R1, R2and X have the meanings described above, and R3mean urea of General formula C(O)NR4R5in which R4and R5mean hydrogen, (ness.)alkyl, or R4and R5together form a residue of the research or

N-methylpiperazin shown in the diagram:

DFP - diphenylphosphinomethyl

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

Pharmaceutically acceptable salts can also be easily obtained in accordance with the methods essentially known, taking into account the nature of the connection, which must be converted into a salt. Suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I are inorganic or organic acids, such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, n-toluensulfonate acid and the like. The compounds of formula I and their pharmaceutically acceptable salts are antagonists of metabotropic receptor is in glutamate and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, disorders of cognitive abilities and defeat memory. Other indications for treatment are limited brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injury, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Other indications for treatment are acute and chronic pain, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as States, which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, drug dependence, 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. The 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 may also be made of rectal is, for example, in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

To obtain pharmaceutical preparations of the compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Appropriate carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; however, in the case of soft gelatin capsules, depending on the nature of the active substance usually do not require any media. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. For aqueous injection solutions of water-soluble salts of compounds of formula I can be used auxiliary substances, such as alcohols, polyols, glycerine, vegetable oils and the like, but typically, it is not necessary. Appropriate carriers for suppositories are, for example, natural or hardened mA is La, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, moistening agents, emulsifiers, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

As mentioned earlier, drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert excipient are also an aim of the present invention, as a method of obtaining such medicines, which involves combining one or more compounds of the formula I or their pharmaceutically acceptable salts and, optionally, one or more of valuable substances in pharmaceutical dosage form together with one or more therapeutically inert carriers.

Dosage form may vary within wide limits and will certainly be tailored to suit the individual requirements in each particular case. In General, the effective dose for oral or parenteral administration is between 0.01-20 mg/kg/day, a dose of 0.1-10 mg/kg/day preferred for all the above indications. Daily dose for an adult person of mass 70 kg is away between 0.7 to 1400 mg/day, preferably between 7-700 mg/day.

The present invention relates also to the use of compounds of the formula I and their pharmaceutically acceptable salts to obtain drugs, especially for the control or prevention of acute and/or chronic neurological disorders aforementioned type.

Compounds of the present invention are antagonists of group II mGlu receptors. The compounds exhibit activity measured in the experiments described below, at a concentration of 50 μm or less, typically 3 μm or less and is 0.5 micron or less. The table below shows some specific values of the pKipreferred compounds.

Binding of [3H]-LY354740 on transfected mGlu2 the membranes of cells Cho (Chinese hamster ovary)

Transfection and cell culture

Received from Professor S. Nakanishi (Kyoto, Japan) cDNA encoding a protein of rat mGlu2 receptor, in the vector pBluescript II and was subcloned into the eukaryotic expression vector pcDNA I-amp from the company Invitrogen (NV Leek, The Netherlands). This vector design (pcDlmGR2) was transfusional together with the plasmid psvNeo that encodes a gene of resistance to neomycin, cells SNO using a modified calcium phosphate method described by Chen and Okayama (1988). Cells were maintained in modi is Anna by the way Dulbecco environment the Needle from the recovered L-glutamine (final concentration 2 mm) and 10% cialisbuynow fetal calf serum from the company Gibco BRL (Base, Switzerland). Selection was performed in the presence of G-418 (final concentration of 1000 µg/ml). Clones identified by reverse transcription of 5 μg total RNA, followed by PCR (polymerase chain reaction) using specific primers of the mGlu2 receptor 5'-atcactgcttgggtttctggcactg-3' and 5'-agcatcactgtgggtggcataggagc-3' in 60 mm Tris-HCl (pH 10), 15 mm (NH4)2SO4, 2 mm MgCl2, 25 units/ml Taq polymerase with 30 cycles of annealing at 60°C for 1 min, elongation at 72°C for 30 s denaturation for 1 min at 95°C.

Membrane preparation

Cells, cultured as described above were collected and washed three times with cold SFR (phosphate buffered saline) and were frozen at -80°C. the Precipitate is again suspended in cold 20 mm buffer HEPES-NaOH (N-[2-hydroxyethyl]piperazine-N'-[4-butanesulfonic acid]-NaOH)containing 10 mm EDTA (ethylenediaminetetraacetic acid) (pH 7.4), and homogenized using Polytron (Kinematica AG, Littau, Switzerland) for 10 sec at 10000 rpm After centrifugation for 30 min at 4°the precipitate was washed once with the same buffer and once with 20 mm buffer HEPES-NaOH containing 0.1 mm EDTA (pH 7.4). The protein content was measured using the method of the Pier (Socochim, Lausanna, Switzerland) and bovine serum albumin as the standard.

Binding of [3H]LY354740

After thawing, the membrane again suspen Aravali in cold 50 mm buffer Tris-HCl, containing 2 mm MgCl2and 2 mm CaCl2(pH 7) (binding buffer). The final concentration of the membranes in the tests was 25 µg/ml experiments on the inhibition was performed with membranes, incubated with 10 nm [3H]-LY354740 at room temperature for 1 h in the presence of different concentrations of the investigated compounds. After incubation, the membranes were separated on glass fiber filters Whatmann GF/C and washed 5 times with cold binding buffer. In the presence of 10 μm DCG IV not mentioned no specific binding. After migration filters in plastic vials containing 10 ml scintillation fluid Ultima gold (Packard, Zürich, Switzerland), radioactivity was measured using liquid scintillation counter Tri-Carb 2500 TR (Packard, Zürich, Switzerland).

Data analysis

Curves of inhibition corresponded chetyrehmetrovuyu logistic equation giving the value of the IC50and the coefficients of the hill.

Examples

The following examples relate to the receipt of tert.-butyl ester (4-iodine-2-nitrophenyl)carbamino acid (synthesis scheme C).

A common way And

Getting 4-iodine-2-nitroaniline ladirovannye 2-nitroaniline (according to Wilson J. Gerald. Hunt Frederick C. Austr. J. Chem. 1983, 36, 2317-25).

To a stirred solution of 2-nitroaniline (1.0 mol) in acetic acid (500 ml)containing anhydrous sodium acetate (93-103 g, 1,125-to 1.25 mol, added monochloride iodine (59-66 ml, 1,125-to 1.25 mol) in acetic acid (300 ml) for 60 minutes the Reaction mixture was heated to a certain temperature until thin layer chromatography (TLC) showed complete conversion of starting material, was stirred another 30 min at 23°With, then slowly diluted with water (1000 ml), which caused the separation of the crystalline product. Stirring was continued for 1 h, the product was filtered, washed from acetic acid and dried in vacuum at 60°C.

Example A1

5-Chloro-4-iodine-2-nitrophenylamino

Was obtained from 5-chloro-2-nitroaniline by ladirovannye with monochloride iodine in a mixture of acetic acid-sodium acetate according to General method A (80°). Received the product as an orange solid.

MS (mass spectrum) (IE) (ionization elektrorazpredelenie): 298 (M+and 300 [(M+2)+]; tpl.202-203°C (decomp.).

Example A2

4-Iodine-5-methyl-2-nitrophenylamino

Was obtained from 5-methyl-2-nitroaniline by ladirovannye with monochloride iodine in a mixture of acetic acid-sodium acetate according to General method A (80°). Received the product as a red solid.

MS (EI): 278 (M+); tPL154°C (decomp.).

Example A3

Methyl ester of 5-amino-2-iodine-4-nitrobenzoic acid

Received from the methyl ester of 3-amino-4-nitrobenzoic acid (22,25 g) {CAS-No. [9952-09-1], obtained in two stages as follows: 3-hydroxy-4-nitrobenzoic acid (30 g, 164 mmole), ammonium chloride (to 21.91 g, 410 mmol) in 25% aqueous ammonia (180 ml) was heated in a steel autoclave at 160°C for 7 h (the internal pressure of 2.3 MPa). Was cooled to 23°and evaporated to dryness. Was dissolved in water (200 ml), brought the pH to 1 with concentrated sulfuric acid, saturated with sodium chloride and extracted with ethyl acetate (6×750 ml), the combined organic layers were dried over MgSO4. Filtration and removal of solvent in vacuo gave pure enough C-amino-4-nitrobenzoic acid (22,26 g, 75%) as an orange solid. This material is suspended in methanol (500 ml)was added concentrated sulfuric acid (3 ml), the mixture was heated to 65°C for 2.5 days. The solvent was removed in vacuo, the solid residue was dissolved in ethyl acetate, washed with saturated solutions of sodium bicarbonate and salt, then dried over MgSO4. Removal of solvent gave a very pure methyl ester of Z-amino-4-nitrobenzoic acid (22,25 g, 93%) as an orange solid by ladirovannye with monochloride iodine in a mixture of acetic acid-sodium acetate according to General method A (35°). Received the product as an orange solid (29,38 g, 80%).

MS (EI): 322 (M+); tpl.168°is (decomp.).

General method B

Getting tert.-butyl ester of (2-nitrophenyl)karbinovykh acids from 2-nitroanilines

Method a: to a solution of diphosgene (4,1 ml, 34.1 mmole) in ethyl acetate (40 ml) at 0°C was added a solution of 4-iodine-2-nitroaniline (45,5 mmole) in ethyl acetate (200-500 ml), the mixture was heated at boiling for 18 hours the Solvent was removed in vacuum, obtaining a brown solid, which was treated with hot hexane (200 ml). The solid material was separated by filtration, the filtrate was concentrated under reduced pressure, obtaining the pure 4-iodine-2-nitrophenylhydrazine in the form of a yellow solid. This material was heated at boiling in a mixture of excess tert.-butanol in methylene chloride for 2.5 hours the solvent gave an orange solid, which was purified column chromatography on silica gel with hexane/ethyl acetate, getting tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid as a yellow solid.

Method b: to a mixture of 4-iodine-2-nitroaniline (142 mmole) and cesium carbonate (55,5 g, 170 mmol) in 2-butanone (740 ml) was added dropwise a solution of BOC2On (37,8 g, 173 mmole) in 2-butanone (170 ml), the mixture was stirred at 52°C for 26 hours the Solvent was removed in vacuo, the residue was treated with a mixture of water (240 ml) and methanol (240 ml) and was extracted with hexane (3×500 ml). United Huck is anew layer was washed with saturated salt solution (200 ml), all aqueous layers was again extracted with hexane (300 ml). All combined hexane layers were dried over MgSO4was filtered , the solvent was evaporated in vacuum, obtaining an orange solid, which was purified column chromatography on silica gel with hexane/ethyl acetate, getting tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid as a yellow solid.

Method b: to a solution of 4-iodine-2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 ml) at 23°was added dropwise over 70 min the solution Vos2(246 g, 1128 mmol) in THF (500 ml) and continued stirring at 23°C for 75 minutes the Entire mixture was evaporated to dryness and dried in high vacuum, getting a dark brown solid (253,59 g). This material was dissolved in DHM (1100 ml), cooled to 0°and was added dropwise TFA (84 ml, 1100 mmol). The mixture was stirred at 0°C for 2 h, poured into ice saturated sodium bicarbonate solution, was extracted with DHM, washed with saturated salt solution and dried over MgSO4. Removal of solvent in vacuo resulted in a dark brown solid substance (199,71 g), which was applied to silica gel and was purified column chromatography on silica gel with hexane/ethyl acetate, getting tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid as a yellow solid fuel is Dogo substances.

Example B1

tert.-Butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid

Received isocyanate of 5-chloro-4-iodine-2-nitrophenylamino (example A1) (7.0 g, 23,45 mmole) diphosgene (2,12 ml, to 17.6 mmole) in ethyl acetate (30 ml), then was treated with tert.-butanol (100 ml) in dichloromethane (100 ml) according to General method B (method a). Received the product as yellow solid (7,1 g, 76%).

MS (EI): 398 (M+and 400 [(M+2)+]; tpl.82-84°C.

Example B2

tert.-Butyl ether (4-iodine-5-methyl-2-nitrophenyl)carbamino acid

Received isocyanate, 4-iodine-5-methyl-2-nitrophenylamino (example A2) (13,51 g, 48.6 per mmole) diphosgene (4,4 ml of 36.4 mmole) in ethyl acetate (50 ml), then was treated with tert.-butanol (150 ml) in dichloromethane (150 ml) according to General method B (method a). Received the product as yellow solid (14.1 g, 77%).

MS (EI): 378 (M+); tpl.99-100°C.

Example B3

Methyl ester 5-tert.-butoxycarbonylamino-2-iodine-4-nitrobenzoic acid

Received isocyanate of the methyl ester of 5-amino-2-iodine-4-nitrobenzoic acid (example A3) (5.5 g, 17 mmol) diphosgene (of 1.55 ml, 13 mmol) in ethyl acetate (135 ml), then was treated with tert.-butanol (20 ml) in dichloromethane (70 ml) according to General method B (method a). Received the product as a yellow solid (5.2 g, 72%).

MS (EPI) (ionization power is Asplenium with the formation of positive ions): 440(M+NH 4)+]; tpl.126°C.

Example B4

tert.-Butyl ester of (5-allyloxy-4-iodine-2-nitrophenyl)carbamino acid

Received isocyanate from 5-allyloxy-4-iodine-2-nitrophenylamino (example 1) (9.0 g, 28.2 mmole) diphosgene (2,6 ml and 21.2 mmole) in ethyl acetate (150 ml), then was treated with tert.-butanol (80 ml) in dichloromethane (80 ml) according to General method B (method a). Received the product as yellow solid (9,16 g, 77%).

MS (EPI): 421 [(M+N)+] 438 [M+NH4)+]; tpl.93-95°C.

Example B5

tert.-Butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid

Received isocyanate, 4-iodine-5-methoxy-2-nitrophenylamino (example 2) (2.85 g, RS 9.69 mmole) diphosgene (0,88 ml, 7,27 mmole) in ethyl acetate (52 ml), then was treated with tert.-butanol (25 ml) in dichloromethane (25 ml) according to General method B (method a). Received the product as a yellow solid (3.0 g, 79%).

MS (EI): 394 (M+); tpl.171°C.

Example B6

tert.-Butyl ester [4-iodine-5-(2-methoxyethoxy)-2-nitrophenyl]carbamino acid

Received isocyanate, 4-iodine-5-(2-methoxyethoxy)-2-nitrophenylamino (example DZ) (2,73 g, 8,08 mmole) diphosgene (0.8 ml, the 6.06 mmole) in ethyl acetate (50 ml), then was treated with tert. -butanol (25 ml) in dichloromethane (25 ml) according to General method B (method a). Received the product in the form of a yellow tenagophila (3.0 g, 86%).

MS (EPI): 439 [(M+N)+], 456 [(M+NH4)+] 461 [(M+Na)+]; tpl.109-111°C.

Example B7

tert.-Butyl ester [4-iodine-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitrophenyl]carbamino acid

Received isocyanate, 4-iodine-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitrophenylamino (example D4) (8.0 g, 17 mmol) diphosgene (1,54 ml, 13 mmol) in ethyl acetate (100 ml), then was treated with tert.-butanol (25 ml) in dichloromethane (25 ml) according to General method B (method a). Received the product as a yellow oil (8.6 g, 89%).

MS (EPI): 588(M+NH4)+].

Example B8

tert.-Butyl ether (RS)-[5-(2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)-2-nitro-4-phenylethylene]carbamino acid

Received from (RS)-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-2-nitro-4-phenylethylenediamine (example L) (2,678 g, 5.7 mmole), Cs2CO3(2,23 g, 6.8 mmole) and Vos2(1.52 g, 7.0 mmol) in 2-butanone (to 36.5 ml) at 52°in accordance with the General method B (method b). Received the product as a yellow foam (2.0 g, 75%).

MS (EPI): 469 [(M+N)+] 486 [M+NH4)+]; tpl.32°C.

Example b [V (R=CN, R ' =Boc)]

tert.-Butyl ester of (5-cyanomethyl-4-iodine-2-nitrophenyl)carbamino acid

Received isocyanate of (5-amino-2-iodine-4-nitrophenyl)acetonitrile (example Ve (R=CN, R"=H)) (5,15 g, 17 mmol) diphosgene (2,05 ml, 17 mmol) in ethyl acetate (150 is l), then was treated with tert.-butanol (25 ml) in dichloromethane (25 ml) according to General method B (method a). Received the product as a yellow solid (4.0 g, 58%).

MS (current IEO) (ionization elektrorazpredelenie with the formation of negative ions): 402 [(M-N)-]; tpl.124-126°C.

Example ± 10

tert.-Butyl ester of [5-(2-tert.-butoxyethoxy)-4-iodine-2-nitrophenyl]carbamino acid

Received di-BOC-derivative of 5-(2-tert.-butoxyethoxy)-4-iodine-2-nitrophenylamino (example D6) (13,9 g of 36.6 mmole) and Vos2On (16,35 g, 75 mmol)was then treated with 2 EQ. TFA in dichloromethane in accordance with the General method B (method b). Received in the form of a yellow solid (14,96 g, 85%).

MS (EPI): 481 [(M+N)+]; tpl.113-116°C.

Example b

tert.-Butyl ester [4-iodine-5-(4-methoxybenzyloxy)-2-nitrophenyl]carbamino acid

Received di-BOC-derivative of 4-iodine-5-(4-methoxybenzyloxy)-2-nitrophenylamino (example d) (2,88 g, 7,20 mmol) and Vos2On (3,30 g, 15.12 mmol), then was treated with 2 EQ. TFA in dichloromethane in accordance with the General method B (method b). Received in the form of a waxy yellow solid (1,74 g).

MS (current IEO): 499 [(M-N)-].

The following methods are getting those tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids, which have nitrogen-containing substituents in position 5 (scheme G).

A common way To

Getting tert.-butyl ester of 5-N-substituted-(4-iodine-2-nitrophenyl)karbinovykh acids

Method a: tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid

Mixed tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) with the desired amine, optionally in toluene or DMSO and/or DIPEA (diisopropylethylamine) at a temperature of 23°100-130°up until TLC showed complete disappearance of chlorinated. The reaction mixture was cooled to 23°C, was poured into a mixture of ice and water, the precipitate was separated by filtration, washed with water and dried in vacuum. In cases where the product did not precipitate, the mixture was extracted with ethyl acetate, washed with water and saturated saline solution, dried over Na2SO4. Filtration and removal of solvent in vacuo gave the crude product, which was purified column chromatography on silica gel with hexane/ethyl acetate, getting a net connection specified in the header.

Method b: 5-chloro-4-iodine-2-nitrophenylamino

A mixture of 5-chloro-4-iodine-2-nitrophenylamino (example A1) (1,49 g, 5.0 mmol), the desired amine (6-25 mmol) and the appropriate base, such as sodium bicarbonate, potassium carbonate, triethylamine or DIPEA (10-15 mmol) was stirred in DMSO, DMF or toluene (20-50 ml) at 60-130°until the PRS, until TLC showed complete disappearance of chlorinated. The reaction mixture was cooled to 23°C, was poured into a mixture of ice and water, neutralized with 1 N. hydrochloric acid, the precipitate was separated by filtration, washed with water and dried in vacuum. In cases where the product did not precipitate, the mixture was extracted with ethyl acetate, washed with water and saturated saline solution, dried over Na2SO4. Filtration and removal of solvent in vacuo gave the crude product, which was purified column chromatography on silica gel with hexane/ethyl acetate, getting a net connection specified in the header. Protection of the amino group was carried out following the General method B.

Example B1

tert.-Butyl ester [4-iodine-5-(4-methylpiperazin-1-yl)-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (2,39 g, 6.0 mmol) and 1-methylpiperazine (1.60 ml, 15 mmol) in toluene (4.5 ml) at 110°C for 18 h in accordance with the General method (method a). Received the product as a yellow solid (2.2 g).

MS (EPI): 463 [(M+N)+]; tpl.134-136°C.

Example B2

tert.-Butyl ether (4-iodine-2-nitro-5-thiomorpholine-4-ylphenyl)carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (2.0 g, 5.0 mmol and thiomorpholine (2.6 ml) in toluene (3.8 ml) and DIPEA (1.7 ml) at 115° C for 48 h in accordance with the General method (method a). Received the product as a yellow solid (1.1 g).

MS (EPI): 466(M+H)+]; tpl.132-134°C.

Example B3

tert.-Butyl ether (4-iodine-5-morpholine-4-yl-2-nitrophenyl)carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (2.0 g, 5.0 mmol) and research (10 ml) at boiling for 3 h in accordance with the General method (method a). Received the product as yellow solid (0,805 g).

MS (EPI): 450 [M+N)+]; tpl.43-44°C.

Example B4

tert.-Butyl ester of [5-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-4-iodine-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (3.0 g, 7,53 mmole), 1,4-dioxa-8 azaspiro[4.5]decane (4,82 ml, 37,63 mmole) and DIPEA (2,58 ml, 15.0 mmol) in toluene (4 ml) at boiling for 6 hours in accordance with the General method (method a). Received the product as an orange solid (4.0 g).

MS (EPI): 506 [(M+N)+]; tpl.132-134°C.

Example B5

tert.-Butyl ester [4-iodine-5-(4-methoxypiperidine-1-yl)-2-nitrophenyl]carbamino acid

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (6,91 g, 15 mmol), 4-methoxypiperidine (4.0 g, 34,73 mmole) and sodium bicarbonate (of 5.83 g, 69,45 mmole) in DMSO (230 ml) at 100°St. accordance with the General method (method b). The obtained brown solid (of 7.95 g) was converted into the connection specified in the header, in accordance with the General method (method b). Received the product as yellow solid (6,55 g).

MS (EPI): 478 [(M+N)+]; tpl.133-135°C.

Example B6

tert.-Butyl ester of {5-[(2-hydroxyethyl)methylamino]-4-iodine-2-nitrophenyl}carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (1,99 g, 5.0 mmol) and 2-methylaminoethanol (2.00 ml, 25.0 mmol) in DMSO (2.5 ml) at 23°in accordance with the General method (method a). Received the product as a yellow resinous substance (1.88 g).

MS (EPI): 438 [(M+N)+].

Example 7

tert.-Butyl ester of [5-(4-hydroxypiperidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (1,99 g, 5.0 mmol) and 4-hydroxypiperidine (2,53 g, 25 mmol) in DMSO (2.5 ml) at 23°in accordance with the General method (method a). Received the product as yellow solid (1.88 g).

MS (EI): 463 (M+); tpl.58-60°C.

Example B8

tert.-Butyl ester of {5-[4-(2-hydroxyethoxy)piperidine-1-yl]-4-iodine-2-nitrophenyl}carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (2.2 g, 5.5 mmol), 4-(2-g is doxetaxel)piperidine {CAS-No. [40256-14-2]} (800 mg, 5.5 mmol) and triethylamine (2.3 ml of 16.5 mmole) in DMSO (2.3 ml) at 23°in accordance with the General method (method a). Received the product as a yellow solid (1.65 g).

MS (EI): 507 (M+); tpl.64-65°C.

Example B9

tert.-Butyl ester of [5-(CIS-3,4-dihydroxypyrrolidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid

Received in two stages as follows: tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (8,73 g of 21.9 mmole) were introduced in the reaction with 3-pyrroline (2.0 ml, to 26.3 mmole, purity 70%, contained 30% of pyrrolidine), triethylamine (9,12 ml, 65.7 mmole) in DMSO (14 ml) and ethanol (5 ml) at 23°in accordance with the General method (method a), receiving the mixture in a ratio of 7:3 tert. butyl ester of [5-(2,5-dihydropyrrol-1-yl)-4-iodine-2-nitrophenyl]carbamino acid and tert.-butyl ether (4-iodine-2-nitro-5-pyrrolidin-1-ylphenyl)carbamino acid. Received the product as yellow solid (8,57 g). Part (or 4.31 g) of this material was dihydroxypropane by the reaction with 4-methylmorpholine-4-oxide (NMO) (1.28 g, 11.0 mmol), 2,5% OsO4in tert.-butanol (1 ml, 0.1 mmole) and K2OsO4(40 mg, 0.1 mmole) in acetone (250 ml) and water (100 ml) at 23°C for 6 days. Received the connection specified in the header, in the form of an amorphous yellow substance (2.50 g).

MS (EPI): 466 [(M+N)+].

Example 10

tert.-Butyl ester of [5-(2-hydroc is ethylamino)-4-iodine-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (3,99 g, 10 mmol) and ethanolamine (3,01 ml, 50 mmol) in DMSO (20 ml) at 23°in accordance with the General method (method a). Received the product as yellow solid (4.53 in).

MS (EPI): 424(M+H)+]; tpl.130-148°C.

Example B11

tert.-Butyl ester of [5-((R)-3-hydroxypyrrolidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1), hydrochloride (R)-3-hydroxypyrrolidine and triethylamine in DMSO at 23°in accordance with the General method (method a). Received the product as yellow solid (3,153 g).

MS (EPI): 45.0 [(M+N)+]; tpl.158°C (decomp.).

The following methods are getting those tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids that have in position 5 sulfur-containing substituents (scheme synthesis G).

General method D

Getting tert.-butyl ester of 5-S-substituted-(4-iodine-2-nitrophenyl)karbinovykh acids from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid

To a solution of thiol (2.2 mmole) in DMF was added a solution of sodium methylate (5.4 M in methanol, of 0.41 ml, 2.2 mmole), then tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (797 mg, 2.0 mmole) is kept stirring at 23° With complete disappearance chlorinated according to TLC. Poured chilled in ice 5% citric acid, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, saturated salt solution, dried over MgSO4. Removal of solvent gave an orange oil, which was purified column chromatography on silica gel with hexane/ethyl acetate, getting a net connection specified in the header.

Example G1

tert.-Butyl ester of [5-(2-dimethylaminoethanol)-4-iodine-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (399 mg, 1.0 mmol), hydrochloride 2-dimethylaminoethanol (312 mg, 2.2 mmole) and 5.4 M solution of sodium methylate in methanol (0.8 ml, 8.8 mmole) in DMF (2 ml) according to General method Was Received this product as a yellow solid (306 mg).

MS (EPI): 468 [(M+N)+]; tpl.144°C.

Example G2

Methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenylarsonic)acetic acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (797 mg, 2.0 mmole), methyl ester of thioglycolic (0.2 ml, 2.2 mmole) and 5.4 M solution of sodium methylate in methanol (0,41 ml, 2.2 mmole) in DMF (2 ml) in accordance with the General method, Received the product in the form of relegating substances (847 mg).

MS (EI): 468 (M+); tpl.110-112°C.

The following methods are getting those tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids that have in position 5 oxygen substituent (scheme D).

General method D

Getting 5-O-substituted-4-iodine-2-nitrophenylamino of 5-chloro-4-iodine-2-nitrophenylamino

To a suspension of potassium hydroxide (85%, 3,62-of 7.96 g, 55-121 mmol) in DMSO (50 ml) was added the alcohol (125-500 ml), the mixture was stirred at 23°to dissolve the potassium hydroxide. Small portions were added 5-chloro-4-iodine-2-nitrophenylamino (example A1) (15.0 g, 50 mmol), the resulting deep-red solution was stirred at 23-60°until the complete disappearance according to TLC chlorinated. The mixture was poured into ice 1 N. hydrochloric acid or chilled with ice saturated solution of ammonium chloride, extracted with ethyl acetate or chloroform, washed with 1 N. hydrochloric acid or a saturated solution of ammonium chloride and salt, dried over MgSO4. Removal of solvent gave a dark red solid, which was purified column chromatography on silica gel, receiving the connection specified in the header.

Example 1

5-Allyloxy-4-iodine-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (15.0 g, 50 mmol), allyl alcohol (50 ml) and potassium hydroxide (of 7.96 g, 121 IMO the ü) in DMSO (50 ml) according to General method D. Received the product as an orange solid (9,38 g).

MS (EI): 320 (M+); tpl.74°C.

Example 2

4-Iodine-5-methoxy-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (2,98 g, 10 mmol), methanol (10 ml) and potassium hydroxide (1.45 g, 22 mmole) in DMSO (10 ml) according to General method D. Received the product as an orange solid (2.9 g).

MS (EPI): 295 [(M+N)+] 312 [(M+NH4)+]; tpl.189°C.

Example 3

4-Iodine-5-(2-methoxyethoxy)-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (2,98 g, 10 mmol), methoxyethanol (7.9 ml, 100 mmol) and potassium hydroxide (1.45 g, 22 mmole) in DMSO (8 ml) according to General method D. Received the product as an orange solid (2.8 g).

MS (current IEO): 337 [(M-N)-]; tpl.121-122°C.

Example D4

4-Iodine-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (9,48 g, 32 mmole), nanometrology ether tetraethyleneglycol (19 g, 91 mmol) and potassium hydroxide (2,31 g, 35 mmol) in DMSO (25 ml) at 60°in accordance with the General method D. Received the product as a red oil (8,4 g).

MS (EPI): 471 [(M+N)+].

Example D5

(RS)-5-(2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)-4-iodine-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (4,48 is, 15 mmol), DL-α,β-isopropylideneglycerol (10 ml, 81 mmol) and potassium hydroxide (1.01 g, 18 mmol) in DMSO (10 ml) at 23°in accordance with the General method D. Received this product as a yellow solid (4.9 g).

MS (current IEO): 393 [(M-N)-]; tpl.151°C.

Example D6

5-(2-tert.-Butoxyethoxy)-4-iodine-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (14.9 g, 50 mmol), 2-tert.-the butoxyethanol (29.5 g, 250 ml) and potassium hydroxide (3,99 g, 60 mmol) in DMSO (25 ml) at 23°in accordance with the General method D. Received this product as a yellow solid (14.3 g).

MS (EPI): 381 [(M+N)+]; tpl.144-146°C.

Example d

4-Iodine-5-(4-methoxybenzyloxy)-2-nitrophenylamino

Was obtained from 5-chloro-4-iodine-2-nitrophenylamino (example A1) (5,97 g, 20 mmol), 4-methoxybenzylamine alcohol (to 4.98 ml, 40 mmol) and potassium hydroxide (1,58 g, 24 mmole) in DMSO (30 ml) at 23°in accordance with the General method D. Received the product as a yellow-brown solid (2,94 g).

MS (current IEO): 399 [(M-N)-]; tpl.183°C.

The following examples relate to obtaining methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenyl)acetic acid and tert.-butyl ether (5-cyanomethyl-4-iodine-2-nitrophenyl)carbamino acid (synthesis scheme (E).

Example XVI (R=CO2Me, R'=Me, R ' =Boc)

Dimethyl ether (5-tert.-butoxycarbonyl is but-2-iodine-4-nitrophenyl)malonic acid

To a solution of tert.-of potassium butyl (0.56 g 5,02 mmole) in DMSO (3 ml) was added dimethyl malonic acid (0,58 ml, 5,02 mmole), then tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (1,00 g of 2.51 mmole), the resulting deep-red solution was stirred at 100°until the complete disappearance according to TLC chlorinated. The mixture was poured into ice 5% citric acid (100 ml), extracted with ethyl acetate (2×100 ml), washed with saturated saline solution, dried over MgSO4. Removal of solvent resulted in a yellow oil, which was purified column chromatography on silica gel with hexane/ethyl acetate (4:1), obtaining specified in the header of a pure compound as a yellow resinous substance (1.13 g, 91%).

MS (EPI): 512 [M+NH4)+] 517 [(M+Na)+].

Example XVII (R=CN, R'=Et, R"=H)

Ethyl ester of (RS)-(5-amino-2-iodine-4-nitrophenyl)tsianuksusnogo acid

Received as described, for example, XVI, 5-chloro-4-iodine-2-nitrophenylamino (example A1) (14.9 g, 50 mmol), ethyl ether tsianuksusnogo acid (14.7 ml, 100 mmol) and tert.-of potassium butyl (11.2 g, 100 mmol) in DMSO (60 ml) at 100°within 2 hours Received the product in the form of a dark-brown resinous substance.

MS (EI): 375 (M+).

Example V (R=CO2Me, R ' =Boc)

Methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenyl)of the criminal code is usnei acid

A mixture of dimethyl 2-(5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenyl)malonic acid (example XVI (R=CO2Me, R'=Me, R ' =Boc) (3,34 g, 6,76 mmole), lithium chloride (573 mg, 13,52 mmole) and water (0,122 ml, 6,76 mmole) in DMSO (46 ml) was stirred at 100°C for 7 hours the Mixture was poured into ice water, extracted with ethyl acetate, washed with saturated saline solution, dried over MgSO4. Removal of solvent resulted in a yellow oil, which was purified column chromatography on silica gel with hexane/ethyl acetate (9:1), obtaining mentioned in the title compound as a yellow solid (1,37 g, 47%).

MS (EI): 436 (M+); tpl.93°C.

Example Ve (R=CN, R"=H)

(5-Amino-2-iodine-4-nitrophenyl)acetonitrile

Received as described in example V of ethyl ester of (RS)-(5-amino-2-iodine-4-nitrophenyl)tsianuksusnogo acid (example XVII (R=CN, R'=Et, R"=H)) (vs. 20.62 g, 55 mmol) and lithium chloride (was 9.33 g, 220 mmol) in DMSO (370 ml) and water (4.4 ml) at 120°for 2.5 hours, the Product was obtained as a green-brown solid.

MS (EI): 303 (M+); tpl.145-183°C.

The following examples relate to the receipt of tert.-butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid, the corresponding simple Tgp-ether, and tert.-butyl ether (5-dimethylaminomethyl-4-iodine-2-nitrophenyl)carbamino acid through the intermediate chlorine is derived (synthesis scheme (E).

Example V

tert.-Butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid

Added LiBH4(0.32 g, 14,78 mmol) to a solution of methyl ester 5-tert.-butoxycarbonylamino-2-iodine-4-nitrobenzoic acid (example BZ) (3.12 g, 7,39 mmole) and methanol (0.6 ml, 14,78 mmole) in THF (44 ml) at 0°C. the Reaction mixture was stirred at 0°C for 15 minutes was Poured into 5% citric acid, and was twice extracted with ethyl acetate, washed with saturated solution of sodium bicarbonate and salt, dried over MgSO4.

Removal of solvent resulted in a yellow oil, which was purified column chromatography on silica gel with a mixture of cyclohexane/ethyl acetate (4:1)to give a pure compound indicated in the title, in the form of a yellow solid (2.64 g, 91%).

MS (EPI): 412 [M+NH4)+]; tpl.>250°C.

Example Vand

tert.-Butyl ether (RS)-[4-iodine-2-nitro-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid

To a mixture of tert.-butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid (example V) (394 mg, 1.0 mmol) and 3,4-dihydro-2H-Piran (of 0.11 ml, 1.2 mmole) in DHM (5 ml) at 0°hydrate was added n-toluenesulfonic acid (about 5 mg), the reaction mixture was stirred at 0°C for 1 h was Diluted with ethyl acetate, washed with saturated solution of sodium bicarbonate and salt, dried over MgSO4. UDA is giving solvent in vacuo resulted in a yellow oil, which was purified column chromatography on silica gel with hexane/ethyl acetate (9:1)to give a pure compound indicated in the title, in the form of a yellow resinous substance (470 mg, 98%).

MS (current IEO): 477 [(M-N)-].

Example VI

tert.-Butyl ester of (5-dimethylaminomethyl-4-iodine-2-nitrophenyl)carbamino acid

To a mixture of tert.-butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid (example V), lithium chloride (3 EQ.) and pyridine (2 EQ.) in DMF at 0°were added methanesulfonamide (1.5 equiv.) the reaction mixture was stirred at 23°C for 24 h was Added dimethylamine in ethanol (10 EQ.) and continued the stirring for 24 h was Diluted with ethyl acetate, washed with saturated solution of sodium bicarbonate and salt, dried over MgSO4. Removal of solvent in vacuo resulted in a yellow oil, which was purified column chromatography on silica gel with a mixture of cyclohexane/ethyl acetate (3:1)to give a pure compound indicated in the title, in the form of a yellow oil (421 mg).

MS (EPI): 422 [(M+N)+].

The following examples relate to the receipt of tert.-butyl ester of(2-amino-4-arylvinyl)karbinovykh acid, tert.-butyl ester of [2-amino-4-(1-alkenyl)phenyl]karbinovykh acid and tert.-butyl ester of (2-amino-4-Arnolfini)karbinovykh acids in the form of pure regioisomers (scheme synthesis B).

General method E.

Getting tert.-butyl ester (4-aryl-2-nitrophenyl)karbinovykh acids by direct condensation Suzuki mpem.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids airborne acids

A mixture of tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (3.0 mmole), airborne acid (4.5 mmole) and PdCl2(PPh3)2(2 mol%) was heated at boiling in 1,4-dioxane (25 ml) and 2 M sodium carbonate solution (7.5 ml) [or alternatively with 1 M sodium bicarbonate solution (7.5 ml), lithium chloride (6.0 mmol) and (Ph3P)4Pd (3% mol.) in DME (dimethoxyethane) (30 ml); alternatively, triethylamine (9.0 mmol), palladium diacetate (3 mol%), by triphenylphosphine (6 mol%) in DMF (10 ml) at 100°] to fully develop improsoned according to TLC. The mixture was transferred into a separating funnel, was added water (25 ml), the product was extracted with ether or ethyl acetate (3×30 ml). The combined organic layers were washed with saturated brine (50 ml) and dried over Na2SO4. Removal of the solvent led to a brown residue, which was purified column chromatography on silica gel with a mixture of cyclohexane/ether or cyclohexane/ethyl acetate, getting listed at the beginning of the connection.

Example E1

tert.-Butyl ether (2-chloro-5-nitrobiphenyl-4-yl)carbamino acid.

Was obtained from tert.-butyl is about ether (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (1.20 g, 3,00 mmole) and phenylboric acid (0,62 g, 3,30 mmole) in accordance with the General method E. Received the product as a yellow oil (843 mg).

MS (EI): 348 (M+and 350 [(M+2)+].

Example E2

tert.-Butyl ether (2-methyl-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methyl-2-nitrophenyl)carbamino acid (example B2) (1,135 g, 3 mmole) and phenylboric acid (630 mg, 3.3 mmole) in accordance with the General method E. Received the product as a yellow oil (971 mg).

MS (EI): 328 (M+).

Example E3

tert.-Butyl ether (RS)-{4'-fluoro-5-nitro-2-[4-(tetrahydropyran-2-yloxy)piperidine-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{4-iodine-2-nitro-5-[4-(tetrahydropyran-2-yloxy)piperidine-1-yl]phenyl}carbamino acid [RO-69-4319/000, obtained from tert.-butyl ester of [5-(4-hydroxypiperidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B7) by treatment with 3,4-dihydro-2H-Piran and as the catalyst, hydrate, n-toluenesulfonic acid in DHM at 0°] (1,09 g, 2.0 mmole) and 4-ftorpolimernoj acid in accordance with the General method E. Received the product as an orange solid (894 mg).

MS (EPI): 516 [(M+N)+]; tpl.144-146°C.

Example E4

tert.-Butyl ether (RS)-(4'-fluoro-5-nitro-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino to the slots

Was obtained from tert.-butyl ether (RS)-(4-iodine-2-nitro-5-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl}phenyl)carbamino acid [RO-69-43559/000, obtained from tert.-butyl ether {5-[4-(2-hydroxyethoxy)piperidine-1-yl]-4-iodine-2-nitrophenyl}carbamino acid (example B8) by treatment with 3,4-dihydro-2H-Piran and as a catalyst for the hydrate p-toluenesulfonic acid in DHM at 0°] (950 mg, of 1.87 mmole) and 4-ftorpolimernoj acid (314 mg, 2.25 mmole) in accordance with the General method E. Received this product as a viscous orange oil (930 mg).

MS (EPI): 560 [(M+N)+]; tpl.144-146°C.

Example E5

tert.-Butyl ether (RS)-[4'-fluoro-5-nitro-2-(tetrahydropyran-2-intoximeter) biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[4-iodine-2-nitro-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example V, And 4-ftorpolimernoj acid in accordance with the General method E. Received the product as an orange oil (1.24 g).

Example E6

tert.-Butyl ether (2-cyanoethoxy-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (5 cyanoethoxy-4-iodine-2-nitrophenyl)carbamino acid (example A2) (838 mg, 2.0 mmole) and 4-ftorpolimernoj acid (392 mg, 2.8 mmole) in accordance with the General method E. Received this product as a yellow solid (333 mg).

MS (EPI): 405 [M+NH4)+ ]; tpl.148°C.

Example E7

tert.-Butyl ether (2-dimethylaminomethyl-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (5-dimethylaminomethyl-4-iodine-2-nitrophenyl)carbamino acid (example VI) and 4-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (1.01 g).

Example E8

tert.-Butyl ester of [2-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-(CIS-2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4-iodine-2-nitrophenyl]carbamino acid [RO-69-4741/000, obtained from tert.-butyl ester of [5-(CIS-3,4-dihydroxypyrrolidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B9) by treatment with 2,2-dimethoxypropane and as the catalyst, hydrate, n-toluenesulfonic acid in DMF at 23°] (845 mg, 1,67 mmole) and 4-

ftorpolimernoj acid (327 mg, of 2.34 mmole) in accordance with the General method E. Received this product as a yellow solid (643 mg).

MS (EPI): 474 [(M+N)+]; tpl.119°C.

Example a

tert.-Butyl ether (4'-fluoro-2-methoxy-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid (example B5) (3,68 g, 9,34 mmole) and 4-ftorpolimernoj acid (3,61 g, 25,male) in accordance with the General method E. Received the product as yellow solid (2,69 g).

MS (current IEO): 361 [(M-N)-]; tpl.250°C.

Example E10

tert.-Butyl ester of [2-(1.4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B4) (4.0 g, 7,02 mmole) and 4-ftorpolimernoj acid (1,33 g, 9.5 mmole) in accordance with the General method E. Received this product as a yellow solid (2,43 g).

tpl.213°C (decomp.).

Example E11

tert.-Butyl ether (4'-fluoro-2-methyl-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methyl-2-nitrophenyl)carbamino acid (example B2) (756 mg, 2.0 mmole) and 4-ftorpolimernoj acid (420 mg, 3.0 mmole) in accordance with the General method E. Received the product as an amorphous yellow substance (611 mg).

MS (current IEO): 345 [(M-N)-].

Example E12

tert.-Butyl ether (4-tert.-butoxycarbonylamino-4'-fluoro-5-nitrobiphenyl-2-yloxy)acetic acid

Was obtained from tert.-butyl ether (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenoxy)acetic acid (example A1) (2.14 g, 4,33 mmole) and 4-ftorpolimernoj acid (728 mg, 5.2 mmole) in accordance with the General method E. Received the product as an orange solid (1.80 g).

MS (current IEO): 461 [(M-N)-]; tpl. 92-93°C.

Example E 13

tert.-Butyl ether (2-chloro-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) and 4-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (625 mg).

MS (EI): 366 (M+).

Example 14

tert.-Butyl ether [4'-fluoro-2-(2-methoxyethoxy)-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(2-methoxyethoxy)-2-nitrophenyl]carbamino acid (example B6) and 4-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (1,833 g).

MS (EI): 406 (M+).

Example E15 motorway

tert.-Butyl ester of [2-(2-tert.-butoxyethoxy)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-tert.-butoxyethoxy)-4-iodine-2-nitrophenyl]carbamino acid (example ± 10) and 4-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (735 mg).

MS (EPI): 449 [(M+N)+].

Example a

tert.-Butyl ether [4'-fluoro-5-nitro-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-2-nitro-5-(2-oxoacridine-3-yl)phenyl]carbamino acid [RO-69-6758/000, obtained from tert.-the etilovogo ester [5-(2-hydroxyethylamino)-4-iodine-2-nitrophenyl]carbamino acid (example 10) by treatment with 1,1'-carbonyl diimidazol in dioxane and then with pyridine, DMAP as a catalyst, every time at 100°] (503 mg, 1.12 mmole) and 4-ftorpolimernoj acid (235 mg, 1.68 mmole) in accordance with the General method E. Received this product as a yellow solid (310 mg).

MS (current IEO): 416 [(M-N)-]; tpl.201°C.

Example E17

tert.-Butyl ether (4'-fluoro-2-methoxy-2'-methyl-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid (example B5) and 4-fluoro-2-methylphenylimino acid in accordance with the General method E. Received this product as a yellow solid (699 mg).

MS (EI): 376 (M+).

Example E18

tert.-Butyl ether (2-tert.-butoxy-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (5-tert.-butoxy-4-iodine-2-nitrophenyl)carbamino acid (example A4) (1.4 g, is 3.21 mmole) and 4-ftorpolimernoj acid (0,67 g of 4.83 mmole) in accordance with the General method E. Received the product as an amorphous yellow substance (1.2 g).

MS (EI): 404 (M+).

Example E19

tert.-Butyl ether (2-tert.-butoxy-2'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (5-tert.-butoxy-4-iodine-2-nitrophenyl)carbamino acid (example A4) (1.4 g, is 3.21 mmole) and 2-ftorpolimernoj acid (0,67 g of 4.83 mmole) in accordance with the General method E. Received the product as an amorphous yellow substance (960 mg).

MS (EI): 404 (M+).

Example E20

tert.-Butyl ether(RS)-{4'-fluoro-5-nitro-2-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{4-iodine-2-nitro-5-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] phenyl} carbamino acid [RO-69-6376/000, obtained from tert.-butyl ester of [5-((R)-3-hydroxypyrrolidine-1-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B11) by treatment with 3,4-dihydro-2H-Piran and as the catalyst, hydrate, n-toluenesulfonic acid in DHM at 0°] and 4-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (1,053 g).

MS (EPI): 502 [(M+N)+].

Example E21

tert.-Butyl ether (2'-fluoro-2-methoxy-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid (example B5) (1,00 g of 2.54 mmole) and 2-ftorpolimernoj acid (0,60 g, 4,32 mmole) in accordance with the General method E. Received the product as an amorphous yellow substance (687 mg).

MS (EI): 362 (M+).

Example E22

tert.-Butyl ester of [2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butovogo ester [5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B4) (1.89 g, 3,47 mmole) and 2-ftorpolimernoj is islote (0,63 g, of 4.49 mmole) in accordance with the General method E. Received this product as a yellow solid (1.46 g).

MS (EPI): 474 [(M+N)+]; tpl.164°C.

Example a

tert.-Butyl ether (2',5'-debtor-2-methoxy-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid (example B5) (3.94 g, 10 mmol) and 2,5-diperpanjang acid (2,21 g, 14 mmol) according to General method E. Received the product as an amorphous yellow substance (1,05 g).

MS (current IEO): 379 [(M-N)-].

Example a

tert.-Butyl ether [2'-fluoro-2-(2-methoxyethoxy)-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(2-methoxyethoxy)-2-nitrophenyl]carbamino acid (example B6) and 2-ftorpolimernoj acid in accordance with the General method E. Received this product as a yellow solid (3,63 g).

MS (current IEO): 405 [(M-N)-].

Example E25

tert.-Butyl ether (RS)-[2'-fluoro-5-nitro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[4-iodine-2-nitro-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example VA) and 2-ftorpolimernoj acid in accordance with the General method E. Received the product as a yellow liquid (2,606 g).

MS (current IEO): 445 [(M-N)-].

Example A

tert.-Butyl EF the R [2'-fluoro-2-(4-methoxybenzyloxy)-5-nitrobiphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(4-methoxybenzyloxy)-2-nitrophenyl]carbamino acid (example b) (1,69 g, to 3.38 mmole) and 2-ftorpolimernoj acid (0,61 g, 4,39 mmole) in accordance with the General method E. Received the product as a yellow foam (940 mg).

MS (EPI): 469 [(M+N)+].

Example E27

tert.-Butyl ether (2-tert.-butoxy-2,'5'-debtor-5-nitrobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (5-tert.-butoxy-4-iodine-2-nitrophenyl)carbamino acid (example A4) (3.00 g, 6,88 mmole) and 2,5-diperpanjang acid (2,23 g, a 14.1 mmole) in accordance with the General method E. Received the product as an amorphous yellow substance (2.30 g).

MS (current IEO): 421 [(M-N)-].

A common way W

Getting tert.-butyl ester (4-aryl-2-nitrophenyl)karbinovykh acids by condensation Suzuki tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids with bis(pinacolato)diboron and subsequent reaction with arylhalides

A mixture of tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (2.0 mmole), bis(pinacolato)Debora (2.2 mmole), potassium acetate (6.0 mmol) and PdCl2(PPh3)2(3 mol%) in 1,4-dioxane (25 ml) was stirred at 100°until the complete disappearance improsoned according to TLC (see Tetr. Lett. 1997, 38, 3841-3844). After addition of arylhalides (4.0 mmole), PdCl2(PPh3)2(3 mol%) and 2 M solution of carbonate is sodium (7.5 ml) and the mixture was stirred at 100° To complete the transformation according to TLC intermediate ester of boric acid. The mixture was transferred into a separating funnel, was added water (30 ml), the product was extracted with ether or ethyl acetate (3×50 ml). The combined organic layers were washed with saturated salt solution (100 ml), dried over Na2SO4. Removal of the solvent led to the formation of a brown precipitate, which was purified column chromatography on silica gel with a mixture of cyclohexane/ether or cyclohexane/ethyl acetate, receiving the connection specified in the header.

General method C

Getting tert.-butyl ester (4-aroyl-2-nitrophenyl)karbinovykh acids by carbonyl condensation Suzuki tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acids airborne acids.

A mixture of tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid (1.0 mmol), airborne acid (1.1 mmole), potassium carbonate (3.0 mmole) and PdCl2(PPh3)2(3 mol%) in anisole (6 ml) was stirred at 80°C in an atmosphere of carbon monoxide to fully develop improsoned according to TLC (see Tetr. Lett. 1993, 34, 7595-7598). The mixture was transferred into a separating funnel, was added water (30 ml), the product was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated brine (50 ml) and dried over Na2SO4. Remove rest is rites led to the formation of a yellow precipitate, which was purified column chromatography on silica gel with hexane/ethyl acetate, receiving the connection specified in the header.

A common way And

Getting tert.-butyl ester (4-aryl-2-nitrophenyl)karbinovykh acid or tert.-butyl ester of (4-{alkenyl-, cycloalkenyl or geteroseksualen}-2-nitrophenyl)karbinovykh acid condensation Still tert.-butyl ether (2-nitro-4-tributylstannyl)carbamino acid with arylhalides or vinylsilane or condensation Still tert.-butyl ether (4-iodine-2-nitrophenyl)carbamino acid with trialkylsilanes

A mixture of tert.-butyl ether (2-nitro-4-butylstannane) carbamino acid (525 mg, 1.0 mmol) [obtained from the corresponding tert.-butyl ether (4-iodine-2-nitrophenyl) carbamino acid (example B) (10 mmol) interaction with hexabutylditin 97,5 ml, 15 mmol) and Pd(PPh3)4(116 mg, 0.1 mmole) in toluene (20 ml) at 60°within 5 days in accordance with Bull. Chem. Soc. Jpn. 1983, 56, 3855-3856], arylhalides or vinestreet (0,95-6.0 mmol), anhydrous lithium chloride (126 mg, 3.0 mmole) and Pd(PPh3)4in DME (3 ml) was stirred at 100°in an argon atmosphere until the complete disappearance of stannane according to TLC. The reaction mixture was cooled to 23°C, stirred with saturated aqueous potassium fluoride (5 ml) for 45 is in, filtered through celite, washed with ether, the filtrate was dried over MgSO4. Removal of solvent in vacuo resulted in the formation of a brown oil, which was purified column chromatography on silica gel with hexane/ethyl acetate, receiving the connection specified in the header.

The following examples relate to the receipt of tert.-butyl ester of (2-amino-4-arelatively)karbinovykh acids in the form of pure regioisomers (scheme synthesis W).

General method L

Getting tert.-butyl ester (4-quinil-2-nitrophenyl)karbinovykh acid condensation Sonogashira tert.-butyl ester (4-iodine-2-nitrophenyl)karbinovykh acid derivative of acetylene: condensation Sonogashira tert.-butyl ester (4-ethinyl-2-nitrophenyl)karbinovykh acids with arylhalides and condensation Sonogashira 8-iodine-4-aryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones derived from acetylene

A mixture of halogen (3.0 to 4.5 mmole), a derivative of acetylene (3.0 to 4.5 mmole), triethylamine (13.5 mmol), PdCl2(PPh3)2(5 mol%) and PPh3(2,5% mol.) in THF (12 ml) [in the case of poorly soluble material could be added DMF (12 ml)] was stirred for 20 min at 23°in a stream of argon. Was added CuI (1,2% mol.) and continued stirring at 60°C in nitrogen atmosphere until complete conversion according to TLC smaller component [see J. Org. Chem.1998, 63, 8551]. A mixture of p is reasily into a separating funnel, was added 5% citric acid (50 ml), the product was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (50 ml) and saturated salt solution (50 ml), then dried over MgSO4. Removal of the solvent led to the formation of a yellow residue, which was purified column chromatography on silica gel with hexane/ethyl acetate and/or processed with hexane or water-ethanol, receiving the connection specified in the header.

Example H1

tert.-Butyl ester of (5-chloro-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-4-iodine-2-nitrophenyl)carbamino acid (example B1) (1.2 g, 3.0 mmole) and phenylacetylene (0.5 ml, 4.5 mmole) in accordance with the General method L Received this product as a yellow solid (944 mg).

MS (current IEO): 371 [(M-N)-] 373 [(M-N+2)-]; tpl.166-167°C.

Example C2

tert.-Butyl ester of (5-methyl-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methyl-2-nitrophenyl)carbamino acid (example B2) (1.13 g, 3.0 mmole) and phenylacetylene (0.5 ml, 4.5 mmole) in accordance with the General method of L. Received the product as a green-yellow solid (794 mg).

MS (EI): 352 (M+); tpl.161-164°C.

Example L3

tert.-Butyl ester of [5-(4-methylpiperid the Jn-1-yl)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(4-methylpiperazin-1-yl)-2-nitrophenyl]carbamino acid (example B1) (1,34 g, 3.0 mmole) and phenylacetylene (0.5 ml, 4.5 mmole) in accordance with the General method of L. Received the product as a green-yellow solid (1.1 g).

MS (EPI): 437 [(M+N)+]; tpl.170°C.

Example L4

tert.-Butyl ester of (5-morpholine-4-yl-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-morpholine-4-yl-2-nitrophenyl)carbamino acid (example B3) (890 mg, 2.0 mmole) and phenylacetylene (0.33 ml, 3.0 mmole) in accordance with the General method of L. Received the product as an orange solid (580 mg).

MS (EPI): 424 [(M+N)+]; tpl.190-191°C.

Example C5

tert.-Butyl ether (2-nitro-4-phenylethynyl-5-thiomorpholine-4-ylphenyl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-2-nitro-5-thiomorpholine-4-ylphenyl)carbamino acid (example B2) (1.0 g, 2.15 mmol) and phenylacetylene (0,36 ml, up 3.22 mmole) in accordance with the General method of L. Received the product as an orange solid (620 mg).

MS (EPI): 440 [(M+N)+] 462 [(M+Na)+]; tpl.201°C (decomp.).

Example L6

tert.-Butyl ester of [5-(1,1-diocletianopolis-4-yl)-2-nitro-4-phenylethylene]carbamino acid

Received in two stages as follows.

To a solution of tert.-Buti is a new ether (4-iodine-2-nitro-5-thiomorpholine-4-ylphenyl)carbamino acid (example B2) (465 mg, 1 mmol) in acetone (25 ml) and water (1 ml) was added 0.3 M solution of ammonium molybdate (0.3 ml) and 33% hydrogen peroxide (2.3 ml) at 0°and the mixture was stirred for 1 h at 23°C. was Obtained tert.-butyl ester of [5-(1,1-diocletianopolis-4-yl)-4-iodine-2-nitrophenyl]carbamino acid (497 mg, 1.0 mmol) as an amorphous yellow substance that was injected into the reaction with phenylacetylene (0.17 ml, 1.5 mmole) in accordance with the General method L Received this product as a yellow solid (245 mg).

MS (EPI): 472 [(M+N)+]; tpl.217-221°C.

Example L 7

tert.-Butyl ester of [5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-iodine-2-nitrophenyl]carbamino acid (example B4) (3.80 g, 7,53 mmole) and phenylacetylene (1,24 ml, 11.3 mmole) in accordance with the General method of L. Received the product as an orange solid (1.8 g).

MS (current IEO): 478 [(M-N)-]; tpl.179-180°C.

Example L

tert.-Butyl ester of [5-(2-dimethylaminoethanol)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-dimethylaminoethanol)-4-iodine-2-nitrophenyl]carbamino acid (example G1) (721 mg, and 1.54 mmole) and phenylacetylene (0.25 ml, 2,mole) in accordance with the General method of L. Received the product as an amorphous yellow what about the substance (595 mg).

MS (EPI): 442 [(M+N)+]; tpl.179-180°C.

Example L 9

Methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylenediamine)acetic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenylarsonic)acetic acid (example D2) (780 mg, 1,67 mmole) and phenylacetylene (with 0.27 ml, 2.5 mmole) in accordance with the General method of L. Received the product as an orange solid (700 mg).

MS (EPI): 460 [M+NH4)+]; tpl.125-127°C.

Example 10

tert.-Butyl ester of [5-(2-methoxyethoxy)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(2-methoxyethoxy)-2-nitrophenyl]carbamino acid (example B6) (876 mg, 2 mmole) and phenylacetylene (0.33 ml, 3 mmole) in accordance with the General method L Received this product as a yellow solid (569 mg).

MS (EPI): 413 [(M+N)+] 430 [(M+NH4)+]; tpl.118-119°C.

Example L

tert.-Butyl ester of (5-methoxy-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-methoxy-2-nitrophenyl)carbamino acid (example B5) (1.18 g, 3,00 mmole) and phenylacetylene (of 0.58 ml, 4.5 mmole) in accordance with the General method L Received this product as a yellow solid (1.1 g).

MS (EI): 368 (M+); tpl.129°C.

Example L

tert.-B is tilby ester [5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester [4-iodine-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitrophenyl]carbamino acid (example B7) (5.7 g, 10.0 mmol) and phenylacetylene (1.65 ml, 15 mmol) according to General method L. Received the product as a yellow oil (5.2 g).

MS (current IEO): 543 [(M-N)-].

Example L

tert.-Butyl ester of (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylene)acetic acid

Was obtained from tert.-butyl ether (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenoxy)acetic acid (example A1) (1,46 g, 2,99 mmole) and phenylacetylene (0,49 ml of 4.49 mmole) in accordance with the General method L Received this product as a yellow solid (1.4 g).

MS (EPI): 486 [M+NH4)+]; tpl.130°C.

Example L

(RS)-5-(2,2-Dimethyl[1,3]dioxolane-4-ylethoxy)-2-nitro-4-phenylethylenediamine

Received from (RS)-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-4-iodine-2-nitrophenylamino (example D5) (4.5 g, 11.4 mmole) and phenylacetylene (of 1.88 ml, 17.1 mmole) in accordance with the General method of L. Received the product as an orange solid (5.4 g).

MS (current IEO): 367 [(M-N)-]; tpl.147-149°C.

Example L

Methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethynyl)benzoic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitro)benzoic acid (example B3) (1.22 g, 2,89 mmole) and phenyl is ethene (of 0.48 ml, 4,34 mmole) in accordance with the General method L Received this product as a yellow solid (793 mg).

MS (EPI): 397 [(M+N)+] 414 [M+NH4)+]; tpl.173°C.

Example L

Methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylene)acetic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenyl)acetic acid (example V (R=CO2Me, R ' =Boc)) (1,32 g, 3,03 mmole) and phenylacetylene (0.5 ml, 4,55 mmole) in accordance with the General method L Received this product as a yellow solid (1.1 g).

MS (EPI): 411 [(M+N)+], 428 [M+NH4)+] 433 [(M+Na)+]; tpl.134°C.

Example L

tert.-Butyl ester of (5-cyanomethyl-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (5-cyanomethyl-4-iodine-2-nitrophenyl)carbamino acid (example b [V (R=CN, R ' =Boc)]) (3,97 g, 9,85 mmole) and phenylacetylene (3,24 ml, 29,56 mmole) in accordance with the General method of L. Received the product in a solid olive color (1.6 g).

MS (EPI): 395 [M+NH4)+]; tpl.166°C.

Example L

tert.-Butyl ether (RS)-[5-(2,3-dihydroxypropane)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether (RS)-[5-(2,3-dihydroxypropane)-4-iodine-2-nitrophenyl]carbamino acid (RO-68-5451/000 (3,23 g, 7,11 mmol), obtained from tre is.-butyl ether (5 allyloxy-4-iodine-2-nitrophenyl)carbamino acid (example B4) (4,20 g, 10.0 mmol) interaction with 4-methylmorpholine-4-oxide (1.28 g, 11.0 mmol), 2,5% solution of OsO4in tert.-butanol (1 ml, 0.1 mmole) and K2OsO4(40 mg, 0.1 mmole) in acetone (250 ml) and water (100 ml) at 23°C for 6 days) and phenylacetylene (1,17 ml, 10,67 mmole) in accordance with the General method L Received this product as a yellow solid (2,74 g).

MS (EPI): 429 [(M+N)+]; tpl.157°C (decomp.).

Example L

tert.-Butyl ester of (5-hydroxymethyl-2-nitro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid (example V) (2,61 g, 6,62 mmole) and phenylacetylene (1,10 ml, to 9.93 mmole) in accordance with the General method L Received this product as a yellow solid (1,76 g).

MS (EPI): 386 [M+NH4)+]; tpl.177°C (decomp.).

Example L

tert.-Butyl ester of [5-(4-methoxypiperidine-1-yl)-2-nitro-4-phenylethylene]carbamino acid

Was obtained from tert. -butyl ester [4-iodine-5-(4-methoxypiperidine-1-yl)-2-nitrophenyl]carbamino acid (example B5) (1.0 g, 2.1 mmole) and phenylacetylene (0,35 ml of 3.15 mmole) in accordance with the General method L Received this product as a yellow solid (799 mg).

tpl.147-150°C.

Example L

tert.-Butyl ester of (5-cyanoethoxy-2-nitro-4-phenylethylene)carbamino acid

Received is from tert.-butyl ether (5 cyanoethoxy-4-iodine-2-nitrophenyl)carbamino acid (example A2) (605 mg, 1.44 mmole) and phenylacetylene (0,24 ml of 2.16 mmole) in accordance with the General method L Received this product as a yellow solid (508 mg).

MS (EI) 393 (M+); tpl.170°C.

Example L

tert.-Butyl ester [4-(4-perforating)-5-hydroxymethyl-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of (5-hydroxymethyl-4-iodine-2-nitrophenyl)carbamino acid (example V) (2.00 g, 5,07 mmole) and 4-perforation (0,91 g,to 7.61 mmole) in accordance with the General method L Received this product as a yellow solid (1.55 g).

MS (current IEO) 385 [(M-N)-]; tpl.198°C.

Example L

tert.-Butyl ether (RS)-(4-(4-perforating)-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}-2-nitrophenyl)carbamino acid

Was obtained from tert.-butyl ether (RS)-(4-iodine-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}-2-nitrophenyl)carbamino acid [RO-69-3820/000, obtained from tert.-butyl ether {5-[(2-hydroxyethyl)methylamino]-4-iodine-2-nitrophenyl}carbamino acid (example B6) by treatment with 3,4-dihydro-2H-Piran and hydrate n-toluenesulfonic acid as catalyst in DHM at 0°] (2,09 g, 4,01 mmole) and 4-perforation (0,72 g, 6.02 mmole) in accordance with the General method of L. Received the product as a yellow-brown solid (1.84 g).

MS (EPI) 514 [(M+N)+]; tpl.134°C.

Example L

tert.-the Hotelowy ether (RS)-{2-nitro-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{4-iodine-2-nitro-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid (example U3) (743 mg, of 1.46 mmole) and phenylacetylene (of 0.24 ml, 2,19 mmole) in accordance with the General method of L. Received the product as a yellow-brown viscous oil (429 mg).

MS (EI) 393 (M+).

Example 25

tert.-Butyl ester of [5-(2-tert.-butoxyethoxy)-4-(4-perforating)-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-tert.-butoxyethoxy)-4-iodine-2-nitrophenyl]carbamino acid (example ± 10) (1.44 g, 3.0 mmole) and 4-perforation (541 mg, 4.5 mmole) in accordance with the General method L Received this product as a yellow solid (777 mg).

MS (EI) 472 (M+); tpl.96-98°C.

Example L

tert.-Butyl ester of [5-tert.-butoxy-4-(4-perforating)-2-nitrophenyl]carbamino acid

Was obtained from tert.-butyl ether (5-tert.-butoxy-4-iodine-2-nitrophenyl)carbamino acid (example A4) (1.40 g, is 3.21 mmole) and 4-perforation (0.66 g, 5,46 mmole) in accordance with the General method of L. Received the product as a brown solid (520 mg).

MS (EI) 428 (M+); tpl.201°C.

A common way M

Getting tert.-butyl ester of (2-AMINOPHENYL)karbinovykh acid recovery tert.-butyl ester of (2-nitrophenyl)karbinovykh acid; obtaining a 4-aryl-1,dihydrobenzo[b][1,4]diazepin-2-ones recovery concomitant cyclization of 3-aryl-N-(2-nitrophenyl)-3-oxopropionate

Method a: catalytic hydrogenation

A mixture of nitro-derivatives (1.0 mmol) in methanol or ethanol and THF (1:1, about 20 ml) and 10% Pd/C (20 mg) or Ni-Raney (20 mg) was intensively stirred at 23°C in an atmosphere of hydrogen until complete conversion according to TLC. The catalyst was separated by filtration, thoroughly washed with methanol or ethanol and THF (1:1), the solvent was removed in vacuum, obtaining the connection specified in the header, which, as a rule, was pure enough for further transformations.

Method b: restore with SnCl2·2H2O

A mixture of nitro-derivatives (1.0 mmol) and SnCl2·2H2O (5.0 mmol) or stirred in ethanol (30 ml) at 70-80°or alternatively in pyridine (3 ml) and DMF (12 ml) at 23°in argon atmosphere until complete conversion according to TLC [see Tetr. Lett. 1984, 25, 839]. In the reaction mixture has set pH 8 by adding saturated sodium bicarbonate solution, extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated saline and dried over Na2SO4. Removal of the solvent led to the formation of a yellow solid, which if necessary, can be purified column chromatography on silica gel.

Method: the recovery of Zn and ammonium chloride

To a mixture of nitro-derivatives (1.0 mmol) in ethanol/THF/feast upon nom solution of ammonium chloride (1:1:1, 30 ml) was added zinc dust (3.0 mmole), the mixture was stirred at 70°in argon atmosphere until complete conversion according to TLC. Water treatment was performed as described in method B.

Method g: the Recovery of Fe and acetic acid

To a mixture of nitro-derivatives (1.0 mmol) and THF/water (4:1, 10-50 ml) was added iron powder (6.0 mmol), the mixture was stirred at 70°in argon atmosphere until complete conversion according to TLC. Water treatment was performed as described in method B.

Example M1

tert.-Butyl ether (2-amino-4-iodine-5-thiomorpholine-4-ylphenyl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-2-nitro-5-thiomorpholine-4-ylphenyl)carbamino acid (example B2) (1,05 g, 2.25 mmole) restoring SnCl2·2H2O (2,54 g, 11.3 mmole) in accordance with the General method M (method b). Received the product as a pale yellow solid (993 mg).

MS (EPI): 436 [(M+N)+]; tpl.125-127°C.

Example M2

tert.-Butyl ether (2-amino-4-iodine-5-morpholine-4-ylphenyl)carbamino acid

Was obtained from tert.-butyl ether (4-iodine-5-morpholine-4-yl-2-nitrophenyl)carbamino acid (example B3) (753 mg, 1.65 mmole) restoring SnCl2·2H2O (1.9 grams, 8,27 mmole) in accordance with the General method M (method b). Received the product as yellow solid (696 mg).

MS (EPI): 420 [(M+N)+]; tpl.39-143° C.

Example M3

tert.-Butyl ether (2-amino-5-chloro-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ester of (5-chloro-2-nitro-4-phenylethylene)carbamino acid (example C1) (742 mg, 2.0 mmole) restoring SnCl2·2H2O (2,245 g, 10 mmol) according to General method M (method b). Received the product as an orange solid (483 mg).

MS (EPI): 343 [(M+N)+] 345 [(M+2+N)+].

Example M4

tert.-Butyl ether (2-amino-5-methyl-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ester of (5-methyl-2-nitro-4-phenylethylene)carbamino acid (example C2) (741 mg, 2.1 mmole) restoring SnCl2·2H2O (2.37 g, 10.3 mmole) in accordance with the General method M (method b). Received the product as light brown solid (419 mg).

MS (EPI): 323 [(M+N)+]; tpl.172-173°C.

Example M5

tert.-Butyl ester of [2-amino-5-(4-methylpiperazin-1-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(4-methylpiperazin-1-yl)-2-nitro-4-phenylethylene]carbamino acid (example C3) (1.08 g, 2,48 mmole) restoring SnCl2·2H2O (2.8 g, 12.4 mmole) in accordance with the General method M (method b). Received the product as an orange solid (1.0 g).

MS (EPI): 407 [(M+N)+]; tpl.81-85°C

Example M6

tert.-Butyl ester of (5-amino-2-chlorobiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-chloro-5-nitrobiphenyl-4-yl)carbamino acid (example E1) (783 mg, of 2.24 mmole) restoring SnCl2·2H2O (2,53 g, 11.2 mmole) in accordance with the General method M (method b). Received the product as yellow solid (684 mg).

MS (EI): 318 (M+and 320 [(M+2)+]; tpl.109-111°C.

Example M7

tert.-Butyl ester of (5-amino-2-methylbiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-methyl-5-nitrobiphenyl-4-yl)carbamino acid (example E2) (921 mg, 2.8 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a white solid (796 mg).

MS (EI): 298 (M+); tpl.122°C.

Example M8

tert.-Butyl ester of [2-amino-5-(2-dimethylaminoethanol)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-dimethylaminoethanol)-2-nitro-4-phenylethylene]carbamino acid (example L) (551 mg, 1.25 mmole) restoring SnCl2·2H2On (1,41 g of 6.25 mmole) in accordance with the General method M (method b). Received the product as an orange foam (510 mg).

MS (EPI): 412 [(M+N)+]; tpl.115-117°C.

Example M9

Methyl ester of (4-amino-5-tert.-butoxy is ebonyline-2-phenylethylenediamine)acetic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylenediamine)acetic acid (example L 9) (634 mg, 1,43 mmole) restoring SnCl2·2H2O (1,62 g, 7,16 mmole) in accordance with the General method M (method b). Received the product as an orange resinous substance (590 mg).

MS (EPI): 413 [(M+N)+], 435 [(M+Na)+] 451 [(M+K)+].

Example M10

Methyl ester of (4-amino-5-tert.-butoxycarbonylamino-2-phenylethylene)acetic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylene)acetic acid (example L) (1,09 g of 2.66 mmole) restoring SnCl2·2H2Oh (3.00 g, 13,28 mmole) in accordance with the General method M (method b). Received the product as a pale yellow solid (900 mg).

MS (EPI): 381 [(M+N)+] 403 [(M+Na)+]; tpl.130°C.

Example M11

tert.-Butyl ester of [2-amino-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-methoxyethoxy)-2-nitro-4-phenylethylene]carbamino acid (example 10) (1,417 g, 3,44 mmole) restoring SnCl2·2H2(3.88 g, 17.2 mmole) in accordance with the General method M (method b). Received the product in the form of not-quite-white solid (1.04 g).

MS (EI): 382 (M+); tpl.105-107°C.

Example M12

Proc. of the so-Butyl ether (2-amino-5-morpholine-4-yl-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (5-morpholine-4-yl-2-nitro-4-phenylethylene)carbamino acid (example L4) (563 mg, 1,329 mmole) restoring SnCl2·2H2About (1.5 g, of 6.65 mmole) in accordance with the General method M (method b). Received the product as a red-brown solid (488 mg).

MS (EPI): 394 [(M+N)+]; tpl.174-176°C.

Example M13

tert.-Butyl ether (2-amino-5-methoxy-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ester of (5-methoxy-2-nitro-4-phenylethylene)carbamino acid (example L) (1,00 g, a 2.71 mmole) restoring SnCl2·2H2(A 3.06 g, 13,57 mmole) in accordance with the General method M (method b). Received the product as yellow solid (870 mg).

MS (EI): 338 (M+); tpl.158°C.

Example M14

Methyl ester of (4-amino-5-tert.-butoxycarbonylamino-2-phenylethyl)benzoic acid

Was obtained from methyl ester (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethynyl)benzoic acid (example L) (754 mg, 1,90 mmole) restoring SnCl2·2H2(2.15 g, of 9.51 mmole) in accordance with the General method M (method b). Received the product as a pink solid (431 mg).

MS (EI): 366 (M+); tpl.164°C.

Example M15

tert.-Butyl ester of [2-amino-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-4-phenylethynyl the Il]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-2-nitro-4-phenylethylene]carbamino acid (example L) (3.0 g, 5,51 mmole) restoring SnCl2·2H2Of (6.2 g, 27,54 mmole) in accordance with the General method M (method b). Received the product as a brown oil (2.9 g).

MS (EPI): 515 [(M+N)+].

Example M16

tert.-Butyl ether (4-amino-5-tert.-butoxycarbonylamino-2-phenylethylene)acetic acid

Was obtained from tert.-butyl ether (5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylene)acetic acid (example L) (1,32 g, 2,82 mmole) restoring SnCl2·2H2(3,18 g, 14,10 mmole) in accordance with the General method M (method b). Received the product in the form amorphous orange substance (1.2 g).

MS (EPI): 439 [(M+N)+] 461 [(M+Na)+].

Example M17

tert.-Butyl ether (2-amino-5-cyanomethyl-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (5-cyanomethyl-2-nitro-4-phenylethylene)carbamino acid (example L) (377 mg, 1.0 mmol) restoring SnCl2·2H2O (1.13 g, 5.0 mmol) according to General method M (method b). Received the product as an orange solid (338 mg).

MS (EPI): 348 [(M+N)+] 370 [(M+Na)+]; tpl.143°C.

Example M18

tert.-Butyl ester of [2-amino-5-(1,4-dioxa-8-Aza the Piro[4.5]Dec-8-yl)-4-phenylethylene]carbamino acid and tert.-butyl ester of [2-amino-5-(4,4-detoxificatin-1-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2-nitro-4-phenylethylene]carbamino acid (example L 7) (1.73 g, 3.6 mmole) restoring SnCl2·2H2Oh (4.0 g, 18.0 mmol) in ethanol in accordance with the General method M (method b). Received the product as a brown solid (418 mg) in the form of a dark brown solid (379 mg), respectively.

MS (EPI): 450 [M+N)+]; tpl.79-82°C; MS (EPI): 480 [(M+N)+]

Example M19

tert.-Butyl ester of [2-amino-5-(1,1-dioxo-6-thiomorpholine-4-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(1,1-dioxo-6-thiomorpholine-4-yl)-2-nitro-4-phenylethylene]carbamino acid (example L6) (235 mg, 0.5 mmole) restoring SnCl2·2H2On (564 mg, 2.5 mmole) in accordance with the General method M (method b). Received the product as a brown solid (418 mg, the crude material was used directly in example 6 without purification and characterization).

Example M20

tert.-Butyl ester of [2-amino-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid.

Was obtained from tert.-butyl ether (RS)-[5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-2-nitro-4-phenylethylene]carbamino acid (example B8) (1.90 g, 4,06 mmole) restoring SnCl2·2H2O (4.6 g, 20,32 mmole) in accordance with the General method M (method b). In the crude product was again introduced protective group, mixing with 2,2-dimethoxypropane (5 ml) and hydrate n-toluenesulfonic acid (1.1 EQ.) in DMF (5 ml) at 23°C for 4 h Received this product as a brown solid (1.1 g).

MS (EPI): 439 [(M+N)+], 461 [(M+Na)+] 477 [(M+K)+].

Example M21

Methyl ester of 4-amino-5-tert.-butoxycarbonylamino-2-identies acid

Was obtained from 5-tert.-butoxycarbonylamino-2-iodine-4-nitrobenzoic acid (example B3) (3.00 g, 7,11 mmole) restoring SnCl2·2H2O (8,02 g, 35,55 mmole) in accordance with the General method M (method b). Received the product as a light red foam (1.9 g).

MS (EPI): 393 [(M+N)+]; tpl.60-78°C.

Example M22

tert.-Butyl ether (RS)-[2-amino-5-(2-oxo[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-nitro-5-(2-oxo[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid [RO-68-8108/000 (411 mg, 0.9 mmole)was obtained from tert.-butyl ether (RS)-[5-(2,3-dihydroxypropane)-2-nitro-4-phenylethylene]carbamino acid (example L) by treatment with 1,1'-carbonyl diimidazol in THF at 0-23°] restoring SnCl2·2H2O (1,02 g, 4.5 mmole) in accordance with the General method M (method b). Received the product in the form of solids apricot color (370 mg).

MS (the EP): 425(M+H) +]; tpl.140°C.

Example M23

tert.-Butyl ether (2-amino-5-ethoxymethyl-4-phenylethylene)carbamino acid

Was obtained from methyl ester 5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylperoxo ester of carbonic acid [RO-68-8481/000, obtained from tert.-butyl ester of (5-hydroxymethyl-2-nitro-4-phenylethylene)carbamino acid (example L) treatment with methylchloroform and triethylamine in THF at 0°] restoring SnCl2·2H2In accordance with the General method M (method b). Received the product in the form of amorphous material, brown (139 mg).

MS (EPI): 367 [(M+N)+].

Example M24

4-Amino-5-tert.-butoxycarbonylamino-2-phenylethylenediamine ether of 2,2-dimethylpropionic acid

Was obtained from 5-tert.-butoxycarbonylamino-4-nitro-2-phenylethylperoxo ether of 2,2-dimethylpropionic acid [RO-68-9779/000, obtained from tert.-butyl ester of (5-hydroxymethyl-2-nitro-4-phenylethylene)carbamino acid (example L) treatment with revalorisation, DMAP as a catalyst in pyridine at 0-23°] restoring SnCl2·2H2In accordance with the General method M (method b). Received the product as an amorphous yellow substance (182 mg).

MS (current IEO): 421 [(M-N)-].

Example M25

tert.-Butyl ether (RS)-[2-amino-4-phenylethynyl-5-(tetrahydropyran-2-oxymethyl)phenyl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-nitro-4-phenylethynyl-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid [RO-69-2829/000, obtained from tert.-butyl ester of (5-hydroxymethyl-2-nitro-4-phenylethylene)carbamino acid (example L) by treatment with 3,4-dihydro-2H-Piran and as the catalyst, hydrate, n-toluenesulfonic acid in DHM at 0°] restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as yellow solid (1.78 g).

MS (current IEO): 421 [(M-N)-]; tpl.158°C.

Example M26

tert.-Butyl ester of [2-amino-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ester of [5-(4-methoxypiperidine-1-yl)-2-nitro-4-phenylethylene]carbamino acid (example L) (727 mg, of 1.61 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as yellow solid (489 mg).

MS (EPI): 422 [(M+N)+]; tpl.173-176°C.

Example M27

tert.-Butyl ether (2-amino-5-cyanoethoxy-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (5 cyanoethoxy-2-nitro-4-phenylethylene)carbamino acid (example L) (395 mg, of 0.91 mmole) restoring SnCl2·2H2In accordance with the General method M (method b). Produces the product as an amorphous yellow substance (219 mg).

MS (EPI): 364 [(M+N)+].

The example covered by M28

tert.-Butyl ether (RS)-[2-amino-4-(4-perforating)-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[4-(4-perforating)-2-nitro-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid [RO-69-3877/000, obtained from tert.-butyl ester [4-(4-perforating)-5-hydroxymethyl-2-nitrophenyl]carbamino acid (example L) by treatment with 3,4-dihydro-2H-Piran and as a catalyst for the hydrate p-toluenesulfonic acid in DHM at 0°] restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as an amorphous light brown substance (990 mg).

MS (EPI): 441 [(M+N)+].

Example M29

tert.-Butyl ether (RS)-(2-amino-4-(4-perforating)-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}phenyl)carbamino acid

Was obtained from tert.-butyl ether (RS)-(4-(4-perforating)-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}-2-nitrophenyl)carbamino acid (example L) (1,79 g, 3,49 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as an amorphous light brown substance (1.20 g).

MS (EPI): 484 [(M+N)+].

Example M30

tert.-Butyl ether (RS)-{2-amino-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}CT the amine acid

Was obtained from tert.-butyl ether (RS)-{2-nitro-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid (example L) (420 mg, of 0.87 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as light brown solid (346 mg).

MS (EPI): 453 [(M+N)+].

Example M31

tert.-Butyl ether (RS)-{5-amino-4'-fluoro-2-[4-(tetrahydropyran-2-yloxy)piperidine-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{4'-fluoro-5-nitro-2-[4-(tetrahydropyran-2-yloxy)piperidine-1-yl] - biphenyl-4-yl}carbamino acid (example E3) (845 mg, of 1.64 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a pale green solid (758 mg).

MS (EPI): 486 [(M+N)+]; tpl.157-161°C.

Example M32

tert.-Butyl ester of [2-amino-5-(2-tert.-butoxyethoxy)-4-(4-perforating)phenyl]carbamino acid

Was obtained from tert.-butyl ester of [5-(2-tert.-butoxyethoxy)-4-(4-perforating)-2-nitrophenyl]carbamino acid (example 25) (744 mg, of 1.57 mmole) recovery c SnCl2·2H2O in accordance with the General method M (method b). Received the product as a pale yellow solid (575 mg).

MS (EPI): 443 [(M+N)+]; tpl.149-150°C.

Example m

tert.-Buti the new ester of (RS)-(5-amino-4'-fluoro-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino acid.

Was obtained from tert.-butyl ether (RS)-(4'-fluoro-5-nitro-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino acid (example E4) (900 mg, of 1.61 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a light brown foam (779 mg).

MS (EPI): 530 [(M+N)+]; tpl.56-58°C.

Example M

tert.-Butyl ether (RS)-[5-amino-4'-fluoro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[4'-fluoro-5-nitro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid (example E5) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as an orange solid (1,15 g).

tpl.139-142°C.

Example M35

tert.-Butyl ester of (5-amino-2-cyanoethoxy-4'-forbiden-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-cyanoethoxy-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example E6) (310 mg, 0.8 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as light brown solid (220 mg).

MS (current IEO): 356 [(M-N)-]; tpl.118-119°C.

Example m

tert.-Butyl ester of (5-amino-2-dimethylaminomethyl-4'-forbiden-4-yl)carbamino sour is you

Was obtained from tert.-butyl ether (2-dimethylaminomethyl-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example E7) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as yellow solid (908 mg).

tpl.97-125°C.

Example M

tert.-Butyl ester of [5-amino-2-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4'-forbiden-4-yl]carbamino acid

Was obtained from tert.-butyl ether [2-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid (example E8) (610 mg, of 1.29 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product in the form of not-quite-white foam (578 mg).

MS (EPI): 444 [(M+N)+].

Example M38

tert.-Butyl ester of (5-amino-4'-fluoro-2-methoxybiphenyl-4-yl) carbamino acid

Was obtained from tert.-butyl ether (4'-fluoro-2-methoxy-5-nitro-biphenyl-4-yl) carbamino acid (example e) (2.64 g, 7,29 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product in the form of not-quite-white solid (2.36 in).

MS (EPI): 333 [(M+N)+]; tpl.155°C (decomp.).

Example m

tert.-Butyl ester of [5-amino-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-4'-forbiden-4-yl]carbamino acid

Was obtained from tert.-butyl is Fira [2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid (example E10) (2.4 g, 5.0 mmol) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a green solid (2.37 g).

MS (EPI): 444 [(M+N)+].

Example M40

tert.-Butyl ester of (5-amino-4'-fluoro-2-methylbiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4'-fluoro-2-methyl-5-nitrobiphenyl-4-yl)carbamino acid (example E11) (560 mg, of 1.62 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as light brown solid (512 mg).

MS (EPI): 317 [(M+N)+]; tpl.112°C.

Example M41

tert.-Butyl ester of (5-amino-4-tert.-butoxycarbonylamino-4'-forbiden-2-yloxy)acetic acid

Was obtained from tert.-butyl ether (4-tert.-butoxycarbonylamino-4'-fluoro-5-nitrobiphenyl-2-yloxy)acetic acid (example E12) (to 2.29 g of 4.95 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a dark blue solid (2.14 g).

MS (EPI): 433 [(M+N)+]; tpl.30-33°C.

Example M42

tert.-Butyl ester of (5-amino-2-chloro-4'-forbiden-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-chloro-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example E13) restoring SnCl2·2H2O in accordance with the General method M (method b) Received the product as a light red solid (544 mg).

MS (EPI): 337 [(M+N)+].

Example M

tert.-Butyl ester of [5-amino-4'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether [4'-fluoro-2-(2-methoxyethoxy)-5-nitrobiphenyl-4-yl]carbamino acid (example E14) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as light brown solid (1,652 g).

MS (EPI): 377 [(M+N)+].

Example M44

tert.-Butyl ester of [5-amino-2-(2-tert.-butoxyethoxy)-4'-forbiden-4-yl]carbamino acid

Was obtained from tert.-butyl ether [2-(2-tert.-butoxyethoxy)-4'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid (example E15 motorway) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a purple solid (547 mg).

MS (EPI): 419 [(M+N)+]; tpl.133°C (decomp.).

Example M45

tert.-Butyl ester of [5-amino-4'-fluoro-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether [4'-fluoro-5-nitro-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid (example e) (280 mg, 0.67 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as yellow solid (277 mg).

MS (EPI): 388 [(M+N)+]; tpl.210°C.

Example M46

tert.-Putilov the th ether (5-amino-4'-fluoro-2-methoxy-2'-methylbiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (4'-fluoro-2-methoxy-2'-methyl-5-nitrobiphenyl-4-yl)carbamino acid (example E17) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a brown solid (588 mg).

MS (EPI): 347 [(M+N)+].

Example m

tert.-Butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-tert.-butoxy-4'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example E18) (1,15 g, 2,84 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a pink solid (747 mg).

MS (EPI): 375 [(M+N)+]; tpl.139°C.

Example M48

tert.-Butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-tert.-butoxy-2'-fluoro-5-nitrobiphenyl-4-yl)carbamino acid (example E19) (930 mg, 2.3 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a pink solid (649 mg).

MS (EPI): 375 [(M+N)+]; tpl.130°C.

Example M49

tert.-Butyl ether (RS)-{5-amino-4'-fluoro-2-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{4'-fluoro-5-nitro-2-[(R)-3-(Tetra is Agropyron-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl}carbamino acid (example E20) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a dark green solid (852 mg).

MS (EPI): 472 [(M+N)+].

Example M50

tert.-Butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2'-fluoro-2-methoxy-5-nitrobiphenyl-4-yl)carbamino acid (example E21) (649 mg, to 1.79 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as light brown solid (352 mg).

MS (EPI): 333 [(M+N)+]; tpl.161°C.

Example M51

tert.-Butyl ester of [5-amino-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-forbiden-4-yl]carbamino acid

Was obtained from tert.-butyl ether [2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-fluoro-5-nitrobiphenyl-4-yl]carbamino acid (example E22) (1.39 g, to 2.94 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a light beige solid (1.01 g).

MS (EPI): 444 [(M+N)+]; tpl.198°C.

Example M52

tert.-Butyl ester of (5-amino-2',5'-debtor-2-methoxybiphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2',5'-debtor-2-methoxy-5-nitrobiphenyl-4-yl)carbamino acid (example e) (1,05 g, was 2.76 mmole) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product in the form of a beige solid substances is TBA (618 mg).

MS (current IEO): 349 [(M-N)-]; tpl.144°C.

Example M53

tert.-Butyl ester of [5-amino-2'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether [2'-fluoro-2-(2-methoxyethoxy)-5-nitrobiphenyl-4-yl]carbamino acid (example I) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product as a purple solid (2,581 g).

Example M54

tert.-Butyl ether (RS)-[5-amino-2'-fluoro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[2'-fluoro-5-nitro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid (example E25) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as a yellow liquid (2,676 g).

MS (EPI): 439 [(M+Na)+].

Example M55

tert.-Butyl ester of [5-amino-2'-fluoro-2-(4-methoxybenzyloxy)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether [2'-fluoro-2-(4-methoxybenzyloxy)-5-nitrobiphenyl-4-yl]carbamino acid (example E25) (0,90 g of 1.92 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as a beige solid (719 mg).

MS (EPI): 439 [(M+N)+].

Example M56

tert.-Butyl ester of (5-amino-2-tert.-butoxy-2',5'-ditto is biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (2-tert.-butoxy-2',5'-debtor-5-nitrobiphenyl-4-yl)carbamino acid (example E27) by catalytic hydrogenation with Pd/C in accordance with the General method M (method a). Received the product in the form of amorphous blue-gray matter (2.37 g).

MS (EPI): 393 [(M+N)+].

Example m

tert.-Butyl ester of [2-amino-5-tert.-butoxy-4-(4-perforating)phenyl]carbamino acid

Was obtained from tert.-butyl ester of [5-tert.-butoxy-4-(4-perforating)-2-nitrophenyl]carbamino acid (example E) (649 mg and 1.51 mmole) restoring SnCl2·2H2O in accordance with the General method M (method b). Received the product as a pale yellow solid (410 mg).

MS (EPI): 399 [(M+N)+]; tpl.183°C.

The following examples relate to obtaining ethyl or tert.-butyl esters of 3-aryl-3-oxopropionate acids (General formula VIla), which serve as structural blocks in the synthesis of the target compounds (synthesis scheme C).

A common way N

Method: obtain ethyl or tert.-butyl esters of 3-aryl-3-oxopropionate acids

Ethyl or tert.-butyl esters of 3-aryl-3-oxopropionate acids were obtained from acid chlorides arolovich acids and the potassium salt of ethyl or tert.-butyl ester of malonic acid [CAS-6148-64-7 and 75486-33-8] in the presence of triethylamine and magnesium dichloride in Aceto is nitrile when 0-23° In accordance with the Synthesis 1993, 290. If this reaction used free arylcarbamoyl acid, carboxyl before interaction with salt malonate activated by treatment with etelcharge.com and triethylamine in a mixture of THF/acetonitrile at 0°C.

Method b): obtain tert.-butyl esters of 3-aryl-3-oxopropionate acids

Alternative tert.-butyl esters of 3-aryl-3-oxopropanoic acid was obtained from methyl or ethyl esters arylcarbamoyl acid interaction with lithium tert.-the butyl acetate (obtained by the interaction of tert.-butyl acetate with diisopropylamide lithium in THF at -78° (C) in the presence of tert.-of butyl lithium in accordance with the Synthesis 1985, 45. If the product after treatment contained unreacted starting material, it could be removed by selective saponification with lithium hydroxide in a mixture of THF/methanol/water at 23°C.

Method: obtaining 3-aryl-3-oxopropionate acids

Received 3-aryl-3-oxopropionate acid from acid chlorides arylcarboxylic acids and bis(trimethylsilyl)malonate with triethylamine and lithium bromide in acetonitrile at 0°in accordance with the Synth. Commun. 1985, 15, 1039 (method B1) or with n-butyllithium in ether at -60°0°in accordance with the Synthesis 1979, 787 (method B2).

Example H1

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

RO-71-2790/000

Was obtained from 3-[1,2,4]triazole-4-eventing acid [RO-71-1432/000, obtained by the interaction of 3-aminobenzoic acid with hydrazine hydrate and triethylorthoformate in acetic acid at 120°] by activation etelcharge.com/triethylamine and interaction with the potassium salt of the ethyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product as 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

Was obtained from 3-[1,2,3]triazole-1-eventing acid [RO-71-3703/000, obtained by heating in boiling methyl ester 3-azidobenzoyl acid [CAS-No. 93066-93-4] trimethylsilylacetamide with subsequent saponification with an aqueous solution of sodium hydroxide in ethanol at boiling] by activation etelcharge.com/triethylamine and interaction with the potassium salt of the ethyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product 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

Was obtained from methyl ester 3-cyanobenzoyl key is lots [CAS-No. 13531-48-1] by treatment with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a light brown oily semi-solid substance.

MS (EI): 245 (M+).

Example H4

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

Received from the methyl ester of 3-(1H-imidazol-1-yl)benzoic acid [obtained from 3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30, 1342) [CAS-No. 108035-47-8] by heating at boiling in a mixture of concentrated sulphuric acid/methanol] by treatment with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as an orange-brown oil.

MS (EPI): 287 [(M+N)+].

Example H5

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

Was obtained from hydrochloride of the acid chloride of 2-imidazol-1-isonicotinic acid [obtained by the interaction of tert.-butyl ether 2-chlorisondamine acid with imidazole and sodium hydride in DMF at 80°With, by treatment with formic acid at 50°and by reaction with thionyl chloride in toluene at 100°] and the potassium salt of tert.-butyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product as a brown solid (10.8 g).

MS (EI): 287 (M+); tpl.80°C (decomp.).

Example N6

tert.-Butyl ether 3-oxo-3-(3-[1,2,4]three the evils-1-ylphenyl)propionic acid

Received from the methyl ester of 3-[1,2,4]triazole-1-eventing acid [CAS-No. 167626-27-9] by treatment with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as an orange liquid (2,41 g).

MS (EI): 287 (M+).

Example H7

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

Received from the methyl ester of 3-(4-Mei-1-yl)benzoic acid [RO-69-6483/000, getting the appropriate acid from 3-isothiocyanatobenzene acid and dimethylacetal 2-aminopropionitrile in accordance with J. Med. Chem. 1987, 30, 1342, followed by heating at boiling in a mixture of concentrated sulphuric acid/methanol] by treatment with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a yellow-brown oil (10,69 g).

MS (EI): 300 (M+).

Example H8

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

Received from the ethyl ester of 3-(2-Mei-1-yl)benzoic acid [RO-69-7480/000, obtained by the interaction of ethyl ester of 3-aminobenzoic acid hydrochloride of ethylacetamide in ethanol at 0°With immediate treatment with diethylacetal of aminoacetaldehyde in ethanol at 23°C, followed by addition of concentrated sulfuric acid and heated at boiling] interaction with l the tie-tert.-the butyl acetate according to General method N. (method b). Received the product as a brown oil (9,66 g).

MS (current IEO): 299 [(M-N)-].

Example H9

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

Received from the ethyl ester of 3-(2,4-dimethylimidazole-1-yl)benzoic acid [RO-71-05 83/000 obtained by the interaction of ethyl ester of 3-aminobenzoic acid hydrochloride of ethylacetamide in ethanol at 0°With immediate treatment with dimethylacetal 2-aminopropionitrile in ethanol at 23°C, followed by addition of concentrated sulfuric acid and heated at boiling] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a yellow-brown oil (6,00 g).

MS (current IEO): 313 [(M-N)-].

Example N10

tert.-Butyl ether 3-(2-cyano-4-yl)-3-oxopropanoic acid

Received from the ethyl ester of 2-lanoitanretni acid [CAS-No. 58481-14-4] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as light brown solid (7,70 d).

MS (current IEO): 245 [(M-N)-].

Example H11

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

Received from the methyl ester of 3-[1,2,4]triazole-4-eventing acid [obtained by the interaction of 3-aminobenzoic acid with hydrazine-Hydra is the fact and triethylorthoformate in acetic acid at 120° With, accompanied by etherification with concentrated sulfuric acid in methanol at boiling] by treatment with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a pale yellow resin (870 mg).

MS (current IEO): 286 [(M-N)-].

Example H12

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

Received from the ethyl ester of 3-(2-ethoxymethyleneamino-1-yl)benzoic acid [obtained by esterification of 3-(2-ethoxymethyleneamino-1-yl)benzoic acid [CAS-No. 108035-46-7] with concentrated sulfuric acid in ethanol followed by treatment with chloromethylation ether and sodium hydride in THF/DMF] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as an orange oil (1,82 g).

MS (EI): 362 (M+).

Example H13

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

Received from the ethyl ester of 3-(2-methylsulfonylamino-1-yl)benzoic acid [obtained by esterification of 3-(2-ethoxymethyleneamino-1-yl)benzoic acid [CAS-No. 108035-46-7] with concentrated sulfuric acid in ethanol followed by treatment with iodine stands and sodium hydride in THF/DMF] interaction with lithium tert.-the butyl acetate in accordance with bsim way H (method b). Received the product as a light brown oil (to 4.41 g).

MS (EPI): 333 [(M+N)+].

Example H14

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

Received from the ethyl ester of 3-(3-methylisoxazol-5-yl)benzoic acid [obtained by the interaction of ethyl ester of 3-ethynylbenzene acid [CAS-No. 178742-95-5] with a mixture of N-chlorosuccinimide (NCS), acetaldoxime, triethylamine and a catalytic amount of pyridine in chloroform at 50°in accordance with Tetrahedron 1984, 40, 2985-2988] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as yellow solid (2.54 g).

MS (EPI): 302 [(M+N)+]; tpl.50-56°C.

Example H15

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

Was obtained from 3-tetrazol-1-eventing acid [CAS-No. 2044196-80-5] by activation etelcharge.com/triethylamine and interaction with the potassium salt of the ethyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product as a pale yellow solid (211 mg).

MS (EI): 260 (M+).

Example H16

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

Was obtained from 3-chloro-2-thiophenecarbonitrile [CAS-No. 86427-02-3] interaction with potassium is Carney ethyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product 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

Received from the ethyl ester of 5-cyano-2-thiophencarboxylic acid [CAS-No. 67808-35-9] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as yellow solid (6,66 g).

MS (EI): 251 (M+); tpl.78°C.

Example n

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

Obtained from the acid chloride of 5-cyano-2-fermenting acid [obtained from the corresponding acid [CAS-No. 146328-87-2] by treatment with thionyl chloride and a catalytic amount of DMF in toluene at 80°] interaction with the potassium salt of the ethyl ester of malonic acid in the presence of triethylamine and magnesium dichloride in acetonitrile according to General method N. (method a). Received the product 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

Received from the ethyl ester of 2-imidazol-1-iltiazem-4-carboxylic acid [CAS-No. 256420-32-3] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as an orange oil (12,0 is).

Example H20

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

Received from the ethyl ester of 2-(4-Mei-1-yl)thiazole-4-carboxylic acid [obtained from the ethyl ester of 2-amino-4-thiazolecarboxamide acid [CAS-No. 256420-32-3] by the following synthetic sequence: 1) sodium hydride, 2-isothiocyanato-1,1-dimethoxypropane, DMF, 23°; 2) an aqueous solution of sulfuric acid at boiling; 3) ethanol, sulfuric acid, 23°S; 4) 30% hydrogen peroxide, acetic acid on 23°] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a brown oil (8,73 g).

MS (EI): 307 (M+).

Example n

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

Received from the ethyl ester of 3-(1-methyl-1H-imidazol-2-yl)benzoic acid [CAS-No. 168422-44-4] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received the product as a pale yellow liquid (1.26 g).

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

The following examples relate to the obtaining of 6-aryl-2,2-dimethyl[1,3]dioxin-4-ones (General formula (VII), which serve as structural blocks in the synthesis of the target compounds (synthesis scheme C).

A common way Of

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

Method and

Received 6-ar the l-2,2-dimethyl[1,3]dioxin-4-ones of the 3-aryl-3-oxopropanoic acid and catalytic amounts of concentrated sulfuric acid or triperoxonane acid (TFA) in isopropenylacetate at 23° In accordance with Chem. Pharm. Bull. 1983, 31, 1896. The final products were purified column chromatography on silica gel with hexane/ethyl acetate.

Method b

Received 6-aryl-2,2-dimethyl[1,3]dioxin-4-ones from tert.-butyl esters of 3-aryl-3-oxopropanoic acid interaction with triperoxonane angidridom (TFCA) in a mixture of TFA and acetone at 23°according to Tetrahedron Lett. 1998, 39, 2253. If necessary, the final products were purified column chromatography on silica gel with hexane/ethyl acetate.

Example O1

2.2-Dimethyl-6-thiophene-2-yl[1,3]dioxin-4-one

Received 3-oxo-3-thiophene-2-ylpropionic acid from the acid chloride thiophene-2-carboxylic acid (5.3 ml, 50 mmol) and bis(trimethylsilyl)malonate (25.6 ml, 100 mmol) with n-butyllithium (1.6 M solution in hexane, 62.5 ml) in ether at -60°in accordance with the General method H (method B2). The crude material (7,88 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and TPA in accordance with the General method (method a). Received the product as yellow solid (4.09 g).

MS (EI): 210 (M+); tpl.42°C (decomp.).

Example O2

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

Received 3-(3-chlorothiophene-2-yl)-3-oxopropionate acid from the acid chloride of 3-chlorothiophene-2-carboxylic acid (of 7.82 g, 43,2 mmole) and bis(trimethylsilyl)malonate (of 11.6 ml of 45.4 mmole) with what riteraminem (12,65 ml, 90,7 mmole) and methyl lithium (3,53 g, and 47.5 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (5,69 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as an orange solid (2.3 g).

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

Example O3

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

Received 3-(3-cyanothiophene-2-yl)-3-oxopropionate acid from the acid chloride of 3-cyanothiophene-2-carboxylic acid (24,33 g, 140,6 mmol) and bis(trimethylsilyl)malonate (38,0 ml of 147.7 mmole) triethylamine (41 ml, 295,4 mmole) and lithium bromide (13.5 g, 154,7 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (24.8 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as an orange solid (5.6 g).

MS (EI): 235 (M+); tpl.116-120°C (decomp.).

Example O4

3-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile

Received 3-(3-cyanophenyl)-3-oxopropionate acid from the acid chloride of 3-cyanobenzoic acid (828 mg, 5 mmol) and bis(trimethyl who ilil)malonate (2,56 ml, 10 mmol) with n-butyllithium (1.6 M solution in hexane, 6,25 ml) in ether at -60 to 0°in accordance with the General method H (method B2). The crude material (1.04 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and TPA in accordance with the General method (method a). Received the product as a pale yellow solid (0.8 g).

MS (EI): 229 (M+); tpl.138°C (decomp.).

Example A5

2.2-Dimethyl-6-(3-triptoreline)[1,3]dioxin-4-one

Received 3-oxo-3-(3-triptoreline)propionic acid from the acid chloride of 3-triftorperasin acid (10 ml, 67,6 mmole) and bis(trimethylsilyl)malonate (18.2 ml, 71 mmol) with triethylamine (20 ml, 142 mmole) and methyl lithium (6,46 g, 74.4 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (7.0 g obtained from the 15.4 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as a pale yellow solid (5.3g).

MS (EI): 272 (M+); tpl.77-78°C (decomp.).

Example O6

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

Received 3-(3-chlorophenyl)-3-oxopropionate acid from the acid chloride of 3-chlorbenzoyl acid (11 ml, 85,7 mmole) and bis(trimethylsilyl)malonate (23,0 ml, 90,0 IMO is her) with triethylamine (25 ml, 180 mmol) and lithium bromide (8,19 g, 94,3 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (17.1 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as a yellow-brown solid (8.0 g).

MS (EI): 238 (M+) and 240(M+2)+]; tpl.87-88°C (decomp.).

Example 7

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

Received 3-(3-itfinal)-3-oxopropionate acid from the acid chloride of 3-identies acid (21,0 g, 78,8 mmole) and bis(trimethylsilyl)malonate (21,0 ml, 82,8 mmole) triethylamine (23 ml, 165,5 mmole) and methyl lithium (rate of 7.54 g, 86,7 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (of 21.9 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as yellow solid (9.6 g).

MS (EI): 330 (M+); tpl.79-80°C (decomp.).

Example A8

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

Received 3-oxo-3-(3-trifloromethyl)propionic acid from the acid chloride of 3-cryptomaterial acid and bis(trimethylsilyl)malonate with three what tiramina and lithium bromide in acetonitrile at 0° In accordance with the General method H (method B1). The crude material was converted to the compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as an orange solid (2,27 g).

MS (EI): 288 (M+); tpl.49-54°C (decomp.).

Example 9

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

Was obtained from 3-oxo-3-pyridin-4-ylpropionic acid [obtained

4-acetylpyridine, methoxamine(methyl)carbonate and CO2in DMF at 120°in accordance with the Journal of Antibiotics 1978, 31, 1245] interaction with acetone, TPA, TFCA in accordance with the General method (method b). Received the product as a white solid (1.3 g).

MS (EI): 205 (M+).

Example A

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

Received 3-(3-imidazol-1-ylphenyl)-3-oxopropionate acid from hydrochloride of the acid chloride of 3-(1H-imidazol-1-yl)benzoic acid [obtained by the interaction of 3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30, 1342) [CAS-No. 108035-47-8] with thionyl chloride] and bis(trimethylsilyl)malonate with triethylamine and lithium bromide in acetonitrile at 0°in accordance with the General method H (method B1). The crude material was converted to the compound indicated in the heading, by mixing in isopropenylacetate and to the centered sulfuric acid in accordance with the General method (method a). Received the product as an orange semi-solid substances (617 mg).

MS (EI): 270 (M+).

Example O11

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

Received 3-(3-methoxyphenyl)-3-oxopropionate acid from the acid chloride of 3-methoxybenzoic acid (10.3 g, 60,4 mmole) and bis(trimethylsilyl)malonate (16.2 ml, 63.4 mmole) triethylamine (17,7 ml, 127 mmol) and lithium bromide (5,77 g, 66,4 mmole) in acetonitrile at 0°in accordance with the General method H (method B1). The crude material (6,38 g) was converted into compound indicated in the heading, by mixing in isopropenylacetate and concentrated sulfuric acid in accordance with the General method (method a). Received the product as a yellow oil (640 mg).

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

Example ø12

2,2-Dimethyl-6-(3-nitrophenyl)[1,3]dioxin-4-one

Received tert.-butyl ether 3-(3-nitrophenyl)-3-oxopropanoic acid from the acid chloride of 3-nitrobenzoic acid (2,71 g of 14.6 mmole) and potassium salt of tert.-butyl ester of malonic acid (6.0 g, 30.0 mmol) with triethylamine (4.5 ml, to 32.2 mmole) and magnesium dichloride (3,48 g, 36,52 mmole) in acetonitrile according to General method N. (method a). The crude material (3.88 g) was converted into compound indicated in the heading, by stirring in a mixture of TFA/acetone with TFCA in accordance with the General method (method b). Received product is in the form of a yellow solid (2.76 g).

MS (EI): 249 (M+); tpl.110-117°C.

Example A13

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

Received tert.-butyl ether 3-oxo-3-(3-[1,2,4]triazole-1-ylphenyl)propionic acid [RO-69-3506/000] methyl ether, 3-[1,2,4]triazole-1-eventing acid [CAS-No. 167626-27-9] interaction with lithium tert.-the butyl acetate according to General method N. (method b). Received from connections (example N6) by stirring in a mixture of TFA/acetone with TFCA in accordance with the General method (method b). Received the product as yellow solid (539 mg).

MS (EI): 271 (M+).

Example A

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

Was obtained from tert.-butyl ester 3-(2-imidazol-1-espiridion-4-yl)-3-oxopropanoic acid (example N5) by stirring in a mixture of TFA/acetone with TFCA in accordance with the General method (method b). Received the product as a brown solid (10.8 g).

MS (EI): 271 (M+); tpl.151°C (decomp.).

The example About 15

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

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

MS (EI): 284 (M+); tpl.122°C./p>

Example O16

4-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)pyridine-2-carbonitrile

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

MS (EI): 230 (M+); tpl.132°C (decomp.).

The following examples are to obtain 4,8-diaryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones, respectively, of 4-aryl-8-allatini-1,3-dihydrobenzo[b][1,4]diazepin-2-ones and 8-aroyl-4-aryl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones in the form of pure regioisomers (scheme of synthesis of A).

A common way N

Getting tert.-butyl ether {2-[3-aryl-3-oxopropionate]-4-arylvinyl}carbamino acid interaction tert.-butyl ester of (2-amino-4-arylvinyl)karbinovykh acids ethyl esters of 3-aryl-3-oxopropanoic acid or 6-aryl-2,2-dimethyl[1,3]dioxin-4-areas: 3-aryl-N-(2-nitro-4-arylvinyl)-3-oxopropionate the interaction of 2-nitro-4-allfamilies with 6-aryl-2,2-dimethyl[1,3]dioxin-4-areas

A mixture of tert.-butyl ether (2-amino-4-arylvinyl)carbamino acid or 2-nitro-4-allterrain (1.0 mmol) and excess (1.2 to 1.5 mmole) ethyl ester of 3-aryl-3-oxopropanoic acid [obtained from the acid chloride arylcarbamoyl acid and potassium salt of ethyl ether m is Lanovoy acid in the presence of triethylamine and magnesium dichloride in acetonitrile at 23° In accordance with the Synthesis 1993, 290] or 6-aryl-2,2-dimethyl[1,3]dioxin-4-it was heated at boiling in toluene (8 ml) until complete disappearance according to TLC amino derivatives. The solution was allowed to cool to 23°With the product, typically crystallized (in cases where crystallization occurred, it was caused by the addition of hexane). A solid substance was separated by filtration, washed with ether or mixtures of ether/hexane and dried in vacuum, obtaining tert.-butyl ester of {2-[3-aryl-3-oxopropionate]-4-arylvinyl}karbinovykh acid or 3-aryl-N-(2-nitro-4-arylvinyl)-3-oxopropionate, which was used directly in the next step, or, if necessary, purified by recrystallization or column chromatography on silica gel.

Example P1

tert.-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-iodine-5-thiomorpholine-4-ylphenyl)carbamino acid

Was obtained from tert.-butyl ether (2-amino-4-iodine-5-thiomorpholine-4-ylphenyl)carbamino acid (example M1) (653 mg, 1.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (690 mg, 2.25 mmole) in accordance with the General method P. Received this product as a yellow solid (629 mg).

MS (EPI): 607 [(M+N)+].

Example P2

tert.-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-iodine-5-morpholine-4-ylphenyl}carbamino acid

The floor is made from tert.-butyl ether (2-amino-4-iodine-5-morpholine-4-ylphenyl)carbamino acid (example M2) (690 mg, 1.65 mmole) and 3-(2,2-dimethyl-6-oxo-6N-[1,3]dioxin-4-yl)benzonitrile (example O4) (566 mg, 2,47 mmole) in accordance with the General method P. Received the product as an orange solid (523 mg).

MS (EPI): 591 [(M+N)+] 613 [(M+Na)+].

Example P3

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

Was obtained from tert.-butyl ester of (5-amino-2-chlorobiphenyl-4-yl)carbamino acid (example M6) (652 mg, of 2.05 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (564 mg, 2,46 mmole) in accordance with the General method P. Received the product in the form of not-quite-white solid (725 mg).

MS (current IEO): 488 [(M-N)-].

Example A4

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(dimethylaminoethanol)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-dimethylaminoethanol)-4-phenylethylene]carbamino acid (example M8) (206 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (138 mg, 0.6 mmole) in accordance with the General method P. Received this product as a yellow solid (210 mg).

MS (EPI): 583 [(M+N)+]; tpl.88°C.

Example P5

Methyl ester {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylenediamine}acetic acid/p>

Was obtained from methyl ester (4-amino-5-tert.-butoxycarbonylamino-2-phenylethylenediamine)acetic acid (example M9) (534 mg, 1.3 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (358 mg, and 1.56 mmole) in accordance with the General method P. Received the product as a yellow foam (457 mg).

MS (EPI): 584 [(M+N)+], 601 [M+NH4)+] 605 [(M+Na)+]; tpl.69-73°C.

Example P6

Methyl ester {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylene}acetic acid

Was obtained from methyl ester (4-amino-5-tert.-butoxycarbonylamino-2-phenylethylene)acetic acid (example M10) (721 mg, 2.0 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (550 mg, 2.4 mmole) in accordance with the General method P. Received the product as a pale yellow solid (886 mg).

MS (EPI): 552 [(M+N)+] 569 [M+NH4)+]; tpl.138°C.

Example A7

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example M11) (415 mg, 1.09 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (373 mg, and 1.63 mmole) in accordance with the General method P. Received the product as light yellow is on solid (137 mg).

MS (EPI): 554 [(M+N)+], 571 [M+NH4)+] 576 [(M+Na)+]; tpl.175-176°C.

Example P8

tert.-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-5-methoxy-4-phenylethylene}carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-methoxy-4-phenylethylene)carbamino acid (example M12) (338 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (252 mg, 1.1 mmole) in accordance with the General method P. Received this product as a yellow solid (388 mg).

MS (EPI): 510 [(M+N)+], 527 [(M+NH4)+] 532 [(M+Na)+]; tpl.169°C.

Example P9

Methyl ester {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethynyl}benzoic acid

Was obtained from methyl ester (4-amino-5-tert.-butoxycarbonylamino-2-phenylethynyl)benzoic acid (example M14) (396 mg, of 1.08 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (273 mg, 1,19 mmole) in accordance with the General method P. Received the product in the form of not-quite-white solid (540 mg).

MS (EPI): 538 [(M+N)+], 555 [M+NH4)+] 560 [(M+Na)+]; tpl.158°C (decomp.).

Example P10

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

Was obtained from tert.-butyl ether (2-amino-5-morpho is in-4-yl-4-phenylethylene)carbamino acid (example M12) (483 mg, of 1.23 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (422 mg, of 1.84 mmole) in accordance with the General method P. Received the product in the form amorphous orange substance (375 mg).

MS (EPI): 565 [(M+N)+] 587 [(M+Na)+].

Example A11

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-4-phenylethylene]carbamino acid (example M15) (514 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (344 mg, 1.5 mmole) in accordance with the General method P. Received the product as a pale yellow solid (353 mg).

MS (EPI): 686 [(M+N)+] 703 [(M+NH4)+]; tpl.135-136°C.

Example A12

tert.-Butyl ester of {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylene} acetic acid

Was obtained from tert.-butyl ether (4-amino-5-tert.-butoxycarbonylamino-2-phenylethylene)acetic acid (example M16) (877 mg, 2.0 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (504 mg, 2.2 mmole) in accordance with the General method P. Received this product as a yellow solid (723 mg).

MS (EPI): 610 [(M+N)+], 627 [(M+NH4)+] 632 [(M+Na)+ ]; tpl.95°C.

Example A13

tert.-Butyl ester of {5-cyanomethyl-2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-cyanomethyl-4-phenylethylene)carbamino acid (example M17) (298 mg, 0,86 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (218 mg, 0.95 mmole) in accordance with the General method P. Received this product as a yellow solid (299 mg).

MS (EPI): 519 [(M+N)+], 536 [(M+NH4)+] 541 [(M+Na)+]; tpl.98°C.

Example A14

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-phenylethylene]carbamino acid (example M18) (393 mg, of 0.87 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (301 mg, 1,31 mmole) in accordance with the General method P. Received the product in the form amorphous orange substance (268 mg).

MS (EPI): 621 [(M+N)+].

Example p

tert.-Butyl ether [2-[3-(3-itfinal)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example M11) (840 mg, 2.2 mmole) and 6-(3-itfinal)-2,2-d is methyl[1,3]dioxin-4-it (example O7) (780 mg, at 2.36 mmole) in accordance with the General method P. Received the product as a white solid (1.3 g).

MS (EPI): 655 [(M+N)+], 672 [(M+NH4)+], 677 [(M+Na)+] 693 [(M+K)+]; tpl.172°C.

Example A16

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-4-phenylethylene)carbamino acid (example M20) (439 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (345 mg, 1.5 mmole) in accordance with the General method P. Received this product as a yellow solid (275 mg).

MS (EPI): 610 [(M+N)+], 627 [(M+NH4)+] 632 [(M+Na)+]; tpl.132-134°C.

Example A17

Methyl ester 5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-identies acid

Received from the methyl ester of 4-amino-5-tert.-butoxycarbonylamino-2-identies acid (example M21) (395 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (254 mg, 1.1 mmole) in accordance with the General method P. Received the product in the form of solids apricot color (435 mg).

MS (EPI): 564 [(M+N)+], 581 [M+NH4)+] 586 [(M+Na)+]; tpl.162-166°C.

Example P

tert.-Butyl ether[2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example M11) (191 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product as a light brown waxy solid (206 mg).

MS (current IEO): 593 [(M-N)-]; tpl.122-129°C.

Example A19

tert.-Butyl ether (RS)-[2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-oxo[1,3]dioxolane-4-ylethoxy)-4-phenylethylene}carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-amino-5-(2-oxo[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid (example M22) (346 mg, of 0.82 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (206 mg, 0.9 mmole) in accordance with the General method of L. Received the product as a pale yellow solid (433 mg).

MS (EPI): 594 [(M+N)+]; tpl.181°C.

Example P

tert.-Butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-5-ethoxymethyl-4-phenylethylene}carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-ethoxymethyl-4-phenylethylene)carbamino acid (example M23) (130 mg, 0.35 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (80 mg, 0.35 mmole) in accordance with the General method of L. Received the product as an amorphous yellow ve is esta (148 mg).

MS (EPI): 538 [(M+N)+].

Example A21

5-tert.-Butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylenediamine ether of 2,2-dimethylpropionic acid

Was obtained from 4-amino-5-tert.-butoxycarbonylamino-2-phenylethylperoxo ether of 2,2-dimethylpropionic acid (example M24) (155 mg, 0.37 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (94 mg, 0,41 mmole) in accordance with the General method of L. Received the product as an amorphous light-orange substance (184 mg).

MS (EPI): 611(M+NH4)+].

Example A22

tert.-Butyl ether (RS)-[2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethynyl-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-amino-4-phenylethynyl-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example M25) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received the product as an amorphous yellow substance (267 mg).

MS (EPI): 635 [(M+N)+].

Example A23

tert.-Butyl ether [2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid (example M26) (236 mg, of 0.56 mmole) and 6-(3-imidazol-1-yl is enyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (151 mg, of 0.56 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (253 mg).

MS (EPI): 634 [(M+N)+].

Example P

tert.-Butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid (example M26) (224 mg, of 0.53 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (125 mg, of 0.53 mmole) in accordance with the General method P. Received the product as a yellow foam (274 mg).

MS (current IEO): 591 [(M-N)-]; tpl.97-100°C.

Example A25

tert.-Butyl ester of {5-cyanoethoxy-2-[3-(3-imidazol-1-yl)-3-oxopropionate]-4-phenylethylene)carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-cyanoethoxy-4-phenylethylene)carbamino acid (example M27) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received the product as an amorphous yellow substance (169 mg).

MS (EPI): 576 [(M+N)+].

Example A26

tert.-Butyl ester of {5-cyanoethoxy-2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid

Was obtained from tert.-butyl ether (2-amino-5-cyanoethoxy-4-phenylethylene)carbamino acid (example M27) (80 mg, 0.22 mmole) and 3-(22-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (55 mg, 0.24 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (96 mg).

MS (current IEO): 533 [(M-N)-].

Example P

tert.-Butyl ether (RS)-[4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-amino-4-(4-perforating)-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example covered by M28) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received the product as an amorphous yellow substance (990 mg).

MS (current IEO): 651 [(M-N)-].

Example P

tert.-Butyl ether (RS)-(4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}phenyl)carbamino acid

Was obtained from tert.-butyl ether (RS)-(2-amino-4-(4-perforating)-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}phenyl)carbamino acid (example M29) (242 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (198 mg).

MS (current IEO): 694 [(M-N)-].

Example P

tert.-Butyl ester of {5-(4,4-detoxificatin-1-yl)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethylene}carbamino the acid

Was obtained from tert.-butyl ether [2-amino-5-(4,4-detoxificatin-1-yl)-4-phenylethylene]carbamino acid (example M18) (321 mg, 0.67 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (240 mg, to 0.89 mmole) in accordance with the General method P. Received the product as an orange foam (295 mg).

MS (EPI): 692 [(M+N)+].

Example P

tert.-Butyl ether (RS)-{2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{2-amino-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid (example M30) (346 mg, from 0.76 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (300 mg, 1,11 mmole) in accordance with the General method P. Received the product as a yellow foam (196 mg).

MS (EPI): 665 [(M+N)+].

Example P

tert.-Butyl ether (RS)-{4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-[4-(tetrahydropyran-2-yloxy)piperidine-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-[2-amino-4-(4-perforating)-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example covered by M28) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received this product as a yellow solid (282 mg).

MS (EPI): 698 [(M+N)+; tpl.129-132°C.

Example P

tert.-Butyl ester of {5-(2-tert.-butoxyethoxy)-4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-(2-tert.-butoxyethoxy)-4-(4-perforating)phenyl]carbamino acid (example M32) (560 mg, of 1.27 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example A) (413 mg, 1,53 mmole) in accordance with the General method P. Received this product as a yellow solid (507 mg).

MS (EPI): 655 [(M+N)+]; tpl.62-65°C.

Example P

tert.-Butyl ether (RS)-(4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ether (RS)-(5-amino-4'-fluoro-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino acid (example m) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received this product as a yellow solid (473 mg).

MS (EPI): 742 [(M+H)+]; tpl.57-58°C.

Example P

tert.-Butyl ether (RS)-[4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[5-amino-4'-fluoro-2-(tetrahydropyran-2-ilok is imethyl)biphenyl-4-yl]carbamino acid (example M) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received the product as a pale yellow solid (330 mg).

Example P

tert.-Butyl ether {2-cyanoethoxy-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-cyanoethoxy-4'-forbiden-4-yl)carbamino acid (example M35) (190 mg, of 0.53 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (164 mg, and 0.61 mmole) in accordance with the General method P. Received the product as a yellow resinous substance (90 mg).

MS (EPI): 570 [(M+N)+].

Example P36

tert.-Butyl ether {2-dimethylaminomethyl-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-dimethylaminomethyl-4'-forbiden-4-yl)carbamino acid (example m) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) in accordance with the General method P. Received the product as a pale yellow solid (329 mg).

Example P

tert.-Butyl ether {2-(2,2-dimethylether[1.3]dioxolo[4.5-C]pyrrol-5-yl)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4'-forbiden-4-yl]carbamino acid (example M) (465 mg, 1.05 mmole) and 6-(3-imidazol-1-Ilf the Nile)-2,2-dimethyl[1,3]dioxin-4-it (example O) (314 mg, 1.16 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (540 mg).

MS (current IEO): 654 [(M-N)-].

Example P

tert.-Butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-4'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M38) (332 mg, 1.0 mmol) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (270 mg, 1.0 mmol) according to General method P. Received this product as a brown amorphous substance (328 mg).

MS (current IEO): 543 [(M-N)-].

Example P39

tert.-Butyl ether {2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4'-forbiden-4-yl]carbamino acid (example m) (444 mg, 1.0 mmol) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (321 mg, 1,19 mmole) in accordance with the General method P. Received the product as a brown solid (457 mg).

MS (current IEO): 654 [(M-N)-]; tpl.110-115°C (decomp.).

Example P

tert.-Butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methylbiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-4'-fluoro-2-methylbut the Nile-4-yl)carbamino acid (example M40) (316 mg, 1.0 mmol) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (297 mg, 1.1 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (361 mg).

MS (EPI): 529 [(M+N)+].

Example P

tert.-Butyl ester {4-tert.-butoxycarbonylamino-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-2-yloxy}acetic acid

Was obtained from tert.-butyl ester of (5-amino-4-tert.-butoxycarbonylamino-4'-forbiden-2-yloxy)acetic acid (example M41) (1.4 g, 3,24 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (885 mg, of 3.27 mmole) in accordance with the General method P. Received the product as light brown solid (759 mg).

MS (EPI): 645 [(M+N)+]; tpl.82-85°C.

Example P

tert.-Butyl ether {2-chloro-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-chloro-4'-forbiden-4-yl)carbamino acid (example M42) (168 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (252 mg, of 0.93 mmole) in accordance with the General method P. Received the product as a pale yellow solid (156 mg).

MS (current IEO): 547 [(M-N)-].

Example P

tert.-Butyl ether [4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino the th acid

Was obtained from tert.-butyl ester of [5-amino-4'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid (example M) (188 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (260 mg, 0.96 mmole) in accordance with the General method P. Received the product as an orange solid (218 mg).

MS (EPI): 589 [(M+N)+]; tpl.61-63°C.

Example P44

tert.-Butyl ether {2-(2-tert.-butoxyethoxy)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2-(2-tert.-butoxyethoxy)-4'-forbiden-4-yl]carbamino acid (example M44) (209 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product in a solid beige color (194 mg).

MS (EPI): 631 [(M+N)+]; tpl.101°C.

Example P

tert.-Butyl ether [4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-amino-4'-fluoro-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid (example M45) (130 mg, 0.34 in mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (92 mg, 0,34 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (86 mg).

The (EPI): 600 [(M+N) +].

Example P46

will wipe away.-Butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxy-2'-methylbiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-4'-fluoro-2-methoxy-2'-methylbiphenyl-4-yl)carbamino acid (example M46) (173 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (199 mg, about 1.47 mmole) in accordance with the General method P. Received the product as an orange solid (182 mg).

MS (EPI): 559 [(M+N)+]; tpl.99-102°C.

Example P

tert.-Butyl ether {2-tert.-butoxy-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carbamino acid (example m) (187 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (237 mg).

MS (current IEO): 585 [(M-N)-].

Example P

tert.-Butyl ether {2-tert.-butoxy-2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (135 mg, 0.5 mmole) according to the following General method P. Received the product as an amorphous yellow substance (234 mg).

MS (current IEO): 585 [(M-N)-].

Example p

tert.-Butyl ether (RS)-{4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ether (RS)-{5-amino-4'-fluoro-2-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl} carbamino acid (example M49) (236 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (200 mg, of 0.74 mmole) in accordance with the General method P. Received the product in an orange solid (188 mg).

MS (EPI): 684 [(M+N)+]; tpl.99-103°C.

Example P

tert.-Butyl ether {2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) (159 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (199 mg).

MS (current IEO): 543 [(M-N)-].

Example P

tert.-Butyl ether {2-tert.-butoxy-5-[3-(3-cyanophenyl)-3-oxopropionate]-4'-forbiden-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carb is mirovoi acid (example m) (187 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (126 mg, 0.55 mmole) in accordance with the General method P. Received the product as an amorphous pale-pink matter (196 mg).

MS (EPI): 546 [(M+N)+].

Example P

tert.-Butyl ether {2-tert.-butoxy-5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-forbiden-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (126 mg, 0.55 mmole) in accordance with the General method P. Received the product as an amorphous pale-pink matter (197 mg).

MS (EPI): 546 [(M+N)+].

Example P

tert.-Butyl ester of {5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) (112 mg, 0.35 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (80 mg, 0.35 mmole) in accordance with the General method P. Received the product as a yellow foam (131 mg).

MS (current IEO): 502 [(M-N)-].

Example P

tert.-Butyl ether (2'-fluoro-2-methoxy-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate)biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxy shall iphenyl-4-yl)carbamino acid (example M50) (249 mg, 0.75 mmole) and tert.-butyl ester 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid (example H8) (275 mg, of 0.92 mmole) in accordance with the General method P. Received this product as a yellow solid (312 mg).

MS (EPI): 559 [(M+N)+]; tpl.83-86°C.

Example P

tert.-Butyl ester of {5-[3-(5-cyanothiophene-2-yl)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) (166 mg, 0.5 mmole) and tert.-butyl ether 3-(5-cyanothiophene-2-yl)-3-oxopropanoic acid (example H17) (138 mg, 0.55 mmole) in accordance with the General method P. Received the product as a pale yellow solid (244 mg).

MS (EPI): 510 [(M+N)+]; tpl.200°C (decomp.).

Example P

tert.-Butyl ether {2'-fluoro-2-methoxy-5-[3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) and ethyl ester of 3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionic acid (example H1) (260 mg, 1.0 mmol) according to General method P. Received the product as a yellow resinous substance (70 mg).

MS (EPI): 546 [(M+N)+].

Example P

tert.-Butyl ester of {5-[3-(2-cyano-4-yl)-3-oxopropionate]-2'-ft is R-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) and tert.-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) in accordance with the General method P. Received the product as a pale yellow solid (189 mg).

MS (EPI): 522(M+NH4)+].

Example P

tert.-Butyl ether (2-tert.-butoxy-4'-fluoro-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carbamino acid (example m) (140 mg, 0.37 mmole) and tert.-butyl ester 3-[3-(2-Mei-1-yl)phenyl]-3-oxopropanoic acid (example H8) (111 mg, 0.37 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (139 mg).

MS (EPI): 601 [(M+N)+].

Example P

tert.-Butyl ester of {5-[3-(5-cyano-2-forfinal)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2'-fluoro-2-methoxybiphenyl-4-yl)carbamino acid (example M50) (166 mg, 0.5 mmole) and ethyl ester of 3-(5-cyano-2-forfinal)-3-oxopropanoic acid (example H18) (141 mg, 0.6 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (165 mg). MS (EPI): 522 [(M+N)+].

Example P

tert.-the Hotelowy ether {2-tert.-butoxy-5-[3-(2-cyano-4-yl)-3-oxopropionate]-4'-forbiden-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carbamino acid (example m) (140 mg, 0.37 mmole) and tert.-butyl ester 3-(2-cyano-4-yl)-3-oxopropanoic acid (example N10) (91 mg, 0.37 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (164 mg).

MS (EPI): 547 [(M+N)+].

Example P

tert.-Butyl ether {2-tert.-butoxy-2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (180 mg, 0,69 mmole) in accordance with the General method P. Received the product as a pale yellow solid (257 mg).

MS (EPI): 588 [(M+N)+]; tpl.47-50°C.

Example P

tert.-Butyl ester of [5-[3-(3-cyanophenyl)-3-oxopropionate]-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-forbiden-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-forbiden-4-yl]carbamino acid (example M51) (222 mg, 0.5 mmole) and tert.-butyl ester 3-(3-cyanophenyl)-3-oxopropanoic acid (example H3) (182 mg, 0.8 mmole) in accordance with the General method P. Received the product in the form of amorphous W is LEGO substances (258 mg).

MS (EPI): 615 [(M+N)+].

Example P

tert.-Butyl ether {2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-forbiden-4-yl]carbamino acid (example M51) (222 mg, 0.5 mmole) and 6-(3-imidazol-1-ylphenyl)-2,2-dimethyl[1,3]dioxin-4-it (example O10) (135 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (294 mg).

MS (EPI): 656 [(M+N)+].

Example P

tert.-Butyl ether (2-tert.-butoxy-2'-fluoro-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and 2,2-dimethyl-6-[3-(2-Mei-1-yl)phenyl][1,3]dioxin-4-it (example O15) (142 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (234 mg).

MS (EPI): 601 [(M+N)+].

Example P

tert.-Butyl ether {2-tert.-butoxy-5-[3-(2-cyano-4-yl)-3-oxopropionate]-2'-forbiden-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and 4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)pyridin-carbonitrile (example O16) (115 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (216 mg).

MS (EPI): 547 [(M+N)+].

Example P

tert.-Butyl ether (2-tert.-butoxy-2'-fluoro-5-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and tert.-butyl ester 3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropanoic acid (example H13) (211 mg, to 0.63 mmole) in accordance with the General method P. Received the product as a pale yellow solid (260 mg).

MS (current IEO): 631 [(M-N)+]; tpl.59-62°C.

Example P

tert.-Butyl ester of {5-[3-(3-cyanophenyl)-3-oxopropionate]-2',5'-debtor-2-methoxybiphenyl-4-yl}carbamino acid

Was obtained from tert.-butyl ester of (5-amino-2',5'-debtor-2-methoxybiphenyl-4-yl)carbamino acid (example M52) (175 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (115 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (136 mg).

MS (EPI): 522 [(M+N)+].

Example P

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

Was obtained from tert.-butyl ester of 5-amino-2',5'-debtor-2-methoxybiphenyl-4-yl)carbamino acid (example M52) (175 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (130 mg, 0.5 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (185 mg).

MS (current IEO): 562 [(M-N)-].

Example P

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

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and 6-(3-cyanothiophene-2-yl)-2,2-dimethyl[1,3]dioxin-4-it (example O3) (130 mg, 0.55 mmole) in accordance with the General method P. Received the product as a yellow oil (278 mg).

MS (current IEO): 550 [(M-N)-].

Example P

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

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2'-forbiden-4-yl)carbamino acid (example M48) (187 mg, 0.5 mmole) and tert.-butyl ether 3-(5-cyanothiophene-2-yl)-3-oxopropanoic acid (example H17) (138 mg, 0.55 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (268 mg).

MS (current IEO): 550 [(M-N)-].

Example P

tert.-Butyl ether {2-tert.-butoxy-4'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid

Recip is of tert.-butyl ester of (5-amino-2-tert.-butoxy-4'-forbiden-4-yl)carbamino acid (example m) (187 mg, 0.5 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (156 mg, 0.6 mmole) in accordance with the General method P. Received the product as a yellow resinous substance (198 mg).

MS (EPI): 588 [(M+N)+].

Example P

tert.-Butyl ester of [5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ester of [5-amino-2'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid (example M53) and 3-(2,2-dimethyl-6-oxo-6H-[l,3]dioxin-4-yl)benzonitrile (example O4) in accordance with the General method P. Received this product as a yellow solid (188 mg).

MS (EPI): 548 [(M+N)+].

Example P

tert.-Butyl ether (RS)-[5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid

Was obtained from tert.-butyl ether (RS)-[5-amino-2'-fluoro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid (example M54) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) in accordance with the General method P. Received this product as a yellow solid (155 mg).

MS (EPI): 548(M+NH4)+].

Example P

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

Received from tre is.-butyl ester of [5-amino-2'-fluoro-2-(4-methoxybenzyloxy)biphenyl-4-yl]carbamino acid (example M55) (438 mg, 1.0 mmol) and tert.-butyl ester 3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropanoic acid (example H14) (301 mg, 1.0 mmol) according to General method P. Received the product as an amorphous yellow substance (561 mg).

MS (EPI): 666 [(M+N)+].

Example P

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

Was obtained from tert.-butyl ester of (5-amino-2-tert.-butoxy-2',5'-diferuloyl-4-yl)carbamino acid (example M56) (196 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (115 mg, 0.5 mmole) in accordance with the General method P. Received the product in the form of amorphous material, beige color (155 mg).

MS (EPI): 564 [(M+N)+].

Example P

tert.-Butyl ester of {5-tert.-butoxy-4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate] phenyl }carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-tert.-butoxy-4-(4-perforating)phenyl]carbamino acid (example m) (160 mg, 0.4 mmole) and tert.-butyl ester 3-(3-imidazol-1-ylphenyl)-3-oxopropanoic acid (example N4) (115 mg, 0.4 mmole) in accordance with the General method P. Received the product as an amorphous yellow substance (140 mg).

MS (EPI): 611 [(M+N)+].

Example P

tert.-Butyl ester of {5-tert.-butoxy-4-(4-perforating)-2-[3-oxo-3-(3-[1.2,3]Tria the ol-1 ylphenyl)propionamido]phenyl}carbamino acid

Was obtained from tert.-butyl ether [2-amino-5-tert.-butoxy-4-(4-perforating)phenyl]carbamino acid (example m) (160 mg, 0.4 mmole) and ethyl ester of 3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionic acid (example H2) (104 mg, 0.4 mmole) in accordance with the General method P. Received the product as a yellow resinous substance (150 mg).

MS (EPI): 612 [(M+N)+].

General method P

Getting 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 or 4-aryl-8-allatini-1,3-dihydrobenzo[b][1,4]diazepin-2-ones

A suspension of tert.-butyl ether {2-[3-aryl-3-oxopropionate]-4-arylvinyl}carbamino acid or tert.-butyl ether {2-[3-aryl-3-oxopropionate]-4-arelatively}carbamino acid (1.0 mmol) in methylene chloride (5 ml) [if necessary, you can add anisole or 1,3-dimethoxybenzene (5-15 mmol)] was treated with TFA (0.5 to 5.0 mmol) at 0°and With continued stirring at 23°until the complete disappearance according to TLC source material. The solvent was removed in vacuo, the residue was treated with a small amount of ether, and it crystallized. The solid was stirred with saturated sodium bicarbonate solution, filtered, washed with water and ether or mixtures of ether/hexane and dried, obtaining the connection specified in the header, which required the spine, can be purified by crystallization from a mixture of THF/methylene chloride/ether/hexane.

A common way To

Getting 4-[3-(amino-4-carbonyl)phenyl]-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-ones catalyzed by palladium carbonyliron amination of 4-(3-itfinal)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it

A solution of 4-(3-itfinal)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-she (1.0 mmol), secondary amine (5.0 mmol), PPh3(6 mol%) or dffp (diphenylphosphinomethyl) (3 mol%), palladium diacetate (3% mol.) triethylamine (2,0 mol) in DMF (4 ml) was stirred at 23°in the atmosphere until complete disappearance according to TLC improsoned. After dilution with ethyl acetate, washing with saturated sodium bicarbonate solution and the salt solution the organic layer was dried over Na2SO4. Removal of the solvent led to the formation of a brown oil, which was purified column chromatography on silica gel with hexane/ethyl acetate, receiving the connection specified in the header.

A common way T

Getting tert.-butyl ester of (5-hydroxy-2-nitrophenyl)karbinovykh acids catalyzed by rhodium plated dezalkilirovania tert.-butyl ester of (5-allyloxy-2-nitrophenyl)karbinovykh acids

A mixture of tert.-butyl ether (5 allyloxy-2-

nitrophenyl)carbamino acid, (PPh3)3PhCl 5% mol.) and DABCO (diazabicyclo[2.2.2]octane) (20 mol%) in ethanol was heated at boiling for 2.5 h in accordance with J. Org. Chem. 1973, 38, 3224. Was added 5% citric acid, stirred at 23°C for 15 min, extracted with ethyl acetate, washed with saturated saline solution, dried over MgSO4. Removal of the solvent led to an orange solid substance, which was purified column chromatography on silica gel with hexane/ethyl acetate, receiving the connection specified in the header.

Example T1

tert.-Butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid

Was obtained from tert.-butyl ether (5 allyloxy-4-iodine-2-nitrophenyl)carbamino acid (example B4), (PPh3)3RhCl (5 mol%) and DABCO (20 mol%) in ethanol according to General method I. Received the product as a yellow solid.

MS (current IEO): 379 [(M-N)-]; tpl.140°C.

A common way

Getting tert.-butyl ester of 5-O-substituted-(4-iodine-2-nitrophenyl)karbinovykh acids from tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid

A mixture of tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid (example T1), potassium bicarbonate and the appropriate alkylating agent were mixed in DMF at 23-60°until complete conversion according to TLC. Dilution with ethyl acetate was followed by water treatment with 5% citric acid, saturated sodium bicarbonate solution, saturated salt rastv the rum and drying over MgSO 4. Removal of solvent resulted in the formation of the crude material, which was purified column chromatography on silica gel with hexane/ethyl acetate, receiving the connection specified in the header.

Example N1

tert.-Butyl ester of (5-tert.-butoxycarbonylamino-2-iodine-4-nitrophenoxy)acetic acid

Was obtained from tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid (example T1) (1.23 g, 3,24 mmole), potassium bicarbonate (0.39 g, to 3.89 mmole) and tert.-butyl ether bromoxynil acid (0,59 ml, with 3.89 mmole) in accordance with the General method of U. Received this product as a yellow solid (1.5 g, 94%).

MS (EPI): 495 [(M+N)+], 512 [(M+NH4)+and 517 [(M+Na)+]; tpl.103°C.

Example U2

tert.-Butyl ester of (5-cyanoethoxy-4-iodine-2-nitrophenyl)carbamino acid

Was obtained from tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid (example T1) (614 mg, of 1.62 mmole), potassium bicarbonate (208 mg, 2,08 mmole) and bromoacetonitrile (of 0.21 ml, and 3.16 mmole) in accordance with the General method of U. Received this product as a yellow solid (574 mg, 85%).

MS (current IEO): 418 [(M-N)-]; tpl.125°C.

Example v3

tert.-Butyl ether (RS)-{4-iodine-2-nitro-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid

Was obtained from tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)CT the amine acid (example T1) (760 mg, 2 mmole), potassium bicarbonate (260 mg, 4 mmole) and 2-(2-bromoethoxy)tetrahydro-2H-Piran (0.6 ml, 2.6 mmole) in accordance with the General method of U. Received the product as an orange oil (804 mg, 79%).

MS (EI): 508 (M)+.

Example A4

tert.-Butyl ester of (5-tert.-butoxy-4-iodine-2-nitrophenyl)carbamino acid

Was added di-tert.-butylacetyl N,N-dimethylformamide (19.2 ml, 80 mmol) dropwise within 15 min to a solution of tert.-butyl ester of (5-hydroxy-4-iodine-2-nitrophenyl)carbamino acid (example T1) (7,60 g, 20 mmol) in toluene at 80°and With continued stirring at 80°C for 3 h (see Synthesis 1983, 135). Received the product as yellow solid (5,97 g, 68%).

MS (current IEO): 435 [(M-N)-]; tpl.94°C.

Example 1

3-(7-Iodine-4-oxo-8-thiomorpholine-4-yl-4.5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-iodine-5-thiomorpholine-4-ylphenyl}carbamino acid (example A1) (629 mg, the 1.04 mmole) interaction with TFA in methylene chloride according to General method P. Received the product in a solid olive green (437 mg).

tpl.227-228°C (decomp.).

Example 2

3-(7-Iodine-8-morpholine-4-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-4-iodine-5-morpholine-4-hilfen the l}carbamino acid (example A2) (518 mg, 0,877 mmole) interaction with TFA in methylene chloride according to General method P. Received the product in a solid beige color (309 mg).

MS (EI): 472 (M+); tpl.224°C (decomp.).

Example 3

3-(8-Chloro-4-oxo-7-phenylethynyl-4.5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether (2-amino-5-chloro-4-phenylethylene)carbamino acid (example M3) (171 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (183 mg, 0.6 mmole) in accordance with the General method P. Received the product in the form of a solid light yellow substance (284 mg). This material was unblocked and cyclically interaction with TFA in methylene chloride according to General method P. Received the product as an orange solid (483 mg).

MS (EPI): 343 [(M+N)+] 345 [M+2+Na)+]; tpl.248-251°C (decomp.).

Example 4

3-(8-Methyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether (2-amino-5-methyl-4-phenylethylene)carbamino acid (example M4) (161 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (230 mg, 0.75 mmole, 75% purity) in accordance with the General method P. Received the product in the form of a solid light yellow substance (227 mg). This material was unblocked and cyclically interaction with TFA in methylene is chloride in accordance with the General method P. Received the product as a pale yellow solid (83 mg).

MS (EPI): 375 (M+); tpl.237-239°C (decomp.).

Example 5

3-[8-(4-Methylpiperazin-1-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-amino-5-(4-methylpiperazin-1-yl)-4-phenylethylene]carbamino acid (example M5) (203 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (230 mg, 0.75 mmole, 75% purity) in accordance with the General method P. using chromatography received the product as an orange oil (181 mg). This material was unblocked and cyclically interaction with TFA in methylene chloride according to General method P. Received the product as an orange solid (82 mg).

MS (EPI): 460,5 [(M+H)+]; tpl.222-224°C (decomp.).

Example 6

3-[8-(1,1-Diocletianopolis-4-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-amino-5-(1,1-dioxo-6-thiomorpholine-4-yl)-4-phenylethylene]carbamino acid (example M19) (220 mg, 0.5 mmole) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (172 mg, 0.75 mmole) in accordance with the General method P. the resulting material was unblocked and cyclically interaction with TFA in methylene chloride according to General method P. Received the product in as Zheltov the solid (47 mg).

MS (EPI): 495(M+H)+]; tpl.>250°C (decomp.).

Example 7

3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {2-chloro-5-[3-(3-cyanophenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example A3) (720 mg, about 1.47 mmole) interaction with TFA in methylene chloride according to General method P. Received the product in the form of not-quite-white solid (457 mg).

MS (EI): 371 (M+) and 373 [(M+2)+]; tpl.242-244°C (decomp.).

Example 8

3-(8-Methyl-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ester of (5-amino-2-methylbiphenyl-4-yl)carbamino acid (example M7) (298 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)benzonitrile (example O4) (460 mg, 1.5 mmole) in accordance with the General method P. the resulting material (351 mg) was unblocked and cyclically interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (206 mg).

MS (EI): 351 (M+); tpl.236-239°C (decomp.).

Example 9

3-[8-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-4-oxo-7-phenylethynyl-4.5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4-phenylethylene]carbamino sour is you (example A14) (265 mg, 0.43 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a brown solid (121 mg).

MS (EPI): 503 [(M+N)+]; tpl.239-243°C (decomp.).

Example 10

3-(8-Morpholine-4-yl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-5-morpholine-4-yl-4-phenylethylene}carbamino acid (example a10) (370 mg, of 0.66 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as light brown solid (216 mg).

MS (EI): 446 (M+); tpl.239-243°C (decomp.).

Example 11

3-[8-(2-Dimethylaminoethanol)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-dimethylaminoethanol)-4-phenylethylene]carbamino acid (example A4) (166 mg, of 0.28 mmole) by treatment with TFA and anisole in methylene chloride according to General method P. Received the product as a pale yellow solid (103 mg).

MS (EPI): 465 [(M+N)+]; tpl.197°C (decomp.).

Example 12

Methyl ester [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulphonyl]acetic acid

Was obtained from methyl EPE is {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylenediamine}acetic acid (example 5) (421 mg, 0.72 mmole) by treatment with TFA and anisole in methylene chloride according to General method P. Received the product as a pale yellow solid (309 mg).

MS (EPI): 465 [(M+N)+]; tpl.201°C (decomp.).

Example 13

[4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulphonyl]acetic acid

A solution of methyl ester [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulphonyl]acetic acid (example 12) (265 mg, 0.57 mmole) and hydrate of lithium hydroxide (26 mg, to 0.63 mmole) in THF (5 ml), methanol (1 ml) and water (1 ml) was stirred at 23°within 24 hours Received the product as a pale yellow solid (257 mg).

MS (EPI): 452 [(M+N)+]; tpl.202°C (decomp.).

Example 14

Methyl ester [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]acetic acid

Was obtained from methyl ester {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylene}acetic acid (example A6) (846 mg, 1,53 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (557 mg).

MS (EI): 433 (M+); tpl.236°C (decomp.).

Example 15

[4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]acetic acid

The solution of the hydrate is hydroxide lithium (54 mg, of 1.28 mmole) in water (2 ml) and methanol (2 ml) was added to methyl ether [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]acetic acid (example 14) (505 mg, of 1.17 mmole) in THF (10 ml), the reaction mixture was stirred at 23°C for 48 hours Received the product as a pale yellow solid (62 mg).

MS (EPI): 452 [(M+N)+]; tpl.248°C (decomp.).

Example 16

Methyl ester of 4-(3-cyanophenyl)-8-iodine-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-carboxylic acid

Was obtained from methyl ester 5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-identies acid (example A17) (430 mg, 0,763 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as an orange-pink solid (199 mg).

MS (EI): 445 (M+); tpl.247-248°C (decomp.).

Example 17

2-[4-(3-Cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]ndimethylacetamide

Processed [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yl]acetic acid (example 15) (48 mg, 0,114 mmole) with Vos2On (37 mg), ammonium bicarbonate (13 mg) and pyridine (6 ml) in DMF (0.6 ml) at 23°C for 24 h [see Tetrahedron Letters 1995, 36, 7115]. Received the product as a pale yellow solid (14 mg).

MS (current IEO): 417 [(M-N)-]; tpl.250°C (decomp.).

Example 18

3-[8-(2-Methoxyethoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example A7) (135 mg, 0,251 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a pale green solid (82 mg).

MS (EI): 435 (M+); tpl.174-176°C (decomp.).

Example 19

Methyl ester of 4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-carboxylic acid

Was obtained from methyl ester 5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylamine acid (example P9) (511 mg, 0.95 mmole) interaction with TFA in methylene chloride according to General method P. Received the product in the form of not-quite-white solid (321 mg).

MS (EI): 419 (M+); tpl.>250°C.

Example 20

3-(8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-5-methoxy-4-phenylethylene}carbamino acid (example A8) (359 mg, 0.7 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a yellow-brown solid (87 mg).

MS (EI): 391 ( +); tpl.>250°C.

Example 21

3-[8-(2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-4-phenylethylene]carbamino acid (example A11) (300 mg, 0,437 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (211 mg).

MS (EI): 435 (M+); tpl.140-141°C (decomp.).

Example 22

[4-(3-Cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetic acid

Was obtained from tert.-butyl ether {5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylene}acetic acid (example A12) (698 mg, 1,14 mmole) by treatment with TFA and anisole in methylene chloride according to General method P. Received this product as a yellow solid (265 mg).

MS (current IEO): 434 [(M-N)-]; tpl.257°C (decomp.).

Example 23

3-(8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {5-cyanomethyl-2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example A13) (266 mg, of 0.51 mmole) interaction with TFA in methylene chloride and is nisole in accordance with the General method P. Received the product as a yellow solid (145 mg).

MS (EI): 400 (M+); tpl.262°C (decomp.).

Example 24

3-[8-(2,3-Dihydroperoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid (example A16) (265 mg, 0,435 mmole) interaction with TFA in methylene chloride and anisole in accordance with the General method P. Received this product as a yellow solid (62 mg).

MS (EPI): 452 [(M+N)+] 474 [(M+Na)+]; tpl.230-234°C (decomp.).

Example 25

4-(3-Itfinal)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether [2-[3-(3-itfinal)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example p) (1.24 g, 1.89 mmole) interaction with TFA in methylene chloride and anisole in accordance with the General method P. Received this product as a yellow solid (517 mg).

MS (EI): 536 (M+); tpl.192°C (decomp.).

Example 26

2-[4-(3-Cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]ndimethylacetamide

Was added the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.22 mmole) of [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]Diaz is pin 7 yloxy]acetic acid (example 22) (50 mg, of 0.11 mmole), ammonium chloride (18 mg, of 0.33 mmole) and 4-methylmorpholine (56 mg, 0.55 mmole) in DMF (1.1 ml) at 0°C, the reaction mixture was stirred at 23°within 2 hours Received this product as a yellow solid (5 mg).

MS (current IEO): 417 [(M-N)-]; tpl.250°C (decomp.).

Example 27

4-(3-Imidazol-1-ylphenyl)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether [2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(2-methoxyethoxy)-4-phenylethylene]carbamino acid (example P) (200 mg, 0,336 mmole) by treatment with TFA in methylene chloride and anisole in accordance with the General method P. Received this product as a yellow solid (28 mg).

MS (EI): 476 (M+); tpl.187-189°C (decomp.).

Example 28

(RS)-3-[4-Oxo-8-(2-oxo[1,3]dioxolane-4-ylethoxy)-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether (RS)-[2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(2-oxo[1,3]dioxolane-4-ylethoxy)-4-phenylethylene]carbamino acid (example A19) (400 mg, 0.67 mmole) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (287 mg).

MS (EI): 477 (M+); tpl.222°C (decomp.).

Example 29

3-(8-Ethoxymethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]bentonite the

Was obtained from tert.-butyl ether {2-[3-(3-cyanophenyl)-3-oxopropionate]-5-ethoxymethyl-4-phenylethylene}carbamino acid (example P) (140 mg, 0.26 per mmole) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (93 mg).

MS (EI): 419 (M+); tpl.229°C.

Example 30

4-(3-Cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ymetray ether of 2,2-dimethylpropionic acid

Was obtained from 5-tert.-butoxycarbonylamino-4-[3-(3-cyanophenyl)-3-oxopropionate]-2-phenylethylperoxo ether of 2,2-dimethylpropionic acid (example A21) (156 mg, of 0.26 mmole) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (75 mg).

MS (EI): 475 (M+); tpl.218°C.

Example 31

3-(8-Hydroxymethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from 4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-Eletropaulo ether of 2,2-dimethylpropionic acid (example 30) (30 mg, 0,063 mmole) and hydrate of lithium hydroxide (8 mg, 0,289 mmole) in THF (2 ml), methanol (0.4 ml) and water (0.4 ml) at 23°C for 3 days. Received the product as a yellow solid (17 mg).

MS (EI): 391 (M+); tpl.>255°C.

Example 32

7-G is proximity-4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-[2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethynyl-5-(tetrahydropyran-2-intoximeter)phenyl]carbamino acid (example A22)) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (77 mg).

MS (EI): 432 (M+); tpl.227°C.

Example 33

4-(3-Imidazol-1-ylphenyl)-7-(4-methoxypiperidine-1-yl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether [2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid (example A23)) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (159 mg).

MS (EPI): 516 [(M+N)+]; tpl.222°C.

Example 34

3-[8-(4-Methoxypiperidine-1-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether [2-[3-(3-cyanophenyl)-3-oxopropionate]-5-(4-methoxypiperidine-1-yl)-4-phenylethylene]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (128 mg).

MS (EPI): 475 [(M+N)+]; tpl.250-251°C.

Example 35

[4-(3-Imidazol-1-ylphenyl)-2-oxo-8-phenylethynyl-2,3-d the hydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetonitrile

Was obtained from tert.-butyl ether {5-cyanoethoxy-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example A25) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (43 mg).

MS (EI): 457 (M+); tpl.214°C.

Example 36

3-(8-Cyanoethoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from tert.-butyl ether {5-cyanoethoxy-2-[3-(3-cyanophenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example A26) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (71 mg).

MS (EI): 416 (M+); tpl.212°C.

Example 37

8-(4-Perforating)-7-hydroxymethyl-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-[4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-(tetrahydropyran-2-intoximeter)-4-phenyl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (462 mg).

MS (EI): 450 (M+); tpl.234°C (decomp.).

Example 38

8-(4-Perforating)-7-[(2-hydroxyethyl)methylamino]-4-(3-imidazol-1-ylphenyl)-1,3-di is hydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-(4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-5-{methyl-[2-(tetrahydropyran-2-yloxy)ethyl]amino}phenyl)carbamino acid (example P)) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (73 mg).

MS (EI): 493 (M+); tpl.217°C (decomp.).

Example 39

4-(3-Imidazol-1-ylphenyl)-7-(4-oxopiperidin-1-yl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {5-(4,4-detoxificatin-1-yl)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethylene}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (180 mg).

MS (EI): 499 (M+); tpl.231°C (decomp.).

Example 40

N-tert.-Butyl-2-[4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]ndimethylacetamide

Was obtained from [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetic acid (example 22) (87 mg, 0.2 mmole) interaction with oxalylamino (26 μl, 0.3 mmole) in DMF (0.6 ml) at 0°C for 1 h, then tert.-- butylamine (106 μl, 1.0 mmol) at 0°C for an additional 30 minutes Received this product as a yellow solid (21 mg).

MS (is e): 490 (M +); tpl.>250°C.

Example 41

2-[4-(3-Cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]-N-methoxyacetate

Was obtained from [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetic acid (example 22) (44 mg, 0.1 mmole) interaction with the hydrochloride of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (38 mg, 0.2 mmole), hydrochloride methoxyamine (9 mg, of 0.11 mmole), 4-methylmorpholine (0,021 ml, 0.3 mmole) and 1-hydroxybenzotriazole (15 mg of 0.11 mmole) in DMF (1 ml) at 0-23°C for 20 hours Received this product as a yellow solid (36 mg).

MS (EPI): 465 [(M+N)+]; tpl.>250°C.

Example 42

7-(2-Hydroxyethoxy)-4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-{2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-4-phenylethynyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (48 mg).

MS (EI): 462 (M+); tpl.224-227°C.

Example 43

8-(4-Forfinal)-7-(hydroxypiperidine-1-yl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-{4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-[4-(tetrahydro the RAS-2-yloxy)piperidine-1-yl] - biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (109 mg).

MS (EPI): 496 [(M+N)+]; tpl.238-240°C.

Example 44

8-(4-Perforating)-7-(2-hydroxyethoxy)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {5-(2-tert.-butoxyethoxy)-4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (83 mg).

MS (EI): 480 (M+); tpl.220-222°C.

Example 45

8-(4-Forfinal)-7-[4-(2-hydroxyethoxy)piperidine-1-yl]-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-(4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]piperidine-1-yl} - biphenyl-4-yl)carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (97 mg).

MS (EPI): 540 [(M+N)+]; tpl.225-227°C.

Example 46

8-(4-Forfinal)-7-hydroxymethyl-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-[4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(tetrahydropyran-2-intoximeter)bifani the-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (162 mg).

MS (EI): 426 (M+); tpl.180-195°C.

Example 47

[8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetonitrile

Was obtained from tert.-butyl ether {2-cyanoethoxy-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (11 mg).

MS (EI): 451 (M+); tpl.164°C.

Example 48

7-Dimethylaminomethyl-8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1.4]diazepin-2-he

Was obtained from tert.-butyl ether {2-dimethylaminomethyl-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P36) interaction with TFA in methylene chloride according to General method P. Received the product as a brown solid (180 mg).

MS (EPI): 454 [(M+N)+]; tpl.115-140°C (decomp.).

Example 49

7-(2,2-Dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid is (example P) interaction with TFA in methylene chloride according to General method P. Received the product as yellow solid (358 mg).

MS (EI): 537 (M+); tpl.240°C (decomp.).

Example 50

7-(CIS-3,4-Dihydroxypyrrolidine-1-yl)-8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Obtained from 7-(2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl)-8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 49) (304 mg, 0.57 mmole) by treatment with 13% hydrochloric acid (15 ml) in THF (50 ml) at 23°C for 16 hours Received the product as a yellow solid (209 mg).

MS (EPI): 498 [(M+N)+]; tpl.244°C.

Example 51

8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-methoxy-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (182 mg).

MS (EI): 426 (M+); tpl.221°C (decomp.).

Example 52

8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-(4-oxopiperidin-1-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-biphenyl-4-yl}carbamino acid (example P39) interaction with TFA in methylene chloride in the accordance with the General method P. Received the product as an orange-brown solid (150 mg).

MS (EPI): 494 [(M+N)+]; tpl.204°C.

Example 53

8-(4-Forfinal)-4-(3-imidazol-ylphenyl)-7-methyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methylbiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (216 mg).

MS (EI): 410 (M+); tpl.196°C.

Example 54

[8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetic acid

Was obtained from tert.-butyl ester {4-tert.-butoxycarbonylamino-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-2-yloxy}acetic acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a beige solid (570 mg).

MS (EPI): 471 [(M+N)+]; tpl.209°C (decomp.).

Example 55

2-[8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]-N-hydroxyacetamido

Received from [8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-2-oxo-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetic acid (example 54) (94 mg, 0.2 mmole) interaction with O-tritylodontidae (61 m is, 0.22 mmole), 1-hydroxybenzotriazole (30 mg, 0.22 mmole), 4-methylmorpholine (66 μl, 0.6 mmole) and the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (77 mg, 0.4 mmole) in DMF (2 ml) at 0-23°C for 18 hours After extraction and chromatography of the obtained orange solid was stirred with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (71 mg).

MS (EPI): 486 [(M+N)+]; tpl.147-157°C (decomp.).

Example 56

7-Chloro-8-(4-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-chloro-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (35 mg).

MS (EI): 430 (M+); tpl.209-211°C.

Example 57

8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-(2-methoxyethoxy)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether [4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (96 mg).

MS (EI): 470 (M+); tpl.196-197°is.

Example 58

8-(4-Forfinal)-7-(2-hydroxyethoxy)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-(2-tert.-butoxyethoxy)-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P44) interaction with TFA in methylene chloride according to General method P. Received the product as a pale green solid (95 mg).

MS (EI): 456 (M+); tpl.225°C.

Example 59

8-(4-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-(2-oxoacridine-3-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether [4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-(2-oxoacridine-3-yl)biphenyl-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (35 mg).

MS (EI): 481 (M+); tpl.230°C.

Example 60

8-(4-fluoro-2-were)-4-(3-imidazol-1-ylphenyl)-7-methoxy-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ester {4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxy-2'-methylbiphenyl-4-yl}carbamino acid (example P46) interaction with TFA in methylene chloride according to General method P. Received this product as a beige solid (101 mg).

MS (EI): 440 (M+); tpl. 225°C.

Example 61

8-(4-Forfinal)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-tert.-butoxy-4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (109 mg).

MS (EI): 412 (M+); tpl.250°C.

Example 62

8-(2-Forfinal)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-tert.-butoxy-2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (132 mg).

MS (EI): 412 (M+); tpl.220°C.

Example 63

8-(4-Forfinal)-7-((R)-3-hydroxypyrrolidine-1-yl)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (RS)-{4'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-[(R)-3-(tetrahydropyran-2-yloxy)pyrrolidin-1-yl] - biphenyl-4-yl}carbamino acid (example p) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (74 mg).

MS (EI): 481 (M+); t pl.155-158°C.

Example 64

8-(2-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-methoxy-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (68 mg).

MS (EI): 426 (M+); tpl.216°C (decomp.).

Example 65

3-[7-(4-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {2-tert.-butoxy-5-[3-(3-cyanophenyl)-3-oxopropionate]-4'-forbiden-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (66 mg).

MS (EI): 371 (M+); tpl.>250°C.

Example 66

3-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {2-tert.-butoxy-5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-forbiden-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (80 mg).

MS (EI): 371 (M+); tpl.>250°C.

Example 67

3-[7-(2-Forfinal)-8-met the XI-4-oxo-4.5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (51 mg).

MS (EI): 385 (M+); tpl.245-247°C.

Example 68

8-(2-Forfinal)-7-methoxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (2'-fluoro-2-methoxy-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (207 mg).

MS (EI): 440 (M+); tpl.220-222°C.

Example 69

5-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiophene-2-carbonitrile

Was obtained from tert.-butyl ether {5-[3-(5-cyanothiophene-2-yl)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (103 mg).

MS (EI): 391 (M+); tpl.>250°C.

Example 70

8-(2-forfinal)-7-methoxy-4-(3-[1,2,4]triazole-4-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl E. the Ira {2'-fluoro-2-methoxy-5-[3-oxo-3-(3-[1,2,4]triazole-4-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a yellow solid (22 mg).

MS (EI): 427 (M+); tpl.188°C (decomp.).

Example 71

4-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was obtained from tert.-butyl ether {5-[3-(2-cyano-4-yl)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (68 mg).

MS (EI): 386 (M+); tpl.240-242°C.

Example 72

8-(4-Forfinal)-7-hydroxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (2-tert.-butoxy-4'-fluoro-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (49 mg).

MS (EPI): 427 [(M+N)+]; tpl.260°C.

Example 73

4-Fluoro-3-[7-(2-forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {5-[3-(5-cyano-2-forfinal)-3-oxopropionate]-2'-fluoro-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received product replacement as yellow solid (52 mg).

MS (EPI): 404 [(M+N)+]; tpl.>250°C.

Example 74

4-[7-(4-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was obtained from tert.-butyl ether {2-tert-butoxy-5-[3-(2-cyano-4-yl)-3-oxopropionate]-4'-forbiden-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (24 mg).

MS (EI): 372 (M+); tpl.164°C.

Example 75

8-(2-Forfinal)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-tert.-butoxy-2'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (61 mg).

MS (EPI): 414 [(M+N)+]; tpl.>250°C.

Example 76

3-[8-(1,4-Dioxa-8 azaspiro[4,5]Dec-8-yl)-7-(2-forfinal)-4-oxo-4,5-dihydro-3H-benzo[b][1,diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ester of [5-[3-(3-cyanophenyl)-3-oxopropionate]-2-(1,4-dioxa-8 azaspiro[4,5]Dec-8-yl)-2'-forbiden-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a yellow Tverdov the substance (132 mg).

MS (EPI): 497 [(M+H)+]; tpl.253°C.

Example 77

7-(1,4-Dioxa-8 azaspiro[4.5]Dec-8-yl)-8-(2-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-2'-fluoro-5-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (133 mg).

MS (EPI): 538 [(M+N)+]; tpl.225°C.

Example 78

8-(2-Forfinal)-4-(3-imidazol-1-ylphenyl)-7-(4-oxopiperidin-1-yl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Obtained from 7-(1,4-dioxa-8 azaspiro[4.5]Dec-8-yl)-8-(2-forfinal)-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 77) (54 mg, 0.1 mmole) with stirring in 1 N. hydrochloric acid (1 ml) and acetone (1 ml) at 23 C for 44 hours Received this product as a yellow solid (39 mg).

MS (EI): 493 (M+); tpl.230°C.

Example 79

8-(2-Forfinal)-7-hydroxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (2-tert.-butoxy-2'-fluoro-5-{3-[3-(2-Mei-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a yellow solid is th substances (111 mg).

MS (current IEO): 425 [(M-N)-]; tpl.>250°C.

Example 80

4-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile

Was obtained from tert.-butyl ether {2-tert.-butoxy-5-[3-(2-cyano-4-yl)-3-oxopropionate]-2'-forbiden-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (47 mg).

MS (current IEO): 371 [(M-N)-]; tpl.>250°C.

Example 81

8-(2-Forfinal)-7-hydroxy-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether (2-tert.-butoxy-2'-fluoro-5-{3-[3-(2-methylsulfonylamino-1-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid (example P)) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (148 mg).

MS (current IEO): 457 [(M-N)-]; tpl.>250°C.

Example 82

3-[7-(2,5-Differenl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {5-[3-(3-cyanophenyl)-3-oxopropionate]-2',5'-debtor-2-methoxybiphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a yellow Tverdov the substance (49 mg).

MS (EI): 403 (M+); tpl.251°C.

Example 83

8-(2,5-Differenl)-7-methoxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2',5'-debtor-2-methoxy-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (78 mg).

MS (EI): 445 (M+); tpl.241°C.

Example 84

2-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile

Was obtained from tert.-butyl ether {2-tert.-butoxy-5-[3-(3-cyanothiophene-2-yl)-3-oxopropionate]-2'-forbiden-4-yl} carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as an orange solid (82 mg).

MS (current IEO): 376 [(M-N)-]; tpl.242°C.

Example 85

5-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiophene-2-carbonitrile

Was obtained from tert.-butyl ether {2-tert.-Bugatti-5-[3-(5-cyanothiophene-2-yl)-3-oxopropionate]-2'-forbiden-4-yl} carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (126 mg).

MS (EI): 377 (M+ ); tpl.

Example 86

8-(4-Forfinal)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {2-tert.-butoxy-4'-fluoro-5-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]biphenyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (78 mg).

MS (EPI): 414 [(M+N)+]; tpl.>250°C.

Example 87

3-[7-(2-Forfinal)-8-(2-methoxyethoxy)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ester of [5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-(2-methoxyethoxy)biphenyl-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (141 mg).

MS (EI): 429 (M+); tpl.211-213°C.

Example 88

3-[7-(2-Forfinal)-8-hydroxymethyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether (RS)-[5-[3-(3-cyanophenyl)-3-oxopropionate]-2'-fluoro-2-(tetrahydropyran-2-intoximeter)biphenyl-4-yl]carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received the product as a pale yellow solid (69 mg).

MS (EI): 385 (M+);t pl.90-91°C.

Example 89

8-(2-Forfinal)-7-hydroxy-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1.4]diazepin-2-he

Was obtained from tert.-butyl ether (2'-fluoro-2-(4-methoxybenzyloxy)-5-{3-[3-(3-methylisoxazol-5-yl)phenyl]-3-oxopropionate}biphenyl-4-yl)carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (278 mg).

MS (EPI): 428 [(M+N)+]; tpl.237°C.

Example 90

3-[7-(2,5-Differenl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

Was obtained from tert.-butyl ether {2-tert.-butoxy-5-[3-(3-cyanophenyl)-3-oxopropionate]-2',5'-diferuloyl-4-yl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (56 mg).

MS (EPI): 390 [(M+N)+]; tpl.>250°C.

Example 91

8-(4-Perforating)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {5-tert.-butoxy-4-(4-perforating)-2-[3-(3-imidazol-1-ylphenyl)-3-oxopropionate]phenyl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (55 mg).

MS (EI): 436 (M+ ); tpl.247°C.

Example 92

8-(4-Perforating)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he

Was obtained from tert.-butyl ether {5-tert.-butoxy-4-(4-perforating)-2-[3-oxo-3-(3-[1,2,3]triazole-1-ylphenyl)propionamido]phenyl}carbamino acid (example P) interaction with TFA in methylene chloride according to General method P. Received this product as a yellow solid (56 mg).

MS (EI): 437 (M+); tpl.243°C.

The following examples show that the 4-aryl-8-iodine-1,3-dihydrobenzo[b][1,4]diazepin-2-ones could also serve as source material for condensation Sonogashira, as shown in the diagram synthesis J.

Example 93

3-(4-Oxo-7-phenylethynyl-8-thiomorpholine-4-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile

Was obtained from 3-(7-iodine-4-oxo-8-thiomorpholine-4-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 1) (437 mg, 0,895 mmole) and phenylacetylene (0.15 ml, 1.34 mmole) in accordance with the General method of L. Received the product in a solid color curry (334 mg).

MS (EI): 391 (M+); tpl.234-235°C (decomp.).

Example 94

(RS)-3-[4-Oxo-8-(1-Osotimehin-4-yl)-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile

A mixture of 3-(4-oxo-7-phenylethynyl-8-thiomorpholine-4-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile (example 27) (50 mg, 0,180 mmol) and Reagan is and Davis (116 mg, 0,432 mmole) in DHM (4,5 ml) was stirred at 23°C for 1 h, the Product was separated by filtration and washed with DHM. Received the product as a pale yellow solid (16 mg).

MS (EPI): 479 [(M+N)+] 501 [(M+Na)+]; tpl.>250°C (decomp.).

Catalyzed by palladium carbonylation of 4-(3-itfinal)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it is in the presence of secondary amines leads directly to the corresponding Amida, as shown in scheme I. synthesis

Example 95

3-[8-(2-Methoxyethoxy)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzamide

Was obtained from 4-(3-itfinal)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-it (example 25) (268 mg, 0.5 mmole) and hexamethyldisilazane (0,52 ml, 2.5 mmole) in accordance with the General method C. Received this product as a yellow solid (102 mg).

MS (EI): 453 (M+); tpl.227-230°C (decomp.).

Example I

Tablets of the following composition was obtained in the usual way:

mg/tablet

Magnesium stearate
The active ingredient100
Powdered lactose95
White corn starch35
Polyvinylpyrrolidone8
Sodium salt of carboxymethyl amylum10
2
Weight pills250

Example II

Tablets of the following composition was obtained in the usual way:

mg/tablet

The active ingredient200
Powdered lactose100
White corn starch64
Polyvinylpyrrolidone12
Sodium salt of carboxymethyl amylum20
Magnesium stearate4
Weight pills400

Example III

Received capsules of the following composition:

mg/capsule

The active ingredient50
Crystalline lactose60
Microcrystalline cellulose34
Talc5
Magnesium stearate1
Loading weight capsules150

The active ingredient with a suitable particle size, crystalline lactose and microcrystalline cellulose were mixed with each other to a homogeneous state, sieved and then mixed with talc and magnesium stearate. Konecne the th mixture was filled in hard gelatin capsule of appropriate size.

1. Derivatives of benzodiazepines General formula

where X denotes a single bond or etendering group, in which when X is single bond,

R1means halogen or phenyl, optionally substituted by halogen, C1-C7by alkyl;

in the case when X is etendering group,

R1means phenyl, optionally substituted by halogen;

R2means halogen, hydroxy, lower alkyl, lower alkoxy, hydroxymethyl, hydroxyethoxy, lower alkoxy(ethoxy)n(n=1-4), cyanoethoxy, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl, 1,1-diocletianopolis-4-yl, 4-oxopiperidin-1-yl, 4-(ness.)alkoxyphenyl-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxyphenyl-1-yl, 4-(ness.)alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(ness.)alkylaminocarbonyl, N,N-bis(nits.)alkylamino(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl, (ness.)alkylcarboxylic(ness.)alkyl, lower alkoxycarbonylmethyl, carboxymethylchitin, 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, carboxy(ness.)alkoxy, cyano(ness.)alkyl, 2-oxo[1,3]dioxolane-4-yl(ness.)alkoxy, (2-hydroxy(ness.)alkyl)-(ness.)alkylamino, 2,2-dimethylether[1,3]dioxolo[4,5-C]pyrrol-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-occaecat the one-3-yl, carbamoylmethyl, carboxy(ness.)alkyl, carbamoylmethyl, hydroxycarbamoyl(ness.)alkoxy, (ness.)alkylcarboxylic lowest alkoxycarbonyl(ness.)alkoxy;

R3means phenyl, thiophenyl, pyridinyl, which is substituted by halogen, cyano, carbamoyl, imidazolyl, 1,2,3-triazolium, 1,2,4-triazolium or isoxazolyl where groups 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl optionally substituted C1-C7the alkyl or C1-C7alkylsulfanyl

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where R3means phenyl, substituted in metaprogram by cyano, halogen or imidazolyl, which is optionally substituted C1-C7the alkyl or methylsulfonyl, 1,2,3-triazolium, 1,2,4-triazolium or isoxazolyl that are not necessarily replaced With1-C7the alkyl.

3. Compounds according to claim 2, representing

3-(8-Chloro-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

3-[8-(4-Methylpiperazin-1-yl)-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

3-(8-Chloro-4-oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

Methyl ester [4-(3-cyanophenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-ylsulphonyl]acetic acid;

2-[4-(3-cyanophenyl)-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-2-yl]diazepin-7-yl]ndimethylacetamide;

3-(8-Methoxy-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

3-(8-Cyanomethyl-4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)benzonitrile;

4-(3-Itfinal)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

4-(3-Imidazol-1-ylphenyl)-7-(2-methoxyethoxy)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

(RS)-3-[4-Oxo-8-(2-oxo[1,3]dioxolane-4-ylethoxy)-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

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

[4-(3-Imidazol-1-ylphenyl)-2-oxo-8-phenylethynyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-7-yloxy]acetonitrile;

8-(4-perforating)-7-hydroxymethyl-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

7-(2-Hydroxyethoxy)-4-(3-imidazol-1-ylphenyl)-8-phenylethynyl-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-Forfinal)-7-[4-(2-hydroxyethoxy)piperidine-1-yl]-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(4-Forfinal)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-methoxy-4-[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4[3-(2-Mei-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-[3-(2-methylsulfonylamino-1-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2,5-Differenl)-7-methoxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

8-(2-Forfinal)-7-hydroxy-4-[3-(3-methylisoxazol-5-yl)phenyl]-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

3-[7-(2,5-Differenl)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]benzonitrile;

8-(4-Perforating)-7-hydroxy-4-(3-imidazol-1-ylphenyl)-1,3, dihydrobenzo[b][1,4] diazepin-2-he;

8-(4-Perforating)-7-hydroxy-4-(3-[1,2,3]triazole-1-ylphenyl)-1,3-dihydrobenzo[b][1,4]diazepin-2-he;

4. Compounds according to claim 1, where R3means thiophenyl, optionally substituted by cyano or halogen; pyridinyl, optionally substituted in position 2 cyano or halogen.

5. Compounds according to claim 4, representing

5-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]thiophene-2-carbonitrile;

2-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]thiophene-3-carbonitrile;

4-[7-(2-Forfinal)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile;

4-[7-(4-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile;

4-[7-(2-Forfinal)-8-hydroxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]pyridine-2-carbonitrile.

6. Lek is rstone means, which is an antagonist of group II mGlu receptors containing the compound according to any one of claims 1 to 5, and pharmaceutically acceptable excipients.

7. The drug according to claim 6 for the treatment or prevention of acute and/or chronic neurological disorders, including psychosis, schizophrenia, Alzheimer's disease, disorders of cognitive abilities and defeat memory.



 

Same patents:

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

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, 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

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

The invention relates to new oxazolidinones derivative of the formula (I), their enantiomers or pharmaceutically acceptable salts, where R is hydrogen or C1-6alkyl, optionally substituted by a group selected from cyano, fluorine, chlorine, hydroxy or carbamoyl; R1and R2independently is fluorine or hydrogen; R3- C1-6alkyl; X Is O, and S

The invention relates to new derivatives (tetrahydro-1-oxido-thiopyran-4-yl)phenyloxazolidine General formula I, in which R1means methyl, ethyl, cyclopropyl, dichloromethyl, R2and R3are identical or different and denote hydrogen or fluorine, or their pharmaceutically acceptable salts, and the new derived (tetrahydro-1,1-oxido-thiopyran-4-yl)phenyloxazolidine General formula II in which R2and R3are identical or different and denote hydrogen or fluorine, R4means ethyl or dichloromethyl, or their pharmaceutically acceptable salts

The invention relates to new triazinyl compounds of formulas Ia and Ib:

< / BR>
or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment

The invention relates to new derivatives of phenyloxazolidine that have a relationship with a 4-8-membered heterocyclic rings of formula I and their pharmaceutically acceptable salts, where X represents NR1, S(O)gor Oh, R1represents H, C1-6alkyl, optionally zamesheny one or more CN or halogen, -(CH2)h-phenyl, -COR1-1, -СООR1-2, -CO-(CH2)h-COR1-1, -SO2- C1-6alkyl or -(CO)i-Het, R2represents H, -CO-(C1-6)alkyl or fluorine, R3and R4are the same or different and represent H or halogen, R5is1-6alkyl and C3-6cycloalkyl, optionally substituted by one or more halogen, g=0, 1, or 2, h=1 or 2, i=0 or 1, m=0, 1, 2, 3, n= 0, 1, 2, 3, provided that m and n taken together, is equal to 1, 2, 3, 4 or 5

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

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

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